Ceftriaxone: An Update of Its Use in The Management of Community-Acquired and Nosocomial Infections

ADIS DRUG EVALUATION Drugs 2002; 62 (7): 1041-1089
0012-6667/02/0007-1041/$30.00/0
© Adis International Limited. All rights reserved.
Ceftriaxone
An Update of its Use in the Management of
Community-Acquired and Nosocomial Infections
Harriet M. Lamb, Douglas Ormrod, Lesley J. Scott and David P. Figgitt
Adis International Limited, Auckland, New Zealand
Various sections of the manuscript reviewed by:

S.L. Block, Physicians To Children & Adolescents, Bardstown, Kentucky, USA; J. Lipman, Intensive Care
Facility and Department of Anaesthesiology and Critical Care, University of Queensland, Royal
Brisbane Hospital, Brisbane, Queensland, Australia; K.G. Naber, Urologische Klinik, Klinikum St. Elisabeth
Straubing, Straubing, Germany; R. Nau, Georg-August-Universitat Göttingen, Göttingen, Germany;
F. Scaglione, Department of Pharmacology, Chemotherapy and Toxicology, Faculty of Medicine, University
of Milan, Milan, Italy; K. Weiss, Hopital Maisonneuve-Rosemont, University of Montreal, Montreal, Quebec,
Canada.
Data Selection
Sources: Medical literature published in any language since 1988 on ceftriaxone, identified using Medline, supplemented by AdisBase (a
proprietary database of Adis International). Additional references were identified from the reference lists of published articles. Bibliographical
information, including contributory unpublished data, was also requested from the company developing the drug.
Search strategy: Medline search terms were ‘ceftriaxone’ or ‘ceftriaxone sodium’ and (lower respiratory tract infections or pneumonia or
bronchitis or AECB or acute otitis media or bacterial otitis media or skin structure infections or urinary tract infections or uncomplicated
gonorrhoea or bacterial septicaemia or bone and joint infections or intra-abdominal infections or meningitis-bacterial or surgical prophylaxis
or febrile neutropenia or pharmacoeconomics). AdisBase search terms were ‘ceftriaxone’ and (lower respiratory tract infections or pneumonia
or bronchitis or AECB or acute otitis media or skin structure infections or urinary tract infections or uncomplicated gonorrhoea or pelvic
inflammatory disease or bacterial septicaemia or bone-and-joint-infections or osteomyelitis or infectious arthritis or meningitis or surgical
prophylaxis or febrile neutropenia). Searches were last updated 13 Mar 2002.
Selection: Studies in patients with community-acquired or nosocomial infections who received ceftriaxone. Inclusion of studies was based
mainly on the methods section of the trials. When available, large, well-controlled, randomised trials with appropriate statistical methodology
were preferred. Relevant in vitro and pharmacokinetic data are also included.
Index terms: Community-acquired pneumonia, otitis media, meningitis, sexually transmitted infections, acute pyelonephritis, paediatric
infections, nosocomial infections, surgical prophylaxis, antibacterial activity, pharmacokinetics, therapeutic use, peritonitis.
Contents
Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1042
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1048
2. Antibacterial Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1048
2.1 Interpreting In Vitro Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1048
2.2 Gram-Positive Bacteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1051
2.2.1 Streptococci . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1051
2.2.2 Staphylococci . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1052
2.2.3 Other Gram-Positive Bacteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1052
2.3 Gram-Negative Bacteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1052
2.3.1 Enterobacteriaceae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1052
2.3.2 Other Gram-Negative Bacteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1053
2.4 Anaerobes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1053
2.5 Mechanisms of Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1053
2.6 Effects on Intestinal Flora . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1054
2.7 Pharmacodynamic/Pharmacokinetic Considerations . . . . . . . . . . . . . . . . . . . . . . 1055
1042 Lamb et al.
3. Pharmacokinetic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1056

3.1 Absorption and Plasma Concentration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1056
3.2 Distribution and Tissue Penetration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1059
3.3. Elimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1059
4. Therapeutic Use in Community-Acquired Infections . . . . . . . . . . . . . . . . . . . . . . . . . . 1060
4.1 Meningitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1061
4.1.1 Infants and Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1061
4.1.2 Adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1062
4.2 Acute Otitis Media (AOM) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1062
4.2.1 Uncomplicated AOM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1063
4.2.2 Previously Treated/Nonresponsive Patients . . . . . . . . . . . . . . . . . . . . . . . . . 1064
4.3 Community-Acquired Pneumonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1064
4.3.1 Hospitalised Adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1064
4.3.2 Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1066
4.4 Invasive Infections Caused by Penicillin-Resistant Streptococcus
pneumoniae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1066
4.4.1 Meningitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1066
4.4.2 AOM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1067
4.4.3 Other Invasive Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1067
4.5 Sexually Transmitted Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1067
4.5.1 Uncomplicated Gonorrhoea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1067
4.5.2 Pelvic Inflammatory Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1068
4.6 Acute Pyelonephritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1068
4.7 Other Paediatric Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1070
4.7.1 Febrile Episodes in Sickle Cell Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1070
4.7.2 Other Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1070
4.7.3 Occult Bacteraemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1071
5. Therapeutic Use in Nosocomial Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1071
5.1 Gram-Negative Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1071
5.2 Pneumonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1072
5.3 Surgical or Procedural Prophylaxis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1072
5.4 Spontaneous Bacterial Peritonitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1074
6. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1074
6.1 Systemic Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1074
6.1.1 Gastrointestinal Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1074
6.1.2 Effects on Flora . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1074
6.1.3 Biliary Pseudolithiasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1075
6.1.4 Other Systemic Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1076
6.2 Local Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1077
6.3 Comparative Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1077
6.3.1 Adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1077
6.3.2 Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1077
7. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1078
8. Place of Ceftriaxone in the Management of Community-Acquired and
Nosocomial Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1078
Summary
Abstract Ceftriaxone is a parenteral third-generation cephalosporin with a long elimination
half-life which permits once-daily administration. It has good activity against
Streptococcus pneumoniae, methicillin-susceptible staphylococci, Haemophilus
influenzae, Moraxella catarrhalis and Neisseria spp. Although active against
Enterobacteriaceae, the recent spread of derepressed mutants which
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Ceftriaxone: An Update 1043
hyperproduce chromosomal β-lactamases and extended-spectrum β-lactamases

has diminished the activity of all third-generation cephalosporins against these
pathogens necessitating careful attention to sensitivity studies.
Extensive data from randomised clinical trials confirm the efficacy of
ceftriaxone in serious and difficult-to-treat community-acquired infections in-
cluding meningitis, pneumonia and nonresponsive acute otitis media. Ceftriaxone
also has efficacy in other community-acquired infections including uncompli-
cated gonorrhoea, acute pyelonephritis and various infections in children. In the
nosocomial setting, extensive data also confirm the efficacy of ceftriaxone with
or without an aminoglycoside in serious Gram-negative infections, pneumonia,
spontaneous bacterial peritonitis and as surgical prophylaxis. Outpatient use of
ceftriaxone, either as part of a step-down regimen or parenterally, is a distinguish-
ing feature of the data gathered on the agent over the last decade. The review
focuses on new applications of the drug and its use in infections in which the
causative pathogens or their resistance patterns have changed over the past de-
cade.
Ceftriaxone has a good tolerability profile, the most common events being
diarrhoea, nausea, vomiting, candidiasis and rash. Ceftriaxone may cause revers-
ible biliary pseudolithiasis, notably at higher dosages of the drug (≥2 g/day);
however, the incidence of true lithiasis is <0.1%. Injection site discomfort or
phlebitis can occur after intramuscular or intravenous administration.
Conclusions: As a result of its strong activity against S. pneumoniae,
ceftriaxone holds an important place, either alone or as part of a combination
regimen, in the treatment of invasive pneumococcal infections, including those
with reduced β-lactam susceptibility. Its once-daily administration schedule al-
lows simplification of otherwise complex regimens in a hospital setting and has
also contributed to its popularity as a parenteral agent in an ambulatory setting.
These properties, together with a well characterised tolerability profile, mean that
ceftriaxone is likely to retain its place as an important third-generation cephalo-
sporin in the treatment of serious community-acquired and nosocomial infections.
Antibacterial Activity According to data from large in vitro studies published since 1998, ceftriaxone
has good activity against Streptococcus pneumoniae, β-haemolytic group strep-
tococci and methicillin-susceptible staphylococci. Its activity is more variable
against viridans group streptococci and, as for other β-lactam agents, ceftriaxone
is inactive against methicillin-resistant staphylococci and enterococci. Although
penicillin-resistant S. pneumoniae are becoming increasingly common, the prev-
alence of resistance to ceftriaxone among S. pneumoniae remains <5% world-
wide.
Ceftriaxone is highly active against Haemophilus influenzae, Moraxella
catarrhalis, Neisseria spp. and has good activity against Salmonella and Shigella
spp. However, data published since 1998 show that ceftriaxone, like other third-
generation cephalosporins, now has variable activity against most Entero-
bacteriaceae. Ceftriaxone has little or no activity against Acinetobacter spp.,
Pseudomonas aeruginosa, Stenotrophomonas maltophilia or Achromobacter
xylosoxidans.
Ceftriaxone is stable against TEM-1, TEM-2, SHV-1 and K1 chromosomal
β-lactamases. Its activity is also unaffected by inducible AmpC β-lactamases.
However, like other third-generation agents, its activity is reduced by derepressed
mutants which hyperproduce chromosomal β-lactamases or extended-spectrum

1044 Lamb et al.
β-lactamases, both of which are now widespread. Other relevant mechanisms

of resistance are modification or acquisition of supplementary penicillin-binding
proteins, usually in Gram-positive bacteria. Resistance attributable to reduced
porin expression or efflux is less common.
Studies in patients show that ceftriaxone reversibly alters the intestinal flora
(suppresses enterobacteria, bifidobacteria, clostridia and Bacteroides and in-
creases enterococci and candida), but is associated with the emergence of fewer
cephalosporin-resistant Gram-negative bacilli than cefotaxime or cefazolin in a
randomised study. Additionally, in a study in 12 patients, the colonic microflora
was found to normalise within 14 days of completion of treatment in all but one
recipient.
The inter-relationship between pharmacodynamic and pharmacokinetic para-
meters is also important in predicting antibacterial activity. A pharmacodynamic
review of the Alexander Project surveillance data indicated that ceftriaxone was
associated with plasma concentrations above the minimum inhibitory concentra-
tion required to inhibit the growth of 90% of isolates (MIC90) of S. pneumoniae,
H. influenzae, M. catarrhalis and Staphylococcus aureus for >50% of the dosage
interval. In healthy adult volunteers, serum concentrations of ceftriaxone (intra-
venous 30 minute infusion of 1g once daily) were bactericidal for 100% of the
dosage interval against clinical isolates of S. pneumoniae, Klebsiella pneu-
moniae, Enterobacter aerogenes, Escherichia coli, Serratia marcescens and H.
influenzae. In an in vitro study evaluating penicillin-susceptible, -intermediate
and -resistant S. pneumoniae clinical isolates, ceftriaxone exerted post antibiotic
effects (PAEs) ranging from 1 to 7.2 hours after isolates had been exposed to
concentrations 10 times the MIC value. In another study, mean PAEs against S.
aureus, S. pneumoniae, H. influenzae and E. coli strains were 0.9, 2.6, –0.8 and
–2.1 hours, respectively, reflecting the fact that cephalosporins generally only
demonstrate a PAE against Gram-positive bacteria.
Pharmacokinetic Profile Intravenous ceftriaxone 0.5, 1 or 2g produces mean peak plasma concentrations
(Cmax) of 82, 151 and 257 mg/L, respectively, whereas intramuscular ceftriaxone
0.5 or 1g achieves Cmax values of 38 and 76 mg/L, respectively, after 2 to 3 hours.
24 hours after intravenous ceftriaxone 2g, mean plasma concentrations range
from 12 to 20 mg/L.
Repeated once-daily intravenous administration of ceftriaxone 2g results in
an 8% increase in mean Cmax, and repeated intramuscular administration of
ceftriaxone 1g results in 11% accumulation of the drug.
Ceftriaxone binds reversibly to albumin and the level of binding decreases
with increasing ceftriaxone plasma concentrations (≈95% at >70 mg/L to ≈58%
at 600 mg/L).
Ceftriaxone distributes widely in the body fluids and tissues. The volume of
distribution of ceftriaxone in healthy volunteers ranges from 5.8 to 15.5L.
Ceftriaxone preferentially localises in bile and mean concentrations of ≈153
and ≈44 mg/L are obtained 1 and ≈3 hours, respectively, after intravenous admin-
istration of 1g dose. The drug is primarily eliminated unchanged by the kidneys;
45 to 60% of a 0.5 to 3g dose is excreted in the urine of healthy subjects within
48 hours. The remainder is secreted in the bile and the faeces as microbiologically
inactive compounds.
Total plasma clearance of ceftriaxone is dose related; it increases from mean

values of 0.61 to 1.0 L/h after a 0.5g intravenous dose to 1.18 and 1.29 L/h after
a 2g intravenous dose.
The mean elimination half-life (t1⁄2) of ceftriaxone in healthy adults is ≈6 to 9
hours, which is considerably longer than that of other cephalosporins (0.6 to 4.4
hours). The t1⁄2 of ceftriaxone does not vary according to dose size, frequency or
route of administration.
Therapeutic Use in Meningitis: In five randomised trials, intravenous ceftriaxone 60 to 100 mg/kg
Community-Acquired sterilised the CSF in 98 to 100% of infants and children with meningitis within
Infections 18 to 36 hours. Similar response rates were observed with alatrofloxacin, cefur-
oxime and cefotaxime (88 to 97% of patients), although cefuroxime was associ-
ated with delayed sterilisation more frequently than ceftriaxone (12 vs 2%).
Neurological sequelae at discharge were reported in 9 to 23% of patients who
received ceftriaxone. Two small comparative studies also showed that ceftriaxone
was effective in the treatment of adults with meningitis.
Acute otitis media: According to data from six randomised trials, a single
intramuscular dose of ceftriaxone 50 mg/kg had similar clinical efficacy to 10-day
oral regimens of amoxicillin plus or minus clavulanic acid, cefaclor or
cotrimoxazole (trimethoprim/sulfamethoxazole) in infants and children with un-
complicated acute otitis media (AOM). In children with AOM unresponsive to
previous antibacterial therapy, three trials showed that a three-dose regimen of
intramuscular ceftriaxone 50 mg/kg/day eradicated 93 to 98% of middle ear
pathogens. Significantly lower eradication rates were observed with one versus
three doses of ceftriaxone in this patient group in one comparative trial (73 vs
98%; p < 0.001).
A flexible approach advocated by McCracken recommends that in uncompli-
cated AOM a single dose of ceftriaxone be given, with additional doses if neces-
sary (after 48 to 72 hours) if there is a clinical failure with the first dose. It is
suggested that the second dose may be given at 48 to 72 hours rather than 24
hours, since the concentration of ceftriaxone exceeds the MIC90 for approxi-
mately 120 hours or longer for most organisms including penicillin-intermediate
and -resistant strains of S. pneumoniae. This approach allows for the possibility
that some children failing the one-dose ceftriaxone regimen may be cured by the
second dose and hence not require the third dose.
Community-acquired pneumonia: According to data from ten randomised tri-
als in hospitalised adults with community-acquired pneumonia (CAP),
ceftriaxone 1 to 4 g/day, alone or as part of a step-down regimen, had similar
efficacy to that of other β-lactam agents (amoxicillin/clavulanic acid, cefepime,
cefpodoxime proxetil, cefodizime), fluoroquinolones (ciprofloxacin, levoflox-
acin, gatifloxacin, trovafloxacin) and linezolid. Clinical success rates with
ceftriaxone-based therapy ranged from 81 to 98% versus 85 to 98% with compa-
rator regimens. A step-down regimen of ceftriaxone 50 mg/kg/day followed by
oral cefixime or amoxicillin/clavulanic acid achieved similar clinical success
rates in children with CAP in a randomised trial.
Additionally, in a nonblind study in 31 patients with CAP, the average length
of stay in hospital was reduced by 1.2 days (4.8 vs 6 days) in patients receiving
step-down therapy with intravenous ceftriaxone (dosage not reported) followed
by oral cefpodoxime proxetil 200mg twice daily compared with those receiving
ceftriaxone followed by other oral treatment regimens (choice of oral agent was

1046 Lamb et al.
at the physician’s discretion). There were no recurrences of primary infection or

readmissions to hospital at 1-month follow-up in either treatment group.
Invasive infections caused by ceftriaxone-nonsusceptible Streptococcus
pneumoniae: In patients with pneumococcal meningitis, treatment failures or
unpredictable responses have been observed with strains with MICs ≥1 mg/L.
Combination therapy with vancomycin or rifampicin is therefore recommended
for patients with ceftriaxone-nonsusceptible strains, although published data con-
cerning the efficacy of these regimens remain very limited. In contrast, recent
data in other pneumococcal infections (predominantly pneumonia and bacter-
aemia) suggest that ceftriaxone can be used effectively to treat infections caused
by S. pneumoniae with ceftriaxone MICs ≤2 mg/L.
Sexually transmitted infections: Single dose intramuscular ceftriaxone 0.25g
consistently produces bacteriological eradication rates of ≥95% in adults with
uncomplicated gonorrhoea according to 15 large randomised trials. Eradication
rates achieved with ceftriaxone were similar to those reported with single doses
of comparator agents (90 to 100%; cefixime, ceftizoxime, cefotaxime, ampicil-
lin/sulbactam plus probenecid, trospectomycin, ciprofloxacin, fleroxacin and en-
oxacin).
A single intramuscular dose of ceftriaxone 0.25g combined with oral doxycy-
cline achieved clinical success in 95% of women with mild to moderate pelvic
inflammatory disease compared with 97% treated with oral clindamycin plus
ciprofloxacin in a randomised trial.
Acute pyelonephritis: In pregnant women with acute pyelonephritis, four
randomised trials showed that parenteral ceftriaxone 1 g/day followed by oral
cefalexin or cefradine achieved bacteriological cure in 92 and 98% of patients.
Treatment was effective whether administered completely or partially on an out-
patient basis, although medical or infectious complications precluded outpatient
management in over 50% of women at >24 weeks gestation. Similar results were
achieved with comparator regimens (intravenous cefazolin or ampicillin plus
gentamicin followed by similar step-down therapy). No differences in birth out-
comes were noted between regimens.
Other paediatric infections: Data from randomised trials also show that
ceftriaxone is effective in the treatment of acute pyelonephritis, multidrug-resis-
tant Salmonella typhi septicaemia, typhoid fever, skin and soft-tissue infections,
bone infections, infectious diarrhoea, febrile episodes in children with sickle
haemoglobinopathies and in the prevention of invasive infections in febrile chil-
dren (aged 3 to 36 months). Furthermore, regimens including ceftriaxone have
proven effective and were generally well tolerated in neonates (including new-
born) with proven or suspected infection.
Therapeutic Use in Gram-negative infections: One large multinational randomised trial showed that
Nosocomial Infections ceftriaxone plus tobramycin achieved similar clinical response rates to
ceftazidime monotherapy in adult hospitalised patients with serious nosocomial
Gram-negative infections (59 to 76% vs 73 to 80% depending on the infection
site).
Pneumonia: In patients with nosocomial pneumonia, intravenous ceftriaxone
2 g/day achieved clinical success in 70% of patients compared with 80% of
patients treated with intravenous cefoperazone in a randomised trial.
Surgical or procedural prophylaxis: Ceftriaxone was associated with wound
infection rates of 3 to 6% after abdominal or biliary surgery, 3% after breast or

gynaecological surgery, 0.5% after orthopaedic surgery and 15% after percuta-
neous endoscopic gastrotomy. In all studies, ceftriaxone was administered intra-
venously as a single 1 or 2g dose prior to or during surgery. The rate of postoperative
wound infections observed with ceftriaxone was generally similar to that
achieved with comparator regimens, except for two studies in which ceftriaxone
was associated with a significantly lower infection rate: 0.5 vs 4% with placebo
in orthopaedic surgery (p < 0.001) and 6 vs 17% with metronidazole in combina-
tion with gentamicin in bowel surgery (p < 0.05).
Spontaneous bacterial peritonitis: In two small prospective trials, empirical
treatment with intravenous ceftriaxone 2 g/day achieved a bacteriological cure in
95 and 100% of patients with spontaneous bacterial peritonitis. This compared
with a bacteriological cure rate of 94% with intravenous cefonicid in a
randomised trial.
Tolerability In general, adverse events associated with ceftriaxone were mild to moderate in
severity and resolved spontaneously. With rare exceptions, severe or serious
events were not observed after single dose treatment with ceftriaxone in adults,
children or infants. In addition, studies in neonates also indicated that ceftriaxone
monotherapy or combination therapy was generally well tolerated.
According to data from clinical trials, gastrointestinal events are the most
common adverse events associated with ceftriaxone. In general, diarrhoea was
reported in 1 to 15% of patients, nausea and vomiting in ≤4%, and abdominal
pain or discomfort in ≤2% of patients. All third-generation cephalosporins, in-
cluding ceftriaxone, have been associated with rare reports of pseudomembran-
ous colitis; therefore, overgrowth of Clostridium difficile should be considered
in patients with diarrhoea. Other systemic events associated with ceftriaxone
included rash in ≤6% of patients, candidiasis (oral or vaginal) in about 4 to 5%
of patients and pruritus, headache and dizziness in ≤3% of patients each.
Ceftriaxone can cause reversible biliary pseudolithiasis, usually at higher dos-
ages (≥2 g/day); however, the incidence of true lithiasis is <0.1%. Data from six
small incidence studies (n = 8 to 118 patients in each study) show that sonographic
abnormalities indicative of pseudolithiasis were observed in 12 to 43% (n = 37
patients in the latter study) of adolescents and children and 21 and 25% of adults
treated with intravenous ceftriaxone. Up to one-third (0 to 33%) of patients de-
veloped symptoms, but pseudolithiasis resolved spontaneously in all cases.
Haematological reactions with ceftriaxone include anaemia, haemolytic anae-
mia, leucopenia, neutropenia, thrombocytopenia, eosinophilia, agranulocytosis
and a positive Coomb’s test. Prolongation of prothrombin time has been observed
rarely with ceftriaxone. As with other third-generation agents, mild reversible
abnormalities in liver function tests have been documented with ceftriaxone.
Ceftriaxone appears to have a low nephrotoxic potential and can be coad-
ministered with aminoglycosides.
Ceftriaxone can cause discomfort or pain at the injection site following intra-
muscular administration, and phlebitis following intravenous injection. In clini-
cal trials, the incidence of these events ranged from 0 to 45% and up to 11%,
respectively. Of note, in comparison with water, 1% lidocaine has been shown to
reduce the severity and duration of pain associated with ceftriaxone injection (250
to 1g) in healthy volunteers (aged 14 to 55 years) in randomised, single- or dou-
ble-blind trials.
Comparative data with ceftriaxone monotherapy are limited because the drug

1048 Lamb et al.
is often administered as part of a step-down regimen or in combination with other

agents. Available data show that the incidence of adverse events with ceftriaxone
is generally similar to that of other β-lactams and fluoroquinolones in adults and
children. Significant differences noted between regimens include fewer adverse
reactions, notably gastrointestinal events, than amoxicillin/clavulanic acid and
fewer gastrointestinal events than cefixime but higher incidences of diarrhoea
than cotrimoxazole and cefpodoxime proxetil and rash compared with oral
amoxicillin.
Dosage and Ceftriaxone can be administered by intravenous or intramuscular injection. The
Administration recommended dose in adults and children (aged ≥12 years) is 1 to 2g once daily
(or in two equally divided doses) in the US or 1g once daily in the UK. The total
daily dose should not exceed 4g. A single intramuscular dose of 250mg is recom-
mended for the treatment of uncomplicated gonorrhoea. For surgical prophylaxis,
a single intravenous 1g dose given 0.5 to 2 hours before surgery is advised.
In children aged <12 years, ceftriaxone 50 to 75 mg/kg/day is recommended
for serious infections and a dose of 100 mg/kg/day is recommended for meningitis
in the US; the dose may be administered once daily or split into two equally
divided doses. In the UK, ceftriaxone 20 to 50 mg/kg once daily is recommended
as the standard dose, with doses of up to 80 mg/kg for severe infections. AOM
should be treated with a single intramuscular dose of 50 mg/kg.
Dosage adjustment is not required in patients with impaired hepatic or renal
function, although plasma concentrations of ceftriaxone should be monitored
regularly in patients with concomitant renal and hepatic dysfunction.
1. Introduction 2. Antibacterial Activity
Ceftriaxone is a parenteral third-generation ce- This section provides an overview of the current
phalosporin. In common with most of the other in vitro antibacterial activity of ceftriaxone. It is
third-generation agents, it has an aminothiazolyl compiled predominantly from studies published
substitution at the R1 position of the β-lactam ring. since 1998 which include more than 1000 clinical
Since the mid 1980s when ceftriaxone was first isolates. Smaller or older studies are used only
introduced, the drug has been used extensively be- where needed to complete the activity profile of
cause of its improved stability against β-la- ceftriaxone against relevant bacteria.
ctamases, efficacy in a broad range of infections A summary of the comparative in vitro activity
and its pharmacokinetic and tolerability profile. of ceftriaxone versus two other broad spectrum par-
Shifting bacterial resistance patterns, increased enteral cephalosporins, ceftazidime and ce-
emphasis on the outpatient management of infec- fepime, is given in table I and a summary of its
tions, and the availability of new anti-infective activity by geographical region is provided in table
drugs have all contributed to the large volume of II.
data published on ceftriaxone over the last decade.
With these changes in mind, this review focuses on 2.1 Interpreting In Vitro Data
the current uses of ceftriaxone and its place in the
treatment of both community-acquired and noso- In this review, in vitro antibacterial activity re-
comial infections. It updates the two previous re- fers to the minimum inhibitory concentrations re-
views of ceftriaxone published in Drugs in the quired to inhibit the growth of 50 (MIC50) or 90%
1980s.[1,2] (MIC90) of strains, respectively. Breakpoints pro-

Table I. Comparative global in vitro antibacterial activity of ceftriaxone. Data are derived from 19 large in vitro or surveillance studies published
since 1998 evaluating >1000 clinical isolates. Studies were performed in North and/or South America,[3-13] Europe,[14-16] multiple countries,[17-
20]
or Australia.[21] In three studies,[4,13,15] isolates were obtained only from nosocomial sources (intensive care, oncology or haematology
units), whereas the remaining studies used isolates from nosocomial and/or community sources. Susceptibility testing was performed using
either the Etest[3,4,6,15,19,21] or broth microdilution techniques[5,7-14,16-18,20]
Organism na Ceftriaxone Ceftazidime Cefepime
MIC50 (mg/L) MIC90 (mg/L) S (%)b MIC90 (mg/L) S (%)b MIC90 (mg/L) S (%)b
Gram-positive bacteria
Staphylococcus aureus 779 4 32->32 75-80 >64 39 >16 81
MS S. aureus 8294 2-6 4-24 77-100 16 15-62 4-8 97-100
MS coagulase-negative 1852 2 4-12 88-100 8-12 75-90 1-4 99-100
staphylococci
Streptococcus pneumoniae 23139 ≤0.03-0.047 0.03-1 65-99c
PS S. pneumoniae 4114 0.023 0.047-≤0.25 100c
PI S. pneumoniae 1542 0.38 0.5-1 67-91c
PR S. pneumoniae 1057 1 2-4 4-21c
β-Haemolytic streptococci 123 0.06-0.094 0.12-0.125 100 1 34 0.19-0.25 98-100
Viridans group streptococci 452 0.047-0.25 2-4 69-84 16 13 3 76
Enterococcus spp. 619 16->32 >32-64 3-34 64->256 1-29 >16->32 1
Enterobacteriaceae
Citrobacter spp. 1110 ≤0.25-32 0.5->32 40-94 0.5->16 30-94 ≤0.12->16 70-100
Enterobacter spp. 3331 ≤0.25-4 8->256 46-90 8->256 48-90 0.25-8 90-100
Escherichia coli 5317 0.064-≤0.25 ≤0.25-32 75-100 0.25-32 73-100 ≤0.12-0.75 97-100
Klebsiella spp. 1079 ≤0.25 ≤0.25->32 60-98 0.5->16 66-100 ≤0.12->16 73-100
K. pneumoniae 991 0.125-4 24->64 46-85 >16->256 48-79 3-4 92-97
Indole+ Proteus spp. 774 ≤0.016 1 99 4 92 0.19 100
Serratia spp. 1162 ≤0.25-2 0.5->32 69-100 0.5-16 78-100 0.5->16 81-100
Other Gram-negative bacteria
Acinetobacter spp. 1226 6->32 32->256 9-94 16->256 19-100 6-48 41-97
Haemophilus influenzae 9946 ≤0.004-≤0.015 0.008-0.03 100
Moraxella catarrhalis 3953 0.06-0.5 0.5-1 100
Pseudomonas aeruginosa 4856 8-72 >32->256 0-54 8-48 65-98 8-24 73-95
a Number of isolates from all studies, except for Hanberger et al.[15] which reported the total number of isolates only (n = 9166).
b Percentage of organisms that were susceptible (S) according to the breakpoints of the US National Committee for Clinical Laboratory
Standards (NCCLS) applicable between 1997 and 1999 (depending on the date of the individual study).
c Application of January 2002 NCCLS[22] interpretive criteria would most likely result in a higher percentage of isolates that were suscepti-
ble to ceftriaxone, since isolates that were previously intermediately susceptible to ceftriaxone are now considered susceptible.
MIC50/90 = minimum inhibitory concentrations required to inhibit the growth of 50 or 90% of strains, respectively; MS = methicillin (or
oxacillin)-susceptible; PI = penicillin intermediate (MIC 0.1-1 mg/L); PR = penicillin resistant (MIC ≥2 mg/L); PS = penicillin susceptible (MIC
≤0.06 mg/L).
posed by the US National Committee for Clinical to determine the percentage of organisms suscep-
Laboratory Standards (NCCLS) are used through- tible to ceftriaxone and other agents (table I and II,
out the review to interpret in vitro data.[22] New and figure 2), since these were the effective
interpretive criteria, including those for the suscep- NCCLS breakpoints at the time the data were an-
tibility of Streptococcus pneumoniae to ceft- alysed. Thus, the percentage of susceptible S.
riaxone in meningitis and non-meningeal infec- pneumoniae isolates is likely to be underestimated
tions, are used when discussing MIC90 values with the introduction of a new resistant breakpoint
(table III).[22] Of note, earlier NCCLS interpretive (MIC ≥4 January 2002 NCCLS guidelines vs MIC
criteria effective between 1997 and 1999 were used ≥2 mg/L prior to 2002) for non-meningeal infec-

1050 Lamb et al.
Table II. In vitro antibacterial activity of ceftriaxone by region. Data are derived from 17 large in vitro or surveillance studies published since 1998
with >1000 clinical isolates. Susceptibility testing was performed using either the Etest[3,4,6,15,19] or broth microdilution techniques[5,8-14,16-18,20]
Organism US[3-6,8,10-12] Canada[8-12] South America[10-13,20] Europe[14-19]
S (%)a nb S (%)a nb S (%)a nb S (%)a nb
Gram-positive bacteria
MS Staphylococcus aureus 77-99 5180 99-100 1458 98 366 95 1290
MS coagulase-negative staphylococci 88-100 843 97-100 232 99-100 104 92 673
Streptococcus pneumoniaec 80-88 11239 96 361 65-99d 7770
Viridans group streptococci 84 62 69 153 81 237
Enterobacteriaceae
Citrobacter spp. 77-84 610 88-94 83 40 10
Enterobacter spp. 68-76 1507 86-90 334 49-76 242 58-74 379
Escherichia coli 93-100 1962 99 441 75-93 689 98-99 1918
Klebsiella spp. 80-97 960 97-98 152 46-85 446 82-96 456
Serratia spp. 85-93 639 100 88 69 36 75-100
Other Gram-negative bacteria
Acinetobacter spp. 51 100 58-94 87 17-32 160 11-39 247
Haemophilus influenzae 100 1760 100 7646
Moraxella catarrhalis 100 712 100 1340
Pseudomonas aeruginosa 7-21 2172 0-72 362 7-42 401 31-54 505
a Percentage of organisms that were susceptible (S) to ceftriaxone according to the breakpoints of the US National Committee for Clinical
Laboratory Standards applicable between 1997 and 1999 (depending on the date of the individual study).
b Number of isolates from all studies, except for Hanberger et al.[15] which reported the total number of isolates only (n = 9166).
c Application of January 2002 NCCLS[22] interpretive criteria would most likely result in a higher percentage of isolates that were suscepti-
ble to ceftriaxone, since isolates that were previously intermediately susceptible to ceftriaxone are now considered susceptible.
d Includes isolates from countries, such as Spain, showing a high level of resistance against ceftriaxone.
MS = methicillin (or oxacillin)-susceptible.
tions, as intermediately penicillin-resistant S. septic arthritis).[23] 166 of the 2100 clinical isolates
pneumoniae are now considered susceptible. (7.9%) collected from these patients were associ-
The resistance breakpoint for ceftriaxone ag- ated with an MIC of ≥1 mg/L against ceftriaxone;
ainst S. pneumoniae, effective up until January 100 of these 166 patients were primarily treated
2002, was greatly influenced by the outcomes re- with β-lactam antimicrobial agents. All but one of
ported in the treatment of pneumococcal meningi- the latter group of patients (a child with bacter-
tis. While this breakpoint appears to be appropriate aemia and otitis media also had severe combined
for meningitis (see section 4.4.1), its relevance for immune deficiency) had a successful clinical out-
other invasive pneumococcal infections (see sec- come, defined as resolution of signs and symptoms
tion 4.4.3) has recently been questioned.[22-26] As a of the infection.[23]
result, new NCCLS interpretive breakpoints for the The new interpretive resistance breakpoint has
susceptibility of ceftriaxone against S. pneumoniae important clinical implications and results in a
in meningitis and non-meningeal infections have marked increase in the percentage of S. pneu-
been implemented (table III).[22] The use of this moniae isolates that are considered susceptible to
new resistance breakpoint (MIC ≥4 mg/L) for non- ceftriaxone. For example, a survey of 9863 non-
meningeal infections is supported by a recent retro- meningeal S. pneumoniae clinical isolates from
spective review of the outcome of treatment in The Surveillance Network (TSN) US database in-
2100 paediatric patients with such infections (indicated that 95.9% of isolates are susceptible to
cluding pneumonia, bacteraemia, cellulitis and ceftriaxone according to the January 2002 NCCLS

resistance breakpoint (MIC ≥4 mg/L), whereas 100
% of strains susceptible at each MIC

only 82.7% of isolates are susceptible to cef-
triaxone using the 2001 NCCLS resistance break- 80
point (MIC ≥2 mg/L) [figure 1].[27]
Another issue of interpretation involves Gram- 60
negative bacteria producing extended-spectrum

β-lactamases (ESBLs). Some ESBLs do not hy- 40
drolyse third-generation cephalosporins strongly

20
and therefore the MICs, although elevated, remain
within the susceptible range according to break-
0
points advocated by the NCCLS. This can lead to ≤0.25 0.5 1 2 4 ≥8
interpretive problems, since these strains are likely MIC (mg/L) distribution
to be clinically resistant despite showing MICs to
third-generation cephalosporins of 1 to 2 mg/L (for Fig. 1. In vitro activity of ceftriaxone. Distribution of minimum
inhibitory concentrations (MIC) for ceftriaxone against 9863
reviews see Livermore[28] and Bush[29]). Therefore, clinical isolates of Streptococcus pneumoniae collected from
all ESBL-producing organisms should be reported patients with non-meningeal infections from January 1996 to
as resistant to all penicillins and first-, second- and December 2000 for The Surveillance Network (TSN) US data-
base.[27]
third-generation cephalosporins, regardless of their
MIC values.[28,30]
0.5 to 1 mg/L and 67 to 91% susceptibility).[5,16,19]
2.2 Gram-Positive Bacteria As for other β-lactam agents, its activity varies ac-
2.2.1 Streptococci cording to the level of penicillin resistance and it
Ceftriaxone has strong activity against S. pneu- has less activity against penicillin-resistant strains
moniae (table I). According to breakpoints based (MIC90 2 mg/L and 21% susceptibility).[5,16,19] Of
on data from patients with meningitis (section 2.1), note, these surveillance analyses were conducted
ceftriaxone is highly active against penicillin-sus- prior to the introduction of the new NCCLS break-
ceptible strains of S. pneumoniae (MIC90 0.047 to points in January 2002; as stated earlier, the appli-
≤0.25 mg/L and 100% susceptibility) and is also ac- cation of new interpretive breakpoints would most
tive against penicillin-intermediate strains (MIC90 likely result in a higher percentage of susceptible
S. pneumoniae isolates. For example, reanalysis of
Table III. Interpretive categories or breakpoints for ceftriaxone two US surveillance studies[5,31] by Sahm et al.[27]
proposed by the US National Committee for Clinical Laboratory indicated that 98.5 to 99.5% of these S. pneu-
Standards[22]
moniae isolates were susceptible to ceftriaxone by
Breakpoint (mg/L)
S I R
2002 NCCLS breakpoints versus 95.7 to 96.8% of
Enterobacteriaceae ≤8 ≥64 isolates using NCCLS 2001 criteria. Notably, re-
Haemophilus spp. ≤2a ports of high level resistance to cefotaxime and
Neisseria gonorrhoeae ≤0.25a ceftriaxone remain rare (MICs 4 to 32 mg/L).[32-34]
Pseudomonas aeruginosa ≤8 ≥64
The incidence of reduced susceptibility to
Staphylococcus aureus ≤8 16-32 ≥64
Streptococcus pneumoniae ≤0.5 1 ≥2
ceftriaxone among S. pneumoniae varies markedly
(meningitis) by geographical region (figure 2). Although the in-
S. pneumoniae ≤1 2 ≥4 cidence of intermediate resistance to ceftriaxone
(non-meningitis)
a The absence of resistant strains precludes defining any break-
varies from 1 to 30% depending on the location,
point categories other than susceptible strains.[22] the incidence of complete resistance to ceftriaxone
I = intermediate; R = resistant; S = susceptible. remains under 5% worldwide (figure 2).

1052 Lamb et al.
Resistant rins, ceftriaxone possesses better activity than

Intermediate ceftazidime (15 to 90% susceptibility; table I) ag-
Susceptible
100 ainst methicillin-susceptible staphylococci but less
90
activity than cefepime (97 to 100% susceptibility;
table I). As for other β-lactam agents, ceftriaxone
80
Percentage of isolates (%)
is inactive against methicillin-resistant staphylo-

70
cocci.[4,14]
60
50 2.2.3 Other Gram-Positive Bacteria
40
Of the more unusual Gram-positive bacteria,
ceftriaxone is active against Micrococcus spp.
30
(MIC90 0.5 mg/L; n = 11),[4] Alloiococcus otitidis
20
(MIC range <0.015 to 0.5 mg/L; n = 12),[35] but has
10
limited activity against Corynebacterium spp.
0
(MIC90 >32 mg/L; n = 17) and Bacillus spp. (MIC90
)
3)
3)
0)
Ja (n = )
0)
8)
>32 mg/L; n = 21).[4] Ceftriaxone is inactive

49
48
21
24
20
34
28
32
37
21
30
41
lia = 1
10
=
against enterococci.[4,14]
=
=
(n
(n
(n
(n
(n
(n
(n
(n
(n
m
ce
ly
Au na
an
SA
SA
ai
pa
Ita
do
an
hi
Sp
ra
m
U
C
ng
Fr
st
er
Ki
2.3 Gram-Negative Bacteria

d
te
ni
U
2.3.1 Enterobacteriaceae
Fig. 2. Susceptibility of Streptococcus pneumoniae to ceftriaxone Although ceftriaxone has retained good activity
by region.[5,6,18,21] Interpretive breakpoints for susceptible, inter-
mediate and resistant categories were MIC ≤0.5, 1 and ≥2 mg/L, against indole-positive Proteus spp. (99% suscep-
respectively. These breakpoints have recently been updated, tible), its activity against other Enterobacteriaceae
and application of January 2002 National Committee for Clinical is more variable (40 to 100% susceptible; table I).
Laboratory Standards[22] criteria would most likely result in a
higher percentage of susceptible isolates (resistant breakpoint When analysed by region (table II), the lowest rates
MIC ≥4 mg/L). MIC = minimum inhibitory concentrations. of susceptibility are clearly restricted to South
America, although there is a degree of variability
Although β-haemolytic group streptococci re- in the susceptibility data from all regions. A recent
main highly susceptible to ceftriaxone (98 to study evaluating >606 000 Enterobacteriaceae
100%), viridans group streptococci tend to be less [Escherichia coli (425 372 isolates), Klebsiella
susceptible to the drug (69 to 84%; table I). The pneumoniae (105 745), K. oxytoca (14 647), P.
activity of ceftriaxone against these bacteria was mirabilis (60 332)] isolates collected in the US
similar to that of cefepime and greater than that of from 1996 to 2000 indicated that >93% were sus-
ceftazidime (table I). ceptible to ceftriaxone.[36] It is also worth noting
that the highest rates of resistance to ceftriaxone
2.2.2 Staphylococci were reported in two surveys which obtained iso-
Ceftriaxone has good activity against methicil- lates from intensive care units.[13,15]
lin-susceptible strains of Staphylococcus aureus The variable activity demonstrated by ceft-
and coagulase-negative staphylococci, with 77 to riaxone against Enterobacteriaceae is a reflection
100% of strains susceptible to the drug (table I). Of of the rapid emergence of derepressed mutants ca-
interest, all studies consistently reported suscepti- pable of hyperproducing AmpC β-lactamases and
bility rates of >90% against these pathogens with also strains expressing ESBLs (section 2.5). As ev-
the exception of a US study which obtained isolates idenced by these data, both of these resistance
from 10 cancer treatment centres.[4] This consis- mechanisms are now widespread, although their
tency of activity is also reflected in the data by prevalence varies from country to country (table
region (table II). Compared with other cephalospo- II). While ceftazidime is similarly affected by these

mechanisms of resistance and therefore has a sim- 2.4 Anaerobes

ilar activity profile to ceftriaxone, cefepime retains
moderate activity against most Enterobacteriaceae Although ceftriaxone has some activity against
compared with ceftriaxone (table I). Bilophila wadsworthia (MIC90 2 mg/L; n = 14),
Limited recent data show that ceftriaxone has Porphyromonas spp. (MIC90 1 mg/L; n = 10), Sut-
terella wadsworthensis (MIC90 1 mg/L; n = 15),
good activity against both Salmonella (MIC90 0.25
Fusobacterium nucleatum (MIC90 2 mg/L; n = 14),
mg/L; n = 70) and Shigella spp. (MIC90 1 mg/L; n
Clostridium perfringens (MIC90 4 to 6 mg/L; n =
= 32).[37] Although resistance to third-generation
35), C. ramosum (MIC90 8 mg/L; n = 10), Pep-
cephalosporins among Salmonella spp. has been tostreptococcus spp. (MIC90 4 to 8 mg/L; n = 49),
reported in parts of Europe, Africa, South America it has variable or little activity against Fusobacte-
and Asia, a large study conducted in the US showed rium spp. (MIC90 0.25 to 256 mg/L; n = 49), Pre-
that only 0.07% of 4008 Salmonella spp. were re- votella spp. (MIC90 16 mg/L; n = 50), Veillonella
sistant to ceftriaxone.[38] spp. (MIC90 8 mg/L; n = 20) and non-spore-form-
ing Gram-positive rods (MIC90 8 mg/L; n = 31).
2.3.2 Other Gram-Negative Bacteria
Ceftriaxone is inactive against Bacteroides frag-
Ceftriaxone is highly active against both the re-
ilis, other B. fragilis group spp., other Bacteroides
spiratory pathogens Haemophilus influenzae and spp., Campylobacter gracilis and C. difficile.[51,52]
Moraxella catarrhalis; all strains were 100% sus-
ceptible to the drug with MIC90 values ranging
2.5 Mechanisms of Resistance
from 0.008 to 0.03 mg/L and 0.5 to 1 mg/L, respec-
tively (table I). This activity was consistent in both Of the three possible mechanisms of resistance
the US and Europe, as evidenced from large sur- that can affect β-lactam agents, β-lactamase pro-
veillance studies conducted in these regions (table duction predominates among Gram-negative bac-
II). teria and alterations to penicillin-binding proteins
Ceftriaxone also has excellent activity against (PBP) among Gram-positive pathogens. A brief
Neisseria spp. Against a total 567 strains of N. summary of mechanisms that confer resistance to
meningitidis, including those with reduced suscep- ceftriaxone and cefotaxime is provided in table IV.
tibility to penicillin, MIC90 values for ceftriaxone Ceftriaxone, like several other third-generation
ranged from ≤0.002 to ≤0.008 mg/L.[39-43] Data cephalosporins, has an oxyimino-aminothiazolyl
from around the world also confirm the excellent 7-acyl side chain which makes it stable against
activity of ceftriaxone against N. gonorrhoeae TEM-1, TEM-2 and SHV-1 β-lactamases and K1
(MIC90 range 0.001 to 0.125 mg/L; n = 17 897); chromosomal β-lactamases of Klebsiella spp.[53,55]
The activity of the third-generation agents is also
isolates included penicillinase-producing strains and
unaffected in bacteria producing inducible AmpC
ciprofloxacin- and tetracycline-resistant strains.[44-50]
β-lactamases, although this is because these drugs
Ceftriaxone, however, has no activity against
do not induce enzyme synthesis rather than them
Chlamydia trachomatis.[50] having stability against these enzymes.[55]
Although ceftriaxone possesses some activity However, stability against β-lactamases in
against Acinetobacter spp., its activity is highly Gram-negative species is difficult to retain and,
variable (table I). Unlike cefepime and ceftazidime since the introduction of the third-generation ceph-
which have antipseudomonal activity, ceftriaxone alosporins, several cephalosporin-resistant organ-
has little activity against Pseudomonas aeruginosa isms have emerged (table IV). An important mech-
(table I). Ceftriaxone has no activity against anism responsible for resistance to these agents is
Stenotrophomonas maltophilia[3,12] or Achromob- selection of derepressed mutants which hyp-
acter xylosoxidans.[3] erproduce chromosomal β-lactamases (table IV).

1054 Lamb et al.
Table IV. Mechanisms of resistance that affect ceftriaxone and A separate problem is that of ESBLs, most of
cefotaxime[53-56]
which are mutants of TEM-1, TEM-2 and SHV-1.
Mechanism Relevant bacteria
Unlike the enzymes from which they are derived,
β-lactamases these β-lactamases are capable of hydrolysing
Chromosomal
aminothiazolyl cephalosporins, including ceft-
AmpC hyperproduction Enterobacter spp.
riaxone. Although ESBLs have differential activity
Citrobacter freundii
Serratia spp.
on the various third-generation cephalosporins (ta-
Morganella morganii ble IV), even low level resistance detected in vitro
Pseudomonas aeruginosa can lead to resistance in vivo (section 2.1).[53] ES-
K1 hyperproduction Klebsiella oxytoca BLs are most prevalent amongst Klebsiella spp.
Plasmid-derived and E. coli, but are also found in other En-
TEM/SHV-derived ESBLa Klebsiella spp. terobacteriaceae.[58] These enzymes are now wide-
Escherichia coli
spread around the world and, of greater concern,
Other Enterobacteriaecae
are also found in outpatient and nursing home pop-
PER-1, PER-2 P. aeruginosa
Salmonella spp.
ulations.[29]
IMP-1 P. aeruginosa There are other β-lactamases that are capable of
Enterobacteriaceae hydrolysing third-generation cephalosporins, but
Sme-1, Imi-1, NMC-Ab these have been slower to spread. These include
Plasmid AmpC K. pneumoniae, E. coli PER-1, a class A enzyme described in Turkey and
PBP modification Argentina, and IMP-1, a plasmid-mediated class B
PBP2′ Staphylococci enzyme, found in Japan (table IV).[53]
PBP5 Enterococcus faecalis
Modification or acquisition of supplementary
PBP1a and PBP2xb Streptococcus pneumoniae
PBP, usually in Gram-positive bacteria, can lead to
Impermeability/efflux reduced affinity for β-lactam agents. Notable ex-
mexAmexBoprM operon P. aeruginosa
amples include methicillin-resistant staphylococci
Stenotrophonomas maltophilia
a TEM-3, 4, 8, 9, 14, 15, 19, 24 and SHV-2 to 6. Note that third-
and Enterococcus faecium which are resistant to all
generation cephalosporins may appear to be susceptible to β-lactams through the production of supplemen-
other ESBLs if high breakpoints are used, but are likely to be tary PBPs (table IV).[55] S. pneumoniae produces
clinically resistant to them if infections involve sites other
than the urinary tract.
PBPs 1a, 2a, 2x and 2b, of which 1a and 2x (table
b Reduced susceptibility. IV) have been implicated in reduced susceptibility
ESBL = extended-spectrum β-lactamases; PBP = penicillin-bind- to the third-generation cephalosporins.[54,59] Resis-
ing proteins. tance attributable to reduced porin expression or
efflux does occur in some Gram-negative bacteria
but is not as frequent as the other resistance mech-
When the third-generation cephalosporins were anisms (table IV).
first introduced, fewer than 5% of Enterobacter,
Citrobacter and Serratia spp. were derepressed 2.6 Effects on Intestinal Flora
producers of β-lactamases[53] compared with inci-
dence rates of 25 to 40% reported in North and Ceftriaxone treatment may be associated with
reversible suppression of intestinal microflora. In-
South America and Europe more recently.[3,12,57]
travenous ceftriaxone, either a single 2g dose (n =
The spread of these enzymes has been further fa- 10)[60] or 1 g/day for 10 days (n = 12)[61] was asso-
cilitated by their transfer onto plasmids (e.g. BIL- ciated with suppression of enterobacteria, bifid-
1, FOX-1, LAT-1). Enterobacteriaceae with plas- obacteria, clostridia and Bacteroides spp. and mar-
mid-mediated AmpC β-lactamases are now ked increases in enterococci and candida in the
widespread in the US.[53] intestinal flora of treated patients.[60,61] Microflora

returned to normal 2 weeks after therapy.[60] In than to a simple comparison of MIC values with
comparison, a step-down regimen of ceftriaxone 1 plasma drug concentrations.[65-67] Although the op-
g/day administered for 2 days followed by oral timal period that antimicrobial agents remain
loracarbef 800 mg/day for a further 8 days (n = 13) above the MIC90 value differs with various classes
was associated with fewer alterations of the intes- of agents and individual pathogens, with cephalo-
tinal microflora; reductions in E. coli, bifidobacte- sporins it is generally accepted that drug concen-
ria and clostridia were observed but with only mi- trations should exceed the MIC90 value for at least
nor increases in enterococci and candida.[61] 50% of the dosage interval against common respi-
However, these effects on colonic microflora were ratory pathogens.[67,68]
typically reversible in a nonblind study in 12 adult A pharmacodynamic review of the Alexander
patients.[62] The colonic microflora was found to Project surveillance data indicated that only ceft-
normalise within 14 days of completing treatment riaxone and amoxicillin/clavulanic acid were asso-
in all but one recipient. All patients received intra- ciated with plasma concentrations above the
venous (injection or short infusion) ceftriaxone MIC90 values of S. pneumoniae, H. influenzae, M.
1.5g twice daily for 7 to 13 days (mean duration of catarrhalis and S. aureus for >50% of the dosage
9 days). interval.[67] On the other hand, cefixime was only
In a hospital setting, ceftriaxone was associated effective against H. influenzae and M. catarrhalis
with the emergence of fewer cephalosporin-resis- for >50% of the dosage interval, whereas cefaclor
tant Gram-negative bacilli in the intestinal tract of and cefuroxime did not exceed the MIC90 values
patients than other cephalosporins in a randomised for >50% of the dosage interval for any of these
study. Although the incidence of cephalosporin-re- four pathogens. In adult volunteers, ceftriaxone
sistant Gram-negative bacilli in each treatment
(1g intravenously or 250mg intramuscularly)
group was similar prior to therapy, resistant strains
showed bactericidal activity and exceeded the MIC
emerged in 3 of 23 (13%) patients treated with
against S. pneumoniae, H. influenzae and M.
ceftriaxone compared with 14 of 38 (37%; p =
catarrhalis for 100% of the dosage interval irre-
0.005 vs controls) treated with cefotaxime, 11 of
spective of the route of administration.[68]
42 (26%; p = 0.04 vs controls) treated with cefazo-
Cefixime (400mg orally) was effective for at least
lin and in 1 of 24 (4%) untreated control patients.
50% of the dosage interval against H. influenzae
It was suggested that the differences between
and M. catarrhalis; against S. pneumoniae,
agents may have been attributable to varying drug
concentrations achieved in the gut (reported as an cefixime exceeded the MIC for 50% of the dosage
abstract).[63] interval but bactericidal activity was not main-
tained.[68]
Ceftriaxone exhibited time-dependent bacteri-
2.7 Pharmacodynamic/Pharmacokinetic
cidal activity against a highly penicillin- and ceph-
Considerations
alosporin-resistant strain of S. pneumoniae (MIC90
Although MIC90 values are one way to predict 4 mg/L) in a rabbit model of meningitis.[69] A
antibacterial activity, they do not necessarily re- twice-daily regimen of ceftriaxone 200 mg/kg was
flect in vivo activity.[64,65] Hence, the inter-rela- associated with CSF concentrations above the
tionships between pharmacodynamic and pharma- MIC90 for 87% of the dosage interval versus 60%
cokinetic parameters are also important in with a once-daily regimen (400 mg/kg) [p =
predicting antibacterial activity.[65,66] 0.03].[69]
For β-lactam antibacterial agents, bactericidal In children with meningitis who received
activity relates more to the time that serum drug ceftriaxone 50 or 75 mg/kg intravenously, mean
concentrations remain above the MIC of a given peak plasma concentrations (Cmax) were 216 and
organism (i.e. time-dependent antibiotic killing) 275 mg/L, respectively.[70] As discussed by

1056 Lamb et al.
Kaplan et al.,[23] other studies in children have re- The post-antibiotic effect (PAE) is defined as
ported Cmax values of 180 to 230 mg/L after a 50 to the delayed regrowth after exposure of an organism
75 mg/kg dose of ceftriaxone; 10 to 12 hours after to an antimicrobial agent; the longer the PAE, the
administration, the mean concentration was ≈30 lower the probability of resumption of bacterial
mg/L.[23] Therefore, even allowing for a minimum growth during the period when concentrations of
free drug fraction of 4%, the free ceftriaxone con- the antimicrobial agent are subinhibitory. In an in
centrations in serum would still be >2 mg/L for vitro study evaluating penicillin-susceptible, -in-
over half of a 12-hour dosage interval after a 50 mg/ termediate and -resistant S. pneumoniae clinical
kg dose and, thus exceed the MICs for most com- isolates, ceftriaxone exerted PAEs ranging from 1
mon pathogens.[23] to 7.2 hours after isolates had been exposed to con-
centrations 10 times the MIC value.[73] Under iden-
The serum bactericidal test is another approach
tical conditions, imipenem (range 1 to 8 hours),
used to estimate antibacterial efficacy through the
benzylpenicillin (1 to 6 hours) and cefpodoxime
interaction of pharmacodynamic and pharmacoki-
proxetil (1 to 6 hours) showed similar PAEs.[73] In
netic parameters. Ceftriaxone showed excellent
another study, mean PAEs against S. aureus, S.
bactericidal activity against pathogens commonly pneumoniae, H. influenzae and E. coli strains were
associated with community-acquired and nosoco- 0.9, 2.6, –0.8 and –2.1 hours, respectively.[74] Th-
mial pneumonia in a study in 19 healthy adult vol- ese latter data are consistent with the fact that ceph-
unteers.[71] Serum concentrations of ceftriaxone alosporins generally only demonstrate a PAE
(intravenous 30 minute-infusion of 1g once daily) against Gram-positive bacteria.[64]
were bactericidal for 100% of the dosage interval
against clinical isolates of S. pneumoniae, K. pneu- 3. Pharmacokinetic Properties
moniae, Enterobacter aerogenes, E. coli, Serratia
The pharmacokinetic profile of ceftriaxone has
marcescens and H. influenzae. In general, similar
been extensively studied and reviewed pre-
results were reported with ceftizoxime (intrave-
viously.[2,75,76] A brief overview is presented here.
nous 30 minute-infusion of 1g every 12 hours), al-
though ceftriaxone showed bactericidal activity 3.1 Absorption and Plasma Concentration
against S. pneumoniae isolates for a significantly
longer period of the dosage interval than In healthy individuals, a 30-minute intravenous
ceftizoxime (100 vs 92%; p < 0.0001); this differ- infusion of ceftriaxone 0.5, 1 or 2g produced mean
ence was not considered clinically relevant.[71] Cmax of 82, 151 and 257 mg/L, respectively (figure
Neither drug showed bactericidal activity against 3a).[70] After intramuscular injection of ceftriaxone
0.5 or 1g, the Cmax values were 38 and 76 mg/L,
S. aureus in this in vitro study.
respectively, and time to Cmax was 2 to 3 hours.[70]
In another in vitro study, both ceftriaxone and
Cmax values after intramuscular and intravenous
cefodizime demonstrated rapid bactericidal activ-
administration of the 1g dose superimpose after
ity (99.9% of organisms killed within 6 to 8 hours) about 2.5 hours and the concentration profiles are
against S. aureus, S. pneumoniae, H. influenzae essentially the same thereafter (figure 3a). Alth-
(both a β-lactamase-positive and a β-lactamase- ough the clearance rate is increased after intrave-
negative strain), E. coli and K. pneumoniae in se- nous administration (figure 3b), overall, the area
rum and in bronchial mucus.[72] Generally, the con- under the plasma concentration-time curves (AUC)
centration of both agents remained at or above the after intravenous or intramuscular administration
MIC90 value for each isolate for the 24-hour dosage are similar, indicating comparable systemic bio-
interval; against S. aureus strains, the MIC90 value availability.[2,76] The mean systemic bioavailability
was exceeded for 50% of the dosage interval with of subcutaneously administered ceftriaxone is
both agents.[72] 96%.[77]

a 2g IV dose-proportionally with intravenous doses

250
1g IV greater than 1g.[2] However, the pharmacokinetic
1g IM
200 0.5g IV parameters of free (unbound) ceftriaxone were lin-
Average plasma concentration (mg/L)
150 0.5g IM ear and dose dependent.[2,76] With increasing

100 doses, the free Cmax increased disproportionately,
60
thus supporting once daily rather than divided-
dose administration.[78] Plasma binding is reduced
40
in neonates, infants and young children compared
with adults.[79]
20
The degree of protein binding in the plasma of
an antibacterial drug is reflected in the concentra-
10
tion of free (unbound) drug available for antibac-
terial activity and diffusion into extravascular
compartments.[80] A study in patients with pleural
0.5 2
1
4 6 8 12 16 24 empyema demonstrated that free and bound serum
b concentrations of ceftriaxone correlated with re-
3000 spective concentrations achieved in the pleural ex-
2000 udate 6 hours after intravenous administration of a
1g dose (mean ratio free : total drug 30.1 vs
Average urinary concentration (mg/L)
1000
800 41.0).[80] Ceftriaxone demonstrated second-order
600 pharmacokinetics in this respect.
400
In surgical patients and those with bacterial in-
200 fections, mean plasma concentrations 24 hours af-
ter intravenous ceftriaxone 2g were between 12
100 and 20 mg/L and Cmax values were 180 to 259
80
60 mg/L.[77,81,82] In nine critically ill patients with
40 normal renal function who received ceftriaxone 2g
20
intravenously, the mean Cmax was 205 mg/L; how-
ever, the plasma clearance was about twice that
reported in healthy volunteers (2.5 vs 0.58 to 1.45
2
4
8
16
8
0-
2-
4-
-2
-4
L/h) suggesting that more frequent administration

8-
16
24
Hours is required in seriously ill patients.[83] Conversely,

there was evidence of drug accumulation in four
Fig. 3. Plasma (a) and urinary (b) concentrations after single
intramuscular (IM) or intravenous (IV) administration of
patients in the same study who had renal failure.
ceftriaxone 0.5 to 2g.[70] The latter data provide support for an earlier study
of ceftriaxone in critical care patients with acute
renal failure in which restricted administration
Ceftriaxone binds reversibly to albumin. The (maximum 2 g/day) was recommended because of
level of binding decreases with increasing ceft- ceftriaxone accumulation.[84]
riaxone concentrations as plasma protein binding Repeated intravenous administration of
sites become saturated: from ≈95% bound at ceftriaxone 0.5 or 1g at 12-hourly intervals re-
plasma concentrations >70 mg/L to ≈58% bound sulted in mean Cmax values that were 32 to 40%
at 600 mg/L.[2] Because of this nonlinear binding, higher after the last dose than after the initial dose;
the plasma concentrations and AUC of total (bound trough plasma concentrations were 34 to 50%
plus unbound) ceftriaxone increased less than higher.[85,86] However, repeated intravenous ad-

1058 Lamb et al.
Table V. Distribution of ceftriaxone after a single intravenous or intramuscular injection

Tissue/fluid No. of Dose Sample time Concentration (mg/L or mg/g) Reference
individuals (hours) plasma tissue/fluid
Abdominal tissues 10a 1g IV 0.5 to ≈4.5b 100 6.2 (fat at opening) 95
56 2.5 (fat at closure)
68 6.0 (pancreatic tissue)
68 2.1 (pancreatic fluid)
68 1179.0 (pancreatic bile)
65 18.0 (liver)
Ascitic fluid 8c 1g IV 4 48d 11d 96
24 13d 8d
14 2g IV 0.33 (serum) 167 18.6 97
1 (ascites)
Bile and gallbladder 11 1g IV 2.88 59.5 44.5 (bile) 98
25.1 (gallbladder)
10 1g IV 1 188.5 153.4 (bile) 99
50.5 (gallbladder)
12 2g IV 1 199 5259 (common duct bile) 100
4533 (gallbladder bile)
Bone 20 2g IV 2.5 146 10.7 (cortical) 101
19.4 (cancellous)
6 1g IV ≈8 39.8 5.8 102
7 1g IV 0.33 120.1 20.9
Brain 17 2g IV 2-13 80.7 1.64e 103
Breast milk 10 1g IV 2 35d 0.31d 104
Cartilage 5 1g IV 1 to <2 97.4 5.6 105
7 18 to <20 8.7 1.2
CSF 11f 50 or 100 4.5 301; 26h 4.0 106
mg/kg IVg
12f (day 3) 80 mg/kg IM 4-6 83.3 5.7 107
14f (day 6) 64.5 5.2
10f (day 9) 38.5 2.0
5 2g IV 1-16 246.3 0.53 108
Epididymis 15 1g IV 0.65; 0.80i 133j 27.2;25.4i 109
Epiploic fat 11 1g IV 0.5 92.7 8.7 110
Fetal serum 46 1g IV ≈0.5 233 (ms) 15 (fs) 111
Lower extremities 6 2g IV 0.33k NR 67.4 (skin) 112
50.6 (muscle)
27.1 (bone)
19.9 (fat)
Middle ear fluid 8; 6 50 mg/kg IM 1.5; 24.3l 171; 19.3l 5.6; 35l 113
Placenta 46 1g IV ≈0.5 18.4 (mp) 13 (fp) 111
Pericardial fluid 20 2g IV 6-7 163 73 114
24 39 56
Peritoneal fluid (after 16 1g IV 1.5 69.5 6.4 115
surgery) 24 3.12 1.79
Peritoneal tissue 10 1g IV 4.18 77.3 19.4 116
Pleural effusion 6 1g IV 1 (tmax for serum) 199 20.1 (peak at 6h) 117
7 1g IM 80.5 15.3 (peak at 12h)
4; 3m 2g IV 6 111; 119m 27; 17.4m 118
Thoracic wall fat 17 1g IV 2 57d 15 119
Vitreous fluid 9 1-2g IM 1-4.5 141.5 5.9 120

a Patients were undergoing duodenopancreatectomy for cancer.

b Simultaneous blood and tissue samples were obtained at time of abdominal opening (fat) during surgery (pancreatic tissue and fluid,
and liver) and at time of closing (fat).
c Patients with alcoholic cirrhosis and ascites.
d Estimated from graph.
e In three patients ceftriaxone concentrations were below minimum detectable levels (<0.03 mg/L) and in one patient concentrations ex-
ceeded the assay maximum (12 mg/kg).
f Children with meningitis who received concomitant dexamethasone.
g Children <18 months of age received 50 mg/kg/day; those older than 18 months received 100 mg/kg/day.
h Peak value obtained 5 minutes after infusion; trough value obtained immediately before infusion.
i Right epididymis; left epididymis.
j Five minutes after infusion.
k A tourniquet was applied to the upper thigh from 0.17 to 4 hours after ceftriaxone administration. The highest tissue penetration was
obtained after 0.33 hours.
l Time of peak plasma concentration; time of peak middle ear fluid concentration.
m Transudative; exudative.
fp = fetal placenta; fs = fetal serum; IM = intramuscular; IV = intravenous; mp = maternal placenta; ms = maternal serum; NR = not reported;
tmax = time to maximum plasma concentration.
ministration of ceftriaxone 2g at 24-hourly inter- may greatly exceed average free drug concentra-
vals resulted in an increase of only 8% in mean tions.[91,93,94]
Cmax, but with a greater degree of tissue penetration Ceftriaxone distributes widely in the body tis-
than with the twice-daily dose.[86] After 7 days’ intra- sues and fluids (table V). Ceftriaxone is generally
muscular administration of ceftriaxone 1g once given once daily so it is important to know the
daily there was 11% accumulation of the drug.[87] tissue/fluid drug concentration 24 hours after a
dose; 24 hours after intravenous administration of
ceftriaxone 1 to 2g, the mean concentration was 7
3.2 Distribution and Tissue Penetration
to 10.4 mg/L in the CSF of adults with meningi-
tis,[2] 2.9 to 7.2 mg/kg in prostatic adenoma tis-
The volume of distribution (Vd) of ceftriaxone sue[2,81] and 5.5 to 11.7 mg/kg in female reproduc-
in healthy volunteers ranges from 5.8 to tive tissues.[82] In the patients with meningitis,
15.5L.[70,75,77,88-90] The Vd for patients with renal ceftriaxone concentrations in the CSF were higher
impairment is at the higher end of this range and in patients with inflamed meninges than in those
does not change significantly with the increasing with noninflamed meninges, and higher in bacte-
severity of renal impairment.[70] The apparent Vd rial than in aseptic meningitis.[121,122]
of total ceftriaxone (bound plus unbound) during Ceftriaxone preferentially localises in bile and
the terminal elimination phase increased with in- mean concentrations of ≈153 and ≈44 mg/L are
creasing dose, but the Vd of free ceftriaxone (un- obtained 1 and ≈3 hours, respectively, after intra-
bound) remained relatively constant.[91] The total venous administration of 1g dose (table V).[98,99]
Vd/unit of body area does not appear to vary with The mean ratio of ceftriaxone in gallbladder bile to
age; however, when expressed on a weight basis that in plasma was 33.[1,79]
the Vd was significantly larger in infants than in
adults.[92] 3.3 Elimination
As discussed in section 3.1, ceftriaxone is
highly protein bound, but binding is concentration- Ceftriaxone is primarily eliminated unchanged
dependent and distinctly nonlinear. With ceft- by the kidneys (figure 3b) and 45 to 60% of an
riaxone, binding sites become saturated and free intravenous dose of 0.5 to 3g is excreted in the
drug concentrations at the time of administration urine of healthy subjects within 48 hours.[1,123] The

1060 Lamb et al.
remainder is secreted in the bile and is ultimately but as this constitutes a small fraction of total clear-
found in the faeces as microbiologically inactive ance, the overall clearance is unaffected.[130]
compounds.[91] After a single 0.5g intramuscular In patients with moderate liver insufficiency and
dose of ceftriaxone, ≈35% was excreted in the normal renal function, there was little change in the
urine during 48 hours and this increased to ≈51% pharmacokinetics of ceftriaxone.[78] However, in a
after administration of multiple doses.[124] After a subgroup of patients with liver failure and ascites
single dose of intravenous ceftriaxone 0.5g, cumu- there was an increase in the average free fraction
lated urinary excretion over 24 hours was 47%.[77] of drug in plasma, systemic clearance and
Total plasma clearance of ceftriaxone is dose-re- Vd. [78]
lated and increases from mean values of between
0.61 and 1.0 L/h after intravenous ceftriaxone 0.5g 4. Therapeutic Use in
to between 1.18 and 1.29 L/h after a single 2g in- Community-Acquired Infections
travenous dose.[1] After 8 doses of ceftriaxone 1g,
renal clearance was 1.45 L/h compared with 1.23 This section focuses on randomised compara-
L/h after the first dose.[1] The renal clearance of tive trials investigating the use of ceftriaxone in
community-acquired infections published since
ceftriaxone based on unbound plasma concentra-
the last review in Drugs.[2] Noncomparative data
tions is ≈9.6 L/h. This is only slightly higher than
are presented only where they add valuable addi-
the glomerular filtration rate indicating that the re-
tional information on the efficacy of the drug or
nal clearance of ceftriaxone is primarily governed
relate to rare infections. Of the indications covered
by glomerular filtration.[90,91]
in this section, meningitis, acute otitis media
The mean elimination half-life (t1⁄2) of ceft-
(AOM) and community-acquired pneumonia
riaxone in healthy adults ranges from ≈6 to 9 hours
(CAP) are supported by extensive and/or recent
after single or multiple doses. The t1⁄2 does not vary data. These indications therefore receive the great-
significantly according to dose size, frequency or est emphasis.
route of administration.[1,77,89] The t1⁄2 of ceftri- Where possible, both clinical and bacteriologi-
axone is considerably longer than that of other cep- cal outcomes are presented for each indication and
halosporins which range from 0.6 to 4.4 hours.[125] bacteriological data are discussed in detail if avail-
In infants <8 days old and the elderly aged >75 able. In the broadest sense, clinical success is de-
years, the t1⁄2 was two to three times that seen in fined as cure or improvement of clinical signs and
young adults (18.6 and 14.2 hours for infants and symptoms and bacteriological success as eradica-
elderly individuals, respectively). However, there tion or presumed eradication of the causative
is no significant variation in t1⁄2 in those aged be- pathogen(s). Since the precise definition given to
tween 9 days and 74 years.[79] each outcome varies according to the infection
In patients with mild to moderately impaired re- type, the exact definitions are detailed in the sum-
nal function, t1⁄2 is only slightly increased to around mary table of each indication. Given the geo-
10 to 15 hours.[1,126-129] In patients with more se- graphic variability in the prevalence of penicillin
vere renal dysfunction [creatinine clearance resistance among S. pneumoniae, the location of
<0.6L/h (<10 ml/min)], t1⁄2 may increase to up to 50 each trial is also given for infections in which S.
hours.[127,129] Nevertheless, dosage adjustment is pneumoniae is a major pathogen.
not recommended in patients with renal dysfunc- In many of these trials, treatment was adminis-
tion provided that hepatic function is intact (section tered either partially or completely on an outpatient
7). Haemodialysis does not affect the clearance of basis. In this context, the term step-down therapy
ceftriaxone.[75,128] In patients undergoing perito- is used to describe a switch from parenteral to oral
neal dialysis, the clearance of ceftriaxone through therapy with the same or different class of agent
the peritoneum is increased approximately 2-fold, (e.g. ceftriaxone followed by cefpodoxime pro-

Table VI. Efficacy of intravenous ceftriaxone (CRO) in infants, children and adults with confirmed bacterial meningitis: summary of randomised
nonblind comparative trials with >35 patients. All were multicentre trials with the exception of Marhoum et al.[136] All drugs were administered
intravenously; adjunctive steroids were used in three trials[137-139]
Reference (country) Age range Dose (mg/kg) × duration (days) No. evaluable Outcome (% evaluable pts)
pts clinical cure sterile
[+ sequelae]a CSFb
In infants and children
Martin et al.[140] 3wk-16y CRO 100 od × 2d, then 60 od × 8-14c 45 89 [100] 100
(Switzerland) CRO 100 od × 2d, then 60 od × 4-7c 47 91 [100] 100
Peltola et al.[141] 3mo-15y CRO 100 od × 7 50 89
(Finland) CTX 37.5 qid × 7 51 76
AM 62.5 qid × 7d 46 68
C 25 qid × 7 53 56
Saez-Llorens et al.[137]e 3mo-12y CRO ± VAN 105 [81] 99
(multiple) ALA 5, then 2.5 q12h 91 [78] 97
Schaad et al.[142] 6wk-16y CRO 100 od × 7 or 9 53 [100] 98
(Switzerland) CXM 60 qid × 7 or 9 53 [100] 88
Scholz et al.[138] 6wk-16y CRO 100, then 75 od × 4 or 7 44 80 [93] 100
(Germany) CTX 50 qid × 4 or 7 38 71 [95] 97
In adults
Marhoum et al.[136] >16y CRO 2g od × 2 16 81 100
(Morocco) P 300 000 IU/kg q4h × 6 20 95 100
Schmutzhard et al.[139] 13-76y CRO 100, then 80 od or CTX 75-100f 22 50 [77] 95
(multiple) q8h × 7-14
MEM 40 q8h × 7-14 23 30 [100] 100
a Cure was defined as resolution/improvement of signs and symptoms with no sequelae. Cure + sequelae was defined as cure with: resid-
ual somatoneural sequelae at 6 mo after discharge,[140] mild sequelae 6-12mo post-treatment,[137] neurological sequelae,[138] neuro-
logical and/or auditory sequelae 6wk to 6mo post-treatment[139] or mild sequelae 8-10wk after discharge.[142]
b After 12-24h[141] or 18-36h of initiating treatment.[136-139,142]
c CRO 100 mg/kg was administered for 2 days and thereafter at a dose of 60 mg/kg subject to susceptibility testing. Only pts with sterile
CSF 15h after the first CRO dose were then randomised to a full or shortened course of treatment, the exact duration of which was
determined by the infecting pathogen; Neisseria meningitidis (8 or 4 days); Haemophilus influenzae type b (12 or 6 days); and Strep-
tococcus pneumoniae (14 or 7 days). 18 pts received CRO intramuscularly after the third-day of treatment.
d Administered in combination with C until pathogen was shown to be sensitive to AM.
e Abstract; dose of CRO and VAN not stated; blinding not reported.
f Dosage based on bodyweight.
ALA = alatrofloxacin; AM = ampicillin; C = chloramphenicol; CTX = cefotaxime; CXM = cefuroxime; MEM = meropenem; od = once daily;
P = benzylpenicillin; pts = patients; qid = four times daily; qxh = every x hours; VAN = vancomycin.
xetil),[131-134] whereas the term sequential therapy been drawn together (table VI), it should be noted
is used to refer to a conversion from parenteral to that there is little consistency in the clinical outcomes
oral treatment with the same agent (e.g. levo- of these trials or the definitions given to them.
floxacin).[135]
4.1.1 Infants and Children
4.1 Meningitis
Intravenous ceftriaxone achieved a clinical cure
in 80 to 91% of infants and children with meningi-
A summary of randomised comparative clinical tis, with sterilisation of the CSF in 89% of patients
trials with intravenous ceftriaxone in patients with within 12 to 24 hours and 98 to 100% of patients
confirmed bacterial meningitis is provided in table within 18 to 36 hours of starting treatment (table
VI. Although all available randomised trials have VI). Ceftriaxone was administered at a dosage of

1062 Lamb et al.
100 mg/kg once daily, which was reduced to 60 to and a 6-day course of benzylpenicillin sterilised the
75 mg/kg once daily after 1 to 2 days in two tri- CSF in all patients with meningococcal meningitis
als;[138,140] vancomycin was also administered with within 24 hours (table VI); one patient who devel-
ceftriaxone in some patients in one trial, although oped fulminant septicaemia required 7 days of
the dosage was not stated.[137] After 18 to 36 hours, ceftriaxone treatment.
similar response rates were observed with al-
atrofloxacin, cefuroxime and cefotaxime, with 4.2 Acute Otitis Media (AOM)
sterile CSF documented in 88 to 97% of patients
(table VI), although cefuroxime was associated Although amoxicillin is still considered to be
with delayed sterilisation (after 48 hours) more fre- the treatment of choice for uncomplicated AOM in
quently than ceftriaxone (12 vs 2%).[142] Lower children,[145,146] the emergence of penicillin-resis-
rates of CSF sterilisation were observed with am- tant S. pneumoniae has made the management of
picillin and chloramphenicol in one trial which per- this common infection increasingly difficult. Re-
formed an earlier assessment (12 to 24 hours), al- cent recommendations devised in the US still sup-
though an overall statistical analysis was not port the use of oral amoxicillin as first-line therapy,
performed.[141] with oral amoxicillin/clavulanic acid, cefuroxime
Neurological sequelae at discharge were re- axetil or a single intramuscular dose of ceftriaxone
ported in 9 to 23% of patients who received recommended in those who do not improve within
ceftriaxone[138,140,142] and persistent sequelae were 3 days.[145] Recent observations suggest that S.
reported in approximately 10% of patients 2 to 6 pneumoniae is more prevalent in children who are
months after therapy.[140-142] This is slightly lower unresponsive to first-line therapy and that isolates
than an incidence of 16% after discharge which tend to be less susceptible than those in patients
was reported in a meta-analysis of 19 prospective with previously untreated AOM.[147] Thus, the rec-
trials performed in children.[143] ommendations further suggest that three doses (1
The incidence of sequelae reported with per day) of ceftriaxone may be required in unre-
ceftriaxone was similar to that of comparator sponsive patients or in those who have received
agents, except for moderate-to-profound sensori- other antimicrobial therapy within the last
neural hearing loss which was observed more fre- month.[145] A flexible approach advocated by
quently with cefuroxime than ceftriaxone in one McCracken[148] recommends that in uncompli-
trial (17 vs 4% of patients; p = 0.052).[142] This cated AOM a single dose be given, with additional
result is consistent with other prospectively col- doses if necessary (after 48 to 72 hours) if there is
lected efficacy data from a US centre which re- a clinical failure with the first dose. It is suggested
ported moderate-to-severe hearing loss in 18% of that the second dose may be given at 48 to 72 hours
cefuroxime 240 to 300 mg/kg/day recipients (n = rather than 24 hours, since the concentration of
139) and 11% of ceftriaxone 75 to 100 mg/kg/day ceftriaxone exceeds the MIC90 for approximately
recipients (n = 148).[144] 120 hours or longer for most organisms including
penicillin-intermediate and -resistant strains of S.
4.1.2 Adults pneumoniae.[113] This approach allows for the pos-
Two small studies have been performed in sibility that some children failing the one-dose
adults with meningitis, the first of which showed ceftriaxone regimen may be cured by the second
that treatment with ceftriaxone or cefotaxime dose and hence not require the third dose.
achieved CSF sterilisation in 95% of patients ver- To this end, two different regimens of
sus 100% with meropenem (table VI). The inci- ceftriaxone have been tested in patients with AOM:
dence of hearing impairment and neurological se- a single dose predominantly in patients with un-
quelae was similar in both treatment groups.[139] In complicated AOM (section 4.2.1) and a 3-dose reg-
the other trial,[136] a 2-day course of ceftriaxone 2g imen in those with unresponsive AOM (section

Table VII. Efficacy of intramuscular ceftriaxone (CRO) in infants and children with uncomplicated acute otitis media: summary of randomised
comparative trials which included >50 evaluable pts. Several trials were multicentre,[150-153] one was double-blind[151] and 2 single-blind.[150,154]
Diagnosis was based on the presence of symptoms consistent with acute otitis media (effusion, otalgia, irritability, fever) and compatible
otoscopic findings (opacity, bulging, impaired mobility, discolouration). One study confirmed the diagnosis using tympanocentesis.[153] All
trials excluded children who had received antibacterial therapy within the last 7 to 28 days. All comparator agents were administered orally
Reference (country) Age range Dose (mg/kg) × duration (days) Clinical successa [no. (%) pts]
10-14 days 28-42 days 90 days
Al Ghamdi et al.[155] 6mo-6y CRO 50 sd 70/77 (91)
(Saudi Arabia) AMC 13.3 tid × 10 107/115 (93)
Barnett et al.[150] 3mo-3y CRO 50 sd 158/197 (80) 108/136 (79)
(US)b TMP/SMX 4/20 bid × 10 174/212 (82) 124/155 (80)
Chamberlain et al.[154] 18mo-6y CRO 50 sd 48/48 (100)c 31/48 (65)c
(US) CEC 40 mg/kg/d × 10 31/31 (100)c 21/31 (68)c
[153]
Cohen et al. 4-30mo CRO 50 sd 186/235 (79) 108/183 (59)
(France) AMC 26.7/3.3 tid × 10 188/228 (83) 103/187 (55)
Green & Rothrock[151] 5mo-5y CRO 50 sd 105/116 (91) 59/81 (73)
(US)b AMX 13.3 tid × 10 107/117 (91) 48/84 (57)
Varsano et al.[152] 4mo-6y CRO 50 sdd 104/109 (95) 70/109 (64)
(Israel)b AMC 12.5/3.3 tid × 10 101/106 (95) 59/106 (56)
a Clinical success was defined as resolution or improvement of clinical symptoms. Success at 28-42 and 90 days was defined as patients
without relapse, recurrence or reinfection; 2 studies also considered persistent effusion to be indicative of treatment failure.[153,154] Re-
sults for the per-protocol populations are given.
b Included some children with recurrent disease (≥3 previous episodes); 14,[152] 19[151] and 41%[150] of evaluable pts.
c Expressed as number of infected ears. 23 pts received CEC and 31 pts received CRO.
d Pts with recurrent infection (n = 15) or whose symptoms persisted/worsened for >48h (n = 10) received a second dose of CRO.
AMC = amoxicillin/clavulanic acid; AMX = amoxicillin; bid = twice daily; CEC = cefaclor; pts = patients; sd = single dose; tid = 3 times daily;
TMP/SMX = cotrimoxazole (trimethoprim/sulfamethoxazole).
4.2.2). A true evaluation of drug efficacy in patients comparator regimens (table VII). In trials that re-
with AOM is complicated by the high rate of spon- ported results at later time points, outcomes be-
taneous resolution (up to 50% of cases caused by tween treatment groups were also similar (table
S. pneumoniae[149]) observed in this infection type. VII). Of note, in one non-peer reviewed US
Bacteriological data are also generally not reported study,[156] clinical response rates with ceftriaxone
in these studies. Unusually, however, the studies (single intramuscular 1g dose) were lower than
performed with ceftriaxone in patients with unre- those achieved with amoxicillin/clavulanic acid
sponsive infections all presented complete bacterio- (10 days’ treatment; no dosages reported) in paedi-
logical data which are the focus of section 4.2.2. atric patients (aged 3 months to 6 years) with AOM
4.2.1 Uncomplicated AOM (74 vs 82% of patients; 95% CI –14.4%, –0.5%).
A single intramuscular dose of ceftriaxone 50 Four studies reported that 60 to 83% of parents
mg/kg demonstrated similar clinical efficacy to 10- expressed a preference for a single injection ver-
day oral courses of amoxicillin 40 mg/kg/day, sus 10 to 32% who preferred oral ther-
amoxicillin/clavulanic acid 37.5 to 80 mg/kg/day, apy,[151,152,155,157] although only those attending
cefaclor 40 mg/kg/day or cotrimoxazole (trimetho- follow-up visits were involved in these analyses.
prim/sulfamethoxazole) 8/40 mg/kg/day in infants In two studies which reported rates of compliance,
and children with AOM (table VII). After 10 to 14 approximately one-third of children assigned to
days, rates of clinical success ranged from 79 to oral therapy did not receive their full course of
100% with ceftriaxone and from 82 to 100% with treatment.[152,153]

1064 Lamb et al.
4.2.2 Previously Treated/Nonresponsive Patients failure to eradicate the organisms from the naso-
Three recent clinical trials, conducted in Is- pharynx rather than the middle ear.[158]
rael[158,159] and France,[160] have investigated the
efficacy of a three-dose regimen of intramuscular
4.3 Community-Acquired Pneumonia
ceftriaxone 50 mg/kg/day in children with AOM
who did not respond to previous antibacterial ther-
apy. One nonrandomised trial compared the effi- 4.3.1 Hospitalised Adults
cacy of one (n = 49) versus three doses (n = 60) of Third-generation cephalosporins, such as
ceftriaxone 50 mg/kg,[158] whereas the other two ceftriaxone and cefotaxime, have an established
trials were noncomparative and investigated the place in the treatment of hospitalised adult patients
three-dose regimen only (n = 94[159] and n = with CAP. They are currently recommended as a
173[160]). Nonresponsive AOM was defined as per- first-line empirical treatment option (with the ad-
sistent or relapsing AOM for which an antibacterial dition of a macrolide for coverage against atypical
agent had been administered for ≥48 hours during pathogens if required) in both Europe[161] and the
the 14 days prior to enrolment[158,159] or as evi- US.[26] Other recommended treatment options in-
dence of failure after ≥72 hours of oral antibacterial clude fluoroquinolones that have coverage against
S. pneumoniae, β-lactam/β-lactamase inhibitors
treatment or treatment discontinuation >48 hours
and other cephalosporins, although there are slight
prior to enrolment.[160]
differences between the treatment guide-
According to data from these trials, a 3-dose
lines.[26,161]
regimen of ceftriaxone 50 mg/kg eradicated 93 to
Randomised comparative trials investigating
98% of pathogens isolated from middle ear
the empirical use of ceftriaxone, either alone or as
fluid.[158,159] In the comparative study, the eradica-
part of a step-down regimen, in the treatment of
tion rate achieved with a single ceftriaxone dose
hospitalised adults with CAP are presented in table
was significantly lower than that with the 3-dose
VIII. Comparator regimens selected in these trials
regimen (73 vs 98%; p < 0.001).[158] Of interest, six
are consistent with current treatment guidelines, al-
of seven patients who failed to respond to the sin-
though the diversity of regimens suggest that infec-
gle-dose regimen, subsequently responded rapidly tions of varying severity were involved. In these
to three further doses of ceftriaxone. This latter trials, ceftriaxone was administered either as a sin-
treatment regimen is in keeping with that advo- gle agent[134,163,165-168] or as part of a step-down
cated by McCracken[148] (section 4.2). regimen to oral therapy with cefpodoxime pro-
Tympanocentesis was performed in all three tri- xetil[132,133,164] or clarithromycin.[162] The decision
als at enrolment and again 3 to 10 days later. Strep- to switch from parenteral to oral therapy was left
tococcus pneumoniae isolates were defined as non- to the investigator’s discretion in each study. Addi-
susceptible [penicillin minimum inhibitory tional coverage for atypical pathogens or anaer-
concentration (MIC) ≥0.1 mg/L] or susceptible obes was permitted in three trials.[162,164,167]
(penicillin MIC <0.1 mg/L). Three doses of Additionally, in a nonblind study in 31 patients
ceftriaxone effectively eradicated all penicillin- with CAP, the average length of stay in hospital
susceptible S. pneumoniae and H. influenzae, and was reduced by 1.2 days (4.8 vs 6 days) in patients
82 to 97% of penicillin-nonsusceptible S. pneu- receiving step-down therapy with intravenous
moniae. A significantly lower eradication rate was ceftriaxone (dosage not reported) followed by oral
observed with single dose ceftriaxone against pen- cefpodoxime proxetil 200mg twice daily compared
icillin-nonsusceptible S. pneumoniae compared with those receiving intravenous ceftriaxone fol-
with the 3-dose regimen (52 vs 97%; p < 0.001); it lowed by other oral treatment regimens (choice of
has been suggested that the higher failure rate ob- oral agent was at the physician’s discretion).[131]
served with this regimen may be attributable to There were no recurrences of primary infection or

Table VIII. Efficacy of ceftriaxone (CRO), either alone or as part of a step-down regimen, in hospitalised adult patients with community-acquired
pneumonia: summary of randomised comparative trials. Trials were double-blind[134,162-164] or nonblind;[132,133,165-168] with 2 exceptions,[162,166]
all trials were multinational and/or multicentre
Reference (country) Severity Dose (g) × mean duration (days) Outcome [no. (%) pts]a
[mortality (% pts)] parenteral oral (or IM) clinical bacteriological
Comparisons with other β-lactams
Bittner et al.[134] Moderate [5%] CRO 1 od IV/IM × 7-14 21/26 (81) 21/21 (100)
(US) CPD 0.2 bid PO × 7-14 28/33 (85) 30/30 (100)
de Palma et al.[165] Mild/severe CRO 1 od IM × 6.7 89/94 (95) 38/41 (93)
(Italy) CDZ 1 od IM × 6.0 92/95 (97) 52/53 (98)
CDZ 1 bid IM × 6.2 92/94 (98) 49/50 (98)
Roson et al.[166]b Moderate/ severe; CRO 1 od IV × 6.2 CRO 1 od IM × 5.6 (89; n = 63) (100)
(Spain) pneumococcal AMC 2/0.2 q8h IV × 5.5 AMC 1/0.125c × 6.3 (91; n = 53) (100)
[9-11%]
Zervos and Mild/severe [4%] CRO 1 q12h IV/IM × 6.5d,e 45/46 (98) 38/39 (97)
Nelson[167] CEP 2 q12h IV/IM × 6.5d,e 38/40 (95) 32/32 (100)
(US)
Comparisons with fluoroquinolones

Dowell et al.[162]b CRO 1-2 od IVd CLR 0.5 bid × 7-14 96/106 (91)
(US/Canada) GAT 0.4 od IV GAT 0.4 od × 7-14 96/99 (97)
Johnson et al.[163] Nosocomial (9%) [5%] CRO 1 od IV × 4.3 CRO 1 od IM × 4.2 38/45 (84) 42/42 (100)
(US) CIP 0.4 q12h IV × 4.9 CIP 0.5 q12h × 4 44/49 (90) 45/48 (94)
Norrby et al.[168] Moderate/ severe; CRO 4 od IV (median 8) (86; n = 139) 71/85 (83)
(multiple) nosocomial (6%) [7%] LEV 0.5 bid IV × 4 LEV 0.5 bid × 5 (87; n = 127) 57/69 (83)
(median) (median)
Williams Hopkins Severe [5%] CRO 1 od IVd CPD 0.2 bidd × 7-14 160/184 (87)
and Daniel[164]b ALA 0.2 od IV TRO 0.2 od × 160/178 (90)
(multiple) 7-14
Comparison with linezolid (LIN)
Cammarata et CRO 1 bid IV CPD 0.2 bid × 11 225/254 (89) 81/93 (87)
al.[132,133]b (multiple) LIN 0.6 bid IV LIN 0.6 bid × 11 247/272 (91) 80/89 (90)
a Clinical success was defined as cure[132,163,168] or cure + improvement of symptoms 0 to 7 days post-therapy; bacteriological success
was defined as eradication or presumed eradication of pathogens 0 to 7 days post-therapy. Per protocol analyses are presented for
all studies.
b Abstract.
c Frequency not stated.
d Concomitant erythromycin,[162,164,167,169] doxycycline[169] or metronidazole[167] were permitted if atypical or anaerobic pathogens were
suspected.
e Seven pts also received other antibacterial agents.
ALA = alatrofloxacin; AMC = amoxicillin/clavulanic acid; bid = twice daily; CDZ = cefodizime; CEP = cefepime; CIP = ciprofloxacin; CLR =
clarithromycin; CPD = cefpodoxime proxetil; GAT = gatifloxacin; IM = intramuscular; IV = intravenous; LEV = levofloxacin; od = once daily;
PO = oral; pts = patients; qxh = every x hours; TRO = trovafloxacin.
readmissions to hospital at 1-month follow-up in to –1.4] and bacteriological (98 vs 85%; 95% CI
either treatment group. –21.6 to –4.8) success rates compared with
ceftriaxone and/or cefuroxime axetil. Of note, pa-
Clinical and Bacteriological Outcomes
In a comparative nonblind trial in 456 evaluable tients in both treatment groups received intrave-
patients by File et al.,[169] sequential therapy with nous and/or oral therapy at the investigator’s dis-
levofloxacin achieved significantly greater clinical cretion; in the ceftriaxone/cefuroxime axetil group
[96 vs 90%; 95% confidence intervals (CI) –10.7 ≈50% and ≈2% of patients received only oral ce-

1066 Lamb et al.
furoxime axetil or intravenous ceftriaxone, respec- cefixime 8 mg/kg once daily (n = 29) or
tively. Hence, data from this study should be inter- amoxicillin/clavulanic acid 40 mg/kg in three di-
preted cautiously, since no subgroup analyses were vided doses (n = 33) for 8 days. On day 11, clinical
undertaken for individual treatment regimens ad- success rates were 100 and 88%, respectively.[170]
ministered in this trial. In a noncomparative trial performed in children
With the exception of the File et al.[169] study, and adolescents (5 months to 15 years) with severe
ceftriaxone 1 to 4 g/day, alone or as part of a step- CAP, intramuscular (n = 135) or intravenous (n =
down regimen, had similar efficacy to that of other 12) ceftriaxone 50 mg/kg once daily for 3 to 7 days
β-lactam agents (amoxicillin/clavulanic acid, achieved a successful response in 142 (97%) pa-
cefepime, cefpodoxime proxetil, cefodizime), tients. A subgroup of 39 patients, who had been
fluoroquinolones (ciprofloxacin, levofloxacin, previously treated unsuccessfully with other anti-
gatifloxacin, trovafloxacin) and the oxazolidinone bacterials, were all cured with ceftriaxone. 121
linezolid (table VIII). Clinical success rates (82%) children who became afebrile after 1 to 2
achieved with ceftriaxone-based therapy ranged days were discharged and completed therapy on an
from 81 to 98% versus 85 to 98% with β-lactam outpatient basis; outpatient therapy saved an esti-
agents, 84 to 91% versus 87 to 97% with mated 383 days of hospitalisation over a 6-month
fluoroquinolones and 89 versus 91% with linezolid period compared with historical controls.[171]
(table VIII). Bacteriological response rates were
also similar between treatment groups (table VIII). 4.4 Invasive Infections Caused by
Rates of clinical success at late follow-up (day Penicillin-Resistant Streptococcus
14 to 30) were 81 to 97% with ceftriaxone-based pneumoniae
therapy versus 83 to 97% with comparators
In the mid 1990s, the NCCLS breakpoints of the
(ciprofloxacin, levofloxacin).[163,164,168] Ceftr-
third-generation cephalosporins for S. pneumoniae
iaxone-based therapy was also effective in patients
were re-evaluated in response to reports of treat-
with concurrent pneumococcal bacteraemia; clini-
ment failures in patients with pneumococcal men-
cal success was reported in 89 to 100% of patients
ingitis.[24,172] As a result, pneumococcal strains
with pneumococcal bacteraemia in two tri-
with an MIC of 1 mg/L were considered interme-
als.[163,164]
diately resistant and those with an MIC of ≥2 mg/L
Bacteriological Outcome by Pathogen were considered resistant (table III). However,
In trials that reported bacteriological data on a clinical data on the efficacy of ceftriaxone in infec-
per pathogen basis, ceftriaxone-based therapy tions caused by nonsusceptible strains of S. pneu-
eradicated 88 to 100% of S. pneumoniae, 83 to 100% moniae remain limited. This section reviews the
of S. aureus, 79 to 100% of H. influenzae, 71 to 100% available data.
of H. parainfluenzae, 86 to 100% of M. catarrhalis
4.4.1 Meningitis
and 100% of K. pneumoniae.[134,162,163,167,168] Er-
Consistent with current NCCLS breakpoints
adication rates achieved with both β-lactam
(table III), treatment failures with ceftriaxone in
(cefepime and cefpodoxime proxetil) and fluoro-
patients with meningitis have been documented
quinolone (levofloxacin, ciprofloxacin and gatifl-
when the infecting strains of S. pneumoniae have
oxacin) comparators were similar to those ob-
ceftriaxone MICs of ≥2 mg/L.[33,173-177] Although
served with ceftriaxone-based therapy in all trials.
ceftriaxone monotherapy can be used effectively to
4.3.2 Children treat intermediately resistant strains (MIC 1 mg/L),
In children (0.5 to 5 years) with CAP, similar it has been suggested that the response is unpre-
rates of clinical success were achieved in those dictable.[25,178]
randomised to receive parenteral ceftriaxone 50 Therefore, in patients with meningitis caused by
mg/kg once daily for 2 days followed by either oral S. pneumoniae nonsusceptible to third-generation

cephalosporins, combination therapy with cef- pneumoniae in meningitis and non-meningitis in-
triaxone (or cefotaxime) plus vancomycin or fections have been introduced (see table III).[22]
rifampicin (rifampin) is recommended.[25] This In an attempt to assess this issue further, Kaplan
recommendation is based on observations of syn- et al.[23] performed a retrospective analysis of clin-
ergism in vivo[179] and in the CSF of children with ical outcomes in children with invasive infections
meningitis[180] (see Quagliarello & Scheld for re- (predominantly pneumonia and bacteraemia)
view[181]). caused by ceftriaxone-nonsusceptible S. pneu-
However, published data concerning the clini- moniae. All but one out of 100 infections were suc-
cal efficacy of these regimens remain very limited. cessfully treated with β-lactam agents; 89 infec-
In all, eight patients with meningitis caused by tions were caused by S. pneumoniae with
pneumococcal isolates with ceftriaxone MICs of 1 ceftriaxone MICs of 1 mg/L and 11 by strains with
or 2 mg/L have been reported in the literature; all MICs of 2 to 4 mg/L. The one treatment failure
were treated successfully with ceftriaxone 100 occurred in a child with bacteraemia and severe
mg/kg plus vancomycin 60 mg/kg/day[182] or combined immunodeficiency who received a sin-
ceftriaxone alone or in combination with vanco- gle dose of ceftriaxone followed by 12 days of
mycin, rifampicin or meropenem (dosages not treatment with an oral cephalosporin. In all, ceftr-
stated).[183] iaxone was used alone, with other parenteral third-
generation agents or as part of a step-down regimen
4.4.2 AOM in 40 of these infections [MIC 1 mg/L (n = 35), MIC
In children with AOM, failures following a 3- 2 mg/L (n = 4) and MIC 4 mg/L (n = 1)].[23]
dose regimen of ceftriaxone have been observed in
those in whom the infecting strains have ceftr- 4.5 Sexually Transmitted Infections
iaxone MICs of 0.5 to 1 mg/L.[158-160] Where de-
tails were provided, patients were successfully 4.5.1 Uncomplicated Gonorrhoea
treated with longer courses of ceftriaxone (5 or 7 Single-dose intramuscular ceftriaxone 0.25g
days).[159] These three trials performed in areas of consistently produced bacteriological eradication
high rates of penicillin resistance showed that the rates of ≥95% in adult patients with confirmed un-
3-dose regimen of ceftriaxone is effective in 93 to complicated gonorrhoea in randomised clinical tri-
98% of patients with nonresponsive AOM.[158-160] als (table IX). Eradication rates achieved with
Further, complete bacteriological results showed ceftriaxone were similar to those reported with sin-
that although the 1- and 3-dose regimens per- gle doses of comparator agents (90 to 100%;
formed equally well against H. influenzae and pen- cefixime, ceftizoxime, cefotaxime, ampicillin/sul-
icillin-susceptible S. pneumoniae, the 3-dose regi- bactam plus probenecid, trospectomycin, cipro-
men was required to effectively eradicate floxacin, fleroxacin and enoxacin; table IX).
penicillin-nonsusceptible S. pneumoniae. Ceftriaxone was effective regardless of the site of
infection (cervix, urethra, rectum or pharynx).[185-
190,194,198]
4.4.3 Other Invasive Infections
The relevance of the previous breakpoints for Penicillinase-producing (prevalence 4 to 66%),
ceftriaxone for invasive infections other than men- tetracycline-resistant (6 to 29%) and chromo-
ingitis has been questioned.[24-26] This is based on somally mediated resistant strains of N. gonor-
the high drug concentrations achieved in the serum rhoeae (8 to 70%) were documented in several
and other tissues (section 3.2) and also because of studies[185,188,189,191-195,197,198] and were effect-
good results achieved with oral penicillins in infec- ively eradicated by ceftriaxone. In keeping with
tions caused by penicillin-nonsusceptible S. pneu- its in vitro activity (section 2.3.2), ceftriaxone
moniae.[25] As a result new NCCLS interpretative did not reliably eradicate C. trachomatis coinfect-
criteria for the susceptibility of ceftriaxone for S. ions.[185,186,189-191,196-198]

1068 Lamb et al.
Table IX. Efficacy of ceftriaxone (CRO) in patients with confirmed Although a single intramuscular dose of
(by Gram stain and/or culture) uncomplicated gonorrhoea: sum-
ceftriaxone 0.25g is recommended for the treat-
mary of comparative randomised trials with >100 patients. Most
trials were multicentre;[184-191] th re e t ri als w ere doubl e- ment of uncomplicated gonorrhoea (section 7), a
blind[186,192,193] and the remainder were nonblind. All drugs were lower 0.125g dose has also been used success-
administered as single doses
fully[2,199] and is currently recommended by the US
Reference Regimen (g) No. Outcomea Centers for Disease Control in this indication.[200]
evaluable (% pts)
pts
Concerns about the possible development of chro-
Baddour et al.[194] CRO 0.25 IM 97 99
mosomally mediated resistance with this dose were
AM/SB 1/0.5 IM 98 95
not supported by a US in vitro study which moni-
Bryan et al.[193]b CRO 250 IM 82 99 tored susceptibility patterns (16 441 isolates) fol-
CIP 250 PO 83 100 lowing the widespread use of this lower dose of
Goldstein et al.[192]b CRO 0.25 IM 98 100 ceftriaxone.[44]
CZX 0.25 IM 106 100
4.5.2 Pelvic Inflammatory Disease
Handsfield et al.[185] CRO 0.25 IM 94 98 A single intramuscular dose of ceftriaxone
CFM 0.4 PO 93 98 0.25g combined with a 14-day course of oral dox-
CFM 0.8 PO 88 96
ycycline 100mg twice daily achieved clinical
Hellmann et al.[195] CRO 0.25 IM 63 95
cure/improvement in 61 of 64 (95%) women with
AM/SB 1/0.5 IM 71 92
mild to moderate pelvic inflammatory disease in a
Hook et al.[186]c CRO 0.25 IM 87 99
randomised double-blind multicentre trial.[201] A
CIP 0.25 PO 94 100
similar response rate [65 of 67 (97%)] was obtained
Jones et al.[187] CRO 0.25 IM 58 100
with the comparator regimen of oral clindamycin
CTX 0.5 IM 57 95
300mg three times daily and ciprofloxacin 250mg
McCormack et al.[188] CRO 0.25 IM 223 99
twice daily administered for 14 days. N. gonor-
CTX 0.5 IM 218 98
rhoeae and C. trachomatis were eradicated in
Mogabgab & Lutz[184] CRO 0.25 IM 81 100
100% (8 of 8) and 90% (9 of 10) of patients receiv-
CTX 0.5 IM 71 99
ing ceftriaxone plus doxycycline and clindamycin
Mroczkowski et al.[196] CRO 0.25 IM 40 95
plus ciprofloxacin, respectively.[201]
TRS 0.25 IM 74 99
Pabst et al.[189] CRO 0.25 IM 75 97
4.6 Acute Pyelonephritis
ENX 0.4 PO 77 95
Plourde et al. [197]
CRO 0.25 IM 63 100 Since the previous review in Drugs,[2] in which
CFM 0.4 PO 121 98 the efficacy of ceftriaxone was established in the
Portilla et al.[198] CRO 0.25 IM 47 100 treatment of acute and complicated urinary tract
CFM 0.4 PO 66 99 infections, new data with ceftriaxone have focused
CFM 0.8 PO 42 95 more on its use in special patient groups, specific-
Rompalo et al.[190] CRO 0.25 IM 35 100d ally in children and pregnant women (table X).
TRS 0.25 IM 68 90d In pregnant women (gestational age of fetus was
≤24 weeks) with acute pyelonephritis, two tri-
[191]
Smith et al. CRO 0.25 IM 271 100
FLE 0.4 PO 286 99 als[202,203] showed that intramuscular or intrave-
a Bacteriological eradication 3 to 10 days post-therapy.
nous ceftriaxone 1g once daily followed by oral
b Men only were recruited to the study.
therapy (10-day course of cefalexin or cefradine 2
c Women only were recruited to the study.
g/day) achieved bacteriological cure in 92 and 98%
d Expressed as a percentage of infected sites.
of patients. The women were discharged after they
AM/SB = ampicillin/sulbactam + oral probenecid 1g; CFM =
cefixime; CIP = ciprofloxacin; CTX = cefotaxime; CZX =
had been afebrile for ≥48 hours. A similar result
ceftizoxime; ENX = enoxacin; FLE = fleroxacin; IM = intramuscular; was achieved with intravenous cefazolin 3 or 6
PO = oral; pts = patients; TRS = trospectomycin. g/day[202,203] or intravenous ampicillin 12 g/day

Table X. Efficacy of ceftriaxone (CRO) as part of a step-down regimen in hospitalised children or pregnant women with acute pyelonephritis:
summary of comparative randomised trials with >50 patients. One trial was double-blind[202] and the remainder were nonblind; three trials
were multicentre[203-205]
Reference Estimated Regimen (g) × duration (days) No Bacteriological
gestational age parenteral orala evaluable pts outcomeb (%
(weeks) pts)
In pregnant women
Millar et al.[206] <24 CRO 1 × 2 doses IMc CN 0.5 qid × 10 60 82
CZ 1 q8h IVd CN 0.5 qid × 10 60 80
Sanchez-Ramos 24 (mean) CRO 1 od IVd CN or CED 0.5 qid × 10 90 92
et al.[202] CZ 2 q8h IVd CN or CED 0.5 qid × 10 88 90
Wing et al.[204] >24 CRO 1 × 2 doses IMe CN 0.5 qid × 10 46 91
CRO 1 × 2 doses IMd CN 0.5 qid × 10 46 93
Wing et al.[203] <24 CRO 1 × 2 doses IMd CN 0.5 q6h × 10 52 98
AM 2 q4h + GM 1.75-2 mg/kg CN 0.5 qid × 10 57 93
q8h IVd
CZ 1 q8h IVd CN 0.5 qid × 10 50 94
In children (aged 6mo-10y)
François et al.[205] CRO 50 mg/kg od + NET 2-2.5 CRO 50 mg/kg od IM × 6f 65 100
mg/kg tid × 4 IV
CRO IV 50 mg/kg od + NET CFM 4 mg/kg bid × 6f 63 98
2-2.5 mg/kg tid × 4 IV
a Unless stated otherwise.
b Negative urine culture (<100,000 colonies/ml) 3 to 5 days[205] or 5 to 14 days post-treatment or after discharge.[202-204,206] All results are
presented as intention-to-treat analyses.
c Pts were treated on an outpatient basis.
d Pts were discharged after they had been afebrile for ≥48h and were switched to oral therapy.
e Pts were discharged after 24h if they were stable.
f Treatment was administered intramuscularly on an inpatient or outpatient basis.
AM = ampicillin; bid = twice daily; CED = cefradine; CFM = cefixime; CN = cefalexin; CZ = cefazolin; IM = intramuscular; IV = intravenous;
GM = gentamicin; NET = netilmicin; od = once daily; pts = patients; qid = four times daily; qxh = every x hours; tid = three times daily.
plus gentamicin 5.25 to 6 mg/kg/day[203] before same ceftriaxone/cefalexin step-down regimen

stepping down to oral cephalosporins (90 to 94%; whether patients were discharged after 24 hours
table X). (91%) or, more conservatively, once they had been
Millar et al.[206] further showed that women afebrile for ≥48 hours (93%; table X).[204] How-
with a fetus of similar gestational age could be ef- ever, medical or infectious complications pre-
fectively managed completely on an outpatient ba- cluded outpatient management in over 50% of re-
sis (table X). Patients received two doses of intra-
cruited patients.[204] None of these studies reported
muscular ceftriaxone 1g followed by a 10-day
any differences in birth outcomes (preterm deliv-
course of oral cefalexin 2 g/day on an outpatient
ery, birthweight, neonatal intensive care admission
basis provided that they were stable and able to
tolerate oral therapy. The bacteriological response and stay) between regimens.[202,204,206]
rate achieved with the outpatient regimen was sim- In children with acute pyelonephritis, intramus-
ilar to that achieved with a step-down regimen of cular ceftriaxone 50 mg/kg/day or oral cefixime 8
cefazolin/cefalexin administered partially on an mg/kg/day for 6 days achieved similar bacteriolog-
outpatient basis (82 vs 80%; table X). ical cure rates (100 vs 98%; table X). All children
In women at a later stage of pregnancy (>24 had received an initial 4-day course of intravenous
weeks), similar results were achieved with the ceftriaxone 50 mg/kg once daily and netilmicin 6

1070 Lamb et al.
to 7.5 mg/kg/day in three divided doses on an in- to be at high risk of sepsis (e.g. fever >40°C, hypo-
patient basis.[205] tension) were excluded from both trials and were
treated on an inpatient basis only.[207,208]
4.7 Other Paediatric Infections
4.7.2 Other Infections
4.7.1 Febrile Episodes in Sickle Cell Disease Four randomised trials show that parenteral
Children with sickle cell disease are susceptible ceftriaxone 50 to 75 mg/kg/day achieves clinical
to pneumococcal sepsis and are at considerable risk response rates of 93 to 100% in hospitalised chil-
of associated morbidity and mortality. Tradition- dren with multidrug-resistant S. typhi septicaemia,
ally, children with sickle cell disease and febrile typhoid fever, skin and soft tissue or bone infec-
episodes were hospitalised for parenteral antibac- tions, or in outpatients with infectious diarrhoea
terial treatment. However, two trials show that out- (table XI). In all studies, the clinical and bacterio-
patient management is possible in selected febrile logical efficacy of ceftriaxone was similar to that
children with sickle haemoglobinopathies.[207,208] of comparator agents (oral azithromycin 10
In these trials, no episodes of sepsis occurred in
mg/kg/day, oral cefixime 15 to 20 mg/kg/day, in-
children who received two intravenous doses of
tramuscular aztreonam 150 to 210 mg/kg/day, in-
ceftriaxone 50 mg/kg 20 to 30 hours apart (n =
travenous ampicillin/sulbactam 100 to 200 mg-
44)[207] or one intravenous dose of ceftriaxone 50
mg/kg followed by 5 to 10 days of oral treatment /kg/day or oral ciprofloxacin 20 mg/kg/day).[209-212]
with cefixime 4 mg/kg twice daily (n = 80).[208] In patients with skin and soft tissue infections, a
Similar results were achieved in one of the trials in delayed response (judged as a treatment failure)
which patients were randomly assigned to a control was reported in three out of 105 ceftriaxone recip-
group to receive inpatient therapy as nominated by ients with cellulitis [S. aureus (n = 2), S. inter-
a haematologist (n = 42).[207] All patients deemed medius (n = 1)].[212]
Table XI. Efficacy of ceftriaxone (CRO) in children with infections at various sites: summary of randomised comparative trials. One trial was
double-blind,[209] with the remainder being nonblind. Children in 3 trials were hospitalised[210-212]
Reference Infection (age range) Dose (mg/kg) × duration (days) Outcome [no. (%) pts]
clinicala bacteriologicalb
Frenck et al. [211]
Typhoid fever (4-17y) CRO 75 od IM × 7 29/30 (97) 29/30 (97)
AZI 10 od PO × 7 31/34 (91) 33/34 (97)
Girgis et al.[210] Multidrug-resistant CRO 50-70 od IM × 5 43/43 (100) 43/43 (100)
Salmonella typhi septicaemia CFM 7.5-10 q12h PO × ≥14 50/50 (100) 50/50 (100)
(2-16y) ATM 50-70 q8h IM × 7 31/31 (100) 31/31 (100)
Kulhanjian et al.[212] Skin and soft tissue and CRO 25-37.5 bid IV × 2-10d 38/41 (93) 29/32 (91)
bone infectionsc (2mo-18y) AM/SB 25-50 qid IV × 2-10d 84/84 (100) 47/47 (100)
Leibovitz et al.[209] Infectious diarrhoea CRO 50 od IM × 3 106/106 (100) e
(6mo-11y) CIP 10 q12h PO × 3 94/95 (99) e
a Defined as cure or improvement of clinical signs and symptoms at end of therapy or 24-48h post-treatment; clinical failure in the trial by
Kulhanjian et al.[212] was defined as a delayed response (no symptom improvement 24-48h after initiating treatment).
b Defined as eradication of the causative pathogen(s) from the site of infection.
c Skin and soft tissue infections (n = 105), arthritis (n = 11) or osteomyelitis (n = 9).
d All patients received an oral first-generation cephalosporin or penicillinase-resistant penicillin after parenteral therapy to complete a 7- to
42-day course, depending on the infection site.
e Eradication rates by causative pathogens for CRO and CIP, respectively, were Shigella spp. (97 vs 100%), Salmonella spp. (80 vs 73%)
and Campylobacter jejuni (83 vs 71%).
AM/SB = ampicillin/sulbactam; ATM = aztreonam; AZI = azithromycin; bid = twice daily; CFM = cefixime; CIP = ciprofloxacin; IM =
intramuscular; IV = intravenous; od = once daily; PO = oral; qid = four times daily; qxh = every x hours.

Furthermore, regimens including ceftriaxone Of the 6637 evaluable patients, 192 (3%) had
have proven effective and were generally well tol- proven bacteraemia. S. pneumoniae accounted for
erated in neonates (including newborn neonates). 85% of proven infections; other pathogens were H.
A nonblind study in 80 neonates with proven or influenzae, N. meningitidis and Salmonella spp.[215]
suspected infection indicated that empirical treat- When the incidence of both probable and definite
ment with a combination therapy regimens con- focal infections were compared, there were no dif-
taining ceftriaxone were effective, with 46 of 74 ferences between treatment groups; however, def-
episodes (62%) of infection in neonates less than inite focal infections occurred in significantly
72 hours of age showing clinical resolution (either fewer ceftriaxone than amoxicillin recipients (0 of
negative culture or resolution of clinical symp- 101 vs 5 of 91; p = 0.02).[215]
toms).[213] Ceftriaxone was also effective in the
treatment of four neonates over 72 hours of age 5. Therapeutic Use in
who had culture-proven ceftriaxone-sensitive in- Nosocomial Infections
fections.[213] Neonates less than 72 hours of age
This section focuses on prospective compara-
received an intravenous infusion (2 minutes) of
tive trials investigating the efficacy of ceftriaxone,
ceftriaxone 50 mg/kg/day plus a slow infusion of
alone or in combination with an aminoglycoside,
ampicillin (100 mg/kg followed by a maintenance
in the treatment of patients with hospital-acquired
dose of 50 mg/kg every 24, 18 or 12 hours in those
or life-threatening infections. Trials which include
with a gestational age of <30, 30 to 34 or >35
a mixture of hospital- and community-acquired in-
weeks, respectively). Neonates aged greater than
fections[216-219] and older studies which use mono-
72 hours received ceftriaxone 50 mg/kg once daily
therapy in infections for which combination treat-
plus vancomycin 15 mg/kg every 24 (bodyweight
ment is now recommended[220-225] will not be
<1250g) or 12 hours (bodyweight >1250g). These
reviewed. Noncomparative data are presented only
data in neonates are supported by a retrospective
in unusual infections.
study[183] in 180 children (aged 3 days to 16.5
years) with pneumococcal meningitis and a rando- 5.1 Gram-Negative Infections
mised nonblind study 82 children (aged 6 weeks to
15 years) with bacterial meningitis.[138] In a large multinational randomised trial,[226]
ceftriaxone plus tobramycin achieved similar clin-
4.7.3 Occult Bacteraemia ical response rates to ceftazidime monotherapy in
Up to 10% of children under 3 years of age with adult hospitalised patients with serious nosocomial
fever and leucocytosis, but no apparent focus of Gram-negative infections (59 to 76% vs 73 to 80%
infection, are at risk of occult bacteraemia.[214,215] depending on the infection site) [figure 4]. The rate
If not cleared by the host defence system, this type of relapse was, however, significantly lower with
of infection can progress to fulminating septicae- ceftazidime than ceftriaxone plus tobramycin (4 vs
mia or a focal infection, such as meningitis or 10%; OR 0.4 : 1; 95% CI 0.2 to 0.9). Intravenous
pneumonia.[214] ceftriaxone 2g was administered once daily with
In a large US multicentre randomised nonblind intramuscular or intravenous tobramycin 3 to 5
trial,[215] children aged 3 to 36 months with fever mg/kg/day (after a 2 mg/kg loading dose; n = 274)
(≥39°C) received empirical treatment with a single and intravenous ceftazidime 2g was administered
intramuscular dose of ceftriaxone 50 mg/kg (n = twice daily (n = 306). Two-thirds of patients had
3333) or oral amoxicillin 20 mg/kg every 8 hours severe or life-threatening infections, and 43% were
for 2 days (n = 3347).[215] In children with otitis in intensive care. Patients with neutropenia were
media (4% of patients), a further 8 days’ treatment excluded from the trial.
with oral amoxicillin 20 mg/kg every 8 hours was On a per pathogen basis, both regimens eradi-
added to both treatment regimens. cated ≥98% of Enterobacteriaceae, whereas

1072 Lamb et al.
90 Ceftriaxone + tobramycin factors which might alter the likely causative

Ceftazidime pathogens.[227] Nonpseudomonal third-generation
Clinical response rate (% patients)
80
70
cephalosporins are also recommended in those
with severe disease provided that infection occurs
60
within <5 days of hospital admission.[227]
50
To date, one randomised trial has investigated
40 the use of ceftriaxone in the treatment of patients
30 with nosocomial pneumonia closely fitting these
20 criteria.[228] In this trial, once-daily intravenous
10 ceftriaxone 2g for a mean of 8.6 days achieved clin-
0
ical success in 35 of 50 (70%) patients compared
Pneumonia Sepsis Urinary tract with 48 of 60 (80%) patients treated with intrave-
(n = 297) (n = 184) infection (n = 99) nous cefoperazone 2g administered every 12 hours
Fig. 4. Clinical efficacy of empirical treatment with ceftriaxone
for a mean of 7.6 days. Superinfections developed
plus tobramycin compared with ceftazidime monotherapy by in 22 and 13% of patients, respectively. 50% of
infection type in adult patients with serious nosocomial infec- patients had nursing-home acquired infection and
tions. Patients received intravenous ceftriaxone 2g once daily
plus intramuscular or intravenous tobramycin 3 to 5 mg/kg/day
16% required mechanical ventilation.
(after a 2 mg/kg loading dose; n = 274) or intravenous
ceftazidime 2g twice daily (n = 306) for a mean duration of 9 (0 5.3 Surgical or Procedural Prophylaxis
to 25) days in a randomised multinational trial. The dose and
dosing interval of tobramycin was modified to obtain peak and
trough serum concentrations of 6 to 12 and <2 mg/L, respec- Ceftriaxone, when administered as surgical pro-
tively. Additional metronidazole was permitted in either treat- phylaxis, was associated with wound infection
ment group if anaerobic infection was suspected. Clinical rates of 3 to 6% after abdominal or biliary surgery,
response was defined as cure or improvement of signs and
symptoms.[233] 3% after breast or gynaecological surgery, 0.5%
after orthopaedic surgery and 15% after percutane-
ous endoscopic gastrotomy (table XII). In all stud-
ceftriaxone plus tobramycin eradicated 92% of ies, ceftriaxone was administered intravenously as
Pseudomonas spp. and 92% of Gram-positive a single 1 or 2g dose prior to or during surgery.
pathogens compared with rates of 86 and 79% with The rate of postoperative wound infections ob-
ceftazidime monotherapy. There were no differ- served with ceftriaxone was generally similar to
ences between the two treatment regimens with re- that achieved with comparator regimens, except for
gard to the incidence of superinfection or the emer- two studies in which ceftriaxone was associated
gence of resistance. Organisms isolated from with a significantly lower infection rate: 0.5 vs 4%
patients with superinfections who were treated with placebo in orthopaedic surgery (p < 0.001)[236]
with ceftriaxone plus tobramycin were and 6 vs 17% with metronidazole in combination
Acinetobacter spp. (n = 7), enterococci (n = 5), with gentamicin in bowel surgery (p < 0.05).[233]
Candida spp. (n = 5), P. aeruginosa (n = 4) and Ceftriaxone prophylaxis also tended to be more
staphylococci (n = 2).[226] effective than comparators in the prevention of all
or specific types of systemic postoperative infec-
5.2 Pneumonia tions (table XII); these included respiratory tract
and urinary tract infections in orthopaedic surgery
Ceftriaxone, and other nonpseudomonal third- (2 vs 10% with placebo; p < 0.001),[236] and in per-
generation cephalosporins, are recommended by cutaneous endoscopic gastrotomy (6 vs 17% with
the American Thoracic Society for the treatment of no prophylaxis; p < 0.05).[229] The incidence of uri-
patients with mild to moderate hospital-acquired nary tract infections was also significantly lower
pneumonia, provided that patients do not have risk with ceftriaxone after transurethral resection of the

Table XII. Efficacy of ceftriaxone (CRO) as surgical or procedural prophylaxis: summary of randomised comparative trials with >100 patients.
Two trials were multicentre,[229,230] two trials were double-blind,[231,232] one was single-blind[233] and the remainder were nonblind
Reference Surgery type Dose (g) × no.a Postoperative infection [no. (%) pts]
woundb systemicc
Abdominal/biliary surgery or procedures

Dormann et al.[229] Percutaneous endoscopic CRO 1 IV × 1 (15; n = 72) (6)*
gastrostomy No prophylaxis (26; n = 69) (17)
Hjortrup et al.[230] Biliary CRO 1 IV × 1 3/112 (3) 6/112 (5)
CXM 1.5 q8h IV × 2 4/107 (4) 8/107 (8)
Luke et al.[231] Abdominal CRO 1 IV × 1d 8/249 (3) 21/249 (8)
AM 2 + MTR 1.5 IV × 1d 12/247 (5) 32/247 (13)
Morris[233] Bowel CRO 1 IV × 1e 6/94 (6)* 16/94 (17)
MTR 0.5 + GM 2 mg/kg q8h IV × 17/102 (17) 34/102 (33)
3e
Breast or gynaecological surgery

Henriques et al.[234] Cervical dilatation and CRO 1 IV × 1 16/383 (4)
evacuation Standard treatmentf 22/403 (6)
Thomas et al.[232] Breast CRO 2 IV × 1 30/883 (3)
CAZ 2 IV × 1 68/883 (8)
von Mandach et al.[235] Caesarean section CRO 1 IV × 1 17/536 (3) 70/536 (13)
FOX 1 q8h IV × 3 20/516 (4) 105/516 (20)
Orthopaedic surgery
Boxma et al.[236] Closed fracture surgery CRO 2 IV × 1 5/1057 (0.5)** (2)**
Placebo 41/1034 (4) (10)
Renal transplantation
Castelao et al.[237] Renal transplantation CRO 1 od + CX 1 q6h IV × 4 22/50 (44)†
days
ATM 1 od + CX 1 q6h IV × 4 days 19/50 (38)
ATM 1 od IV + AMC 1/0.2 q8h × 28/100 (28)
4 daysg
Urological surgery
Raz et al.[238] TURP CRO 1g IV × 2h 6/51 (12)*
No prophylaxis 20/50 (40)
a The first dose of prophylaxis was administered any time from 1h before surgery to intraoperatively.
b Assessed 10 days to 1 month postsurgery.
c Generally included pneumonia, urinary tract and other infections (pelvic inflammatory disease or endometritis in gynaecological surgery).
Urological surgery studies considered urinary tract infections only.
d 77 pts had visible peroperative contamination from the bowel; in the CRO group, these pts received CRO 1g + MTR 1.5g once daily for
3 days (n = 42) and, in the other treatment group, pts received AM 2g bid + MTR 1.5g once daily + netilmicin 160mg (frequency not
stated) for 3 days (n = 35).
e 28 pts with inflammatory bowel disease received 5 days of treatment.
f High-risk patients (defined as those with a history suggestive of pelvic inflammatory or sexually transmitted disease) received AM 1g +
MTR 0.5g IV peroperatively followed by oral MTR 0.5g + pivampicillin 0.5g three times daily for 4 days.
g Pts were not randomised to the ATM + AMC treatment group; route of administration of AMC not stated.
h The second dose was administered 3 to 4 days later on removal of the suprapubic catheter.
AM = ampicillin; AMC = amoxicillin/clavulanic acid; ATM = aztreonam; bid = twice daily; CAZ = ceftazidime; CX = cloxacillin; CXM =
cefuroxime; FOX = cefoxitin; GM = gentamicin; IV = intravenous; MTR = metronidazole; od = once daily; pts = patients; qxh = every x hours;
TURP = transurethral resection of the prostate; * p < 0.05; ** p < 0.001 vs comparator; † p < 0.05 vs ATM + AMC.

1074 Lamb et al.
prostate (12 vs 40% with no prophylaxis; p < were attributable to Pseudomonas sp. and E.
0.05),[238] bowel surgery (1 vs 8% with metronida- faecalis.[242] In both trials, over two-thirds of pa-
zole plus gentamicin; p = 0.04),[233] and caesarean tients had Child-Pugh stage C cirrhosis.
section (10 vs 18% with cefoxitin; p < 0.001).[235] Ceftriaxone was administered for 5 days in one
Significantly higher rates of urinary tract infection trial[242] and a mean of 9.1 days in the other.[241]
were reported after renal transplantation with a 4-
day regimen of ceftriaxone plus cloxacillin (44%) 6. Tolerability
than with aztreonam plus amoxicillin/clavulanic This section provides a brief overview of the
acid (28%; p < 0.05), although patients were not tolerability profile of ceftriaxone. The data used to
randomised to the latter treatment option in this compile it are derived from clinical trials, predom-
study.[237] inantly from sections 4 and 5, which evaluated
A large (n = 4477) German prospective study ceftriaxone monotherapy. Where possible, a com-
evaluated surgical prophylactic treatment versus parative assessment of the tolerability of
no perioperative prophylaxis in patients who had ceftriaxone is provided, although comparative data
undergone cholecystectomy.[239] Patients in the are limited because many of the trials used
prophylactic group were treated with one of several ceftriaxone either in combination with other anti-
antibacterial agents (e.g. ceftriaxone, cefotiam, bacterial agents or as part of a step-down regimen.
amoxicillin); 44% (975 patients) received a single Table XIII provides a summary of the tolerabil-
dose of ceftriaxone. Recipients of prophylaxis had ity profile of ceftriaxone by regimen. In general,
a significantly (p < 0.05, all comparisons) better adverse events associated with ceftriaxone were
prognosis in terms of wound infections, postoper- mild to moderate in severity and resolved sponta-
ative complications, postoperative pneumonia, neously. With rare exceptions,[184,230,232] severe or
postoperative complications, reoperation, serious events were not observed after single dose
relaparotomy, wound exploration and postopera- treatment with ceftriaxone in adults, children or in-
tive death.[239] fants. In addition, studies in neonates also indicated
that ceftriaxone monotherapy or combination ther-
5.4 Spontaneous Bacterial Peritonitis apy was generally well tolerated.[138,183,213]
Spontaneous bacterial peritonitis is defined as 6.1 Systemic Events
an infection of the ascitic fluid without any obvious
abdominal source of infection. It affects between 8 6.1.1 Gastrointestinal Events
and 27% of patients with cirrhosis and leads to Gastrointestinal events, namely diarrhoea, nau-
death in approximately half of these patients.[240] sea, vomiting and abdominal pain or discomfort,
Enteric Gram-negative bacteria and streptococci are the events most commonly reported with
are responsible for about 80 to 85% of infec- ceftriaxone (table XIII). Diarrhoea, the most fre-
tions,[240] whereas E. faecalis and B. fragilis are quent event, was generally reported in 1 to 15% of
only rarely involved.[241,242] adult patients, although higher rates (19 to 38%)
In two prospective trials, empirical treatment were reported in three trials performed in chil-
with intravenous ceftriaxone 2g once daily dren[140,141,150] (table XIII). Nausea and vomiting
achieved a bacteriological cure in 95 (n = 40)[242] were reported in fewer than 4% of patients, and
and 100% (n = 30) of patients with spontaneous abdominal pain or discomfort in fewer than 2% of
bacterial peritonitis.[241] This compared with a bac- patients, except in one trial in which the agent was
teriological cure rate of 94% (n = 30) with intrave- administered for 4 weeks (7%; table XIII).[243]
nous cefonicid 2g twice daily in one trial, which 6.1.2 Effects on Flora
was of randomised comparative design.[241] The Like other third-generation cephalosporins,
two treatment failures observed with ceftriaxone ceftriaxone can alter the normal flora at different

Table XIII. Incidence of adverse events with intramuscular or intravenous ceftriaxone monotherapy in adults, children and infants by regimen:
summary of data from clinical trials. Events listed are those which were reported in >1 trial
Event Incidence by regimen (% of patients)
children and infants adults
50 mg/kg × 50 mg/kg × 60-100 mg/kg × 0.25g × 1 dose 1g × 1 or 2 1-4g × 5-15d 2g × 4wk
1 dose 3 doses 4-14d doses
Systemic events
Diarrhoea 3-24 4 6-38 0.6-4a 6-9 1-15 12
Nausea/vomiting 0.9 3 0.3-1 3 4
Abdominal pain /discomfort 0.6-0.9 2 7
Rash 8-10 0.5 2-4 0.7-1 0.9-6 3 3
Pruritus 0.9-3 0.9-2
Headache 0.5 0.3-3 0.9-3
Dizziness 0.3-1 3
Pseudomembranous colitis 0.6-1
Candidiasisb 4 1 1-7 4 5
Diaper rash 2-4
Local events
Injection site pain/reaction 0-8 0.5 2-45 3-14
Phlebitis 0-11 10
Laboratory changes
Elevated liver enzymes 5-7 3
Neutropenia 3
Overall 14 0-14 0-19 39-54
References 150-153 158 138,140-142 184-188,190, 230,232-235, 134,163,165- 243,244
191,194-198 238 168,241
a Includes patients with flatulence.
b Oral or vaginal.
sites in the body, notably the gastrointestinal tract the incidence of true lithiasis is less than 0.1%.[70]
and vagina, leading to overgrowth or super- Pseudolithiasis is thought to occur because a sub-
infections with yeasts or other organisms (section stantial proportion of the drug is excreted in the
2.6).[245] Superinfecting organisms with the third- bile (40 to 55%; section 3.3). In addition, the drug
generation cephalosporins include E. faecalis, P. exists in solution as a divalent anion[247] which has
aeruginosa and Candida spp.[245] All third-gener- high affinity for calcium.[248] This combination of
ation cephalosporins, including ceftriaxone, have properties can lead to precipitation of calcium-
been associated with rare reports of pseudo- ceftriaxone in the biliary tract, particularly at high
membranous colitis;[245] therefore, overgrowth of
doses of the drug (≥2 g/day).[246] Although patients
C. difficile should be considered in patients with
of any age can develop biliary pseudolithiasis, it is
diarrhoea.[246] Candidiasis (oral or vaginal) was
more likely in infants and small children who re-
generally reported in about 4 to 5% of patients with
ceftriaxone (table XIII). ceive larger doses of the drug on a per bodyweight
basis[246] (60 to 100 mg/kg equates with a 4 to 7g
6.1.3 Biliary Pseudolithiasis dose in a 70kg adult). No other risk factors for the
An event unique to the tolerability profile of event have been conclusively identified (for re-
ceftriaxone is reversible biliary pseudolithiasis or view see Bonnet et al.[249]).
gallbladder sludge, which is detected as sono- According to the manufacturer’s prescribing in-
graphic abnormalities in the gallbladder; however, formation,[70] ceftriaxone may cause true lithiasis

1076 Lamb et al.
Table XIV. Incidence of sonographic abnormalities (pseudolithiasis or biliary sludge) with ceftriaxone in adults, adolescents and children with
serious infections: summary of prospective studies. Ceftriaxone was administered intravenously in all studies
Reference Daily dose × duration (days) Incidence [no. patients (%)] Time to: [range (mean) days]
sonographic symptomsa onset resolution after
abnormalities treatment
In children and adolescentsb
Bonnet et al.[249] 50 mg/kg × 5c 5/34 (15) 0/5 (0) 3-5 60-150
Palanduz et al.[250] 100 mg/kg × 7-21 20/118 (17) 0/20 (0) 5-15 (9) 3-15 (8)
Schaad et al.[251] 60 or 100 mg/kg × 4-33c 16/37 (43)d 3/16 (19) 4-22 (9) 2-63 (15)
Stabile et al.[252] 50-80 mg/kg 5/41 (12) 1/5 (20) 7 10 or 30
In adults
Heim-Duthoy et 2g × 14 6/28 (21) 2/6 (33) 9-44
al.[253] Placebo 1/8 (12) 0/1 (0) 44
Pigrau et al.[254] 5-104e × 5-29 5/20 (25)d 0/20 (0) 4-17 (9) 7-26 (16)
a Symptoms included colicky upper abdominal pain, nausea and vomiting,[251] upper quadrant tenderness[252] or vomiting.[253]
b Patients were aged 0.25 to 15 years,[249] 0.25 to 14 years,[250] 0.1 to 19 years[251] and 2 to 12 years.[252]
c Coadministered with an aminoglycoside (n = 22)[249] or flucloxacillin 150-200 mg/kg/day (n = 5).[251]
d Family history of cholelithiasis or nephrolithiasis in one[251] and four patients.[254]
e Total dose.
(incidence <0.1%), notably at higher dosages of tion[258] and acute pancreatitis[259] have, however,
the drug. However, incidence studies (n = 8 to 118 been documented with ceftriaxone. Nephrolithia-
patients in each study) show that sonographic ab- sis has also been reported rarely with the
normalities indicative of biliary pseudolithiasis are drug.[260,261] Conservative, nonsurgical manage-
observed in 12 to 43% (n = 37 in this latter study) ment is therefore recommended in patients in
of adolescents and children[249-252] and 21 and 25% whom sonographic abnormalities are detected
of adults treated with intravenous ceftriaxone (ta- (section 7). Importantly, it should be noted that
ble XIV).[253,254] Of note, all patients in these stud- ceftriaxone-associated biliary pseudolithiasis has
ies had serious infections and were therefore characteristics on ultrasound which resemble gall-
treated with relatively high doses of the drug (table stones and can be misinterpreted as such.[247,253] In
XIV). The time to onset of detectable biliary isolated cases this has led to unnecessary cholecys-
pseudolithiasis is approximately 9 (range 3 to 22) tectomy.[251,258]
days, although it has been reported after two to 6.1.4 Other Systemic Events
three doses of the drug in rare cases.[249,255] Follow- Cutaneous reactions reported with ceftriaxone
up sonograms showed that abnormalities re- include maculopapular rash, exanthema, pruritus,
solved spontaneously in all patients; the time to urticaria, oedema and allergic dermatitis.[246] In
resolution varied from 2 to 150 days after the end clinical trials, pruritus was observed in fewer than
of treatment, although some of the variation was 3% of patients and rash was generally observed in
attributable to intermittent follow-up trial proto- fewer than 6% of patients following administration
cols (table XIV). of ceftriaxone (table XIII), except for children with
In terms of clinical significance, ceftriaxone-as- AOM in whom slightly higher rates of rash (8 to
sociated pseudolithiasis is generally asymptomatic 10%) were reported.[150,151] Isolated cases of se-
and reversible; up to one-third (0 to 33%) of pa- vere reactions (e.g. erythema multiforme, Stevens
tients with sonographic evidence of biliary pseudo- Johnson Syndrome) have been reported with
lithiasis developed symptoms (table XIV). Isolated ceftriaxone[246] and, like other third-generation
cases of lithiasis,[256,257] reversible biliary obstruc- cephalosporins, the drug can cause serious allergic

reactions and should be used with caution in pa- children with typhoid fever, despite the addition of
tients with a history of allergy to β-lactams.[245] lidocaine and rotation of injection sites.[211]
Other systemic events, namely headache and diz- Likewise, phlebitis following intravenous in-
ziness, were consistently reported in fewer than 3% jection of ceftriaxone was reported in up to 11% of
of patients (table XIII). patients in clinical trials (table XIII). The incidence
Haematological reactions with ceftriaxone in- of local phlebitis can be minimised by slow injec-
clude anaemia, haemolytic anaemia, leucopenia, tion over 2 to 4 minutes.[246]
neutropenia, thrombocytopenia, eosinophilia, agr-
anulocytosis and a positive Coomb’s test. Prolon- 6.3 Comparative Tolerability
gation of prothrombin time has been observed
6.3.1 Adults
rarely with ceftriaxone.[246] Fatal haemolysis fol-
When administered as a single intramuscular
lowing ceftriaxone administration has been re-
dose in adults, ceftriaxone 0.25g is associated with
ported in three children with haematological disor-
a similar incidence of events as intramuscular cefo-
ders.[262-264]
taxime,[184,187,188] sulbactam/ampicillin,[194,195] ce-
As with other third-generation agents, mild re- ftizoxime[192] or oral ciprofloxacin.[186] Although a
versible abnormalities in liver function tests have similar incidence of adverse events was reported
been documented with ceftriaxone (table XIII).[245] with ceftriaxone and oral cefixime in 1 trial,[197]
As over 90% of ceftriaxone is bound to serum pro- ceftriaxone was associated with fewer adverse
teins (section 3.1),[265] it may displace bilirubin events (0 vs 10%)[198] and gastrointestinal events
and produce hyperbilirubinaemia. For this reason, than cefixime (4 vs 8 and 18% with cefixime 400
ceftriaxone is contraindicated in neonates with and 800mg, respectively; p = 0.004 for 800mg
jaundice or in whom bilirubin binding is likely to dose vs ceftriaxone) in 2 other trials.[185]
be impaired.[246] Ceftriaxone appears to have a low In patients with CAP, intravenous or intramus-
nephrotoxic potential[245] and can be coadminist- cular ceftriaxone had a similar incidence of events
ered with aminoglycosides without increasing the as intravenous ciprofloxacin,[163] intravenous/oral
nephrotoxicity of these agents.[246] levofloxacin,[168] oral cefpodoxime proxetil[134]
and intravenous or intramuscular cefepime,[167]
6.2 Local Events but a significantly greater incidence of diarrhoea
than oral cefpodoxime proxetil (15 vs 0%; p =
0.03).[134]
Like other third-generation cephalosporins,
ceftriaxone can cause discomfort or pain at the in- 6.3.2 Children
jection site immediately following intramuscular In children, although intramuscular ceftriaxone
administration. In randomised single- and double- was associated with significantly higher inci-
blind trials in healthy volunteers (aged 14 to 55 dences of diarrhoea than oral cotrimoxazole (24 vs
years), coadministration (ceftriaxone 250mg to 1g) 9%; p < 0.001)[150] and rash compared with oral
with 1% lidocaine effectively reduced the severity amoxicillin (8 vs 1%; p = 0.02),[151] ceftriaxone
and duration of injection-related pain compared had a better tolerability profile than oral amoxicil-
with coadministration with water[266-268] and thus, lin/clavulanic acid. Ceftriaxone was associated
1% lidocaine is recommended as a diluent for with fewer adverse reactions than amoxicil-
ceftriaxone (section 7). In clinical trials, injection lin/clavulanic acid in two trials (14 vs 31%; p <
site reactions (most commonly pain) were reported 0.0001[153] and 0 vs 4%[155] and a lower rate of
in 0 to 45% of patients, although the trial which withdrawal (0 vs 8%).[153] It was also associated
reported the highest rate did not appear to admin- with significantly less diarrhoea (14 vs 27%[153]
ister the drug with lidocaine.[190] One other trial and 3 vs 16%: p = 0.002[152]) and vomiting than
reported pain for more than 24 hours in 20% of amoxicillin/clavulanic acid (0.9 vs 11%; p =

1078 Lamb et al.
0.004).[152] In another trial, ceftriaxone was asso- rial otitis media should be treated with a single in-
ciated with fewer serious reactions than tramuscular dose of 50 mg/kg (not to exceed 1g).[269]
ciprofloxacin (0 vs 5 events).[209] Dosage adjustment is not required in patients
with impaired hepatic or renal function; however,
plasma concentrations of ceftriaxone should be
7. Dosage and Administration monitored at regular intervals and dosage adjust-
ments made as necessary in patients with concom-
Ceftriaxone can be administered by intravenous itant renal and hepatic dysfunction.[246,269] In pa-
or intramuscular injection. As for other antibacte- tients with preterminal renal failure [creatinine
rial agents, the dose, route and frequency of admin- clearance <0.6 L/h (<10 ml/min)], the ceftriaxone
istration, and the duration of therapy are deter- dosage should not exceed 2 g/day.[246] Supplemen-
mined by the severity of infection, susceptibility of tary doses are not required in patients undergoing
the infecting organism and the general health of the haemodialysis.[246] In the UK, ceftriaxone is con-
patient. traindicated in neonates with jaundice or with con-
The recommended dosage in adults and children ditions in which impaired bilirubin binding is
(aged ≥12 years) is 1 to 2g once daily (or in two likely.[246] In patients developing biliary pseudo-
equally divided doses) in the US[269] or 1g once lithiasis, conservative nonsurgical management is
daily in the UK.[246] The total daily dose should not recommended and discontinuation of ceftriaxone
exceed 4g.[269] Generally ceftriaxone therapy should be considered.[246]
should be continued for at least 2 days after the For intravenous administration, ceftriaxone
signs and symptoms of infection have dissipated. should be reconstituted in sterile water and injected
This usually requires 4 to 14 days of therapy, al- over 2 to 4 minutes[246] or infused over at least 30
though complicated infections may require minutes.[246,269] For intramuscular injection, ceftr-
longer.[269] iaxone should be dissolved in lidocaine 1% solu-
A single intramuscular dose of 250mg is recom- tion.[246] The solution should be injected well
mended for the treatment of uncomplicated gonor- within the body of a relatively large muscle and not
rhoea.[246,269] Since ceftriaxone is inactive against more than 1g should be injected at a single
C. trachomatis, adjunctive antichlamydial therapy site.[246,269]
should be used if this organism is suspected.[270]
For surgical prophylaxis, a single intravenous 1g 8. Place of Ceftriaxone in the
dose given 0.5 to 2 hours before surgery is ad- Management of Community-Acquired
vised.[246,269] and Nosocomial Infections
In children <12 years of age, ceftriaxone 50 to
75 mg/kg/day (not to exceed 2g) administered once In each section of this review, stringent select-
daily (or as two equally divided doses) is recom- ion criteria have been applied to select the best
mended for skin and soft tissue infections and other available evidence on ceftriaxone. These sections
serious infections (except for meningitis) in the provide a complete and current assessment of the
US.[269] For the treatment of meningitis, the recom- antibacterial activity and tolerability profile of the
mended daily dosage is 100 mg/kg (not to exceed drug, together with its efficacy in both community-
4g) given as a single daily dose (or two equally acquired and nosocomial infections. Rather than
divided doses) usually for 7 to 14 days.[269] In the discussing all uses of ceftriaxone, this section will
UK, ceftriaxone 20 to 50 mg/kg once daily is rec- focus instead on new applications of the drug and
ommended as the standard dose, with doses of up its use in infections in which the causative patho-
to 80 mg/kg for severe infections; it is suggested gens or their resistance patterns have changed over
that doses >80 mg/kg should be avoided because the past decade. Infections in which ceftriaxone
of the risk of biliary precipitates.[246] Acute bacte- has a well-established place, for example gonor-

rhoea, or unusual infections which only comprise MIC values for S. pneumoniae by 100-fold, an ob-
only a small part of its use, for example spontane- servation which has led to its recommendation for
ous bacterial peritonitis, will not be discussed fur- use in invasive infections caused by penicillin-
ther. nonsusceptible strains in immunocompetent pa-
One of the most influential factors driving tients.[25] Likewise, it has been suggested that, in
change in the management of community-acquired patients with pneumonia, ceftriaxone is likely to
infections has been the emergence of penicillin-re- be effective for the treatment of strains with MIC
sistant S. pneumoniae. This has led to ongoing re- values ≤4 mg/L.[24] In support of these suggest-
visions to treatment guidelines for pneumococcal ions, data from a recent retrospective study show
infections and has also increased the demand for that ceftriaxone, alone or in combination with
agents with reliable activity against this pathogen. other β-lactam agents, can be used effectively in
As cephalosporins with strong activity against S. immunocompetent patients with bacteraemia and
pneumoniae, ceftriaxone and cefotaxime are im- pneumonia caused by S. pneumoniae with MICs of
portant agents in these infections. Not surprisingly, 1 or 2 mg/L against ceftriaxone; a single infection
the greatest volume of recent data on ceftriaxone caused by a strain with an MIC of 4 mg/L also
concerns pneumococcal infections and the impli- responded to treatment.[23] These observations ha-
cations of penicillin resistance for its use. ve brought about a rethinking of NCCLS break-
For patients with bacterial meningitis, an infec-
points for ceftriaxone (table III) for invasive pneu-
tion in which S. pneumoniae is now a major patho-
mococcal infections other than meningitis,[24-26,273]
gen,[271,272] ceftriaxone and cefotaxime have been
with new separate breakpoints becoming effective
the empirical treatments of choice for over a de-
recently.[22]
cade.[24] Comparative studies confirm that both
The rapid spread of penicillin-resistant S. pneu-
agents have similar efficacy in this serious infec-
moniae also means that ceftriaxone is now indi-
tion, although ceftriaxone has a simpler adminis-
cated for another difficult-to-treat pneumococcal
tration schedule (1 or 2 vs 3 or 4 daily doses). How-
infection, AOM. Although there are trials docu-
ever, attention is now focused on how best to use
menting its use in uncomplicated infections (sec-
these agents in infections caused by S. pneumoniae
with reduced β-lactam susceptibility. For tion 4.2.1), current treatment recommendations
ceftriaxone, data in both adults and children with from the US Drug-Resistant S. pneumoniae Ther-
meningitis have served to confirm its efficacy as apeutic Working Group[145] suggest that ceftriax-
an empirical monotherapy in infections caused by one should be reserved for patients with AOM un-
susceptible S. pneumoniae (ceftriaxone MICs ≤0.5 responsive to first-line therapy. One or three daily
mg/L). For nonsusceptible strains (MICs ≥1 intramuscular doses of the drug are advocated al-
mg/L), however, combination therapy with either though, at the time the recommendations were
vancomycin or rifampicin is needed to avoid treat- published, clinical experience with the 3-dose reg-
ment failure.[25,272] Supporting clinical data for the imen was limited. Since then, three trials per-
efficacy of combination regimens with ceftri- formed in areas of high rates of penicillin resis-
axone, although available, remain limited (section tance show that the 3-dose regimen of ceftriaxone
4.4.1). is effective in 93 to 98% of patients with non-
Although drug concentrations achieved in the responsive AOM (section 4.4.2).[158-160] Unusu-
CSF generally allow little scope for treating pneu- ally, these studies reported complete bacteriologi-
mococcal isolates with elevated MICs, the same is cal results which showed that, although the 1- and
not true for infections at other sites in the body. 3-dose regimens performed equally well against H.
Ceftriaxone achieves concentrations in the serum influenzae and penicillin-susceptible S. pneu-
after recommended doses that often exceed the moniae, the 3-dose regimen was required to effec-

1080 Lamb et al.
tively eradicate penicillin-nonsusceptible S. pneu- or as part of a step-down regimen, in adult patients

moniae. with CAP but also its equivalence to comparator
Currently, 10-day courses of either oral regimens.
amoxicillin/clavulanic acid or cefuroxime axetil A further 10 years of use in the clinic have also
are also recommended for nonresponsive confirmed the good tolerability profile of
AOM.[145] Although there are no direct compari- ceftriaxone (section 6). As is the case of other ceph-
sons with cefuroxime axetil, comparative data sug- alosporins, adverse events are generally mild to
gest that ceftriaxone and amoxicillin/clavulanic moderate in severity and gastrointestinal events,
acid are equally effective but that ceftriaxone has a notably diarrhoea, are most commonly observed.
better tolerability profile, especially with regard to Available comparative data show that the incidence
gastrointestinal events (section 6.3.2). Further- of adverse events with ceftriaxone is generally sim-
more, both cefuroxime axetil and amoxicillin- ilar to that seen with the fluoroquinolones and other
/clavulanic acid suspension formulations are β-lactams, although minor differences in gastroin-
among the least palatable formulations avail- testinal events with some cephalosporins are re-
able.[274] Other putative, but unproven, benefits of ported. Although there have been rare reports of
ceftriaxone in patients with AOM are good compli- true lithiasis and other more severe related events,
ance with a short parenteral regimen, especially ceftriaxone-associated biliary pseudolithiasis is
given that approximately one-third of children generally asymptomatic in at least two-thirds of
randomised to oral treatment in clinical trials did
patients and resolves spontaneously after comple-
not receive their full course of therapy (section
tion of treatment and appears to be more common
4.2.1). Therefore, it has been suggested that
in those treated with dosages ≥2 g/day. Conserva-
ceftriaxone may be particularly useful in those in
tive and nonsurgical management of this event is
whom compliance may be compromised as well as
therefore recommended.
in those who are unable to absorb or refuse to take
A defining feature of the data covered in this
oral medications and in those with high fever or
review has been the extent to which ceftriaxone is
concurrent bacteraemia.[152,153,274] Potential disad-
now used on an outpatient basis, either as part of a
vantages of ceftriaxone therapy include injection
site discomfort and having to split the dose in two step-down regimen or parenterally. Although the
in heavier children as the maximum injection vol- need for cost containment is a key driver for the
ume is ≈2ml (see Bradley[274] for review). How- growing popularity of both practices, technologi-
ever, the recent approval of a 350 mg/ml formula- cal advances in vascular access and infusion de-
tion of ceftriaxone ensures a single injection in vices together with the availability of an infrastruc-
children up to 15kg bodyweight.[269] ture to deliver community-based parenteral therapy,
Another important indication for ceftriaxone is particularly in North America, have contributed to
CAP, for which it, along with other third-genera- the increased use of parenteral agents on an outpa-
tion cephalosporins, is recommended as a first-line tient basis.[275] Although a detailed discussion of
empirical treatment option in hospitalised adult pa- the factors which influence drug choice for outpa-
tients in both Europe[161] and the US.[26] Other rec- tient parenteral therapy is beyond the scope of this
ommended treatment options for this patient group review (for reviews see Craig[276] and Williams et
include fluoroquinolones with activity against S. al.[275]), the long t1⁄2 and once-daily regimen of
pneumoniae, β-lactam/β-lactamase inhibitors, ma- ceftriaxone offers a unique advantage over other
crolides and other cephalosporins,[26,161] against parenteral cephalosporins (including cefotaxime),
which ceftriaxone has been compared in several all of which require multiple daily doses. This
large randomised trials. These trials not only serve property is likely to have contributed to the well-
to confirm the efficacy of ceftriaxone, either alone documented popularity of ceftriaxone in the outpa-

tient setting[275-277] (for review see Barman Balfour References

and Lamb[278]).
1. Richards DM, Heel RC, Brogden RN, et al. Ceftriaxone: a re-
Infections treated on an outpatient basis with view of its antibacterial activity, pharmacological properties
ceftriaxone include CAP, AOM and acute pyelo- and therapeutic use. Drugs 1984; 27: 469-527
2. Brogden RN, Ward A. Ceftriaxone: a reappraisal of its antibac-
nephritis. Ceftriaxone can also be readily com- terial activity and pharmacokinetic properties, and an update
bined with an aminoglycoside as a once-daily reg- on its therapeutic use with particular reference to once-daily
administration. Drugs 1988 Jun; 35: 604-45
imen, as first demonstrated by the European 3. Jones RN, Pfaller MA, Doern GV, et al. Antimicrobial activity
Organization for Research and Treatment of Can- and spectrum investigation of eight broad-spectrum β-lactam
drugs: a 1997 surveillance trial in 102 medical centers in the
cer.[279] United States. Diagn Microbiol Infect Dis 1998 Mar; 30: 215-28
Unlike many other antimicrobial agents where 4. Diekema DJ, Coffman SL, Marshall SA, et al. Comparison of
activities of broad-spectrum β-lactam compounds against
patterns of resistance emerge, the long-term use of 1,128 Gram-positive cocci recently isolated in cancer treat-
parenterally administered ceftriaxone has not been ment centers. Antimicrob Agents Chemother 1999 Apr; 43:
940-3
associated with an increase in resistance to the 5. Thornsberry C, Jones ME, Hickey ML, et al. Resistance sur-
drug. In fact, high level resistance to ceftriaxone veillance of Streptococcus pneumoniae, Haemophilus in-
fluenzae and Moraxella catarrhalis isolated in the United
remains rare. Of concern, however, has been the States, 1997-1998. J Antimicrob Chemother 1999 Dec; 44:
emergence and spread of resistance to third-gener- 749-59
6. Jones RN, Pfaller MA, Doern GV. Comparative antimicrobial
ation agents among Gram-negative pathogens ei- activity of trovafloxacin tested against 3049 Streptococcus
ther through the selection of derepressed mutants pneumoniae isolates from the 1997-1998 respiratory infec-
tion season. Diagn Microbiol Infect Dis 1998 Oct; 32: 119-26
which hyperproduce chromosomal β-lactamases 7. Doern GV, Jones RN, Pfaller MA, et al. Bacterial pathogens
or ESBLs. Although minor infections caused by isolated from patients with skin and soft tissue infections:
frequency of occurrence and antimicrobial susceptibility pat-
pathogens harbouring these enzymes may still be terns from the SENTRY Antimicrobial Surveillance Program
(United States and Canada, 1887). Diagn Microbiol Infect Dis
treated effectively with third-generation agents, 1999 May; 34: 65-72
other treatment options are likely to be required for 8. Jones RN, Jenkins SG, Hoban DJ, et al. In vitro activity of
selected cephalosporins and erythromycin against staphylo-
more serious infections when these pathogens are cocci and pneumococci isolated at 38 North American medi-
present.[280] Prudent use of third-generation ceph- cal centers participating in the SENTRY Antimicrobial
Surveillance Program, 1997-1998. Diagn Microbiol Infect
alosporins is also important for the control of these Dis 2000 Jun; 37: 93-8
difficult-to-treat infections.[280] 9. Low DE, de Azavedo J, Canadian Bacterial Surveillance Net-
work. In vitro activity of cefepime against multidrug-resistant
In conclusion, as a result of its strong activity Gram-negative bacilli, viridans groups streptococci and
against S. pneumoniae, ceftriaxone holds an im- Streptococcus pneumoniae from a cross-Canada surveillance
study. Can J Infect Dis 1999 Mar-Apr; 10: 122-7
portant place, either alone or as part of a combina- 10. Diekema DJ, Pfaller MA, Jones MA, et al. Trends in antimicro-
tion regimen, in the treatment of invasive pneumo- bial susceptibility of bacterial pathogens isolated from pa-
tients with bloodstream infections in the USA, Canada and
coccal infections, including those with reduced Latin America. Int J Antimicrob Agents 2000; 13: 257-71
β-lactam susceptibility. Its once-daily administra- 11. Pfaller MA, Jones RN, Doern GV, et al. Survey of blood stream
infections attributable to gram-positive cocci: frequency of
tion schedule allows simplification of otherwise occurrence and antimicrobial susceptibility of isolates col-
complex regimens in a hospital setting and has also lected in 1997 in the United States, Canada, and Latin Amer-
ica from the SENTRY Antimicrobial Surveillance Program.
contributed to its popularity as a parenteral agent Diagn Microbiol Infect Dis 1999; 33: 283-97
in an ambulatory setting. These properties, to- 12. Diekema DJ, Pfaller MA, Jones RN, et al. Survey of blood-
stream infections due to gram-negative bacilli: frequency of
gether with a well characterised tolerability pro- occurrence and antimicrobial susceptibility of isolates col-
file, mean that ceftriaxone is likely to retain its lected in the United States, Canada, and Latin America for the
SENTRY Antimicrobial Surveillance Program, 1997. Clin In-
place as an important third-generation cephalospo- fect Dis 1999 Sep; 29: 595-607
13. Santos JI, Arredondo JL, Vazquez V. Bacterial isolates from
rin in the treatment of both serious community- hematology, oncology, and intensive care units: susceptibility
acquired and nosocomial infections. to cefpirome and other beta-lactam antibiotics in a multicen-

1082 Lamb et al.
ter study in Mexico. Curr Ther Res Clin Exp 2000 May; 61: 30. National Committee for Clinical Laboratory Standards. Meth-
266-76 ods for dilution antimicrobial susceptibility tests for bacteria
14. Fluit AC, Jones ME, Schmitz F-J, et al. Antimicrobial suscep- that grow aerobically; approved standard. 5th ed. v. 17. Wayne
tibility and frequency of occurrence of clinical blood isolates (PA): NCCLS, 2000. (NCCLS document M7-A5)
in Europe from the SENTRY Antimicrobial Surveillance Pro- 31. Thornsberry C, Ogilvie PT, Holley HP, et al. Survey of suscep-
gram, 1997 and 1998. Clin Infect Dis 2000 Mar; 30: 454-60 tibilities of Streptococcus pneumoniae, Haemophilus in-
15. Hanberger H, Garcia-Rodriguez J-A, Gobernado M, et al. An- fluenzae, and Moraxella catarrhalis isolates to 26
tibiotic susceptibility among aerobic gram-negative bacilli in antimoicrobial agents: a prospective US study. Antimicrob
intensive care units in 5 European countries. JAMA 1999 Jan Agents Chemother 1999; 43: 2612-23
6; 281: 67-71 32. Johnson AP, Livermore DM, Woodford N, et al. High-level β-
16. Baquero F, Garcia-Rodriguez JA, Garcia de Lomas J, et al. An- lactam resistance in strains of Streptococcus pneumoniae iso-
timicrobial resistance of 1,113 Streptococcus pneumoniae lated in the UK [letter]. J Antimicrob Chemother 1998 Jul; 42:
isolates from patients with respiratory tract infections in 115-6
Spain: results of a 1-year (1996-1997) multicenter surveil- 33. Sloas MM, Barrett FF, Chesney PJ, et al. Cephalosporin treat-
lance study. Antimicrob Agents Chemother 1999 Feb; 43: ment failure in penicillin- and cephalosporin-resistant Strep-
357-9 tococcus pneumoniae meningitis. Pediatr Infect Dis J 1992;
17. Felmingham D, Gruneberg RN, Alexander PG. The Alexander 11 (8): 662-6
Project 1996-1997: latest susceptibility data from this inter- 34. Karlowsky JA, Jones ME, Mayfield DC, et al. In vitro evalua-
national study of bacterial pathogens from community-ac- tion of ceftriaxone activity against recent Gram-positive clinical
quired lower respiratory tract infections. J Antimicrob isolates: results from the TSN database-US, 1996-2000 [abstract
Chemother 2000 Feb; 45: 191-203 no. P1299]. Clin Microbiol Infect 2001; 7 Suppl. 1: 275
18. Sahm DF, Jones ME, Hickey ML, et al. Resistance surveillance 35. Unzaga MJ, Rojo P, Melero P, et al. Antibiotic susceptibility of
of Streptococcus pneumoniae, Haemophilus influenzae and 12 strains of Alloiococcus otitidis [abstract]. 37th Interscience
Moraxella catarrhalis isolated in Asia and Europe, 1997- Conference on Antimicrobial Agents and Chemotherapy 1997
1998. J Antimicrob Chemother 2000 Apr; 45: 457-66 Sep 28; 118
19. Jones RN, Hare RS, Sabatelli FJ, et al. In vitro Gram-positive 36. Mayfield DC, Karlowsky JA, Sahm DF, et al. In vitro evaluation
antimicrobial activity of evernimicin (SCH 27899), a novel of ceftriaxone activity against recent Gram-negative clinical
oligosaccharide, compared with other antimicrobials: a multi- isolates: results from the TSN database-US, 1996-2000 [ab-
centre international trial. J Antimicrob Chemother 2001 Jan; stract no. P1300]. Clin Microbiol Infect 2001; 7 Suppl. 1: 275
47: 15-25 37. Fuchs PC, Barry AL, Brown SD, et al. Survey of antimicrobial
20. Thornsberry C, Sahm DF. Antimicrobial resistance in respira- activity of four commonly used third generation cephalospo-
tory tract pathogens: results of an international surveillance rins tested against recent bacterial isolates from ten American
study. Chemotherapy Basel 2000; 46 Suppl. 1: 15-23 medical centers, and assessment of disk diffusion test perfor-
21. Turnidge JD, Bell JM, Collignon PJ, et al. Rapidly emerging mance. Diagn Microbiol Infect Dis 1996 Apr; 24: 213-9
antimicrobial resistances in Streptococcus pneumoniae in 38. Herikstad H, Hayes PS, Hogan J, et al. Ceftriaxone-resistant
Australia. Med J Aust 1999 Feb 15; 170: 152-5 Salmonella in the United States. Pediatr Infect Dis J 1997 Sep;
22. National Committee for Clinical Laboratory Standards. Perfor- 16: 904-5
mance standards for antimicrobial susceptibility testing: 39. Abadi FJR, Yakubu DE, Pennington TH. Antimicrobial suscep-
twelfth informational supplement. Wayne (PA): NCCLS, tibility of penicillin-sensitive and penicillin-resistant menin-
2002. NCCLS document M100-S12 gococci. J Antimicrob Chemother 1995 May; 35: 687-90
23. Kaplan Jr SL, Mason EO, Barson WJ, et al. Outcome of invasive 40. Blondeau JM, Yaschuk Y. In vitro activities of ciprofloxacin,
infections outside the central nervous system caused by Strep- cefotaxime, ceftriaxone, chloramphenicol, and rifampin
tococcus pneumoniae isolates nonsusceptible to ceftriaxone against fully susceptible and moderately penicillin-resistant
in children treated with beta-lactam antibiotics. Pediatr Infect Neisseria meningitidis. Antimicrob Agents Chemother 1995
Dis J 2001 Apr; 20 (4): 392-6 Nov; 39: 2577-9
24. Klugman KP, Feldman C. Penicillin- and cephalosporin-resis- 41. Pascual A, Joyanes P, Martínez-Martínez L, et al. Comparison
tant Streptococcus pneumoniae: emerging treatment for an of broth microdilution and E-test for susceptibility testing of
emerging problem. Drugs 1999 Jul; 58: 1-4 Neisseria meningitidis. J Clin Microbiol 1996 Mar; 34: 588-91
25. American Academy of Pediatrics: Committee on Infectious Dis- 42. Marshall SA, Rhomberg PR, Jones RN. Comparative evalua-
eases. Therapy for children with invasive pneumococcal in- tion of Etest for susceptibility testing Neisseria meningitidis
fections. Pediatrics 1997 Feb; 99 (2): 289-99 with eight antimicrobial agents: an investigation using U.S.
26. Bartlett JG, Dowell SF, Mandell LA, et al. Practice guidelines food and drug administration regulatory criteria. Diagn
for the management of community-acquired pneumonia in Microbiol Infect Dis 1997 Mar; 27: 93-7
adults. Clin Infect Dis 2000 Aug; 31: 347-82 43. van de Beek D, Hensen EF, Spanjaard L, et al. Meropenem
27. Sahm DF, Thornsberry C, Mayfield DC, et al. In vitro activities susceptibility of Neisseria meningitidis and Streptococcus
of broad-spectrum cephalosporins against nonmeningeal iso- pneumoniae from meningitis patients in The Netherlands. J
lates of Streptococcus pneumoniae: MIC interpretation using Antimicrob Chemother 1997 Dec; 40: 895-7
NCCLS M100-S12 recommendations. J Clin Microbiol 2001; 44. Schwebke JR, Whittington W, Rice RJ, et al. Trends in suscep-
40: 669-74 tibility of Neisseria gonorrhoeae to ceftriaxone from 1985
28. Livermore DM. β-Lactamases in laboratory and clinical resis- through 1991. Antimicrob Agents Chemother 1995 Apr; 39:
tance. Clin Microbiol Rev 1995; 8 (4): 557-84 917-20
29. Bush K. Is it important to identify extended-spectrum beta- 45. Tansuphasiri U, Kabklang S, Wongba C. Comparative in vitro
lactamase-producing isolates? Eur J Clin Microbiol Infect Dis activities of nine antimicrobials against pencillinase produc-
1996; 15 (5): 361-4 ing (PPNG) and nonproducing (nonPPNG) Neisseria gonor-

rhoeae isolated from patients attending Bangrak hospital, crobial Agents and Chemotherapy 1995 Sep 17; San Fran-
Bangkok. J Infect Dis Antimicrob Agents 1998 Sep-Dec; 15: cisco, California, 64
129-37 64. Cars O. Efficacy of beta-lactam antibiotics: integration of phar-
46. Wenling C, Xibao Z, Shi F, et al. Analysis of the antibiotic macokinetics and pharmacodynamics. Diagn Microbiol In-
sensitivity of Neisseria gonorrheae in Guangzhou, Peoples fect Dis 1997; 27: 29-33
Republic of China. Sex Transm Dis 2000 Sep; 27: 480-2 65. Craig WA. Choosing an antibiotic on the basis of pharmacody-
47. Tanaka M, Nakayama H, Haraoka M, et al. Antimicrobial re- namics. Ear Nose Throat Journal 1998; 77 Suppl.: 7-12
sistance of Neisseria gonorrhoeae and high prevalence of 66. Cazzola M, Matera MG, Donner CF. Pharmacokinetics and
ciprofloxacin-resistant isolates in Japan, 1993 to 1998. J Clin pharmacodynamics of newer oral cephalosporins: implica-
Microbiol 2000 Feb; 38: 521-5 tions for treatment of community-acquired lower respiratory
48. Tapsall JW, Phillips EA. The sensitivity of 173 Sydney isolates tract infections. Clin Drug Invest 1998; 16: 335-46
of Neisseria gonorrhoeae to cefpodoxime and other antibiot- 67. Drusano GL, Goldstein FW. Relevance of the Alexander Proj-
ics used to treat gonorrhea. Pathology 1995 Jan; 27: 64-6 ect: pharmacodynamic considerations. J Antimicrob Chemo-
49. Chevalier B, Crenn Y, Cavallo JD, et al. Comparative activity ther 1996; 38 Suppl. A: 141-54
of azithromycin against 100 strains of Neisseria gonorrhoeae 68. Owens Jr RC, Tessier P, Nightingale CH, et al. Pharmacody-
[in French]. Pathol Biol 1995 Apr; 43: 281-3 namics of ceftriaxone and cefixime against community-ac-
50. Talbot H, Romanowski B. In vitro activities of sparfloxacin, quired respiratory tract pathogens. Int J Antimicrob Agents
ceftriaxone, penicillin, tetracycline and doxycycline against 2001; 17: 483-9
Chlamydia trachomatis and Neisseria gonorrhoeae. Can J 69. Lutsar I, Ahmed A, Friedl IR, et al. Pharmacodynamics and
Infect Dis 1992 May-Jun; 3: 114-7 bactericidal activity of ceftriaxone therapy in experimental
51. Wexler HM, Molitoris D, Finegold SM. In vitro activities of cephalosporin-resistant pneumococcal meningitis. Anti-
MK-826 (L-749,345) against 363 strains of anaerobic bacte- microb Agents Chemother 1997; 41 (11): 2414-7
ria. Antimicrob Agents Chemother 2000 Aug; 44: 2222-4 70. Roche US Pharmaceuticals. Rocephin (ceftriaxone sodium) for
52. Hamilton-Miller JMT, Shah S. Comparative anti-anaerobic ac- injection. 2000 Sep. available from http://www.rocheusa.com/
tivity of Men 10700, a penem antibiotic. Int J Antimicrob products/rocephin/pi.html (acccessed 15/05/01)
Agents 1998 Nov; 10: 321-4
71. Belliveau PP, Freeman CD, Nicolau DP, et al. Serum bacterici-
53. Livermore DM. β-Lactamase-mediated resistance and opportu- dal activity of ceftizoxime and ceftriaxone against patho-
nities for its control. J Antimicrob Chemother 1998; 41 Suppl.
gens associated with community-acquired and nosocomial
D: 25-41
pneumonias. Am J Health System Pharm 1996 May 1; 53:
54. Moosdeen F. The evolution of resistance to cephalosporins. 1024-7
Clin Infect Dis 1997 Mar; 24: 487-93
72. Blandino G, Milazzo I, Musumeci R, et al. Comparative activity
55. Livermore DM. Are all β-lactams created equal? Scand J Infect of cefodizime and ceftriaxone against respiratory pathogens
Dis 1996 Suppl. 101: 33-43
in an in vitro pharmacodynamic model simulating concentra-
56. Pitout JDD, Sanders CC, Sanders Jr WE, et al. Antimicrobial tion-time curves. J Chemother 2000; 12: 503-8
resistance with focus on β-lactam resistance in gram-negative
73. Spangler SK, Lin G, Jacobs MR, et al. Postantibiotic effect of
bacilli. Am J Med 1997 Jul; 103: 51-9
sanfetrinem compared with those of six other agents against
57. Sanders CC, Sanders Jr WE. β-Lactam resistance in Gram-neg-
12 penicillin-susceptible and -resistant pneumococci. Anti-
ative bacteria: global trends and clinical impact. Clin Infect
microb Agents Chemother 1997 Oct; 41: 2173-6
Dis 1992 Nov; 15: 824-39
74. Odenholt I, Lowdin E, Cars O. In vitro pharmacodynamic stud-
58. Du Bois SK, Marriott MS, Amyes SGB. TEM- and SHV-de-
ies of L-749,345 in comparison with imipenem and
rived extended-spectrum β-lactamases: relationship between
ceftriaxone against Gram-positive and Gram-negative bacte-
selection, structure and function. J Antimicrob Chemother
1995; 35: 7-22 ria. Antimicrob Agents Chemother 1998 Sep; 42: 2365-70
75. Patel IH, Kaplan SA. Pharmacokinetic profile of ceftriaxone in
59. Coffey TJ, Daniels M, McDougal LK, et al. Genetic analysis of
clinical isolates of Streptococcus pneumoniae with high-level man. Am J Med 1984; 19: 17-25
resistance to expanded-spectrum cephalosporins. Antimicrob 76. Yuk JH, Nightingale CH, Quintiliani R. Clinical pharmacoki-
Agents Chemother 1995 Jun; 39: 1306-13 netics of ceftriaxone. Clin Pharmacokinet 1989 Oct; 17: 223-35
60. Cavallaro V, Catania V, Bonaccorso R, et al. Effect of a broad- 77. Borner K, Lode H, Hampel B, et al. Comparative pharmacoki-
spectrum cephalosporin on the oral and intestinal microflora netics of ceftriaxone after subcutaneous and intravenous ad-
in patients undergoing colorectal surgery. J Chemother 1992; ministration. Chemotherapy 1985; 31: 237-45
4 (2): 82-7 78. Stoeckel K, Koup JR. Pharmacokinetics of ceftriaxone in pa-
61. Vogel F, Boedn G, Nilsson-Ehle I, et al. Effect of step-down tients with renal and liver insufficiency and correlations with
therapy of ceftriaxone plus loracarbef versus parenteral ther- a physiologic nonlinear protein binding model. Am J Med
apy of ceftriaxone on the intestinal microflora in patients with 1984 Oct 19; 77: 26-32
community-acquired pneumonia [abstract]. Clin Microbiol 79. Hayton W, Stoeckel K. Biliary excretion of ceftriaxone [letter].
Infect 2000; 6 Suppl. 1: 137 Eur J Clin Pharmacol 1986; 31 (1): 123-4
62. Nilsson-Ehle I, Nord CE, Ursing B. Ceftriaxone: pharmacoki- 80. Scaglione F, Raichi M, Fraschini F. Serum protein binding and
netics and effect on the intestinal flora in patients with acute extravascular diffusion of methoxyimino cephalosporins.
bacterial infections. Scand J Infect Dis 1985; 17: 77-82 Time courses of free and total concentrations of cefotaxime
63. Laing F, Ramotar K, Krulicki W, et al. Comparison of cefotax- and ceftriaxone in serum and pleural exudate. J Antimicrob
ime and ceftriaxone on the induction of cephalosporin-resis- Chemother 1990 Sep; 26 Suppl. A: 1-10
tant Gram-negative bacilli in the intestinal tract of hospital 81. Adam D, Naber KG. Concentrations of ceftriaxone in prostate
patients [abstract]. 35th Interscience Conference on Antimi- adenoma tissue. Chemotherapy 1984; 30: 1-6

1084 Lamb et al.
82. De Grandi P, Bauen J-F. Pharmacokinetics of ceftriaxone in 103. Lucht F, Dorche G, Aubert G, et al. The penetration of
serum and gynecological tissues. Chemotherapy 1986; 32: ceftriaxone into human brain tissue. J Antimicrob Chemother
473-7 1990 Jul; 26: 81-6
83. Joynt GM, Lipman J, Gomersall CD, et al. The pharmacokinet- 104. Kafetzis DA, Brater DC, Fanourgakis JE, et al. Ceftriaxone
ics of once-daily dosing of ceftriaxone in critically ill patients. distribution between maternal blood and fetal blood and tis-
J Antimicrob Chemother 2001; 47: 421-9 sues at parturition and blood and milk postpartum. Antimicrob
84. Heinemeyer G, Link J, Weber W, et al. Clearance of ceftriaxone Agents Chemother 1983; 23 (6): 870-3
in critical care patients with acute renal failure. Intensive Care 105. Lang R, Saba K, Folman Y, et al. Penetration of ceftriaxone into
Med 1990; 16 (7): 448-53 the intervertebral disc. J Bone Joint Surg Am 1994 May; 76:
85. Holazo AA, Patel IH, Weinfeld RE, et al. Ceftriaxone pharma- 689-91
cokinetics following multiple intramuscular dosing. Eur J 106. Gaillard J-L, Abadie V, Cheron G, et al. Concentrations of
Clin Pharmacol 1986; 30: 109-12 ceftriaxone in cerebrospinal fluid of children with meningitis
86. Lebel M, Grégoire S, Caron M, et al. Difference in blister fluid receiving dexamethasone therapy. Antimicrob Agents Chem-
penetration after single and multiple doses of ceftriaxone. other 1994 May; 38: 1209-10
Antimicrob Agents Chemother 1985 Jul; 28 (1): 123-7 107. Bradley JS, Farhat C, Stamboulian D, et al. Ceftriaxone therapy
87. Fraschini F, Braga PC, Scarpazza G, et al. Human pharmacoki- of bacterial meningitis: cerebrospinal fluid concentrations
netics and distribution in various tissues of ceftriaxone. Che- and bactericidal activity after intramuscular injection in chil-
motherapy 1986; 32: 192-9 dren treated with dexamethasone. Pediatr Infect Dis J 1994
88. McNamara PJ, Stoeckel K, Ziegler WH. Pharmacokinetics of Aug; 13: 724-8
ceftriaxone following intravenous administration of a 3 g 108. Nau R, Prange HW, Muth P, et al. Passage of cefotaxime and
dose. Eur J Clin Pharmacol 1982; 22 (1): 71-5 ceftriaxone into cerebrospinal fluid of patients with uni-
89. Scully BE, Fu KP, Neu HC. Pharmacokinetics of ceftriaxone nflamed meninges. Antimicrob Agents Chemother 1993 Jul;
after intravenous infusion and intramuscular injection. Am J 37: 1518-24
Med 1984; 77: 112-6 109. Geny F, Costa P, Bressolle F, et al. Ceftriaxone pharmacokinet-
90. Stoeckel K. Pharmacokinetics of Rocephin, a highly active new ics in elderly subjects and penetration into epididymis.
cephalosporin with an exceptionally long biological half-life. Biopharm Drug Dispos 1993 Mar; 14: 161-9
Chemotherapy 1981; 27 Suppl. 1: 42-6
110. Steib A, Jacoberger B, Von Bandel M, et al. Concentrations in
91. Stoeckel K, McNamara PJ, Brandt R, et al. Effects of concen- plasma and tissue penetration of ceftriaxone and ornidazole
tration-dependent plasma protein binding on ceftriaxone ki- during liver transplantation. Antimicrob Agents Chemother
netics. Clin Pharmacol Ther 1981; 29 (5): 650-7 1993 Sep; 37: 1873-6
92. Schaad UB, Hayton WL, Stoeckel K. Single dose ceftriaxone
111. Lang R, Shalit I, Segal J, et al. Maternal and fetal serum and
kinetics in the newborn. Clin Pharmacol Ther 1985; 37: 522-8
tissue levels of ceftriaxone following preoperative prophy-
93. Fiset C, Vallée F, LeBel M, et al. Protein binding of ceftriaxone:
laxis in emergency cesarean section. Chemotherapy Basel
comparison of three techniques of determination and the ef-
1993 Mar-Apr; 39: 77-81
fect of 2-hydroxybenzoylglycine, a drug-binding inhibitor in
uremia. Ther Drug Monit 1986; 8: 483-9 112. Papaioannou N, Kalivas L, Kalavritinos J, et al. Tissue concen-
trations of third-generation cephalosporins (ceftazidime and
94. Le Van Thoi J, Koumare B, Lhoste F, et al. Human pharmacol-
ceftriaxone) in lower extremity tissues using a tourniquet.
ogy of ceftriaxone [in French]. Pathol Biol 1982; 30 (6): 345-7
Arch Orthop Trauma Surg 1994 Apr; 113 (3): 167-9
95. Martin C, Cottin A, Francois-Godfroy N, et al. Concentrations
of prophylactic ceftriaxone in abdominal tissues during pan- 113. Gudnason T, Gudbrandsson F, Barsanti F, et al. Penetration of
creatic surgery. J Antimicrob Chemother 1997 Sep; 40: 445-8 ceftriaxone into the middle ear fluid of children. Pediatr Infect
96. Hary L, Andrejak M, Leleu S, et al. The pharmacokinetics of Dis J 1998; 17 (3): 258-60
ceftriaxone and cefotaxime in cirrhotic patients with ascites. 114. Neidhart P, Velebit V, Gunning K, et al. A comparative study of
Eur J Clin Pharmacol 1989; 36 (6): 613-6 cefamandole and ceftriaxone as prophylaxis in cardiac sur-
97. Ducroix JP, Guerlin M, Hary L, et al. Clinical study and phar- gery. Infection 1990; 18 (2): 101-4
macokinetics of ceftriaxone in the treatment of 14 ascitic fluid 115. Gerstner GJ, Kronich W, Adam D. Interstitial fluid concentra-
infections [in French]. Pathol Biol 1988 Oct; 36 (8): 1007-10 tions of ceftriaxone (1 g i.v.) in the subperitoneal space after
98. Orda R, Berger SA, Levy Y, et al. Penetration of ceftriaxone and hysterectomy. Chemotherapy Basel 1990 Aug; 36: 245-50
cefoperazone into bile and gallbladder tissue in patients with 116. Berger SA, Dan M, Serour F, et al. Penetration of third-genera-
acute cholecystitis. Dig Dis Sci 1992 Nov; 37: 1691-3 tion cephalosporins into human peritoneal tissue. Chemother-
99. Berger SA, Levy Y, Halevy A, et al. Penetration of cefazolin, apy 1989; 35: 326-9
ceftriaxone, cefoperazone, and ceftazidime into human gall- 117. Goonetilleke AKE, Dev D, Aziz I, et al. A comparative analysis
bladder tissue and bile. World J Surg 1988; 12: 641-4 of pharmacokinetics of ceftriaxone in serum and pleural fluid
100. Brogard JM, Blickle JF, Jehl F, et al. High biliary elimination in humans: a study of once daily administration by intramus-
of ceftriaxone in man. Int J Clin Pharmacol Ther Toxicol cular and intravenous routes. J Antimicrob Chemother 1996
1988; 26 (4): 167-72 Dec; 38: 969-76
101. Scaglione F, de Martini G, Peretto L, et al. Pharmacokinetic 118. Kimura M, Matsushima T, Nakamura J, et al. Comparative
study of cefodizime and ceftriaxone in sera and bones of pa- study of penetration of lomefloxacin and ceftriaxone into
tients undergoing hip arthroplasty. Antimicrob Agents Chem- transudative and exudative pleural effusion. Antimicrob
other 1997; 41 (10): 2292-4 Agents Chemother 1992 Dec; 36: 2774-7
102. Lovering AM, Walsh TR, Bannister GC, et al. The penetration 119. Martin C, Ragni J, Lokiec F, et al. Pharmacokinetics and tissue
of ceftriaxone and cefamandole into bone, fat and haematoma penetration of a single dose of ceftriaxone (1,000 milligrams
and relevance of serum protein binding to their penetration intravenously) for antibiotic prophylaxis in thoracic surgery.
into bone. J Antimicrob Chemother 2001; 47: 483-6 Antimicrob Agents Chemother 1992 Dec; 36: 2804-7

120. Sharir M, Triester G, Kneer J, et al. The intravitreal penetration 138. Scholz H, Hofmann T, Noack R, et al. Prospective comparison
of ceftriaxone in man following systemic administration. In- of ceftriaxone and cefotaxime for the short-term treatment of
vest Ophthalmol Vis Sci 1989 Oct; 30: 2179-83 bacterial meningitis in children. Chemotherapy 1998 Mar-
121. Martin E, Koup JR, Paravicini U, et al. Pharmacokinetics of Apr; 44: 142-7
ceftriaxone in neonates and infants with meningitis. J Pediatr 139. Schmutzhard E, Williams KJ, Vukmirovits G, et al. A
1984 Sep; 105 (3): 475-81 randomised comparison of meropenem with cefotaxime or
122. Martin E. Once-daily administration of ceftriaxone in the treat- ceftriaxone for the treatment of bacterial meningitis in adults.
ment of meningitis and other serious infection in children. Meropenem Meningitis Study Group. J Antimicrob Chemo-
European Journal of Clinical Microbiology 1983 Oct; 2 (5): ther 1995 Jul; 36 Suppl. A: 85-97
509-15 140. Martin E, Hohl P, Guggi T, et al. Short course single daily
123. Balant L, Dayer P, Auckenthaler R. Clinical pharmacokinetics ceftriaxone monotherapy for acute bacterial meningitis in
of the third generation cephalosporins. Clin Pharmacokinet children: results of a Swiss multicenter study. Part I: clinical
1985; 10: 101-43 results. Infection 1990 Mar-Apr; 18: 70-7
124. Pickup ME, Bird HA, Lowe JR, et al. A pharmacokinetic and 141. Peltola H, Antilla M, Renkonen O-V, et al. Randomised com-
tolerance study of Ro13-9904, a new cephalosporin antibi- parison of chloramphenicol, ampicillin, cefotaxime and
otic. Br J Clin Pharmacol 1981; 12: 111-5 ceftriaxone for childhood bacterial meningitis. Lancet 1989
125. Marshall WF, Blair JE. The cephalosporins. Mayo Clin Proc Jun 10: 1281-6
1999 Feb; 74: 187-95 142. Schaad UB, Suter S, Gianella-Borradori A, et al. A comparison
126. Koup JR, Keller E, Neumann H, et al. Ceftriaxone pharmaco- of ceftriaxone and cefuroxime for the treatment of bacterial
kinetics during peritoneal dialysis. Eur J Clin Pharmacol meningitis in children. N Engl J Med 1990 Jan 18; 322: 141-7
1986; 30: 303-7 143. Baraff LJ, Lee SI, Schriger DL. Outcomes of bacterial menin-
127. Stoeckel K, McNamara PJ, Hoppe-Seyler G, et al. Single-dose gitis in children: a meta-analysis. Pediatr Infect Dis J 1993;
ceftriaxone kinetics in functionally anephric patients. Clin 12 (5): 389-94
Pharmacol Ther 1983 May; 33 (5): 633-41 144. Lebel MH, Hoyt MJ, McCracken Jr GH. Comparative efficacy
128. Ti T-Y, Fortin L, Kreeft JH, et al. Kinetic disposition of intra- of ceftriaxone and cefuroxime for treatment of bacterial men-
venous ceftriaxone in normal subjects and patients with renal ingitis. J Pediatr 1989; 114 (6): 1049-54
failure on hemodialysis or peritoneal dialysis. Antimicrob 145. Dowell SF, Butler JC, Giebink GS, et al. Acute otitis media:
Agents Chemother 1984 Jan; 25 (1): 83-7 management and surveillance in an era of pneumococcal re-
129. Wise R, Wright N. The pharmacokinetics of cefotaxime and sistance - a report from the Drug-resistant Streptococcus
ceftriaxone in renal and hepatic dysfunction. Infection 1985; pneumoniae Therapeutic Working Group. Pediatr Infect Dis
13 Suppl. 1: S145-50 J 1999; 18 (1): 1-9
130. Favre H, Probst P. Pharmacokinetics of ceftriaxone after intra- 146. Block SL. Management of acute otitis media in the 1990s: a
venous administration to CAPD-patients with and without decade of resistant pneumococcus. Paediatr Drugs 1999 Jan-
peritonitis. Chemioterapia 1987 Jun; 62 Suppl. 2: 273-4 Mar; 1: 31-50
131. Hendrickson JR, North DS. Pharmacoeconomic benefit of an- 147. Leibovitz E, Raiz S, Piglansky L, et al. Resistance pattern of
tibiotic step-down therapy: converting patients from intrave-
middle ear fluid isolates in acute otitis media recently treated
nous ceftriaxone to oral cefpodoxime proxetil. Ann
with antibiotics. Pediatr Infect Dis J 1998; 17: 463-9
Pharmacother 1995 Jun; 29: 561-5
148. McCracken Jr GH. Prescribing antimicrobial agents for treat-
132. Cammarata SK, Bermudez M, Golin V, et al. Comparison of
ment of acute otitis media. Pediatr Infect Dis J 1999 Dec; 18:
linezolid versus ceftriaxone/cefpodoxime in the treatment of
1141-6
hospitalized community-acquired pneumonia [abstract]. 9th
International Congress on Infectious Diseases 2000 April 10- 149. Klein JO. Review of consensus reports on management of acute
13; Buenos Aires, Argentina; 182 otitis media. Pediatr Infect Dis J 1999; 18: 1152-5
133. Cammarata SK, San Pedro GS, Timm JA, et al. Comparison of 150. Barnett ED, Teele DW, Klein JO, et al. Comparison of
linezolid versus ceftriaxone/cefpodoxime in the treatment of ceftriaxone and trimethoprim-sulfamethoxazole for acute oti-
hospitalized patients with community-acquired pneumonia tis media. Greater Boston Otitis Media Study Group. Pediat-
[abstract]. Clin Microbiol Infect 2000; 6 Suppl. 1: 136 rics 1997 Jan; 99: 23-8
134. Bittner MJ, Toney JF, Eleftheriou PD, et al. Randomized, dou- 151. Green SM, Rothrock SG. Single-dose intramuscular
ble-blind comparison of oral cefpodoxime and parenteral ceftriaxone for acute otitis media in children. Pediatrics 1993
ceftriaxone in hospitalized adults with community-acquired Jan; 91: 23-30
pneumonia. J Clin Outcomes Manage 1999 Mar; 6: 38-45 152. Varsano I, Volovitz B, Horev Z, et al. Intramuscular ceftriaxone
135. Nathwani D, Tillotson G, Davey P. Sequential antimicrobial compared with oral amoxicillin-clavulanate for treatment of
therapy - the role of quinolones. J Antimicrob Chemother acute otitis media in children. Eur J Pediatr 1997 Nov; 156:
1997; 39: 441-6 858-63
136. Marhoum EFK, Noun M, Chakib A, et al. Ceftriaxone versus 153. Cohen R, Navel M, Grunberg J, et al. One dose ceftriaxone vs
penicillin G in the short-term treatment of meningococcal ten days of amoxicillin/clavulanate therapy for acute otitis
meningitis in adults. Eur J Clin Microbiol Infect Dis 1993 media: clinical efficacy and change in nasopharyngeal flora.
Oct; 12: 766-8 Pediatr Infect Dis J 1999 May; 18: 403-9
137. Saez-Llorens X, Feris JM, Klugman KP, et al. Use of a 154. Chamberlain JM, Boenning DA, Waisman Y, et al. Single-dose
quinolone in children with bacterial meningitis: a compara- ceftriaxone versus 10 days of cefaclor for otitis media. Clin
tive study of trovafloxacin and ceftriaxone +/- vancomycin Pediatr Phila 1994 Nov; 33: 642-6
[abstract]. 40th Interscience Conference on Antimicrobial 155. Al Ghamdi YS, El Kafrawi M, Aglan YI, et al. Efficacy of
Agents and Chemotherapy 2000 Sep 17; Toronto, Canada, single-dose intramuscular ceftriaxone for treatment of acute
479 otitis media in children. Saudi Med J 1999; 20 (1): 41-5

1086 Lamb et al.
156. Roche Laboratories. Rocephin. In: Murray L, editor. Physi- 171. Leibovitz E, Tabachnik E, Fliedel O, et al. Once-daily intramus-
cians’ Desk Reference. 55th ed. Montvale: Medical Econom- cular ceftriaxone in the outpatient treatment of severe com-
ics company, 2001. 2765-2768 munity-acquired pneumonia in children [published erratum
157. Bauchner H, Adams W, Barnett E, et al. Therapy for acute otitis appears in Clin Pediatr (Phila) 1991 May;30(5):326]. Clin
media: preference of parents for oral or parenteral antibiotic Pediatr Phila 1990 Nov; 29: 634-9
[see comments]. Arch Pediatr Adolesc Med 1996 Apr; 150: 172. París MM, Ramilo O, McCracken Jr GH. Management of men-
396-9 ingitis caused by penicillin-resistant Streptococcus pneu-
158. Leibovitz E, Piglansky L, Raiz S, et al. Bacteriologic and clin- moniae. Antimicrob Agents Chemother 1995 Oct; 39 (10):
ical efficacy of one day vs. three day intramuscular 2171-5
ceftriaxone for treatment of nonresponsive acute otitis media 173. Kleiman MB, Weinberg GA, Reynolds JK, et al. Meningitis
in children. Pediatr Infect Dis J 2000; 19 (11): 1040-5 with beta-lactam-resistant Streptococcus pneumoniae: the
159. Leibovitz E, Piglansky L, Raiz S, et al. Bacteriologic efficacy need for early repeat lumbar puncture. Pediatr Infect Dis J
of a three-day intramuscular ceftriaxone regimen in non- 1993; 12: 782-3
responsive acute otitis media. Pediatr Infect Dis J 1998 Dec; 174. Bradley JS, Connor JD. Ceftriaxone failure in meningitis caused
17: 1126-31
by Streptococcus pneumoniae with reduced susceptibility to
160. Gehanno P, Nguyen L, Barry B, et al. Eradication by ceftriaxone
beta-lactam antibiotics. Pediatr Infect Dis J 1991 Nov; 10:
of Streptococcus pneumoniae isolates with increased resis-
871-3
tance to penicillin in cases of acute otitis media. Antimicrob
175. Friedland IR, Shelton S, Paris M, et al. Dilemmas in diagnosis
Agents Chemother 1999 Jan; 43 (1): 16-20
and management of cephalosporin-resistant Streptococcus
161. Huchon G, Woodhead M. Management of adult community-ac-
quired lower respiratory tract infections. European Study on pneumoniae meningitis. Pediatr Infect Dis J 1993; 12: 196-200
Community Acquired Pneumonia (EOSCAP) Committee. 176. Lonks JR, Durkin MR, Meyerhoff AN, et al. Meningitis due to
Eur Resp Rev 1998; 8 (61): 391-426 ceftriaxone-resistant Streptococcus pneumoniae. N Engl J
162. Dowell ME, Mayer H, Anderson A, et al. A randomized, dou- Med 1995 Mar 30; 332: 893-4
ble-blind, multicenter, comparative study of gatifloxacin 400 177. Tan TQ, Schutze GE, Mason Jr EO, et al. Antibiotic therapy and
mg IV and PO versus ceftriaxone plus or minus erythromycin acute outcome of meningitis due to Streptococcus pneu-
in treatment of community-acquired pneumonia requiring moniae considered intermediately susceptible to broad-spec-
hospitalization [abstract]. 39th Interscience Conference on trum cephalosporins. Antimicrob Agents Chemother 1994
Antimicrobial Agents and Chemotherapy 1999; San Fran- May; 38 (5): 918-23
cisco, California; 702 178. Cabellos C, Viladrich PF, Verdaguer R, et al. A single daily dose
163. Johnson RH, Levine S, Traub SL, et al. Sequential intrave- of ceftriaxone for bacterial meningitis in adults: experience
nous/oral ciprofloxacin compared with parenteral ceftriaxone with 84 patients and review of the literature. Clin Infect Dis
in the treatment of hospitalized patients with community-ac- 1995 May; 20: 1164-8
quired pneumonia. Infect Dis Clin Pract 1996 May; 5: 265-72 179. Friedland IR, Paris M, Ehrett S, et al. Evaluation of antimicro-
164. Williams HD, Daniel R, Trovafloxacin Study Group. bial regimens for treatment of experimental penicillin- and
Trovafloxacin vs ceftriaxone/cepodoxime ± erythromycin in cephalosporin-resistant pneumococcal meningitis. Anti-
hospitalised community-acquired pneumonia. Drugs 1999; microb Agents Chemother 1993 Aug; 37 (8): 1630-6
58 Suppl. 2: 318-9 180. Klugman KP, Friedland IR, Bradley JS. Bactericidal activity
165. De Palma M, Rocchi D, Canepa G, et al. Single daily dose of against cephalosporin-resistant Streptococcus pneumoniae in
cefodizime in patients with community-acquired pneumonia: cerebrospinal fluid of children with acute bacterial meningi-
an open-label, controlled, randomized study. Clin Ther 1995 tis. Antimicrob Agents Chemother 1995 Sep; 39: 1988-92
May-Jun; 17: 413-24 181. Quagliarello VJ, Scheld WM. Treatment of bacterial meningi-
166. Roson B, Carratala J, Tubau F, et al. Randomized trial of tis. N Engl J Med 1997 Mar 6; 336 (10): 708-16
amoxicillin-clavulanate vs ceftriaxone for the treatment of 182. Olivier C, Cohen R, Begué P, et al. Bacteriologic outcome of
pneumococcal pneumonia in hospitalized patients [abstract]. children with cefotaxime- or ceftriaxone-susceptible and -
38th Interscience Conference on Antimicrobial Agents and
nonsusceptible Streptococcus pneumoniae meningitis. Pedi-
Chemotherapy 1998 Sep 24; San Diego, California, 580
atr Infect Dis J 2000 Oct; 19 (10): 1015-7
167. Zervos M, Nelson M. Cefepime versus ceftriaxone for empiric
183. Arditi M, Mason Jr EO, Bradley JS, et al. Three-year multicen-
treatment of hospitalized patients with community-acquired
ter surveillance of pneumococcal meningitis in children: clin-
pneumonia. Cefepime Study Group [see comments]. Anti-
microb Agents Chemother 1998 Apr; 42: 729-33 ical characteristics, and outcome related to penicillin
susceptibility and dexamethasone use. Pediatrics 1998 Nov;
168. Norrby SR, Petermann W, Willcox PA, et al. A comparative
study of levofloxacin and ceftriaxone in the treatment of hos- 102: 1087-97
pitalized patients with pneumonia. Scand J Infect Dis 1998; 184. Mogabgab WJ, Lutz FB. Randomized study of cefotaxime ver-
30 (4): 397-404 sus ceftriaxone for uncomplicated gonorrhea. South Med J
169. File Jr TM, Segreti J, Dunbar L, et al. A multicenter, randomized 1994 Apr; 87: 461-4
study comparing the efficacy and safety of intravenous and/or 185. Handsfield HH, McCormack WM, Hook III EW, et al. A com-
oral levofloxacin versus ceftriaxone and/or cefuroxime axetil parison of single-dose cefixime with ceftriaxone as treatment for
in treatment of adults with community-acquired pneumonia. uncomplicated gonorrhea. Gonorrhea Treatment Study Group
Antimicrob Agents Chemother 1997 Sep; 41: 1965-72 [see comments]. N Engl J Med 1991 Nov 7; 325: 1337-41
170. Amir J, Harel L, Eidlitz-Markus T, et al. Comparative evalua- 186. Hook III EW, Jones RB, Martin DH, et al. Comparison of
tion of cefixime versus amoxicillin-clavulanate following ciprofloxacin and ceftriaxone as single-dose therapy for un-
ceftriaxone therapy of pneumonia. Clin Pediatr 1996 Dec; 35: complicated gonorrhea in women. Antimicrob Agents Chem-
629-33 other 1993 Aug; 37: 1670-3

187. Jones RB, Mogabgab WJ, McCormack WM, et al. Randomized 204. Wing DA, Hendershott CM, Debuque L, et al. Outpatient treat-
comparison of cefotaxime and ceftriaxone in patients with ment of acute pyelonephritis in pregnancy after 24 weeks.
uncomplicated gonorrhea. Clin Ther 1991 Sep-Oct; 13: 550-6 Obstet Gynecol 1999 Nov; 94: 683-8
188. McCormack WM, Mogabgab WJ, Jones RB, et al. Multicenter, 205. Francois P, Bensman A, Begue P, et al. Assessment of the effi-
comparative study of cefotaxime and ceftriaxone for treat- cacy and cost efficiency of two strategies in the treatment of
ment of uncomplicated gonorrhea. Sex Transm Dis 1993 Sep- acute pyelonephritis in children: Oral cefixime or parenteral
Oct; 20: 269-73 ceftriaxone after an initial IV combination therapy [in
189. Pabst KM, Siegel NA, Smith S, et al. Multicenter, comparative French]. Med Mal Infect 1997 Jun; 27 Spec. Iss.: 667-73
study of enoxacin and ceftriaxone for treatment of uncompli- 206. Millar LK, Wing DA, Paul RH, et al. Outpatient treatment of
cated gonorrhea. Sex Transm Dis 1989 Jul-Sep; 16: 148-51 pyelonephritis in pregnancy: a randomized controlled trial.
190. Rompalo AM, Colletta L, Caine VA, et al. Efficacy of 250 mg Obstet Gynecol 1995 Oct; 86 (Pt 1): 560-4
trospectomycin sulfate IM vs 250 mg ceftriaxone IM for treat- 207. Wilimas JA, Flynn PM, Harris S, et al. A randomized study of
ment of uncomplicated gonorrhea. Sex Transm Dis 1994 Jul- outpatient treatment with ceftriaxone for selected febrile chil-
Aug; 21: 213-6 dren with sickle cell disease. N Engl J Med 1993 Aug 12; 329:
191. Smith BL, Mogabgab WJ, Dalu ZA, et al. Multicenter trial of 472-6
fleroxacin versus ceftriaxone in the treatment of uncompli- 208. Williams LL, Wilimas JA, Harris SC, et al. Outpatient therapy
cated gonorrhea. Am J Med 1993 Mar; 94: 81S-4S with ceftriaxone and oral cefixime for selected febrile chil-
192. Goldstein AMB, Clark JH, Wickler MA. Comparison of single- dren with sickle cell disease. J Pediatr Hematol Oncol 1996
dose ceftizoxime or ceftriaxone in the treatment of uncompli- Aug; 18: 257-61
cated urethral gonorrhea. Sex Transm Dis 1991 Jul-Sep; 18: 209. Leibovitz E, Janco J, Piglansky L, et al. Oral ciprofloxacin vs.
180-2 intramuscular ceftriaxone as empiric treatment of acute inva-
193. Bryan JP, Hira SK, Brady W, et al. Oral ciprofloxacin versus sive diarrhea in children. Pediatr Infect Dis J 2000; 19 (11):
ceftriaxone for the treatment of urethritis from resistant Neis- 1060-7
seria gonorrhoeae in Zambia. Antimicrob Agents Chemother 210. Girgis NI, Sultan Y, Hammad O, et al. Comparison of the effi-
1990 May; 34 (5): 819-22 cacy, safety and cost of cefixime, ceftriaxone and aztreonam
in the treatment of multidrug-resistant Salmonella typhi sep-
194. Baddour LM, Busby L, Shapiro E, et al. Evaluation of treatment
ticemia in children. Pediatr Infect Dis J 1995 Jul; 14: 603-5
with single-dose ampicillin/sulbactam with probenecid or
211. Frenck Jr RW, Nakhla I, Sultan Y, et al. Azithromycin versus
ceftriaxone in patients with uncomplicated gonorrhea. Sex
ceftriaxone for the treatment of uncomplicated typhoid fever
Transm Dis 1992 Nov-Dec; 19: 341-5
in children. Clin Infect Dis 2000 Nov; 31: 1134-8
195. Hellmann NS, Nsubuga PS, Baingana-Baingi DJ, et al. Single-
212. Kulhanjian J, Dunphy MG, Hamstra S, et al. Randomized com-
dose ampicillin/sulbactam versus ceftriaxone as treatment for
parative study of ampicillin/sulbactam vs. ceftriaxone for
uncomplicated gonorrhoea in a Ugandan STD clinic popula-
treatment of soft tissue and skeletal infections in children.
tion with a high prevalence of PPNG infection. J Trop Med
Pediatr Infect Dis J 1989 Sep; 8: 605-10
Hyg 1995 Apr; 98: 95-100
213. Van Reempts PJ, Van Overmeire B, Mahieu LM, et al. Clinical
196. Mroczkowski TF, Millikan LE, Martin DH, et al. Treatment of experience with ceftriaxone treatmetn in the neonate. Chemo-
gonococcal infections with a single 250 mg intramuscular therapy 1995; 41: 316-22
injection of trospectomycin sulphate vs ceftriaxone sodium.
214. Bass JW, Steele RW, Wittler RR, et al. Antimicrobial treatment
Drugs Exp Clin Res 1993; 19: 41-6
of occult bacteremia: a multicenter cooperative study. Pediatr
197. Plourde PJ, Tyndall M, Agoki E, et al. Single-dose cefixime Infect Dis J 1993 Jun; 12 (6): 466-73
versus single-dose ceftriaxone in the treatment of antimicro- 215. Fleisher GR, Rosenberg N, Vinci R, et al. Intramuscular versus
bial-resistant Neisseria gonorrhoeae infection. J Infect Dis oral antibiotic therapy for the prevention of meningitis and
1992 Oct; 166: 919-22 other bacterial sequelae in young, febrile children at risk for
198. Portilla I, Lutz B, Montalvo M, et al. Oral cefixime versus occult bacteremia. J Pediatr 1994 Apr; 124 (4): 504-12
intramuscular ceftriaxone in patients with uncomplicated 216. Simmons BP, Gelfand MS, Grogan J, et al. Cefotaxime twice
gonococal infections. Sex Transm Dis 1992 Mar-Apr; 19: 94-8 daily versus ceftriaxone once daily: a randomized controlled
199. Freedman LD. Reduced dosage of ceftriaxone for uncompli- study in patients with serious infections. Diagn Microbiol
cated gonorrhea in women. J Fam Pract 1990 Aug; 31: 201-2, Infect Dis 1995 May-Jun; 22: 155-7
205 217. Shah PM, Stille W, German PSG. Cefotaxime versus
200. Centers for Disease Control and Prevention. 1998 guidelines ceftriaxone for the treatment of nosocomial pneumonia: re-
for treatment of sexually transmitted diseases. Morbidity and sults of a multicenter study. Diagn Microbiol Infect Dis 1995
Mortality Weekly Report 1998 Jan; 47 (R-1): 1-118 May-Jun; 22: 171-2
201. Arredondo JL, Diaz V, Gaitan H, et al. Oral clindamycin and 218. Bassetti D, Cruciani M, Solbiati M, et al. Comparative efficacy
ciprofloxacin versus intramuscular ceftriaxone and oral dox- of ceftriaxone versus ceftazidime in the treatment of nosoco-
ycycline in the treatment of mild-to-moderate pelvic inflam- mial lower respiratory tract infections. Chemotherapy 1991;
matory disease in outpatients. Clin Infect Dis 1997 Feb; 24: 37: 371-5
170-8 219. ter Braak EW, de Vries PJ, Bouter KP, et al. Once-daily dosing
202. Sanchez-Ramos L, McAlpine KJ, Adair CD, et al. Pyelonephri- regimen for aminoglycoside plus β-lactam combination ther-
tis in pregnancy: once-a-day ceftriaxone versus multiple apy of serious bacterial infections: comparative trial with
doses of cefazolin: a randomized, double-blind trial. Am J netilmicin plus ceftriaxone. Am J Med 1990; 89 (1): 58-66
Obstet Gynecol 1995 Jan; 172 (Pt 1): 129-33 220. Rolston KVI, Jones PG, Fainstein V, et al. Single agent therapy
203. Wing DA, Hendershott CM, Debuque L, et al. A randomized for infections in cancer patients: a prospective randomized
trial of three antibiotic regimens for the treatment of pyelo- trial comparing 3 extended-spectrum cephalosporins. Eur J
nephritis in pregnancy. Obstet Gynecol 1998 Aug; 92: 249-53 Clin Microbiol Infect Dis 1991; 3: 139-45

1088 Lamb et al.
221. Petrilli AS, Melaragno R, Barros KVT, et al. Fever and neu- 236. Boxma H, Broekhuizen T, Patka P, et al. Randomised controlled
tropenia in children with cancer: a therapeutic approach re- trial of single-dose antibiotic prophylaxis in surgical treat-
lated to the underlying disease. Pediatr Infect Dis J 1993; 12: ment of closed fractures: the Dutch Trauma Trial. Lancet 1996
916-21 Apr 27; 347: 1133-7
222. D’Antonio D, Fioritoni G, Iacone A, et al. Randomized com- 237. Castelao AM, Soto K, Grinyo JM, et al. Prophylaxis of urinary
parison of ceftriaxone versus ceftriaxone plus amikacin for tract infection in renal transplantation: comparison of three
the empirical treatment of infections in patients with altered different protocols using ceftriaxone-cloxacillin, aztreonam-
host defences: microbiological and clinical evaluation. Che- cloxacillin, or aztreonam-amoxycillin-clavulanic acid. Trans-
motherapy 1992; 38: 420-7 plant Proc 1995 Aug; 27: 2277-9
223. Wang L-S, Cheng D-L, Hinthorn DR, et al. Short-course treat- 238. Raz R, Almog D, Elhanan G, et al. The use of ceftriaxone in the
ment of bacteremia with ceftriaxone monotherapy. J Formos prevention of urinary tract infection in patients undergoing
Med Assoc 1990 Feb; 89: 115-20 transurethral resection of the prostate (TUR-P). Infection
224. Thomas PD, Daly S, Misan G, et al. Comparison of the efficacy 1994 Sep-Oct; 22: 347-9
and adverse effect profile of cefotaxime, 3 g.day, and 239. Lippert H, Gastinger J. Antimicrobial prophylaxis in
ceftriaxone, 2 g.day, in the treatment of nosocomial lower laproscopic and conventional cholecystectomy:conclusions
respiratory tract infections in ICU patients. Eur Resp Rev of a large prospective multicenter quality assurance study in
1994 Sep; 4 (22): 321-8 Germany. Chemotherapy 1998; 44: 355-63
225. Mandell LA, Bergeron MG, Ronald AR, et al. Once-daily ther- 240. Bhuva M, Ganger D, Jensen D. Spontaneous bacterial peritoni-
apy with ceftriaxone compared with daily multiple-dose ther- tis: an update on evaluation, management, and prevention.
apy with cefotaxime for serious bacterial infections: a Am J Med 1994 Aug; 97: 169-75
randomized, double-blind study. J Infect Dis 1989 Sep; 160 241. Gomez-Jimenez J, Ribera E, Gasser I, et al. Randomized trial
(3): 433-41 comparing ceftriaxone with cefonicid for treatment of spon-
226. Rubinstein E, Lode H, Grassi C. Ceftazidime monotherapy vs. taneous bacterial peritonitis in cirrhotic patients. Antimicrob
ceftriaxone/tobramycin for serious hospital-acquired gram- Agents Chemother 1993 Aug; 37: 1587-92
negative infections. Antibiotic Study Group [published erra- 242. Javid G, Khan BA, Khan BA, et al. Short-course ceftriaxone
tum appears in Clin Infect Dis 1995 Jun;20(6):1582]. Clin therapy in spontaneous bacterial peritonitis. Postgrad Med J
Infect Dis 1995 May; 20: 1217-28 1998 Oct; 74: 592-5
227. American Thoracic Society. Hospital-acquired pneumonia in 243. Francioli P, Etienne J, Hoigné R, et al. Treatment of streptococ-
adults: diagnosis, assessment of severity, initial antimicrobial cal endocarditis with a single daily dose of ceftriaxone sodium
therapy, and preventative strategies: a consensus statement. for 4 weeks: efficacy and outpatient treatment feasibility.
Am J Respir Crit Care Med 1996; 153: 1711-25 JAMA 1992 Jan 8; 267 (2): 264-7
228. Mangi RJ, Peccerillo KM, Ryan J, et al. Cefoperazone versus
244. Sexton DJ, Tenenbaum MJ, Wilson WR, et al. Ceftriaxone once
ceftriaxone monotherapy of nosocomial pneumonia. Diagn
daily for four weeks compared with ceftriaxone plus genta-
Microbiol Infect Dis 1992 Jul; 15: 441-7
micin once daily for two weeks for treatment of endocarditis
229. Dormann AJ, Wigginghaus B, Risius H, et al. A single dose of due to penicillin-susceptible streptococci. Clin Infect Dis
ceftriaxone administered 30 minutes before percutaneous en- 1999 Dec; 27: 1470-4
doscopic gastrostomy significantly reduces local and sys-
245. Fekety FR. Safety of parenteral third-generation cephalospo-
temic infective complications. Am J Gastroenterol 1999 Nov;
rins. Am J Med 1990; 88 Suppl. 4A: 38S-44S
94: 3220-4
246. Roche Products Limited. Rocephin. In: ABPI Compendium of
230. Hjortrup A, Moesgaard F, Jensen F, et al. Antibiotic prophylaxis
Data Sheets and Summaries of Product Characteristics. 1999-
in high risk biliary surgery: one dose of ceftriaxone compared
2000: 1357-9
with two doses of cefuroxime. Eur J Surg 1991 Jun-Jul; 157:
403-5 247. Kim YS, Kestell MF, Lee SP. Gall-bladder sludge: lessons from
231. Luke M, Iversen J, Sondergaard J, et al. Ceftriaxone vs. ampi- ceftriaxone. J Gastroenterol Hepatol 1992; 7: 618-21
cillin + metronidazole as prophylaxis against infections after 248. Shiffman ML, Keith FB, Moore EW. Pathogenesis of
clean-contaminated abdominal surgery. Eur J Surg 1991 Jan; ceftriaxone-associated biliary sludge: in vitro studies of cal-
157: 45-9 cium-ceftriaxone binding and solubility. Gastroenterology
232. Thomas R, Alvino P, Cortino GR, et al. Long-acting versus 1990; 99 (6): 1772-8
short-acting cephalosporins for preoperative prophylaxis in 249. Bonnet JP, Abid L, Dabhar A, et al. Early biliary pseudolithiasis
breast surgery: a randomized double-blind trial involving during ceftriaxone therapy for acute pyelonephritis in chil-
1,766 patients. Chemotherapy 1999; 45: 217-23 dren: a prospective study in 34 children. Eur J Pediatr Surg
233. Morris WT. Cetriaxone is more effective than gentamicin/met- 2000; 10: 368-71
ronidazole prophylaxis in reducing wound and urinary tract 250. Palanduz A, Yalçin I, Tonguç E, et al. Sonographic assessment
infections after bowel operations. Results of a controlled, ran- of ceftriaxone-associated biliary pseudolithiasis in children. J
domized, blind clinical trial. Dis Colon Rectum 1993 Sep; 36: Clin Ultrasound 2000 May; 28 (4): 166-8
826-33 251. Schaad UB, Wedgwood-Krucko J, Tschaeppeler H. Reversible
234. Henriques CU, Wilken-Jensen C, Thorsen P, et al. A randomised ceftriaxone-associated biliary pseudolithiasis in children.
controlled trial of prophylaxis of post-abortal infection: Lancet 1988 Dec 17: 1411-3
ceftriaxone versus placebo [see comments]. Br J Obstet 252. Stabile A, Ferrara P, Marietti G, et al. Ceftriaxone-associated
Gynaecol 1994 Jul; 101: 610-4 gallbladder lithiasis in children [letter]. Eur J Pediatr 1995 Jul;
235. von-Mandach U, Huch R, Malinverni R, et al. Ceftriaxone (sin- 154: 590
gle dose) versus cefoxitin (multiple doses): success and fail- 253. Heim-Duthoy KL, Caperton EM, Pollock R, et al. Apparent
ure of antibiotic prophylaxis in 1052 cesarean sections. J biliary pseudolithiasis during ceftriaxone therapy. Antimicrob
Perinat Med 1993; 21: 385-97 Agents Chemother 1990; 34 (6): 1146-9

254. Pigrau C, Pahissa A, Gropper S, et al. Ceftriaxone-associated 270. Roche Pharmaceuticals. Rocephin (ceftriaxone sodium) for in-
biliary pseudolithaisis in adults. Lancet 1989 Jul 15: 165 jection. 2000 Sep
255. Blais C, Duperval R. Biliary pseudolithiasis in a child associ- 271. Täuber MG. Management of bacterial meningitis in adults. Curr
ated with 2 days of ceftriaxone therapy. Pediatr Radiol 1994; Opin Crit Care 1998 Oct; 4: 276-81
24: 218-9 272. Friedland IR, McCracken Jr GH. Management of infections
256. Robertson FM, Crombleholme TM, Barlow SE, et al. caused by antibiotic-resistant Streptococcus pneumoniae. N
Ceftriaxone choledocholthiasis. Pediatrics 1996; 98: 133 Engl J Med 1994 Aug 11; 331 (6): 377-82
257. Lopez AJ, O’Keefe P, Morrissey M, et al. Ceftriaxone-induced 273. Heffelfinger JD, Dowell SF, Jorgenson JH, et al. Management
cholelithiasis. Ann Intern Med 1991; 115: 712-4 of community-acquired pneumonia in the era of pneumococ-
258. Zinberg J, Chernaik R, Coman E, et al. Reversible symptomatic cal resistance: a report from the Drug-ResistanT Streptococ-
biliary obstruction associated with ceftriaxone pseudolithia- cus pneumoniae Therapeutic Working Group. Arch Intern
sis. Am J Gastroenterol 1991; 86 (9): 1251-4 Med 2000; 160: 1399-408
259. Zimmermann AE, Katona BG, Jodhka JS, et al. Ceftriaxone-in- 274. Bradley JS. Oral vs. intramuscular antibiotic therapy for acute
duced acute pancreatitis. Ann Pharmacother 1993 Jan; 27: 36-7 otitis media: which is best? Pediatr Infect Dis J 1999; 18 (12):
260. De Moor RA, Egberts AC-G, Schröder CH. Ceftriaxone-asso- 1147-51
ciated nephrolithiasis and biliary pseudolithiasis. Eur J Pedi- 275. Williams DN, Rehm SJ, Tice AD, et al. Practice guidelines for
atr 1999 Dec; 158: 975-7 community-based parenteral anti-infective therapy. Clin In-
261. Grasberger H, Otto B, Loeschke K. Ceftriaxone-associated fect Dis 1997 Oct; 25: 787-801
nephrolithiasis [1] [letter]. Ann Pharmacother 2000; 34 (9):
276. Craig WA. Antibiotic selection factors and description of a hos-
1076-7
pital-based outpatient antibiotic therapy program in the USA.
262. Scimeca PG, Weinblatt ME, Boxer R. Hemolysis after treat-
Eur J Clin Microbiol Infect Dis 1995; 14 (7): 636-42
ment with ceftriaxone [1]. J Pediatr 1996; 128 (1): 163
263. Bernini JC, Mustafa MM, Sutor LJ, et al. Fatal hemolysis in- 277. Tice AD. Experience with a physician-directed, clinic-based
duced by ceftriaxone in a child with sickle cell anemia. J program for outpatient parenteral antibiotic therapy in the
Pediatr 1995; 126: 813-5 USA. Eur J Clin Microbiol Infect Dis 1995; 14 (7): 655-61
264. Lascari AD, Amyot K. Fatal hemolysis caused by ceftriaxone. 278. Barman Balfour JA, Lamb HM. Outpatient parenteral antibac-
J Pediatr 1995; 126: 816-7 terial therapy of serious infections: the role of ceftriaxone. Dis
265. Martin E, Fanconi S, Kälin p, et al. Ceftriaxone - bilirubin - Manage Health Outcomes 1998 Oct; 4 (4): 225-36
albumin interactions in the neonate: an in vivo study. Eur J 279. International Antimicrobial Therapy Cooperative Group of the
Pediatr 1993; 152: 530-4 European Organization for Research and Treatment of Can-
266. Hayward CJ, Nafziger AN, Kohlhepp SJ, et al. Investigation of cer. Efficacy and toxicity of single daily doses of amikacin
bioequivalence and tolerability of intramuscular ceftriaxone and ceftriaxone versus multiple daily doses of amikacin and
injections by using 1% lidocaine, buffered lidocaine, and ster- ceftazidime for infection in patients with cancer and
ile water diluents. Antimicrob Agents Chemother 1996 Feb; granulocytopenia. Ann Intern Med 1993 Oct 1; 119 (7 Pt 1):
40: 485-7 584-93
267. Schichor A, Bernstein B, Weinerman H, et al. Lidocaine as a 280. Gold HS, Moellering Jr RC. Antimicrobial-drug resistance. N
diluent for ceftriaxone in the treatment of gonorrhea: does it Engl J Med 1996 Nov 7; 335 (19): 1445-53
reduce the pain of the injection? Arch Pediatr Adolesc Med
1994 Jan; 148: 72-5
268. Patel IH, Weinfeld RE, Konikoff J, et al. Pharmacokinetics and
tolerance of ceftriaxone in humans after single-dose intra-
Correspondence and reprints: Lesley J. Scott, Adis Interna-
muscular administration in water and lidocaine diluents. Anti-
microb Agents Chemother 1982; 21 (6): 957-62 tional Limited, 41 Centorian Drive, Private Bag 65901,
269. Roche Laboratories. Rocephin (ceftriaxone sodium) for injec- Mairangi Bay, Auckland 10, New Zealand. E-mail:
tion. In: Physician’s desk reference. 54th ed. 2000: 2652-4 demail@adis.co.nz

Ceftriaxone: An Update of Its Use in The Management of Community-Acquired and Nosocomial Infections

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Ceftriaxone: An Update of Its Use in The Management of Community-Acquired and Nosocomial Infections

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ADIS DRUG EVALUATION Drugs 2002; 62 (7): 1041-1089

© Adis International Limited. All rights reserved.

Various sections of the manuscript reviewed by:

3. Pharmacokinetic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1056

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hyperproduce chromosomal β-lactamases and extended-spectrum β-lactamases

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β-lactamases, both of which are now widespread. Other relevant mechanisms

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at the physician’s discretion). There were no recurrences of primary infection or

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is often administered as part of a step-down regimen or in combination with other

1. Introduction 2. Antibacterial Activity

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resistance breakpoint (MIC ≥4 mg/L), whereas 100

% of strains susceptible at each MIC

negative bacteria producing extended-spectrum

drolyse third-generation cephalosporins strongly

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Resistant rins, ceftriaxone possesses better activity than

is inactive against methicillin-resistant staphylo-

>32 mg/L; n = 21).[4] Ceftriaxone is inactive

2.3 Gram-Negative Bacteria

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mechanisms of resistance and therefore has a sim- 2.4 Anaerobes

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a 2g IV dose-proportionally with intravenous doses

150 0.5g IM ear and dose dependent.[2,76] With increasing

L/h) suggesting that more frequent administration

Hours is required in seriously ill patients.[83] Conversely,

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Table V. Distribution of ceftriaxone after a single intravenous or intramuscular injection

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a Patients were undergoing duodenopancreatectomy for cancer.

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Comparisons with fluoroquinolones

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plus gentamicin 5.25 to 6 mg/kg/day[203] before same ceftriaxone/cefalexin step-down regimen

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(6mo-11y) CIP 10 q12h PO × 3 94/95 (99) e

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90 Ceftriaxone + tobramycin factors which might alter the likely causative

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Abdominal/biliary surgery or procedures

Breast or gynaecological surgery

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