Cephalosporins

19/08/13 19:26

Official reprint from UpToDate

www.uptodate.com 2013 UpToDate

Cephalosporins
Author
Stephen B Calderwood, MD

Section Editor
David C Hooper, MD

Deputy Editor
Allyson Bloom, MD

Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jul 2013. | This topic last updated: Aug 15, 2013.
INTRODUCTION Beta-lactam antibiotics are among the most commonly prescribed drugs, grouped together based
upon a shared structural feature, the beta-lactam ring. Cephalosporins cover a broad range of organisms, are generally
well-tolerated, and are easy to administer; thus, these agents are frequently used beta-lactam drugs.
The classification, spectrum of activity, and pharmacology of the cephalosporins will be reviewed here. The mechanisms
of action and resistance and major adverse reactions of the beta-lactam antibiotics, and the penicillins and other betalactam drugs are discussed separately. (See "Beta-lactam antibiotics: Mechanisms of action and resistance and adverse
effects" and "Penicillins" and "Extended-spectrum beta-lactamases".)
CLASSIFICATION OF CEPHALOSPORINS Cephalosporins include the closely related cephamycin compounds. The
parenteral agents are commonly classified into the following categories:
First generation (cefazolin)
Second generation
A. Subgroup with activity against Haemophilus influenzae (cefuroxime)
B. Cephamycin subgroup with activity against Bacteroides spp (cefoxitin)
Third generation
A. Subgroup with broad gram negative activity but poor activity against Pseudomonas aeruginosa (cefotaxime,
ceftriaxone, and ceftizoxime)
B. Subgroup with broad gram negative activity including good activity against Pseudomonas aeruginosa
(ceftazidime)
Fourth generation (cefepime)
Fifth generation (ceftaroline)
SPECTRUM OF ACTIVITY AND CLINICAL USE Most of the available cephalosporins are semi-synthetic derivatives
of cephalosporin C, a compound with antibacterial activity produced by the fungus Cephalosporium. The closely related
cephamycin compounds (derived from Streptomyces spp) are regarded as members of the cephalosporin class. In
clinical practice, these antibiotics have frequently been grouped into five "generations" based upon their spectrum of
activity against aerobic and facultative gram-negative bacilli and gram-positive bacteria.
Parenteral agents
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First generation Cephalothin is the oldest of the first generation cephalosporins and was previously used as the
prototype of this group. Cephalothin is active against most gram-positive cocci (including penicillinase-producing
staphylococci), but does not have clinically useful activity against enterococci, Listeria, oxacillin-resistant staphylococci
[1], or penicillin-resistant pneumococci [2-4]. (See "Microbiology of methicillin-resistant Staphylococcus aureus" and
"Resistance of Streptococcus pneumoniae to beta-lactam antibiotics".)
Cephalothin is active against most strains of Escherichia coli, Proteus mirabilis, and Klebsiella pneumoniae, but has little
activity against indole-positive Proteus, Enterobacter, Serratia, and the non-enteric gram-negative bacilli such as
Acinetobacter spp and Pseudomonas aeruginosa. Gram-negative cocci (such as the gonococcus and meningococcus)
and H. influenzae are generally resistant. Cephalothin is active against most of the common anaerobic pathogens, with
certain exceptions such as Bacteroides species, particularly B. fragilis.
Cefazolin has a similar spectrum of activity to cephalothin, is available worldwide, and is now the only parenteral first
generation cephalosporin available in the United States. Cefazolin achieves substantially higher serum levels than
cephalothin, and has a longer half-life of elimination. Cefazolin is less stable than cephalothin in vitro to the type A
penicillinase of staphylococci [5]; the relevance of this for clinical therapy, however, is not certain.
Second generation The second generation cephalosporins are somewhat less active against gram-positive cocci
than the first generation agents but are more active against certain gram-negative bacilli. This generation of compounds
can be divided into two subgroups, one with activity against H. influenzae and the other, the cephamycins, with activity
against Bacteroides.
Activity against Haemophilus influenzae In the first subgroup, cefuroxime is available parenterally and is
more active than cefazolin in vitro against strains of Enterobacter and indole-positive Proteus. However, this agent
induces the chromosomal beta-lactamases of these organisms, leading to resistance and failures of clinical therapy [6].
(See "Beta-lactam antibiotics: Mechanisms of action and resistance and adverse effects", section on 'Mechanisms of
bacterial resistance'.)
Cefuroxime is also more active than cefazolin against H. influenzae, and cefuroxime is quite stable to the TEM betalactamase in ampicillin-resistant strains. Although cefuroxime is approved for the therapy of H. influenzae meningitis,
delayed responses and treatment failures have occurred, and a third generation cephalosporin is now preferred for
therapy of meningitis due to ampicillin-resistant strains [7]. Cefuroxime is also highly active against beta-lactamase
producing Moraxella catarrhalis.
Cephamycin subgroup (active against Bacteroides) The cephamycin subgroup of the second generation
cephalosporins includes cefoxitin and cefotetan. This subgroup is active against most strains of E. coli, P. mirabilis and
Klebsiella like the first generation cephalosporins. The cephamycins are quite stable to many plasmid-mediated betalactamases, but the activity of this group against Enterobacter and indole-positive Proteus is limited by induction of
chromosomal cephalosporinases of these species and selection of stably derepressed mutants [6].
Unlike the first generation cephalosporins, the cephamycins are active against many strains of Bacteroides. The
combination of activity against common aerobic and facultative gram-negative bacilli plus Bacteroides has led to the use
of the cephamycins in the prophylaxis and therapy of infections in the abdominal and pelvic cavities (where these
organisms predominate) [8]. The cephamycins have no clear advantages over the first generation cephalosporins for
infections outside of the abdominal and pelvic areas.
Overall resistance rates to cephamycins range from 10 to 80 percent for different members of the Bacteroides fragilis
group, compared with 15 to 30 percent for clindamycin, and essentially no resistance for the carbapenems,
chloramphenicol, or metronidazole [9].
Third generation The third generation cephalosporin class [10] is marked by stability to the common betalactamases of gram-negative bacilli, and these compounds are highly active against Enterobacteriaceae (E. coli, Proteus
mirabilis, indole-positive Proteus, Klebsiella, Enterobacter, Serratia, Citrobacter), Neisseria, and H. influenzae. They are
the therapy of choice for gram-negative meningitis due to susceptible Enterobacteriaceae. Third generation
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cephalosporins may also be useful alternatives to the aminoglycosides in treating gram-negative infections resistant to
other beta-lactams, particularly in the patient with renal dysfunction. However, mutants of Enterobacter, indole-positive
Proteus, Serratia, and Citrobacter, with stable derepression of the chromosomal beta-lactamase, are resistant to these
antibiotics [6,11]. Even if these organisms (Enterobacter, indole-positive Proteus, Serratia, and Citrobacter) test
susceptible to cephalosporins, use of a third generation cephalosporin as a single agent for treatment of serious
infections due to these bacteria can lead to the emergence of resistance during therapy.
The third generation cephalosporins are less active against most gram-positive organisms than the first generation
cephalosporins and are inactive against enterococci, Listeria, oxacillin-resistant staphylococci, and Acinetobacter.
Cefotaxime and ceftriaxone are usually active against pneumococci with intermediate susceptibility to penicillin, but
strains fully resistant to penicillin are often resistant to the third generation cephalosporins as well. In 1998, for example,
25 percent of strains of S. pneumoniae in the United States were intermediately or fully resistant to penicillin, and 14
percent were resistant to third generation cephalosporins [2-4,12-14]. (See "Resistance of Streptococcus pneumoniae to
beta-lactam antibiotics".)
Treatment with third generation cephalosporins may be complicated by superinfection (particularly with enterococci or
Candida) or by the emergence of resistance on therapy (particularly when used as single agents for Enterobacter,
indole-positive Proteus, or P. aeruginosa infections) [15].
Third generation cephalosporins are not currently recommended for prophylactic use in surgery.
Poor activity against Pseudomonas One subgroup of the third generation cephalosporins, including
cefotaxime and ceftriaxone, has poor activity against P. aeruginosa. Within this subgroup, cefotaxime has the shortest
serum half-life (1 hour) because of partial metabolism in the liver to desacetyl-cefotaxime. However, this metabolite also
has antibacterial activity and a longer half-life in serum (1.7 hours), allowing dosing every six hours.
Ceftriaxone has the longest serum half-life of this group (6.4 hours) and can be administered once or twice a day.
Ceftriaxone has been particularly recommended for the therapy of penicillin-resistant gonorrhea, Lyme disease involving
the central nervous system or joints, meningitis due to ampicillin-resistant H. influenzae, and meningitis in children [7,16].
One of the complications of ceftriaxone therapy, however, has been the formation in the biliary tract of "sludge"
composed of ceftriaxone crystals, causing the syndrome of biliary pseudolithiasis [17].
Activity against Pseudomonas The other subgroup of the third generation cephalosporins, including
cefoperazone and ceftazidime, has activity against P. aeruginosa. Cefoperazone was the first available drug in this
subgroup, but is currently not used as often due to decreased stability to the plasmid-mediated beta-lactamases of gramnegative bacilli that make it less active against Enterobacteriaceae than the other third generation cephalosporins. The
newer member of the subgroup, ceftazidime, is quite stable to the common plasmid-mediated beta-lactamases and is
highly active against Enterobacteriaceae, Neisseria, and H. influenzae. Ceftazidime is also particularly active against P.
aeruginosa and is an effective therapy for serious infections due to P. aeruginosa when the organism is resistant to the
anti-pseudomonal penicillins or the patient is penicillin allergic. In addition, it is effective therapy for meningitis caused by
P. aeruginosa. As with the anti-pseudomonal penicillins, however, ceftazidime should generally be given at least initially
in combination with an aminoglycoside for treatment of serious P. aeruginosa infection. Ceftazidime has poor activity
against gram-positive organisms and should be reserved for use in infections proven or highly suspected to be due to P.
aeruginosa.
Cefoperazone contains an N-methylthiotetrazole (NMTT) side chain. This NMTT group can dissociate from the parent
antibiotic in solution or in vivo and competitively inhibit vitamin K action, leading to prolongation of the prothrombin time
and bleeding [18]. This side chain is also associated with a disulfiram-like reaction to alcohol.
Fourth generation Cefepime is the fourth generation cephalosporin currently available. It has a positively
charged quaternary ammonium attached to the dihydrothiazone ring, which results in better penetration through the
outer membrane of gram-negative bacteria and a lower affinity than the third generation cephalosporins for certain
chromosomal beta-lactamases of gram-negative bacilli.
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Cefepime has similar activity to cefotaxime and ceftriaxone against pneumococci (including penicillin-intermediate
strains) and oxacillin-sensitive S. aureus. Like the earlier third generation agents, it is active against the
Enterobacteriaceae, Neisseria, and H. influenzae but has greater activity against the gram-negative enterics that have a
broad-spectrum, inducible, chromosomal AmpC beta-lactamase (Enterobacter, indole-positive Proteus, Citrobacter, and
Serratia) [19]. The role of cefepime in therapy of infections due to stably-derepressed mutants of these organisms has
not yet been fully defined, but preliminary data suggest that it may be effective. In a study of 96 patients with infections
due to laboratory-confirmed AmpC beta-lactamase producing organisms, 96 percent of the isolates were susceptible to
cefepime [20]. Among patients who received cefepime, the 30 day mortality rate and duration of hospitalization were
similar to those observed in a matched subset of patients who received meropenem.
Cefepime is as active as ceftazidime for Pseudomonas aeruginosa, and is active against some ceftazidime-resistant
isolates. As with the anti-pseudomonal penicillins, cefepime should generally be given in combination with an
aminoglycoside for treatment of serious P. aeruginosa infection. There has not been enough clinical experience with
cefepime in meningitis to recommend its routine use for this purpose. It is also not currently recommended for
prophylactic use in surgery. Acinetobacter isolates are frequently resistant to cefepime.
Despite these potential advantages over third generation cephalosporins, especially against organisms with inducible,
chromosomal resistance, comparative trials of third and fourth generation cephalosporins have not yet been performed.
A review by the United States Food and Drug Administration (FDA) of cefepime safety data was initiated in 2007
following findings of a meta-analysis that raised concern regarding increased all-cause mortality associated with
cefepime use (risk ratio 1.26, 95% CI 1.08-1.49) [21]. The FDA reviewed these study data, conducted additional
analyses based on other data, and determined that the data do not indicate a higher rate of death in cefepime-treated
patients [22]. Cefepime remains an appropriate therapy for its approved indications [23].
Treatment with cefepime may be complicated by superinfection (particularly with enterococci or Candida) [15]. Cefepime
use also carries a risk of seizures (specifically nonconvulsive status epilepticus), particularly in patients with renal failure
for whom the dose is not appropriately adjusted downwards [24]. (See "Beta-lactam antibiotics: Mechanisms of action
and resistance and adverse effects", section on 'Neurologic reactions'.)
Fifth generation Ceftaroline is a fifth generation cephalosporin whose active metabolite has a spectrum of in vitro
activity similar to ceftriaxone but with improved gram-positive activity. In particular, ceftaroline has higher affinity for
PBP2a in oxacillin-resistant staphylococci, and has activity against MRSA, as well as vancomycin-intermediate
Staphylococcus aureus (VISA) and hetero-VISA. In addition, ceftaroline has activity for Streptococcus pneumoniae that
is intermediate or resistant to penicillin or ceftriaxone. Ceftaroline is not active for enterococci nor against AmpCoverproducing or ESBL-producing Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter baumannii, or
Bacteroides fragilis. Several randomized, double-blind controlled clinical trials have suggested that ceftaroline is
noninferior to vancomycin plus aztreonam for treatment of complicated skin and soft tissue infections including those due
to MRSA, and to ceftriaxone for therapy of community-acquired pneumonia [25-27]. The efficacy of this anti-MRSA
cephalosporin is not yet known for hospital-acquired MRSA pneumonia or for bacteremia. (See "Antibiotic studies for the
treatment of community-acquired pneumonia in adults", section on 'Ceftaroline versus ceftriaxone' and "Pharmacology of
antimicrobial agents for treatment of methicillin-resistant Staphylococcus aureus and vancomycin resistant
enterococcus", section on 'Ceftaroline'.)
Ceftobiprole is an investigational cephalosporin also capable of binding to penicillin binding protein 2a, the protein
conferring S. aureus resistance to beta-lactam antibiotics [28]. It can also bind penicillin binding protein 2x in penicillinresistant S. pneumoniae. It has in vitro activity similar to that of ceftazidime or cefepime against Enterobacteriaceae; it
also has activity against enterococci [29,30]. In addition, ceftobiprole appears to have a low potential for selection of
resistance [31].
Clinical trial data on these agents for use in MRSA infections are detailed separately. (See "Treatment of invasive
methicillin-resistant Staphylococcus aureus infections in adults", section on 'Ceftaroline' and "Treatment of invasive
methicillin-resistant Staphylococcus aureus infections in adults", section on 'Ceftobiprole'.)
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Oral agents Cephalosporins available for oral use include cephalexin, cefadroxil, cefaclor, cefuroxime axetil,
cefprozil, cefixime, cefpodoxime proxetil, ceftibuten, cefdinir, and cefditoren.
Cefadroxil has a longer serum half-life than cephalexin and is generally given in a dose of 500 to 1000 mg every 12
hours. The oral cephalosporins are poorly active against penicillin-resistant pneumococci [2].
The oral second generation cephalosporins, cefaclor, cefuroxime axetil, and cefprozil, have improved activity against H.
influenzae compared with the first generation oral cephalosporins and may be useful in treating otitis, sinusitis, and
respiratory tract infections.
The oral third generation cephalosporins, cefixime, cefpodoxime proxetil, ceftibuten, cefdinir, and cefditoren, are active
against streptococci, H. influenzae (including beta-lactamase producing strains), and M. catarrhalis. They are more
active than the other oral cephalosporins against enteric gram-negative bacilli, including E. coli, P. mirabilis, and
Klebsiella. However, they have poor activity against most strains of Enterobacter, Acinetobacter, P. aeruginosa, and the
anaerobes. Cefixime and ceftibuten have little activity against staphylococci, but cefpodoxime proxetil and cefdinir have
more activity. Ceftibuten is also only weakly active against pneumococci. Its spectrum of activity is otherwise similar to
those of cefdinir and cefpodoxime.
These antibiotics are relatively stable to many plasmid-mediated beta-lactamases but are much less stable to common
chromosomally-mediated cephalosporinases. Although these antibiotics are promoted as oral third generation
cephalosporins, they are less active against the enteric gram-negative bacilli than the parenteral third or fourth
generation cephalosporins. These antibiotics are recommended as therapy for otitis media, upper and lower respiratory
tract infections, and urinary tract infections (cefixime, cefpodoxime, and cefdinir). These indications are shared with the
oral second generation cephalosporins, amoxicillin-clavulanate, and trimethoprim-sulfamethoxazole. Cefixime and
ceftibuten have little or no activity against staphylococci in contrast to some of these other agents.
PHARMACOLOGY Many of the available parenteral cephalosporins have short serum half-lives (generally one hour
or less) and should be administered on an every four hour basis when treating serious systemic infections in patients
with normal renal function (table 1). Certain cephalosporins have longer serum half-lives and may be dosed less
frequently (eg, cefazolin Q8h and ceftriaxone Q24h). All of the cephalosporins except cefoperazone and ceftriaxone
require dose modification in the presence of severe renal failure (table 1).
All of the cephalosporins achieve therapeutic levels in pleural, pericardial, peritoneal, and synovial fluids, and urine.
Biliary concentrations exceed serum levels (in the absence of obstruction) and are particularly high for cefazolin,
cefoperazone, and ceftriaxone.
First and second generation cephalosporins (except cefuroxime) penetrate the cerebrospinal fluid (CSF) barrier poorly
and should not be used to treat infections of the central nervous system. The third generation cephalosporins achieve
much more reliable CSF levels in patients with meningeal irritation. Peak CSF concentrations of several cephalosporins
given at meningeal doses are shown in the table (table 2). Cefotaxime, ceftriaxone, and ceftazidime are approved for the
treatment of bacterial meningitis.
Fatal reactions due to calcium-ceftriaxone precipitates in the lungs and kidneys of neonates have been reported.
Ceftriaxone should not be reconstituted or mixed with a calcium-containing product (eg, Ringer's or Hartmann's solution
or parenteral nutrition). In addition, ceftriaxone should be avoided in infants aged 28 days if they are receiving or
expected to receive intravenous calcium-containing products. However, ceftriaxone and calcium-containing products
may be used concomitantly in patients aged >28 days, provided that the infusion lines are thoroughly flushed between
infusions [32].
SUMMARY
First generation cephalosporins, including cefazolin, are active against most gram-positive cocci except for
enterococci, oxacillin-resistant staphylococci, and penicillin-resistant pneumococci. They are also active against
most strains of E. coli, P. mirabilis, and K. pneumoniae. (See 'First generation' above.)
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The second generation cephalosporins include two subgroups. One subgroup has activity against H. influenzae
and M. catarrhalis. The other subgroup consists of the cephamycins, which are active against many strains of
Bacteroides. (See 'Second generation' above.)
Third generation cephalosporins have less activity against most gram-positive organisms than first generation
agents but are highly active against Enterobacteriaceae, Neisseria, and H. influenzae. Ceftazidime and
cefoperazone are also active against P. aeruginosa. The fourth generation cefepime has similar activity as the
third generation cephalosporins, including against P. aeruginosa, with the addition of greater activity against
enteric gram-negative rods that have an inducible chromosomal beta-lactamase. (See 'Third generation' above
and 'Fourth generation' above.)
The fifth generation cephalosporins have activity against oxacillin-resistant staphylococci, penicillin-resistant
pneumococci and enteric gram-negative rods. (See 'Fifth generation' above.)
Oral cephalosporins are also divided into different generations and their spectra of activity generally mirror those
parenteral agents of the corresponding generation. However, oral third generation drugs are less active against
enteric gram-negative bacteria than the parenteral third generation cephalosporins. Second and third generation
oral cephalosporins have similar indications, namely otitis media, respiratory tract infections, and urinary tract
infections. (See 'Oral agents' above.)
Most of the available parenteral cephalosporins have short serum half-lives and require frequent administration.
All of the cephalosporins except cefoperazone and ceftriaxone require dose modification in the presence of
severe renal failure (table 1). (See 'Pharmacology' above.)
All of the cephalosporins achieve therapeutic levels in pleural, pericardial, peritoneal, and synovial fluids, and
urine. First and second generation cephalosporins enter into cerebrospinal fluid poorly. Third generation
cephalosporins achieve more reliable cerebrospinal fluid levels in patients with meningeal irritation. (See
'Pharmacology' above.)

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22. Kim PW, Wu YT, Cooper C, et al. Meta-analysis of a possible signal of increased mortality associated with
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Topic 480 Version 12.0

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GRAPHICS
Dose of parenteral cephalosporins with adjustments for renal failure
Glomerular filtration rate (GFR) mL/min*
Drug

>50 (normal renal

function)

10-50

<10

Removal by
dialysis

Cefazolin

1-2 g Q 8 h

0.5-1 g Q 12 h

0.5-1 g Q 24 h

Yes (HD), No (PD)

Cefuroxime

0.75-1.5 g Q 6-8 h

0.75-1.5 g Q 812 h

0.75 g Q 24 h

Yes (HD, PD)

Cefoxitin

1-2 g Q 4-6 h

1-2 g Q 8-12 h

0.5-1 g Q 24 h

Yes (HD), No (PD)

Cefotetan

1-2 g Q 12 h

1-2 g Q 24 h

1-2 g Q 48 h

Yes (HD)

Cefotaxime

1-2 g Q 6 h

1-2 g Q 8-12 h

1-2 g Q 12-24
h

Yes (HD), No (PD)

Ceftizoxime

1-2 g Q 6-8 h

0.25-1 g Q 812 h

0.25-1 g Q 24
h

Yes (HD), No (PD)

Ceftriaxone

1-2 g Q 12-24 h

NC

NC

No (HD)

Ceftazidime

1-2 g Q 8 h

1-2 g Q 12-24
h

0.5-1 g Q 2448 h

Yes (HD, PD)

Cefepime

1-2 g Q 8-12 h

0.5-2 g Q 1224 h

0.25-1 g Q 24
h

Yes (HD)

Ceftaroline

600 mg Q 12 h

300-400 mg Q
12 h

200-400 mg Q
12 h

Yes (HD)

HD: hemodialysis; PD: peritoneal dialysis; NC: no change.

* Usual adult dosing and renal adjustments shown are for moderate to severe infections. For specific
dosing recommendations, see related disease treatment topics and Lexi-Comp drug information included
with UpToDate.
Not available in the United States or Canada.
1 hour infusion.

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Cephalosporins

19/08/13 19:26

Peak CSF concentrations of cephalosporins in bacterial meningitis

Cephalothin

0.16-0.31 g/mL

Cefoxitin

<1.56-12.5 g/mL

Cefuroxime

4.3-9.3 g/mL

Cefotaxime

6.8-27.2 g/mL

Ceftriaxone

2-42 g/mL

Ceftazidime

2.5-30 g/mL

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