ARTICLES
Infectious Diseases
Differences Between Ceftriaxone and Cefotaxime:
Microbiological Inconsistencies
John G Gums, D Wesston Boatwright, Mark Camblin, Diane C Halstead, Mark E Jones, and Roger Sanderson
he past decade has seen increasing
T resistance rates among clinical iso-
lates of Streptococcus pneumoniae in the
US, specifically to penicillin and ery-
thromycin.1 The percentage of isolates
causing nonmeningeal syndromes non-
susceptible to penicillin ranged from
24.3% in 1998 to 26.5% in 2000 and was
consistently higher among isolates causing
meningitis.2 Emergence of this resistance
has been linked to development of pneu-
mococcal strains with mosaic penicillin-
binding proteins, 6 of which have been
identified in S. pneumoniae.3
Ceftriaxone and cefotaxime are extend-
ed-spectrum third-generation cephalo-
sporin β-lactam antimicrobial agents that
historically have possessed similar in vitro
susceptibility for S. pneumoniae.4 In 2003,
the National Committee for Clinical Labo-
ratory Standards (NCCLS; now the Clini-
cal and Laboratory Standards Institute
[CLSI]) M100-S13 guideline Table 1A
(minimum inhibitory concentration [MIC]
testing) stated that either ceftriaxone or
cefotaxime could be tested against S.
pneumoniae.5 Strains of S. pneumoniae
susceptible to or having intermediate resis-
tance to penicillin were usually also sus-
ceptible in vitro to ceftriaxone and cefo-
taxime.6 As outlined by the then-NCCLS
recommendations, most clinical laborato-
Author information provided at the end of the
text.
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OBJECTIVE: To review data to determine why pneumococcal isolates appear to be
increasingly resistant to cefotaxime, historically regarded as having the same in
vitro susceptibility to ceftriaxone, and what this observation might imply clinically.
DATA SOURCES: Literature was accessed through MEDLINE (1966–October
2007) using the MeSH terms cefotaxime, ceftriaxone, susceptibility, microbial
sensitivity tests, antibiotics, pneumococcal infections, Streptococcus pneumoniae,
resistance, and cephalosporin resistance. Abstracts and surveillance databases
were reviewed and unpublished data were provided by state departments of health
and institutions.
STUDY SELECTION AND DATA EXTRACTION: All articles published in the English
language that were identified from the data sources were evaluated.
DATA SYNTHESIS: An experimental model of pneumococcal infection in mice
conducted 2 decades ago predicted that the delta T minimum inhibitory concen-
tration (MIC) varied less for ceftriaxone than for cefotaxime. Studies of plasma and
serum concentrations show that ceftriaxone remains at a concentration above the S.
pneumoniae MIC for 100% of the dosing interval at 12 hours. Types of MIC
susceptibility test methods for ceftriaxone and cefotaxime used against S.
pneumoniae respiratory isolates were found to be similar. Data from state and
county health departments found microbiological discrepancies between ceftriaxone
and cefotaxime. In areas with high rates of penicillin-resistant S. pneumoniae
(PRSP), isolates were twice as susceptible to ceftriaxone versus cefotaxime.
Surveillance databases consistently show differences between susceptibility of S.
pneumoniae to cefotaxime versus ceftriaxone over time. MIC and pulsed-field gel
electrophoresis studies suggest that phenotypic discrepancies may account for
penicillin resistance. Ongoing studies are examining S. pneumoniae isolates at the
molecular level to determine the basis of difference in resistance to cefotaxime
and ceftriaxone.
CONCLUSIONS: An increase in rates of PRSP and differences in S. pneumoniae
isolate susceptibility between ceftriaxone and cefotaxime emphasize the necessity
for hospital laboratories to detect these changes as they occur. Clinicians should
select the most appropriate agent for patients with S. pneumoniae.
KEY WORDS: cefotaxime, ceftriaxone, Streptococcus pneumoniae.
Ann Pharmacother 2008;42:71-9.
Published Online, 19 Dec 2007, www.theannals.com, DOI 10.1345/aph.1H620
THIS ARTICLE IS APPROVED FOR CONTINUING EDUCATION CREDIT
ACPE UNIVERSAL PROGRAM NUMBER: 407-000-08-001-H01
The Annals of Pharmacotherapy n 2008 January, Volume 42 n 71
JG Gums et al.
ries tested against one agent in the class and extrapolated
MIC interpretations of susceptible, intermediate, or resistant
to other drugs in the same class. MIC interpretations were
rarely reported together for similar agents within the same
class.
However, in March 2001, at a hospital laboratory in
Florida, adjacent comparison of local surveillance docu-
ments noted that ceftriaxone and cefotaxime susceptibili-
ties to S. pneumoniae displayed a 20% discrepancy, with
the isolates significantly more susceptible to ceftriaxone.
Subsequent observations within the State Departments of
Health of Florida and Oklahoma found similar discrepan-
cies. Further investigation in the fall of 2001, using data
from the Antimicrobial Resistance Management (ARM)
program (www.armprogram.com), demonstrated a nation-
al susceptibility difference of 80.4%a for ceftriaxone versus
69.2% for cefotaxime.7,a This report was the first publica-
tion from a surveillance system to note a significant differ-
ence between these 2 agents. At that time, the ARM pro-
gram contained approximately 10 million isolates in aggre-
gate containing 21,127 isolates of S. pneumoniae. A
retrospective review of these data suggests that a separa-
tion between the 2 drugs began to occur when the cefo-
taxime dosing interval apparently was changed from every
8 hours to every 12 hours in 1995 in various hospitals in
the Southeast, a short-lived phenomenon not recommend-
ed by the then-NCCLS.8 Figure 1 shows national trends for
ceftriaxone and cefotaxime from 1995 to 2003.
In this article, we detail results of investigations that
have consistently documented the initial observation of the
S. pneumoniae isolate susceptibility discrepancy between
ceftriaxone and cefotaxime. Before the 2002 changes to
the current breakpoints, these antibiotics were treated like
penicillin, with one breakpoint, regardless of where the
isolate originated. With the change, breakpoints for non-
meningeal sources of S. pneumoniae were increased (eg, to
2 µg/mL for intermediate, and ≥4 µg/mL for resistant iso-
lates), while those for meningeal sources remained the
same. Had the penicillin breakpoints originally differentiat-
ed between meningeal and nonmeningeal sources, it re-
mains to be seen whether the level of resistance to the
third-generation cephalosporins cefotaxime and ceftriax-
one would have arisen and, if so, had this difference been
more specifically addressed, whether the current discrep-
ancy would have been observed.
Data Sources
Literature was accessed through a MEDLINE search
(1966–October 2007) using the MeSH terms cefotaxime,
a
Throughout the article, this footnote indicates that values were obtained using pre-
2002 NCCLS breakpoints.
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ceftriaxone, susceptibility, microbial sensitivity tests, an-
tibiotics, pneumococcal infections, Streptococcus pneumo-
niae, resistance, and cephalosporin resistance. Abstracts
and surveillance databases were received and unpublished
data were provided by the authors, state departments of
health, and institutions.
Study Selection and Data Extraction
All articles published in English identified from the data
sources were evaluated.
Data Synthesis
To delineate why the observed differences in S. pneu-
moniae isolate susceptibility discrepancy between ceftriax-
one and cefotaxime might be occurring, we reviewed data
from a number of different sources (Table 1). Both broth
microdilution and pulsed-field gel electrophoresis (PFGE)
test methods have identified phenotypic differences among
clinical S. pneumoniae isolates.
In January 2002, the then-NCCLS published new MIC
interpretative breakpoints for meningeal and nonmeningeal
S. pneumoniae isolates that increased the nonmeningeal
pneumococcal susceptibility breakpoints for cefotaxime and
ceftriaxone.9 The intermediate breakpoint for nonmeningeal
isolates was 2.0 µg/mL and the resistant breakpoint was
greater than or equal to 4.0 µg/mL. For meningeal isolates,
the breakpoints remain unchanged (1.0 µg/mL for intermedi-
ate, ≥2.0 µg/mL for resistant). The data represented in this re-
port show susceptibilities observed through various years.
Data prior to 2002 may reflect old breakpoints and thus arti-
ficially suppress susceptibility; reports from 2002 and later
years should not be directly compared with reports from
previous years that used old breakpoints unless they have
been corrected. Current breakpoints at 1.0 µg/mL, 2.0
µg/mL, and 4.0 µg/mL for nonmeningeal isolates for cef-
triaxone nationally have been reported at greater than or
equal to 96% susceptibility in various surveillance reports.6
Susceptibility Testing Methods
In a study conducted to determine what types of MIC test
methods for ceftriaxone and cefotaxime were used against S.
pneumoniae respiratory isolates, 150 institutions participat-
ing in The Surveillance Network (TSN) Database—USA in
1997–2000 were surveyed (data provided by Dr. Jones).
Two test methods were found to be primarily in use: E-test
and microdilution MIC method manual. In fact, given that
S. pneumoniae is a fastidious organism, until recently,
many laboratories used only either the Kirby-Bauer or the
E-test. Institutions reported using the E-test for 56.6% of
their S. pneumoniae isolate testing against ceftriaxone and
61.2% against cefotaxime and the microdilution MIC
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method manual for 30% of their tests against ceftriaxone
and 26.3% against cefotaxime. These results suggest that
the test methods used were similar and not likely to con-
tribute to the susceptibility differences noted between cef-
triaxone and cefotaxime.
Using the same database, quantitative data from non-
meningeal isolates of S. pneumoniae concomitantly tested
against ceftriaxone and cefotaxime collected from 117 hos-
pitals in 33 states from 2000 to 2002 were analyzed using
pre-2002 NCCLS breakpoints to determine whether differ-
ences in susceptibility by state and/or by test method exist-
ed.10 Three test methods were used to test the majority of
the isolates: MicroScan MICro Strep panel (33.4%), E-test
strips (19.2%), and Vitek 2 (21.3%). The nonmeningeal S.
pneumoniae isolates were found to be consistently more
susceptible to ceftriaxone than to cefotaxime, regardless of
year or test method, leading the investigators to suggest
that the differences were not artifactual. Among all isolates
tested, ceftriaxone susceptibility was noted to be 2.3%
higher than that of cefotaxime, a difference that was geo-
graphically widespread. In 10 of 16 states, greater than
2.5% higher susceptibility rates for ceftriaxone were found
for at least 1 of the 3 years; in Washington, DC (which
used only MicroScan MICro Strep) and Louisiana (which
used only E-test), this difference in susceptibility was not-
ed for all 3 years (range 2.7–17%).
Pharmacokinetic/Pharmacodynamic Observations
The in vitro antibacterial effects of β-lactams are due to
a time-dependent killing mechanism. For maximal β-lac-
tam antibacterial activity to Pneumococcus and gram-neg-
Table 1. Areas of Data Synthesis
Susceptibility testing methods
Pharmacokinetic/pharmacodynamic observations
Department of Health data
Institutional data
Figure 1. National trends for Streptococcus pneumoniae susceptibility in the Antimicrobial Resistance Management Program, 1995–2003.
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Differences Between Ceftriaxone and Cefotaxime: Microbiological Inconsistencies
ative bacteria, the unbound drug concentration should ex-
ceed the MIC (T>MIC) for at least 40–60% of the dosing
interval.11 For other gram-positive bacteria, the unbound β-
lactam concentration can exceed the MIC for as little as
25% of the dosing interval for efficacy.11,12 Increases in
MIC may affect the pharmacodynamic parameter for an-
tibacterials, which can lower efficacy in vivo. However, an
increase in bacterial MICs to antibacterials with an effica-
cy parameter dependent on T>MIC (eg, cephalosporins)
does not always result in a proportional reduction in the
pharmacokinetic/pharmacodynamic parameter unless the
increase in MIC is severe enough to intersect the break-
point. Small increases in MIC are least likely to signifi-
cantly impact drugs with a long elimination half-life, such
as ceftriaxone (5.8–8.7 h), because T>MIC is preserved.
This would not apply to cefotaxime due to its short half-
life (~1 h), which imparts more dramatic concentration
peaks and troughs, increasing the likelihood that drug con-
centration dips below the MIC.12 Thus, the magnitude of
change in MIC (known as “MIC creep”) can prevent target
antibiotic exposure from being attained. In fact, an experi-
mental model of pneumococcal infection in mice conduct-
ed in 1987 predicted that the delta T MIC varied less for
ceftriaxone than for cefotaxime.13 Susceptibility changes
for drugs that have long half-lives, and efficacy dependent
on T>MIC may not affect the percentage of patients who
achieve target exposures. Current methods for breakpoint
determination do not consider this interpatient variability.12
Initial research conducted to determine the effect of
MIC breakpoint changes on category interpretation for S.
pneumoniae respiratory isolates from 1997 to 2000 found
subtle differences between cefotaxime and ceftriaxone for
Surveillance databases
Minimum inhibitory concentration and
pulsed-field gel electrophoresis studies
The Annals of Pharmacotherapy n 2008 January, Volume 42 n 73
JG Gums et al.

both the then-current (≤0.5, 1, ≥2 µg/mL) and proposed
(now current 1, 2, ≥4 µg/mL) breakpoints, with isolates
more susceptible to ceftriaxone.
In data presented to the NCCLS during discussions of
the breakpoint changes, one study showed that the popula-
tion meeting the efficacy target of T>MIC equal to at least
50% of the dosing interval at an MIC of 1.0 µg/mL was
99.3% for ceftriaxone 1 g every 24 hours and 37.3% for
cefotaxime 1 g every 12 hours.14 At an MIC of 2.0 µg/mL,
the rate was 73.1% for ceftriaxone and 16.2% for cefo-
taxime. When the study was repeated with cefotaxime 1 g
every 8 hours, 88.2% of patients met the MIC less than or
equal to 50% efficacy target at 1.0 µg/mL and 65.6% of
patients at 2.0 µg/mL.
Studies of plasma and serum concentrations of the 2
agents show that a single intravenous dose of ceftriaxone 1
g produces a 24-hour plasma trough concentration of 9.3
µg/mL, whereas a single intravenous dose of cefotaxime 1
g has an 8-hour serum trough concentration limit that is
below detection (0.3 µg/mL).15 A 24-hour study of un-
bound concentrations (pleural exudate) of ceftriaxone dis-
played a concentration of 4.4 µg/mL at 50% of the dosing
interval at 12 hours. Therefore, the concentration was
above the S. pneumoniae MIC of 1.0 µg/mL for 100% of
the dosing interval (2.0 µg/mL at 24 h).16
Additionally, from 1996 to 2000, ceftriaxone not only re-
mained the most potent β-lactam agent studied against com-
mon gram-positive clinical isolates in the TSN Database—
susceptibility data included erythromycin 36.8%, clin-
damycin 18.0%, and imipenem 36.1%. Similar trends
were seen for Orange and Duval Counties; overall, only 2
counties in Florida reported similar ceftriaxone and cefo-
taxime susceptibilities.
A surveillance study of S. pneumoniae susceptibility to
ceftriaxone and cefotaxime from the Florida Department
of Health for 2000 found that, as measured by percentage
of isolates categorized as intermediate or resistant, 21.6%a
were nonsusceptible to ceftriaxone and 32.8%a were non-
susceptible to cefotaxime (Table 2). Most (90%) of the iso-
lates were from blood. The infection type was reported for
65% of cases. Of these 1051 cases, bacteremia (n = 503)
was the most common (47.9%); pneumonia (n = 369) rep-
resented 35.1%, meningitis (n = 122) 11.6%, otitis media
(n = 31) 2.9%, and other (n = 26) 2.5%. Nearly 40% of the
cases were children 5 years of age or younger, and 23%
were adults aged 55 years or older.18 A comparison of spe-
cific counties representing the major metropolitan areas in
Florida showed nonsusceptibility rates to be consistent
with observations from the state as a whole, with the high-
Table 2. Streptococcus pneumoniae Clinical Isolate
Susceptibility to Ceftriaxone and Cefotaxime in
Florida, 2000a,b
Ceftriaxone Cefotaxime

USA, but had the most consistent in vitro activity, demon- Location % Isolates (n) % Isolates (n)

strating stability over time: resistance was 6.3%a in 1996 State

and 5.4%a in 2000.17 Florida S 78.4 1130 67.2 1065
I 16.3 22.9
The influence of the active metabolite of cefotaxime, R 5.3 9.9
desacetylcefotaxime, was not factored into the overall ac-
County
tivity of the assessment of cefotaxime’s activity—or lack Orange S 93.3 112 82.2 134
of activity—against S. pneumoniae. Furthermore, if no in- I 1.7 13.4
formation was provided stating whether figures for ceftri- R 5.0 3.7
Dade–Miami S 82.8 163 64.9 154
axone had been corrected for protein binding, we assumed
I 12.3 20.1
them to be reported uncorrected. R 4.9 14.9
Duval S 82.4 51 64.4 73
Department of Health Data I 13.7 20.5
R 3.9 15.1
Data from Florida state and county health departments Broward S 81.5 146 76.9 26
I 15.8 19.2
demonstrated similar trends in pneumococcal susceptibili-
R 2.7 3.8
ty for ceftriaxone and cefotaxime and support the hypothe- Hillsborough S 67.2 45 53.6 67
sis that microbiological discrepancies between these 2 I 23.9 36.8
drugs exist. Furthermore, these findings show that isolates R 9.0 9.6
that are twice as susceptible to ceftriaxone compared with Palm Beach S 76.4 110 70.7 92
I 16.4 19.6
cefotaxime consistently occur in areas with high rates of R 7.3 9.8
penicillin-resistant S. pneumoniae (PRSP). In Florida, Pinellas S 72.6 62 52.7 55
which has S. pneumoniae on its reportable diseases list, I 17.7 25.5
penicillin nonsusceptibility rates were 56.5% in 2000 and R 9.7 21.8

48.9% in 2001. For Dade–Miami County alone in 2000,
PRSP susceptibility was 64.5%; nonsusceptibility to ceftri-
axone was 17.2%a and to cefotaxime, 35.0%.a Other non-
I = intermidiate; R = resistant; S = susceptible.
a
Based on pre-2002 changes in breakpoints.
b
Some percentages do not equal 100% due to rounding.

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 Differences Between Ceftriaxone and Cefotaxime: Microbiological Inconsistencies

est percentage nonsusceptibility discrepancies to cefo-
taxime.
Data from other regions suggest that the discrepancy in
susceptibility rates for ceftriaxone and cefotaxime may be
more prevalent in the southern US states. In Wisconsin in
2002, for example, of 352 pneumococcal isolates reported
(334 were nonmeningeal), 96.7% were susceptible to cefo-
taxime and 98.8% to ceftriaxone, using the 2003 NCCLS
breakpoints.19
Institutional Data
Several institutions have conducted studies to confirm
anecdotal reports of the susceptibility differences between
ceftriaxone and cefotaxime for S. pneumoniae isolates. In
Tennessee, a hospital analyzed S. pneumoniae isolates by
E-test from 2000 to 2001 and found 58% to be susceptible
to penicillin, 78% to cefotaxime, and 90% to ceftriaxone.
Among PRSP isolates alone, nonsusceptibility to ceftriax-
one was 58% and to cefotaxime, 92% (data provided by
Dr. Camblin).
A community medical center in central Florida conduct-
ed an E-test of S. pneumoniae isolates from July 2001 to
June 2002 using the new NCCLS breakpoints. Of the iso-
lates, 40% were PRSP. Nonsusceptibility to ceftriaxone
was 8% and, to cefotaxime, 25%. Similarly, an academic
medical center in northeastern Florida conducted an E-test
of S. pneumoniae isolates using the new NCCLS break-
points and found 4% to be nonsusceptible to ceftriaxone
versus 26% to cefotaxime (personal communication, Noel
Gomez, Supervisor, Clinical Microbiology Laboratory,
SHANDS Jacksonville, Jacksonville, FL, November 1,
2006). An academic medical center in Alabama tested 118
isolates from 2001 using E-test and found a greater per-
centage of isolates to be susceptible to ceftriaxone (94.9%)
than to cefotaxime (84.7%) (personal communication, Ken
Waites MD, Professor, Departments of Pathology, Micro-
biology, Physical Medicine and Rehabilitation, Diagnostic
and Critical Care, University of Alabama, Birmingham,
School of Medicine, Birmingham, AL, November 1,
2006).
A study of S. pneumoniae resistance trends
conducted among a consortium of hospitals in
north Florida from 1995 to 2001 found that
susceptibility to penicillin decreased from 70% Table 3. Nonsusceptible Streptococcus pneumoniae Isolates in the
to 49% and susceptibility to cefotaxime de-
creased from 83% to 75%, while susceptibility
to ceftriaxone increased from 81% to 93% Antibiotic 1996 1997 1998 1999 2000
(pre-2002 NCCLS breakpoints).20 A separate Penicillin
analysis found that the most dramatic differ- Cefotaxime
Ceftriaxone
ence between cefotaxime and ceftriaxone oc-
curred in the pediatric population (data provid- CSF = cerebral spinal fluid.
a
ed by Dr. Halstead) (Table 3). This finding New National Csommittee on Clinical Laboratory Standards 2002 Streptococcus
pneumoniae CSF/non-CSF breakpoints.
supports pharmacokinetic and pharmacody-
namic data which show that cefotaxime use may result in
cefotaxime resistance, especially with twice daily dosing,
because cefotaxime is used more in the pediatric popula-
tion due to ceftriaxone being contraindicated in infants due
not only to the potential risk for hepatobiliary sludging, but
also from bilirubin displacement associated with the high
protein binding of ceftriaxone.
In Oklahoma, a city hospital with a reported 67% preva-
lence of penicillin-nonsusceptible S. pneumoniae isolates
tested 48 isolates during a 5-month period in 1997 and
1998 for antibiotic susceptibility and repeat-tested the
same isolates at 2 other hospital laboratories (Hospitals A
and B).21 Of the 48 isolates, Hospital A found 31 (65%) to
be penicillin-nonsusceptible S. pneumoniae and 23 (48%) to
be highly penicillin resistant; Hospital B showed a similar
(62%) prevalence, although fewer (29%) isolates were highly
resistant. Both hospitals used the E-test to evaluate suscepti-
bility to third-generation cephalosporins, with Hospital A us-
ing cefotaxime as the test antibiotic and Hospital B, ceftriax-
one. Hospital A reported 13 (27%) isolates to be resistant to
cefotaxime, compared with 4 (8%) isolates resistant to ceftri-
axone at Hospital B. The authors concluded that if con-
firmed, this finding would have relevance in clinical settings
where one antibiotic is used to test for susceptibility and the
other for treatment, given that S. pneumoniae may not have
equal susceptibility to both agents.
Surveillance Databases
Reports from several surveillance databases such as the
ARM Program, SENTRY Europe, and TSN Database—
USA have documented and/or observed a trend in the di-
vergence in susceptibility to S. pneumoniae isolates be-
tween ceftriaxone and cefotaxime.
Established in 1997, the ARM program includes a na-
tional surveillance database that currently includes more
than 30 million isolates of 19 organisms and 48 antibiotics.
In the program’s initial report in 2001, PRSP was 37.5%
among all isolates in the database.7 Nationally, differences
were noted between susceptibility of S. pneumoniae to cef-
otaxime (69.2%a) and ceftriaxone (80.4%a). For both
North Florida Pediatric Population, 1996–2003
Nonsusceptible, %
2001 2002 2003
49 58 66 63 75 68 63 64
45 36 46 37 47 61 52/25a 30/16a
20 14 33 25 32 42 36/9a 17/13a

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JG Gums et al.
drugs, susceptibility rates were higher in the Northeast
(89.6%a for cefotaxime and 90.5%a for ceftriaxone) and
lower in the Southeast (61.8%a for cefotaxime and 77.8%a
for ceftriaxone).
In 2002, a follow-up report detected a consistent differ-
ence nationally for each year analyzed from 1995 to 2001,
with resistance rates higher for cefotaxime than for ceftri-
axone.8 This discrepancy was attributed primarily to iso-
lates collected in the Southeast, which showed an overall
susceptibility of 65%a to cefotaxime and 77.7%a to ceftri-
axone. The aggregate sensitivity numbers for both cefo-
taxime and ceftriaxone were calculated using NCCLS
breakpoints in place prior to January 2002.
For 1995–2002, a national susceptibility to ceftriaxone
and cefotaxime was found to be similar to that previously
reported for S. pneumoniae (ie, 83.2% for ceftriaxone,
74.5% for cefotaxime), with the greatest difference ob-
served in the Southeast (81.4% for ceftriaxone, 69.6% for
cefotaxime).22
SENTRY data from 1997 to 2000 in Europe reported
PRSP rates ranging from 24.5% to 41.3%; cefotaxime re-
sistance was 0.9–7.5% at MIC 90% at 1 µg/mL from 1997
to 1999, while ceftriaxone resistance was 4.8% for 2000.23
MIC and PFGE Studies
Six pneumococcal strains with mosaic penicillin-bind-
ing proteins (PBPs) have been identified in S. pneumoniae.
Five are high-molecular-mass PBPs (80–90 kDa; PBP 1A,
1B, 2A, 2B, and 2X) and one is a low-molecular-mass
PBP (45 kDa; PBP 3). The primary targets of penicillin are
the PBPs 2X and 2B, with high-level resistance to peni-
cillin occurring via alterations of the PBPs 2X, 2B, and
1A, among other mechanisms.3,24,25 Changes within PBP
1A and 2X cause resistance in pneumococci to extended-
spectrum cephalosporins.
An MIC study of 1000 isolates was conducted to con-
firm the existence of a divergence between S. pneumoniae
isolate susceptibility to ceftriaxone and cefotaxime and to
rule out differences that might occur due to different test-
ing methods.10 Isolates collected from 18 states in the
South (Alabama, Florida, Georgia, Louisiana, Oklahoma,
Tennessee), Northeast (Massachusetts, New York, New
Jersey, Pennsylvania), West (Arizona, California, Wash-
ington, Utah), and Central (Iowa, Illinois, Minnesota, Wis-
consin) US regions from October 2001 to May 2002 were
tested against ceftriaxone and cefotaxime.
S. pneumoniae isolates were tested side-by-side using
broth microdilution and E-test methods, and MICs were
interpreted using NCCLS 2003 guidelines.10 By broth mi-
crodilution method, 92.6% of the PRSP isolates were sus-
ceptible to ceftriaxone, compared with 81.9% for cefo-
taxime; using the E-test method, 91.0% were susceptible
to ceftriaxone and 77.7% to cefotaxime. When examined
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by region using both methods, PRSP isolates were more
susceptible to ceftriaxone than to cefotaxime by the widest
margin in the South. For broth microdilution, 92% of the
PRSP isolates were susceptible to ceftriaxone versus 79%
for cefotaxime; by E-test method, these results were 91%
for ceftriaxone and 75% for cefotaxime. The smallest mar-
gin occurred in the West: by broth microdilution, 87% of
PRSP isolates were susceptible to both antimicrobial
agents; by E-test method, susceptibility was 84% for ceftri-
axone and 82% for cefotaxime.
Of the 1000 S. pneumoniae isolates tested, 666 were
found to be penicillin susceptible, 146 penicillin intermedi-
ate, and 188 PRSP.10 Of the 188 PRSP isolates, 26 (13.8%)
displayed phenotype discrepancies by MIC interpretation.
By broth microdilution, 18 were ceftriaxone susceptible
and cefotaxime intermediate, 6 were ceftriaxone interme-
diate and cefotaxime resistant, and 2 were ceftriaxone sus-
ceptible and cefotaxime resistant. The majority (65%)
were from the southern US states (Alabama, Florida, Ten-
nessee, Louisiana, Oklahoma, Georgia).
Among the 26 isolates with different MIC interpretative
phenotypes, 5 serogroups and serotypes (6, 9, 14, 19, 23)
were found that are commonly associated with penicillin-
resistant isolates.3 A SmaI PFGE to serotype, the non-
meningeal S. pneumoniae isolates identified in the MIC
study found 8 isolates not related to any of the others. The
differences between the 2 agents in these studies were due
solely to their activities against penicillin-resistant isolates,
with both broth microdilution and E-test methods confirm-
ing a greater than 10% higher susceptibility to ceftriaxone
than to cefotaxime in PRSP isolates. Discrepant isolates
were more often associated with a clonal PFGE type or
subtype and serotype when compared with the control iso-
lates.
Three recent studies in children have identified increas-
ing resistance among penicillin-resistant pneumococcal
isolates linked to specific serotypes. In Taiwan in 2005, ap-
proximately 90% of ceftriaxone-nonsusceptible isolates
were found to be serotypes 6B, 14, 19F, and 23F.26 The au-
thors noted that while some reports have indicated that
PBP 2B is not a target for extended-spectrum cephalo-
sporins and therefore does not necessarily correlate with
penicillin resistance, they found that altered PBP 2B was
involved in the development of ceftriaxone nonsusceptibil-
ity in pneumococci, with 7 amino acid alterations in the
transpeptidase-encoding region of PBP 2B specifically
contributing to the resistance. Serotypes 6B, 14, 19F, and
23F are covered by the pneumococcal conjugate vaccine
(not yet in use in Taiwan); nonetheless, Messina et al.27
found invasive pneumococcal disease (IPD) caused by
nonvaccine serotypes to be prevalent among children in
Texas, with several highly penicillin-resistant and interme-
diately cefotaxime-resistant strains emerging in 2004 and
2005. Serotype 19A was found to have caused 40% of IPD
www.theannals.com

cases in 2005. Mason et al.,28 in investigating the cause of
recurrent systemic pneumococcal disease, found that 7 of
16 children with less than 30 days between infections had
acquired a new strain, suggesting that pneumococcal iso-
lates be documented to determine whether they have the
same serotype as well as the same PFGE patterns.
Ongoing Phenotyping/Mutagenesis Studies
Two ongoing studies are examining S. pneumoniae iso-
lates at the molecular level to determine the basis of resis-
tance to the β-lactam antibiotics and to confirm the mutation
responsible for the discrepancies noted between ceftriaxone
and cefotaxime. The first, in which the southern US is better
represented, includes 26 pneumococcal isolates from the
original 1000 in the MIC/PFGE studies. They are primarily
outpatient isolates.29 Initial results found that isolates with dif-
ferential ceftriaxone/cefotaxime susceptibility phenotypes are
highly clonal; given that they are related to penicillin-resistant
international clones, they have the potential to become
widespread. In addition, within clonal clusters, PBP 1A, 2B,
and 2X RFLP data showed defined patterns. Strains with di-
vergent ceftriaxone and cefotaxime MICs demonstrated
high-level resistance to both penicillin and amoxicillin.
The second study, being conducted by the Centers for
Disease Control and Prevention (CDC) Active Bacterial
Core surveillance program, includes 82 primarily inpatient
PRSP isolates upon which MIC, PFGE, and mutagenesis
studies are being performed. Results will help determine
whether there is a molecular basis for the difference in cef-
otaxime and ceftriaxone susceptibilities.
Discussion
Our investigation of resistance trends for ceftriaxone
and cefotaxime has shown that over time, and specifically
in the southern US, pneumococcal isolates have grown in-
creasingly resistant to penicillin, leading to nonsusceptibil-
ity rates among PRSP isolates for cefotaxime that are more
than twice those for ceftriaxone. A similar divergence is ob-
served in the Northeast and Central regions of the country, al-
beit occurring more slowly, but not yet in the West. These ap-
parent geographical differences in susceptibility are consis-
tent with the clonal phenomenon described by the MIC and
PFGE studies. Clinically, the subtherapeutic concentrations
that followed every-12-hours dosing with cefotaxime may
have stimulated mutational change within the organism.
Also, differences in susceptibility patterns with an assumed
equivalent breakpoint may have resulted in patients being ex-
posed to a less than maximally effective agent (ie, cefo-
taxime). For example, in some cases, a clinician may have
assumed clinical efficacy based on laboratory reports using
ceftriaxone; however, the hospital pharmacy may have sub-
stituted cefotaxime for ceftriaxone.
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Differences Between Ceftriaxone and Cefotaxime: Microbiological Inconsistencies
The study by Karlowsky et al.10 confirms significant dif-
ferences in rates of susceptibilities between ceftriaxone
and cefotaxime, with certain PRSP isolates less susceptible
to cefotaxime than to ceftriaxone. The incidence of PRSP
isolates appears to dictate prevalence, with the South being
the regional epicenter. These differences are not dependent
upon the test method used and are clonal in nature. With
PRSP increasing within certain communities and hospital
settings, it will become increasingly important to select the
antimicrobial agent most likely to cover the source of the
infection and less likely to select for the discrepant pheno-
types. Cefotaxime is anticipated to select further via new
clones or by increasing the expansion of existing clones.
As noted in the Infectious Diseases Society of America
December 2003 practice guidelines for community-ac-
quired pneumonia, S. pneumoniae resistance concerns in
North America continue to increase in various antibiotic
classes.30 The PROTEKT study described in the guidelines
reports pockets of nonsusceptibility to levofloxacin to S.
pneumoniae ranging from 5.6% to 21.8%.31 Therefore, the
need for local and regional tracking of S. pneumoniae is
paramount, as is testing pathogen susceptibilities using the
antibiotic subsequently prescribed to ensure optimal out-
comes in patients with pneumococcal infections. The CDC
has recommended that institutions provide treatment based
on local surveillance data, with antimicrobial susceptibility
testing influencing a clinician’s choice of antibiotics.32 De-
termining exactly what isolates are being tested and which
breakpoints are being applied is essential: if susceptibility
breakpoints promote the use of narrower-spectrum antibi-
otics to treat pneumococcal disease, resistance to broader-
spectrum antibiotics may be slowed.
The S. pneumoniae susceptibility profile may also affect
healthcare resource utilization. In a 3-year study of 231
hospitalized patients on the pharmacoeconomic considera-
tions in PRSP, Klepser et al.33 found that 142 patients who
had susceptible S. pneumoniae isolates had a 10-day
length of stay compared with 14 days for 89 patients with
nonsusceptible isolates. Overall costs were $1600 higher
for the patients with the nonsusceptible isolates, 1 in 4 of
whom was admitted to the intensive care unit. Similarly, a
study on pneumococcal resistance at an urban hospital
found that the average length of stay was 10.5 days for pa-
tients with PRSP versus 5.7 days for those with susceptible
S. pneumoniae isolates.34
Summary
The increase in rates of PRSP and the differences noted
in S. pneumoniae isolate susceptibility between ceftriaxone
and cefotaxime emphasize the necessity for institutions to
detect these changes as they occur and to ensure that their
sensitivity reporting systems allow the most appropriate
antimicrobial therapy to be selected for patients with S.
The Annals of Pharmacotherapy n 2008 January, Volume 42 n 77
JG Gums et al.
pneumoniae. Results of ongoing studies will outline the
patterns of resistance among pneumococcal isolates and
further delineate causality and/or mechanistic differences
between these 2 agents. In the meantime, we encourage all
institutions to urge the CLSI to adopt rigorous breakpoints
for cefotaxime and ceftriaxone that are based on suscepti-
bility data derived after 1995. Correlation of breakpoints to
clinical outcomes is ideal. In the absence of such data, the
CLSI is encouraged to consider that cefotaxime and ceftri-
axone are not interchangeable and to request institutions
and laboratories to evaluate each of these choices indepen-
dently based on local resistance patterns.
John G Gums PharmD, Professor, Pharmacy and Medicine, Direc-
tor of Clinical Research in Family Medicine, Departments of Pharma-
cy Practice and Family Medicine, University of Florida, Gainesville, FL
D Wesston Boatwright PharmD, Senior Medical Liaison, Medi-
cal Affairs, Roche Laboratories, Inc., Jacksonville, FL
Mark Camblin PhD, Technical Director, Microbiology/Immuno-
Serology, St. Mary’s Health System, Knoxville, TN
Diane C Halstead PhD D(ABMM) F(AAM), Director, Infectious Dis-
ease Laboratories, Jacksonville Pathology Associates, P.A./Baptist
Health, Jacksonville, FL
Mark E Jones PhD, Scientific Director, Eurofins Medinet Inc., Hern-
don, VA
Roger Sanderson MA BSN, Epidemiologist, Florida Department
of Health, Tampa, FL
Reprints: Dr. Gums, Departments of Pharmacy Practice and Fam-
ily Medicine, University of Florida, 625 SW Fourth Ave., Gainesville,
FL 32601, fax 352/392-7766, jgums@ufl.edu
This research was supported in part with financial suppoert from the
Investigator-Sponsored Study Program of AstraZeneca and by un-
restricted educational grants from Roche and Wyeth.
Dr. Gums participates in speaker programs for Sanofi-Aventis and
Schering-Plough and has received grant support from Roche, Astra-
Zeneca, Wyeth, Novartis, Merck, and Pfizer.
We thank Debra Hughes for research and editing assistance.
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Diferencias entre Ceftriaxona y Cefotaxima: Inconsistencias
Microbiológicas
JG Gums, DW Boatwright, M Camblin, DC Halstead, ME Jones, y R
Sanderson
Ann Pharmacother 2008;42:71-9.
EXTRACTO
OBJETIVO: Revisar los datos para determinar por qué parecen incrementarse
las resistencias a cefotaxima en las muestras de neumococos, que tradi-
cionalmente se ha considerado que presentan la misma susceptibilidad a
ceftriaxona y qué puede implicar clínicamente esta observación.
FUENTES DE DATOS: La recopilación de artículos se efectuó mediante una
búsqueda en MEDLINE (1966– octubre 2007) utilizando los términos
del MeSH: cefotaxime, ceftriaxone, susceptibility, microbial sensitivity
tests, antibiotics, pneumococcal infections, Streptococcus pneumoniae,
resistance, y cephalosporin resistance. Se revisaron resúmenes y bases
de datos de vigilancia y se obtuvieron datos no publicados de los
departamentos de salud estatales e instituciones.
SELECCIÓN DE ESTUDIOS Y EXTRACIÓN DE DATOS: Se evaluaron todos los
artículos publicados en inglés que se localizaron en las fuentes
utilizadas.
SÍNTESIS DE DATOS: Un modelo experimental de infección neumocócica
en ratones predijo hace dos décadas que la delta T MIC variaba menos
para ceftriaxona que para cefotaxima. Los estudios de concentraciones
plasmáticas y séricas muestran que ceftriaxona permanece a
concentraciones por encima de la MIC para S. pneumoniae en el 100%
del intervalo de dosificación a las 12 horas. Se encontró que los tipos de
test de susceptibilidad de muestras respiratorias de S. pneumoniae
utilizados para ceftriaxona y cefotaxima fueron similares. Los datos de
los departamentos de salud de los estados y condados mostraron diferencias
microbiológicas entre ceftriaxona y cefotaxima. En áreas con altas tasas
de S. pneumoniae resistente a penicilina (PRSP), las muestras fueron
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Downloaded from aop.sagepub.com at UQ Library on June 2, 2014
dos veces más susceptibles a ceftriaxona que a cefotaxima. Las bases de
datos de vigilancia muestran diferencias entre la susceptibilidad de S.
pneumoniae a cefotaxima y a ceftriaxona consistentemente a lo largo del
tiempo. La MIC y los estudios de electroforesis en gel en campo pulsado
(PFGE) sugieren que la resistencia a penicilina pueden deberse a
diferencias fenotípicas. Se están realizando estudios examinando muestras
de S. pneumoniae a nivel molecular para determinar la base de las
diferencias en las resistencias a cefotaxima y a ceftriaxona.
CONCLUSIONES: El aumento de las tasas de PRSP y las diferencias en la
susceptibilidad de las muestras de S. pneumoniae a ceftriaxona y a
cefotaxima enfatizan la necesidad de detectar estos cambios en los
laboratorios hospitalarios a medida que ocurren. Los clínicos deben
seleccionar el agente más apropiado para los pacientes con S.
pneumoniae.
Traducido por Juan del Arco
Différences entre la Ceftriaxone et le Céfotaxime : Incohérence des
Données Microbiologiques
JG Gums, DW Boatwright, M Camblin, DC Halstead, ME Jones, et R
Sanderson
Ann Pharmacother 2008;42:71-9.
RÉSUMÉ
OBJECTIF: Revoir les données pour déterminer les raisons pour lesquelles
les isolats semblent devenir de plus en plus résistants à la Céfotaxime,
molécule anciennement connue comme ayant la même sensibilité in
vitro que la Ceftriaxone, et l’implication clinique que pourrait avoir cette
observation.
SOURCES DE DONNÉES: Les références ont été recueillies à l’aide d’une
recherche MEDLINE (1966– octobre 2007) utilisant les mots clés
Céfotaxime, Ceftriaxone, sensibilité, analyses de sensibilité
microbienne, antibiotiques, infections à pneumocoques, Streptococcus
pneumoniae, résistance, et résistance aux céphalosporines. Les résumés
d’articles et les bases de données de surveillance ont été révisés et des
données non publiées ont été fournies par le Département de Santé de
l’État et les institutions.
SÉLECTION DES ÉTUDES ET EXTRACTION DES DONNÉES: Tous les articles de
langue anglaise identifiés à partir des sources de données ont été
évalués.
SYNTHESE DES DONNÉES: Un modèle expérimental d’infection à
pneumocoques chez des souris effectué il y a 2 décennies, avait prédit
que la CMI delta T variait moins pour la Ceftriaxone que pour la
Céfotaxime. Des études sur les concentrations sériques et plasmatiques
ont démontrées que la Ceftriaxone demeurait à une concentration au-
dessus de la CMI pour le S. pneumoniae durant toute la durée de
l’intervalle de 12 heures. Les types de méthodes pour tester la sensibilité
des CMI pour la Ceftriaxone et la Céfotaxime utilisées contre les isolats
respiratoires de S. pneumoniae ont été démontrées similaires. Les données
provenant de l’État et des départements de santé des comtés ont montré
des différences entre la Ceftriaxone et la Céfotaxime. Dans les endroits
où on enregistre de hauts taux de résistance du S. pneumoniae à la
pénicilline, les isolats étaient deux fois plus sensibles à la Ceftriaxone
qu’à la Céfotaxime. Les bases de données de surveillance ont montré de
façon constante les différences entre la sensibilité du S. pneumoniae à la
Céfotaxime par rapport à la Ceftriaxone à travers le temps. Des études
de la CMI et à l’aide de l’électrophorèse en champs pulsé (PFGE)
suggèrent que des différences de phénotypes pourraient être en cause
pour la résistance à la pénicilline. Des études en cours examinent les
isolats de S. pneumoniae au niveau moléculaire pour déterminer la base
des résistances à la Céfotaxime et à la Ceftriaxone.
CONCLUSIONS: Une augmentation du taux de S. pneumoniae résistant à la
pénicilline et les différences de sensibilité dans les isolats de S. pneumoniae
entre la Ceftriaxone et la Céfotaxime mettent l’emphase sur la nécessité
pour les laboratoires hospitaliers de détecter ces changements lorsqu’ils
surviennent. Les cliniciens devraient sélectionner l’agent le plus
approprié pour les patients avec du S. pneumoniae.
Traduit par Chantal Guévremont
n 2008 January, Volume 42 n 79