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Antimicrobial Agents and Chemotherapy, July 1998, p. 1869-1870, Vol. 42, No. 7
0066-4804/98/$00.00+0
LETTERS TO THE EDITOR
Bactericidal Activities of Ceftizoxime and Cefotaxime
against Streptococcus pneumoniae
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LETTER |
Patel et al. (4) compared the serum bactericidal titers
(SBTs) and the time serum drug concentrations remained above the MICs
(T > MIC) of ceftizoxime and cefotaxime against three
intermediately penicillin-resistant Streptococcus pneumoniae
isolates. MICs were 
1.0 µg/ml, SBTs were > 1:2, and
T > MIC exceeded 50% of dosage intervals. They
concluded that ceftizoxime's longer T > MIC
compensates for its lower microbiologic activity, that both agents
should produce comparable clinical outcomes in the treatment of
infections caused by intermediately penicillin-resistant S. pneumoniae, and that the two agents can be viewed as being
therapeutically similar. While we do not dispute the accuracy of the
data, some conclusions are not justified based on the information
presented. Furthermore, Patel et al. (4) do not address
other clinical and laboratory implications regarding the choice of a
cephalosporin for hospital formularies.
Even though T > MIC is important for predicting
bactericidal activities and clinical success of cephalosporins,
achievable concentrations in serum are also quite relevant when MICs
approach or exceed such concentrations. Maximum concentrations of
cefotaxime and ceftizoxime after a 1-g dose were 53.9 ± 11.2 and
56 ± 9.1 µg/ml, respectively, in Patel et al.'s study
(4). In our study of 66 penicillin-resistant or
intermediately resistant S. pneumoniae isolates
(6), the ceftizoxime MICs were 
64 µg/ml for 5 isolates. Haas et al. (1) reported ceftizoxime MICs of 256 µg/ml for some intermediately penicillin-resistant S. pneumoniae isolates versus a maximum cefotaxime MIC of 4 µg/ml.
These findings, and those of others (2), indicate that the
microbiologic activity of ceftizoxime can be 32-fold less than that of
cefotaxime. It is unrealistic to expect uniformly favorable outcomes
for infections treated with a drug when MICs exceed peak concentration
(T > MIC = 0).
Stratton et al. (5) concluded that an infection with an
S. pneumoniae isolate for which the cefotaxime or
ceftizoxime MIC was 0.5 to 1.0 µg/ml should respond to treatment with
either agent. However, like Patel et al. (4), they provided
data for organisms with minimal resistance and made no claims regarding
organisms which required higher MICs. To our knowledge, no clinical
trials using ceftizoxime against microbiologically documented invasive S. pneumoniae infections have been performed since the
widespread dissemination of beta-lactam resistance of the past few
years.
Among 121 S. pneumoniae isolates tested at the University of
Alabama Hospital in 1997, 71 (55%) were susceptible, 36 (30%) were
intermediately resistant, and 22 (17%) were resistant to penicillin.
These numbers reflect an ever-increasing shift towards higher MICs of
penicillin and other beta-lactams which is being experienced elsewhere.
It is impossible to predict on a clinical basis which infections will
be due to a resistant organism or what the cephalosporin MICs will be
for intermediately penicillin-resistant or resistant isolates. This
clinical uncertainty coupled with the fact that in many instances there
may be no organisms isolated to test for susceptibility dictate that
empiric treatment cover all possibilities.
Patel et al. (4) stated that S. pneumonia has
intermediate to high-level resistance to cefotaxime, ceftriaxone, and
ceftizoxime as delineated by MIC breakpoints in a National Committee
for Clinical Laboratory Standards (NCCLS) document (3).
Although the NCCLS provides interpretive breakpoints for cefotaxime and
ceftriaxone, none are published for ceftizoxime and this agent is not
recommended for in vitro susceptibility testing against S. pneumoniae. This omission can be problematic for laboratories
asked to provide susceptibility data for ceftizoxime. Although many
laboratories use the Etest (AB Biodisk, Solna, Sweden) to determine the
MICs of penicillin and cefotaxime or ceftriaxone, ceftizoxime is not available in appropriate concentrations for use against S. pneumoniae.
For the reasons stated above, we have not considered ceftizoxime for
formulary inclusion with therapeutic equivalency to cefotaxime or
ceftriaxone.
| |
REFERENCES |
| 1.
|
Haas, D. W.,
C. W. Stratton,
J. P. Griffin,
L. Weeks, and S. C. Alls.
1995.
Diminished activity of ceftizoxime in comparison to cefotaxime and ceftriaxone against Streptococcus pneumoniae.
Clin. Infect. Dis.
20:671-676[Medline].
|
| 2.
|
Liñares, J.,
T. Alonso,
J. L. Perez,
J. Ayats,
M. A. Dominguez,
R. Pallares, and R. Martin.
1992.
Decreased susceptibility of penicillin-resistant pneumococci to twenty-four  -lactam antibiotics.
J. Antimicrob. Chemother.
30:279-288[Abstract/Free Full Text].
|
| 3.
|
National Committee for Clinical Laboratory Standards.
1994.
Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. Approved standard M7-A3.
National Committee for Clinical Laboratory Standards, Villanova, Pa.
|
| 4.
|
Patel, K. B.,
D. P. Nicolau,
C. H. Nightingale, and R. Quintiliani.
1996.
Comparative serum bactericidal activities of ceftizoxime and cefotaxime against intermediately penicillin-resistant Streptococcus pneumoniae.
Antimicrob. Agents Chemother.
40:2805-2808[Abstract].
|
| 5.
|
Stratton, C. W.,
K. E. Aldridge, and M. Gelfand.
1995.
In vitro killing of penicillin-susceptible, -intermediate, and -resistant strains of Streptococcus pneumoniae by cefotaxime, ceftriaxone, and ceftizoxime: a comparison of bactericidal and inhibitor activity with achievable CSF levels.
Diagn. Microbiol. Infect. Dis.
22:43-48[Medline].
|
| 6.
|
Waites, K. B.,
E. Swiatlo, and B. M. Gray.
1996.
Comparative activities of parenteral cephalosporins against penicillin-resistant Streptococcus pneumoniae isolated from pediatric patients.
Curr. Ther. Res.
57:489-496.
|
| | | | |
Ken B. Waites
Department of Pathology
University of Alabama at Birmingham
Birmingham, Ala. 35233
|
| | | | |
Thomas Rivers
Department of Pharmacy
Baptist Medical Center
Birmingham, Ala.
|
| |
AUTHOR'S REPLY |
Unfortunately, the comments by Waites and Rivers represent the common
mistake of predicting clinical responses solely based on a comparison
of the microbiological activity (i.e., MIC) of one antibiotic versus
that of another against a specific bacterium. An accurate prediction
can occur only if one performs a pharmacodynamic analysis comparing the
microbiological activity, pharmacokinetics, and mode of bacterial
killing of one agent versus those of another and then correlates this
information with the results of animal models of sepsis and volunteer
studies and clinical outcome information.
Interestingly, these authors quote the data by Haas et al.
(1) reporting higher MICs of ceftizoxime compared with those of cefotaxime against penicillin-resistant Streptococcus
pneumoniae, suggesting a difference in outcomes from this
microbiological observation alone without any clinical information to
support such a speculation. Moreover, they fail to mention that the
Stratton et al. study they cite comes from the same laboratory as the
Haas et al. study but that the authors of this later publication
predict that the clinical response would be the same whether one uses cefotaxime or ceftizoxime in the treatment of intermediately
penicillin-resistant S. pneumoniae infection (2).
Although it has been known for years that ceftizoxime typically
exhibits higher MICs against penicillin-resistant S. pneumoniae compared with those of the other expanded-spectrum
cephalosporins cefotaxime and ceftriaxone, there are no clinical
outcome data available indicating that there is any difference in
clinical outcomes in the management of S. pneumoniae
infections (penicillin sensitive or resistant, bacteremic or
nonbacteremic) whether one administers any one of these
expanded-spectrum cephalosporins (3). In fact, there is even
no difference if one uses penicillin, ampicillin, amoxacillin, or a
narrow-spectrum cephalosporin like cefazolin (4).
Poor outcomes in the management of penicillin-resistant S. pneumoniae have been reported only in meningeal infections, and most of these outcomes have occurred with the use of ceftriaxone (5). This is not surprising owing to the poor penetration of all beta-lactam antibiotics into cerebrospinal fluid where it is
difficult to obtain adequate time above the MIC, especially for the
highly resistant strains of S. pneumoniae (MICs 2 µg/ml), with these expanded-spectrum cephalosporins. In any case,
until antibiotic susceptibility data are available, the empirical
treatment for pneumococcal meningitis requires the use of vancomycin
with or without any of the expanded-spectrum cephalosporins.
We have used ceftizoxime as our primary expanded-spectrum cephalosporin
at Hartford Hospital, one of the largest tertiary hospitals in New
England, for over 3 consecutive years without any evidence of problems
in the management of both community- and hospital-acquired lung
infections or any other nonmeningeal infections in which streptococci
are the proven or suspected pathogens. Interestingly, compared with
cefotaxime and ceftriaxone, ceftizoxime has significantly greater
anaerobic activity and has even been used as monotherapy for
community-acquired intra-abdominal infection.
Despite the slightly lower microbiological activity of
ceftizoxime against penicillin-resistant S. pneumoniae
and its slightly greater activity against anaerobes compared with
those of cefotaxime and ceftriaxone, it still remains scientifically
sound to view these three cephalosporins as therapeutically similar
antibiotics and subject to competitive bidding.
| |
REFERENCES |
| 1.
|
Hass, D. W.,
C. W. Stratton,
J. P. Griffin,
L. Weeks, and S. C. Alls.
1995.
Diminished activity of ceftizoxime in comparison to cefotaxime and ceftriaxone against Streptococcus pneumoniae.
Clin. Infect. Dis.
20:671-676.
|
| 2.
|
Stratton, C. W.,
K. E. Aldridge, and M. S. Gelfand.
1995.
In-vitro killing of penicillin-susceptible, -intermediate, and -resistant strains of Streptococcus pneumoniae by cefotaxime, ceftriaxone, and ceftizoxime: a comparison of bactericidal and inhibitory activity with achievable CSF levels.
Diagn. Microbiol. Infect. Dis.
22:35-42[Medline].
|
| 3.
| Quintiliani, R., D. P. Nicolau, and C. H. Nightingale. 1996. Clinical relevance of penicillin-resistant
Streptococcus pneumoniae, with particular attention to
therapy with ceftizoxime, cefotaxime, and ceftriaxone. Infect. Dis.
Clin. Pract. 5(Suppl.):S37-S41.
|
| 4.
|
Klugman, K. P.
1994.
Management of antibiotic-resistant pneumococcal infections.
J. Antimicrob. Chemother.
34:191-193[Free Full Text].
|
| 5.
|
Bradley, J. S., and J. D. Connor.
1991.
Ceftriaxone failure in meningitis caused by Streptococcus pneumoniae with reduced susceptibility to beta-lactam antibiotics.
Pediatr. Infect. Dis.
10:871-873.
|
| | | | |
Richard Quintiliani
Hartford Hospital
Hartford, CT 06102
|
Antimicrobial Agents and Chemotherapy, July 1998, p. 1869-1870, Vol. 42, No. 7
0066-4804/98/$00.00+0
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