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Antimicrobial Agents and Chemotherapy, May 2001, p. 1601-1602, Vol. 45, No. 5
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.5.1601-1602.2001
LETTERS TO THE EDITOR
Is OmpK35 Specific for Ceftazadime Penetration?
 |
LETTER |
In a recent article, Rasheed et al. postulated that OmpK35 in
Klebsiella pneumoniae is specific for ceftazadime
penetration (2). The conclusion is based on kinetic data
from their study and an observation from a previous study by
Martínez-Martínez et al. (1).
According to the kinetic data reported by Rasheed et al., the relative
hydrolytic efficiency of cefotaxime was approximately 15 times greater
than that of ceftazidime; cefotaxime resistance was therefore thought
to be higher than that of ceftazidime due to the higher affinity.
Unpredictably, the MICs of ceftazidime and cefotaxime for K. pneumoniae K6 were 32 and 8 µg/ml, respectively. Subsequently, the authors found ompK35 was not expressed in
K. pneumoniae K6. Rasheed et al. thought that porin
loss may help explain why the MIC of ceftazidime is higher that
of cefotaxime. The study by Martínez-Martínez et al.
was cited in support of this conclusion. My principal objection
to this explanation is that Martínez-Martínez et al.
never discussed the contribution of ceftazidime resistance due to
OmpK35 loss (1). In that study, an OmpK36 gene
carrier was cloned back into an OmpK35- and ompK36-deficient strain,
and a reduction in the MIC of cefotaxime was observed. Although
the MIC of ceftazdime had not changed, SHV-5 production in the
deficient strain cannot be excluded. In addition, the MIC of cefotaxime
remained at 4 µg/ml for the cloned strain, suggesting that
SHV-5 plays an important role in resistance. Rasheed et al. state
that SHV-5 is thought to have little effect on the hydrolysis of
cefotaxime but is necessary for resistance to ceftazidime. Therefore, conclusions about OmpK35 are premature, since production of
the extended-spectrum 
-lactamase cannot be excluded. Secondly, for a transconjugant (HB101 TC-K6/1) of an SHV-18 carrier, the MICs of
cefotaxime and ceftazidime were 1 and 8 µg/ml, respectively (2). A 16-fold reduction in the MIC of cefotaxime for
TC-K6/1 was observed compared to the original K6. On the other hand, a fourfold reduction in the MIC of ceftazidime was detected. If OmpK35 is
specific for ceftazidime, the MIC of ceftazidime should be
significantly reduced and the MIC of cefotaxime should not be affected
much. Further experimental work should be conducted.
| |
FOOTNOTES |
*
Fax: 886-2-2789-0254 E-mail: lksiu{at}mail.nhri.org.tw
| |
REFERENCES |
| 1.
|
Martínez-Martínez, L.,
S. Hernández-Allés,
S. Albertí,
J. M. Tomás,
V. J. Benedi, and G. A. Jacoby.
1996.
In vivo selection of porin-deficient mutants of Klebsiella pneumoniae with increased resistance to cefoxitin and expanded-spectrum cephalosporins.
Antimicrob. Agents Chemother.
40:342-348[Abstract].
|
| 2.
|
Rasheed, J. K.,
G. J. Anderson,
H. Yigit,
A. M. Queenan,
A. Doménech-Sánchez,
J. M. Swenson,
J. W. Biddle,
M. J. Ferraro,
G. A. Jacoby, and F. C. Tenover.
2000.
Characterization of the extended-spectrum -lactamase reference strain, Klebsiella pneumoniae K6 (ATCC 700603), which produces the novel enzyme SHV-18.
Antimicrob. Agents Chemother.
44:2382-2388[Abstract/Free Full Text].
|
| | | | |
L. K. Siu
Division of Clinical Research
National Health Research Institute
128 Yen Chiu Yuan Road
Taipei 11529, Taiwan
Phone: 886-2-2652-4094
|
Enzyme kinetics, in particular the ratio of
Vmax to Km, predict that
cefotaxime should be a better substrate than ceftazidime for most TEM-
and SHV-type extended-spectrum -lactamases (ESBLs) (3), including SHV-18, studied by Rasheed et al. Despite
these in vitro findings, MICs are typically higher for ceftazidime than for cefotaxime. This paradox can be explained by the slower rate of
diffusion of ceftazidime compared to cefotaxime, measured by Yoshimura
and Nikaido through porins OmpF and OmpC of Escherichia coli
(4). To our knowledge, analogous measurements have not been performed with porins OmpK35 and OmpK36 of K. pneumoniae, but similar results are expected because of their high
homology to OmpF and OmpC, respectively.
Using a set of isogenic strains deficient in -lactamase and with
variable levels of porin expression, it has been shown that the MICs of
ceftazidime and cefotaxime against mutants deficient in either OmpK35
or OmpK36 are the same as those for a wild-type strain expressing both
porins but are four (ceftazidime) or eight (cefotaxime) times lower
than those for a mutant deficient in both porins (1).
These findings suggest that either porin allows the diffusion of both
cephalosporins. In this group of strains, MICs of ceftazidime were
higher than those of cefotaxime, suggesting a higher diffusion rate for
cefotaxime, although other mechanisms (for example, active efflux)
could also be involved.
Most of the information on the role of K. pneumoniae porins
in antimicrobial resistance has been gained with OmpK36. The data from
our report cited by Rasheed et al. as suggesting that OmpK35 is
specific for ceftazidime are inconclusive on this point. We reported
that restoration of OmpK36 expression in a porin-deficient strain of
K. pneumoniae producing SHV-5 changed the MIC of cefotaxime from 64 to 2 µg/ml while the MIC of ceftazidime remained >256 µg/ml. The value >256 µg/ml, however, could hide a considerable change in MIC. In another strain deficient in OmpK35 and OmpK36, K. pneumoniae C1 producing TEM-6, expression of OmpK36
caused the ceftazidime MIC to drop from >256 to 32 µg/ml
(2). Thus, OmpK36 allows diffusion of ceftazidime into
K. pneumoniae, indicating that OmpK35 is not a specific
ceftazidime channel. The ompK35 gene was recently cloned and
sequenced. Preliminary data from strain CSUB10R (ESBL producer,
deficient in both OmpK35 and OmpK36) indicated that expression of
either OmpK35 or OmpK36 significantly decreased MICs of ceftazidime,
cefotaxime, and other -lactams and that, in absolute terms, the MICs
of cephalosporins for a transconjugant expressing OmpK35 were lower
than those for a transconjugant expressing OmpK36 (A. Doménech-Sánchez, S. Hernández-Allés, M. C. Conejo, L. Martínez-Martínez, and V. J. Benedí, Abstr. 39th Intersci. Conf. Antimicrob. Agents
Chemother., abstr. 808, 1999).
It should not be stated that OmpK35 is either specific or
exclusive for ceftazidime, but, like the OmpF homologue in
E. coli, it provides slower entry for ceftazidime
than for cefotaxime and, for this reason, greater
augmentation of -lactamase-mediated resistance. We agree with
L. K. Siu that further work is necessary to complete our
understanding of the role of OmpK35 and other porins in antimicrobial
resistance of K. pneumoniae.
| |
AUTHORS' REPLY |
Our suggestion that the loss of OmpK35 by K. pneumoniae K6
may have specifically contributed to the elevated MIC of ceftazidime was intended to be speculative. This, indeed, remains to be proven. We
do, however, appreciate Dr. Siu's alternative explanation, which
may warrant further study.
| |
FOOTNOTES |
*
Phone:
(781) 744-8608 Fax: (781) 744-1264 E-mail:
george.a.jacoby{at}lahey.org
| |
REFERENCES |
| 1.
|
Hernández-Allés, S.,
M. Conejo,
A. Pascual,
J. M. Tomás,
V. J. Benedí, and L. Martínez-Martínez.
2000.
Relationship between outer membrane alterations and susceptibility to antimicrobial agents in isogenic strains of Klebsiella pneumoniae.
J. Antimicrob. Chemother.
46:273-277[Abstract/Free Full Text].
|
| 2.
|
Martínez-Martínez, L.,
A. Pascual,
S. Hernández-Allés,
D. Alvarez-Díaz,
A. I. Suárez,
J. Tran,
V. J. Benedí, and G. A. Jacoby.
1999.
Roles of -lactamases and porins in activities of carbapenems and cephalosporins against Klebsiella pneumoniae.
Antimicrob. Agents Chemother.
43:1669-1673[Abstract/Free Full Text].
|
| 3.
|
Sirot, D.,
C. Chanal,
R. Labia,
M. Meyran,
J. Sirot, and R. Cluzel.
1989.
Comparative study of five plasmid-mediated ceftazidimases isolated in Klebsiella pneumoniae.
J. Antimicrob. Chemother.
24:509-521[Abstract/Free Full Text].
|
| 4.
|
Yoshimura, F., and H. Nikaido.
1985.
Diffusion of -lactam antibiotics through the porin channels of Escherichia coli K-12.
Antimicrob. Agents Chemother.
27:84-92[Abstract/Free Full Text].
|
| | | | |
J. Kamile Rasheed
Centers for Disease Control and Prevention
Atlanta, Georgia
|
| | | | |
Luis Martínez-Martínez
Department of
Microbiology
School of Medicine
University of Seville
Seville,
Spain
|
| | | | |
George A. Jacoby*
Lahey
Clinic
Burlington, Massachusetts 01805
|
Antimicrobial Agents and Chemotherapy, May 2001, p. 1601-1602, Vol. 45, No. 5
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.5.1601-1602.2001
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Domenech-Sanchez, A., Martinez-Martinez, L., Hernandez-Alles, S., del Carmen Conejo, M., Pascual, A., Tomas, J. M., Alberti, S., Benedi, V. J.
(2003). Role of Klebsiella pneumoniae OmpK35 Porin in Antimicrobial Resistance. Antimicrob. Agents Chemother.
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