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Journal of Clinical Microbiology, September 2005, p. 4891-4894, Vol. 43, No. 9
0095-1137/05/$08.00+0     doi:10.1128/JCM.43.9.4891-4894.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

CASE REPORT

Failure of Cefepime Therapy in Treatment of Klebsiella pneumoniae Bacteremia

Wonkeun Song,1 Ellen S. Moland,1 Nancy D. Hanson,1 James S. Lewis,2 James H. Jorgensen,3 and Kenneth S. Thomson1*

Center for Research in Antiinfectives and Biotechnology, Department of Medical Microbiology and Immunology, Creighton University School of Medicine, 2500 California Plaza, Omaha, Nebraska 68178,1 Departments of Pharmacology,2 Pathology, The University of Texas Health Science Center, San Antonio, Texas 782293

Received 19 April 2005/ Returned for modification 12 May 2005/ Accepted 29 June 2005


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ABSTRACT
 
A case of failure of cefepime treatment of a bloodstream infection with AmpC-producing Klebsiella pneumoniae is reported. The failure was attributed to extended-spectrum ß-lactamase (ESBL) acquisition by the isolate, possibly during therapy. Problems encountered with ESBL detection in AmpC-producing isolates are discussed.


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CASE REPORT
 
A pretherapy blood culture isolate of Klebsiella pneumoniae (strain 272) was recovered from a 50-year-old man with end stage liver disease and awaiting transplant. Cefepime therapy was initiated on the basis of in vitro susceptibility results. Sputum culture after 13 days of cefepime therapy yielded an isolate of K. pneumoniae (strain 273) that was less susceptible to cefepime. The patient died shortly afterwards. An isolate of K. pneumoniae (strain 274) with an identical susceptibility pattern was subsequently cultured from a tracheal aspirate obtained from a second patient.

Antibiotic susceptibilities were determined by CLSI (formerly NCCLS) microdilution methodology (11, 13) using TREK frozen microdilution MIC panels (Sensititre; TREK Diagnostics Systems, Westlake, OH) containing doubling dilutions of cefotaxime, cefotaxime plus 4 µg/ml clavulanate, ceftazidime, ceftazidime plus 4 µg/ml clavulanate, cefpodoxime, cefpodoxime plus 4 µg/ml clavulanate, cefepime, cefepime plus 10 µg/ml clavulanate, cefoxitin, aztreonam, and imipenem. Additional testing was done by disk diffusion methodology (12) with the following disks: cefotaxime, cefotaxime-clavulanate, cefpodoxime, cefpodoxime-clavulanate, ceftazidime, ceftazidime-clavulanate, cefotetan, amikacin, gentamicin, kanamycin, ciprofloxacin, chloramphenicol, and trimethoprim-sulfamethoxazole (BD Diagnostic Systems, Sparks, MD). Resistance phenotypes were also investigated by double-disk potentiation (3) and the AmpC disk test (2a).

The MICs of cefpodoxime, ceftazidime, cefoxitin, and imipenem for all three isolates were the same (>128, 128, >16, and 0.06 µg/ml, respectively). MICs of cefepime and aztreonam differed, with the pretreatment isolate (isolate 272) being more susceptible (0.5 and 16 µg/ml, respectively) than the posttreatment isolate (isolate 273) and the isolate from the second patient (isolate 274), both of which had MICs of cefepime and aztreonam of 16 and 64 µg/ml, respectively. Although the disk tests indicated that isolates 272, 273, and 274 were all susceptible to cefepime, the respective zone diameters of 28, 18, and 18 mm indicated that the pretreatment isolate was more susceptible. The disk tests also determined that all isolates were susceptible to amikacin and resistant to cefotetan and ciprofloxacin, with differing test results obtained with gentamicin, kanamycin, chloramphenicol, and trimethoprim-sulfamethoxazole—the pretreatment isolate being susceptible and isolates 273 and 274 being resistant (data not shown).

The CLSI extended-spectrum ß-lactamase (ESBL) confirmatory tests (based on clavulanate potentiation of cefotaxime and ceftazidime) were negative for the three isolates by microdilution methodology (Table 1). Both CLSI disk and double-disk ESBL confirmatory tests were negative for isolate 272 and positive for K. pneumoniae 273. However, isolate 274 was positive only by the double-disk method, with clavulanate potentiating the activities of cefepime, cefotaxime, and aztreonam (Table 2). This isolate was negative by the CLSI method, probably reflecting the different drugs tested (cefotaxime and ceftazidime) and differing levels of sensitivity of the two tests. The latter view was supported by repeating the CLSI test with a higher-than-standard inoculum (1 McFarland unit instead of 0.5) to increase the amount of ESBL involved in the test. This adjustment yielded a positive result (6-mm increase in the cefotaxime zone; data not shown). The AmpC disk test was positive for all three isolates (Table 2).


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  		TABLE 1. Isoelectric points and ß-lactam susceptibilities of K. pneumoniae isolates and E. coli conjugants


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  		TABLE 2. ESBL and AmpC ß-lactamase detection test results

Conjugations were performed by the filter mating method (17) using the recipient Escherichia coli J53 Azir strain (7). The transconjugants were selected on Mueller-Hinton agar plates containing 200 µg/ml of sodium azide and either 16 µg/ml of chloramphenicol or 4 µg/ml of cefepime. The conjugation assays with K. pneumoniae 272 failed. However, in each instance, one of the four plasmids that had been detected in each of strains K. pneumoniae 273 and 274 (data not shown) was transferred to the E. coli J53 Azir strain. Compared to the clinical isolates, both transconjugants were more susceptible to all ß-lactams tested except imipenem (Table 1), which reflected the transfer of the ESBL-encoding plasmid but not the AmpC-encoding plasmid. The absence of the plasmid-mediated AmpC ß-lactamase made it possible to use cefpodoxime- and ceftazidime-based tests to phenotypically confirm the presence of an ESBL in the transconjugants (Table 1). Disk susceptibilities of non-ß-lactams of parents K. pneumoniae 273 and 274 and the E. coli transconjugants of K. pneumoniae 273 and 274 indicated that resistance to chloramphenicol and cotrimoxazole was encoded on the plasmid that was transferred (data not shown).

Previously described isoelectric focusing (IEF) overlay procedures were used to determine the pIs of ß-lactamases, the capabilities of clavulanate and cloxacillin to inhibit the ß-lactamases, and the capabilities of the ß-lactamases to hydrolyze cefotaxime (2, 18). Sonic extracts of the three isolates yielded two ß-lactamase bands with pI values of 7.2 and 7.6. A pI 7.6 band was present in the two transconjugants. The pI 7.2 ß-lactamase hydrolyzed cefotaxime and was inhibited by cloxacillin but not by clavulanate in the IEF overlay procedure, indicating the presence of an AmpC ß-lactamase. The pI 7.6 bands were inhibited by clavulanate but not by cloxacillin, and hydrolysis of cefotaxime was exhibited only by the preparations from posttherapy isolates 273 and 274.

Pulsed-field gel electrophoresis (PFGE) was performed according to the methods of Miranda et al. (9) with the following modifications. K. pneumoniae cells from a blood agar plate were suspended in 1 ml of PIV (1 M Tris, 1 M NaCl, pH 7.6) buffer. Plugs were washed four times with TE (5 mM Tris, 5 mM EDTA) buffer. Fifty units of SpeI (Roche, Indianapolis, IN) in 400 µl of accompanying buffer was used for restriction endonuclease digestion. The pulse time was 5 to 60 seconds for 16 h at 200 V. The three isolates had identical PFGE patterns (data not shown).

For PCR testing, DNA template preparation and PCR amplifications were carried out as described previously (6), using a final volume of 50 µl with 2 µl of template DNA (1/250 volume) and an annealing temperature of 55°C. The ß-lactamase genes were amplified on a Thermal Cycler 9600 instrument (Applied Biosystems, Norwalk, CT). The primers used for PCR amplification and sequencing are listed in Table 3. The amplicons generated using the primers specific for blaSHV were sequenced directly after treatment with ExoSAP-IT (U.S. Biochemical Corp., Cleveland, OH) using automated PCR cycle sequencing with dye terminator chemistry using an ABI Prism 3100-Avant genetic analyzer. Multiplex ampC PCR was used to genetically identify "imported" ampC ß-lactamase genes as previously described (15). PCR amplicons for blaSHV and blaFOX were present from DNA prepared from all three isolates. Sequence analysis of the SHV-specific PCR products resulting from amplification of DNA prepared from the transconjugants revealed that the ß-lactamase gene that was transferred encoded a ß-lactamase with an amino acid sequence that was 100% identical to the amino acid sequence of the SHV-2 ß-lactamase.


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  		TABLE 3. Primers used for amplification, sequencing, and RFLP

Because pI values do not differentiate between SHV-1 and SHV-2, restriction fragment length polymorphism (RFLP) analysis was used to help analyze the presence or absence of blaSHV-1/2 within isolates K. pneumoniae 272, 273, and 274. SHV-specific PCR products were used directly in an NheI restriction endonuclease assay (14). The primers used to generate the PCR amplicon for RFLP analysis are listed in Table 3. Fragments were resolved by gel electrophoresis using 2% agarose and a 1x Tris-acetate-EDTA buffer system. Control strains included SHV-1-producing E. coli Misc 128 and SHV-2-producing E. coli Misc 208. As expected, in the presence of NheI, no cleavage of the SHV-1 control amplicon occurred but cleavage of the SHV-2 control amplicon occurred (data not shown). SHV-specific PCR products amplified from template DNA prepared from K. pneumoniae 273 and 274 showed both full-length and cleaved products, indicating that both strains produced SHV-1 and SHV-2, but their transconjugants showed only cleaved products, indicating that only DNA encoding SHV-2 was transferred. No NheI cleavage of the SHV-specific amplicon generated using template DNA from K. pneumoniae 272 occurred, indicating that this strain produced only SHV-1 (data not shown).

Klebsiella pneumoniae is an important human pathogen with a propensity to acquire newer ß-lactamases such as ESBLs, plasmid-mediated AmpC ß-lactamases (also known as mobile, imported, foreign, or transmissible AmpC ß-lactamases), and class A carbapenemases (1, 4, 8, 10, 16). This report documents issues that arose after therapy with cefepime was commenced to treat K. pneumoniae bacteremia. Given that the resistance of the blood isolate to cefotetan indicated the possibility of a plasmid-mediated AmpC ß-lactamase, therapy with cefepime was considered to be a reasonable therapeutic choice. Unlike other available cephalosporins, the activity of cefepime is not significantly impaired by high-level AmpC production (19). The subsequent therapeutic failure and death of the patient correlated with the detection of a sputum isolate of K. pneumoniae that produced an additional ß-lactamase, the SHV-2 ESBL. The occurrence of SHV-2 in this isolate suggested that either in vivo acquisition of SHV-2 or an amino acid change that converted the SHV-1 enzyme to SHV-2 occurred during therapy, and cefepime was unable to prevent the emergence of the less susceptible strain. It was not possible to determine exactly how or when the ESBL was acquired because the patient did not produce a pretherapy sputum specimen. However, based on PFGE analysis and the ESBL-negative status of the initial isolate it is assumed that the ESBL was acquired during therapy.

A clinically relevant point of concern arose with the isolate cultured from the second patient (assumed to have been acquired from the first patient). The sensitivity of ESBL detection for this isolate was method dependent. It is important not to overlook the fact that coproduction of an AmpC ß-lactamase can interfere with ESBL detection tests (5, 20, 21). This is an important issue if therapy with cephalosporins is being considered because these agents are contraindicated for ESBL-associated infections (13). Vigilance is therefore necessary to recognize isolates in which AmpC production may cause problems with routine ESBL testing and which necessitate the use of more sensitive ESBL tests. In this study the double-disk test with cefepime proved to be a more sensitive ESBL confirmatory test than the CLSI tests based on cefotaxime and ceftazidime. The double-disk test with cefepime was also superior to the corresponding microdilution test because the latter yielded a false-positive ESBL result with the ESBL-negative K. pneumoniae 272. The reason for this was not determined but might be due to the high concentration of clavulanate (10 µg/ml) used in this test.

In conclusion, this report documents the emergence of reduced susceptibility to cefepime due to ESBL acquisition leading to therapeutic failure during therapy with cefepime and reinforces the need for more sensitive ESBL detection tests for accurate testing of isolates that coproduce an ESBL and a plasmid-mediated AmpC ß-lactamase.


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ACKNOWLEDGMENTS
 
We thank Ashfaque Hossain for expert advice and technical support with PCR and DNA sequencing. We also thank Jennifer A. Black and T. J. Lockhart for expert technical support with conjugation experiments, enzyme preparation, and susceptibility testing and Cindy Kelly for performing the PFGE typing donated by Jan Patterson's Epidemiology Laboratory at The University of Texas Health Science Center at San Antonio.


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FOOTNOTES
 
* Corresponding author. Mailing address: Center for Research in Antiinfectives and Biotechnology, Department of Medical Microbiology and Immunology, Creighton University School of Medicine, 2500 California Plaza, Omaha, NE 68178. Phone: (402) 280-2921. Fax: (402) 280-1875. E-mail: kstaac{at}creighton.edu. Back


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Journal of Clinical Microbiology, September 2005, p. 4891-4894, Vol. 43, No. 9
0095-1137/05/$08.00+0     doi:10.1128/JCM.43.9.4891-4894.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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