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Antimicrobial Agents and Chemotherapy, September 2006, p. 3179-3182, Vol. 50, No. 9
0066-4804/06/$08.00+0     doi:10.1128/AAC.00218-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Endocarditis Caused by Extended-Spectrum-ß-Lactamase-Producing Klebsiella pneumoniae: Emergence of Resistance to Ciprofloxacin and Piperacillin-Tazobactam during Treatment despite Initial Susceptibility

Oren Zimhony,1* Inna Chmelnitsky,3 Rita Bardenstein,1 Sorel Goland,2 Orly Hammer Muntz,3 Shiri Navon Venezia,3 and Yehuda Carmeli3

Infectious Diseases Division,1 Cardiology Division, Kaplan Medical Center Rehovot, Hebrew University and Hadassah, Jerusalem,2 Division of Epidemiology, Molecular Epidemiology Laboratory, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel3

Received 20 February 2006/ Returned for modification 20 March 2006/ Accepted 24 June 2006


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ABSTRACT
 
Three episodes of bacteremia occurred in the course of prosthetic valve endocarditis caused by an extended-spectrum-ß-lactamase (ESBL)-producing Klebsiella pneumoniae strain. The second isolate developed resistance to ciprofloxacin and the third isolate to piperacillin-tazobactam (PIP-TZ) following sequential therapy with each agent. The first isolate was resistant to PIP-TZ only at high inocula, the second isolate acquired increased transcription of the acrA gene, and the third isolate became resistant to PIP-TZ due to loss of ß-lactamase inhibition by TZ. We question if and how PIP-TZ susceptibility should be reported for ESBL-producing Enterobacteriaceae.


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TEXT
 
Extended-spectrum-ß-lactamase (ESBL)-producing Enterobacteriaceae are almost universally susceptible to carbapenems, while susceptibilities to fluoroquinolones, aminoglycosides, and ß-lactam-ß-lactamase combinations (BL-BLC) are variable (18, 19, 24). The correlation between in vitro susceptibility of ESBL-producing bacteria to noncarbapenem antimicrobials and clinical efficacy has been questioned by two recent observational studies which documented an advantage of imipenem treatment over either ciprofloxacin (CIP) or any other noncarbapenem treatment of bacteremia caused by ESBL-producing Klebsiella pneumoniae. This advantage was unrelated to an apparent susceptibility of the respective isolates to noncarbapenem agents (5, 20).

We carried out phenotypic and genotypic analyses of three consecutive isolates of an ESBL-producing K. pneumoniae strain causing hospital-acquired prosthetic mitral valve (MV) endocarditis.

The patient, a 45-year-old woman, was admitted with pulmonary congestion due to a thrombus, impairing the movement of a prosthetic MV as revealed by transesophageal echocardiography. She was treated with heparin and on the 16th hospital day developed sepsis due to line infection (the clinical events are presented in Fig. 1). Blood culture yielded an ESBL-producing K. pneumoniae strain resistant to cefepime and susceptible to CIP and piperacillin-tazobactam (PIP-TZ) (Table 1, isolate 1). Empirical therapy with cefepime was discontinued and intravenous CIP and amikacin (AMK) therapy started. On the 28th hospital day, a second episode of sepsis recurred with bacteremia with CIP-resistant K. pneumoniae (Table 1, isolate 2). A repeated transesophageal echocardiography showed a large echogenic mobile mass on the posterior aspect of the MV annulus. An abdominal computed tomography scan showed splenic infarcts. Endocarditis was diagnosed, and the cardiothoracic surgery service suggested that valve replacement was premature. Treatment with PIP-TZ (instead of CIP) was started. Sepsis with bacteremia with a PIP-TZ-resistant K. pneumoniae isolate recurred on the 44th day.


Figure 1
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  		FIG. 1. Clinical course of treatment, including documentation of bacteremia and antimicrobial regimens used, for the patient described in the text. Cefepime was given at a dose of 2 g twice a day, ciprofloxacin at 400 mg twice a day, piperacillin-tazobactam at 4.5 g three times a day, amikacin at 500 mg twice a day, and meropenem at 1 g three times a day.


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  		TABLE 1. MICs of the three clinical K. pneumoniae isolates for the relevant antimicrobials used for treatment and effects of increased inoculum

Therapy with meropenem (MEM) replaced therapy with PIP-TZ, and the patient underwent a splenectomy followed by MV replacement. Vegetations were identified on the MV, with a myocardial abscess. Another K. pneumoniae isolate, phenotypically similar to isolate 3, was grown from the removed spleen and the myocardial abscess. Following the operation, the patient's condition improved and treatment with MEM and AMK was continued for six additional weeks with an uneventful course.

K. pneumoniae isolates 1, 2, and 3 were identified and susceptibilities were determined by use of the VITEK-1 and -2 systems (12). MICs for cefepime, CIP, MEM, and cefoxitin were determined by Etest (AB Biodisk, Sweden), and susceptibility to nalidixic acid was determined by disk diffusion (16). Other MICs were determined by the broth microdilution method using inocula of 105 and 107 CFU/ml (verified by plate counts for PIP-TZ and MEM) with drug concentrations from 0.12 to 128 µg/ml (12, 16). An ESBL-producing phenotype was confirmed by the CLSI (formerly NCCLS) confirmatory disk diffusion assay (16).

Pulsed-field gel electrophoresis analysis was performed as described previously (26). Cell extracts were used for ß-lactamase hydrolysis assays in the presence and absence of tazobactam (4 µg/ml; Wyeth) (17), and pIs were identified by isoelectric focusing electrophoresis (14).

The presence of ß-lactamase (bla) genes and quinolone resistance genes, including gyrA, parC, and the qnr genes (qnrA, qnrB1, and qnrB2), was determined by PCR (Table 2) using the following conditions: 15 min at 95°C and 40 cycles of 1 min at 94°C, 2 min at annealing temperature, 3 min at 72°C, and 10 min at 72°C. PCR products of the CTX-M-2 gene were sequenced using T7 and SP6 promoter primers following ligation into pGEM-T easy PCR cloning vector. The remaining bla and quinolone resistance genes were sequenced using the primers listed (Table 2).


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  		TABLE 2. List of oligonucleotides used for PCR amplification

The transcription of acrAB (15) was assessed by Northern blot analysis, and prehybridization and hybridization were performed as described previously (22). A 1.2-kb PCR product of the acrA gene from Escherichia coli strain ATCC 25922 was labeled with [{alpha}-32P]dCTP for use as a probe. The signal was quantitated and expressed as values relative to 16S rRNA on the same blot.

All K. pneumoniae isolates possessed the same pulsotype by pulsed-field gel electrophoresis and were identified as ESBL producers. The isolates were resistant to nalidixic acid and to cefepime with a MIC of 48 µg/ml. The MICs to other antimicrobials and the effects of the inocula on the MICs for PIP-TZ and MEM are described in Table 1. A 492-bp gene fragment, corresponding to nucleotide positions 91 to 583 in the K. pneumoniae parC sequence, and a 625-bp gene fragment of gyrA (31) were amplified from isolates 1 and 2, respectively, sequenced, and analyzed. No mutation was identified in the parC gene, whereas a substitution of aspartic acid to tyrosine in position 87 of the gyrA gene was found in both strains compared to sequences of homologous strains of K. pneumoniae (GenBank accession number AF303641 for parC and AF303606 for gyrA). PCR for the qnr genes showed no products (7, 29).

The levels of acrA transcription in strains 2 and 3 increased by 35% and 70%, respectively.

The ß-lactamase activity modestly increased from isolate 1 to isolate 3 (Fig. 2). Tazobactam decreased the ß-lactamase activity of isolates 1 and 2 by 86% and 81%, respectively. The ß-lactamase activity in the presence of TZ increased by nearly fourfold from isolate 2 to isolate 3, resulting in suppression of only 37% of this activity in isolate 3. The same PCR products were amplified from bla genes for all isolates (three narrow-spectrum [TEM-1, SHV-1, and OXA-2] and one extended-spectrum [CTX-M-2] ß-lactamase), and no mutations were identified in any of the bla genes. An identical isoelectric focusing pattern was observed for all isolates with pIs of 5.4, 7.6, and 7.9, compatible with TEM-, SHV-, and CTX-M-type ß-lactamases, respectively. A pI of 7.7, compatible with OXA-2, was not visualized.


Figure 2
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  		FIG. 2. Determination of ß-lactamase activity in cell-free crude extract by use of nitrocefin hydrolysis with and without tazobactam. ß-Lactamase activity is expressed as units per milligram protein per minute.

K. pneumoniae endocarditis was described previously (1), including one case caused by an ESBL-producing strain (25). The MIC of isolate 1 to ciprofloxacin is below the susceptibility breakpoint of ≤1 µg/ml but above the typical MIC of fully susceptible Enterobacteriaceae of <0.25 µg/ml (5). Replacement of aspartic acid 87 with tyrosine as a sole mutation explains the resistance to nalidixic acid but has been reported only rarely for Enterobacteriaceae as a cause for an increased MIC to CIP (9, 10). The increased transcription level of acrA could explain the increased MIC of CIP, as previous studies using Western blot analysis showed that increased expression of AcrA protein in the range of 15% to 100% is sufficient to confer high-level fluoroquinolone resistance in K. pneumoniae (15, 30, 32). Interestingly, further increase in acrA transcription in isolate 3 did not translate to a higher MIC.

Therapy with PIP-TZ ended with a highly PIP-TZ-resistant isolate (isolate 3). The fourfold-increased ß-lactamase activity of this isolate in the presence of TZ, despite only a marginal increase in total ß-lactamase activity, almost excludes the mechanism of enzyme hyperproduction (6, 8). The absence of mutations in any of the bla genes rules out an inhibitor-resistant ß-lactamase (IRT) mechanism (11). A porin loss mechanism, which was correlated in previous studies (13) with a high-level resistance to cefoxitin, is unlikely because the susceptibility to cefoxitin minimally increased between isolates 1 and 2 to isolate 3, ending in intermediate susceptibility. Variability in resistance to PIP-TZ between different strains of Enterobacteriaceae and within identical strains was described previously (2), and the relationships between amount and number of ß-lactamase(s) were neither consistent nor universal. Therefore, other mechanisms for resistance of ß-lactamases to ß-lactamase inhibitors should be identified in future studies (2).

The inoculum effect on ß-lactam agents (20, 28) was described most consistently for cephalosporins but was identified also with BL-BLC; specifically, the proportion of PIP-TZ-susceptible strains of K. pneumoniae decreased from 67% to 22% when the inoculum was raised to 107 CFU/ml (28). PIP-TZ efficacy in experimental infections caused by susceptible isolates (21, 27) was dependent on a higher concentration of TZ and a higher ratio of TZ to PIP than the formulation of 1/8 used clinically (27).

Current susceptibility test results for ESBL-producing Enterobacteriaceae report all noncarbapenem ß-lactams as resistant, with the exception of BL-BLC. Susceptibility tests alone may fail to guide initial selection of antimicrobial therapy especially for antimicrobials with inoculum-dependent susceptibility. Moreover, in most infections, unlike in this case, the failure of antibiotic therapy would not translate into positive blood cultures.

Therefore, we question whether BL-BLC should not be reported as resistant in all instances when ESBL production is detected. Lowering the cutoff point for the MIC denoting resistance for these agents is an alternative option, however, as our case illustrates that a reduction below 4 µg/ml is required, which is practically equivalent to reporting all isolates as resistant. Alternatively, the clinical laboratory may add a warning to susceptibility reports that clinical failure can be expected when BL-BLC are used to treat serious infections caused by an ESBL producer.


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FOOTNOTES
 
* Corresponding author. Mailing address: Division of Infectious Diseases, Kaplan Medical Center Rehovot, Hebrew University and Hadassah, P.O. Box 1, Rehovot 76100, Israel. Phone: 972-8-9441993. Fax: 972-8-9441765. E-mail: oren_z{at}clalit.org.il. Back


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Antimicrobial Agents and Chemotherapy, September 2006, p. 3179-3182, Vol. 50, No. 9
0066-4804/06/$08.00+0     doi:10.1128/AAC.00218-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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