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Antimicrobial Agents and Chemotherapy, June 2009, p. 2700-2701, Vol. 53, No. 6
0066-4804/09/$08.00+0     doi:10.1128/AAC.00290-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

LETTER TO THE EDITOR

Activity of Temocillin against KPC-Producing Klebsiella pneumoniae and Escherichia coli{triangledown}


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LETTER
 
Temocillin, a 6-{alpha}-methoxy derivative of ticarcillin, is currently approved for treatment of infections due to members of the Enterobacteriaceae in Belgium and the United Kingdom. It is stable against hydrolysis by most β-lactamases, including extended-spectrum β-lactamases (ESBLs) and AmpC-type β-lactamases, with studies reporting MICs at which 90% of bacteria are inhibited (MIC90s) between 16 and 32 µg/ml (3, 4, 8). Temocillin is thus drawing attention as a potential alternative to carbapenems in treatment of infections caused by the Enterobactericeae producing these broad-spectrum β-lactamases.

Carbapenem-resistant Klebsiella pneumoniae producing KPC-type β-lactamase has emerged in recent years and caused hospital outbreaks of serious infections in the United States and other parts of the world (7). Furthermore, KPC-type β-lactamase is increasingly identified in other species of the Enterobacteriaceae as well, including Escherichia coli. One concerning recent phenomenon is the occurrence of urinary tract infections due to KPC-producing organisms at nursing homes (10). Currently, the limited treatment options for infections due to KPC-producing organisms include colistin and tigecycline. Concern over nephrotoxicity due to colistin limits its use outside closely monitored settings, whereas tigecycline does not achieve a therapeutic concentration in urine (2). Furthermore, emergence of resistance to these agents has recently been recorded for the Enterobacteriaceae (5, 6).

The present study was conducted to evaluate the in vitro activities of temocillin against clinical isolates of K. pneumoniae and E. coli producing KPC-type β-lactamase. A total of 33 KPC-producing clinical isolates (30 K. pneumoniae isolates and 3 E. coli isolates) were used. KPC production was confirmed by an ertapenem resistance phenotype, a positive modified Hodge test, and positive PCR for the KPC structural gene. The isolates were collected from hospitals in three states in the United States. The MIC of temocillin was determined by the standard agar dilution method (1). Temocillin was provided by Eumedica (Brussels, Belgium). In addition, MICs of temocillin against an E. coli isogenic clone producing KPC-3 were tested to determine the direct effect of KPC production on the temocillin MIC. E. coli ATCC 25922 was used as the control strain.

Table 1 summarizes the results. For K. pneumoniae, the MICs ranged between 16 µg/ml and 64 µg/ml (MIC at which 50% of bacteria were inhibited = 32 µg/ml; MIC90 = 32 µg/ml). The E. coli clinical isolates had MICs between 8 and 16 µg/ml. E. coli DH10B both with and without the cloning vector pBCSK– (Stratagene, La Jolla, CA) encoding blaKPC-3 had an MIC of 8 µg/ml. An inoculum effect was not observed at 105 CFU, whereas a mild inoculum effect averaging within a twofold MIC difference was seen with K. pneumoniae when 106 CFU was inoculated (Table 1). This result was in line with those of a previous study documenting a modest inoculum effect of temocillin for non-KPC-producing isolates (9). The frequencies of mutants of representative clinical isolates that grew at their MICs and at 2x MICs were calculated to be approximately 1 x 10–10 and 0 for K. pneumoniae and 3 x 10–10 and 1 x 10–10 for E. coli, respectively.


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  		TABLE 1. Susceptibilities of KPC-producing K. pneumoniae and E. coli isolates to temocillin

Currently, the British Society for Antimicrobial Chemotherapy (BSAC) is the only organization that defines temocillin MIC breakpoints for the Enterobacteriaceae. The BSAC defines temocillin susceptibilities at ≤8 and ≤32 µg/ml in systemic and urinary tract infections, respectively (http://www.bsac.org.uk/). One gram of temocillin is known to achieve a peak serum concentration of approximately 160 µg/ml, with serum binding of 85% and a half-life of 4 to 5 h (9). The urinary concentration after a 500-mg dose is approximately 500 µg/ml (9). These pharmacokinetic properties of temocillin make it a potential alternative treatment option for mild to moderate urinary tract infections caused by KPC-producing members of the Enterobacteriaceae.


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ACKNOWLEDGMENTS
 
This study was supported by funding from Eumedica Pharmaceuticals, Brussels, Belgium.


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FOOTNOTES
 
{triangledown} Published ahead of print on 30 March 2009. Back


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Jennifer M. Adams-Haduch
Brian A. Potoski
Hanna E. Sidjabat
Division of Infectious Diseases
University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania

David L. Paterson
University of Queensland
UQ Centre for Clinical Research
Royal Brisbane and Women's Hospital
Brisbane, Queensland, Australia

Yohei Doi*
Division of Infectious Diseases
University of Pittsburgh Medical Center
S829 Scaife Hall
3550 Terrace Street
Pittsburgh, Pennsylvania 15213

* Phone: (412) 648-9445 Fax: (412) 648-8521 Email: yod4{at}pitt.edu

Antimicrobial Agents and Chemotherapy, June 2009, p. 2700-2701, Vol. 53, No. 6
0066-4804/09/$08.00+0     doi:10.1128/AAC.00290-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.




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