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Antimicrobial Agents and Chemotherapy, August 2007, p. 3044-3045, Vol. 51, No. 8
0066-4804/07/$08.00+0     doi:10.1128/AAC.00194-07

LETTER TO THE EDITOR

Effects of Imipenem-Cilastatin, Ertapenem, Piperacillin-Tazobactam, and Ceftriaxone Treatments on Persistence of Intestinal Colonization by Extended-Spectrum-ß-Lactamase-Producing Klebsiella pneumoniae Strains in Mice{triangledown}


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LETTER
 
Antibiotics that are excreted into the intestinal tract may promote colonization by antibiotic-resistant pathogens due to the disruption of indigenous microflora (2). However, such antibiotics may also have a protective effect if they inhibit the growth of pathogens (2, 6). For example, ceftriaxone, piperacillin-tazobactam, and ertapenem did not promote the establishment of colonization by a strain of extended-spectrum-ß-lactamase (ESBL)-producing Klebsiella pneumoniae during treatment in mice (MICs for the test strains were 4, 4, and <0.25 µg/ml, respectively) (6). In similar experiments, piperacillin-tazobactam inhibited the establishment of colonization by vancomycin-resistant enterococci during treatment (the MIC for the test strain was 512 µg/ml); however, piperacillin-tazobactam promoted persistent overgrowth of vancomycin-resistant enterococci in mice and patients after high-density colonization was established (2). In this study, we tested the hypothesis that piperacillin-tazobactam and ceftriaxone would promote the persistence of established high-density colonization by ESBL-producing K. pneumoniae strains with intermediate or high-level resistance to these agents. We hypothesized that ertapenem would inhibit the strains, which were carbapenem susceptible.

The two ESBL-producing K. pneumoniae test strains have been used in previous mouse model studies (3). The broth dilution MICs for P62 and P10045 were as follows: imipenem-cilastatin, 1 and 2 µg/ml, respectively; ertapenem, <0.25 and 0.25 µg/ml, respectively; piperacillin-tazobactam (8:1 ratio of piperacillin to tazobactam), 4 and 156 µg/ml, respectively; ceftriaxone, 4 and 78 µg/ml, respectively.

The experimental protocol was approved by the Animal Care Committee of the Cleveland Veterans Affairs Medical Center. Female CF1 mice (Harlan Sprague-Dawley, Indianapolis, IN), weighing 25 to 30 g, were housed individually. To establish high-density colonization, mice received subcutaneous clindamycin for 3 days in conjunction with orogastric gavage of 106 CFU of the test strains on day 1 of treatment. Two days after discontinuation of clindamycin, the mice were divided into the following treatment groups: normal saline (controls), imipenem-cilastatin, ertapenem, piperacillin-tazobactam, and ceftriaxone. Mice received subcutaneous antibiotic treatment daily in 0.2 ml of phosphate-buffered saline for 9 days. The dose of the antibiotics was based on the daily dose recommended for human adults (in milligrams per kilogram of body weight). The density of ESBL-producing K. pneumoniae in stool was measured at baseline and on days 1, 3, 6, and 9 after orogastric gavage as previously described (3, 6). All experiments were performed twice with eight total mice per treatment group.

Data analyses were performed with the use of Stata software (version 6.0; Stata, College Station, TX). A one-way analysis of variance was performed to compare the groups with P values adjusted for multiple comparisons using the Scheffe correction.

The effect of antibiotic treatment on the persistence of colonization is shown in Fig. 1. At baseline, the mice had high densities of ceftazidime-resistant, gram-negative bacilli in stool. In comparison to saline controls, ceftriaxone treatment promoted persistent overgrowth of both strains (P < 0.001), whereas ertapenem suppressed levels of both strains (P < 0.001). The densities of P10045 and P62 in stool of imipenem-cilastatin-treated mice did not differ from those in stool of saline-treated mice (P > 0.87). In comparison to saline controls, piperacillin-tazobactam promoted persistent overgrowth of P10045 (P < 0.001), but not of the more susceptible P62 strain (P > 0.42), which was suppressed in some mice, but not in others.


Figure 1
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  		FIG. 1. Effect of subcutaneous antibiotic treatment on persistence of colonization with ESBL-producing Klebsiella pneumoniae strains P62 (A) and P10045 (B) in mice. High-density colonization was established by administering 106 CFU of the test strains by orogastric gavage in conjunction with subcutaneous clindamycin for 3 days. Two days after discontinuation of clindamycin (day 0), mice received subcutaneous antibiotic treatment once daily for 9 days. If the pathogens were not detected in stool, the lower limit of detection (~2 log10 CFU/g) was assigned. Error bars indicate standard errors.

In summary, although ceftriaxone and piperacillin-tazobactam inhibited the establishment of colonization in mice after ingestion of 10,000 CFU of K. pneumoniae strain P62 (5), in mice with established high-density colonization, ceftriaxone promoted persistent overgrowth and piperacillin-tazobactam did not consistently suppress colonization. In addition, both agents promoted persistent overgrowth of the more resistant strain P10045. These results suggest that the ability of antibiotics to inhibit colonization by gram-negative pathogens is reduced after high-density colonization is established, particularly if more resistant strains are present. The failure to eliminate established colonization may be related to the increased inocula of organisms. In addition, pathogens may occupy a protected niche in association with the lining of the intestinal tract after colonization is established (2).

Ertapenem suppressed colonization by both K. pneumoniae strains. Both strains were susceptible to ertapenem, and this agent is excreted in significant concentrations into the intestinal tract (5). We previously showed that ertapenem did not promote the establishment of colonization by strain P62. Our findings are consistent with those of a recent clinical study in which intestinal colonization with resistant Enterobacteriaceae increased significantly in patients receiving piperacillin-tazobactam or ceftriaxone plus metronidazole, but not in patients receiving ertapenem (1). That imipenem-cilastatin did not promote or suppress colonization by the K. pneumoniae strains is probably due to the fact that it is not excreted in significant concentrations into the intestinal tract and does not disrupt the indigenous microflora (4, 6-8). We have previously shown that the stool concentrations of the study antibiotics in mice were similar to levels previously reported in human volunteers (6-8).


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ACKNOWLEDGMENTS
 
This work was supported by a grant from Merck Pharmaceuticals and by the Department of Veterans Affairs.


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FOOTNOTES
 
{triangledown} Published ahead of print on 11 June 2007. Back


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REFERENCES
 
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  1. Dinubile, M. J., I. Friedland, C. Y. Chan, M. R. Motyl, H. Giezek, M. Shivaprakash, R. A. Weinstein, and J. P. Quinn. 2005. Bowel colonization with resistant gram-negative bacilli after antimicrobial therapy of intra-abdominal infections: observations from two randomized comparative clinical trials of ertapenem therapy. Eur. J. Clin. Microbiol. Infect. Dis. 24:443-449.[CrossRef][Medline]
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  3. Hoyen, C. K., N. J. Pultz, D. L. Paterson, D. C. Aron, and C. J. Donskey. 2003. Effect of parenteral antibiotic administration on establishment of intestinal colonization in mice by Klebsiella pneumoniae strains producing extended-spectrum ß-lactamases. Antimicrob. Agents Chemother. 47:3610-3612.[Abstract/Free Full Text]
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  4. Nord, C. E., L. Kager, A. Philipson, and G. Stiernstedt. 1985. Effect of imipenem/cilastatin on the colonic microflora. Rev. Infect. Dis. 7(Suppl. 3):S432-S434.[Medline]
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  5. Pletz, M. W., M. Rau, J. Bulitta, et al. 2004. Ertapenem pharmacokinetics and impact on intestinal microflora, in comparison to those of ceftriaxone, after multiple dosing in male and female volunteers. Antimicrob. Agents Chemother. 48:3765-3772.[Abstract/Free Full Text]
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  6. Stiefel, U., M. J. Pultz, and C. J. Donskey. 2007. Effect of carbapenem administration on establishment of intestinal colonization by vancomycin-resistant enterococci and Klebsiella pneumoniae in mice. Antimicrob. Agents Chemother. 51:372-375.[Abstract/Free Full Text]
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Michael J. Pultz
Curtis J. Donskey*
Infectious Diseases Section (111 W)
Louis Stokes Cleveland Veterans Affairs Medical Center
10701 East Blvd.
Cleveland, OH 44106

* Phone: (216) 791-3800, ext. 5103, Fax: (216) 229-8509, E-mail: curtisd123{at}yahoo.com

Antimicrobial Agents and Chemotherapy, August 2007, p. 3044-3045, Vol. 51, No. 8
0066-4804/07/$08.00+0     doi:10.1128/AAC.00194-07





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