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. 1992 Sep;36(9):1883–1889. doi: 10.1128/aac.36.9.1883

Piperacillin, tazobactam, and gentamicin alone or combined in an endocarditis model of infection by a TEM-3-producing strain of Klebsiella pneumoniae or its susceptible variant.

H Mentec 1, J M Vallois 1, A Bure 1, A Saleh-Mghir 1, F Jehl 1, C Carbon 1
PMCID: PMC192204  PMID: 1329634

Abstract

The efficacy of tazobactam, a beta-lactamase inhibitor, in combination with piperacillin, was studied in vitro and in rabbit experimental endocarditis due to a Klebsiella pneumoniae strain (KpR) producing an extended-spectrum beta-lactamase, TEM-3, or its nonproducing variant (KpS). In vitro, piperacillin was active against KpS (MIC = 4 micrograms/ml, MBC = 8 micrograms/ml with 10(7)-CFU/ml inoculum) but not against KpR (MIC = MBC = 256 micrograms/ml). Tazobactam (1 microgram/ml) restored the activity of piperacillin against KpR (MIC = 2 micrograms/ml, MBC = 4 micrograms/ml). Gentamicin was active against both strains (MIC = 0.25 and 0.5 micrograms/ml for KpS and KpR, respectively). The piperacillin-tazobactam-gentamicin combination was synergistic in vitro. The piperacillin/tazobactam ratio in plasma and in vegetations was always lower than the 4/1 injected dose ratio. In vivo, piperacillin (300 mg/kg of body weight four times a day [QID]) was active against KpS but not against KpR. Tazobactam (75 mg/kg QID) was able to restore the in vivo effect of piperacillin (300 mg/kg QID) against KpR (-3.0 log10 CFU/g of vegetation versus that of controls). Gentamicin (4 mg/kg twice a day [BID]) was active against both strains. Compared with controls, the combination of gentamicin plus piperacillin against KpS (-5.6 log10 CFU/g of vegetation), and the gentamicin-piperacillin-tazobactam combination against KpR (-4.4 log10 CFU/g of vegetation) achieved the greatest decrease in bacterial counts in vegetations and were the only regimens that significantly increased the proportion of sterile vegetations. It is concluded that (i) tazobactam was able to restore the effect of piperacillin against a TEM-3 extended-spectrum Beta-lactamase-producing strain of K. pneumoniae, both in vitro and in a severe experimental infection with high inoculum, when used in a 4/1 piperacillin/tazobactam dose ratio; (ii) gentamicin alone was effective because of the high peak/MBC ratio in plasma; (iii) piperacillin-tazobactam-gentamicin, probably because of the effect of gentamicin in reducing bacterial inoculum in vivo, as stressed by the results obtained by piperacillin-gentamicin against KpS, may be the most effective regimen against KpR.

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Selected References

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  1. Acar J. F., Gutmann L., Kitzis M. D. Beta-lactamases in clinical isolates. Spectrum implications of sulbactam/ampicillin. Drugs. 1988;35 (Suppl 7):12–16. doi: 10.2165/00003495-198800357-00004. [DOI] [PubMed] [Google Scholar]
  2. Appelbaum P. C., Jacobs M. R., Spangler S. K., Yamabe S. Comparative activity of beta-lactamase inhibitors YTR 830, clavulanate, and sulbactam combined with beta-lactams against beta-lactamase-producing anaerobes. Antimicrob Agents Chemother. 1986 Nov;30(5):789–791. doi: 10.1128/aac.30.5.789. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Aronoff S. C., Jacobs M. R., Johenning S., Yamabe S. Comparative activities of the beta-lactamase inhibitors YTR 830, sodium clavulanate, and sulbactam combined with amoxicillin or ampicillin. Antimicrob Agents Chemother. 1984 Oct;26(4):580–582. doi: 10.1128/aac.26.4.580. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Aronoff S. C., Jacobs M. R., Labrozzi P. H., Yamabe S. Synergy of amoxycillin combined with clavulanate and YTR 830 in experimental infections in mice. J Antimicrob Chemother. 1986 Aug;18(2):271–276. doi: 10.1093/jac/18.2.271. [DOI] [PubMed] [Google Scholar]
  5. Bayer A. S., Selecky M., Babel K., Hirano L., Yih J., Parr T. R., Jr Bactericidal interactions of a beta-lactam and beta-lactamase inhibitors in experimental Pseudomonas aeruginosa endocarditis caused by a constitutive overproducer of type Id beta-lactamase. Antimicrob Agents Chemother. 1987 Nov;31(11):1750–1755. doi: 10.1128/aac.31.11.1750. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Brun-Buisson C., Legrand P., Philippon A., Montravers F., Ansquer M., Duval J. Transferable enzymatic resistance to third-generation cephalosporins during nosocomial outbreak of multiresistant Klebsiella pneumoniae. Lancet. 1987 Aug 8;2(8554):302–306. doi: 10.1016/s0140-6736(87)90891-9. [DOI] [PubMed] [Google Scholar]
  7. Caron F., Gutmann L., Bure A., Pangon B., Vallois J. M., Pechinot A., Carbon C. Ceftriaxone-sulbactam combination in rabbit endocarditis caused by a strain of Klebsiella pneumoniae producing extended-broad-spectrum TEM-3 beta-lactamase. Antimicrob Agents Chemother. 1990 Nov;34(11):2070–2074. doi: 10.1128/aac.34.11.2070. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Chiesa C., Labrozzi P. H., Aronoff S. C. Decreased baseline beta-lactamase production and inducibility associated with increased piperacillin susceptibility of Pseudomonas cepacia isolated from children with cystic fibrosis. Pediatr Res. 1986 Nov;20(11):1174–1177. doi: 10.1203/00006450-198611000-00026. [DOI] [PubMed] [Google Scholar]
  9. Contrepois A., Vallois J. M., Garaud J. J., Pangon B., Mohler J., Meulemans A., Carbon C. Kinetics and bactericidal effect of gentamicin and latamoxef (moxalactam) in experimental Escherichia coli endocarditis. J Antimicrob Chemother. 1986 Feb;17(2):227–237. doi: 10.1093/jac/17.2.227. [DOI] [PubMed] [Google Scholar]
  10. Cremieux A. C., Maziere B., Vallois J. M., Ottaviani M., Azancot A., Raffoul H., Bouvet A., Pocidalo J. J., Carbon C. Evaluation of antibiotic diffusion into cardiac vegetations by quantitative autoradiography. J Infect Dis. 1989 May;159(5):938–944. doi: 10.1093/infdis/159.5.938. [DOI] [PubMed] [Google Scholar]
  11. Daschner F. D., Just M., Spillner G., Schlosser V. Penetration of piperacillin into cardiac valves, subcutaneous and muscle tissue of patients undergoing open-heart surgery. J Antimicrob Chemother. 1982 Jun;9(6):489–492. doi: 10.1093/jac/9.6.489. [DOI] [PubMed] [Google Scholar]
  12. Dougherty P. F., Yotter D. W., Matthews T. R. Microdilution transfer plate technique for determining in vitro synergy of antimicrobial agents. Antimicrob Agents Chemother. 1977 Feb;11(2):225–228. doi: 10.1128/aac.11.2.225. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. English A. R., Girard D., Cimochowski C., Faiella J., Retsema J. A., Lynch J. E. Activity of sulbactam/ampicillin in screening and discriminative animal models of infection. Rev Infect Dis. 1986 Nov-Dec;8 (Suppl 5):S535–S542. doi: 10.1093/clinids/8.supplement_5.s535. [DOI] [PubMed] [Google Scholar]
  14. Fantin B., Pangon B., Potel G., Caron F., Vallée E., Vallois J. M., Mohler J., Buré A., Philippon A., Carbon C. Activity of sulbactam in combination with ceftriaxone in vitro and in experimental endocarditis caused by Escherichia coli producing SHV-2-like beta-lactamase. Antimicrob Agents Chemother. 1990 Apr;34(4):581–586. doi: 10.1128/aac.34.4.581. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Fantin B., Pangon B., Potel G., Vallois J. M., Caron F., Bure A., Carbon C. Ceftriaxone-netilmicin combination in single-daily-dose treatment of experimental Escherichia coli endocarditis. Antimicrob Agents Chemother. 1989 May;33(5):767–770. doi: 10.1128/aac.33.5.767. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Gutmann L., Kitzis M. D., Yamabe S., Acar J. F. Comparative evaluation of a new beta-lactamase inhibitor, YTR 830, combined with different beta-lactam antibiotics against bacteria harboring known beta-lactamases. Antimicrob Agents Chemother. 1986 May;29(5):955–957. doi: 10.1128/aac.29.5.955. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Jacobs M. R., Aronoff S. C., Johenning S., Shlaes D. M., Yamabe S. Comparative activities of the beta-lactamase inhibitors YTR 830, clavulanate, and sulbactam combined with ampicillin and broad-spectrum penicillins against defined beta-lactamase-producing aerobic gram-negative bacilli. Antimicrob Agents Chemother. 1986 Jun;29(6):980–985. doi: 10.1128/aac.29.6.980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Jacobs M. R., Aronoff S. C., Johenning S., Yamabe S. Comparative activities of the beta-lactamase inhibitors YTR 830, clavulanate and sulbactam combined with extended-spectrum penicillins against ticarcillin-resistant Enterobacteriaceae and pseudomonads. J Antimicrob Chemother. 1986 Aug;18(2):177–184. doi: 10.1093/jac/18.2.177. [DOI] [PubMed] [Google Scholar]
  19. Jarlier V., Nicolas M. H., Fournier G., Philippon A. Extended broad-spectrum beta-lactamases conferring transferable resistance to newer beta-lactam agents in Enterobacteriaceae: hospital prevalence and susceptibility patterns. Rev Infect Dis. 1988 Jul-Aug;10(4):867–878. doi: 10.1093/clinids/10.4.867. [DOI] [PubMed] [Google Scholar]
  20. Jehl F., Birckel P., Monteil H. Hospital routine analysis of penicillins, third-generation cephalosporins and aztreonam by conventional and high-speed high-performance liquid chromatography. J Chromatogr. 1987 Jan 23;413:109–119. doi: 10.1016/0378-4347(87)80218-9. [DOI] [PubMed] [Google Scholar]
  21. Jolley M. E. Fluorescence polarization immunoassay for the determination of therapeutic drug levels in human plasma. J Anal Toxicol. 1981 Sep-Oct;5(5):236–240. doi: 10.1093/jat/5.5.236. [DOI] [PubMed] [Google Scholar]
  22. Kitzis M. D., Billot-Klein D., Goldstein F. W., Williamson R., Tran Van Nhieu G., Carlet J., Acar J. F., Gutmann L. Dissemination of the novel plasmid-mediated beta-lactamase CTX-1, which confers resistance to broad-spectrum cephalosporins, and its inhibition by beta-lactamase inhibitors. Antimicrob Agents Chemother. 1988 Jan;32(1):9–14. doi: 10.1128/aac.32.1.9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Knothe H., Shah P., Krcmery V., Antal M., Mitsuhashi S. Transferable resistance to cefotaxime, cefoxitin, cefamandole and cefuroxime in clinical isolates of Klebsiella pneumoniae and Serratia marcescens. Infection. 1983 Nov-Dec;11(6):315–317. doi: 10.1007/BF01641355. [DOI] [PubMed] [Google Scholar]
  24. Kuck N. A., Jacobus N. V., Petersen P. J., Weiss W. J., Testa R. T. Comparative in vitro and in vivo activities of piperacillin combined with the beta-lactamase inhibitors tazobactam, clavulanic acid, and sulbactam. Antimicrob Agents Chemother. 1989 Nov;33(11):1964–1969. doi: 10.1128/aac.33.11.1964. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Pangon B., Joly V., Vallois J. M., Abel L., Buré A., Brion N., Contrepois A., Carbon C. Comparative efficacy of cefotiam, cefmenoxime, and ceftriaxone in experimental endocarditis and correlation with pharmacokinetics and in vitro efficacy. Antimicrob Agents Chemother. 1987 Apr;31(4):518–522. doi: 10.1128/aac.31.4.518. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Perlman B. B., Freedman L. R. Experimental endocarditis. II. Staphylococcal infection of the aortic valve following placement of a polyethylene catheter in the left side of the heart. Yale J Biol Med. 1971 Oct;44(2):206–213. [PMC free article] [PubMed] [Google Scholar]
  27. Philippon A., Labia R., Jacoby G. Extended-spectrum beta-lactamases. Antimicrob Agents Chemother. 1989 Aug;33(8):1131–1136. doi: 10.1128/aac.33.8.1131. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Sirot D., Sirot J., Labia R., Morand A., Courvalin P., Darfeuille-Michaud A., Perroux R., Cluzel R. Transferable resistance to third-generation cephalosporins in clinical isolates of Klebsiella pneumoniae: identification of CTX-1, a novel beta-lactamase. J Antimicrob Chemother. 1987 Sep;20(3):323–334. doi: 10.1093/jac/20.3.323. [DOI] [PubMed] [Google Scholar]
  29. Sirot J., Chanal C., Petit A., Sirot D., Labia R., Gerbaud G. Klebsiella pneumoniae and other Enterobacteriaceae producing novel plasmid-mediated beta-lactamases markedly active against third-generation cephalosporins: epidemiologic studies. Rev Infect Dis. 1988 Jul-Aug;10(4):850–859. doi: 10.1093/clinids/10.4.850. [DOI] [PubMed] [Google Scholar]
  30. Washburn R. G., Durack D. T. Efficacy of ampicillin plus a beta-lactamase inhibitor (CP-45,899) in experimental endocarditis due to Staphylococcus aureus. J Infect Dis. 1981 Sep;144(3):237–243. doi: 10.1093/infdis/144.3.237. [DOI] [PubMed] [Google Scholar]
  31. Williams J. D. Importance of beta-lactamases and clinical implications of their inhibitors. Drugs. 1988;35 (Suppl 7):3–11. doi: 10.2165/00003495-198800357-00003. [DOI] [PubMed] [Google Scholar]

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