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

Abstract

The efficacy of tazobactam, a 1-lactamase inhibitor, in combination with piperacillin, was studied in vitro and in rabbit experimental endocarditis due to a Klebsiella pneumoniae strain (KpR) producing an extendedspectrum 13-lactamase, TEM-3, or its nonproducing variant (KpS). In vitro, piperacillin was active against KpS (MIC = 4 ,g/ml, MBC = 8 ,Lg/ml with 107-CFU/ml inoculum) but not against KpR (MIC = MBC = 256 p.g/ml). Tazobactam (1 jg/ml) restored the activity of piperacillin against KpR (MIC = 2 ,ug/ml, MBC = 4 jig/ml). Gentamicin was active against both strains (MIC = 0.25 and 0.5 ,ug/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 log1o CFU/g of vegetation), and the gentamicin-piperacillin-tazobactam combination against loglo 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 I-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.

Infective Endocarditis

“…149 A combination of a third-generation cephalosporin and an aminoglycoside (either gentamicin or amikacin) is recommended for Klebsiella endocarditis. Certain ␤-lactam/␤-lactamase inhibitor combinations (eg, piperacillintazobactam 150 but not ceftriaxone-sulbactam 151 ) are active in vivo in experimental models of Klebsiella endocarditis induced by TEM-3-producing isolates in animals and deserve further evaluation in combination with an aminoglycoside in humans with this disease. The specific aminoglycoside used is a critical variable and cannot be totally predicted from MIC data alone because pharmacodynamic characteristics differ markedly in animal models of IE caused by Gram-negative aerobic bacilli.…”

Cefepime, Piperacillin-Tazobactam, and the Inoculum Effect in Tests with Extended-Spectrum β-Lactamase-Producing Enterobacteriaceae

“…Many ESBL-producing isolates of K. pneumoniae or E. coli are susceptible in vitro to piperacillin-tazobactam (3,7,11,24), but MICs may increase substantially in tests with a higher-than-standard inoculum (10,14). Efficacy has been reported in animal models of infection (17,21,32,33,43), but clinical failure was reported in a patient with spontaneous bacterial peritonitis who was awaiting liver transplantation for end-stage liver disease (28). In some of these reports the presence of ESBLs was inferred from indirect tests and the actual enzymes involved were not identified (14,28).…”

In vitro activities of various beta-lactam antimicrobial agents against clinical isolates of Escherichia coli and Klebsiella spp. resistant to oxyimino cephalosporins

“…Studies on the in vitro activity of various ␤-lactams, including the newer agents piperacillin-tazobactam (6) and cefepime (1), against clinical isolates of ESBL producers are limited in number (13,19,20), and to our knowledge no studies using large numbers of clinically derived ESBL-producing isolates have examined the in vitro activities of these newer ␤-lactams. Therefore, such a collection of Escherichia coli and Klebsiella sp.…”