Extended-spectrum β-lactamases (ESBLs) are found in numerous Enterobacteriaceae, mainly in Klebsiella pneumoniae. We investigated the pharmacodynamics of two new extended-spectrum cephalosporins, cefepime and cefpirome, alone and combined with either amikacin or gentamicin or ciprofloxacin by means of time-kill curves against ESBL-producing, amino-glycoside-resistant K. pneumoniae. When used alone, cefepime (8 and 16 mg/l) resulted in a 2 and 3 log decrease at 6 h, respectively, but at 24 h regrowth occurred. The combination of cefepime (8 mg/l) with amikacin (4 mg/l) resulted in a 4 log decrease at 6 h, but there were no surviving bacteria at 6 h when combined with amikacin (8 mg/l). The combination of cefepime (16 mg/l) with gentamicin (4 mg/l) resulted in a 4 log decrease in 24 h. The antimicrobial combiantion of cefepime (32 mg/l) with ciprofloxacin (2 mg/l) resulted in a 4 log decrease in 24 h. Cefpirome (8 mg/l) induced a 2 log decrease at 4 h; 32 mg/l cefpirome resulted in a 3 log decrease followed by regrowth at 24 h. The regrowth observed in the late phase with cefpirome alone disappeared when combined with aminoglycoside. When cefpirome (32 mg/l) was used in combination with ciprofloxacin (1 mg/l), it resulted in a 4 log decrease in 24 h.
The objective of the present study was to investigate the potential bactericidal activity of amoxicillinclavulanate against -lactamase-producing Escherichia coli strains and to elucidate the extent to which enzyme production affects the activity. Six adult Yucatan miniature pigs received a single intravenous dose of 1.1 g of amoxicillin-clavulanate as an intravenous infusion over 30 min. The pharmacokinetic parameters were determined for the serum samples and compared to the published data for humans (2.2-g intravenous dose). The parameters were comparable for the two species, and therefore, the miniature pig constitutes a good model for pharmacodynamic study of amoxicillin-clavulanate. Therefore, the model was used in an ex vivo pharmacodynamic study of amoxicillin-clavulanate against four strains of Escherichia coli producing -lactamases at different levels. The E. coli strains were cultured with serial dilutions (1:2 to 1:256) of the serum samples from the pharmacokinetic study, and the number of surviving bacteria was determined after 1, 3, and 6 h of exposure. Amoxicillin-clavulanate at concentrations less than the MIC and the minimal bactericidal concentration had marked bactericidal potency against the strain that produced low levels of penicillinase. For high-level or intermediate-level -lactamase-producing strains, the existence of a clavulanate concentration threshold of 1.5 to 2 g/ml, below which there was no bactericidal activity, was demonstrated. The index of surviving bacteria showed the existence of mixed concentration-and time-dependent actions of amoxicillin (in the presence of clavulanate) which varied as a function of the magnitude of -lactamase production by the test strains. This study shows the effectiveness of amoxicillin-clavulanate against low-and intermediate-level penicillinase-producing strains of E. coli. These findings are to be confirmed in a miniature pig experimental infection model.Amoxicillin-clavulanate is a combination of a -lactam with a -lactamase inhibitor which restores the potency of amoxicillin against strains producing -lactamases. The potential for the clinical use of such combinations depends in part on the concentrations achieved in serum and tissue after the administration of the usual dosages compared to the MIC for the infecting organism. In particular, it is necessary to obtain concentrations sufficiently inhibitory for the -lactamase in vivo to inactivate the enzymes produced by the bacteria at the infection site.The sensitivity of Escherichia coli to the combination of amoxicillin plus clavulanate depends on the strain's level of -lactamase production. The number of resistant or intermediate-resistant strains is increasing (1); and in E. coli overproduction of chromosomal -lactamases of class C (cephalosporinase) or plasmid enzymes, e.g., TEM-1, TEM-2, and OXA (1,3,23), is the most common mode of -lactam resistance.The aim of the present study was to evaluate the bactericidal potency of amoxicillin-clavulanate in an ex vivo bactericidal model using...
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