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Sir, Optimal therapy of patients with infections caused by highlevel gentamicin-resistant (HLGR) enterococci remains to be determined. A combination of ampicillin and ciprofloxacin has been shown to be bactericidal in vitro against HLGR strains exhibiting low-level resistance to ciprofloxacin (MICs 4 mg/L), but, in an endocarditis animal model, failed to sterilize vegetations infected with a HLGR strain of Enterococcus faecium which was also highly resistant to ampicillin. We have recently reported that the in-vitro activity of this combination was influenced by the composition of the medium in which the activity was evaluated, i.e. ampicillin together with ciprofloxacin exhibited bactericidal activity in Mueller–Hinton broth (MHB), but only bacteriostatic activity in the enriched media, Brain Heart Infusion (BHI) broth and human serumsupplemented MHB. The reduced activity of the combination in the latter media was attributed, at least in part, to the high cation content, which is known to be inhibitory to ciprofloxacin. The present study was undertaken to assess the effects of two additional factors—the level of resistance to ampicillin and an inoculum effect—on the in-vitro activity of the combination against HLGR enterococci. The strains included in the study, five HLGR E. faecium isolates exhibiting low-level resistance to ampicillin (MICs 32–64 mg/L) and ciprofloxacin (MICs 2–4 mg/L), were stored at –70oC in BHI broth (Difco, Detroit, MI, USA) containing 10% glycerol. The effects of the variables were investigated by time–kill studies. The medium used was MHB (Difco) and the strains were incubated in the presence of ampicillin alone, ciprofloxacin alone, both ampicillin and ciprofloxacin or no antibiotic (control), as described previously. The concentrations of ampicillin and ciprofloxacin were 20 and 2 mg/L, respectively, and the suspensions initially contained 5 10 cfu/L. Bactericidal activity was defined as a reduction in the initial suspension of 3 log10 cfu/L after incubation at 37oC for 24 h. All experiments were carried out at least twice and the results expressed as the means. High-level resistance to ampicillin was induced in one of the five strains, No. 662 (initial MIC 32 mg/L), following daily passage in Mueller–Hinton II broth (MHB II; BBL Becton Dickinson, Cockeysville, MD, USA) containing increasing (4–8 mg at a time) concentrations of ampicillin and subsequent passage on agar that also contained ampicillin. Each resultant mutant for which the MIC had increased two-fold underwent at least 10 passages in antibiotic-free medium, after which the MIC of ampicillin was redetermined. This procedure yielded three mutants, identified as numbers 662.1, 662.2 and 662.3 and confirmed to be strains of E. faecium by conventional laboratory techniques, including the API Strep test (bioMérieux, Marcy l’Etoile, France). The MICs of ampicillin for the mutants were 64, 128 and 150 mg/L, respectively, these being the ‘true MICs’ (defined as the actual inhibitory concentrations which lie anywhere between two two-fold dilutional steps); the MICs of ciprofloxacin and gentamicin for the mutants were the same as those for the parental strain. The effect of the level of ampicillin resistance on the activity of the combination was assessed by repeating the time–kill studies with both the parental and mutant strains in MHB. The influence of the size of the initial inoculum on the activity of the combination was also assessed. Overnight cultures of the five strains were diluted in MHB to give inocula of 10 cfu/L and 10 cfu/L and the time–kill studies were repeated, as described above, with each inoculum. As shown in the Table, there was an inverse relationship between the level of ampicillin resistance and the activity of the ampicillin/ciprofloxacin combination (which produced changes in log10 cfu/L after incubation for 24 h ranging from –3.92 to –0.45). The combination exerted only bacteriostatic activity against strains for which the MICs of ampicillin were 64 mg/L. This observation is at variance with a previous report in which we described the combination as being bactericidal against strains with MICs of 64 mg/L.

the journal of antimicrobial chemotherapy/journal of antimicrobial chemotherapy

The effects of the level of ampicillin resistance and the inoculum size on the in-vitro bactericidal activity of the combination of ampicillin and ciprofloxacin against high-level gentamicin-resistant strains of Enterococcus faecium