Activities of Trovafloxacin and Ampicillin-Sulbactam Alone or in Combination versus Three Strains of Vancomycin- Intermediate Staphylococcus aureus in an In Vitro Pharmacodynamic Infection Model

Abstract

The recent isolation of clinical strains of methicillin-resistant Staphylococcus aureus (MRSA) with intermediate susceptibility (MICs, 8 g/ml) to vancomycin (vancomycin-intermediate S. aureus [VISA]) emphasizes the importance of developing novel antimicrobial regimens and/or agents for future treatment. We studied the activities of ampicillin-sulbactam and trovafloxacin alone or in combination against three unique strains of VISA in an in vitro infection model. Two VISA strains were trovafloxacin susceptible (MICs, <2 g/ml); one VISA strain was trovafloxacin resistant (MIC, 4 g/ml). Trovafloxacin was administered to simulate a dose of 200 or 400 mg every 24 h. Ampicillin-sulbactam was administered to simulate a dose of 3 g every 6 h. Samples were removed from the infection models over 48 h, and reductions in colony counts were compared between regimens. Trovafloxacin (200 mg) produced rapid killing of a control MRSA strain over the 48-h experiment but produced only slight killing of all three VISA strains. The higher dose of trovafloxacin improved killing but did not produce bactericidal activity at 48 h. Ampicillin-sulbactam produced rapid bactericidal activity against all four strains tested, and colony counts at 8 h were at the limits of detection. However, regrowth occurred by 48 h for each strain. The combination of ampicillin-sulbactam and trovafloxacin provided additive activity against two of the three VISA strains. In conclusion, trovafloxacin or ampicillin-sulbactam alone did not provide adequate activity against the VISA strains for the 48-h evaluation period, but the combination could help improve activity against some strains of VISA.Infections due to methicillin-resistant Staphylococcus aureus (MRSA) continue to be a significant problem in the 1990s, especially since the glycopeptide antibiotic vancomycin often is the only antimicrobial agent available with reliable activity. The recent isolation of MRSA with intermediate susceptibility (MICs, 8 g/ml) to vancomycin (vancomycin-intermediate S. aureus [VISA]) in both Japan and the United States (8, 9, 10) indicates that MRSA soon will become fully resistant to the last line of defense against this virulent organism. The expression of decreased vancomycin susceptibility in staphylococci is heterogeneous (1, 18; J. M. Boyce, A. A. Medeiros, and K. Hiramatsu, Abstr. 37th Intersci. Conf. Antimicrob. Agents Chemother., abstr. LB-15, 1997; K. Hiramatsu, H. Hanaki, S. Boyle-Vavra, R. S. Daum, H. Labischinski, and F. C. Tenover, Abstr. 37th Intersci. Conf. Antimicrob. Agents Chemother., abstr. C-166, 1997) and appears to be associated with thickened cell walls (25, 27, 29-31) and increased production of cell wall precursors (29,30). Interestingly, these strains express increased quantities of penicillin binding proteins (PBPs) (17, 21) and have improved susceptibility to methicillin (30).The recent isolation of clinical strains of VISA emphasizes the importance of developing novel antimicrobial regimens and/or agents for future treatment considerations. Am...

The Potential Role of Sulbactam and Cephalosporins Plus Daptomycin Against Daptomycin-Nonsusceptible VISA and H-VISA Isolates: An In Vitro Study

“…The time-killing methods also showed an additional synergistic effect with the addition of sulbactam to the combination of cephalosporin and daptomycin. Although previous studies [31][32][33] have shown a synergistic effect of sulbactam in various combinations, such as arbekacin with ampicillin-sulbactam, ours is the first to report a synergistic effect of daptomycin and cephalosporins with sulbactam against daptomycin-nonsusceptible VISA/h-VISA.…”

A Novel In Vitro Pharmacokinetic/Pharmacodynamic Model Based on Two‐Compartment Open Model Used to Simulate Serum Drug Concentration‐Time Profiles

“…[1] where α is the first-order elimination rate constant of the distribution phase (α phase), β is the first-order elimination rate constant of the elimination phase (β phase), and A and B are the zero-time intercepts for the α and β phases, respectively. To simulate the drug concentration-time profile described by equation [1], circuit A ( Fig. 2) was devised by being based on the elementary circuits (i) and (ii) ( Fig.…”

“…when tϾT d (i.e., after the drip infusion), [7] where the above parameters are the same as in equation [1], except that dosing is finished at T d .…”