When antibiotic combinations are used to provide a broader spectrum of antimicrobial activity or in an attempt to prevent the emergence of resistant organisms, it is rarely necessary or practical to perform tests of drug interactions in vitro. In vitro testing of combinations may be useful when combinations are used in an attempt to attain synergistic interactions. In some cases, screening methods can be used as substitutes for formal synergy testing. This paper examines the mechanisms of antibiotic interaction leading to synergism or antagonism, surveys attempts to correlate in vitro observations with efficacy in animal models, and reviews clinical data providing evidence for or against a useful role of synergistic antibiotic interactions in the treatment of human infections.

Methicillin-resistant Staphylococcus aureus is becoming increasingly prevalent as both a nosocomial and a community-acquired pathogen. Daptomycin, a lipopeptide antibiotic now in phase III clinical trials, is rapidly bactericidal in vitro against a range of gram-positive organisms, including methicillin-resistant S. aureus (MRSA). In this study, we compared the efficacy of daptomycin with that of vancomycin, each with or without rifampin, in a model of experimental aortic valve endocarditis due to MRSA. The infecting strain (MRSA strain 32) was susceptible to daptomycin (MIC ‫؍‬ 1 g/ml), vancomycin (MIC ‫؍‬ 0.5 g/ml), and rifampin (MIC ‫؍‬ 0.5 g/ml). Daptomycin was administered at 25 or 40 mg/kg q24h (q24h) by subcutaneous injection in an attempt to simulate human doses of 4 and 6 mg/kg q24h, respectively. Vancomycin was given at 150 mg/kg q24h by continuous intravenous infusion. Rifampin was given at 25 mg/kg by intramuscular injection q24h. Treatment was started 6 h postinoculation and continued for 4.5 days. Outcome was assessed by counting the residual viable bacteria in vegetations. The mean peak daptomycin levels in serum at 2 h after subcutaneous administration of 25 and 40 mg/kg were 64 and 91 g/ml, respectively. Daptomycin was undetectable in serum at 24 h. The total exposure was comparable to that achieved clinically in humans receiving the drug. Bacterial counts (mean log 10 number of CFU per gram ؎ the standard deviation) in untreated controls reached 10.6 ؎ 0.8. In treated rats, bacterial counts were as follows: vancomycin, 7.1 ؎ 2.5; daptomycin at 25 mg/kg, 5.5 ؎ 1.7; daptomycin at 40 mg/kg, 4.2 ؎ 1.5. The difference between daptomycin at 40 mg/kg and vancomycin at 150 mg/kg was statistically significant (P ‫؍‬ 0.004). In the study of combination therapy, vegetation bacterial counts were as follows: daptomycin at 40 mg/kg, 4.6 ؎ 1.6; rifampin, 3.6 ؎ 1.3; vancomycin plus rifampin, 3.3 ؎ 1.1; daptomycin plus rifampin, 2.9 ؎ 0.8. The difference between daptomycin and daptomycin plus rifampin was statistically significant (P ‫؍‬ 0.006). These results support the continued evaluation of daptomycin for serious MRSA infections, including infective endocarditis.Daptomycin is a lipopeptide antibiotic derived from Streptomyces roseosporus with potent bactericidal activity in vitro against most clinically relevant gram-positive organisms, including methicillin-resistant Staphylococcus aureus (MRSA), coagulase-negative staphylococci, vancomycin-resistant enterococci, and penicillin-resistant Streptococcus pneumoniae (1,2,10,11,24,28). The mechanism of action, while not yet fully elucidated, appears to involve the disruption of bacterial plasma membrane function (3,6,13,16).To date, daptomycin has been studied in complicated skin and soft-tissue infections (P. A. Matthews and M. F. DeBruin, Infect. Dis. Soc. Am., abstr. 112, 2001) and bacteremia due to gram-positive bacteria (29). A previous study was performed with daptomycin in bacterial endocarditis (data on file: study B8B-MC-AVAG, Cubist Pharmaceuticals, I...

The in vitro activity of the fluoroquinolone CP-99,219 against gram-positive bacteria was compared with those of five other antimicrobial agents. Against ciprofloxacin-susceptible staphylococci and against streptococci, MICs were <0.12 and .0.5 ,ig/ml, respectively. 219 was also more active than ciprofloxacin against ciprofloxacin-resistant staphylococci, most enterococci, Leuconostoc spp., and lactobacilli. Table 1. Against ciprofloxacinsusceptible strains of staphylococci, MICs for 90% of isolates tested (MIC90s) of CP-99,219 were '0.12 ,ug/ml, and the new agent was more active than ciprofloxacin and temafloxacin against these strains. Among the ciprofloxacinsusceptible strains of S. aureus, isolates that were methicillin susceptible or resistant demonstrated comparable susceptibilities to CP-99,219. The new drug was the most active quinolone against ciprofloxacin-resistant isolates, but relatively high concentrations were required for inhibition (MIC0s, 8 to 16 ,ug/ml). CP-99,129 was four-to eightfold more active than temafloxacin or ciprofloxacin against streptococci (groups A, B, and G and viridans group streptococci) and pneumococci. Activity of sparfloxacin against these strains fell between that of CP-99,219 and those of ciprofloxacin and temafloxacin. CP-99,219 was fourfold more active than ciprofloxacin against ciprofloxacin-susceptible Enterococcus faecalis (MIC90s, 0.25 to 0.5 ,g/ml) and against both vancomycin-susceptible and -resistant Enterococcus faecium (MIC90s, 4 ,ug/ml). The new quinolone was the most active drug tested against Leuconostoc spp. and Pediococcus spp. and was the most potent quinolone against Corynebacterium jeikeium. Inhibitory concentrations of CP-99,219 against the latter varied over a wide range, however, and were relatively high. Only vancomycin proved to be uniformly active against these strains. There was no difference in the activity against recent isolates of ciprofloxacin-susceptible S. aureus and that against strains collected more than 10 years ago for either CP-99,219 or ciprofloxacin.Against most species we have tested, CP-99,219 was more active than ciprofloxacin and temafloxacin. While the new quinolone was generally more active than sparfloxacin, MIC90s of these two drugs against the more-common patho-

Several antimicrobial regimens were evaluated in the treatment of experimental enterococcal endocarditis due to a ,(-lactamase-producing, highly gentamicin-resistant strain of Enterococcus faecalis. Ampicillin alone cleared bacteremia in the majority of rats and reduced titers of bacteria within vegetations (6.84 versus 8.80 log1o CFU/g in controls) but did not sterilize valves. Ampicillin-sulbactam combinations, vancomycin, daptomycin, and imipenem each reduced residual bacterial titers within vegetations to 4.01 loglo CFU/g or less;in 26 to 43% of animals receiving 5 days of therapy, titers of bacteria were reduced to undetectable levels. In a separate experiment, rats received ampicillin-sulbactam, daptomycin, or vancomycin for 10 days and were then observed for 10 days after termination of therapy for evidence of relapse. In surviving rats, valves remained sterile in four of five rats treated with ampicillin-sulbactam, in five of seven treated with daptomycin, but in only one of eight receiving vancomycin.