cefamandole and quinupristin-dalfopristin

Quinupristin-dalfopristin (Q-D) is an injectable streptogramin active against most gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). In experimental endocarditis, however, Q-D was less efficacious against MRSA isolates constitutively resistant to macrolide-lincosamide-streptogram B (C-MLS(B)) than against MLS(B)-susceptible isolates. To circumvent this problem, we used the checkerboard method to screen drug combinations that would increase the efficacy of Q-D against such bacteria. beta-Lactams consistently exhibited additive or synergistic activity with Q-D. Glycopeptides, quinolones, and aminoglycosides were indifferent. No drugs were antagonistic. The positive Q-D-beta-lactam interaction was independent of MLS(B) or beta-lactam resistance. Moreover, addition of Q-D at one-fourth the MIC to flucloxacillin-containing plates decreased the flucloxacillin MIC for MRSA from 500 to 1,000 mg/liter to 30 to 60 mg/liter. Yet, Q-D-beta-lactam combinations were not synergistic in bactericidal tests. Rats with aortic vegetations were infected with two C-MLS(B)-resistant MRSA isolates (isolates AW7 and P8) and were treated for 3 or 5 days with drug dosages simulating the following treatments in humans: (i) Q-D at 7 mg/kg two times a day (b.i.d.) (a relatively low dosage purposely used to help detect positive drug interactions), (ii) cefamandole at constant levels in serum of 30 mg/liter, (iii) cefepime at 2 g b.i.d., (iv) Q-D combined with either cefamandole or cefepime. Any of the drugs used alone resulted in treatment failure. In contrast, Q-D plus either cefamandole or cefepime significantly decreased valve infection compared to the levels of infection for both untreated controls and those that received monotherapy (P < 0.05). Importantly, Q-D prevented the growth of highly beta-lactam-resistant MRSA in vivo. The mechanism of this beneficial drug interaction is unknown. However, Q-D-beta-lactam combinations might be useful for the treatment of complicated infections caused by multiple organisms, including MRSA.

Topics: Animals; Anti-Bacterial Agents; Cefamandole; Cefepime; Cephalosporins; Disease Models, Animal; Drug Resistance, Microbial; Drug Resistance, Multiple; Drug Therapy, Combination; Endocarditis, Bacterial; Humans; Lincosamides; Macrolides; Microbial Sensitivity Tests; Rats; Staphylococcal Infections; Staphylococcus aureus; Time Factors; Virginiamycin

The susceptibility of clinical isolates of methicillin-susceptible and -resistant staphylococci from cancer patients with central venous catheter bacteremia to quinupristin/dalfopristin, a semisynthetic streptogramin, was determined in vitro. Susceptibility of these isolates to nine other antistaphylococcal antibiotics was also determined for comparison. A total of 197 staphylococcal strains were tested from 1983 to 1992. Quinupristin/dalfopristin was bactericidal against all isolates, independent of their resistance to methicillin. Its activity was similar to that of vancomycin but superior to that of teicoplanin. Quinupristin/dalfopristin may prove to be an important addition to our armamentarium against catheter-related staphylococcal infections.

Topics: Anti-Bacterial Agents; Anti-Infective Agents; Antibiotics, Antitubercular; Bacteremia; Catheterization, Central Venous; Cefamandole; Cephalosporins; Ciprofloxacin; Clindamycin; Daptomycin; Humans; Methicillin; Methicillin Resistance; Microbial Sensitivity Tests; Neoplasms; Novobiocin; Oxacillin; Penicillins; Rifampin; Staphylococcal Infections; Staphylococcus aureus; Staphylococcus epidermidis; Teicoplanin; Vancomycin; Virginiamycin