Testing a new weapon against nosocomial staph
Drug fares better against MSSA than MRSA
Source: Sambatakou H, et al. In-vitro activity and killing effect of quinupristin/dalfopristin (RP59500) on nosocomial Staphylococcus aureus and interactions with rifampicin and ciproflox acin against methicillin-resistant isolates. J Antimicrob Chemother 1998; 41:349-355.
Quinupristin/dalfopristin, known previously as RP59500, is a combination of two streptogramins, semisynthetic derivatives of insoluble pristinamycins IA and IIB, respectively. A commercial product under the name Synercid is expected on the U.S. market soon for parenteral use only. This study from Athens Medical School in Greece offers some of the most current data for Synercid's activity against nosocomial strains of Staphylococcus aureus. Sambatakou and colleagues seek to determine three traits of Synercid: 1) its in vitro inhibitory activity against 101 methicillin-resistant S. aureus (MRSA) strains and 53 methicillin-susceptible S. aureus (MSSA) isolates; 2) its killing effect against 24 MRSA and seven MSSA isolates; and 3) its interactions with rifampicin and ciprofloxacin against 18 MRSA isolates, six susceptible to both rifampicin and ciprofloxacin and 12 resistant to both.
Killing curves supported the superior activity of quinupristin/dalfopristin against MSSA strains: 50% of MRSA strains were killed by 4 MIC (minimum inhibitory concentration) at 24 hours as compared to 100% of MSSA isolates at the same time and concentration. Three (12.5%) of the 24 MRSA strains tested were not killed after 24 hours incubation at 1 MIC, and two (8.3%) were not killed after 24 hours at 2 MIC, whereas at 4 MIC, no resistance to killing was observed. The combination of quinupristin/dalfopristin plus ciprofloxacin or rifampicin at 4 MIC was bactericidal in 100% of MSSA isolates at 24 hours. The combination was bactericidal in 75% (ciprofloxacin) and 83% (rifampicin) of MRSA isolates at 24 hours. For one MRSA isolate, neither ciprofloxacin nor rifampicin was bactericidal, but the combination using ciprofloxacin or rifampicin at their mean serum levels was bactericidal at 24 hours for 2 MIC and at 6 hours or less at 4 MIC.
Comment by Joseph F. John, MD, professor of medicine and microbiology, Robert Wood Johnson Medical School, New Brunswick, NJ.
The arrival of quinupristin/dalfopristin (Synercid) has been anticipated for several years. Preliminary data suggest it has good activity against gram-positive bacteria, but there are few clinical data published. Although the present study does not use case studies, the in vitro data presented here using only nosocomial strains of S. aureus are reassuring to a certain degree. The combination is highly inhibitory and bactericidal against MSSA. On the other hand, the data for MRSA show less inhibitory effect, and the bactericidal concentration is reduced fourfold (0.25-2.0 mg/L). For 50% of the MRSA isolates that were not killed by 4 MIC of quinupristin/dalfopristin, a synergistic effect was seen with both ciproflox acin and rifampicin at 2 MIC and 4 MIC, even if the isolates were resistant to ciprofloxacin and rifampicin.
What is exciting about this study is that soon there should be an alternative anti-staphylococcal chemotherapy. For those patients who are intolerant to both penicillin and vancomycin and who have MSSA infections, quinupristin/dalfopristin should prove a reasonable alternative. For those patients who have MRSA infections, perhaps more analysis of such strains will be necessary. If there are no other alternatives for MRSA infections, this study suggests that use of ciprofloxacin or rifampicin in combination with quinupristin/ dalfopristin may be an effective regimen. In compassionate-use programs, 10 of 11 cases of MRSA bacteremia were successfully treated with the streptogramin in combination. Quinupristin/dalfopristin seems to be generally well-tolerated but has some distinctive adverse effects, including joint and muscle pain and venous intolerance. As Synercid becomes available, clinicians will need to weigh a body of data from in vitro studies like that of Sambatakou et al, as well as data from additional trials, to determine the niche this novel antibiotic will fill.
Jarvis WR. Epidemiology, appropriateness, and cost of vancomycin use. Clin Infect Dis 1998; 26:1,200-1,203.
Inappropriate use of vancomycin is known to contribute to increased prevalence of resistant pathogens, but it may also contribute to spiraling costs in hospital pharmaceutical budgets, the author notes.
Overall pharmaceutical costs, which approach $40 billion annually, account for about 8% of health care costs. Prescription drugs represent 5% to 20% of the total hospital budget, and antimicrobials account for 20% to 50% of hospital pharmaceutical costs. Some investigators estimate that the worldwide market for pharmaceuticals will continue to increase, the author reports. Costs were estimated at $75 billion in 1980, $150 billion in 1990, and are expected to rise to $270 billion by 2000. Studies also show that vancomycin use is increasing and that dosing is often inappropriate. Because of the emergence of multidrug-resistant coagulase-positive or -negative Staphylococcus, Enterococcus, and Streptococcus pneumoniae, vancomycin use has dramatically increased during the last several years in the United States. In addition, one study found that of 101 orders, vancomycin use was in compliance with the CDC recommendations in only 35 instances (35%). Oncology, neurosurgery, and cardiovascular surgery patients are particularly more likely to receive vancomycin inappropriately.
The few studies that have assessed the cost of vancomycin use indicate that it is costly, the author reports. A prospective cohort study performed at a community hospital reported that 100 infected adults received almost 1,400 doses of vancomycin. Duration of therapy (at a dosage of 2,000 mg/d) lasted a mean of 10 days. Phlebitis was the most common adverse reaction, occurring in 38 patients. The investigators considered various costs, including pharmacy preparation, drug administration by nurses, monitoring serum concentrations, and, most important, treating adverse reactions. They found that the overall cost for preparation and administration was almost $24,000 (mean, $17.50 per dose), and the cost for monitoring serum concentrations was about $1,700 (mean, $15 per assay). Finally, the cost for treatment of adverse reactions was about $4,700 (mean, about $94 per adverse reaction). Thus, the total cost was about $30,000.
"The appropriateness of antimicrobial use, including vancomycin, needs to be assessed in our hospitals, in health maintenance organizations, in outpatient settings, and in home therapy," the author concludes. "Pharmacy databases, particularly in the inpatient setting, should be developed and used for monitoring antimicrobial use, not just for billing."
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