New Antimicrobial Agents Look Good Against Nosocomial Staphylococci
ABSTRACT & COMMENTARY
Source: Sambatakou H, et al. In-vitro activity and killing effect of quinupristin/dalfopristin (RP59500) on nosocomial Staphylococcus aureus and interactions with rifampicin and ciprofloxacin 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 will probably come to the U.S. market soon and be available for parenteral use only. This study from Athens Medical School in Greece offers the most current data for Synercid's activity against hospital 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.
Of the 164 isolates tested, 93% were from pus and only six from blood. A microdilution technique was used to determine the MICs, and MBCs were determined by plating all the clear wells onto agar, with the MBC defined as the lowest concentration that killed 99.9% of the inoculum. For 11 antimicrobials tested, the MIC90 was in the resistant range for oxacillin, imipenem, gentamicin, erythromycin, clindamycin, tetracycline, and co-trimoxazole. The range of susceptibilities for ciprofloxacin and rifampicin was from 0.5 or less to 4.0 or higher. Quinupristin/dalfopristin was more active against MSSA than MRSA: The MIC50, MIC90, MBC50, and MBC90 for MSSA were 0.015 or less, 0.06, 0.015 or less, and 0.25 mg/L, respectively, compared to 0.015 or less, 2, 0.12, and 2 mg/L, respectively, for MRSA, noting that the major difference is a reduced bactericidal effect against the MRSA isolates.
Killing curves supported the superior activity of quinupristin/dalfopristin against MSSA strains: 50% of MRSA strains were killed by 4´MIC 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 (³ 7 log decreases) in 100% of MSSA isolates at 24 hours but was bactericidal in fewer-75% (ciprofloxacin) and 83% (rifampicin), of MRSA isolates, respectively-at 24 hours.
For one MRSA isolate graphically presented, 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
The arrival of quinupristin/dalfopristin (Synercid) has been anticipated for several years. Preliminary data suggest that 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. Against MSSA, the combination is highly inhibitory and bactericidal. On the other hand, the data for MRSA show less inhibitory effect, and the bactericidal concentration is reduced four-fold (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 ciprofloxacin 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 (e.g., to determine the MBC before committing patients to long-term therapy of proven or suspected endothelial infections). 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 a traditional Journal of Antimicrobial Chemo- therapy leading article format appearing in the same issue with the article from Sambatakou et al, Rahman discusses other current and expectant alternatives to vancomycin (J Antimicrob Chemother 1998;41:325-328). Rahman seems to have little concern about a lack of alternatives to treat MRSA infections. In his clinical microbiology laboratory in central England, Rahman has found that 90-98% of MRSA strains from that region are susceptible to rifampicin, fusidic acid, gentamicin, trimethoprim, and tetracycline (in decending frequency). About 75% were susceptible to chloramphenicol and clindamycin. Thus, Rahman feels there are many alternatives to glycopeptides, particularly in the United Kingdom. In the United Kingdom, it seems that fusidic acid combined with trimethoprim is effective against MRSA infections, and, when it's not, use of intravenous teichoplanin is effective. Perhaps the United Kingdom, in fact, has less cross-resistant strains while having the added luxury of fusidic acid. Here in the United States, I think we go directly to vancomycin therapy for MRSA, save for mild infections caused by strains that may be susceptible to co-trimoxazole or clindamycin.
As for investigational agents, Rahman points expectantly to quinupristin/dalfopristin, the oxazolidinones (mostly bacteriostatic against MRSA), new glycopeptides, new quinolones including the newly released trovofloxacin (see page 126), glycylcyclines, and new carbapenems. The problem with the new agents, as pointed out by Rahman, is that there are very few clinical trials with these agents including quinupristin/dalfopristin. In compassionate-use programs, 10 of 11 cases of MRSA bacteremia were successfully treated with the streptogram 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 uncontrolled trials, to determine the niche that this novel streptogram will fill.