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By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD
The fda has approved a new two-drug antibiotic that promises to be effective against resistant bacteria. Rhône Poulenc Rorer’s Synercid pairs the antimicrobials quinupristin and dalfopristin, both members of a new class of antibiotics known as streptogramins. The drugs work synergistically against a range of bacterium, including vancomycin-resistant Enterococcus faecium (VREF) and other gram-positive bacteria.1 Synercid was given an accelerated approval as it qualified as a product for use in life-threatening conditions when other alternatives are not available.
Quinupristin/dalfopristin is indicated for the treatment of patients with serious or life-threatening infections associated with vancomycin-resistant Enterococus faecium (VREF) bacteremia. It is also indicated for the treatment of complicated skin and skin structure infections caused by Staphyloccus aureaus (methicillin susceptible) or Streptococcus pyogenes.
The recommended dosages are 7.5 mg/kg every 8 hours for VREF and 7.5 mg/kg every 12 hours for complicated skin and skin structure infections. The drug is administered by intravenous infusion over a 60-minute period. The minimum duration of treatment is 7 days for complicated skin and skin structure infections and duration should be determined by the site and severity of VREF infections.2 In the clinical trials the average duration of therapy of VREF was 14.5 ± 10.7 days.5
No dosage adjustment is required in the elderly or in patients with renal impairment. The manufacturer did not have a recommendation for dosage reduction in patients with hepatic impairment since the half life of the two components did not change but the area under curve (AUC) increased by about 180% and 50%, respectively.2
Quinupristin/dalfopristin is supplied as 500 mg (150 mg of quinupristin and 350 mg of dalfopristin) in single-dose 10 mL vials.
Quinupristin/dalfopristin has demonstrated good activity against a number of resistant gram-positive bacteria including methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecium, and penicillin-resistant Streptococcus pneumoniae.1,3,4 Quinupristin/dalfopristin is bacteriostatic against Enterococcus faecium and bactericidal against methicillin-susceptible and methicillin-resistant Staphylococcus aureus.2 Cross-resistance to other classes of antibiotics has not been reported.1
The FDA approved the drug combination for serious infections caused by vancomycin-resistant Enterococcus faecium. Despite the short elimination half-lives of quinupristin and dalfopristin (< 1 hour), the post-antibiotic effect and active metabolites permit dosing every 8-12 hours.1,2
Emergence of resistance to quinupristin/dalfopristin has been reported during treatment of VREF.1 Quinupristin/dalfopristin is not active against Enterococcus faecalis.1,2 It is important to differentiate these enterococcal species.1 The drug is an inhibitor of cytochrome P450 isoenzyme 3A4. Drugs metabolized by this pathway may have their plasma levels increased. The most common adverse effects are injection-site-related side effects such as pain (40%), inflammation (42%), and edema (17%). Other side effects include nausea (4%), vomiting (3.7%), arthralgia, and myalgia (7%).
The most common laboratory abnormalities are increases (5 ´ ULN) of total and conjugated bilirubin (25-35%).1
Quinupristin/dalfopristin was approved based on a surrogate marker, clearance of VREF bacteremia, not the cure or improvement of the underlying infection. The validity of this surrogate end point has not been validated.1 In two open-label comparative trials in patients with complicated skin and skin structure infections, bacteriological success rates for selected bacteria1 suggest that quinupristin/dalfopristin may be less effective against gram-positive pathogens than the comparator drug (66.6% vs 77.7%; P = 0.004). This difference was largely explained by lower success against methicillin-sensitive S. aureus (64.3% vs 76.%).6
Quinupristin/dalfopristin is a mixture of two semisynthetic derivatives of pristinamycin at a 30:70 mixture. These two drugs act synergistically against gram-positive bacteria by inhibiting protein synthesis at different sites on the bacterial ribosomes.1 The drug was given an accelerated approval by the FDA permitted for drugs to be used for life-threatening conditions with limited or no alteratives. Quinupristin/dalfopristin was studied in noncomparative emergency use settings in infections caused by vancomycin-resistant Enterococcus faecium.5 In a published report of two prospective studies, the overall success rate (clinical and bacteriologic cure) was 65.8% (95% CI, 57.9%, 72.9) in 156 evaluable patients. However, this may be misleading as only 24.4% of the total 1222 patients in four studies were evaluable due to variability in data collection. When all the evaluable patients were considered (n = 298) the overall success was 52.3%. FDA approval was based on a 90% clearance of VREF bacteremia within the first 48 to 72 hours.1 In two randomized, open-label trials in patients with complicated skin and skin structure infections (S. aureus most commonly isolated) quinupristin/dalfopristin produced comparable success rates compared to oxacillin or cefazolin (68% vs 71%).6 Vancomycin may be substituted if MRSA is suspected or confirmed, or if the initial comparator is not appropriate. These studies did not assess the drug against methicillin-resistant S. aureus, as only 2.7% of the infections were caused by MRSA. The FDA approval for this indication only included methicillin-susceptible S. aureus.
Quinupristin/dalfopristin is priced at $103 per 500 mg vial or roughly $200-300 per day.
Treating infections caused by vancomycin-resistant E. faecium has been problematic due to the limited number of therapeutic options. In vitro data suggest that quinupristin/dalfopristin is active against VREF. However, clinical data are limited due to emergency-use protocols severely limiting the number of evaluable patients. This is further complicated by the use of a surrogate end point that has not been validated in VREF infections, making clinical results difficult to evaluate. Given the lack of viable therapeutic options for VREF however, quinupristin/dalfopristin becomes a reasonable option. Findings from published data on skin and skin structure infections suggest that quinupristin/dalfopristin was no better than oxacillin/vancomycin or cefazolin/vancomycin. As for infections caused by methicillin-resistant S. aureus, more clinical data are needed to establish clinical efficacy.
1. Bryson HM, et al. Drugs 1996;52(3):406-415.
2. Synercid product information. Rhône-Poulenc Rorer Pharmaceuticals Inc. September 1999.
3. Kang SL, et al. J Antimicrob Chemother 1997;30: 33-39.
4. Low DE, et al. J Antimicrob Chemother 1997;30:53-58.
5. Moellering RC, et al. J Antimicrob Chemother 1999; 44(2):251-261.
6. Nichols RL, et al. J Antimicrob Chemother 1999;44: 19-23.