Dalfopristin

Synercid (RP 59500), the first injectable streptogramin antibiotic, is composed of two semisynthetic pristinamycin derivatives, quinupristin and dalfopristin. Individually, each component has bacteriostatic activity against staphylococci and streptococci, but together, the agents exhibit synergy, leading to bactericidal activity. The combination drug, however, is bacteriostatic against Enterococcus faecium and has poor activity against Enterococcus faecalis. Despite a short half-life, an extended postantibiotic effect allows the agent to be dosed every 8-12 hours. Both drugs are largely hepatically metabolized and excreted in bile. Although not metabolized by cytochrome P450 3A4, quinupristin-dalfopristin can inhibit agents that are metabolized through this pathway. Dosage adjustments may be necessary in patients with hepatic dysfunction. Alterations in renal function have minimal effects on the agent's pharmacokinetics. Adverse events include arthralgia, myalgias, and infusion-related pain. Based on available data, quinupristin-dalfopristin appears to have a role in treating severely ill patients with infections due to multiresistant gram-positive pathogens.

Quinupristin/dalfopristin is a streptogramin antibacterial with a wide spectrum of Gram-positive antibacterial activity. The drug has minimal oral absorption and is administered intravenously as a fixed 30 : 70 ratio of quinupristin to dalfopristin. A linear relationship has been observed between the dose administered and maximum plasma concentrations. Single-dose administration of 7.5 mg/kg produced a maximal plasma concentration of 2.3-2.7 mg/L for quinupristin and 6.1-8.2 mg/L for dalfopristin. The area under the concentration-time curve (AUC) obtained with the same dose was 2.7-3.3 and 6.5-7.7 mg. h/L for quinupristin and dalfopristin, respectively. Repeated administration results in 13-21% increases in maximum plasma concentrations and 21-26% increases in AUC for both quinupristin and dalfopristin. Quinupristin and dalfopristin exhibit steady-state volumes of distribution of 0.46-0.54 and 0.24-0.30 L/kg, respectively. Quinupristin exhibits higher protein binding (55-78%) than dalfopristin (11-26%), though both entities distribute well into tissues. Concentrations exceeding those in blood have been reported for the kidney, liver, spleen, salivary glands and white blood cells of primates. Extravascular penetration, as measured in blister fluid, is 40-80%. Both quinupristin and dalfopristin are extensively metabolised via nonenzymatic reactions. Quinupristin is conjugated to form two active compounds, a cysteine moiety and a glutathione moiety. Dalfopristin is hydrolysed to the active metabolite pristinamycin IIA. The metabolites exert antibacterial activity similar to that of the parent compounds. Quinupristin/dalfopristin is excreted primarily in the faeces (75-77%), with lesser renal excretion (15-19%). The elimination half-lives of quinupristin and dalfopristin are similar, and are 0.7-1.3 hours after single doses. The metabolites have slightly longer half-lives, ranging from 1.2 to 1.8 hours. With repeated doses, plasma clearance of quinupristin and dalfopristin is reduced by approximately 20% compared with single doses, resulting in clearances of 0.7-0.8 L/h/kg. Saturable protein binding has been hypothesised as a causative mechanism. Quinupristin/dalfopristin is an inhibitor of cytochrome P450 3A4, resulting in multiple drug interactions. Ciclosporin AUC increased by 5-222% when coadministered with quinupristin/dalfopristin. Careful monitoring of patients receiving drugs that are substrates of cytochrome P450 3A4 is suggested.Quinupristin/dalfopristin is administered at 7.5 mg/kg every 8-12 hours, depending upon the severity of infection. The pharmacodynamic parameter linked with antibacterial activity for quinupristin/dalfopristin appears to be the ratio of AUC to the minimal inhibitory concentration. The additional activity of a prolonged post-antibiotic effect may also be important for efficacy.

Quinupristin-dalfopristin (RP 59500) is an injectable streptogramin antibiotic. It possesses a wide spectrum of activity against Gram-positive bacteria including methicillin-resistant staphylococci, glycopeptide-resistant. Enterococcus faecium and penicillin-resistant pneumococci. Quinupristin-dalfopristin has activity against some anaerobes and selected Gram-negative pathogens. Quinupristin-dalfopristin, by way synergism of between its 2 components, is unaffected by most forms of bacterial resistance. Rare forms of macrolide-lincosamide-streptogramin group B resistance may affect its activity; however, at present the incidence of strains with this type of resistance remains low. Quinupristin-dalfopristin is bactericidal against streptococci and staphylococci but has weak or no bactericidal activity against enterococci. In a compassionate use programme, 67% of 95 evaluable patients with vancomycin-resistant Gram-positive infections or intolerant of vancomycin showed improvement with eradication of infection.