Quinupristin+dalfopristin

Pharmacokinetics

Quinupristin + dalfopristin 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 AUC obtained with the same dose was 2.7–3.3 and 6.5–7.7 h mg/l for quinupristin and dalfopristin, respectively. Repeated administration results in 13–21% increases in maximum plasma concentrations and 21–26% increases in the AUCs of quinupristin and dalfopristin. Quinupristin is more highly protein bound (55–78%) than dalfopristin (11–26%), though both distribute well into tissues. Quinupristin and dalfopristin have steady-state volumes of distribution of 0.46–0.54 and 0.24–0.30 l/kg respectively. 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 metabolized via non-enzymatic reactions. Quinupristin is conjugated to form two active compounds, a cysteine moiety and a glutathione moiety. Dalfopristin is hydrolysed to the active metabolite pristinamycin. Quinupristin + dalfopristin is excreted primarily in the feces (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 hypothesized as a causative mechanism.

General adverse effects and adverse reactions

Adverse reactions include arthralgia, myalgia, and pain at the infusion site [ ]. Infusion-site reactions occurred in 42% of cases, infusion-site pain in 40%, edema in 17%, arthralgias in 47%, myalgias in 6%, gastrointestinal effects in 3–5%, rash in 2.5%, headache in 1.6%, pruritus in 1.5%, and hyperbilirubinemia in 25% [ , ].

Observational studies

In a small, open, phase II pilot study, low-dose quinupristin + dalfopristin (5 mg/kg intravenously every 8 hours; n = 11) and high-dose quinupristin + dalfopristin (7.5 mg/kg intravenously every 8 hours; n = 15) were compared with vancomycin (1 g intravenously every 12 hours; n = 13) in the treatment of catheter-related staphylococcal bacteremia [ ]. In patients with a baseline pathogen, the outcome was comparable in all groups. Adverse clinical events in the quinupristin + dalfopristin group consisted of arm and chest pain, chills, fever, arthritis, and phlebitis or pain at the injection site; quinupristin + dalfopristin was withdrawn in 12% of patients (compared with 15% of vancomycin-treated patients).

In healthy volunteers receiving quinupristin + dalfopristin, 7.5 mg/kg infused over 1 hour bd, mean fecal antibiotic concentrations were 291 and 42 μg/g of feces for quinupristin and dalfopristin respectively by the fifth day of treatment [ ].

The safety profile of quinupristin + dalfopristin has been evaluated in more than 2000 patients [ ]. The most common adverse effect was pain and inflammation at the infusion site. However, treatment withdrawal was reported in under 10% of patients. Other adverse effects include arthralgias (9%) and myalgias (6%), which have led to the withdrawal of quinupristin + dalfopristin in one-third to a half of affected patients. Other common systemic adverse events have been nausea (4.6%), diarrhea (2.7%), vomiting (2.7%), rash (2.5%), headache (1.6%), pruritus (1.5%), and pain (1.5%). Liver function abnormalities have occurred in about 1% of patients who received quinupristin + dalfopristin. However, these effects have generally been mild and transient. No significant effects on renal function have been reported and bone marrow toxicity has been rare.

Comparative studies

The pooled results of two multicenter, phase III, randomized comparisons of quinupristin + dalfopristin (7.5 mg/kg intravenously every 12 hours; n = 450) with established comparators (cefazolin, oxacillin, vancomycin; n = 443) for complicated skin and skin structure infections have been reported [ ]. The success rate was equivalent in the two groups: 63% of patients given quinupristin + dalfopristin (versus 54%) reported at least one adverse event, most commonly nausea, vomiting, rash, pain, or pruritus. Although most of the adverse events were mild to moderate, the drug was withdrawn in 19% of patients treated with quinupristin + dalfopristin (versus 4.7%) owing to an untoward event. Adverse venous events (atrophy, edema, hemorrhage, hypersensitivity, inflammation, thrombophlebitis, pain) were reported by 66% of patients treated with quinupristin + dalfopristin (versus 28%) and required withdrawal of the drug in 12% of these patients (versus 2%).