Quinupristin/Dalfopristin

Abstract

Quimipristin/dalfopristin is the first parenteral streptogramin antibacterial agent, and is a 30: 70 (w/w) ratio of 2 semisynthetic pristinamycin derivatives. The combination has inhibitory activity against a broad range of Gram-positive bacteria including methicillin-resistant staphylococci, vancomycin-resistant Enterococcus faecium (VREF), drug-resistant Streptococcus pneumoniae, other streptococci, Clostridium perfringens and Peptostreptococcus spp. The combination also has good activity against selected Gram-negative respiratory tract pathogens including Moraxella catarrhalis, Legionella pneumophila and Mycoplasma pneumoniae. Quinupristin/dalfopristin has poor activity against E. faecalis. The combination is bactericidal against staphylococci and streptococci, although constitutive erythromycin resistance can affect its activity. As for many other agents, quinupristin/dalfopristin is generally bacteriostatic against E. faecium. In patients with methicillin-resistant S. aureus (MRSA) or VREF infections participating in prospective emergency-use trials, quinupristin/dalfopristin 7.5 mg/kg every 8 or 12 hours achieved clinical or bacteriological success in ≥64% of patients. Emergence of resistance to quinupristin/dalfopristin was uncommon (4% of patients) in those with VREF infections. Quinupristin/dalfopristin 7.5 mg/kg 8- or 12-hourly also achieved similar clinical success rates to comparator agents in patients with presumed Gram-positive complicated skin and skin structure infections or nosocomial pneumonia (administered in combination with aztreonam) in 3 large multicentre randomised trials. Systemic adverse events associated with quinupristin/dalfopristin include gastrointestinal events (nausea, vomiting and diarrhoea), rash and pruritus. Myalgias and arthralgias also occur at an overall incidence of 1.3%, although higher rates (2.5 to 31%) have been reported in patients with multiple comorbidities. Venous events are common if the drug is administered via a peripheral line; however, several management options (e.g. use of central venous access, increased infusion volume) may help to minimise their occurrence. Hyperbilirubinaemia has been documented in 3.1% of quinupristin/dalfopristin recipients versus 1.3% of recipients of comparator agents. Quinupristin/dalfopristin inhibits cytochrome P450 3A4 and therefore has the potential to increase the plasma concentrations of substrates of this enzyme. Conclusions: Quinupristin/dalfopristin, the first parenteral streptogramin, offers a unique spectrum of activity against multidrug-resistant Gram-positive bacteria. In serious Gram-positive infections for which there are other treatment options available, the spectrum of activity and efficacy of quinupristin/dalfopristin should be weighed against its tolerability and drug interaction profile. However, in VREF or unresponsive MRSA infections, where few proven treatment options exist, quinupristin/dalfopristin should be considered as a treatment of choice for these seriously ill patients. Quinupristin/dalfopristin (30: 70 ratio) is a parenteral streptogramin agent. Both quinupristin and dalfopristin possess inhibitory antibacterial activity; however, as a combination, they demonstrate markedly increased or synergistic activity. Varying the ratio of quinupristin to dalfopristin or replacing dalfopristin with its active metabolite (RP 12536) does not appear to affect the in vitro inhibitory activity of the combination. An overview of published in vitro data reveals that quinupristin/dalfopristin has inhibitory activity against a broad range of Gram-positive bacteria including: staphylococci (regardless of methicillin susceptibility), Enterococcus faecium (regardless of vancomycin susceptibility), Streptococcus pneumoniae (regardless of penicillin or erythromycin susceptibility), S. pyogenes, S. agalactiae, viridans streptococci, Clostridium perfringens and Peptostreptococcus spp. Quinupristin/dalfopristin has more variable activity against Corynebacterium jeikeium, Listeria monocytogenes, Leuconostoc spp. and other Gram-positive anaerobes. The combination also has good activity against selected Gram-negative pathogens including Moraxella catarrhalis, Legionella pneumophila, Neisseria meningitidis and Mycoplasma pneumoniae. It possesses little or no activity against E. faecalis or Haemophilus influenzae. Although resistance to the macrolide, lincosamide and streptogramin (MLS) family of antibiotics is common, resistance to quinupristin/dalfopristin is unusual. When characterised in staphylococci, quinupristin/dalfopristin resistance was always associated with 2 to 4 resistance genes (i.e. vga, vgb, vatB and/or erm). Rare clinical isolates of E. faecium. are resistant (minimum inhibitory concentration of ≥8 mg/L) to quinupristin/dalfopristin; characterised strains possessed the satA gene. In enterococci and streptococci, but not staphylococci, quinupristin acts as an inducer of MLS_B resistance. Quinupristin/dalfopristin is rapidly bactericidal against some strains of staphylococci and streptococci, but generally has bacteriostatic activity against E. faecium. Quinupristin/dalfopristin is not consistently bactericidal against staphylococcal strains with constitutive MLS_B resistance. Compared with vancomycin, quinupristin/dalfopristin demonstrated greater bactericidal activity against some staphylococcal strains (p < 0.05 in 1 study), but similar or less activity against others. Quinupristin/dalfopristin has a postantibiotic effect (PAE) against Gram-positive bacteria. Against methicillin-resistant Staphylococcus aureus (MRSA), rifampicin is synergistic with quinupristin/dalfopristin. Against VREF, doxycycline showed synergism with quinupristin/dalfopristin and also prevented or...