Introduction
Quinupristin and dalfopristin (marketed as Synercid) is a combination antibacterial agent belonging to the streptogramin class. This intravenous antibiotic consists of two distinct pristinamycin derivatives that work synergistically to combat resistant Gram-positive infections. The combination was approved by the FDA in 1999 specifically for treating serious infections caused by vancomycin-resistant Enterococcus faecium (VREF) and complicated skin and skin structure infections.
Mechanism of Action
Quinupristin and dalfopristin act synergistically through sequential binding to the bacterial 50S ribosomal subunit. Dalfopristin binds first to the 23S rRNA component, inducing conformational changes that create higher affinity binding sites for quinupristin. This dual mechanism inhibits protein synthesis through: 1) Blocking substrate attachment to the peptidyl transferase center (dalfopristin) and 2) Preventing peptide chain elongation (quinupristin). The combination demonstrates bactericidal activity against most streptogramin-susceptible organisms due to this irreversible ribosomal inhibition.
Indications
FDA-approved indications:
- Vancomycin-resistant Enterococcus faecium (VREF) bacteremia
- Complicated skin and skin structure infections caused by Staphylococcus aureus (methicillin-susceptible) or Streptococcus pyogenes
Off-label uses (based on clinical evidence):
- Infections caused by other resistant Gram-positive pathogens
- Alternative therapy for patients with beta-lactam allergies
- Salvage therapy for multidrug-resistant infections
Dosage and Administration
Standard dosing: 7.5 mg/kg administered intravenously every 8-12 hours Infusion method: Dilute in 250 mL D5W and infuse over 60 minutes Duration: Typically 7-14 days depending on infection severity and clinical response Special populations:- Renal impairment: No dosage adjustment required
- Hepatic impairment: Consider dose reduction in severe cirrhosis
- Elderly: Use standard dosing with careful monitoring
- Pediatrics: Safety established for children ≥16 years; limited data for younger patients
Pharmacokinetics
Absorption: IV administration only; complete bioavailability Distribution: Widely distributed with Vd ~0.45 L/kg; poor CNS penetration Metabolism: Hepatic metabolism via non-enzymatic conjugation and hydrolysis Elimination: Primarily biliary excretion (75-77%); renal elimination accounts for 15-19% Half-life: Quinupristin: ~0.85 hours; Dalfopristin: ~0.70 hours Protein binding: Moderate (55-78%)Contraindications
- Known hypersensitivity to quinupristin, dalfopristin, or other streptogramins
- Patients taking medications metabolized by CYP3A4 that have narrow therapeutic indices (concurrent administration contraindicated)
Warnings and Precautions
Black Box Warning: Concomitant use with cyclosporine requires careful monitoring due to increased exposure of both drugs Venous irritation: High incidence of infusion-related phlebitis requiring central venous access Hyperbilirubinemia: Monitor liver function tests weekly Musculoskeletal effects: Arthralgia and myalgia reported in up to 10% of patients Pseudomembranous colitis: Possible Clostridium difficile-associated diarrhea Superinfections: Possible emergence of resistant organismsDrug Interactions
Major interactions:- CYP3A4 substrates: Increased concentrations of drugs metabolized by CYP3A4 (e.g., cyclosporine, midazolam, nifedipine, quinidine)
- Drugs that prolong QTc interval: Additive risk of cardiac arrhythmias
- Other antibiotics: Potential antagonism with bacteriostatic agents
- Hepatotoxic drugs: Increased risk of liver enzyme elevations
Adverse Effects
Very common (>10%):- Infusion site reactions (pain, inflammation, edema)
- Hyperbilirubinemia
- Nausea, vomiting, diarrhea
- Arthralgia, myalgia
- Rash, pruritus
- Headache
- Elevated transaminases
- Severe hypersensitivity reactions
- Clostridium difficile infection
- Thrombophlebitis
- QTc prolongation
Monitoring Parameters
Baseline:- Complete blood count with differential
- Comprehensive metabolic panel (including LFTs)
- Culture and susceptibility results
- Assessment of venous access options
- Daily assessment of infusion sites
- Weekly liver function tests
- Signs/symptoms of arthralgia or myalgia
- Temperature and WBC trends
- Repeat blood cultures as clinically indicated
- Resolution of infection markers
- Monitoring for late-onset adverse effects
Patient Education
- Report any muscle or joint pain immediately
- Understand importance of completing full course of therapy
- Be aware of potential infusion site reactions
- Report any signs of allergic reaction (rash, itching, swelling)
- Inform all healthcare providers about this medication
- Notify physician if diarrhea develops during or after treatment
- Understand that this medication requires specialized venous access
- Be aware of potential drug interactions with other medications
References
1. FDA Prescribing Information: Synercid (quinupristin and dalfopristin) 2. Moellering RC et al. Efficacy and safety of quinupristin/dalfopristin for treatment of infections caused by vancomycin-resistant Enterococcus faecium. J Antimicrob Chemother. 1999 3. Linden PK et al. Quinupristin/dalfopristin in the treatment of vancomycin-resistant Enterococcus faecium infections. Clin Infect Dis. 2001 4. Drew RH et al. Quinupristin-dalfopristin: a review of its use in the management of serious gram-positive infections. Drugs. 2000 5. NCCN Guidelines: Prevention and Treatment of Cancer-Related Infections 6. IDSA Guidelines for the Treatment of Vancomycin-Resistant Enterococci