Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, powder for reconstitution:
Synercid®: 500 mg: Quinupristin 150 mg and dalfopristin 350 mg
Pharmacology
Mechanism of Action
Quinupristin/dalfopristin inhibits bacterial protein synthesis by binding to different sites on the 50S bacterial ribosomal subunit thereby inhibiting protein synthesis
Pharmacokinetics/Pharmacodynamics
Distribution
Quinupristin: 0.45 L/kg; dalfopristin: 0.24 L/kg
Metabolism
Quinupristin is conjugated with glutathione and cysteine to active metabolites; dalfopristin is hydrolyzed to an active metabolite
Excretion
Feces (75% to 77% as unchanged drug and metabolites); urine (15% to 19%)
Half-Life Elimination
Quinupristin: 0.85 hour; Dalfopristin: 0.7 hour (mean elimination half-lives, including metabolites: 3 and 1 hours, respectively)
Use: Labeled Indications
Skin and skin structure infections, complicated: Treatment of complicated skin and skin structure infections caused by methicillin-susceptible Staphylococcus aureus or Streptococcus pyogenes
Use: Off Label
Bacteremia (methicillin-resistant Staphylococcus aureus)yes
Based on the Infectious Diseases Society of America (IDSA) Practice Guidelines for the Treatment of Methicillin-Resistant Staphylococcus aureus, quinupristin and dalfopristin may be considered for the treatment of persistent MRSA bacteremia associated with vancomycin failure and when reduced susceptibility to vancomycin and daptomycin is present.
Infective endocarditis (methicillin resistant Staphylococcus aureus), treatmentc
Data from a multicenter, open-label, non-comparative trial in patients with culture proven methicillin resistant staphylococcus aureus (MRSA) infections, including patients with infective endocarditis, suggested that quinupristin/dalfopristin may be considered as a treatment option in patients with MRSA infective endocarditis who do not respond to other clinically appropriate antibiotics Drew 2000. Additional data is necessary to further define the role of quinupristin/dalfopristin in the treatment of this condition. Overall, the use of quinupristin and dalfopristin has fallen out of favor, including in cases requiring salvage therapy, because of severe side effects (eg, intractable muscle pain), bacteriostatic activity, and need for a central line for administration Fuchs 2000, Kullar 2016.
Based on the 2015 European Society of Cardiology guidelines for the management of infective endocarditis, the use of quinupristin/dalfopristin with or without a beta-lactam has been suggested as an alternative in the treatment of patients with infective endocarditis due to MRSA. The 2015 American Heart Association guidelines for infective endocarditis in adults do not formally recommend quinupristin/dalfopristin in patients with MRSA infective endocarditis (AHA [Baddour 2015]).
Infective endocarditis (multidrug resistant Enterococcus faecium), treatmentcyes
Data from in vitro checkerboard and time-kill assays suggest that the use of quinupristin/dalfopristin in combination with other antimicrobial agents may be useful in the treatment of patients with infective endocarditis due to multidrug resistant Enterococcus faecium (Matsumura 1999). In addition, data from two case reports in patients with infective endocarditis due to vancomycin-resistant E. faecium, experienced cure with the use of quinupristin/dalfopristin in combination with other antibiotics (eg, high-dose ampicillin or the combination of doxycycline and rifampin) Matsumura 1998, Thompson 2003. Additional data is necessary to further define the role of quinupristin/dalfopristin in the treatment of this condition.
Based on the 2015 European Society of Cardiology guidelines for the management of infective endocarditis, the use of quinupristin/dalfopristin may be considered as an alternate agent in the treatment of patients with infective endocarditis due to multidrug-resistant E. faecium. The 2015 American Heart Association guidelines for infective endocarditis in adults do not formally recommend quinupristin/dalfopristin in patients with infective endocarditis due to multidrug-resistant E. faecium and state that although active in vitro against strains of E. faecium, it is rarely used because of severe side effects (eg, intractable muscle pain) AHA [Baddour 2015].
Intravascular catheter-associated bloodstream infection (methicillin-resistant coagulase negative staphylococci or ampicillin- and vancomycin-resistant E. faecium)yes
Based on the Infectious Diseases Society of America (IDSA) guidelines for the diagnosis and management of intravascular catheter-related infection, quinupristin and dalfopristin is suggested as an alternative treatment for infection due to methicillin-resistant coagulase negative staphylococci or ampicillin- and vancomycin-resistant E. faecium.
Meningitis, bacterial and ventriculitis (vancomycin-resistant E. faecium)cyes
Data from a limited number of patients suggest that quinupristin-dalfopristin, administered intrathecally or intraventricularly, may be beneficial as an alternative adjunct to systemic therapy for the treatment of bacterial meningitis or ventriculitis caused by vancomycin-resistant E. faecium Garey 2001, Tan 2000, Tush 1998, Williamson 2002.
Based on the Infectious Diseases Society of America (IDSA) guidelines for the management of bacterial meningitis and healthcare-associated ventriculitis and meningitis, quinupristin and dalfopristin, administered intraventricularly, is suggested as an alternative treatment for infection due to vancomycin-resistant E. faecium.
Contraindications
Hypersensitivity to quinupristin, dalfopristin, other streptogramins (eg, pristinamycin, virginiamycin), or any component of the formulation
Dosage and Administration
Dosing: Adult
Skin and skin structure infection, complicated: IV: 7.5 mg/kg every 12 hours for at least 7 days
Bacteremia (methicillin-resistant Staphylococcus aureus) (off-label use): IV: 7.5 mg/kg every 8 hours (Liu 2011). Note: May be considered with vancomycin failure and when reduced susceptibility to vancomycin and daptomycin is present.
Infective endocarditis (methicillin-resistant Staphylococcus aureus), treatment (off-label use): IV: 7.5 mg/kg every 8 hours with or without additional antibiotics (Chesi 2006; ESC [Habib 2015]). Additional data is necessary to further define the role of quinupristin/dalfopristin in the treatment of this condition.
Infective endocarditis (multidrug-resistant Enterococcus faecium), treatment (off-label use): IV: 7.5 mg/kg every 8 hours with other antibiotics (eg, high-dose ampicillin or the combination of doxycycline and rifampin) (ESC [Habib 2015]; Matsumura 1998; Thompson 2003)
Intravascular catheter-associated bloodstream infection (methicillin-resistant coagulase negative staphylococci or ampicillin- and vancomycin-resistant E. faecium) (off-label use): IV: 7.5 mg/kg every 8 hours (IDSA [Mermel 2009])
Meningitis, bacterial and ventriculitis (alternative adjunct to systemic therapy for vancomycin-resistant E. faecium) (off-label use): Note: Use a preservative-free preparation:
Intrathecal: 1 to 4 mg daily (Garey 2001).
Intraventricular: 2 mg daily (Tush 1998; Williamson 2002) or 2 to 5 mg daily (IDSA [Tunkel 2004]; IDSA [Tunkel 2017]; Tan 2000).
When administered via a ventricular drain, clamp drain for 15 to 60 minutes after administration (allows solution to equilibrate in cerebrospinal fluid [CSF]) (IDSA [Tunkel 2017]). Note: Intraventricular administration is generally reserved for use in patients who fail parenteral therapy despite removal of CSF shunt or when CSF shunt cannot be removed (Baddour 2018).
Dosing: Geriatric
Refer to adult dosing.
Dosing: Pediatric
Dosage is expressed in terms of combined “mg” of quinupristin plus dalfopristin:
General dosing, susceptible infection: Severe infection: Infants, Children, and Adolescents: Limited data available in infants and children <12 years: IV: 7.5 mg/kg every 8 to 12 hours (Liu 2011; Loeffler 2002; Red Book [AAP 2018])
Enterococcus faecium, vancomycin resistant (VREF): Limited data available: Infants, Children, and Adolescents: IV: 7.5 mg/kg/dose every 8 hours; dosing based on an Emergency-Use Program (n=127, mean age: 7.3 years [range: 1.2 months to 17 years]) (Loeffler 2002) and two case series (total n=17, range: 10 months to 18 years) (Gray 2000; Verma 2001)
MRSA infection, vancomycin failure salvage therapy: Limited data available: Infants, Children, and Adolescents: IV: 7.5 mg/kg/dose every 8 hours (Liu 2011; Loeffler 2002)
Skin and skin structure infection; complicated, treatment: Infants, Children, and Adolescents: Limited data available in infants and children <12 years: IV: 7.5 mg/kg/dose every 12 hours for at least 7 days (Red Book [AAP 2018])
VP-shunt infection, ventriculitis; multidrug resistant: Limited data available: Infants, Children, and Adolescents: Intraventricular/intrathecal (use a preservative-free preparation): Usual dose: 1 to 2 mg/day; reported range: 1 to 5 mg; in adults, the usual range is 2 to 5 mg/day; use in combination with IV quinupristin/dalfopristin therapy (IDSA [Tunkel 2017]; Nachman 1995; Tush 1998)
Reconstitution
Reconstitute vial with 5 mL of D5W or sterile water for injection to provide a final concentration of 100 mg/mL. Swirl gently to dissolve; do not shake (to limit foam formation). The reconstituted solution should be further diluted within 30 minutes. Reconstituted solution should be added to at least 250 mL of D5W for peripheral administration (increase to 500 mL or 750 mL if necessary to limit venous irritation). An infusion volume of 100 mL may be used for central line infusions.
Administration
IV: Line should be flushed with 5% dextrose in water prior to and following administration. Infusion should be completed over 60 minutes (toxicity may be increased with shorter infusion). If severe venous irritation occurs following peripheral administration, quinupristin/dalfopristin may be further diluted (to 500 mL or 750 mL), infusion site changed, or infused by a central venous catheter. In general, administration by central venous catheter is required to avoid phlebitis (Kullar 2016; O'Driscoll 2015).
Intrathecal/Intraventricular (off-label route): Use preservative-free preparations only. When administered through a ventricular drain, clamp drain for 15 to 60 minutes before opening the drain to allow quinupristin-dalfopristin solution to equilibrate in the CSF (IDSA [Tunkel 2017]).
Storage
Store intact vials at 2°C to 8°C (36°F to 46°F). Stability of the solution diluted in D5W prior to the infusion is 5 hours at room temperature or 54 hours at 2°C to 8°C (36°F to 46°F); do not freeze. Extended storage information may be available; contact product manufacturer to obtain current recommendations.
Drug Interactions
ARIPiprazole: CYP3A4 Inhibitors (Weak) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations. Monitor therapy
CycloSPORINE (Systemic): Quinupristin may increase the serum concentration of CycloSPORINE (Systemic). Monitor therapy
Dofetilide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Dofetilide. Monitor therapy
Flibanserin: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Flibanserin. Monitor therapy
Lemborexant: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Lemborexant. Management: The maximum recommended dosage of lemborexant is 5 mg, no more than once per night, when coadministered with weak CYP3A4 inhibitors. Consider therapy modification
Lomitapide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Lomitapide. Management: Patients on lomitapide 5 mg/day may continue that dose. Patients taking lomitapide 10 mg/day or more should decrease the lomitapide dose by half. The lomitapide dose may then be titrated up to a max adult dose of 30 mg/day. Consider therapy modification
NiMODipine: CYP3A4 Inhibitors (Weak) may increase the serum concentration of NiMODipine. Monitor therapy
Pimozide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Pimozide. Avoid combination
Triazolam: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Triazolam. Management: Consider triazolam dose reduction in patients receiving concomitant weak CYP3A4 inhibitors. Consider therapy modification
Ubrogepant: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Ubrogepant. Management: In patients taking weak CYP3A4 inhibitors, the initial and second dose (if needed) of ubrogepant should be limited to 50 mg. Consider therapy modification
Adverse Reactions
>10%:
Hepatic: Hyperbilirubinemia (3% to 35%)
Local: Local pain (40% to 44%), local inflammation (at infusion site: 38% to 42%), localized edema (17% to 18%), infusion site reaction (12% to 13%)
Neuromuscular & skeletal: Arthralgia (≤47%), myalgia (≤47%)
1% to 10%:
Cardiovascular: Thrombophlebitis (2%)
Central nervous system: Pain (2% to 3%), headache (2%)
Dermatologic: Skin rash (3%), pruritus (2%)
Endocrine & metabolic: Increased lactate dehydrogenase (3%), increased gamma-glutamyl transferase (2%), hyperglycemia (1%)
Gastrointestinal: Nausea (3% to 5%), vomiting (3% to 4%), diarrhea (3%)
Hematologic & oncologic: Anemia (3%)
Neuromuscular & skeletal: Increased creatine phosphokinase (2%)
<1%, postmarketing, and/or case reports: Abdominal pain, anaphylactoid reaction, anxiety, apnea, blood coagulation disorder, brain disease, cardiac arrhythmia, chest pain, confusion, constipation, dermal ulcer, diaphoresis, dizziness, dysautonomia, dyspepsia, dyspnea, fever, gastrointestinal hemorrhage, gout, hematuria, hemolysis, hemolytic anemia, hepatitis, hyperkalemia, hypersensitivity reaction, hypertonia, hypoglycemia, hyponatremia, hypotension, hypoventilation, hypovolemia, increased blood urea nitrogen, increased serum creatinine, increased serum transaminases, infection, insomnia, leg cramps, maculopapular rash, mesenteric artery occlusion, myasthenia, neck stiffness, neuropathy, oral candidiasis, ostealgia, palpitations, pancreatitis, pancytopenia, paraplegia, paresthesia, pericarditis, peripheral edema, phlebitis, pleural effusion, pseudomembranous colitis, respiratory distress, seizure, shock, stomatitis, syncope, thrombocytopenia, tremor, urticaria, vaginitis, vasodilation
Warnings/Precautions
Concerns related to adverse effects:
- Arthralgias/myalgias: May cause arthralgias and/or myalgias, sometimes severe; reversible with treatment discontinuation. Reduction of dosing frequency has led to improvement in some patients.
- Hyperbilirubinemia: May cause hyperbilirubinemia (>5 times ULN; primarily conjugated bilirubin) possibly through competition for excretory pathways.
- Phlebitis: May cause pain and phlebitis when infused through a peripheral line (not relieved by hydrocortisone or diphenhydramine).
- Superinfection: Prolonged use may result in fungal or bacterial superinfection, including C. difficile-associated diarrhea (CDAD) and pseudomembranous colitis; CDAD has been observed >2 months postantibiotic treatment.
Concurrent drug therapy issues:
- Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
Monitoring Parameters
Culture and sensitivity, conjugated bilirubin if clinically indicated
Pregnancy
Pregnancy Considerations
Adverse events have not been observed in animal reproduction studies.
Patient Education
- Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
- Patient may experience diarrhea. Have patient report immediately to prescriber muscle pain, joint pain, injection site pain or irritation, yellow skin, or signs of Clostridium difficile (C. diff)-associated diarrhea (abdominal pain or cramps, severe diarrhea or watery stools, or bloody stools) (HCAHPS).
- Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.
