Quinupristin/Dalfopristin (Monograph)

Drug class: Streptogramins
- Synergistin Antibiotics
VA class: AM900
Chemical name: (S)-4-[4-(Dimethylamino)-N-methyl-l-phenylalanine]-5-[5-[(1-azabicyclo[2.2.2]oct-3-ylthio)methyl]-4-oxo-l-2-piperidinecarboxylic acid]-virginiamycin
Molecular formula: C₅₃H₆₇N₉O₁₀SC₃₄H₅₀N₄O₉S
CAS number: 120138-50-3

Medically reviewed by Drugs.com on May 22, 2023. Written by ASHP.

Introduction

Antibacterial; fixed combination of quinupristin and dalfopristin, 2 semisynthetic streptogramin antibiotics that act synergistically against susceptible bacteria.

Uses for Quinupristin/Dalfopristin

Skin and Skin Structure Infections

Treatment of complicated skin and skin structure infections caused by susceptible Staphylococcus aureus (methicillin-susceptible [oxacillin-susceptible] strains) or Streptococcus pyogenes (group A β-hemolytic streptococci, GAS).

For information on diagnosis and management of skin and skin structure infections, consult current IDSA clinical practice guidelines available at [Web].

Methicillin-resistant Staphylococcus aureus Infections

Has been used as salvage therapy in critically ill patients for treatment of severe infections (e.g., bacteremia, infective endocarditis) caused by methicillin-resistant S. aureus^{† [off-label]} (MRSA; also known as oxacillin-resistant S. aureus or ORSA) when vancomycin was ineffective.

Some clinicians state quinupristin/dalfopristin is one of several options for treatment of persistent MRSA bacteremia in adults who fail to respond to vancomycin or when the infection is known to be caused by MRSA with reduced susceptibility to vancomycin and daptomycin.

For information on treatment of infections caused by MRSA, consult current IDSA clinical practice guidelines available at [Web]. For information on diagnosis and management of infective endocarditis caused by MRSA, consult current AHA guidelines available at [Web].

Vancomycin-resistant Enterococcus faecium Infections

Has been used for treatment of serious or life-threatening infections caused by susceptible vancomycin-resistant Enterococcus faecium^{† [off-label]}, including bacteremia, infective endocarditis, intra-abdominal infections, skin and skin structure infections, and urinary tract infections.

Treatment of vancomycin-resistant E. faecium infections no longer included in FDA-approved labeling; some clinicians suggest reserving quinupristin/dalfopristin for refractory vancomycin-resistant E. faecium infections that fail to respond to other anti-infectives.

Quinupristin/Dalfopristin Dosage and Administration

Administration

Administer by IV infusion over 60 minutes.

IV Infusion

For solution and drug compatibility, see Compatibility under Stability.

Do not administer by rapid IV infusion or injection. An infusion pump or device may be used to control the rate of infusion.

Following completion of peripheral infusions, flush vein with 5% dextrose injection to decrease incidence of venous irritation. If necessary, use a peripherally inserted central catheter (PICC) or central venous catheter to administer quinupristin/dalfopristin. (See Administration Precautions under Cautions.)

Do not add other drugs to quinupristin/dalfopristin solutions.

If same IV line used for sequential infusion of different drugs, flush IV line with 5% dextrose injection before and after infusion of quinupristin/dalfopristin. Because of incompatibility, do not use sodium chloride injection or heparin solutions to flush IV line.

Reconstitution and Dilution

Reconstitute single-dose vial containing 500 mg (150 mg of quinupristin and 350 mg of dalfopristin) with 5 mL of 5% dextrose injection or sterile water for injection to provide a solution containing 100 mg/mL. Gently swirl vial to ensure dissolution; avoid shaking to limit foaming. Allow vial to sit for a few minutes until all the foam disappears; resulting solution should be clear.

Reconstituted solution must be further diluted with 5% dextrose injection within 30 minutes. For peripheral infusion, dilute appropriate dose of reconstituted solution in 250 mL of 5% dextrose injection. For infusion via a central line, appropriate dose may be diluted in 100 mL of 5% dextrose injection.

Because of incompatibility, do not use sodium chloride injections to dilute quinupristin/dalfopristin.

If moderate to severe venous irritation occurs (see Administration Precautions under Cautions), consider increasing infusion volume to 500 or 750 mL, changing the infusion site, or infusing via a PICC or central venous catheter.

Use reconstituted and diluted solutions of quinupristin/dalfopristin as soon as possible.

Rate of Administration

Administer by IV infusion over 60 minutes.

Avoid rapid IV infusion. (See Administration Precautions under Cautions.)

Dosage

Available as fixed combination containing 30:70 (w/w) ratio of quinupristin to dalfopristin.

Dosage of quinupristin/dalfopristin is expressed in terms of the total dosage of the 2 components (i.e., dosage of quinupristin plus dosage of dalfopristin).

Each single-dose vial of quinupristin/dalfopristin contains a total of 500 mg (i.e., 150 mg of quinupristin and 350 mg of dalfopristin).

Pediatric Patients

Skin and Skin Structure Infections

IV

Children ≥12 years of age^{† [off-label]}: 7.5 mg/kg every 12 hours. (See Pediatric Use under Cautions.)

Adults

Skin and Skin Structure Infections

IV

7.5 mg/kg every 12 hours for ≥7 days.

Methicillin-resistant Staphylococcus aureus Infections† [off-label]

IV

7.5 mg/kg every 8 hours has been used when vancomycin was ineffective.

Vancomycin-resistant Enterococcus faecium Infections† [off-label]

IV

7.5 mg/kg every 8 hours has been used.

Special Populations

Hepatic Impairment

Pharmacokinetics in patients with hepatic cirrhosis (Child-Pugh class A and B) suggest that dosage adjustments may be needed; manufacturer states data insufficient to make specific recommendations for dosage modifications. (See Hepatic Impairment under Cautions.)

Renal Impairment

Dosage adjustments not needed in patients with renal impairment or in those undergoing peritoneal dialysis. (See Renal Impairment under Cautions.)

Geriatric Patients

Dosage adjustments not needed.

Cautions for Quinupristin/Dalfopristin

Contraindications

• Known hypersensitivity to quinupristin/dalfopristin or other streptogramins (e.g., pristinamycin, virginiamycin).

Warnings/Precautions

Warnings

Interactions

Concomitant use with drugs that are metabolized by CYP3A4 and have a narrow therapeutic index requires caution and monitoring (e.g., cyclosporine) or should be avoided (e.g., drugs that prolong the QT interval corrected for rate [QT_c]). (See Specific Drugs under Interactions.)

Sensitivity Reactions

Anaphylactic shock and angioedema reported.

Rash, urticaria, and pruritus also reported.

General Precautions

Administration Precautions

Adverse effects at IV infusion site (e.g., inflammation, pain, edema) often occur, especially with peripheral infusions; thrombophlebitis also reported.

Concomitant use of hydrocortisone or diphenhydramine does not appear to alleviate venous inflammation or pain.

To minimize venous irritation, flush IV infusion lines with 5% dextrose injection following completion of quinupristin/dalfopristin peripheral infusion. Because of incompatibilities, do not flush IV infusion lines with sodium chloride injections or heparin solutions.

If moderate to severe venous irritation occurs, consider increasing infusion volume to 500 or 750 mL, changing the infusion site, or infusing via a PICC or central venous catheter.

Do not exceed recommended IV infusion rate. Rapid IV administration of quinupristin/dalfopristin in animals was associated with greater toxicity than slow IV infusion.

Musculoskeletal Effects

Arthralgia and myalgia (sometimes severe) reported. Etiology unknown.

In some patients receiving the drug every 8 hours, symptoms improved when frequency of administration changed to every 12 hours. Symptoms usually resolve following discontinuance.

Hepatic Effects

Increased total bilirubin (>5 times ULN) reported in approximately 25% of patients in clinical studies. In some patients, isolated hyperbilirubinemia (principally increased conjugated bilirubin) occurred during treatment, possibly because of competition for excretion.

Use of Fixed Combinations

Consider cautions, precautions, contraindications, and drug interactions associated with both drugs in the fixed combination. Consider cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) for both drugs.

When prescribing, preparing, and dispensing quinupristin/dalfopristin, consider that dosage of the fixed combination is expressed as the total (sum) of the dosage of each of the 2 active components (i.e., dosage of quinupristin plus dosage of dalfopristin). (See Dosage under Dosage and Administration.)

Superinfection/Clostridium difficile-associated Colitis

Possible emergence and overgrowth of nonsusceptible organisms. Institute appropriate therapy if superinfection occurs.

Treatment with anti-infectives alters normal colon flora and may permit overgrowth of Clostridium difficile. C. difficile infection (CDI) and C. difficile-associated diarrhea and colitis (CDAD; also known as antibiotic-associated diarrhea and colitis or pseudomembranous colitis) reported with nearly all anti-infectives, including quinupristin/dalfopristin, and may range in severity from mild diarrhea to fatal colitis. C. difficile produces toxins A and B which contribute to development of CDAD; hypertoxin-producing strains of C. difficile are associated with increased morbidity and mortality since they may be refractory to anti-infectives and colectomy may be required.

Consider CDAD if diarrhea develops during or after therapy and manage accordingly. Obtain careful medical history since CDAD may occur as late as ≥2 months after anti-infective therapy is discontinued.

If CDAD suspected or confirmed, discontinue anti-infectives not directed against C. difficile whenever possible. Initiate appropriate supportive therapy (e.g., fluid and electrolyte management, protein supplementation), anti-infective therapy directed against C. difficile (e.g., metronidazole, vancomycin), and surgical evaluation as clinically indicated.

Specific Populations

Pregnancy

Category B.

No adequate and well-controlled studies in pregnant women; use during pregnancy only if clearly needed.

Lactation

Distributed into milk in rats; not known whether distributed into human milk.

Use with caution in nursing women.

Pediatric Use

Safety and efficacy not established in children <16 years of age^†.

Has been given in a dosage of 7.5 mg/kg every 8 or 12 hours in a limited number of pediatric patients under emergency-use conditions. (See Skin and Skin Structure Infections under Dosage and Administration.)

Geriatric Use

Frequency, type, and severity of adverse effects in geriatric patients similar to that reported in younger adults.

Hepatic Impairment

AUC increased in patients with hepatic impairment (Child-Pugh class A and B). Dosage adjustments may be needed; manufacturer states data insufficient to make specific dosage recommendations.

Clinical studies suggest that incidence of adverse effects in patients with chronic hepatic disease or cirrhosis is comparable to that in patients with normal hepatic function.

Renal Impairment

Dosage adjustments not needed in patients with renal impairment or in those undergoing peritoneal dialysis.

Common Adverse Effects

Adverse effects at IV infusion site (pain, burning, inflammation, edema), GI effects (nausea, vomiting, diarrhea, anorexia), arthralgia and myalgia, hyperbilirubinemia, headache, thrombophlebitis, pain, asthenia, rash, pruritus.

Drug Interactions

Not metabolized by CYP isoenzymes.

Inhibits CYP3A4; does not inhibit CYP1A2, 2A6, 2C9, 2C19, 2D6, or 2E1.

Drugs Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interactions likely with drugs that are substrates of CYP3A4; may increase plasma concentrations of CYP3A4 substrates, resulting in increased or prolonged therapeutic effects and/or increased risk of adverse effects associated with the drugs.

Drugs that Prolong QT Interval

Avoid concomitant use with drugs that are CYP3A4 substrates and are known to prolong QT_c interval.

Specific Drugs

Quinupristin/Dalfopristin Pharmacokinetics

Absorption

Special Populations

Hepatic impairment (Child-Pugh class A and B): AUC of quinupristin and its major metabolites and AUC of dalfopristin and its major metabolites increased by 180 and 50%, respectively.

Renal impairment: AUC of quinupristin and its major metabolites and AUC of dalfopristin and its major metabolites increased by 40 and 30%, respectively, in those with Cl_cr of 6–28 mL/minute.

Body mass index ≥30: Peak plasma concentrations and AUC of quinupristin increased by 30% and peak plasma concentrations and AUC of dalfopristin increased by 40%.

Distribution

Extent

Quinupristin and dalfopristin and their metabolites distributed into blister fluid.

Animal studies indicate only low or negligible amounts of quinupristin and dalfopristin are distributed into CSF or across the placenta.

Distributed into milk in rats; not known whether distributed into human milk.

Plasma Protein Binding

Quinupristin: Total protein binding is higher than that of dalfopristin.

Dalfopristin: <30% bound to plasma proteins.

Elimination

Metabolism

Both quinupristin and dalfopristin are metabolized in the liver to several major active metabolites by conjugation and hydrolysis.

Metabolism is not dependent on CYP isoenzymes or glutathione-transferase enzyme activities.

Elimination Route

Quinupristin and dalfopristin and their metabolites are eliminated principally by fecal excretion. About 75–77% of a dose excreted in feces as the parent drugs and metabolites; 15–19% of the dose eliminated in urine.

Negligible amounts of quinupristin, dalfopristin, and their metabolites removed by CAPD; removal by hemodialysis unlikely.

Half-life

Elimination half-lives of quinupristin and dalfopristin are approximately 0.85 and 0.7 hours, respectively.

Quinupristin and its metabolites: Half-life at steady-state is approximately 3 hours.

Dalfopristin and its metabolites: Half-life at steady-state is approximately 1 hour.

Special Populations

Pediatric patients <16 years of age: Pharmacokinetics not evaluated.

Geriatric individuals: Pharmacokinetics in those 69–74 years of age similar to that in younger adults.

Hepatic impairment (Child-Pugh class A and B): Terminal half-lives of quinupristin and dalfopristin not affected, but AUCs of both drugs and their metabolites increased.

Stability

Storage

Parenteral

Powder for IV Infusion

2–8°C.

Following reconstitution with 5% dextrose injection or sterile water for injection, further dilute in 5% dextrose injection within 30 minutes. Use diluted solution as soon as possible to minimize risk of microbial contamination; stable for up to 5 hours at room temperature or up to 54 hours when refrigerated at 2–8°C. Do not freeze.

Compatibility

Parenteral

Solution CompatibilityHID

Drug CompatibilityHID

Actions and Spectrum

• Fixed combination of 2 semisynthetic streptogramin antibiotics. Quinupristin is derived from pristinamycin I and is a type B streptogramin; dalfopristin is derived from pristinamycin II_A and is a type A streptogramin.

• Quinupristin and dalfopristin act synergistically against susceptible bacteria, resulting in antibacterial activity greater than either drug alone. Both drugs are metabolized in vivo to several active metabolites that also contribute to the synergistic antibacterial activity of the fixed combination.

• Mechanism of action of quinupristin/dalfopristin, like other streptogramins, involves inhibition of protein synthesis. Quinupristin and dalfopristin bind to different sites on the 50S subunit of the bacterial ribosome.

• Dalfopristin affects an early phase of protein synthesis and directly inhibits peptidyl transferase activity; quinupristin affects a later phase of protein synthesis and inhibits peptide chain elongation. Synergy results in part because quinupristin's affinity for the 50S subunit is enhanced by the conformational change produced when dalfopristin binds to the 50S subunit.

• Usually bactericidal against susceptible staphylococci and streptococci, but bacteriostatic against susceptible enterococci.

• Active in vitro and in clinical infections against Staphylococcus aureus (methicillin-susceptible [oxacillin-susceptible strains) and S. pyogenes (group A β-hemolytic streptococci, GAS). Although clinical importance unknown, also active in vitro against methicillin-resistant S. aureus (MRSA; also known as oxacillin-resistant S. aureus or ORSA), S. epidermidis (including methicillin-resistant strains), S. pneumoniae, S. agalactiae (group B streptococci, GBS), groups C and G streptococci, viridans streptococci, Listeria monocytogenes, and Corynebacterium jeikeium.

• Active in vitro against Enterococcus faecium, including vancomycin-resistant E. faecium and multidrug-resistant E. faecium. However, E. faecalis generally require high concentrations of quinupristin/dalfopristin for in vitro inhibition and most strains are intrinsically resistant to the drug.

• Resistance to quinupristin/dalfopristin reported and has emerged during treatment with the drug.

• Resistance reported only rarely in staphylococci or S. pyogenes.

• Reduced susceptibility or resistance to quinupristin/dalfopristin has emerged in vancomycin-resistant E. faecium during treatment with quinupristin/dalfopristin.

• Advise patients that diarrhea is a common problem caused by anti-infectives and usually ends when the drug is discontinued. Importance of contacting a clinician if watery and bloody stools (with or without stomach cramps and fever) occur during or as late as 2 months or longer after the last dose.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as concomitant illnesses.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of advising patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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