Quinupristin and Dalfopristin

Class: Streptogramins
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: C₅₃H₆₇N₉O₁₀S
CAS Number: 120138-50-3
Brands: Synercid

Introduction

Antibacterial; fixed combination of quinupristin and dalfopristin, 2 semisynthetic streptogramin (synergistin) antibiotics that act synergistically against susceptible gram-positive bacteria.^{1 2 3 4 5}

Uses for Quinupristin and Dalfopristin

Vancomycin-resistant Enterococcus faecium Infections

Treatment of serious or life-threatening infections caused by susceptible vancomycin-resistant Enterococcus faecium (VREF), including infections associated with VREF bacteremia.^{1 2 3 4 6 7 9}

Slideshow: 10 Things to Know About Antibiotic Resistance

Skin and Skin Structure Infections

Treatment of complicated skin and skin structure infections caused by susceptible Staphylococcus aureus (oxacillin-susceptible [methicillin-susceptible] strains) or Streptococcus pyogenes (group A β-hemolytic streptococci).^{1 2 3 4 8}

Quinupristin and Dalfopristin Dosage and Administration

Administration

IV Administration

Administer by IV infusion over 60 minutes.¹ Do not administer by rapid IV infusion or injection.¹

Reconstitution and Dilution

Reconstitute vial containing 500 mg (150 mg of quinupristin and 350 mg of dalfopristin) with 5 mL of 5% dextrose or sterile water for injection.^{1 a} Gently swirl vial to ensure dissolution; avoid shaking to limit foaming.¹ Use strict aseptic technique since product contains no preservative; vials are for single use only.¹ Resulting solution contains 100 mg/mL.^{1 a}

Reconstituted solution must be further diluted within 30 minutes.¹ For peripheral infusion, dilute to a final concentration of ≤2 mg/mL in 250 mL of 5% dextrose injection;^{1 12} 100 mL may be used if infused via a central line.¹ Because of incompatibility, do not use sodium chloride injections to dilute quinupristin and dalfopristin or flush infusion lines.¹

If moderate to severe venous irritation occurs, consider increasing infusion volume to 500–750 mL, changing the infusion site, or infusing via a peripherally inserted central catheter (PICC) or central venous catheter and a rate-controlled device (e.g., pump).¹

Rate of Administration

IV infusions are given over 60 minutes.¹

Dosage

Available as fixed combination containing quinupristin and dalfopristin; dosage expressed in terms of combined mg of quinupristin and dalfopristin (i.e., in terms of “Synercid”).¹

Pediatric Patients

Vancomycin-resistant Enterococcus faecium Infections

IV

Children <16 years of age†: 7.5 mg/kg every 8 hours.¹

Adolescents ≥16 years of age: 7.5 mg/kg every 8 hours.^{1 7 9}

Skin and Skin Structure Infections

IV

Children <16 years of age†: 7.5 mg/kg every 12 hours for ≥7 days.¹

Adolescents ≥16 years of age: 7.5 mg/kg every 12 hours for ≥7 days.^{1 8}

Adults

Vancomycin-resistant Enterococcus faecium Infections

IV

7.5 mg/kg every 8 hours.^{1 7 9}

Skin and Skin Structure Infections

IV

7.5 mg/kg every 12 hours for ≥7 days.^{1 8}

Special Populations

Hepatic Impairment

Pharmacokinetics in patients with hepatic cirrhosis (Child-Pugh class A or B) suggest that dosage adjustments may be needed; data insufficient to make specific dosage recommendations.¹

Renal Impairment

No dosage adjustments needed in those with renal impairment or undergoing peritoneal dialysis.¹

Geriatric Patients

No dosage adjustments needed.¹

Cautions for Quinupristin and Dalfopristin

Contraindications

• Known hypersensitivity to quinupristin, dalfopristin, or other streptogramins (e.g., pristinamycin, virginiamycin).¹

Warnings/Precautions

Warnings

Interactions

Concomitant use with certain drugs not recommended (e.g., drugs metabolized by CYP3A4 that may prolong QT interval) or require particular caution (cyclosporine).¹ (See Specific Drugs under Interactions.)

Superinfection/Clostridium difficile-associated Colitis

Possible emergence and overgrowth of nonsusceptible organisms.¹ Institute appropriate therapy if superinfection occurs.¹

Treatment with anti-infectives, including quinupristin and dalfopristin, may permit overgrowth of clostridia.¹ Consider Clostridium difficile-associated diarrhea and colitis (antibiotic-associated pseudomembranous colitis) if diarrhea develops and manage accordingly.¹

Some mild cases of C. difficile-associated diarrhea and colitis may respond to discontinuance alone.¹ Manage moderate to severe cases with fluid, electrolyte, and protein supplementation; appropriate anti-infective therapy (e.g., oral metronidazole or vancomycin) recommended if colitis is severe.¹

Sensitivity Reactions

Anaphylactic shock and angioedema reported rarely.¹

General Precautions

Local Reactions

Adverse local reactions at the infusion site (e.g., thrombophlebitis, pain) may occur.¹ Concomitant hydrocortisone or diphenhydramine does not alleviate venous pain or inflammation.¹

Flush infusion lines with 5% dextrose injection following completion of peripheral infusions to minimize venous irritation.¹ Do not flush with sodium chloride injection or heparin solutions because of possible incompatibilities.¹

If moderate to severe venous irritation occurs, consider increasing infusion volume to 500–750 mL, changing the infusion site, or infusing via a peripherally inserted central catheter (PICC) or central venous catheter.¹

Musculoskeletal Effects

Arthralgia and myalgia (sometimes severe).^{1 7} Reducing frequency of administration to every 12 hours may improve symptoms; resolution usually occurs following discontinuance.¹

Hepatic Effects

Increased total bilirubin (>5 times ULN) reported.¹ In some patients, isolated hyperbilirubinemia (primarily conjugated) occurred during treatment, possibly because of competition for excretion.¹

Use of Fixed Combination

When used in fixed combination with other agents, consider the cautions, precautions, and contraindications associated with the concomitant agents.

Specific Populations

Pregnancy

Category B.¹

Lactation

Distributed into milk in rats; not known whether distributed into human milk.¹ Use with caution.¹

Pediatric Use

Safety and efficacy not established in children <16 years of age†.¹ Has been used in a limited number of children <16 years of age under emergency-use conditions.¹

Geriatric Use

Frequency, type, and severity of adverse effects in geriatric patients similar to that reported in younger adults.¹

Hepatic Impairment

Increased plasma concentrations in patient with hepatic impairment.¹ Dosage adjustments may be necessary; data insufficient to make specific dosage recommendations.¹

Renal Impairment

No dosage adjustment is necessary, including for peritoneal dialysis patients.¹

Common Adverse Effects

Local reactions at infusion site (pain, burning, inflammation, edema, thrombophlebitis and thrombosis);^{1 2 6 8} GI effects (nausea, diarrhea, vomiting); rash; pruritus.¹

Interactions for Quinupristin and Dalfopristin

Not metabolized by CYP isoenzymes^{1 b}

Inhibits CYP3A4;^{1 b} does not inhibit CYP1A2, 2A6, 2C9, 2C19, 2D6, or 2E1.¹

Drugs Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interactions likely with drugs that are substrates of CYP3A with possible alteration in metabolism of the other drug and increased risk of adverse effects.¹

Specific Drugs

Drug	Interaction	Comments
Antiarrhythmic agents (disopyramide, lidocaine, quinidine)	Possible increased antiarrhythmic agent concentrations; potential for serious or life-threatening effects (e.g., cardiac arrhythmias)1	Caution and close monitoring if used concomitantly1
Antihistamines (astemizole, terfenadine)	Possible pharmacokinetic interaction and potential for serious or life-threatening reactions (e.g., cardiac arrhythmias) with astemizole or terfenadine (drugs no longer commercially available in the US)1	Avoid concomitant use1
Antineoplastic agents (docetaxel, paclitaxel, vinblastine)	Possible increased concentrations of the antineoplastic agent and increased risk of adverse effects1	Caution and close monitoring if used concomitantly1
Benzodiazepines (diazepam, midazolam)	Possible increased benzodiazepine concentrations and increased risk of adverse effects1	Caution and close monitoring if used concomitantly1
Calcium-channel blocking agents (diltiazem, nifedipine, verapamil)	Possible increased concentrations of the calcium-channel blocking agent1	Caution and close monitoring if used concomitantly1
Carbamazepine	Possible increased carbamazepine concentrations and increased risk of adverse effects1	Caution and close monitoring if used concomitantly1
Cisapride	Possible increased cisapride concentrations and increased risk of adverse effects1	Caution and close monitoring if used concomitantly1
Corticosteroids (methylprednisolone)	Possible increased concentrations of corticosteroids with potential for increased risk of adverse effects1	Caution and close monitoring if used concomitantly1
Delavirdine	Possible increased delavirdine concentrations with potential for increased risk of adverse effects1	Caution and close monitoring if used concomitantly1
Digoxin	Pharmacokinetic interaction unlikely1 Possibility of interaction since quinupristin and dalfopristin has in vitro activity against Eubacterium lentum and digoxin is metabolized in part by gut bacteria1
HMG-CoA reductase inhibitors	Possible increased concentrations of some HMG-CoA reductase inhibitors (e.g., lovastatin) with potential for increased risk of adverse effects1	Caution and close monitoring if used concomitantly1
Immunosuppressive agents (cyclosporine, tacrolimus)	Increased cyclosporine concentrations and AUC; possible increased tacrolimus concentrations1	Caution and close monitoring if used concomitantly1
Indinavir	Possible increased indinavir concentrations with potential for increased risk of adverse effects1	Caution and close monitoring if used concomitantly1
Nevirapine	Possible increased nevirapine concentrations with potential for increased risk of adverse effects1	Caution and close monitoring if used concomitantly1
Ritonavir	Possible increased ritonavir concentrations with potential for increased risk of adverse effects1	Caution and close monitoring if used concomitantly1

Quinupristin and Dalfopristin Pharmacokinetics

Absorption

Special Populations

In patients with hepatic impairment (Child-Pugh class A and B), AUC of quinupristin and dalfopristin and their major metabolites is increased by 180 and 50%, respectively.¹

In patients with Cl_cr 6–28 mL/minute, AUC of quinupristin and dalfopristin and their major metabolites is increased by 20 and 30%, respectively.¹

Distribution

Extent

Quinupristin and dalfopristin and their metabolites distributed into blister fluid.¹

Plasma Protein Binding

Both quinupristin and dalfopristin moderately bound to plasma proteins.¹

Elimination

Metabolism

Both quinupristin and dalfopristin are metabolized in the liver^b to several active metabolites by conjugation and hydrolysis.¹

Metabolism is not dependent on CYP isoenzymes^{1 b} or glutathione-transferase enzyme activities.^a

Elimination Route

Principal elimination route for quinupristin and dalfopristin and their metabolites is fecal excretion.¹ About 75–77% of a dose excreted in feces as the parent drugs and metabolites;¹ 15–19% of the dose eliminated in urine.¹

Negligible amounts of quinupristin, dalfopristin, and their metabolites are probably removed by CAPD; unlikely that the drugs would be removed by hemodialysis.¹

Half-life

Plasma half-life of quinupristin and metabolites is approximately 3.07 hours; half-life of dalfopristin and metabolites is approximately 1.04 hours.¹

Special Populations

Pharmacokinetics in geriatric individuals 69–74 years of age similar to that in younger adults.¹

In patients with hepatic dysfunction (Child-Pugh A or B), terminal half-life not affected, but AUC of both drugs and their metabolites increased.¹

Stability

Storage

Parenteral

Powder for IV Infusion

2–8°C.¹

Following reconstitution with 5% dextrose injection or sterile water for injection, solution should be further diluted within 30 minutes.¹ Diluted solutions should be used as soon as possible to minimize risk of microbial contamination, but are stable for 5 hours at room temperature or 54 hours at 2–8°C.¹ Do not freeze.¹

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility^HID

Compatible
Dextrose 5% in water
Incompatible
Sodium chloride containing solutions

Drug Compatibility^HID

Y-Site Compatibility

Compatible
Aztreonam
Ciprofloxacin
Fenoldopam mesylate
Fluconazole
Haloperidol lactate
Metoclopramide HCl
Potassium chloride

Actions and Spectrum

• Fixed combination of 2 semisynthetic streptogramin (synergistin) antibiotics derived from pristinamycin I and II_a.^{1 2 3 4 6 12}

• Quinupristin and dalfopristin act synergistically against susceptible gram-positive bacteria resulting in antibacterial activity greater than either drug alone.^{1 2 3 4 5 6 7 8 9 11} Both drugs are metabolized in vivo to several active metabolites that also contribute to the synergistic antibacterial activity of the fixed-combination.^{1 2}

• Quinupristin inhibits late (peptide chain elongation inhibition) and dalfopristin inhibits early (peptidyl transferase inhibition and resultant conformational changes) phases of protein synthesis by binding at different sites on the 50S subunit of the bacterial ribosome.^{1 2 3 4 6}

• Usually bacteriostatic^{1 2 6} against Enterococcus faecium^{1 2 3 4 5 6 7 9 11} and bactericidal^{1 6} against staphylococci (including oxacillin-resistant [methicillin-resistant] strains).^{1 2 3 4 8}

• Active in vitro and in clinical infections against most strains of E. faecium, including vancomycin-resistant strains (VREF) and multidrug-resistant strains.^{1 2 3 4 5 6 7 9 11} Inactive against E. faecalis.^{1 2 3 4 6}

• Active in vitro and in clinical infections against Staphylococcus aureus (oxacillin-susceptible [methicillin-susceptible strains) and Streptococcus pyogenes (group A β-hemolytic streptococci).^{1 2 3 4 6 8} Also active in vitro against Corynebacterium jeikeium, S. aureus (oxacillin-resistant strains), S. epidermidis (including oxacillin-resistant strains), and S. agalactiae (group B streptococci).^{1 2 3 4 6 8}

• VREF resistant to quinupristin and dalfopristin have emerged during therapy;^{1 4 11} these strains are cross-resistant to both drugs.¹

Advice to Patients

• Necessity of reporting possible manifestations of adverse effects such as infusion site reactions, arthralgias, myalgias, diarrhea, or hepatotoxicity promptly to clinicians.¹

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.¹

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹

• Importance of advising patients of other important precautionary information.¹ (See Cautions.)

Preparations

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

Quinupristin and Dalfopristin

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	For injection, for IV infusion	150 mg of quinupristin and 350 mg of dalfopristin (labeled as a combined total potency of 500 mg)	Synercid	Monarch