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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

Warning(s)

  • Indication for treatment of serious or life-threatening infections associated with vancomycin-resistant Enterococcus faecium (VREF) bacteremia is based on FDA's accelerated review process that allows marketing of products for use in life-threatening conditions when other therapies are not available.1 Approval for this indication is based on analysis of surrogate markers of response (i.e., clearance of bacteremia) rather than clinical end points such as cure of infection or survival.1

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

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Always get your pet's drug and dose recommendation from the veterinarian.

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

For solution and drug compatibility, see Compatibility under Stability.

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 isoenzymes1 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 Clcr 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 liverb to several active metabolites by conjugation and hydrolysis.1

Metabolism is not dependent on CYP isoenzymes1 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 CompatibilityHID

Compatible

Dextrose 5% in water

Incompatible

Sodium chloride containing solutions

Drug CompatibilityHID
Y-Site Compatibility

Compatible

Anidulafungin

Aztreonam

Caspofungin acetate

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 IIa.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 bacteriostatic1 2 6 against Enterococcus faecium1 2 3 4 5 6 7 9 11 and bactericidal1 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

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions September 4, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Aventis Pharmaceuticals Inc. Synercid I.V. (quinupristin/dalfopristin) for injection prescribing information. Bridgewater, NJ; 2000 Dec.

2. Bryson HM, Spencer CM. Quinupristin-dalfopristin. Drugs. 1996; 52:406-15. [PubMed 8875130]

3. Rubinstein E, Bompart F. Activity of quinupristin/dalfopristin against Gram-positive bacteria: clinical applications and therapeutic potential. J Antimicrob Chemother. 1999; 39(Suppl A)139-43.

4. Leclercq R, Courvalin P. Streptogramins: an answer to antibiotic resistance in gram-positive bacteria. Lancet. 1998; 352:591-2. [IDIS 411650] [PubMed 9746015]

5. Lorian V, Fernandes F. Synergic activity of vancomycin–quinupristin/dalfopristin combination against Enterococcus faecium. J Antimicrob Chemother. 1997; 39(Suppl A):63-6. [IDIS 388042] [PubMed 9511065]

6. Fuller RE, Drew RH, Perfect JR. Treatment of vancomycin-resistant enterococci, with a focus on quinupristin-dalfopristin. Pharmacotherapy. 1996; 16:584-92. [IDIS 370966] [PubMed 8840364]

7. Moellering RC, Linden PK, Reinhardt J et al. The efficacy and safety of quinupristin/dalfopristin for the treatment of infections caused by vancomycin-resistant Enterococcus faecium: Synercid Emergency-Use Study Group. J Antimicrob Chemother. 1999; 44:251-61. [IDIS 435629] [PubMed 10473233]

8. Nichols RL, Graham DR, Barriere SL et al. Treatment of hospitalized patients with complicated gram-positive skin and skin structure infections: two randomized, multicentre studies of quinupristin/dalfopristin versus cefazolin, oxacillin or vancomycin: Synercid Skin and Skin Structure Infection Group. J Antimicrob Chemother. 1999; 44:263-73. [IDIS 435630] [PubMed 10473234]

9. Linden PK, Pasculle AW, McDevitt D et al. Effect of quinupristin/dalfopristin on the outcome of vancomycin-resistant Enterococcus faecium bacteraemia: comparison with a control cohort. J Antimicrob Chemother. 1997; 39(Suppl A):145-51. [IDIS 388048] [PubMed 9511079]

10. Bergeron M, Montay G. The pharmacokinetics of quinupristin/dalfopristin in laboratory animals and in humans. J Antimicrob Chemother. 1997; 39(Suppl A):129-38. [IDIS 388046] [PubMed 9511077]

11. Eliopoulos GM, Wennerstein CB, Gold HS et al. Characterization of vancomycin-resistant Enterococcus faecium isolates from the United States and their susceptibility in vitro to dalfopristin/quinupristin. Antimicrob Agents Chemother. 1998; 42:1088-92. [IDIS 404902] [PubMed 9593132]

12. Rhone-Poulenc Rorer, Collegeville, PA; Personal communication.

a. Monarch. Synercid I.V. (quinupristin/dalfopristin) for injection prescribing information. Bristol, TN; 2003 Jul.

b. Delgado G Jr, Neuhauser MM, Bearden DT et al. Quinupristin-dalfopristin: an overview. Pharmacotherapy. 2000; 20:1469-85. [PubMed 11130220]

HID. Trissel LA. Handbook on injectable drugs. 17th ed; Bethesda, MD: American Society of Health-System Pharmacists; 2013:1000.

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