VA Class:AM900

AHFS Class:

• Streptogramins 8:12.28.32

Generic Name(s):

• Quinupristin and Dalfopristin

• Quinupristin

• Dalfopristin

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

• C₃₄H₅₀N₄O₉S

Quinupristin and dalfopristin (quinupristin/dalfopristin) is a fixed combination containing 2 semisynthetic streptogramin antibiotics;1,2,4,39,41,42 quinupristin and dalfopristin act synergistically against susceptible bacteria, resulting in increased antibacterial activity compared with either drug alone.1,2,4,41,42

Skin and Skin Structure Infections

Quinupristin and dalfopristin (quinupristin/dalfopristin) is used IV for the treatment of complicated skin and skin structure infections caused by Staphylococcus aureus (methicillin-susceptible [oxacillin-susceptible] strains) or Streptococcus pyogenes (group A β-hemolytic streptococci, GAS).1,2,8

In 2 randomized, open-label, phase 3, comparator-controlled studies in adults with complicated skin and skin structure infections (e.g., erysipelas, postoperative infections, traumatic wound infections), efficacy and safety of quinupristin/dalfopristin (7.5 mg/kg given IV every 12 hours) was compared with oxacillin (2 g given IV every 6 hours) or cefazolin (1 g given IV every 8 hours).1,8 In the comparator groups, vancomycin (1 g given IV every 12 hours) could be substituted for the comparator drug if necessary (e.g., β-lactam hypersensitivity, suspected or confirmed methicillin-resistant S. aureus [MRSA; also known as oxacillin-resistant S. aureus or ORSA]).1,8 The clinical success rate (defined as cure or improvement) in the clinically evaluable population in these 2 studies was 50 or 66% in those treated with quinupristin/dalfopristin versus 52 or 64% in those treated with the comparator anti-infective.1 Drug discontinuance because of adverse effects occurred more than 4 times as often in the quinupristin/dalfopristin treatment groups than in the comparator treatment groups;1,8 approximately 50% of those who discontinued quinupristin/dalfopristin did so because of adverse effects at the IV infusion site.1 (See Administration Precautions under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

For information on diagnosis and management of skin and skin structure infections, the current clinical practice guidelines from the Infectious Diseases Society of America (IDSA) available at [Web] should be consulted.43

Methicillin-resistant Staphylococcus aureus Infections

Quinupristin/dalfopristin has been used IV as salvage therapy in critically ill patients for the treatment of severe infections (e.g., bacteremia, infective endocarditis) caused by methicillin-resistant S. aureus † (MRSA; also known as oxacillin-resistant S. aureus or ORSA) when vancomycin was ineffective.3,21,26,32,127

Although safety and efficacy of quinupristin/dalfopristin for the treatment of MRSA infections has not been established, some clinicians state that the drug is one of several options for the 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.32

For information regarding the treatment of infections caused by MRSA, the current clinical practice guidelines from IDSA available at [Web] should be consulted.32 For information on diagnosis and management of infective endocarditis caused by MRSA, the current AHA guidelines available at [Web] should be consulted.127

Vancomycin-resistant Enterococcus faecium Infections

Quinupristin/dalfopristin has been used IV for the treatment of serious or life-threatening infections caused by susceptible vancomycin-resistant Enterococcus faecium †, including bacteremia, infective endocarditis, intra-abdominal infections, skin and skin structure infections, and urinary tract infections.2,3,6,7,9,24,28,29,33,34 Although quinupristin/dalfopristin has been effective in some patients for the treatment of infections caused by vancomycin-resistant E. faecium ,7,9,33,34 this indication is no longer included in FDA-approved labeling for the drug because data submitted to FDA failed to confirm clinical benefit.30 Some clinicians suggest that use of quinupristin/dalfopristin for the treatment of infections caused by vancomycin-resistant E. faecium should be reserved for refractory infections that fail to respond to other anti-infectives.29,33

Efficacy of quinupristin/dalfopristin for the treatment of serious infections caused by vancomycin-resistant S. faecium varies depending on the site of infection.7,34 Data from 2 prospective emergency-use studies indicated lower success rates when the drug was used for the treatment of bacteremia of unknown origin (52%) or intra-abdominal infections (59%) caused by vancomycin-resistant S. faecium 7 and higher success rates when the drug was used for the treatment of skin and skin structure infections (72%), central catheter-related bacteremia (83%), or urinary tract infections (89%) caused by vancomycin-resistant S. faecium .7

Administration

Quinupristin and dalfopristin (quinupristin/dalfopristin) is administered by IV infusion over 60 minutes.1

Quinupristin/dalfopristin should not be given by rapid IV infusion or injection.1 An infusion pump or device may be used to control the rate of infusion.1

Following completion of peripheral infusions of quinupristin/dalfopristin, the vein should be flushed with 5% dextrose injection to decrease the incidence of venous irritation.1 If necessary, a peripherally inserted central catheter (PICC) or central venous catheter can be used to administer quinupristin/dalfopristin.1 (See Administration Precautions under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Other drugs should not be added to quinupristin/dalfopristin solutions.1

If the same IV line is used for sequential infusion of different drugs, the IV line should be flushed with 5% dextrose injection before and after infusion of quinupristin/dalfopristin.1 Because of incompatibilities, sodium chloride injections or heparin solutions should not be used to flush the IV line.1

IV Infusion

Reconstitution and Dilution

Quinupristin/dalfopristin powder for injection must be reconstituted and then further diluted prior to IV infusion.1 Strict aseptic technique must be observed when preparing IV solutions of quinupristin/dalfopristin since the drug contains no preservatives.1

The manufacturer states that only 5% dextrose injection or sterile water for injection should be used to reconstitute quinupristin/dalfopristin powder for injection and only 5% dextrose injection should be used to dilute the reconstituted drug.1 Because of incompatibility, sodium chloride injections should not be used.1

Single-dose vials labeled as containing 500 mg (150 mg of quinupristin and 350 mg of dalfopristin) should be reconstituted by slowly adding 5 mL of 5% dextrose injection or sterile water for injection to provide a solution containing 100 mg/mL.1 The vial should be gently swirled by manual rotation to ensure dissolution;1 shaking should be avoided to limit foaming.1 The vial should then be allowed to sit for a few minutes until all the foam has disappeared;1 the resulting solution should be clear.1

Reconstituted solutions of quinupristin/dalfopristin must be further diluted in 5% dextrose injection within 30 minutes.1 The appropriate dose of reconstituted solution should be diluted in 250 mL of 5% dextrose injection.1 For infusion via a central line, the appropriate dose of reconstituted solution may be diluted in 100 mL of 5% dextrose injection.1

If moderate or severe venous irritation occurs (see Administration Precautions under Warnings/Precautions: Other Warnings and Precautions, in Cautions), consideration should be given to increasing the infusion volume to 500 or 750 mL, changing the infusion site, or infusing the drug via a PICC or central venous catheter.1

Reconstituted and diluted solutions of quinupristin/dalfopristin should be used as soon as possible.1 The manufacturer states that diluted solutions of the drug are stable for up to 5 hours at room temperature or up to 54 hours when refrigerated at 2-8°C.1 Quinupristin/dalfopristin solutions should not be frozen.1

Reconstituted and diluted solutions of quinupristin/dalfopristin should be inspected visually for particulate matter prior to administration.1

Rate of Administration

Quinupristin/dalfopristin solutions should be administered by IV infusion over 60 minutes.1

Rapid IV infusion should be avoided.1 (See Administration Precautions under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Dosage

Quinupristin/dalfopristin is a fixed combination containing a 30:70 (w/w) ratio of quinupristin to dalfopristin.1

Dosage of the fixed combination quinupristin/dalfopristin is expressed in terms of the total dosage of the 2 components (i.e., dosage of quinupristin plus dosage of dalfopristin).1

Each single-dose vial of quinupristin/dalfopristin contains a total of 500 mg (i.e., 150 mg of quinupristin and 350 mg of dalfopristin).1

Skin and Skin Structure Infections

The recommended dosage of quinupristin/dalfopristin for the 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) in adults is 7.5 mg/kg every 12 hours.1 The minimum recommended treatment duration for complicated skin and skin structure infections is 7 days.1

Although safety and efficacy of quinupristin/dalfopristin have not been established in pediatric patients younger than 16 years of age (see Pediatric Use under Warnings/Precautions: Specific Populations, in Cautions),1 the manufacturer states that the recommended dosage of the drug for children 12 years of age or older is 7.5 mg/kg every 12 hours.1 Dosage recommendations are not available for pediatric patients younger than 12 years of age.1

Methicillin-resistant Staphylococcus aureus Infections

Quinupristin/dalfopristin has been given in a dosage of 7.5 mg/kg every 8 hours for salvage therapy in the treatment of severe infections caused by methicillin-resistant S. aureus † (MRSA; also known as oxacillin-resistant S. aureus or ORSA) when vancomycin was ineffective.3,21,26,32,127

Vancomycin-resistant Enterococcus faecium Infections

Quinupristin/dalfopristin has been given in a dosage of 7.5 mg/kg every 8 hours for the treatment of vancomycin-resistant Enterococcus faecium infections†.3,7,9,28,34

Special Populations

Hepatic Impairment

Although quinupristin/dalfopristin pharmacokinetic data in patients with hepatic cirrhosis (Child-Pugh class A and B) suggest that dosage reductions may be necessary in patients with hepatic impairment, the manufacturer states that data are insufficient to make specific recommendations for dosage modifications in such patients.1 (See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Renal Impairment

Dosage adjustments are not necessary when quinupristin/dalfopristin is used in patients with renal impairment or in those undergoing peritoneal dialysis.1 (See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Geriatric Patients

Dosage adjustments are not necessary when quinupristin/dalfopristin is used in geriatric patients.1

Contraindications

Quinupristin and dalfopristin (quinupristin/dalfopristin) is contraindicated in patients with known hypersensitivity to quinupristin/dalfopristin or other streptogramins (e.g., pristinamycin, virginiamycin).1

Warnings/Precautions

Warnings

Interactions

Concomitant use of quinupristin/dalfopristin and drugs that are metabolized by cytochrome P-450 (CYP) 3A4 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]).1 (See Drug Interactions.)

Sensitivity Reactions

Anaphylactic shock and angioedema have been reported in patients receiving quinupristin/dalfopristin.1

Rash,1,7,8,26,34 urticaria,1 and pruritus1,2,6,7,8,26 also have been reported.

Other Warnings and Precautions

Administration Precautions

Adverse effects at the quinupristin/dalfopristin IV infusion site often occur, especially with peripheral infusions.1,2,6,7,8 In comparative clinical trials, inflammation or pain was reported in 38-45%, edema in 17-18%, and thrombophlebitis in 2% of patients receiving quinupristin/dalfopristin.1 Concomitant use of hydrocortisone or diphenhydramine in clinical trials did not appear to alleviate venous inflammation or pain associated with quinupristin/dalfopristin.1

To minimize venous irritation, IV infusion lines should be flushed with 5% dextrose injection following completion of peripheral infusions of quinupristin/dalfopristin.1 Because of possible incompatibilities, IV infusion lines should not be flushed with sodium chloride injections or heparin solutions.1

If moderate to severe venous irritation occurs following IV infusion of quinupristin/dalfopristin that has been diluted in 250 mL of 5% dextrose injection, consideration should be given to increasing the infusion volume to 500 or 750 mL, changing the infusion site, or establishing central venous access.1

Rapid IV administration of quinupristin/dalfopristin in animals was associated with greater toxicity than slow IV infusion of the drug.1 Because safety of rapid IV injection of the drug has not been studied in humans and because clinical trial experience has exclusively involved IV infusion over 60 minutes, the manufacturer states that more rapid IV infusion rates cannot be recommended.1

Musculoskeletal Effects

Arthralgia and myalgia, severe in some cases, have been reported in patients receiving quinupristin/dalfopristin.1,7,26,33 In some patients receiving the drug every 8 hours, symptoms improved when frequency was changed to every 12 hours.1 In those available for follow-up, symptoms resolved after the drug was discontinued.1 The etiology of these myalgias and arthralgias is unknown.1

Hepatic Effects

Hyperbilirubinemia, with total bilirubin concentrations exceeding 5 times the upper limit of normal, occurred in approximately 25% of patients receiving quinupristin/dalfopristin in noncomparative clinical studies.1 In some patients, isolated hyperbilirubinemia (principally increased conjugated bilirubin) can occur during treatment, possibly as the result of competition between bilirubin and quinupristin/dalfopristin for excretion.1

In comparative clinical studies, AST and ALT elevations occurred with similar frequency in those receiving quinupristin/dalfopristin or comparator therapy.1

Precautions Related to Use of Fixed Combinations

When quinupristin/dalfopristin is used, the cautions, precautions, contraindications, and drug interactions associated with both drugs in the fixed combination must be considered.1 Cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) should be considered for each drug.1

When prescribing, preparing, and dispensing quinupristin/dalfopristin, healthcare professionals should 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).1 (See Dosage and Administration: Dosage.)

Superinfection/Clostridium difficile-associated Diarrhea and Colitis

Use of quinupristin/dalfopristin may result in overgrowth of nonsusceptible organisms.1 If superinfection occurs, appropriate therapy should be instituted.1

Treatment with anti-infectives alters normal colon flora and may permit overgrowth of Clostridium difficile .1,12,14,15 C. difficile infection (CDI) and C. difficile -associated diarrhea and colitis (CDAD; also known as antibiotic-associated diarrhea and colitis or pseudomembranous colitis) have been reported with nearly all anti-infectives, including quinupristin/dalfopristin, and may range in severity from mild diarrhea to fatal colitis.1,12,14,15 C. difficile produces toxins A and B which contribute to the development of CDAD;1,12 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.1

CDAD should be considered in the differential diagnosis of patients who develop diarrhea during or after anti-infective therapy.1,12,14,15 Careful medical history is necessary since CDAD has been reported to occur as late as 2 months or longer after anti-infective therapy is discontinued.1

If CDAD is suspected or confirmed, anti-infective therapy not directed against C. difficile should be discontinued whenever possible.1,12 Patients should be managed with 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.1,12,14,15

Specific Populations

Pregnancy

Category B.1 (See Users Guide.)

There are no adequate and well-controlled studies evaluating quinupristin/dalfopristin in pregnant women;1 the drug should be used during pregnancy only if clearly needed.1

Lactation

Quinupristin and dalfopristin are distributed into milk in rats;1 it is not known whether the drugs are distributed into human milk.1

Quinupristin/dalfopristin should be used with caution in nursing women.1

Pediatric Use

Safety and efficacy of quinupristin/dalfopristin have not been established in pediatric patients younger than 16 years of age.1 In addition, pharmacokinetics of the drug have not been studied in pediatric patients younger than 16 years of age.1 Quinupristin/dalfopristin 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.1 (See Skin and Skin Structure Infections under Dosage and Administration: Dosage.)

Geriatric Use

No overall differences in frequency, type, or severity of adverse effects, including cardiovascular effects, have been observed in geriatric adults 65 years of age or older compared with younger adults.1 Results of a study in adults 69-74 years of age indicate that the pharmacokinetics of quinupristin/dalfopristin in geriatric adults are similar to pharmacokinetics reported in younger adults.1

Hepatic Impairment

In patients with hepatic impairment (Child-Pugh class A and B), the areas under the plasma concentration-time curves (AUCs) of quinupristin and dalfopristin and their major metabolites are increased.1 However, because the effect of reducing the dose or increasing the dosing interval on the pharmacokinetics of quinupristin and dalfopristin has not been studied, the manufacturer states that specific recommendations for dosage modifications in patients with hepatic impairment cannot be made.1

Clinical studies suggest that the incidence of adverse effects in patients with chronic hepatic disease or cirrhosis is comparable to that in patients without hepatic impairment.1

Renal Impairment

Although the AUCs of quinupristin and dalfopristin and their major metabolites are increased in patients with creatinine clearances of 6-28 mL/minute, the manufacturer states that dosage adjustments are not necessary in patients with renal impairment or in those undergoing peritoneal dialysis.1

Only negligible amounts of quinupristin, dalfopristin, and their metabolites are removed by continuous ambulatory peritoneal dialysis (CAPD);1 it is unlikely that the drugs would be removed by hemodialysis.1

Common Adverse Effects

Adverse effects at the IV infusion site (pain, burning, inflammation, edema) occur in a large percentage of patients, particularly when quinupristin/dalfopristin is given by peripheral infusion.1,2,6,7,8 (See Administration Precautions under Warnings/Precautions: Other Warnings and Precautions, in Cautions.) Other adverse effects occurring in 1% or more of patients include GI effects (nausea, vomiting, diarrhea, anorexia),1,7,8,26,34 arthralgia and myalgia,1,7,26,34 hyperbilirubinemia,1 headache,1 thrombophlebitis,1 pain,1,7,8,26 asthenia,7,34 rash,1,7,8,26,34 or pruritus.1,2,6,7,8,26

Drugs Metabolized by Hepatic Microsomal Enzymes

Quinupristin and dalfopristin (quinupristin/dalfopristin) inhibits cytochrome P-450 (CYP) isoenzyme 3A4 and may increase plasma concentrations of drugs metabolized by this hepatic enzyme, resulting in increased or prolonged therapeutic effects and/or increased adverse effects associated with the drugs.1 Caution is advised if quinupristin/dalfopristin is used concomitantly with drugs that are CYP3A4 substrates and have a narrow therapeutic index.1

Quinupristin/dalfopristin does not have a clinically important effect on CYP isoenzymes 1A2, 2A6, 2C9, 2C19, 2D6, or 2E1;1 drug interactions with drugs metabolized by these CYP isoenzymes are not expected.1

Drugs That Prolong QT Interval

Concomitant use with drugs that are CYP3A4 substrates and are known to prolong the QT interval corrected for rate (QT_c) should be avoided.1

Antiarrhythmic Agents

Possible pharmacokinetic interactions between antiarrhythmic agents metabolized by CYP3A4 (e.g., disopyramide, lidocaine, quinidine) and quinupristin/dalfopristin (increased plasma concentrations of the antiarrhythmic agent).1 Caution is advised if quinupristin/dalfopristin is used concomitantly with an antiarrhythmic agent metabolized by CYP3A4.1

Antibacterial Agents

There is some in vitro evidence that the antibacterial effects of vancomycin and quinupristin/dalfopristin are synergistic against vancomycin-resistant Enterococcus faecium .5

In vitro studies indicate that the antibacterial effects of quinupristin/dalfopristin and certain aminoglycosides (gentamicin), β-lactams (amoxicillin, ampicillin, cefepime), glycopeptides (vancomycin), quinolones (ciprofloxacin), tetracyclines (doxycycline), or chloramphenicol are not antagonistic against staphylococci or enterococci.1

In vitro studies indicate that the antibacterial effects of quinupristin/dalfopristin and certain aminoglycosides (gentamicin), β-lactams (aztreonam, cefotaxime), or quinolones (ciprofloxacin) are not antagonistic against Enterobacteriaceae or Pseudomonas aeruginosa .1

Antineoplastic Agents

Possible pharmacokinetic interactions between vinca alkaloids (e.g., vinblastine), docetaxel, or paclitaxel and quinupristin/dalfopristin (increased plasma concentrations of the antineoplastic agent).1 Caution is advised if quinupristin/dalfopristin is used concomitantly with any of these antineoplastic agents.1

Antiretroviral Agents

Possible pharmacokinetic interactions between quinupristin/dalfopristin and certain antiretrovirals metabolized by CYP3A4, including some HIV nonnucleoside reverse transcriptase inhibitors such as delavirdine and nevirapine and some HIV protease inhibitors such as indinavir and ritonavir (increased plasma concentrations of the antiretroviral).1 Caution is advised if quinupristin/dalfopristin is used concomitantly with antiretroviral agents metabolized by CYP3A4.1

Benzodiazepines

Concomitant use of midazolam (single dose) and quinupristin/dalfopristin in healthy individuals increased the peak plasma concentration and area under the plasma concentration-time curve (AUC) of midazolam by 14 and 33%, respectively.1

Possible pharmacokinetic interactions between other benzodiazepines metabolized by CYP3A4 (e.g., diazepam) and quinupristin/dalfopristin (increased plasma concentrations of the benzodiazepine).1

Caution is advised if quinupristin/dalfopristin is used concomitantly with benzodiazepines metabolized by CYP3A4.1

Calcium-channel Blocking Agents

Concomitant use of nifedipine and quinupristin/dalfopristin in healthy individuals increased the peak plasma concentration and AUC of nifedipine by 18 and 44%, respectively.1

Possible pharmacokinetic interactions between other calcium-channel blocking agents metabolized by CYP3A4 (e.g., diltiazem, verapamil) and quinupristin/dalfopristin (increased plasma concentrations of the calcium-channel blocker).1

Caution is advised if quinupristin/dalfopristin is used concomitantly with calcium-channel blocking agents metabolized by CYP3A4.1

Carbamazepine

Possible pharmacokinetic interactions between carbamazepine and quinupristin/dalfopristin (increased plasma concentrations of the anticonvulsant).1 Caution is advised if carbamazepine and quinupristin/dalfopristin are used concomitantly.1

Cisapride

Possible pharmacokinetic interactions between cisapride and quinupristin/dalfopristin (increased plasma concentrations of cisapride).1 Caution is advised if cisapride and quinupristin/dalfopristin are used concomitantly.1

Corticosteroids

Possible pharmacokinetic interactions between methylprednisolone and quinupristin/dalfopristin (increased plasma concentrations of the corticosteroid).1 Caution is advised if methylprednisolone and quinupristin/dalfopristin are used concomitantly.1

Digoxin

Pharmacokinetic interactions between digoxin and quinupristin/dalfopristin based on CYP3A4 inhibition are unlikely.1 However, in vitro data indicate that quinupristin/dalfopristin inhibits Eubacterium lentum ; therefore, the drug possibly may interfere with GI metabolism of digoxin that occurs via intestinal bacteria.1

HMG-CoA Reductase Inhibitors

Possible pharmacokinetic interactions between HMG-CoA reductase inhibitors (statins) metabolized by CYP3A4 (e.g., lovastatin) and quinupristin/dalfopristin (increased plasma concentrations of the statin).1 Caution is advised if quinupristin/dalfopristin is used concomitantly with statins metabolized by CYP3A4.1

Immunosuppressive Agents

Cyclosporine

Concomitant use of cyclosporine and quinupristin/dalfopristin affects the pharmacokinetics of cyclosporine and has resulted in a 30% increase in peak plasma concentrations, 63% increase in AUC, 77% increase in plasma half-life, and 34% decrease in clearance of the immunosuppressive agent.1

If cyclosporine and quinupristin/dalfopristin must be used concomitantly, caution is advised and cyclosporine plasma concentrations should be monitored.1

Tacrolimus

Possible pharmacokinetic interactions between tacrolimus and quinupristin/dalfopristin (increased plasma concentrations of tacrolimus).1 Tacrolimus and quinupristin/dalfopristin should be used concomitantly with caution.1

Description

Quinupristin and dalfopristin (quinupristin/dalfopristin) is a fixed combination containing 2 semisynthetic streptogramin antibiotics.1,2,4,6,39,41,42 Naturally occurring streptogramin antibiotics (e.g., pristinamycin, virginiamycin) are produced by certain Streptomyces bacteria and contain 2 macrocyclic lactone peptolide components (i.e., streptogramin type A and streptogramin type B) that act synergistically against susceptible bacteria.4,39,40,41,42,6 Quinupristin is derived from pristinamycin I1 and is a type B streptogramin;4,39,41,42 dalfopristin is derived from pristinamycin II_A1 and is a type A streptogramin.4,39,41,42

Quinupristin/dalfopristin is commercially available as a lyophilized powder containing a 30:70 (w/w) ratio of quinupristin to dalfopristin.1 Unlike pristinamycin, quinupristin and dalfopristin are both water-soluble and therefore suitable for IV administration.2,4,6,10 In vitro studies indicate that metabolism of quinupristin and dalfopristin is not dependent on cytochrome P-450 (CYP) isoenzymes or glutathione transferase enzymes.1

Quinupristin and dalfopristin act synergistically against susceptible bacteria, and the in vitro activity of the fixed combination is greater than that of each individual component.1,4,39,41 In addition, quinupristin is partially converted in vivo to 2 major active metabolites (a glutathione conjugate and a cysteine conjugate) and quinupristin is partially converted in vivo to a major active metabolite formed by hydrolysis.1 These major active metabolites contribute to the antibacterial activity of quinupristin/dalfopristin since they have antibacterial activity and act synergistically with the parent drugs.1,2

The mechanism of action of quinupristin/dalfopristin, like other streptogramins, involves inhibition of protein synthesis.4,39,40,41,42 The 2 components of quinupristin/dalfopristin bind to different sites on the 50S subunit of the bacterial ribosome.2,4,6,39,41,42 Dalfopristin (a type A streptogramin) affects an early phase of protein synthesis and inhibits peptidyl transferase activity;1,2,4,6,41,42 quinupristin (a type B streptogramin) affects a later phase of protein synthesis and inhibits peptide chain elongation.1,2,4,6,41,42 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.4,39,41,42

Quinupristin/dalfopristin usually is bactericidal against susceptible staphylococci and streptococci,2,3,4,6,35,36 but bacteriostatic against susceptible enterococci.1,2,3,4,6,7,9,33,35

Spectrum

Quinupristin/dalfopristin is active in vitro and in clinical infections caused by methicillin-susceptible (oxacillin-susceptible) Staphylococcus aureus and Streptococcus pyogenes (group A β-hemolytic streptococci, GAS).1 Although the clinical importance in unknown, quinupristin also has in vitro activity against methicillin-resistant S. aureus (MRSA; also known as oxacillin-resistant S. aureus or ORSA),1,35 S. epidermidis (including methicillin-resistant strains),1 S. pneumoniae ,4,27,36 S. agalactiae (group B streptococci, GBS),1,4 groups C and G streptococci,4 viridans streptococci,4,35 Listeria monocytogenes ,4 and Corynebacterium jeikeium .1,4 The MIC₉₀ of quinupristin/dalfopristin for most susceptible staphylococci and streptococci is 1 mcg/mL or less.4,35,36

Quinupristin/dalfopristin is active in vitro against Enterococcus faecium , including vancomycin-resistant E. faecium and multidrug-resistant E. faecium .4,5,7,9,11,22,25,27,33,35,37 The drug appears to be equally active in vitro against VanA and VanB phenotypes of vancomycin-resistant E. faecium .11 Susceptible E. faecium , including vancomycin-resistant strains, are usually inhibited in vitro by quinupristin/dalfopristin concentrations of 2 mcg/mL or less.4,5,7,9,11,27,35,37 However, E. faecalis generally require high concentrations of quinupristin/dalfopristin for in vitro inhibition and most strains are intrinsically resistant to the drug.4,35,37,38,39

Although the clinical importance is unclear, quinupristin/dalfopristin has in vitro activity against some aerobic gram-negative bacteria,4 including Haemophilus influenzae ,4,42 Legionella ,42 Moraxella catarrhalis ,4,42 and Neisseria ,4,42 and some anaerobic bacteria, including Clostridium 42 and Lactobacillus .42 Quinupristin/dalfopristin is inactive against Enterobacteriaceae, Pseudomonas aeruginosa , and Acinetobacter .4

Resistance

Resistance to quinupristin/dalfopristin has been reported and has emerged during treatment with the drug.1,4,7,11,23,28,29,34 Resistance to streptogramins, including quinupristin/dalfopristin, can occur as the result of alterations in the ribosomal target site, enzymatic inactivation, or efflux systems that actively transport the drugs out of the bacterial cell.4,40,42

Resistance to quinupristin/dalfopristin has been reported only rarely in staphylococci or S. pyogenes .4

Reduced susceptibility or resistance to quinupristin/dalfopristin has emerged in vancomycin-resistant E. faecium during treatment with quinupristin/dalfopristin.4,7,11,23,28,34,35

The manufacturer states that cross-resistance between quinupristin/dalfopristin and aminoglycosides, β-lactams, glycopeptides, quinolones, macrolides, lincomycins, and tetracyclines has not been reported.1

Advice to Patients

Advise patients that diarrhea is a common problem caused by anti-infectives and usually ends when the drug is discontinued.1 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.1

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

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

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

Additional Information

Overview (see Users Guide). For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. Pfizer. Synercid^® I.V. (quinupristin and dalfopristin) for injection prescribing information. New York, NY; 2013 Oct.

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 . 1997; 39 Suppl A:139-43. [PubMed 9511078]

4. Murray BE, Arias BE, Nannini EC. Glycopeptides (Vancomycin and Teicoplanin), Streptogramins (Quinupristin-Dalfopristin), Lipopeptides (Daptomycin), and Lipoglycopeptides (Telavancin. In: Bennett JE, Dolin R, Blaser MJ eds. Mandell, Douglas and Bennett's principles and practices of infectious disease. 8th ed. Philadelphia, PA: Saunders, Elsevier; 2015.

5. Lorian V, Fernandes F. Synergic activity of vancomycin-quinupristin/dalfopristin combination against Enterococcus faecium . J Antimicrob Chemother . 1997; 39(Suppl A):63-6. [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. [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. [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. [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. [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. [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. [PubMedCentral][PubMed 9593132]

12. Cohen SH, Gerding DN, Johnson S et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol . 2010; 31:431-55. [PubMed 20307191]

14. Fekety R for the American College of Gastroenterology Practice Parameters Committee. Guidelines for the diagnosis and management of Clostridium difficile -associated diarrhea and colitis. Am J Gastroenterol . 1997; 92:739-50. [PubMed 9149180]

15. American Society of Health-System Pharmacists Commission on Therapeutics. ASHP therapeutic position statement on the preferential use of metronidazole for the treatment of Clostridium difficile -associated disease. Am J Health-Syst Pharm . 1998; 55:1407-11. [PubMed 9659970]

21. Sander A, Beiderlinden M, Schmid EN et al. Clinical experience with quinupristin-dalfopristin as rescue treatment of critically ill patients infected with methicillin-resistant staphylococci. Intensive Care Med . 2002; 28:1157-60. [PubMed 12185441]

22. Rosa RG, Schwarzbold AV, Dos Santos RP et al. Vancomycin-resistant Enterococcus faecium Bacteremia in a tertiary care hospital: epidemiology, antimicrobial susceptibility, and outcome. Biomed Res Int . 2014; 2014:958469. [PubMedCentral][PubMed 24729981]

23. Chow JW, Donahedian SM, Zervos MJ. Emergence of increased resistance to quinupristin/dalfopristin during therapy for Enterococcus faecium bacteremia. Clin Infect Dis . 1997; 24:90-1. [PubMed 8994759]

24. Erlandson KM, Sun J, Iwen PC et al. Impact of the more-potent antibiotics quinupristin-dalfopristin and linezolid on outcome measure of patients with vancomycin-resistant Enterococcus bacteremia. Clin Infect Dis . 2008; 46:30-6. [PubMed 18171210]

25. Yameen MA, Iram S, Mannan A et al. Nasal and perirectal colonization of vancomycin sensitive and resistant enterococci in patients of paediatrics ICU (PICU) of tertiary health care facilities. BMC Infect Dis . 2013; 13:156. [PubMedCentral][PubMed 23536967]

26. Drew RH, Perfect JR, Srinath L et al. Treatment of methicillin-resistant staphylococcus aureus infections with quinupristin-dalfopristin in patients intolerant of or failing prior therapy. For the Synercid Emergency-Use Study Group. J Antimicrob Chemother . 2000; 46:775-84. [PubMed 11062197]

27. Jones RN, Ballow CH, Biedenbach DJ et al. Antimicrobial activity of quinupristin-dalfopristin (RP 59500, Synercid) tested against over 28,000 recent clinical isolates from 200 medical centers in the United States and Canada. Diagn Microbiol Infect Dis . 1998; 31:437-51. [PubMed 9635235]

28. Chong YP, Lee SO, Song EH et al. Quinupristin-dalfopristin versus linezolid for the treatment of vancomycin-resistant Enterococcus faecium bacteraemia: efficacy and development of resistance. Scand J Infect Dis . 2010; 42:491-9. [PubMed 20524781]

29. Heintz BH, Halilovic J, Christensen CL. Vancomycin-resistant enterococcal urinary tract infections. Pharmacotherapy . 2010; 30:1136-49. [PubMed 20973687]

30. US Food and Drug Administration. Supplement approval letter to King Pharmaceuticals. 2010 Nov 12. From FDA website. [Web]

32. Liu C, Bayer A, Cosgrove SE et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis . 2011; 52:e18-55. [PubMedCentral]

33. O'Driscoll T, Crank CW. Vancomycin-resistant enterococcal infections: epidemiology, clinical manifestations, and optimal management. Infect Drug Resist . 2015; 8:217-30. [PubMedCentral][PubMed 26244026]

34. Linden PK, Moellering RC, Wood CA et al. Treatment of vancomycin-resistant Enterococcus faecium infections with quinupristin/dalfopristin. Clin Infect Dis . 2001; 33:1816-23. [PubMed 11668430]

35. Shonekan D, Handwerger S, Mildvan D. Comparative in-vitro activities of RP59500 (quinupristin/dalfopristin), CL 329,998, CL 331,002, trovafloxacin, clinafloxacin, teicoplanin and vancomycin against Gram-positive bacteria. J Antimicrob Chemother . 1997; 39:405-9. [PubMed 9096191]

36. Pankuch GA, Lichtenberger C, Jacobs MR et al. Antipneumococcal activities of RP 59500 (quinupristin-dalfopristin), penicillin G, erythromycin, and sparfloxacin determined by MIC and rapid time-kill methodologies. Antimicrob Agents Chemother . 1996; 40:1653-6. [PubMedCentral][PubMed 8807057]

37. Evans PA, Norden CW, Rhoads S et al. In vitro susceptibilities of clinical isolates of vancomycin-resistant enterococci. Antimicrob Agents Chemother . 1997; 41:1406. [PubMedCentral][PubMed 9174211]

38. Singh KV, Murray BE. Differences in the Enterococcus faecalis lsa locus that influence susceptibility to quinupristin-dalfopristin and clindamycin. Antimicrob Agents Chemother . 2005; 49:32-9. [PubMedCentral][PubMed 15616272]

39. Noeske J, Huang J, Olivier NB et al. Synergy of streptogramin antibiotics occurs independently of their effects on translation. Antimicrob Agents Chemother . 2014; 58:5269-79. [PubMedCentral][PubMed 24957822]

40. Cocito C, Di Giambattista M, Nyssen E et al. Inhibition of protein synthesis by streptogramins and related antibiotics. J Antimicrob Chemother . 1997; 39 Suppl A:7-13. [PubMed 9511056]

41. Harms JM, Schlünzen F, Fucini P et al. Alterations at the peptidyl transferase centre of the ribosome induced by the synergistic action of the streptogramins dalfopristin and quinupristin. BMC Biol . 2004; 2:4. [PubMedCentral][PubMed 15059283]

42. Mukhtar TA, Wright GD. Streptogramins, oxazolidinones, and other inhibitors of bacterial protein synthesis. Chem Rev . 2005; 105:529-42. [PubMed 15700955]

43. Stevens DL, Bisno AL, Chambers HF et al. Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the infectious diseases society of America. Clin Infect Dis . 2014; 59:147-59. [PubMed 24947530]

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

127. Baddour LM, Wilson WR, Bayer AS et al. Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications: A scientific statement for healthcare professionals from the American Heart Association. Circulation . 2015; 132:1435-86. [PubMed 26373316]