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Quinupristin and Dalfopristin

Molecular Formula: C53H67N9O10S

Quinupristin and dalfopristin is a combination of 2 semisynthetic streptogramin (synergistin) antibiotics that act synergistically against susceptible gram-positive bacteria.

Uses

Vancomycin-resistant Enterococcus faecium Infections Quinupristin and dalfopristin is used IV in adults for the treatment of serious or life-threatening infections caused by susceptible strains of vancomycin-resistant Enterococcus faecium (VREF), including infections associated with VREF bacteremia. Quinupristin and dalfopristin became commercially available in the US for this indication under the principles and procedures of FDA’s accelerated review process that allows approval 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.Controlled clinical studies are underway to confirm the validity of this surrogate marker.

Quinupristin and Dalfopristin

As a result of the accelerated review, labeling for use of quinupristin and dalfopristin in VREF-infected individuals (with multiple comorbidities and/or physiologic impairments) was based on surrogate marker data obtained from 4 noncomparative studies; 3 were prospective and the fourth was a collection of individual emergency-use requests. The overall efficacy rate (defined as clinical success and clearance of bacteremia) in the evaluable patients was 52.3%, with site-specific rates of 46.3., and 73.9% for intra-abdominal, skin and skin structure, and urinary tract infections, respectively. All-cause mortality in the 4 studies ranged from 49.5-54%.

Skin and Skin Structure Infections

Quinupristin and dalfopristin is used IV for the treatment of complicated skin and skin structure infections caused by Staphylococcus aureus (methicillin-susceptible strains) or Streptococcus pyogenes (group A b-hemolytic streptococci). In 2 randomized, open-label, comparator (oxacillin or cefazolin [vancomycin in either for resistance])-controlled studies of quinupristin and dalfopristin in complicated skin and skin structure infections, the clinical success rate (infection cured or improved) for the combination was similar to the comparator agents (49.5-66.4% for quinupristin and dalfopristin versus 51.9-64.2% for the comparator antibiotics). Drug discontinuance because of adverse effects occurred more than 4 times as often in the quinupristin and dalfopristin versus comparator antibiotic groups; 50% of discontinuance with the combination was because of adverse venous effects.

Cautions

Contraindications

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

Warnings/Precautions

Major Toxicities Cardiovascular Effects Avoid concomitant therapy with cytochrome P-450 (CYP) isoenzyme 3A4 substrates that may cause QTc prolongation. Other CYP3A4 Substrates In vitro studies demonstrated quinupristin and dalfopristin inhibits CYP3A4 isoenzyme metabolism of cyclosporine, midazolam, nifedipine, or terfenadine (no longer commercially available in the US). Serum/blood concentration monitoring of cyclosporine should be performed if the drug must be used concomitantly with the antibiotic. CYP3A4 substrates administered concomitantly with quinupristin and dalfopristin may result in increased serum concentrations of those substrates, and potentially prolonged/increased therapeutic or adverse effects. Caution when utilizing narrow therapeutic window CYP3A4 substrates concomitantly with the antibiotic. GI Effects Because Clostridium difficile-associated diarrhea and colitis has been reported with quinupristin and dalfopristin, ranging in severity from mild to life-threatening, it should be considered in the differential diagnosis of patients who develop diarrhea during or following therapy with the drug.

General Precautions

Administration Effects

Adverse venous effects (e.g., thrombophlebitis, pain) may occur; therefore, flush infusion lines with 5% dextrose injection following completion of peripheral infusions with quinupristin and dalfopristin. Do not flush with sodium chloride injection or heparin solutions because of possible incompatibilities. Recommended measures for moderate-to-severe reactions include increasing the infusion volume, changing infusion sites, or establishing central venous access. Concomitant hydrocortisone or diphenhydramine did not alleviate adverse venous effects during clinical studies. Toxicity increased with rapid IV (“bolus”) injection compared with slow infusion in animals. Safety of rapid IV injection not studied in humans; clinical trial experience is exclusively with IV infusion over 60 minutes, and other rates cannot be recommended. Hepatic Effects Hyperbilirubinemia exceeding 5 times the upper limit of normal was noted in 25% of patients in noncomparative studies. However, in comparative studies, elevations in AST and ALT occurred with similar frequency for quinupristin and dalfopristin versus comparator therapy. Musculoskeletal Effects Arthralgia and myalgia, severe in some cases, have been reported; etiology is unknown. Some patients improved with a reduction in dosing frequency to every 12 hours. Superinfection Overgrowth of nonsusceptible organisms may occur. Careful observation of the patient is essential. If superinfection occurs, appropriate therapy should be instituted. Specific Populations Pregnancy Category B. Lactation Quinupristin and dalfopristin is distributed into milk in rats; caution if used in nursing women. Pediatric Use Safety and efficacy not established in children younger than 16 years of age; quinupristin and dalfopristin has been used in a limited number of children in this age group under emergency-use conditions at dosages of 7.5 mg/kg every 8 or 12 hours. Pharmacokinetics not studied. Geriatric Use No substantial differences in safety and efficacy nor in pharmacokinetics relative to younger adults. Renal Impairment No dosage adjustment is necessary, including for peritoneal dialysis patients. Hepatic Impairment No specific manufacturer recommendations to date.

Common Adverse Effects

Local venous effects occur in most patients, particularly with peripheral infusion, and include pain, burning, inflammation, and edema at the infusion site; infusion site reactions; and thrombophlebitis and thrombosis.Other effects occurring in 1% or more of patients include nausea, diarrhea, vomiting, rash, arthralgia, myalgia, hepatic abnormalities, headache, pain, or pruritus. The most frequent reasons for drug discontinuance included venous irritation, rash, nausea, vomiting, pain, and pruritus. The discontinuance rate secondary to adverse reactions possibly related to quinupristin and dalfopristin was approximately 5%.

Drug Interactions

CYP 3A4 Substrates The following list is not all-inclusive: antihistamines (astemizole, terfenadine [neither drug currently available commercially]); nonnucleoside reverse transcriptase inhibitors and HIV protease inhibitors (delavirdine, nevirapine, indinavir, ritonavir); antineoplastics (vinca alkaloids, docetaxel, paclitaxel); benzodiazepines (midazolam, diazepam); calcium-channel blocking agents (dihydropyridines [e.g., nifedipine], verapamil, diltiazem); HMG-CoA reductase inhibitors (e.g., lovastatin); GI motility agents (cisapride); immunosuppressive agents (cyclosporine, sirolimus, tacrolimus); corticosteroids (methylprednisolone); other (carbamazepine, quinidine, lidocaine, disopyramide); potential pharmacokinetic interaction-increased CYP3A4 substrate plasma concentrations. Digoxin Potential pharmacokinetic interaction based on inhibition of GI metabolism via Eubacterium lentum eradication.

Description

Quinupristin and dalfopristin is a combination of 2 semisynthetic streptogramin (synergistin) antibiotics, which are structurally unrelated to other commercially available antibiotics in the US. Quinupristin and dalfopristin are derived from pristinamycin I and IIa,respectively, and act synergistically against susceptible gram-positive bacteria. Unlike pristinamycin, quinupristin and dalfopristin are water-soluble and therefore suitable for IV administration; the drugs are present in the powder for injection in a ratio of 30:70 (w/w), respectively. Quinupristin and dalfopristin are converted to several major active metabolites: 2 conjugated (with glutathione and cysteine) metabolites for quinupristin and one nonconjugated (formed by hydrolysis) metabolite for dalfopristin, which also act synergistically with the complementary parent drug. This conversion occurs in vitro by nonenzymatic reactions independent of cytochrome P-450 (CYP) and glutathione transferase enzymes.

Mechanism of Action

The unique mechanism of action for quinupristin and dalfopristin is inhibition of the late (peptide chain elongation inhibition) and early (peptidyl transferase inhibition and resultant conformational changes) phases of protein synthesis, respectively, by binding at different sites on the 50S subunit of the bacterial ribosome. Antagonism of b-lactams, aminoglycosides, glycopeptides, quinolones, macrolides, lincosamides, or tetracyclines has not occurred in vitro.

Spectrum and Resistance

Quinupristin and dalfopristin is bacteriostatic against Enterococcus faecium and bactericidal against methicillin-susceptible and -resistant staphylococci. The combination has been shown to be active both in vitro and clinically against most strains of E. faecium (vancomycin- [VREF] and multidrug-resistant strains), S. aureus (methicillin-susceptible strains), and Streptococcus pyogenes (group A b-hemolytic streptococci) and in vitro (with limited clinical experience) against most strains of Corynebacterium jeikeium, S. aureus (methicillin-resistant strains), S. epidermidis (including methicillin-resistant strains), and Streptococcus agalactiae (group B streptococci). Quinupristin and dalfopristin is not active against Enterococcus faecalis, and enterococcal species differentiation is important to avoid misidentification of this resistant organism. Resistant strains of VREF have emerged during therapy with quinupristin and dalfopristin, and resistance is associated with both components of the combination.

Advice to Patients

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs. Importance of women informing clinicians if they are or plan to become pregnant. Necessity of reporting possible manifestations of adverse effects such as infusion site reactions, arthralgias, myalgias, diarrhea, or hepatotoxicity promptly to clinicians. Importance of reporting persistent or worsening symptoms of infection (e.g., pain, erythema). Overview. 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.

Preparations

Quinupristin and Dalfopristin Parenteral For injection, for 150 mg of quinupristin and Synercid®, IV infusion 350 mg of dalfopristin Aventis (labeled as a combined total potency of 500 mg)

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