SYNERCID

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
Reconstitution:
-Reconstitute the 500 mg single dose vial by slowly adding 5 ml of D5W or sterile water for injection to a concentration of 100 mg/ml.
-Gently swirl the vial by manual rotation without shaking to ensure dissolution of contents.
-Allow the solution to sit for a few minutes until all of the foam has disappear. The resulting solutions should be clear.
-Storage after reconstitution: The reconstituted solution should be diluted within 30 minutes.
Dilution:
-Add the appropriate dose of the reconstituted solution to 250 ml of D5W for peripheral administration. An infusion volume of 100 ml may be used for central line administrations. Smaller volumes in children have been used but not defined.
-If venous irritation occurs with peripheral administration using 250 ml, consider increasing the infusion volume to 500-750 ml, changing the infusion site, or infusing via a peripherally inserted central catheter (PICC) or a central line.
-Storage after dilution: The diluted solution is stable for 5 hours at room temperature or for 54 hours refrigerated (2-8 degrees C or 36-46 degrees F). Do not freeze.
Intravenous infusion:
-Infuse over 60 minutes.
-An infusion pump or device may be used to control the rate of infusion.

Gastrointestinal adverse event reported with dalfopristin; quinupristin in the general population include nausea (2.8-4.9%), vomiting (2.7-3.7%), and diarrhea (2.7%). Other GI-related adverse events occurring with an incidence of < 1% include abdominal pain, constipation, dyspepsia, pancreatitis, and stomatitis.

In the general population, dalfopristin; quinupristin) has been associated with episodes of arthralgia (<= 7.8%) and myalgia (<= 6.8%); some episodes were severe. In some patients, improvement was noted with a reduction in dose frequency to every 12 hours. In those patients available for follow-up, treatment discontinuation resulted in resolution of symptoms. In a review of 11 pediatric patients, 4 patients had to discontinue treatment due to arthralgia and myalgia with a mean time to stopping treatment of 7 days (range 7-35 days). All required analgesics with 3 requiring narcotics. The incidence in children may be difficult to assess, especially in younger children that are unable to vocalize these types of symptoms. Myasthenia was also reported in < 1% of patients during general clinical trials. Bone pain and neck rigidity were noted in < 0.1% of patients.

Microbial overgrowth and superinfection can occur with antibiotic use. C. difficile-associated diarrhea (CDAD) or pseudomembranous colitis (less than 1%) has been reported with dalfopristin, quinupristin. If pseudomembranous colitis is suspected or confirmed, ongoing antibacterial therapy not directed against C. difficile may need to be discontinued. Institute appropriate fluid and electrolyte management, protein supplementation, C. difficile-directed antibacterial therapy, and surgical evaluation as clinically appropriate. Oral candidiasis and vaginitis have been reported in less than 1% of patients.

Elevated hepatic enzymes (7%) and hyperbilirubinemia (25%) with values > 5 times the upper limit of normal were reported in pediatric patients during a clinical trial (n = 131). However, these values shifted from normal to abnormal in 42% and 44% of patients, respectively, at some point during treatment. In the general population, hyperbilirubinemia has been reported in non-comparative studies of dalfopristin; quinupristin. Elevations of total bilirubin greater than 5 times the upper limit of normal were noted in 25% the general population and increases in conjugated bilirubin were reported in 34.6% of patients. In some patients, isolated hyperbilirubinemia (primarily conjugated) can occur during treatment, possibly resulting from competition between the components of dalfopristin; quinupristin and bilirubin for excretion. In comparative trials, elevated hepatic enzymes (ALT, AST, alkaline phosphatase, GGT) occurred at a similar frequency in both the dalfopristin; quinupristin (0.4-1.9%) and comparator groups. Hepatitis and jaundice were reported in < 0.1% of patients.

Venous irritation has been associated with the use of dalfopristin; quinupristin. In a pediatric trial, venous adverse events were reported in 4 of 126 (3%) patients who received dalfopristin; quinupristin via a central line and 1 of 5 patients who received the drug via a peripheral line. In the general population, an injection site reaction (11.6-13.4%), inflammation at the infusion site (38.2-42%), pain at the infusion site (40-44.7%), and edema at the infusion site (17.3-18%) have been reported. Thrombus (thrombosis) or thrombophlebitis (phlebitis) was reported in 1.7% of patients in one study and phlebitis was noted in <= 2.4% in another study.

Hypersensitivity and dermatologic reactions have occurred with the use of dalfopristin; quinupristin in the general population. Rash (unspecified) was noted in 2.5-3.1% of patients and pruritus occurred in 1.5% of patients during trials in the general population. Maculopapular rash was reported in 2% of pediatric patients (n = 131) during a trial. Allergic reaction, sweating (diaphoresis), and urticaria were all reported in < 1% of patients. Anaphylactoid reactions and skin ulcer occurred in < 0.1% of patients during trials. Angioedema and anaphylactic shock have been noted in post-marketing reports.

Headache was reported in 1.6% of patients during clinical trials in the general population with dalfopristin; quinupristin. Anxiety, confusion, dizziness, hypertonia, insomnia, leg cramps, paresthesias, and peripheral vasodilation were noted in < 1% of patients. Serious adverse events reported in < 0.1% of patients included convulsion (seizures), dysautonomia, encephalopathy, grand mal convulsion, peripheral neuropathy, paraplegia, syncope, and tremor.

In a pediatric trial, 2% of patients (n = 131) reported unspecified pain with dalfopristin; quinupristin. General adverse events reported during dalfopristin; quinupristin clinical trials in the general population include unspecified pain (<= 3.1%), worsening of underlying illness (< 1%), chest pain (unspecified) (< 1%), and fever (< 1%).

Palpitations were reported in < 1% of patients during dalfopristin; quinupristin clinical trials in the general population. Other serious cardiac adverse events reported in < 0.1% of patients included arrhythmia, cardiac arrest, hypovolemia, pericardial effusion, pericarditis, supraventricular tachycardia (SVT), ventricular extrasystoles, and ventricular fibrillation. Hypotension was noted in < 0.2% of patients.

Gout and peripheral edema have been reported in < 1% of patients during dalfopristin; quinupristin clinical trials in the general population.

Dyspnea and pleural effusion were noted in < 1% of patients during dalfopristin; quinupristin clinical trials in the general population. Other serious respiratory adverse events reported in < 0.1% of patients include apnea, hypoventilation, hypoxia, and acute respiratory distress syndrome (ARDS).

Hematuria was reported in < 1% of patients during dalfopristin; quinupristin clinical trials in the general population. Elevated serum creatinine (0.1%) and elevated BUN (0.3%) have also been noted in trials.

Serious coagulation and hematologic adverse events reported in < 0.1% of patients during dalfopristin; quinupristin clinical trials in the general population include cerebral hemorrhage, cerebrovascular accident (stroke), coagulation disorder, hemolysis, hemolytic anemia, hypoplastic anemia, mesenteric arterial occlusion, and pancytopenia. GI bleeding was noted in < 0.2% of patients. Hemoglobin < 9 g/dL (anemia) was reported in 2.6% of patients during trials, while hematocrit > 60% was noted in 0.2% of patients. Platelets > 1,000,000/mm3 (thrombocytosis) occurred in 0.2% of patients and platelets < 50,000/mm3 (thrombocytopenia) occurred in 0.6% of patients.

Serious laboratory abnormalities that have been reported in < 0.1% of patients during dalfopristin; quinupristin clinical trials in the general population include acidosis, hypoglycemia, and hyponatremia. Elevated LDH (2.6%), elevated CPK (1.6%), elevated blood glucose (1.3%), decreased blood glucose (0.1%), elevated bicarbonates (0.3%), decreased bicarbonates (0.5%), decreased CO2 (0.2%), decreased sodium (0.5%), and elevated potassium (0.3%) have also been reported.

Dalfopristin; quinupristin is contraindicated in patients with known hypersensitivity to dalfopristin or quinupristin or with prior streptogramin hypersensitivity (e.g., pristinamycin or virginiamycin hypersensitivity).

Consider pseudomembranous colitis in patients presenting with diarrhea after antibacterial use. Careful medical history is necessary as pseudomembranous colitis has been reported to occur over 2 months after the administration of antibacterial agents. Almost all antibacterial agents, including dalfopristin; quinupristin, have been associated with pseudomembranous colitis or C. difficile-associated diarrhea (CDAD) which may range in severity from mild to life-threatening. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

Dalfopristin; quinupristin should be used cautiously in patients with hepatic disease. Following a single 1-hour infusion of dalfopristin; quinupristin to patients with hepatic insufficiency, plasma concentrations were significantly increased. However, the effect of dose reduction or increase in dosing interval on the pharmacokinetics of dalfopristin; quinupristin in these patients has not been studied.

Description: Dalfopristin and quinupristin are intravenous streptogramins which are isolated from Streptomyces pristinaespiralis. When administered together, these antibiotics appear to act synergistically against susceptible bacteria. The combination product has up to 16 times the activity of each agent alone. Dalfopristin; quinupristin is approved to treat skin and skin structure infections and has been studied for resistant gram-positive infections in an emergency-use program. Venous irritation as well as arthralgias and myalgias are the major adverse events reported. Dalfopristin; quinupristin is FDA-approved in patients as young as 12 years.

Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: Corynebacterium jeikeium, Staphylococcus aureus (MRSA), Staphylococcus aureus (MSSA), Staphylococcus epidermidis, Streptococcus agalactiae (group B streptococci), Streptococcus pyogenes (group A beta-hemolytic streptococci)
NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.

This drug may also have activity against the following microorganisms: Enterococcus faecium
NOTE: Some organisms may not have been adequately studied during clinical trials; therefore, exclusion from this list does not necessarily negate the drug's activity against the organism.

For the treatment of serious or life-threatening infections such as bacteremia*:
Intravenous dosage:
Infants, Children, and Adolescents: 7.5 mg/kg/dose IV every 8 hours. Clinical practice guidelines suggest dalfopristin; quinupristin as an option in adult patients with persistent MRSA bacteremia that has reduced susceptibilities to vancomycin and daptomycin; however, pediatric-specific recommendations are not available. Pediatric patients treated with dalfopristin; quinupristin in a global emergency-use program (n = 131) had a mean age of 7.3 years (range 0.1 to 17.8 years) and were treated for bacteremia, intra-abdominal infections, respiratory tract infections, bone and joint infections, UTIs, endocarditis, and other infections. Other case reports include treatment for a shunt infection as well as immunosuppressed patients, including organ and stem-cell transplant patients. Dalfopristin; quinupristin will not treat E. faecalis.

For the treatment of complicated skin and skin structure infections:
-for the treatment of unspecified complicated skin and skin structure infections:
Intravenous dosage:
Infants* and Children 1 to 11 years*: 7.5 mg/kg/dose IV every 12 hours.
Children and Adolescents 12 to 17 years: 7.5 mg/kg/dose IV every 12 hours for at least 7 days.
-for the treatment of necrotizing infections of the skin, fascia, and muscle:
Intravenous dosage:
Infants* and Children 1 to 11 years*: 7.5 mg/kg/dose IV every 12 hours until further debridement is not necessary, the patient has improved clinically, and fever has been absent for 48 to 72 hours as an alternative for necrotizing infections due to S. aureus or Streptococcus in patients with severe penicillin hypersensitivity.
Children and Adolescents 12 to 17 years: 7.5 mg/kg/dose IV every 12 hours until further debridement is not necessary, the patient has improved clinically, and fever has been absent for 48 to 72 hours as an alternative for necrotizing infections due to S. aureus or Streptococcus in patients with severe penicillin hypersensitivity.

Maximum Dosage Limits:
-Neonates
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established; however, doses up to 22.5 mg/kg/day IV have been used off-label.
-Children
1 to 11 years: Safety and efficacy have not been established; however, doses up to 22.5 mg/kg/day IV have been used off-label.
12 years: 15 mg/kg/day IV is FDA-approved; however, doses up to 22.5 mg/kg/day IV have been used off-label.
-Adolescents
15 mg/kg/day IV is FDA-approved; however, doses up to 22.5 mg/kg/day IV have been used off-label.

Patients with Hepatic Impairment Dosing
Increased serum concentrations of dalfopristin, quinupristin, and their metabolites increase significantly in patients with hepatic dysfunction. Dosage reduction may be necessary; however, specific guidelines are not available. In the emergency-use trial, the FDA advised a dose of 7.5 mg/kg/dose IV every 12 hours in patients with abnormal liver function tests instead of the 7.5 mg/kg/dose IV every 8 hours used in the majority of patients.

Patients with Renal Impairment Dosing
No dosage adjustment necessary. In patients with creatine clearance 6-28 ml/min, the AUC of dalfopristin and quinupristin in combination with their major metabolites increased about 30% and 40%, respectively.

Intermittent hemodialysis
Dalfopristin; quinupristin is likely not removed by hemodialysis due to the high molecular weight of both components; no dosage adjustment is required in renal impairment.

Peritoneal dialysis
No dosage adjustment are necessary for CAPD. The clearance of dalfopristin, quinupristin, and their metabolites is negligible in patients undergoing CAPD. Peritoneal concentrations after IV dosing may not be adequate to treat CAPD peritonitis.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Dalfopristin and quinupristin are two streptogramin antibiotics that act synergistically. Streptogramins inhibit bacterial protein synthesis by irreversibly blocking ribosome functioning. Dalfopristin binds to the 70S or 50S ribosomal particle and inhibits the early phase of protein synthesis; quinupristin binds to the 50S subunit of the 70S bacterial ribosome and inhibits the late phase of protein synthesis. The binding of both agents to the ribosome constricts the exit channel on the ribosome through which nascent polypeptides are extruded; proper functioning of the ribosome is blocked and transfer RNA (tRNA) synthetase activity is inhibited leading to a decrease in free tRNA within the cell. Without these tRNAs, the bacterial cell cannot properly incorporate amino acids into peptide chains and this leads to bacterial cell death. The activity of dalfopristin; quinupristin is bactericidal against staphylococci and streptococci, but may be bacteriostatic for enterococci.

The susceptibility interpretive criteria for dalfopristin; quinupristin are delineated by pathogen. The MICs are defined for E. faecium, beta-hemolytic streptococci, S. viridans group, Staphylococcus sp., S. pneumoniae, and Corynebacterium sp. as susceptible at 1 mcg/mL or less, intermediate at 2 mcg/mL, and resistant at 4 mcg/mL or more.

Pharmacokinetics: Dalfopristin; quinupristin is administered by intravenous infusion. In humans, dalfopristin and quinupristin are the main active components circulating in plasma. Protein binding of dalfopristin; quinupristin is moderate. The protein binding of quinupristin is higher than that of dalfopristin. Penetration of unchanged dalfopristin and quinupristin in noninflammatory blister fluid correlates to about 11% and 19% of that estimated in plasma, respectively. The penetration into blister fluid of dalfopristin and quinupristin in combination with their major metabolites was in total about 40% compared to that in plasma.

Dalfopristin and quinupristin are converted to several active major metabolites; one non-conjugated metabolite for dalfopristin (formed by hydrolysis) and two conjugated metabolites for quinupristin (one with glutathione and one with cysteine). In vitro, the transformation of the parent drugs into their major active metabolites occurs by non-enzymatic reactions and is not dependent on cytochrome P450 or glutathione-transferase enzyme activities.

The main route of elimination for both dalfopristin and quinupristin and their metabolites (75-77% of an administered dose) is fecal excretion. Urinary excretion accounts for approximately 19% of the dalfopristin and 15% of the quinupristin dose. Preclinical animal data have shown that approximately 80% of an administered dose is excreted in the bile and suggest that in man, biliary excretion is probably the principal route for fecal elimination. The elimination half-lives of dalfopristin and quinupristin in adults are approximately 0.70 and 0.85 hours, respectively.

Affected cytochrome P450 isoenzymes: CYP3A4
Dalfopristin; quinupristin is a significant inhibitor of cytochrome P450 3A4 isoenzymes; however, it is not a substrate of any cytochrome P450 isoenzymes.


-Route-Specific Pharmacokinetics
Intravenous Route
In adults, the pharmacokinetic parameters for every 12 hour dosing and every 8 hour dosing is proportional. After every 8 hour dosing, the mean Cmax in adults for dalfopristin and its metabolite is 7.96 +/- 1.3 mcg/ml and the mean Cmax for quinupristin and its metabolites is 3.2 +/- 0.67 mcg/ml.


-Special Populations
Hepatic Impairment
In adult patients with hepatic dysfunction (Child-Pugh class A and B), the terminal half-lives of dalfopristin and quinupristin are not modified. However, the AUCs of dalfopristin and quinupristin in combination with their major metabolites increased about 50% and 180%, respectively.

Renal Impairment
In patients with creatine clearance 6-28 ml/min, the AUC of dalfopristin and quinupristin in combination with their major metabolites increased about 30% and 40%, respectively. The clearance of dalfopristin, quinupristin, and their metabolites is negligible in patients undergoing continuous ambulatory peritoneal dialysis (CAPD). Dalfopristin; quinupristin is unlikely to be removed by hemodialysis. Peritoneal concentrations after IV dosing may not be adequate to treat CAPD peritonitis.