Pharmacokinetics: Quinupristin and dalfopristin are the main active components circulating in plasma in human subjects. Quinupristin and dalfopristin are converted to several active major metabolites: two conjugated metabolites for quinupristin (one with glutathione and one with cysteine) and one non-conjugated metabolite for dalfopristin (formed by drug hydrolysis).
Pharmacokinetic profiles of quinupristin and dalfopristin in combination with their metabolites were determined using a bioassay following multiple 60-minute infusions of Synercid in two groups of healthy young adult male volunteers. Each group received 7.5 mg/kg of Synercid intravenously q12h or q8h for a total of 9 or 10 doses, respectively. The pharmacokinetic parameters were proportional with q12h and q8h dosing; those of the q8h regimen are shown in the following table:
Mean Steady-State Pharmacokinetic Parameters of Quinupristin and Dalfopristin in Combination with their Metabolites (± SD1) (dose = 7.5 mg/kg q8h; n=10)
| C max2 (μg/mL) || AUC 3 (μg.h/mL) || t 1/24 (hr) |
1 SD= Standard Deviation
2 Cmax = Maximum drug plasma concentration
3 AUC = Area under the drug plasma concentration-time curve
4 t 1/2 = Half-life
| Quinupristin and metabolites ||3.20 ± 0.67 ||7.20 ± 1.24 ||3.07 ± 0.51 |
| Dalfopristin and metabolite ||7.96 ± 1.30 ||10.57 ± 2.24 ||1.04 ± 0.20 |
The clearances of unchanged quinupristin and dalfopristin are similar (0.72 L/h/kg), and the steady-state volume of distribution for quinupristin is 0.45 L/kg and for dalfopristin is 0.24 L/kg. The elimination half-life of quinupristin and dalfopristin is approximately 0.85 and 0.70 hours, respectively.
The protein binding of Synercid is moderate.
Penetration of unchanged quinupristin and dalfopristin in noninflammatory blister fluid corresponds to about 19% and 11% of that estimated in plasma, respectively. The penetration into blister fluid of quinupristin and dalfopristin in combination with their major metabolites was in total approximately 40% compared to that in plasma.
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.
Synercid has been shown to be a major inhibitor (in vitro inhibits 70% cyclosporin A biotransformation at 10 μg/mL of Synercid) of the activity of cytochrome P450 3A4 isoenzyme. (See WARNINGS.)
Synercid can interfere with the metabolism of other drug products that are associated with QTc prolongation. However, electrophysiologic studies confirm that Synercid does not itself induce QTc prolongation. (See WARNINGS.)
Fecal excretion constitutes the main elimination route for both parent drugs and their metabolites (75 to 77% of dose). Urinary excretion accounts for approximately 15% of the quinupristin and 19% of the dalfopristin dose. Preclinical data in rats have demonstrated that approximately 80% of the dose is excreted in the bile and suggest that in man, biliary excretion is probably the principal route for fecal elimination.
Elderly: The pharmacokinetics of quinupristin and dalfopristin were studied in a population of elderly individuals (range 69 to 74 years). The pharmacokinetics of the drug products were not modified in these subjects.
Gender: The pharmacokinetics of quinupristin and dalfopristin are not modified by gender.
Renal Insufficiency: In patients with creatinine clearance 6 to 28 mL/min, the AUC of quinupristin and dalfopristin in combination with their major metabolites increased about 40% and 30%, respectively.
In patients undergoing Continuous Ambulatory Peritoneal Dialysis, dialysis clearance for quinupristin, dalfopristin and their metabolites is negligible. The plasma AUC of unchanged quinupristin and dalfopristin increased about 20% and 30%, respectively. The high molecular weight of both components of Synercid suggests that it is unlikely to be removed by hemodialysis.
Hepatic Insufficiency: In patients with hepatic dysfunction (Child-Pugh scores A and B), the terminal half-life of quinupristin and dalfopristin was not modified. However, the AUC of quinupristin and dalfopristin in combination with their major metabolites increased about 180% and 50%, respectively. (See DOSAGE AND ADMINISTRATION and PRECAUTIONS.)
Obesity (body mass index ≥30): In obese patients the Cmax and AUC of quinupristin increased about 30% and those of dalfopristin about 40%.
Pediatric Patients: The pharmacokinetics of Synercid in patients less than 16 years of age have not been studied.
Microbiology: The streptogramin components of Synercid, quinupristin and dalfopristin, are present in a ratio of 30 parts quinupristin to 70 parts dalfopristin. These two components act synergistically so that Synercid's microbiologic in vitro activity is greater than that of the components individually. Quinupristin's and dalfopristin's metabolites also contribute to the antimicrobial activity of Synercid. In vitro synergism of the major metabolites with the complementary parent compound has been demonstrated.
Synercid is bacteriostatic against Enterococcus faecium and bactericidal against strains of methicillin-susceptible and methicillin-resistant staphylococci.
The site of action of quinupristin and dalfopristin is the bacterial ribosome. Dalfopristin has been shown to inhibit the early phase of protein synthesis while quinupristin inhibits the late phase of protein synthesis.
In vitro combination testing of Synercid with aztreonam, cefotaxime, ciprofloxacin, and gentamicin against Enterobacteriaceae and Pseudomonas aeruginosa did not show antagonism.
In vitro combination testing of Synercid with prototype drugs of the following classes: aminoglycosides (gentamicin), β-lactams (cefepime, ampicillin, and amoxicillin), glycopeptides (vancomycin), quinolones (ciprofloxacin), tetracyclines (doxycycline) and also chloramphenicol against enterococci and staphylococci did not show antagonism.
The mode of action differs from that of other classes of antibacterial agents such as β-lactams, aminoglycosides, glycopeptides, quinolones, macrolides, lincosamides and tetracyclines. There is no cross resistance between Synercid and these agents when tested by the minimum inhibitory concentration (MIC) method.
In non-comparative studies, emerging resistance to Synercid during treatment of VREF infections occurred. Resistance to Synercid is associated with resistance to both components (i.e., quinupristin and dalfopristin).
Synercid has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections, as described in the INDICATIONS AND USAGE section.
Aerobic gram-positive microorganisms
Enterococcus faecium (Vancomycin-resistant and multi-drug resistant strains only)
Staphylococcus aureus (methicillin-susceptible strains only)
NOTE: Synercid is not active against Enterococcus faecalis. Differentiation of enterococcal species is important to avoid misidentification of Enterococcus faecalis as Enterococcus faecium.
The following in vitro data are available, but their clinical significance is unknown.
The combination of quinupristin and dalfopristin (Synercid) exhibits in vitro minimum inhibitory concentrations (MIC's) of ≤1.0 μg/mL against most (≥90%) isolates of the following microorganisms; however, the safety and effectiveness of Synercid in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.
Aerobic gram-positive microorganisms
Staphylococcus aureus (methicillin-resistant strains)
Staphylococcus epidermidis (including methicillin-resistant strains)
Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of microorganisms to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution1 method (broth or agar) or equivalent using standardized inoculum concentrations, and standardized concentrations of quinupristin/dalfopristin (Synercid) in a 30:70 ratio made from powder of known potency. The MIC values should be interpreted according to the following criteria:
For Susceptibility Testing of Enterococcus faecium, Staphylococcus spp., and Streptococcus spp. (excluding Streptococcus pneumoniae)a.
| MIC (μg/mL) || Interpretation |
a.The interpretive values for Streptococcus spp. are applicable only to broth microdilution susceptibility testing using cation-adjusted Mueller-Hinton broth with 2 to 5% lysed horse blood.
|≤1.0 ||Susceptible (S) |
|2.0 ||Intermediate (I) |
|≥4.0 ||Resistant (R) |
A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the concentration of the antimicrobial compound in the blood reaches usually achievable levels. A report of “Intermediate” indicates that the result should be considered equivocal, and if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.
A standardized susceptibility test procedure requires the use of laboratory control organisms to control the technical aspects of the laboratory procedures. Standard quinupristin/dalfopristin powder in a 30:70 ratio should provide the following MIC values with the indicated quality control strains:
| Microorganisms (ATCC® #) || MIC (μg/mL) |
| Enterococcus faecalis (29212)||2.0 to 8.0|
| Staphylococcus aureus (29213)||0.25 to 1.0|
Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure2 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 15 μg quinupristin/dalfopristin in a ratio of 30:70 (Synercid) to test the susceptibility of microorganisms to quinupristin/dalfopristin. Reports from the laboratory providing results of the standard single-disk susceptibility test with a 15 μg quinupristin/dalfopristin disk should be interpreted according to the following criteria:
For Susceptibility Testing of Enterococcus faecium, Staphylococcus spp., and Streptococcus spp. (excluding Streptococcus pneumoniae)b.
| Zone Diameter (mm) || Interpretation |
b.The zone diameter for Streptococcus spp. are applicable only to tests performed using Mueller-Hinton agar supplemented with 5% sheep blood when incubated in 5% CO2.
|≥19 ||Susceptible (S) |
|16 to 18 ||Intermediate (I) |
|≤15 ||Resistant (R) |
Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for quinupristin/dalfopristin.
As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 15 μg quinupristin/dalfopristin (30:70 ratio) disk should provide the following zone diameter with the quality control strain listed below:
| Microorganism (ATCC® #) || Zone Diameter Range (mm) |
| Staphylococcus aureus (25923) ||21 to 28 |
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