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 Table 1:
Table 1: Mean Steady-State Pharmacokinetic Parameters of Quinupristin and Dalfopristin in Combination with their Metabolites (± SD1) (dose = 7.5 mg/kg q8h; n=10)
|t 1/2 4 (hr)
|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
|1 SD= Standard Deviation
2 Cmax = Maximum drug plasma concentration
3 AUC = Area under the drug plasma concentration-time curve
4 t1/2 = Half-life
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 total protein binding of quinupristin is higher than that of dalfopristin. Synercid does not
alter the in vitro binding of warfarin to proteins in human serum.
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
Synercid has been shown to be a major inhibitor (in vitro inhibits 70% cyclosporin A
biotransformation at 10 mcg/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.
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.
The pharmacokinetics of quinupristin and dalfopristin are not modified by gender.
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
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%.
The pharmacokinetics of Synercid in patients less than 16 years of age have
not been studied.
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.
Mechanism Of Action
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. Synercid is bactericidal against isolates of methicillin-susceptible and methicillin-resistant staphylococci. The mode of action of Synercid differs from that of other classes of antibacterial agents such as ß-lactams, aminoglycosides, glycopeptides, quinolones, macrolides, lincosamides and tetracyclines. Therefore, there is no cross resistance between Synercid and these agents when tested by the minimum inhibitory concentration (MIC) method.
Resistance to Synercid is associated with resistance to both components (i.e., quinupristin and dalfopristin). In non-comparative studies, emerging resistance to Synercid has occurred.
Interaction With Other Antibacterials
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.
Synercid has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections, as described in the INDICATIONS AND USAGE section.
Staphylococcus aureus (methicillin-susceptible isolates only)
The following in vitro data are available, but their clinical significance is unknown.
At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration
(MIC) less than or equal to the susceptible breakpoint for quinupristin and dalfopristin (Synercid)
against isolates of similar genus or organism group. However, the efficacy of Synercid in treating
clinical infections due to these bacteria has not been established in adequate and well-controlled
Staphylococcus aureus (methicillin-resistant isolates)
Staphylococcus epidermidis (including methicillin-resistant isolates)
Susceptibility Test Methods
When available, the clinical microbiology laboratory should provide cumulative reports of in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug for treatment.
Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure1 (broth and/or agar). MIC values should be determined using quinupristin/dalfopristin in a 30:70 ratio. The MIC values should be interpreted according to the criteria in Table 2.
Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using standard test methods1. This procedure uses paper disks impregnated with 15 mcg quinupristin/dalfopristin in a ratio of 30:70 to test the susceptibility of bacteria to quinupristin/dalfopristin. The disk diffusion breakpoints are provided in Table 2.
Table 2: Susceptibility Interpretive Criteria for Quinupristin/Dalfopristin
|Pathogen and Isolate Source
||Minimum Inhibitory Concentrations
|Disk Diffusion (zone diameter in mm)
|a.The interpretive values for Streptococcus pyogenes are applicable only to broth microdilution susceptibility testing
using cation-adjusted Mueller-Hinton broth with 2 to 5% lysed horse blood.
b.The zone diameter for Streptococcus pyogenes are applicable only to tests performed using Mueller-Hinton agar
supplemented with 5% sheep blood when incubated in 5% CO2.
A report of Susceptible (S) indicates that the antimicrobial drug is likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration usually achievable at the site of infection. A report of Intermediate (I) 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 that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of Resistant (R) indicates that the antimicrobial drug is not likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentrations usually achievable at the infection site; other therapy should be selected.
Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and techniques of the individuals performing the test1. Standard quinupristin/dalfopristin powder in a 30:70 ratio
should provide the following range of MIC values noted in Table 31. For the diffusion technique using the 15 mcg quinupristin/dalfopristin disk in a ratio of 30:70, the criteria in Table 3 should be achieved.
Table 3: Acceptable Quality Control Ranges for Quinupristin/Dalfopristin Susceptibility
|Quality Control Organism
||Minimum Inhibitory Concentration Range (MIC in mcg/mL)
||Disk Diffusion Zone Diameter (mm)
|Staphylococcus aureus ATCC 29213
|Staphylococcus aureus ATCC 25923
|Streptococcus pneumoniae ATCC 49619a
|a Streptococcus pneumoniae is used when testing Streptococcus pyogenes. ATCC® is a registered trademark of the American Type Culture Collection
1. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility testing. CLSI document M100-S26. CLSI, 950 West Valley Rd., Suite 2500, Wayne, PA 19807, 2016.