Source: Health Products and Food Branch (CA)
SYNERCID (quinupristin and dalfopristin in the ratio of 30:70) is a streptogramin antibacterial agent for intravenous administration. The streptogramin components of SYNERCID, quinupristin and dalfopristin, individually possess bacteriostatic activity against Gram-positive bacteria, as do the principal components, PI and PIIA, of the naturally occurring streptogramin, pristinamycin. The main target of quinupristin and dalfopristin is the bacterial ribosome. When combined, quinupristin and dalfopristin, as SYNERCID, exert bactericidal activity by inhibiting early and late phases of bacterial protein synthesis and interact synergistically at the ribosomal site so that SYNERCID’s activity is much greater than that of the components individually. The mode of action of streptogramins, e.g., SYNERCID, differs somewhat from that of the macrolides and lincosamides. SYNERCID differs in chemical structure and mode of action from other classes of antimicrobial agents such β-lactams, glycopeptides and quinolone antibiotics. Therefore, microorganisms resistant to these latter classes of antimicrobial agents may be susceptible to SYNERCID. SYNERCID is bacteriostatic against Enterococcus faecium and bactericidal against strains of methicillin susceptible staphylococci.
A prolonged post-antibiotic effect (PAE) of SYNERCID was observed with Staphylococcus aureus (10 hours) and Streptococcus pneumoniae (9.1 hours) in the neutropenic mouse thigh abscess model, supporting in vitro data.
Antagonism was generally not reported for any Gram-positive pathogens. In vitro tests with antibiotics active against Pseudomonas aeruginosa or Enterobacteriaceae, e.g. cefotaxime, ciprofloxacin, aztreonam, or gentamicin, did not show antagonism with SYNERCID.
Quinupristin and dalfopristin’s metabolites also contribute to the antimicrobial activity of SYNERCID because their MICs range from comparable (4-64 µg/mL) to several fold lower (0.5-2 µg/mL) than those of either quinupristin or dalfopristin. In addition, in vitro synergism of the major metabolites with the complementary parent compound has been demonstrated.
Pharmacokinetic profiles of quinupristin and dalfopristin in combination with their metabolites were determined using bioassay following multiple 60-minute infusions of SYNERCID in two groups of healthy young male volunteers. Each group received 7.5 mg/kg intravenously q12h or q8h for a total of 9 and 10 doses, respectively. The pharmacokinetic parameters were comparable with q12h or 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 (± SD) - selective bioassays:
| # volunteers | Cmax (µg/mL) | AUC (µg.h/mL) | t1/2 (h) | Tmax (h) | |
|---|---|---|---|---|---|
| Quinupristin and Metabolites | 10 | 3.20 ± 0.67 | 7.20 ± 1.24 | 3.07 ± 0.51 | 0.92 |
| Dalfopristin and metabolites | 10 | 7.96 ± 1.30 | 10.57 ± 2.24 | 1.04 ± 0.20 | 0.92 |
The clearances of unchanged quinupristin and dalfopristin are similar (0.7 L/h/kg), and the apparent volume of distribution for both products is approximately 1.0 L/kg. The elimination half-life of quinupristin and dalfopristin is approximately 0.9 and 0.75 hours, respectively.
The protein binding ranges from 55 to 78% for quinupristin and from 11 to 26% for dalfopristin.
Quinupristin and dalfopristin are the main active components circulating in plasma in human subjects. Quinupristin and dalfopristin are, however, converted to several major metabolites: two conjugated metabolites for quinupristin (one with glutathione and one with cysteine) and one non-conjugated for dalfopristin (formed by drug hydrolysis). (See MICROBIOLOGY)
A tolerance and pharmacokinetic study of SYNERCID conducted in healthy male volunteers (a single infusion of SYNERCID 5 mg/kg (n=36); 10 mg/kg (n=13); 15 mg/kg (n=12); placebo (n=20)) assessed the electrocardiographic effects of SYNERCID. Although there was a slightly higher incidence of patients that had QTc prolongation of 30-60 msec over baseline at the dose of 15 mg/kg, the difference between the dosage groups was not statistically significant (Fisher’s exact test p=0.139). There is no clear evidence to indicate QTc prolongation following SYNERCID administration at a dose of ≤10 mg/kg. None of the individuals had a QTc above 430 msec following administration of SYNERCID at any of these doses.
SYNERCID can interfere with the metabolism of other drug products that are associated with QTc prolongation (see WARNINGS: Drug interactions).
Fecal excretion constitutes the main elimination route for both parent drugs and their metabolites (75-77% 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 are not affected by age (age range 69 to 74).
Gender: No significant gender effect was seen for the pharmacokinetic profile of SYNERCID. Patients with renal insufficiency (creatinine clearance 6-28 mL/min): The AUC of quinupristin and dalfopristin in combination with their major metabolites increased about 140% and 130%, respectively (See DOSAGE AND ADMINISTRATION).
Mean pharmacokinetic parameters of quinupristin and dalfopristin in patients with severe renal insufficiency (± SD) - selective bioassays:
| # patients | Cmax (µg/mL) | AUC (µg.h/mL) | t1/2 (h) | Tmax (h) | |
|---|---|---|---|---|---|
| Quinupristin and metabolites 13 | 3.00 ± 0.75 | 5.32 ± 1.29 | 2.38 ± 1.26 | 0.92 | |
| Dalfopristin and metabolites 13 | 9.51 ± 2.39 | 11.7 ± 3.8 | 0.77 ± 0.15 | 0.92 |
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 120% and 130%, respectively (See DOSAGE AND ADMINISTRATION). The high molecular weight of both components of SYNERCID suggests that it is unlikely to be removed by hemodialysis.
Patients with hepatic insufficiency: In patients with hepatic dysfunction (Child-Pugh scores A or 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 by approximately 180% and 50%, respectively. The pharmacokinetics of SYNERCID in patients with severe hepatic impairment have not been studied. (See DOSAGE AND ADMINISTRATION and PRECAUTIONS: Special populations: Patients with hepatic insufficiency).
Mean pharmacokinetic parameters of quinupristin and dalfopristin in patients with hepatic insufficiency (± SD) - selective bioassays:
| # patients* | Cmax (µg/mL) | AUC (µg.h/mL) | t1/2 (h) | Tmax (h) | |
|---|---|---|---|---|---|
| Quinupristin and metabolites | Group A = 2 | 4.87 ± 0.52 | 8.69 ± 1.05 | 2.04 ± 0.60 | 0.92 |
| Group B = 7 | 4.17 ± 0.95 | 12.16 ± 3.64 | 3.31 ± 0.93 | 0.92 | |
| Dalfopristin and metabolites | Group A = 2 | 11,28 ± 2.66 | 16.03 ± 4.28 | 1.75 ± 0.43 | 0.92 |
| Group B = 7 | 8.94 ± 1.49 | 13.00 ± 3.26 | 1.96 ± 0.62 | 0.92 |
* Group A: patients with Child-Pugh A score; Group B: patients with Child-Pugh B score.
The study was a single 1-hour infusion of Synercid (7.5 mglkg).
Obese patients: In obese patients, the Cmax and AUC of quinupristin increased about 130% and those of dalfopristin about 140% (See DOSAGE AND ADMINISTRATION).
Pediatric patients: The pharmacokinetics of SYNERCID in pediatric patients have not been studied.
The in vitro activity of SYNERCID (quinupristin and dalfopristin in the ratio of 30:70) against clinical isolates is summarized in the following table:
| Microorganism | # of clinical Isolates | MIC (µg/mL) | |||
|---|---|---|---|---|---|
| MIC50 | MIC90 | Range | |||
| Aerobic gram-positive microorganisms | |||||
| Enterococcus faecium* | 1667 | 0.5 | 1 | 0.06 – 16 | |
| Enterococcus faecalis | 109 | >4 | 16 | 0.5 – 32 | |
| Staphylococcus aureus | 3598 | 0.5 | 1 | 0.016 – 32 | |
| Staphylococcus epidermidis | 1760 | 0.25 | 0.5 | 0.03 – 16 | |
| Streptococcus agalactiae | 221 | 0.5 | 1 | 0.03 – 32 | |
| Streptococcus pyogenes | 928 | 0.06 | 0.25 | 0.16 – 2 | |
| Streptococcus pneumoniae | 3036 | 0.25 | 0.5 | 0.008 – 4 | |
| Staphylococcus capitis | 45 | 0.5 | 1 | 0.12 -2 | |
| Staphylococcus haemolyticus | 223 | 0.5 | 1 | 0.12 – 8 | |
| Staphylococcus hominis | 165 | 0.25 | 1 | 0.03 – 16 | |
| Staphylococcus saprophyticus | 109 | 0.5 | 1 | 0.12 – 4 | |
| Staphylococcus simulans | 45 | 0.25 | 0.5 | 0.12 – 2 | |
| Staphylococcus warneri | 56 | 0.5 | 1 | 0.12 – 1 | |
| Viridans group streptococci | 131 | 0.5 | 1 | 0.12 – 4 | |
| Aerobic gram-negative microorganisms | |||||
| Legionella pneumophila | 267 | - | 1 | 1 | |
| Legionella spp. | 292 | - | 1 | 1 | |
| Moraxella catarrhalis | 644 | 0.25 | 0.5 | 0.016 – 8 | |
| Neisseria gonorrhoeae | 256 | 0.25 | 0.5 | 0.016 – 2 | |
| Neisseria meningitidis | 135 | 0.25 | 0.5 | 0.016 – 0.5 | |
* While Synercid is active in vitro against E. faecium (see table above), Synercid is not active (MIC90s of >4 µg/mL) against E.faecalis (MIC90: 16 µg/mL) and some other species of enterococci (E. durans, E. casseliflavus including Van C strains and E. gallinamm including Van C strains).
In vitro tests with S. aureus, including methicillin- and erythromycin-resistant strains, often show SYNERCID may act synergistically with some β-lactam agents, especially the cephalosporins. In vitro tests with some strains of vancomycin-resistant E. faecium show SYNERCID may act synergistically with glycopeptides.
Dilution techniques: 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 procedure. Standardized procedures are based on a dilution method (broth or agar, NCClS) or equivalent with standardized inoculum concentrations and standardized concentrations of quinupristin/dalfopristin (30:70) powder. The MIC values should be interpreted according to the following criteria:
For testing rapidly growing aerobic microorganisms and S. pneumoniae:
| MIC (µg/mL) | Interpretation |
|---|---|
| ≤1 | Susceptible (S) |
| 2 | Moderately susceptible (MS) |
| ≥4 | Resistant (R) |
A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable.
A report of “Moderately susceptible” indicates that the result should be considered equivocal, and if the infection cannot be treated with alternative, clinically feasible drugs, the test should be repeated. 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.
Standardized susceptibility test procedures require the use of laboratory control organisms to control the technical aspects of the laboratory procedures. Standard quinupristin/dalfopristin powder should providethe following MIC values:
| Microorganism | MIC (µg/mL) |
|---|---|
| Staphylococcus aureus ATCC 29213 | 0,25 to 1 |
| Streptococcus pneumoniae ATCC 49619* | 0,25 to 1 |
| Enterocoausfaecalis ATCC 29212 | 2 to 8 |
* This quality control range is applicable to only S. pneumoniae ATCC 49619 tested by a broth microdilution procedure using cation-adjusted Mueller-Hinton broth with 2-5% lysed (freeze thaw method) horse blood.
Diffusion techniques: Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 15 µg quinupristin/dalfopristin (30:70) to test the susceptibility of microorganisms to SYNERCID.
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 testing rapidly growing aerobic microorganisms and S. pneumoniae:
| Zone Diameter (mm) | Interpretation |
|---|---|
| ≥19 | Susceptible (S) |
| 16 to 18 | Moderately susceptible (MS) |
| ≤15 | Resistant (R) |
Interpretation should be 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 organisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 15 µg quinupristin/dalfopristin disk should provide the following zone diameters in these laboratory test quality control strains:
| Microorganism | Zone Diameter (mm) |
|---|---|
| Staphylococcus aureus ATCC 25923 | 23-29 |
| Streptococcus pneumoniae ATCC 49619* | 19-24 |
* This quality control range is applicable to only S. pneumoniae ATCC 49619 using MuellerHinton agar supplemented with 5% whole sheep blood incubated in 5% CO2.
On the basis of MIC frequency distributions of random clinical isolates, pre/post therapy or emerging resistant MICs related to patient outcomes, genotypic resistance markers, and human pharmacokinetic data, SYNERCID’s interpretive criteria for agar disk diffusion and MIC dilution susceptibility testing have been reviewed and approved by the Subcommittee for Antimicrobial Susceptibility Testing the NCCLS.
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