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Intravenous Dilution Guidelines

Synercid (150mg of quinupristin and 350mg of dalfopristin)

The authors make no claims of the accuracy of the information contained herein; and these suggested doses and/or guidelines are not a substitute for clinical judgment. Neither GlobalRPh Inc. nor any other party involved in the preparation of this document shall be liable for any special, consequential, or exemplary damages resulting in whole or part from any user's use of or reliance upon this material.    PLEASE READ THE DISCLAIMER CAREFULLY BEFORE ACCESSING OR USING THIS SITE. BY ACCESSING OR USING THIS SITE, YOU AGREE TO BE BOUND BY THE TERMS AND CONDITIONS SET FORTH IN THE DISCLAIMER.

Usual Diluents

D5W

Standard Dilutions   [Amount of drug] [Infusion volume] [Infusion rate]

[Prescribed dose] [250ml] [60 min]

Note: if patient complains of pain at injection site add prescribed dose to 500 ml D5W.

Stability / Miscellaneous

Stability: RT: 5hr ; REF: 54 hr.
Label: refrigerate.
Reconstitution: dilute vial with 5 ml sterile water or D5W (concentration = 100 mg/ml). Do not shake. // If patient has a central line, may add prescribed dose to 100 ml D5W.

Supplied: 500mg vial (150mg of quinupristin and 350mg of dalfopristin) --keep refrigerated.

Dosing: 7.5 mg/kg every 8 to 12 hours. Dosage adjustment not required in renal failure.
One of Synercid's approved indications is for the treatment of patients with serious or life-threatening infections associated with vancomycin-resistant Enterococcus faecium (VREF) bacteremia. Synercid has been approved for marketing in the United States for this indication under FDA's accelerated approval regulations that allow marketing of products for use in life-threatening conditions when other therapies are not available. Approval of drugs for marketing under these regulations is based upon a demonstrated effect on a surrogate endpoint that is likely to predict clinical benefit.

Approval of this indication is based upon Synercid's ability to clear VREF from the bloodstream, with clearance of bacteremia considered to be a surrogate endpoint. There are no results from well-controlled clinical studies that confirm the validity of this surrogate marker. However, a study to verify the clinical benefit of therapy with Synercid on traditional clinical endpoints (such as cure of the underlying infection) is presently underway.

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), ß-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 ß-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)
Streptococcus pyogenes

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 less than or equal1.0 µg/mL against most (greater than or equal90%) 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
Corynebacterium jeikeium
Staphylococcus aureus (methicillin-resistant strains)
Staphylococcus epidermidis (including methicillin-resistant strains)
Streptococcus agalactiae

INDICATIONS AND USAGE

Synercid is indicated in adults for the treatment of the following infections when caused by susceptible strains of the designated microorganisms.


Vancomycin-resistant Enterococcus faecium (VREF)
Synercid is indicated for the treatment of patients with serious or life-threatening infections associated with vancomycin-resistant Enterococcus faecium (VREF) bacteremia. (See PACKAGE INSERT FOR CLINICAL STUDIES)

One of Synercid's approved indications is for the treatment of patients with serious or life-threatening infections associated with vancomycin-resistant Enterococcus faecium (VREF) bacteremia. Synercid has been approved for marketing in the United States for this indication under FDA's accelerated approval regulations that allow marketing of products for use in life-threatening conditions when other therapies are not available. Approval of drugs for marketing under these regulations is based upon a demonstrated effect on a surrogate endpoint that is likely to predict clinical benefit.

Approval of this indication is based upon Synercid's ability to clear VREF from the bloodstream, with clearance of bacteremia considered to be a surrogate endpoint. There are no results from well-controlled clinical studies that confirm the validity of this surrogate marker. However, a study to verify the clinical benefit of therapy with Synercid on traditional clinical endpoints (such as cure of the underlying infection) is presently underway.

Complicated skin and skin structure infections caused by Staphylococcus aureus (methicillin susceptible) or Streptococcus pyogenes. (See PACKAGE INSERT FOR CLINICAL STUDIES)


DOSAGE AND ADMINISTRATION
Synercid should be administered by intravenous infusion in 5% Dextrose in Water solution over a 60-minute period. (See WARNINGS.) The recommended dosage for the treatment of infections is described in the table below. An infusion pump or device may be used to control the rate of infusion. If necessary, central venous access (e.g., PICC) can be used to administer Synercid to decrease the incidence of venous irritation.

Dose
Vancomycin-Resistant Enterococcus faecium: 7.5 mg/kg q8h
Complicated Skin and Skin Structure Infection: 7.5 mg/kg q12h

The minimum recommended treatment duration for Complicated Skin and Skin Structure Infections is seven days. For Vancomycin-Resistant Enterococcus faecium infection, the treatment duration should be determined based on the site and severity of the infection.

Preparation and administration of solution:
Reconstitute the 500 mg single dose vial by slowly adding 5 mL of 5% Dextrose in Water or Sterile Water for injection.

Reconstitute the 600 mg single dose vial by slowly adding 6 mL of 5% Dextrose in Water or Sterile Water for injection.

GENTLY swirl the vial by manual rotation without shaking to ensure dissolution of contents while LIMITING FOAM FORMATION.
Allow the solution to sit for a few minutes until all the foam has disappeared. The resulting solution should be clear. Vials reconstituted in this manner will give a solution of 100 mg/mL. CAUTION: FURTHER DILUTION REQUIRED BEFORE INFUSION.

According to the patient's weight, the reconstituted Synercid solution should be added to 250 mL of 5% Dextrose solution. An infusion volume of 100 mL may be used for central line infusions.

If moderate to severe venous irritation occurs following peripheral administration of Synercid diluted in 250 mL of Dextrose 5% in water, consideration should be given to increasing the infusion volume to 500 or 750 mL, changing the infusion site, or infusing by a peripherally inserted central catheter (PICC) or a central venous catheter.

The desired dose should be administered by intravenous infusion over 60 minutes.
NOTE: As for other parenteral drug products, Synercid should be inspected visually for particulate matter prior to administration

Source: [package insert]
Disclaimer
The authors make no claims of the accuracy of the information contained herein; and these suggested doses are not a substitute for clinical judgment. Neither GlobalRPh Inc. nor any other party involved in the preparation of this program shall be liable for any special, consequential, or exemplary damages resulting in whole or part from any user's use of or reliance upon this material.  PLEASE READ THE DISCLAIMER CAREFULLY BEFORE ACCESSING OR USING THIS SITE. BY ACCESSING OR USING THIS SITE, YOU AGREE TO BE BOUND BY THE TERMS AND CONDITIONS SET FORTH IN THE DISCLAIMER.
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