VancomycinJohn C. Rotschafer, Pharm D, FCCPProfessorCollege of PharmacyUniversity of MinnesotaObjectives Identify the mechanism/s of action and resistance(VRE) ofvancomycin.. Be able to define resistance using MIC values. Identify whether vancomycin exhibits concentration dependentor independent bacterial killing and an appropriate monitoringparameter/s. Be able to identify CDC(MMWR) approved and non-approveduses of vancomycin. Be able to identify an appropriate pharmacokinetic method tocharacterize vancomycin as well as appropriate values for peak& trough concentrations. Be able to identify merits and drawbacks to monitoring patientswith serum concentrations. Be able to identify the impact of CDP-1 on the therapeuticmonitoring of vancomycin and what can be done to prevent theproblem. Identify 3 relatively common adverse drug reactions associatedwith vancomycin.Vancomycin Background By the 1950’s, it was apparent that penicillin wasnot going to remain effective for Staphylococci Prompted search for biologic source for newdrug Came from a soil sample containing S. orientalisreceived from a medical missionary in Africa Because of impurities in initial extracts,originally called “Mississippi Mud” Named vancomycin because it was going tovanquish penicillinase producing S. aureus Impurities associated with infusion reactionsVancomycin Introduced in the mid to late 1950’s Over the years has undergone several different formulation changes Bactericidal drug with a limited antimicrobial spectrum Primarily used for Gram positive infectionsSource: IMS Health Retail & Provider PerspectiveYTD June 2002Hospital68%HomeHealthCare18%Clinics4%LTC6%FederalFacilities3%Retail1%Vancomycin Use in United StatesSystemic 30%• Sepsis / Septicemia 14%• Bacteremia 8.5%• Indwelling VenousCatheter 5%Vancomycin Use by Diagnosesin the Hospital (US)Source: AMR US Hospital Audit Jan – Dec2001.Lower Respiratory 19%• HAP 8.5%• CAP 6%Skin / Soft Tissue 28%• Surgical / TraumaticWound Infection 10%• Cellulitis 9%• Diabetic Foot 4%Other 13%Genitourinary 7%Bone & Joint Infection 5%Increasing Vancomycin UseIMS MIDAS [data on file].Injectable Vancomycin UseUnited States, 1989–200105,00010,00015,00020,0001989199019911992199319941995199619971998199920002001Actual Use (kg)How good an antibiotic is Vancomycin? For gram positive pathogens, the killing rate of vancomycin is: A. Superior to a beta-lactam B. Inferior to a beta-lactam C. About equal to a beta-lactam Against gram positive pathogens, vancomycin is an example of: A. A concentration dependent killer B. A concentration independent killer C. Exhibits both types of behavior When using vancomycin, I would A. Monitor peak concentrations B. Monitor trough concentrations C. Monitor both D. Monitoring serum concentrations would not be requiredLarsson A. Antimicrob Agents Chemother. 1996;33:589.Time (Hours)10LogCFU/mL98765432105 15Growth control with alpha phaseGrowth control40 µg/mL with alpha phase40 µg/mL20 µg/mL10 µg/mL5 µg/mLS aureus #29213 vsVancomycin Under Aerobic ConditionsVancomycin Pharmacodynamic Profile Concentration independent killer Goal is to maintain unbound Cp-min > MIC Long terminal half-life Avoid need for continuous infusion Large distribution volume Avoid need to drive drug to infected site– Possible exceptions meningitis & endocarditis Low protein binding High free fraction of active drugVancomycin Clinically effective and well tolerated Favorable pharmacokinetic profile PAE of several hours for gram positivebacteria Bacterial resistance increasing Enterococci and S. haemolyticus Becoming more dependent on vancomycin for resistant organismsMultiple Mechanisms of Actionfor Vancomycin Prevents the polymerization of the phosphodisaccharide-pentapeptide-lipidcomplex – primary effect Alters permeability of the cell membrane Selectively inhibits RNA synthesis Bacterial resistance to all 3 modes of actionunlikelyRev. Infect. Dis., 3(Suppl):S210, 1981Antimicrobial Resistance Patterns ~90% of S. aureus and S. epidermidis are beta-lactamaseproducers ~50% of S. aureus in the hospital are MRSA 20% of Staphylococci from community are MRSA ~80% of S. epidermidis are MRSE Trend of S. haemolyticus and enterococci towardvancomycin resistant Limited reports of VISA or GISA Three reports that enterococcal plasmids were transferedto S. aureus (VRSA 2- 2002 & 1- 2004)Vancomycin Susceptibility Sensitive (VSSA) Vancomycin MIC < 4 mg/L S. aureus Reduced Susceptibility (SARV or heterovariant) Vancomycin MIC = 1-4 mg/L (Still NCCLS Sensitive) Intermediate (VISA or GISA) Vancomycin MIC = 8-16 mg/L Resistant (VRSA) Vancomycin MIC > 32 mg/L Lab needs to backup primary testing with 6mg/L vancomycin overnightplateEnterococcal Glycopeptide ResistanceAdapted Pootoolal, J., Neu, J. & Wright G. Annu Rev Pharmacol Toxicol 42:381-408, 2002Terminal MICPhenotype Peptidoglycan (mg/L) Source InductionVanA D-Ala-D-Lact V>64 Acquired InducibleT>16 Tn 1546VanB D-Ala-D-Lact V>4 Acquired Inducible Tn 1547VanC D-Ala-D-Ser V>2 IntrinsicConstitutive& InducibleVanD D-Ala-D-Lact V>16 IntrinsicConstitutiveT>2VanE D-Ala-D-Ser V=16 Acquired InducibleVan G D-Ala-D-Ser? V=16 ? ?Vancomycin as an AntibioticVancomycin: The Gold Standard Until the introduction ofquinupristin/dalfopristin linezolid, & nowdaptomycin, vancomycin was the last line ofdefense for MRSA Because vancomycin served as a product of lastresort the drug has not rigorously evaluated inregards to efficacy or toxicity For these reasons, we may have an alteredperception of the drugVancomycin vs Beta-lactam Vancomycin kills bacteria at a slower rate than beta-lactam– Levine, D: Ann. Intern. Med. 115:574, 1991 Ann Intern Med 115: 739, 1991 Higher mortality with vancomycin treated patientsvs beta-lactam– Gonzalez: CID 29:1171, 1999 40% of S. aureus lower respiratory infections failedon vancomycin therapy Moise, P. & Schentag, J. Intern J AntimicrobAgents 16:S31-S34, 2000Vancomycin vs Beta-lactam Cloxacillin/gentamicin significantly better thanVancomycin or Teicoplanin/gentamicin in shortcourse therapy of right side endocarditis– Fortun: CID 33:120-125, 2001 Vancomycin is an independent risk factor for thedevelopment of