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MRSA treatment Facts & Myths

Dr Suresh Kumar Infectious Diseases Unit Hospital Sungai Buloh. MRSA treatment Facts & Myths. Creeping MICs and Vancomycin troughs. More Vancomycin Failures at Higher MICs. 100. Vancomycin MIC 0.5 µg/mL Vancomycin MIC 1 µg/mL Vancomycin MIC 2 µg/mL. 80. 60. Vancomycin Clinical

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MRSA treatment Facts & Myths

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  1. Dr Suresh Kumar Infectious Diseases Unit Hospital Sungai Buloh MRSA treatmentFacts & Myths

  2. Creeping MICs and Vancomycin troughs Suresh, HSB

  3. More Vancomycin Failures at Higher MICs 100 Vancomycin MIC 0.5 µg/mL Vancomycin MIC 1 µg/mL Vancomycin MIC 2 µg/mL 80 60 Vancomycin Clinical Success (%) 40 20 0 Sakoulas, et al Moise-Broder, et al Hidayat, et al Sakoulas G, Moise-Broder PA, Schentag J, Forrest A, Moellering RC Jr, Eliopoulos GM. Relationship of MIC and bactericidal activity to efficacy of vancomycin for treatment of methicillin-resistant Staphylococcusaureus bacteremia. J Clin Microbiol. 2004;42(6):2398-2402; Moise-Broder PA, Sakoulas G, Eliopoulos GM, Schentag JJ, Forrest A, Moellering RC Jr. Accessory gene regulator group II polymorphism in methicillin-resistant Staphylococcusaureus is predictive of failure of vancomycin therapy. Clin Infect Dis. 2004;38(12):1700-1705; Hidayat LK, Hsu DI, Quist R, Shriner KA, Wong-Beringer A. High-dose vancomycin therapy for methicillin-resistant Staphylococcusaureus infections: efficacy and toxicity. Arch Intern Med. 2006;166(19): 2138-2144. Suresh, HSB

  4. Initial response based on target trough Hidayat LK,et al Arch Intern Med. 2006;166(19): 2138-2144. Suresh, HSB

  5. Suresh, HSB Hidayat LK,et al Arch Intern Med. 2006;166(19): 2138-2144.

  6. Treatment Failure in Patients With High and Low Vancomycin MIC 50 2.4-fold increase in failure 36.4 40 P=.049 30 Percent of failure 20 15.4 10 0 High Vancomycin MIC (≥1.5 µg/L) (n=66) Low Vancomycin MIC (<1 µg/L) (n=26) Lodise TP, Graves J, Evans A, et al. Relationship between vancomycin MIC and failure among patients with methicillin-resistant Staphylococcus aureus bacteremia treated with vancomycin. Antimicrob Agents Chemother. 2008;52:3315-3320. Suresh, HSB

  7. High trough vancomycin levels 15 – 20 mg/L 10.4 – 13.8 µmol/L Vancomycin dose - 15 – 20mg/kg given every 8 – 12 hours Consider loading dose in seriously ill – 25 – 30mg/kg • Bactermia, • Endocarditis, • Osteomyelitis, • Meningitis, • HAP Suresh, HSB

  8. Another reason for high troughs • Always aim to maintain the trough concentrations above 10mg/L (6.9 µmol/L) S aureus exposure to trough vancomycin concentrations of < 10mg/L (6.9 µmol/L) can produce strains with VISA like characteristics Suresh, HSB

  9. Recomendations • In patients who fail to respond to vancomycin after a week of therapy, • consider foreign body that requires removal, or abscesses or infective foci that requires surgical drainage/removal. • If antibiotic failure seems the most likely explanation, request for vancomycin MICs and consider switching to alternative agents if MICs are between 1-2mcg/l. Suresh, HSB

  10. Vancomycin • Pharmacokinetic parameter – AUC/MIC • Trough levels is the best surrogate marker for AUC • 500mg q6h or 1gm q12h – same • No likely added benefit with continuous infusions • Infusion times • 1gm – 1 hour infusion • 1.5gm – 1.5 hour infusion • 2gm – 2 hr infusion Suresh, HSB

  11. Vancomycin Red Man Syndrome • Flushing, erythema, and pruritus, usually affecting the upper body, neck, and face more than the lower body. • Rarely more severe symptoms including pains and muscle spasms in the back and chest, dyspnea, and hypotension may occur. • Occurs more frequently at faster rates of administration. • It is not a true allergic reaction. Suresh, HSB

  12. Vancomycin Red Man Syndrome • Mild reactions: symptoms resolve in minutes. • Restart the infusion at half the previous rate. • For more severe reactions • Administer antihistamines and restart the infusions at half the previous rates. • Consider premedication with antihistamines 1 hour before subsequent doses. Suresh, HSB

  13. MRSA bacteremia – Does one size fit all? Suresh, HSB

  14. Complicated Infections Among Patients With Complicated S. aureusBacteremia Infective endocarditis was diagnosed in 39% of patients who had a complicated infection. 282/724 Infective endocarditis Septic arthritis Deep-tissue abscess Vertebral osteomyelitis Epidural abscess Septic thrombophlebitis Psoas abscess Meningitis Other complications 14 12 12 10 8 7 Patients (%) 6 6 4 3 2 2 2 2 2 2 0 n=89 n=54 n=41 n=22 n=18 n=17 n=13 n=12 n=16 Type of Complicated Infection Fowler VG Jr, Olsen MK, Corey GR, et al. Clinical identifiers of complicated Staphylococcus aureus bacteremia. Arch Intern Med. 2003;163:2066-2072.

  15. Multivariate analysis – Risk of complications Fowler VG Jr, et al. Arch Intern Med. 2003;163:2066-2072. Suresh, HSB

  16. Prospective evaluation of 53 patients with prosthetic joints and 27 patients with other orthopedic prosthetic devices who developed Staphylococcus aureusbacteremia (SAB). • Risk of a prosthesis becoming infected by means of hematogenous seeding after SAB was • 34% (15 of 44 patients) for prosthetic joints and • 7% (1 of 15 patients) for other orthopedic prostheses Suresh, HSB

  17. Duration of therapy for SAB depends on Has the presumed source of SAB been removed? Does the patient have any evidence of IE or other deep seated infection? Does the patient have any underlying predisposition to complications (eg. Prosthetic devices, immunosuppression)? Suresh, HSB

  18. Does the lines need to come out? Mortality and hematogenous complications significantly increased if line removal is delayed The risk of developing hematogenous complications increases by ~13%(6-12%) for each day the line is left in Attempts to salvage long term lines (antibioitc locks etc.) – only < 20% successful with S. aureus Suresh, HSB

  19. JAC Advance Access published online on March 31, 2009 Suresh, HSB

  20. Short course treatment – 2 weeks If ALL of the following criteria are met: • No diagnosed deep focus of infection • Line source if present removed within 48 hrs of diagnosis • No evidence of regurgitantvalvular lesions or vegetations on transthoracic echocardiogram • Blood cultures taken after 72 hours of antibiotics are negative. • Patient is NOT receiving renal dialysis Suresh, HSB

  21. Longer course – 4 - 6 weeks • Infective endocarditis • Deep seated infections • Osteomyelitis, mediastinitis, deep abscess • Persistent SAB • Positive blood cultures > 72 hrs after starting therapy Suresh, HSB

  22. Alternatives for VancomycinHow promising are the newer drugs? Suresh, HSB

  23. Linezolid Ben Mansour, EH, Jacob, E, Monchi, M, et al. Occurrence of MRSA endocarditis during linezolid treatment. Eur J Clin Microbiol Infect Dis 2003; 22:372. Corne, P, Marchandin, H, Macia, JC, Jonquet, O. Treatment failure of methicillin-resistant Staphylococcus aureus endocarditis with linezolid. Scand J Infect Dis 2005; 37:946. • 100% bioavailable • Bacteriostatic • Treatment of nosocomial pneumonia and complicated skin and skin-structure infections (cSSSI) • Resistance and treatment failures reported • Safety concerns • thrombocytopenia, anemia, lactic acidosis, peripheral neuropathy and ocular toxicity Suresh, HSB

  24. Cumulative percentage of patients with myelosuppression over time during the course of linezolid therapy for orthopedic infections. Mayo Clin Proc. 2004;79(9):1137-1144 Suresh HSB

  25. Rapid Bactericidal Activity of Daptomycinvs MRSA In Vivo* Saline Vancomycin Daptomycin 0 h 2 h 4 h *The clinical significance of in vivo data has not been established. Mortin LI, LI T, Van Praagh ADG, Zhang S, Zhang X-X, Alder JD. Rapid bactericidal activity of daptomycin against methicillin-resistant and methicillin-susceptible Staphylococcus aureus peritonitis in mice as measured with bioluminescent bacteria. Antimicrob Agents Chemother. 2007;51:1787-1794. Suresh, HSB

  26. S. aureusBacteremia and Endocarditis StudySuccess Rates at 6-Week Test of Cure in MRSA and MSSA: Pathogen-Specific Therapy (ITT Population) Daptomycin Difference in Success Rates (95% CI): 11.8% (–8.3, 32.1) Difference in Success Rates (95% CI): –2.1% (–19.0, 14.9) Vancomycin* + gentamicin 70 60 Semisynthetic penicillin + gentamicin 46.7 50 44.6 44.4 40 Success Rate (%) 32.6 30 20 10 20/45 14/43 33/74 28/60 0 MRSA MSSA ITT=intent-to-treat; CI=confidence interval. *Mean trough was 14.1 µg/mL. Data on file. Cubist Pharmaceuticals, Inc; Lexington, MA.

  27. Relationship between Daptomycin and Vancomycin resistance clinical relevance of this relationship is unclear Patel JB et al CID 2006 Suresh, HSB

  28. Alternatives for Vancomycin Suresh, HSB

  29. Rifampicin • Exceptional antistaphylococcal activities against both actively dividing and stationary-phase microbes • Excellent penetration into soft tissues, bone, abscess cavities, and into PMNs. • Readily develop resistance esp if microbial burden is high – single mutation • Intrinsic resistance to rifampin occurs naturally among staphylococci with a frequency of 1 in 107 colony-forming units Suresh, HSB

  30. Rifampicin • Always needs a companion drug which has the same pharmocokinetics • Drugs that penetrate poorly into tissues may not be optimal. • Rifampicin resistance develops when used in combination with vancomycin • Simon LG, Smith RH, Sande MA. Rev Infect Dis. 1983;5(suppl 3):S507-S508. Suresh, HSB

  31. Fusidic acid Use of topical fusidic acid monotherapy has been associated with subsequent infection with fusidic acid resistant staphylococcal infection Suresh, HSB

  32. Dumb and Dumber! Suresh, HSB

  33. Ca-MRSA: new bug, old drugs Suresh, HSB

  34. Treatment Ca-MRSA • Mild infections • Cotrimoxazole • Clindamycin • Doxycycline • Severe infections • Vancomycin Suresh, HSB

  35. Using clindamycin for treating S aureus infections – D test MLS(B)-resistance mechanism Efflux pump resistance mechanism Suresh, HSB

  36. Summary • Vancomycin MICs to MRSA are creeping up • Aim for higher troughs for adequate treatment and to prevent further reduction in MICs • Consider alternative drugs if MICs >1 – 2 mg/L and patient is not responding • Duration of treatment of SAB depends on • Removal of presumed foci • Infective endocarditis • Prosthesis Suresh, HSB

  37. Summary Suresh, HSB Newer MRSA agents have their limitations Avoid indiscriminate use of rifampicin and fusidic acid

  38. Thank you Suresh, HSB

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