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

2. Creeping MICs and Vancomycin troughs
Suresh, HSB

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

6. Treatment Failure in Patients With High and Low Vancomycin MIC
High Vancomycin MIC
(≥1.5 µg/L)
(n=66)
Low Vancomycin MIC
(<1 µg/L)
(n=26)
36.4
15.4
Percent of failure 20 30 40 50 10
2.4-fold increase in failure
Antimicrob Agents Chemother Sep;52(9): Epub 2008 Jun 30. Links
Relationship between vancomycin MIC and failure among patients with methicillin-resistant Staphylococcus aureus bacteremia treated with vancomycin.
Lodise TP, Graves J, Evans A, Graffunder E, Helmecke M, Lomaestro BM, Stellrecht K.
Department of Pharmacy Practice, Albany College of Pharmacy, Albany, New York , USA.
There is growing concern that vancomycin has diminished activity for methicillin-resistant Staphylococcus aureus (MRSA) infections, with vancomycin MICs at the high end of the CLSI susceptibility range. Despite this growing concern, there are limited clinical data to support this notion. To better elucidate this, a retrospective cohort study was conducted among patients with MRSA bloodstream infections who were treated with vancomycin between January 2005 and May The inclusion criteria were as follows: at least 18 years old, nonneutropenic, with an MRSA culture that met the CDC criteria for bloodstream infection, had received vancomycin therapy within 48 h of the index blood culture, and survived >24 h after vancomycin administration. Failure was defined as 30-day mortality, bacteremia >or=10 days on vancomycin therapy, or a recurrence of MRSA bacteremia within 60 days of vancomycin discontinuation. Classification and regression tree (CART) analysis identified the vancomycin MIC breakpoint associated with an increased probability of failure. During the study period, 92 patients met the inclusion criteria. The vancomycin MIC breakpoint derived by CART analysis was >or=1.5 mg/liter. The 66 patients with vancomycin MICs of >or=1.5 mg/liter had a 2.4-fold increase in failure compared to patients with MICs of <or=1.0 mg/liter (36.4% and 15.4%, respectively; P = 0.049). In the Poisson regression, a vancomycin MIC of >or=1.5 mg/liter was independently associated with failure (adjusted risk ratio, 2.6; 95% confidence interval, 1.3 to 5.4; P = 0.01). These data strongly suggest that patients with MRSA bloodstream infections with vancomycin MICs of >or=1.5 mg/liter respond poorly to vancomycin. Alternative anti-MRSA therapies should be considered for these patients.
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:
Suresh, HSB

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

8. Another reason for high troughs
S aureus exposure to trough vancomycin concentrations of < 10mg/L (6.9 µmol/L) can produce strains with VISA like characteristics
Always aim to maintain the trough concentrations above 10mg/L (6.9 µmol/L)
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?
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14. Type of Complicated Infection
Complicated Infections Among Patients With Complicated S. aureus Bacteremia
Infective endocarditis
Septic arthritis
Deep-tissue abscess
Vertebral osteomyelitis
Epidural abscess
Septic thrombophlebitis
Psoas abscess
Meningitis
Other complications
Patients (%)
n=89
n=54
n=41
n=22
n=18
n=17
n=13
n=12
n=16 12 7 6 3 2 8 10 14 4
Type of Complicated Infection
282/724
Infective endocarditis was diagnosed in 39% of patients who had a complicated infection.
Fowler VG Jr, Olsen MK, Corey GR, et al. Clinical identifiers of complicated Staphylococcus aureus bacteremia. Arch Intern Med. 2003;163:

15. Multivariate analysis – Risk of complications
Fowler VG Jr, et al. Arch Intern Med. 2003;163:
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16. Prospective evaluation of 53 patients with prosthetic joints and 27 patients with other orthopedic prosthetic devices who developed Staphylococcus aureus bacteremia (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
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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)?
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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
Objectives: We describe treatment failure rates by antibiotic duration for prosthetic joint infection (PJI)
managed with debridement, antibiotics and implant retention (DAIR).
Methods: We retrospectively collected data from all the cases of PJI that were managed with DAIR over
a 5 year period. Surgical debridement, microbiological sampling, early intravenous antibiotics and prolonged
oral follow-on antibiotics were used.
Results: One hundred and twelve cases of PJI were identified. Twenty infections (18%) recurred during
a mean follow-up of 2.3 years. The mean duration of antibiotic use was 1.5 years. Failure was more
common after arthroscopic debridement, for previously revised joints and for Staphylococcus aureus
infection. There were 12 failures after stopping antibiotics and 8 while on antibiotics [hazard ratio
(HR)54.3, 95% confidence interval (CI) 1.4–12.8, P50.01]. However, during the first 3 months of
follow-up, there were eight failures after stopping antibiotics and two while on antibiotics (HR57.0,
95% CI 1.5–33, P50.015). The duration of antibiotic therapy prior to stopping did not predict outcome.
Conclusions: PJI may be managed by DAIR. The risk of failure with this strategy rises after stopping
oral antibiotics, but lengthening antibiotic therapy may simply postpone, rather than prevent, failure.
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 regurgitant valvular lesions or vegetations on transthoracic echocardiogram
Blood cultures taken after 72 hours of antibiotics are negative.
Patient is NOT receiving renal dialysis
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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
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22. Alternatives for Vancomycin How promising are the newer drugs?
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23. Linezolid 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
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.
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24. Cumulative percentage of patients with myelosuppression over time during the course of linezolid therapy for orthopedic infections.
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Mayo Clin Proc. 2004;79(9):

25. Rapid Bactericidal Activity of Daptomycin vs 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:
Suresh, HSB

26. Difference in Success Rates (95% CI):
S. aureus Bacteremia and Endocarditis Study Success Rates at 6-Week Test of Cure in MRSA and MSSA: Pathogen-Specific Therapy (ITT Population)
44.6
44.4
Success Rate (%) 10 20 30 40 50 60 70
MRSA
MSSA
Daptomycin
20/45
33/74
32.6
Difference in Success
Rates (95% CI):
11.8% (–8.3, 32.1)
14/43
Vancomycin* + gentamicin
46.7
Difference in Success Rates (95% CI):
–2.1% (–19.0, 14.9)
28/60
Semisynthetic penicillin + gentamicin
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
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Patel JB et al CID 2006

28. Alternatives for Vancomycin
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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
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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
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32. Dumb and Dumber!
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33. Ca-MRSA: new bug, old drugs
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35. Treatment Ca-MRSA Mild infections Severe infections Cotrimoxazole
Clindamycin
Doxycycline
Severe infections
Vancomycin
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36. Using clindamycin for treating S aureus infections – D test
MLS(B)-resistance mechanism
Efflux pump resistance mechanism
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37. 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

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

39. Thank you
Suresh, HSB