Dr Suresh KumarInfectious Diseases Unit

Hospital Sungai Buloh

Suresh, HSB 2

Creeping MICs and Vancomycin troughs

More Vancomycin Failures at Higher MICs

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):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 Staphylococcus aureus 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 Staphylococcus aureus infections: efficacy and toxicity. Arch Intern Med. 2006;166(19): 2138-2144.

Vanco

myci

n C

linic

al

Succ

ess

(%

)

Sakoulas, et al Moise-Broder, et al Hidayat, et al

Vancomycin MIC 0.5 µg/mLVancomycin MIC 1 µg/mLVancomycin MIC 2 µg/mL

0

60

80

20

40

100

3Suresh, HSB

Initial response based on target trough

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): 2138-2144. 5Suresh, HSB

Treatment Failure in Patients With High and Low Vancomycin MIC

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.

P=.049

High Vancomycin MIC(≥1.5 µg/L)

(n=66)

Low Vancomycin MIC(<1 µg/L)(n=26)

36.4

15.4

Perc

ent

of

failu

re

0

20

30

40

50

10

2.4-fold increase in failure

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High trough vancomycin levels

Bactermia, Endocarditis, Osteomyelitis, Meningitis, HAP

15 – 20 mg/L10.4 – 13.8 µmol/L

Vancomycin dose - 15 – 20mg/kg given every 8 – 12 hoursConsider loading dose in seriously ill – 25 – 30mg/kg

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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

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Always aim to maintain the trough concentrations above 10mg/L (6.9 µmol/L)

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.

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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

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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.

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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.

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MRSA bacteremia – Does one size fit all?

Complicated Infections Among Patients With Complicated S. aureus Bacteremia

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;163:2066-2072.

Infective endocarditisSeptic arthritisDeep-tissue abscessVertebral osteomyelitisEpidural abscessSeptic thrombophlebitisPsoas abscessMeningitisOther complications

Pati

ents

(%

)

n=89 n=54 n=41 n=22 n=18 n=17 n=13 n=12 n=16

12

76

32 2 2 2 2

0

8

10

12

14

6

4

2

Type of Complicated Infection

14

282/724

Multivariate analysis – Risk of complications

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Fowler VG Jr, et al. Arch Intern Med. 2003;163:2066-2072.

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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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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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

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Suresh, HSB 19

JAC Advance Access published online on March 31, 2009

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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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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Alternatives for Vancomycin

How promising are the newer drugs?

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

Suresh, HSB 23

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.

Suresh HSB

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

Rapid Bactericidal Activity of Daptomycin vs MRSA In Vivo*

*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.

Saline Vancomycin Daptomycin

0 h

2 h

4 h

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S. aureus Bacteremia and Endocarditis Study

Success Rates at 6-Week Test of Cure in MRSA and MSSA: Pathogen-Specific Therapy (ITT Population)

ITT=intent-to-treat; CI=confidence interval.

*Mean trough was 14.1 µg/mL.

Data on file. Cubist Pharmaceuticals, Inc; Lexington, MA.

44.644.4

Succ

ess

Rate

(%

)

0

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

Relationship between Daptomycin and Vancomycin resistance

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clinical relevance of this relationship is unclear

Patel JB et al CID 2006

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Alternatives for Vancomycin

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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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.

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Fusidic acid

Use of topical fusidic acid monotherapy has been associated with subsequent infection with fusidic acid resistant staphylococcal infection

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Dumb and Dumber!

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Suresh, HSB 33

Ca-MRSA: new bug, old drugs

Treatment Ca-MRSA

Mild infections Cotrimoxazole Clindamycin Doxycycline

Severe infections Vancomycin

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Using clindamycin for treating S aureus infections – D test

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Efflux pump resistance mechanism

MLS(B)-resistance mechanism

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

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Newer MRSA agents have their limitations

Avoid indiscriminate use of rifampicin and fusidic acid

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Summary

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