The MRSA Superbug

The MRSA SuperbugBrad M. Wright, PharmD, BCPSAssistant Clinical ProfessorAuburn University Harrison School of PharmacyAdjunct Assistant ProfessorUniversity of South Alabama College of MedicineDisclosureProgramming offered by Auburn University Harrison School of Pharmacy shall exhibit balance, providing the audience information of different perspectives from which to develop an informed professional opinion.

I, Brad Wright, have the following to disclose:Grant Funding Novartis PharmaceuticalsObjectives1.Describe Methicillin-resistant Staphylococcus aureus (MRSA) and the impact associated with infection

2.Explain the differences between hospital and community-associated MRSA

3.Discuss appropriate treatment options for MRSA infection

In the HospitalStaph often adds danger, days to a patient stay Portland Tribune

Drug-resistant staph lurks in many places USA Today

Staph Superbug May Be Infecting Patients- ABC news

Problem of Hospital Acquired Infections, Antibiotic Resistance is Growing Homeland SecurityCommunityMRSA Hospitalizations Surge, as Drug Resistant Superbug Moves Outside Hospital Settings

MRSA "Superbug" Claims Life Of Another Texas Teen CBS

Schools On Alert For 'Superbug' Staph Infections CBS

Bacteria that killed Virginia teen found in other schools - CNN

Headlines

What is MRSA?Methicillin-resistant Staphylococcus aureus

Leading cause of infections in both the hospital and the community

Commonly found on the skin and in the nose of the general population

Causes multiple types of infectionsInvasive Bloodstream, pneumonia, etcNon-invasive Skin

Associated with a high risk of morbidity and mortality and increased health care costs85% of all invasive MRSA infections asociated with health care settings.

8What MRSA is notA death sentence

A new, never seen before type of infection or bug

Untreatable by current antibiotics

Only associated with dirty hospitals

A reason patients should not be around others or stay at home9Burden of MRSA1999 295,000 hospitalization due to S. aureus Of these an estimated 127,000 (43%) were due to MRSA

2005 478,000 hospitalizations due to S. aureusOf these, an estimatetd 278,000 (58%) were due to MRSA

Hospitalizations associated with S. aureus infection increased 62% or ~ 8.4% per yearMRSA infections increased 119% or ~14% per year.

Dramatic increase in skin infectionsEmerg Infect Dis 2007;13:1840-6, www.cdc.govBurden of MRSA

Emerg Infect Dis 2007;13:1840-6, How did we get here?1928 Penicillin discovered1941 Penicillin available in US 1940s Resistance emerges 1958 Vancomycin introduced1959 Methicillin introduced1961 First cases of MRSA1968 First hospital outbreak followed by an increase in prevelance in hospitals1980s - 90s First community outbreaks

12Where is MRSA?Initially MRSA was endemic to US hospitals and long-term care facilitiesIll and elderly patientsHealthcare-associated MRSA (HA-MRSA)

MRSA is no longer limited to just hospitalized patients1980s - IV drug users in the community1990s - US Children

Outbreaks in communities worldwideCommunity-acquired MRSA (CA-MRSA)13Where is MRSA In HospitalsThe proportion of healthcare-associated staphylococcal infections that are due to MRSA has been increasing 2% in 1974 64% in 2004More recent data describes a stabilization or decrease in this trend56% of device-associated infections with S. aureus reported as MRSA in 2006-2007 Most recent estimates show decreases in these infections in the U.S.MRSA bloodstream infections demonstrated a 34% decrease in incidence between 2005 and 2008Clin Infect Dis 2006;42:389-91, www.cdc.gov, Infect Control Hosp Epidemiol 2008;29:996-1011 Most common infections in the hospital14Where is MRSA - CommunityMost Community-acquired MRSA presents as SSTI

In 2005, approximately14 million outpatient healthcare visits were made for suspected S. aureus skin and soft tissue infections

In 2004 >75% of SSTIs presenting to ED were S. aureus~60% - MRSA

Most common CA-MRSA InfectionsN Engl J Med 2005; 352:1436-144416HA-MRSA vs CA-MRSAHA-MRSA infections occur in patients who are in or recently have been in hospitals or other health-care settingsOften are related to surgery or medical devices Often found in the blood, tissues, lungs, heart valvesResistant to many different drugs

CA-MRSA infections are found in patients in the communityUsually limited to skin infectionsMay be susceptible to more types of antibioticsDefinition of CA-MRSACDC definition:

Diagnosis of MRSA in the outpatient setting or positive culture within 48 hours of hospital admissionNo history in the past year of:HospitalizationAdmission to nursing home, skilled nursing facility, or hospiceDialysisSurgeryNo permanent indwelling catheters or medical deviceswww.cdc.govCA-MRSANot spill over of HA-MRSA to the community

Separate and distinct clones of MRSAUSA 300

Panton-Valentine leukocidin (PVL) gene Virulence factor found in almost all strains of CA-MRSACauses necrosis and inflamationCommonly found in CA-MRSA not in HA-MRSA

Most common presentation is minor skin and soft tissue infectionsSpider bitesSkin and Soft-tissue InfectionsImpetigoSecondary infection - skin lesionsAbscessFuruncleCarbunclePurulunt cellulitisNonpurulent cellulitisComplicatetd SSTINonpurulent cellulitis often caused by strep, not staph20Who is at Risk CA-MRSA?Factors associated with increased risk:Close contactCuts/abrasions openings in the skinContaminated items and surfacesCrowded living conditionsPoor hygiene

These factors are common in: DormsAthletic facilitiesMilitary barracks PrisonsDaycaresHA-MRSA vs CA-MRSACA MSAHA-MRSATime of culture after hospital admission 48hrsCloneUSA 300USA 100Presence of PVL toxinCommonRareRisk factorsUsually none; Close physical contact, activities associated with poor communal hygieneRecent hospitalization, surgery, prior antibioticsTypical patientYoung, healthyChronically ill, hospitalizedType of infectionSkin abscesses and cellulitisPneumonia, bloodstream, cSSIResistanceBeta-lactams; typically resistant to fewer agentsMultiple-drug resistantTreatment of CA-MRSA SSTIPrimary - Incision and drainageWith or without antibiotic therapy

No further benefit associated with antibiotic therapy for simple abscessesStudies have shown high cure rates whether or not an antibiotic is usedTrials comparing TMP/SMX with placebo show no difference in cure rateAntibiotic may prevent development of new lesionsRetrospective trials suggest improved cure rates with antibioticsClin Infect Dis 2011;52:1-38Treatment of CA-MRSA SSTIAntibiotic therapy is recommended for abscesses associated with:Severe or extensive diseaseRapid progressionSigns and symptoms of systemic illnesAssociated comorbidities or immunosuppresionExtremes of ageAbscess in an area difficult to drainAssociated septic phlebitisLack of response to incision and drainage

24Treatment of CA-MRSA SSTIOutpatients with purulent cellulitisEmpirical antibiotic therapy for CA-MRSA5-10 days of therapy

Outpatients with nonpurulent cellulitisEmpirical antibiotic therapy for infection due to beta-hemolytic streptococci5-10 days of therapyCA-MRSA coverage for those who do not respond to beta-lactam therapy

If you suspect Staph, treat for MRSA25Treatment of CA-MRSA SSTIOral antibiotic options for outpatients with SSTIClindamycinTMP-SMXTetracyclinesLinezolid

Coverage for streptococci Clindamycin aloneTMP-SMX or tetracycline + beta-lactamLinezolid alone

ClindamycinFDA approved to treat serious infections caused by Staphylococcus aureus (not MRSA)

Mechanism of action: Inhibits protein synthesis

Typical Adult Dose: 300-450 mg PO TID600mg PO/IV TID (cSSTI)

ADRs: Diarrhea, GI upsetClostridium difficile associated disease

Pregnancy cateory BBacteriostatic not recommended for endovascular infection (infective endocardidtis or septic thrombophlebitis)Excellent tissue penetration, particularly in bone and abscessesSusceptibility to clindamycin are higher among CA-MRSA than HA-MRSADiarrhea most common adverse effect and occurs in up to 20% of pts.C. DiffOral suspension not well tolerated in childrenPregnancy category B27ClindamycinClindamycin ResistanceIn Vitro susceptibility higher for CA-MRSA than HA-MRSAInducible resistanceD-TestErythromycin disk is placed near clindamycin diskEvaluate for D zone of inhibition

Clin Infect Dis. 2005;40(2):280-285. Detection of inducible clindamycin resistance in erythromycin-resistant, clinda-susceptible isolates28Trimethoprim - SulfamethoxazoleNo FDA-labeled indication for Staphylococcal infection

Mechanism of Action - TMP and SMX each block folate synthesis at a different step in the pathway which synergistically results in a bactericidal effect

Dose: 1-2 double-strength (DS) tabs BID

Almost 100% of CA-MRSA strains are susceptible in vitro29Trimethoprim-SulfamethoxazoleAdverse Reactions:Common: Rash, Nausea, Vomiting, HyperkalemiaSevere: Cytopenias, Stevens-Johnson syndrome, Nephritis

Drug interactions: Increased levels of warfarin, methotrexate, phenytoinACEi

Caution in elderly, especially those with kidney disease

Pregnancy category C/DNot recommended in 3rd trimester

30TetracyclinesDoxycycline is FDA-approved for the treatment of SSTI due to S. aureus.Not FDA approved for MRSA

Tetracycline, Doxycycline, and Minocycline

Mechanism of action: Inhibition of bacterial protein synthesis

Doses:Minocycline - 200mg x1, then 100mg po BIDDoxycycline - 100mg po BIDEffective for treatment of SSTI, but data are lacking to support their use in more-invasive infectionsMinocycline is available IV and oralTigecycline bacteriostatic againstt MRSA, caution should be used in treating patients with bacteremia31TetracyclinesContraindications: Children < 8 years of age Pregnancy

ADRs:Photosensitivity, N/V

Drug Interactions:Decreased absorption with food,dairy, or antacids

Studies show tetracyclines are well tolerated with success of 95-100% in CA-MRSA SSTITet(k) confers resistance to tetracycline and inducible resistance to doxy therefore minocycline may be most preferredPregnancy category D No children under 8

Results of Antimicrob Agents and Chemother, Sept 2007, p. 3298-3303More patients in the beta-lactam group were likely to have a surgical service to the I and d.

Treatment success was seen in 96% of the doxycycline group vs. 88% of the beta-lactam group

12% of the beta-lactam group changed therapy at day 4 to an active agent

The only predictor of clinical failure in a bivariate analyses was beta lactam therapyItems that were not predictors included: severity of underlying illness, presense of SIRS (17% of each group), or demographics

In a subgroup analyses of patients who only received I&D: betalactam therapy was associated with a negative outcome (n=225; adjust OR 3.39; 95% CI (1.07 10.75, p = 0.04)

Conclusion:

Probably the largest study to date (published in september 2007) evaluating the use of tetracyclines/doxycycline in CA-MRSA SSTI. Therapy was well tolerated and had a success rate of 96%. At present, most laboratories are not testing mino or doxy versus s aureus. Until they do, you should assume that tetracycline resistance confers resistance to the class. May be useful in patients with sulfa allergy. This study emphasizes the importance of surgical drainage as primary therapy.

The limitations to this study: retrospective, no randomization, patients excluded/did not follow up could have altered results

32LinezolidFDA approvedTreatment of SSTI and nosocomial pneumonia due to MRSA

MOA: Inhibits protein synthesisInhibits PVL

Dose: 600mg BID (IV or PO)High bioavailability

Used for hospital-acquired and community-associated infections

More expensive than other alternatives

Only orally available agent for which efficacy against MRSA infection has been demonstrated in controlled trialsGreat activity vs Group A strep

Has in vitro activity vs VISA and VRSA100% bioavalability only give IV if GI absorption problem or pt cant take oralResistance is rare.33Linezolid - ADRsMyelosuppression:Associated with long term therapy (>2 weeks)S/Sx: thrombocytopenia, anemia, pancytopenia

Serotonin SyndromeLinezolid = Mild MAO InhibitorConcomitant use with SSRIs and SNRIs can lead to increase levels of serotoninConcomitant use should be avoidedUse caution and monitor for s/sx if used together

Pharmacotherapy. 2007 Aug;27(8):1189-97Long-term use is limited by hematologic toxicity, with thrombocytopenia occuring more frequently than anemia and neutropenia, peripheran and optic neuropathy, and lactic acidosis. Weak, nonselective, reversible inhibitor of MAO and has been associated with serotonin syndrome in pts taking concurrent SSRIsLess bone marrow suppression in children than adultsMost commor ADRs diarrhea, vomiting, loose stools, anauseaPregnancy - C34Topical TreatmentsNeosporin/Polysporin

Mupirocin (Bactroban)

Retapamulin (Altabax)Recurrent MRSA SSTIsDefinition - 2 or more discrete SSTI episodes at different sites over a 6-month period

Multidimensional approachEngage the patient in personal and environmental hygiene measuresPreventive education on personal hygiene and wound careCover infected skin and draining woundsMaintain good personal hygieneAvoid sharing personal itemsUse cleaners or detergents to clean surfacesClin Infect Dis 2011;52:1-38; www.cdc.gov/mrsa/enfironment/index.htmlRecurrent MRSA SSTIs -DecolonizationEliminate S. aureus carriage

May be considered for patients with:Multiple recurrent SSTI despite hygiene measuresOngoing transmission in a well-defined, closely associated cohort

Should be offered in conjunction with ongoing reinforcement of hygeiene measures

www.cdc.gov/ncidod/dhqp/ar_mrsa_ca.html; Clin Infect Dis;52:1-38 Given the potential role of colonization in the pathogenesis of recurrent SSTI, prevention strategies have also focused on decolonization, the use of antimicrobial or antiseptic agents to suppress or eliminate S. Aureus carriage as a means of preventing auto-infection or transmission

No published datta to support its efficacy in patients with recurrent MRSA SSTI optimal regimen, frequency of application, and duration of therapy are unclear. Unknown whether it will select for or result in replacement with more resistant or more-virulent strains37Recurrent MRSA SSTIsDecolonization strategiesNasal mupirocin 5 day courseMupirocin + topical antiseptic (chlorhexidine)Oral antibioticsRifampin + TMP-SMX/doxycycline5-10 daysCombine with hygiene measures and /or topic antiseptic

If household transmission is suspected:Personal and environmental hygiene measuresEvaluation and treatment of symptomatic contacts

Am J Infect Control 2007;35:16-14; Clin Infect Dis 2007;44:178-85; Clin Infect Dis;52:1-38 38Treatment of Complicated SSTIComplicated SSTI (cSSTI) is defined as:Deeper soft-tissue infectionsSurgical/traumatic wound infectionMajor abscessesCellulitisInfected ulcers and burns

Also patients with systemic toxicity and/or rapidly progressing or worsening infection

Inpatient management with surgical debridement and broad-spectrum antibiotics

Clin Infect Dis;2011;52:1-38Treatment of Complicatted SSTIEmpirical therapy for MRSA should be considered pending culture data

Options for hospitalized patients include:VancomycinLinezolidDaptomycinTelavancinClindamycin CeftarolineBeta-lactam may be considered with nonpurulent cellutis

7-14 days of therapy is recommended

Clin Infect Dis 2011;52:1-38VANC:Mainstay of parenteral therapy for MRSA infectionsPreferred option in hospitalized patients15-20mg/kg/dose IV every 8-12 hoursEfficacy has come into question, with concerns over its slow bactericidal activity, the emergence of resistant strains, and possible MIC Creep among susceptible strainsInferior to beta-lactams for MSSA bacteremia and infective endocarditisTissue penetration is highly variable and depends upon the degree of inflamationLimited penetration into bone, lung epithelial lining fluid and CSFPregnancy category CDAPTOMYCIN:4mg/kg/dose IV dailyLess likely to develop resistanceCan not be used for pneumoniaCEFTAROLINE:4mg/kg/dose IV dailyLess likely to develop resistanceCan not be used for pneumonia

40MRSA PneumoniaCA - MRSA has emerged as a cause of community-acquired pneumonia (CAP)Secondary to influenza infection

Empirical therapy for MRSA should be considered in patients with severe CAP defined by any of the following:ICU admissionNecrotizing or cavitary infiltratesEmpyema

Chest 2010;138:130-6; Clin Infect Dis 2011;52:1-38Discontinue if blood or sputum cultures do not grow Staph41MRSA PneumoniaFor HA-MRSA or CA-MRSA consider the following treatment options:IV vancomycinLinezolid IV/POClindamycin IV/PO TID

Recommended length of therapy 7-21 days

Empyema Antibiotics in conjunction with drainageClin Infect Dis 2011;52:1-38MRSA osteomyelitisMRSA bone infections result from:Hematogenous seedingContiguous focus of infectionDirect inoculation from trauma or medical procedure

Surgical debridement of necrotic bone and drainage of adjacent abscessMainstay of therapyCombine with antibiotics

MRSA Osteomyelitis Antibiotic TherapyOptimal route of administration has not been established

Parenteral antibiotics include:VancomycinDaptomycin 6mg/kg/doseTMP-SMX 4mg/kg/dose BID w/ RifampinLinezolid PO/IVClindamycin IV/PO

Optimal duration of therapy is unknown but a minimum of 8 weeks is recommended

Parenteral, oral, or initial parenteral followed by oral therapy may be usedDepends on individual patient circumstances44SummaryMRSA is no longer confined to the hospital

CA MRSA often presents as a skin infectionTreatment usually consists of TMP/SMX, clindamycin, tetracyclines, or linezolidMore severe infections treated with IV antibiotics

Treatment should also consist of hygiene counseling

ReferencesCenters for disease control and prevention. MRSA infections. http://www.cdc.gov/mrsa.html (Accessed 9/28/11)Liu C, Bayer A, Cosgrove SE, et al. Clinical Practice Guidelines by the Infectious Deseases Society of America for the Treatment of Methiciliin-Resistant Staphylococcus Aureus Infections in Adults and Children. Clin Infect Dis. (2005) 40 (2): 280-285. Klein E, Smith DL, Laxminarayan R. Hospitalizations and Deaths Caused by Methicillin-Resistant Staphylococcus aureus, United States, 19992005 Emerg Infect Dis 2007;13:1840-6.Klevens RM, Edwards JR, Tenover FC, et al. Changes in the epidemiology of methicillin-resistant Staphylococcus aureus in intensive care units in US hospitals, 19922003. Clin Infect Dis 2006;42:389-91.Hidron AI, Edwards JR, Patel J, et al, National Healthcare Safety Network Team; Participating National Healthcare Safety Network Facilities: Antimicrobial-resistant pathogens associated with healthcare-associated infections: Annual summary of data reported to the Natioanl Healthcare Safety Network at the Centes for Disease Control and Prevention, 2006-2007. Infect Control Hosp Epidmiol 2008, 29:996-1011.Fridkin SK, Hageman JC, Morrison M, et al. Methicillin-Resistant Staphylococcus aureus Disease in Three Communities. N Engl J Med 2005; 352:1436-1444.Lewis JS, Jorgensen JH. Inducible Clindamycin Resistance in Staphylococci: Should Clinicians and Microbiologists be Concerned? Clin Infect Dis. 2005;40(2):280-285.Narita M, Tsuji BT, Yu VL. Linezolid-associated peripheral and optic neuropathy, lactic acidosis, and serotonin syndrome. Pharmacotherapy. 2007 Aug;27(8):1189-97Simor AE, Phillips E, McGeer A, et al. Randomized controlled trial of chlorhexidine gluconate for washing, intranasal mupirocin, and rifampin and doxycycline versus no treatment for the eradication of methicillin-resistant Staphylococcus aureus colonization. Clin Infect Dis 2007;44:178-85.Lobo LJ, Reed KD, Wunderink RG. Expanded clinical presentation of community-acquired methicillin-resistant Staphylococcus aureus pneumonia. Chest 2010;138:130-6.

The MRSA SuperbugBrad M. Wright, PharmD, BCPSAssistant Clinical ProfessorAuburn University Harrison School of PharmacyAdjunct Assistant ProfessorUniversity of South Alabama College of Medicine