Community-acquired MRSA: Portrait of a Killer

From 2008 Update on Infectious Diseases, presented by the University of Wisconsin School of Medicine and Public Health

Dennis G. Maki, MD, Ovid O. Meyer Professor, Department of Medicine, Section of Infectious Diseases,
University of Wisconsin School of Medicine and Public Health, and Attending Physician,
Center for Trauma and Life Support, University of Wisconsin Hospital and Clinics, Madison

Educational Objectives

The goal of this program is to improve outcomes in patients with methicillin-resistant Staphylococcus aureus (MRSA) infections. After hearing and assimilating this program, the clinician will be better able to:

1.   Detail the factors that increase clinical suspicion for MRSA.

2.   Compare and contrast methicillin-sensitive S aureus, hospital-acquired MRSA, and community-acquired MRSA, with regard to clinical picture, management approach, and outcomes.

3.   Discuss the clinical relevance of antimicrobial resistance and the implications of inadequate initial therapy for MRSA.

4.   Select appropriate antimicrobial therapy for patients with MRSA infections.

5.   Prevent and manage recurrent infection with S aureus.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any per­sonal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, Dr. Maki and the plan­ning committee reported nothing to disclose.

Acknowledgments

Dr. Maki was recorded at 2008 Update on Infectious Diseases, presented by the University of Wisconsin School of Medicine and Public Health, and held July 23-25, 2008, in Middleton, WI. The Audio-Digest Foundation thanks Dr. Maki and the University of Wisconsin School of Medicine and Public Health for their cooperation in the production of this program.

Impact of antibiotic therapy on survival: community-acquired pneumonia (CAP)  —  today, mortality rate »5% (higher for hospitalized patients); in preantibiotic era, mortality rate »33%; bacterial meningitis  —  5% to 10% mortality rate today (outcome improves with early treatment); in pre-antibiotic era, 98% of infected children died, and survivors se­verely impaired; septic shock  —  25% to 30% mortality rate today; in pre-antibiotic era, 90% of patients died (survival more common with appendicitis or urosepsis caused by obstruction; draining appendix or relieving obstruction im­proved chance for survival)

Staphylococcus aureus

Infections: lesions  —  abscesses common (prototypic lesion); invasive infection may cause miliary abscesses and  se­vere metastatic infection; S aureus rarely causes purely superficial infections (streptococcal pathogen likely), but responsible for most soft-tissue infections with focal purulence; breast abscesses typically caused by S aureus; bacteremia  —  in hospital settings, catheter-associated S aureus infections responsible for 90% of cases; endocarditis  —  no other pathogen has higher capacity to cause infective endocarditis in patients with normal heart valves; acute syndrome with very large vegetations; embolization into carotid artery may result in hemiparesis; as­sociated with high mortality rate (especially with methicillin-resistant S aureus [MRSA]), high risk for metastasis, and rapid destruction of intracardiac structures (major cause of death); bone and joint infections  —  in children, in­fections typically occur near diaphyses of long bones; in adults, infection mainly affects axial skeleton (S aureus most common cause of vertebral osteomyelitis); surgical site infections  —  eg, sternotomy infections; commonly as­sociated with S aureus; ventilator-associated pneumonia (VAP)  —  incidence has increased markedly over last 10 to 15 yr; toxigenic food poisoning  —  caused by, eg, S aureus contamination of produce; toxic shock syndrome (TSS)  —  first identified in association with S aureus, but few isolates produce toxin

Diagnosis: Gram stain useful for examining cultures from pus, sputum, joint aspirate, or cerebrospinal fluid; cytology  —clusters generally indicative of S aureus; chains or pairs indicative of streptococcal infection; coagulase test  —  S aureus usually coagulase-positive

Virulence factors: immune system evasion  —  cell wall resistant to phagocytosis; isolates can live (in latent form) in lymph nodes for years; exotoxins  —  cause food poisoning or tissue destruction; Panton-Valentine toxin (pro­duced by 90% of community-acquired MRSA [CA-MRSA] isolates; associated with substantial destruction of soft tissues); TSS superantigen stimulates immune system to launch extreme inflammatory response (resulting in tissue destruction and shock); antibiotic resistance  —  increases risk for poor outcomes

Antimicrobial Resistance

General: in early 1950s, thought that antibiotic therapies would result in elimination of bacterial infections; since then, only two major bacterial pathogens (Treponema pallidum and group A streptococci) remain susceptible to original drug of choice; all others have developed resistance, necessitating changes in antibiotic therapy

Development of MRSA: penicillin available in 1940s; all strains of S aureus susceptible; by 1950, »60% of hospital strains resistant, and 90% resistant by 1960; by 1970, 80% to 90% of community strains resistant; mechanism  —  resistance conferred by enzyme that hydrolyzes penicillin; gene contained on plasmid; clinical implications  —  in 1950s, no treatment available for penicillin-resistant strains; 5% to 10% of surgical wounds infected with resistant S aureus; management relied on drainage; new antibiotics  —  methicillin, oxacillin, and nafcillin became available between 1959 and 1960; resistance emerged in Europe within several years, but United States spared until late 1980s; initially, MRSA confined to hospital settings (especially large teaching hospitals); now, almost 60% of hos­pital-acquired S aureus isolates resistant (rates even higher in intensive care units [ICUs]); resistant rates in devel­oping countries twice those of North American countries; vancomycin  —available since 1950s; after 30 yr of heavy use, vancomycin-resistant enterococcus (VRE) emerged and quickly spread; resistance emerged within S aureus relatively soon thereafter; isolates resistant to methicillin and vancomycin identified from multiple geographic re­gions

Community-acquired MRSA: formally identified in United States »10 yr ago; incidence has increased globally; gene complex that confers resistance transferred to community strains (more genetically diverse than nosocomial strains); virulence  —  more virulent than nosocomial strains; more likely to produce toxins; incidence  —  recent study of metropolitan emergency departments identified MRSA in 60% of isolates from community-acquired complex soft-tissue infections; MRSA vs methicillin-susceptible S aureus (MSSA)  —  MRSA associated with much more tissue damage, severe purulence, and presence of Panton-Valentine virulence factor; susceptibility  —  compared to hospital-acquired (HA)-MRSA, CA-MRSA more likely susceptible to trimethoprim-sulfamethoxa­zole (TMP-SMZ), clindamycin, and minocycline; CA-MRSA may have some susceptibility to imipenem

Prevalence: high rates in American Indian populations (emerged on reservations before general population); factors that increase risk include intravenous (IV) drug use, HIV infection, homelessness, and sharing hot tubs; high rates also seen in sports teams, among military personnel (screening has shown 3%-4% carriage rates among healthy young recruits), and in prisons (difficulty isolating inmates); sports teams  —  problematic in contact sports (eg, football, wrestling); factors that increase spread include sharing towels, soap basins, and whirlpools, bodily contact with other players, and cosmetic shaving (eg, in swimmers); infected cuts and abrasions quickly become purulent; national estimates  —  incidence quickly increasing; projected estimate >300  000 cases/yr (likely underestimated), including 95  000 invasive cases; 31.8 cases per 100  000 individuals (for comparison, in­cidence of Lyme disease is 2-3 per 100  000); increased risk among older adults, blacks, and American Indians; Europe  —prevalence varies widely in different countries, likely related to different practices of prevention and control

Clinical relevance: study in ICUs identified factors that predict survival among patients with bacteremia; inadequate antimicrobial therapy (ie, cultures showed resistance to empiric agent) during first 48 hr associated with mortality rate of 70% (7 times higher than that of patients who received adequate initial therapy); empiric therapy often did not cover MRSA or gram-negative rods; results validated by other studies; mortality rates  —  in United Kingdom, incidence of MRSA infections increased by 25-fold from 1993 to 2002 (with commensurate increase in mortality); in United States, more people die from MRSA infections than from AIDS or breast cancer; compared to MSSA, MRSA associated with higher mortality rates (3-fold higher among patients with sternotomy infections; doubled among patients with bacteremia); population-based study showed high mortality associated with CA-MRSA infec­tions in older adults (22% died within 1 yr, compared with 5% for age-matched controls); contributing factors in­clude virulence and delay in appropriate therapy

Susceptibility to vancomycin: S aureus considered susceptible to vancomycin (in vitro) if minimum inhibitory con­centration (MIC) <4 mg/mL, intermediate if MIC 4 to 8 mg/mL, and resistant if MIC >16 mg/mL; however, studies show that MICs ³1 g/mL associated with very high rates of failure and mortality; study looking at MRSA bactere­mia found »50% failure rate associated with MIC of 0.5 mg/mL; among isolates of MRSA, MIC₉₀ (MIC that en­compasses 90% of isolates) has increased ³8-fold over last 25 yr; Centers for Disease Control and Prevention looked at MICs for 250  000 isolates of MRSA; 16% of isolates had MICs ³2 mg/mL

Selection for resistance: adaptive genetic mutation improves survival of organism (allowing clonal expansion); bac­teria also may transfer plasmids (containing genes that confer resistance) to previously susceptible bacteria; plas­mids often contain multiple genes, conferring resistance to >1 antibiotic; antibiotic pressure increases likelihood that resistant strains become dominant; epidemiologic studies show heavy use of antibiotics most important factor determining resistance rates; cross-resistance  —heavy use of cephalosporins, other b-lactams, and clindamycin has contributed to development and spread of methicillin resistance; vancomycin resistance driven, in part, by heavy use of cephalosporins and agents that cover anaerobic organisms

Therapeutic implications: management of life-threatening infections requires algorithmic protocols that address di­agnosis, source control, antibiotic therapy, and supportive and adjunctive therapy; diagnosis  —  staphylococcal soft-tissue infections require culture and susceptibility testing; source control  — thorough drainage necessary; persis­tence of focal infection will result in treatment failure, even if pathogen susceptible to agent; for catheter-related in­fections, remove catheter; initial antimicrobial therapy  —  for patients with life-threatening infections (eg, septic shock), even short delays result in decreased survival (85% when antibiotics given within 30 min of presentation; 45% when given »6 hr after presentation); best to administer antibiotics within 1 hr

Antimicrobial Therapy

Ineffective agents: third-generation cephalosporins  —  effective against pneumonia, meningitis, and gram-negative infections, but no activity against MRSA; monotherapy inappropriate for patients with community-acquired sepsis or any HA-S aureus infection (require coverage for MRSA); carbapenems  —  imipenem and meropenem effective against gram-negative organisms, but no activity against MRSA; fluoroquinolones  —  effective for use in patients with CAP, but ineffective against MRSA

Linezolid: advantages  —  excellent bioavailability; bid dosing; disadvantages  —  expensive; long-term use causes bone-marrow suppression and may cause peripheral neuropathy or optic neuritis; use  —  speaker generally limits to 7 to 10 days; effective against MRSA (possibly more effective than vancomycin for treating patients with soft-tis­sue infections); to avoid emergence of resistance, use only when indicated by susceptibility tests (ie, avoid use in empiric therapy)

Daptomycin: most bactericidal antistaphylococcal agent; effective against gram-positive organisms resistant to other agents; decreases number of colony-forming units faster than vancomycin; associated with decreased length of stay among patients with skin and soft-tissue infections

Other agents: tigecycline  —  some activity against MRSA; not recommended for treating patients with MRSA pneu­monia or bacteremia; experimental drugs  —  dalbavancin and telavancin active against MRSA

Antibiotic selection: for S aureus infections, treat as MRSA until proven otherwise (especially if infection life-threatening); fluoroquinolones inadequate; for inpatients, use vancomycin, linezolid, tigecycline, or daptomycin; for outpatients, use TMP-SMZ, minocycline, or clindamycin, based on susceptibility tests; TMP-SMZ may be used for MRSA bacteremia (in absence of endocarditis); recommendations  —consider linezolid for MRSA pneumonia (associated with higher survival compared to vancomycin, likely due to higher concentrations in epithelial lining) and daptomycin for MRSA endocarditis; avoid fluoroquinolones; use nafcillin or cephalosporin for MSSA pneu­monia

Case: initial laboratory results  —  2 blood cultures grow gram-positive cocci clusters; antibiotic therapy  —  treat as MRSA (until proven otherwise); initiate IV vancomycin or IV daptomycin (preferred by speaker); source control  —  incise and drain abscesses; change catheters (failure to remove focus of infection associated with in­creased mortality); obtain blood cultures daily, until bacteremia cleared and patient clearly responding; imaging  —  order transesophageal echocardiogram (TEE) to look for endocarditis (TEE more sensitive than transthoracic echocardiogram at identifying vegetations); aggressively treat patients with MRSA endocarditis; follow-up  —  watch for remote metastatic infection (eg, endocarditis, osteomyelitis) in patients with bacteremia; presence of sec­ondary focus increases risk for recurrence and requires longer, more intensive therapy; duration of therapy  —  10 to 14 days if patient improves after focal infection removed, has no valvular heart disease or prosthetic heart valve, is immunocompetent, has no evidence of metastatic infection, and TEE shows no vegetations; if patient does not meet above criteria, treat for 6 wk

MRSA endocarditis: multicenter trial compared daptomycin to vancomycin; daptomycin associated with decreased mortality (statistically nonsignificant; study underpowered, but suggests superiority of daptomycin)

Questions and Answers

MRSA pneumonia with comorbid influenza: combination associated with very high mortality; for patients with pneumonia during influenza season, empiric treatment should cover MRSA (adjust therapy based on susceptibility tests); linezolid recommended for MRSA pneumonia

Recurrent furunculosis: MSSA  —  suppressive therapy with dicloxacillin (500 mg/day); MRSA  —  no long-term sup­pressive therapy available; at first sign of boil (eg, focal tenderness, folliculitis), can use clindamycin, TMP-SMZ, or minocycline; alternatively, patient can apply bacitracin and transparent dressing (“tenting” dressing to hold bac­itracin); strategy often averts need for oral antibiotic therapy

Decolonization: eliminating S aureus from anterior vestibule of nose may prevent recurrence; options  —  topical mu­pirocin in both nares, applied tid for 1 wk; oral therapy with rifampin plus TMP-SMZ or minocycline; vancomycin, fluoroquinolones, linezolid, and rifampin monotherapy ineffective; factors that prevent decolonization  — unresolved focal infection; colonization at multiple sites; open wound; eczema or psoriasis (associated with chronic carriage of S aureus); invasive device (eg, catheter, central line); efficacy  —  »80% among healthy patients with none of above conditions

Suggested Reading

Ammerlaan HS et al: Eradication of MRSA carriage: a systematic review. Clin Infect Dis 48:922, 2009; Biedenbach DJ, Jones RN: Multicenter evaluation of the in vitro activity of dalbavancin tested against staphylococci and streptococci in 5 European countries: results from the DECIDE Surveillance Program (2007). Diagn Microbiol Infect Dis Feb 25, 2009 [Epub ahead of print]; Bounthavong M et al: Cost-effectiveness analysis of linezolid vs vancomycin in treating MRSA complicated skin and soft tissue infections using a decision analytic model. Int J Clin Pract 63:376, 2009; Hanson MR, Chung CL: Antibiotic selection for MRSA: case presentations and review of the literature. J Drugs Dermatol 8:281, 2009; Kaplan SL: Challenges in the evaluation and management of bone and joint infections and the role of new antibiotics for gram positive infections. Adv Exp Med Biol 634:111, 2009; Leclercq R: Epidemiological and resistance issues in multi­drug-resistant staphylococci and enterococci. Clin Microbiol Infect 15:224, 2009; Maor Y et al: Clinical features of hetero­resistant vancomycin-intermediate Staphylococcus aureus bacteremia versus those of methicillin-resistant S aureus bacteremia. J Infect Dis 199:619, 2009; McConeghy KW et al: Agents for the decolonization of methicillin-resistant Staphylococcus aureus. Pharmacotherapy 29:263, 2009; Niederman MS: Community-acquired pneumonia: the US per­spective. Semin Respir Crit Care Med 30:179, 2009; Rodriguez-Baño J et al: Impact of inappropriate empirical therapy for sepsis due to health care-associated MRSA. J Infect 58:131, 2009; Sakoulas G et al: Relationship of MIC and bactericidal activity to efficacy of vancomycin for treatment of MRSA bacteremia. J Clin Microbiol 42:2398, 2004; Traczewski MM et al: Inhibitory and bactericidal activity of daptomycin, vancomycin and teicoplanin against MRSA collected from 1985 to 2007. Antimicrob Agents Chemother Feb 17, 2009 [Epub ahead of print]; Zilberberg MD et al: Growth and geographic variation in hospitalizations with resistant infections, United States, 2000-2005. Emerg Infect Dis 14:1756, 2008.