MRSAPhillip O. Coffin, MD MIA

Division of Infectious Disease, CPMCDirector of Substance Use Research, SFDPH

Assistant Clinical Professor, UCSF

Disclosures

Sadly, none

Outline

• Definition

• When / how to treat

• Cases

CA-MRSA is genetically distinct from HA-MRSA

• Novel SCC mec element (type IV)

• Lack of multiple antibiotic resistance genes

• Presence of additional genetic elements, potential virulence factors (Panton-Valentine leukocidin, ACME, phenol-soluble modulins etc.)

ccr mecA

ccr mecAAntibiotic resistance genes

CA-MRSA

HA-MRSA

Type IV

Type I-III

Epidemiology of MRSA Infection in San Francisco

USA300

Miller and Diep Clinical Infectious Diseases 2008

Who “has” MRSA (or SA)?

Infection image

Antibiotic options

Outpatient

• Trim-sulfa (2 tabs DS BID)

• Doxycycline

• Linezolid

• Clindamycin

Inpatient

• Vancomycin

• Linezolid (ZyvoxTM)

• Daptomycin (CubicinTM)

• Telavancin (VibativTM)

• Ceftaroline (TeflaroTM)

• Tigecycline (TygacilTM)

• Quinupristin/dalfopristin

Additives

• Rifampin

• Gentamicin

• Beta-lactams

Linezolid

• Pros• May treat other foci (bone,

lung) poorly penetrated by other drugs

• 100% oral bioavailability

• Case reports suggest efficacy in R-sided endocarditis

• Cons• Toxicity profile

• Bacteriostatic• Limited data• Typically used in combo with

cidal drug• Relapse

Daptomcyin

• Pros• Convenient dosing• Not nephrotoxic• Bactericidal• Potent in animal models• Most evidence based

• Cons• FDA approved dose too low• Resistance emerges on therapy• Toxicity at higher doses?• Cross-resistance with VISA

Telavancin

• Pros• Bactericidal• Potent in animal models• Active against VISA• Once daily dosing

• Cons• Nephrotoxic• Only 3 (very messy) cases• May have cross-sensitivity with

vancomycin

Ceftaroline

• Pros• Bactericidal• Potent in animal models• Active against VISA• Beta-lactam safety profile

• Cons• Uncertain dosing• Limited clinical experience,

only 16 cases

Mortality: Linezolid v. Vancomycin for MRSA HAP/VAP

Group (n) Linezolid Vancomycin

ITT (1184) 15.7% 17%

MRSA/mITT (448) 28.1% 26.3%

MRSA VAP (221) 19.4% 18.4%

Wunderink, et al, Clin Infect Dis 54:621, 2012 Mark Kunkel: Abstract 5047, IDSA 2010 Annual Meeting

Decolonization

• Administration of topical antimicrobial or antiseptic agents, with or without systemic antimicrobial therapy, to colonized patients for the purposes of eradicating or suppressing the carrier state.

Prevent transmission to others, thereby preventing infection in other patients

Prevent endogenous infection

Decolonization: PRO

• 2008 Cochrane Review: Mupirocin for prevention of S. aureus infections in nasal carriers 9 RCTs: 4 surgical; 3 dialysis; 1 non-surgical; 1 MRSA

colonized in rate of nosocomial S. aureus infection

• All studies (RR 0.55, 95% CI 0.34-0.89)• High-quality studies (RR 0.69, 95% CI 0.47-1.00)• Benefit in surgical, dialysis pts; none in non-surgical pts, MRSA

carriers No in rate of S. aureus surgical site infections

RR 0.63, 95% CI 0.38-1.04

Van Rijen Cochrane Reviews 2008

Decolonization: CON

• 2003 Cochrane Review: Antimicrobial drugs for treatment of MRSA colonization 6 RCTs: all prior to CA-MRSA, variety of topical and systemic

therapies No in MRSA carriage rates One study, short-term eradication at 30, not 90 days Adverse events with systemic agents, emergence of

resistance

Recolonization occurs in about 25% of successful cases within 4 weeks; 50-75% after a few months

Van Rijen Cochrane Reviews 2008

Regimens

• Topical• Nasal mupirocin 2% bid x5-7 days • chlorhexidine 2-4% baths daily

• +/- trim-sulfa or doxycycline

• +/- environmental / family decontamination

1Van Rijen Cochrane Reviews 2008

Case 1

• 32 y/o man with 3 days of an enlarging, painful lesion below his L knee which he attributes to a “spider bite”.

T 37.3 BP 118/70 P 82

What is the appropriate management?

A. Incision and drainage alone

B. Incision and drainage plus oral anti-MRSA antimicrobial agent

C. Oral anti-MRSA antimicrobial agent

Management of Abscess

Primary Rx - incision & drainage (AII)

No difference in outcomes whether an active antibiotic is used1

Randomized trial of patients with skin abscesses (mostly MRSA), high cure rates in all: cephalexin (84.1%); placebo (90.5%)2

Additional benefit of MRSA active oral antibiotic beyond I&D is unknown; clinical trials underway.

Consider empiric Rx for CA-MRSA if: systemic symptoms, severe local symptoms, immunosuppression, extremes of patient age, critical location, failure to respond to I&D

1Lee MC PIDJ ‘04; Young DM Arch Surg ‘04; Fridkin SK NEJM ‘05; Moran G NEJM ‘06 2Rajendran PM AAC’07

Case 2

• 42 year old F presents w/ progressive erythema of her L lower leg x 24 hours.

T 37.0 BP 132/70 P 78

What is the appropriate management?

A. Clindamycin 300 mg PO tid

B. Amoxicillin 875 mg PO bid, monitor clinically with addition of TMP/SMX if no response

C. Amoxicillin 875 mg PO bid and TMP/ SMX 2 DS tab PO bid

Management of Uncomplicated Cellulitis

With purulent drainage: Empiric Rx for CA-MRSA is recommended (AII).

Pure cellulitis*: Empiric Rx for -hemolytic streptococci is recommended. Empiric Rx for CA-MRSA may be considered (CIII).

*Pure cellulitis: without purulent drainage, focal induration, associated abscess

MRSA

Purulent woundsCellulitis with purulent drainage

53%47%

(Moran GJ NEJM 2006)

Uncomplicated SSTIs: Antimicrobial Therapy

• Empiric oral antimicrobial therapy for CA-MRSA:

Clindamycin, trimethoprim-sulfamethoxazole (TMP/SMX), or a tetracycline* (e.g. doxycycline or minocycline) (AII)

• If empiric therapy for -hemolytic streptococci and CA-MRSA is clinically indicated:

Clindamycin (AIII)

OR

-lactam (e.g. amoxicillin) and TMP/SMX or a tetracycline* (AIII)

• NIH-sponsored clinical trials underway*Avoid in children < 8 years old

Management of Complicated SSTIs

• Management of cSSTI and necrotizing fasciitis

Surgical evaluation and debridement (AIII)

Empiric Rx for MRSA is recommended1 (AII)

• Empiric Rx for MRSA cSSTI and necrotizing fasciitis

Vancomycin, daptomycin2, linezolid3, tigecycline4 (AI)

• No significant difference in primary outcome of clinical cure1Kollef MH CID 2008; Miller LG NEJM 2005; Young LM Surgical Infections 2008. 2Arbeit RD et al CID 2004; 3Weigelt J et al AAC 2005; 4Breedt J AAC 2005

Case 3

• 35 y/o man presents with 4 days of fever, chills, myalgias, and cough. Now with increasing dyspnea and hemoptysis x 24 hours.

• T38.7 P120 BP96/60 R28 92%RA

• Moderate respiratory distress with coarse rhonchi

• 15>44<425, left shift

• Rapid flu: + influenza A Frazee B. Ann Emerg Med. 2006

In addition to starting anti-influenza therapy, would you treat with antibiotics and if so which?

A. None

B. Ceftriaxone and azithromycin

C. Vancomycin and cefepime

D. Vancomycin and ceftriaxone and azithromycin

E. Linezolid and cefepime

Is MRSA a cause of community-acquired pneumonia (CAP)?

• MRSA is an infrequent cause of CAP, empiric Rx for MRSA not routinely recommended1

• MRSA: a complication of influenza? 2003-04 and 2006-07 influenza seasons2

majority of staphylococcal CAP was due to MRSA morbidity & mortality

No clinical, laboratory, radiographic findings that distinguish patients with MRSA from other etiologies of CAP

1IDSA/ ATS 2007 CAP guidelines; 2Hageman JC EID 2006; Kallen A Ann Emerg Med 2008

Management of MRSA Pneumonia

• Empiric Rx for MRSA is recommended for patients with severe CAP and1…(AIII) Preceding/concurrent influenza-like illness Necrotizing or cavitary infiltrates ICU admission

• Vancomycin or linezolid is recommended (AII). Superiority of either antibiotic unclear2

Daptomycin is not indicated in PNA

1Francis JL CID 2005; Gonzalez BE Clin Infect Dis 2005; Hageman JC EID 2006; MMWR 2007; Mandell L CID 2007; Finelli L Pediatrics 2008; 2Rubinstein E CID 2001; Wunderink RG Clin Therap 2003; Wunderink RG Chest 2003;

Case 4

• 45 y/o man w/ 5 days of an enlarging, painful buttock lesion now with 2 days of fever/chills

• T 38.5 BP 103/67 P 104 RR 16 Wt: 100 kg

• Obese

• Heart: 2/6 systolic murmur at RUSB

• Right buttock: 6 x 2 cm tender, fluctuant mass with purulent drainage and surrounding erythema

Case 4 (continued)

• Labs: 12.5 > 38 > 350; Cr 0.8

• Started on Vancomycin 1g IV q12 hrs

• HD #1 blood cx: 2/2 MRSA

• HD #3 blood cx: 2/2 MRSA

• TTE: 5 mm vegetation on tricuspid valve

• Vancomycin trough: 9.2 g/mL

In addition to I&D, what is the most appropriate management of this patient?

A. Add gentamicin to vancomycin

B. Add rifampin to vancomycin

C. Increase vancomycin dose to 1.5 g IV q12, and adjust to achieve goal trough of 15-20 g/mL

D. Discontinue vancomycin and start IV daptomycin

Median duration of S. aureus bacteremia

• MRSA: 7-9 days

• MSSA: 3-4 days

Levine Ann Intern Med 1991, Fowler NEJM 2006 , Korzeniowski Ann Intern Med 1982

Echocardiography for Staph. aureus Bacteremia (SAB)

• Generally recommended for all patients with SAB• Approx. 20% of all comers will have evidence of endocarditis• Compliance is low • TEE vs TTE?

• TTE may be adequate in low risk patients• Uncomplicated, prompt conversion of blood cultures to negative, no

embolic phenomenon, no prosthetics/pacemaker, high quality study

• Echo may not needed in low risk patients with• Nosocomial bacteremia (prevalence of endocarditis 4-9%) AND no

hemodialysis

Lancet ID 11:208, 2011; Clin Infect Dis 53:31, 2011

Vancomycin Dosing and Monitoring

• Vancomycin 15-20 mg/kg (actual body weight) every 8-12 hours in patients with normal renal function1 (AIII).

• For patients with serious infections (e.g. bacteremia, endocarditis, osteomyelitis, meningitis, pneumonia), target trough concentrations of 15-20 g/mL1 (BIII). Higher vancomycin doses may be associated with increased

nephrotoxicity; careful monitoring is recommended.2

• Trough levels should be obtained just prior to the next dose at steady state conditions (before the 4th dose) (BII).1Rybak M Am J Health Syst Pharm 2009; Moise-Broder PA Clin Pharmacokinet 2004;

Jeffres MN Chest 2006; 2Jeffres MN Clin Ther 2007; Lodise T AAC 2008

Management of MRSA Bacteremia and Endocarditis

• Vancomycin or daptomycin 6 mg/kg IV once daily (AII)

Daptomycin is noninferior to vancomycin + gentamicin1

Some experts recommend daptomycin 8-10 mg/kg IV once daily2 (BIII). • Doses of up to 12 mg/kg for 2 wks safe in healthy volunteers3

• Clinical trial underway to further evaluate safety and efficacy

1Markowitz N Annals of Internal Med 1991; Fowler VG NEJM 2006; 2Cunha BA Heart Lung 2006; Cunha BA Heart Lung 2008; 3Benvenuto M AAC 2006 4Ardura MI PIDJ 2007

Duration of Therapy: S. aureus Bacteremia

Duration Indications14 days • Fever resolves by day 3

• Sterile blood culture after 2-3 days• Easily removed focus of infection• No metastatic infection (e.g., osteo)• Negative echo, no evidence of endocarditis• No predisposing valvular abnormalities • No implanted prosthetic devices• (No DM, immunosuppression)

4-6 weeks • Failure to meet one or more of above criteria • Osteo, endocarditis, epidural abscess, septic

arthritis (3 wk), PNA (3-4 wk), complicated UTI

Clin Infect Dis 49:1, 2009; Clin Infect Dis 52:285, 2011

MRSA Bacteremia and Endocarditis: Role of Combination Therapy?

• Addition of gentamicin is not recommended for bacteremia or native-valve endocarditis (AII). No clear evidence of benefit Increased risk of nephrotoxicity1

• Addition of rifampin is not recommended for bacteremia or native valve endocarditis (AI). No clear evidence of benefit2 Increased risk of drug interactions and development of rifampin resistance3

1Rybak MJ AAC 1990; Goetz, MJ JAC 1993; Rybak MJ AAC 1999; Cosgrove SE CID 2009 2Levine D Annals of Intern Med 1991; Riedel DJ AAC 2008; 3Riedel DJ AAC 2008

Thank you!

• Thanks to Henry Chambers and Catherine Liu of UCSF for sharing multiple slides for this talk.

phillip.coffin@sfdph.org