The Continuing Challenge of MRSA Jim Thigpen, PharmD, BCPS Assistant Professor Bill Gatton College of Pharmacy

Disclosure Statement of Financial Interest I, Jim Thigpen, I, Jim Thigpen, DO NOT have a financial interest/arrangement or affiliation with one or more organizations that could be perceived as a real or apparent conflict of interest in the context of the subject of this presentation. DO NOT have a financial interest/arrangement or affiliation with one or more organizations that could be perceived as a real or apparent conflict of interest in the context of the subject of this presentation.

Disclosure Statement of Unapproved/Investigative Use I, Jim Thigpen, DO anticipate discussing the unapproved/investigative use of a commercial product/device during this activity or presentation.

Learning Outcomes Describe the clinical presentation and diagnosis of MRSA Classify the therapeutic options available for the treatment of MRSA Formulate a therapeutic plan for the treatment of MRSA in various situations

A little history Staphylococcus was first identified in Aberdeen, Scotland in 1880 by the surgeon Sir Alexander Ogston in pus from a surgical abscess in a knee joint Staph is the most common isolated human pathogen MRSA was first identified and coined in 1961 Boston had the first U.S. outbreak in 1968 David MZ, Daum RS. Clin Microbiol Rev July 2010,

A little more history In 1975, 2.4% of Staph were MRSA, by 1991, it was 29% Into the ’90s, the term “MRSA” was used to describe infections in hospitals, other healthcare environments, and in their patients Since the mid ’90s, there has been an explosion of MRSA in populations lacking risk factors for exposure to the healthcare system David MZ, Daum RS. Clin Microbiol Rev July 2010,

What is MRSA? Hospital-Acquired (HA-MRSA) – These strains carry a large staphylococcal chromosomal cassette mec (SCCmec) belonging to Type I, II, or III. They carry the mecA gene, which is nearly universal among MRSA isolates. – In HA-MRSA, the mecA gene usually confers resistance to most non-β-lactam antibiotics Isolated largely from people exposed in a healthcare setting and are older with risk factors More often causes PNA, bacteremia, and invasive infections David MZ, Daum RS. Clinical Infectious Diseases 2010;23(3):

What is MRSA? Community Acquired (CA-MRSA) – Carry smaller mec elements, most commonly SCCmec type IV or V. They also carry the mecA gene, but are more sensitive to non-β-lactam antibiotics than HA-MRSA – Frequently carry genes for Panton-Valentine leucocidin (PVL) PVL is a leucocidin that can lyse the cell membrane of human neutrophils and may inactivate mitochondia Shown to be dermonecrotic, possibly explaining the characteristic skin lesions associated with CA-MRSA David MZ, Daum RS. Clinical Infectious Diseases 2010;23(3):

What is MRSA? Community Acquired (CA-MRSA) – Carry Arginine Catabolic Mobile Element (ACME), which may help CA-MRSA colonize the skin of healthy people and spread – CA-MRSA usually affects a different population and causes different clinical syndromes Previously healthy younger patients Mainly SSTIs, but PNA and sepsis are also seen David MZ, Daum RS. Clinical Infectious Diseases 2010;23(3):

The Challenge Continues “escaped” or “feral” strains of HA-MRSA – Blended strains are even more resistant In some regions, CA-MRSA accounts for 75% of Staph in children Increased pressure on vancomycin has resulted in VISA and VRSA strains MIC “creep” Clinical Infectious Diseases 2006;42 (Suppl 1) S40-S50.

Why has this happened? CA-MRSA isolates occurred in the late ’90s in tandem with ↑ use of fluoroquinolones – No mechanism to link them – Elimination of MSSA strains from nasal mucosa? CA-MRSA isolated occurred as routine childhood pneumococcal vaccines were introduced – CA-MRSA may have filled the niche left by Strep pneumoniae David MZ, Daum RS. Clinical Infectious Diseases 2010;23(3):

Risk Factors HA-MRSA – In the setting or has prior exposure – HD, surgery, LTCF resident, indwelling catheter CA-MRSA – MRSA infection diagnosed within 48 hours of admission and without risk factors David MZ, Daum RS. Clinical Infectious Diseases 2010;23(3):

Clinical Manifestations Skin and soft tissue infections (SSTIs) account for up to 95% Often look like a spider bite Cellulitis may typically develop on unbroken skin Septic arthritis, osteomyelitis and pyomyositis are most common invasive infections in kids David MZ, Daum RS. Clinical Infectious Diseases 2010;23(3):

Mainstay Drugs and Resistance AntibioticIntroducedResistance Reported Mechanism of Resistance Penicillin β-lactamase Methicillin Penicillin binding protein (PBP) 2a Tetracycline Efflux pumps, and ribosomal protection proteins Vancomycin /2002Abundance of D-alanyl D-adanine/shift to D-alanyl D-lactate Trimethoprim Mutation in dihydrofolate reductase Linezolid Mutation in 23S ribosomal RNA Daptomycin2003NR

Mainstay Drugs/Adverse Reactions DrugDosageNotes Vancomycin15-20 mg/kg q8-12h, adjust for renal fx Poorly predictable drug levels, monitor trough concentrations at steady state. “Red-man” reaction seen with infusion ↑ in nephrotoxicity seen with higher doses/drugs Clindamycin600 mg IV q6-8h Inducible resistance is possible (D-test) Decreases toxin production Daptomycin4-6 mg/kg q24h Not for PNA (inactivated by surfactant) monitor CPK Linezolid600 mg IV/PO q12h Monitor for marrow suppression (<58 yr, Hb<10.5, ETOH, DM), decreases toxin production Doxycycline100 mg q12hContraindicated in children, pregnancy Rifampin600 mg q24hAdjunctive only, LFTs, CBC, SCr, drug interactions TMP/SMX1 DS PO q12h or 5mg/kg q12h Rare but severe skin reactions (SJS, TEN) Rare cases of hepatic necrosis, agranulocytosis, aplastic anemia and other blood dyscrasias

Treatment Skin and Skin Structure Infections (SSTIs) – Incision and drainage is primary treatment Clindamycin vs Cephalexin showed equal efficacy when treating an uncomplicated SSTI † – Nearly all children had active or passive drainage of purulent collections before antibiotics were started Higher rates of recurrent SSTIs have been reported within 10 days in a study comparing SMX/TMP to placebo ‡ † Chen AE, Carroll K, et al. Pediatrics 2011;127;e573 ‡ Duong M, Markwell S et al. Ann Emerg Med. 2010;55(5):

Treatment Skin and Skin Structure Infections (SSTIs) – Antibiotic therapy is recommended for abscesses associated with the following conditions: Severe or extensive diseaseRapid progression w/cellulitis S&S of systemic illnessComorbidities or imunosuppression Extremes of ageAbscess on face, hands, genitalia Associated septic phlebitisLack of response to drainage David MZ, Daum RS. Clinical Infectious Diseases 2010;23(3):

Treatment Skin and Skin Structure Infections (SSTIs) – Cellulitis with purulent drainage (cannot be drained) Oral clindamycin, SMX/TMP, doxy- or minocycline, or linezolid – Cellulitis with non-purulent drainage Think β-hemolytic strep (penicillin or cephalexin) If unresponsive to β-lactam or systemic toxicity present, then cover CA-MRSA also with clindamycin alone, SMX/TMP or tetracycline in combination with amoxicillin, or linezolid alone – 5 – 10 days of therapy – Use of rifampin as a single agent or adjunct is NOT recommended David MZ, Daum RS. Clinical Infectious Diseases 2010;23(3):

Treatment Skin and Skin Structure Infections (SSTIs) – For hospitalized ADULT patients with complicated SSTIs (deeper, surgical or traumatic wound infections, major abscesses, cellulitis and infected ulcers or burns), in addition to surgical drainage and broad spectrum antibiotics, MRSA therapy should also be added pending culture results IV vancomycin PO or IV linezolid IV daptomycin IV or PO clindamycin IV telavancin – 7 to 14 days of therapy David MZ, Daum RS. Clinical Infectious Diseases 2010;23(3):

Treatment Skin and Skin Structure Infections (SSTIs) – For CHILDREN with minor skin infections (impetigo) and secondarily infected skin lesions, mupirocin 2% can be used – In HOSPITALIZED children IV vancomycin (15 mg/kg/dose q6h, with TDM) If stable without ongoing bacteremia or intravascular infection, IV clindamycin (40 mg/kg/day q6-8h) if resistance is low, if strain susceptible, switch to oral Linezolid (10 mg/kg/dose q8h PO/IV, or adult dose if ≥ 12) – 7 to 14 days of therapy David MZ, Daum RS. Clinical Infectious Diseases 2010;23(3):

Treatment MRSA Bacteremia (adults) – Uncomplicated bacteremia (+ cultures and NO endocarditis, no implanted prostheses, follow-up cultures at hours do not grow, AF in 72 hours and no other evidence of infection) Vancomycin or daptomycin – 14 days of therapy David MZ, Daum RS. Clinical Infectious Diseases 2010;23(3):

Treatment MRSA Bacteremia (adults) – Complicated bacteremia Vancomycin Daptomycin 6 mg/kg once daily, some recommend 8-10 mg/kg once daily 4 – 6 weeks of IV therapy – Addition of gentamicin to vancomycin is NOT recommended – Addition of rifampin to vancomycin is NOT recommended David MZ, Daum RS. Clinical Infectious Diseases 2010;23(3):

Treatment MRSA Bacteremia (children) – Vancomycin for 2 – 6 weeks – Daptomycin 6-10 mg/kg once daily is an option Not a lot of evidence – Clindamycin or linezolid should not be used if there is a concern for endocarditis or if an endovascular source of infection is suspected – Data supporting the use of rifampin or gentamicin is insufficient, choice to use is individualized David MZ, Daum RS. Clinical Infectious Diseases 2010;23(3):

Treatment MRSA Pneumonia – For HA-MRSA or CA-MRSA IV vancomycin IV/PO linezolid IV/PO clindamycin – 7 – 21 days therapy David MZ, Daum RS. Clinical Infectious Diseases 2010;23(3):

Treatment MRSA Pneumonia (children) – IV vancomycin – IV clindamycin if resistance rate is low – IV/PO linezolid 600 mg q12h for ≥ 12 years – IV/PO linezolid 10 mg/kg/dose q8h David MZ, Daum RS. Clinical Infectious Diseases 2010;23(3):

Treatment MRSA Bone and Joint Infections (adults) – IV vancomycin – Daptomycin – TMP/SMX 4 mg/kg/dose q12h + rifampin 600 mg daily – Linezolid – Clindamycin – Some experts recommend rifampin to all of the above, started after bacteremia has cleared 8 weeks of therapy for osteomyelitis, 3-4 weeks is usually sufficient for septic arthritis David MZ, Daum RS. Clinical Infectious Diseases 2010;23(3): Healthtap.com

Treatment MRSA Bone and Joint Infections (children) – IV vancomycin – IV clindamycin If stable and clindamycin resistance is low – IV Daptomycin – IV Linezolid weeks of therapy for osteomyelitis, 3-4 weeks is usually sufficient for septic arthritis David MZ, Daum RS. Clinical Infectious Diseases 2010;23(3):

Treatment MRSA infections in the CNS – Vancomycin + rifampin – Linezolid – TMP/SMX 5 mg/kg/dose q8-12h – Clindamycin does not penetrate the CNS Meningitis – 2 weeks Abscess, etc – 4 to 6 weeks Vancomycin for pediatrics David MZ, Daum RS. Clinical Infectious Diseases 2010;23(3):

Adjunctive Therapies Clindamycin and linezolid are NOT routinely recommended as adjunctive therapy for the management of invasive MRSA disease The use of adjunctive IVIG is not recommended Some experts may consider these agents in selected situations David MZ, Daum RS. Clinical Infectious Diseases 2010;23(3):

Vancomycin Dosing Adults – 15 – 20 mg/kg/dose (actual body weight) q8-12h, NTE 2 grams/dose is recommended with normal renal function – A loading dose of mg/kg may be considered in seriously ill patients – Loading doses and larger doses should be infused over 2 hours to minimize “red-man” reaction diphenhydramine David MZ, Daum RS. Clinical Infectious Diseases 2010;23(3):

Vancomycin Dosing Adults – For most patients with SSTI who have normal renal function and are not obese, traditional doses of 1 gram q12h are adequate and serum levels are not required – For serious infections (bacteremia, endocarditis, osteo, meningitis, PNA, and severe SSTI, vancomycin trough levels of 15 – 20 mcg/ml are recommended David MZ, Daum RS. Clinical Infectious Diseases 2010;23(3):

Vancomycin Dosing

Why do we need these levels? – AUC/MIC best relates to antibacterial effect of vancomycin – (AUC 24 )/MIC of ≥ 400 is the target – This number can be achieved with trough levels of ≥ 15 mcg/ml When is this really important? – MIC of vancomycin is > 1 mcg/ml – More severe infections

Vancomycin Dosing What is the risk? – There is an increased risk of nephrotoxicity seen with vancomycin where troughs are > 15 mcg/ml ¥ Nephrotoxicity was defined as a rise in serum creatinine of 0.5 mg/dl or a >50% increase from baseline level for two consecutive labs An incidence of 29.6% was observed when trough levels exceeded 15 mcg/ml What does this mean to us? ¥ Bosso JA, Nappi J, et al. Antimicrobial Agents and Chemotherapy 2011;55(12):5475-9

Treatment Alternatives (when MRSA won’t clear or vanco fails) High dose daptomycin (10 mg/kg/day) in combination with gentamicin 1 mg/kg IV q8h, rifampin, linezolid, or TMP/SMX If reduced susceptibility to vancomycin or daptomycin are present, quinupristin/dalfopristin, TMP/SMX, linezolid or telavancin should be considered either alone or in combination David MZ, Daum RS. Clinical Infectious Diseases 2010;23(3):

What else do we have? Tigecycline – Protein synthesis inhibitor “souped-up doxy” – Low serum levels and probably not effective for pneumonia limit it’s use Quinupristin/dalfopristin – Protein synthesis inhibitor – Frequent side effects, drug interactions, limited data in severe disease

What else do we have? New Lipoglycopeptides – Developed by altering the structure of vancomycin – Added a lipophilic “tail”, increasing the antimicrobial activity, and a hydrophilic moiety, improving the pharmacokinetics Telavancin (VIBATIV ® ) Dalbavancin Oritavancin Zhanel GG, Calic D, et al. Drugs 2010;70(7):

What else do we have? Telavancin (VIBATIV ® ) – Two mechanisms of action – FDA approved for SSTIs, HAP – Non-inferiority trials with vs vancomycin – Some concerns with nephrotoxicity Not as effective in patients with CrCl < 50 – Pregnancy test (problems in animal models) – Active against VISA, not VRSA Zhanel GG, Calic D, et al. Drugs 2010;70(7):

What else do we have? Dalbavancin (investigational) – Effective for SSTIs – Once weekly dosing due to long half-life Oritavancin (investigational) – May be dosed once for the course – May also be effective vs VRSA Zhanel GG, Calic D, et al. Drugs 2010;70(7):

What else do we have? Fusidic acid – A protein synthesis inhibitor – Has been used effectively across the globe – “Resurrected” for use in the U.S. – Less active vs β-hemolytic strep – Oral availability Moellering, R, Corey G. Clinical Infectious Diseases 2011;52(S7):S467-S468

What else do we have? Ceftaroline (Teflaro ® ) – FDA approved for CABP (Strep pneumo) and SSTIs (MRSA) – Not as effective vs resistant gram-negatives Ceftibiprole (investigational) – MRSA activity, gram-negative activity similar to cefepime Tedizolid (investigational) – Shorter course and fewer side effects

Learning Outcomes Describe the clinical presentation and diagnosis of MRSA Classify the therapeutic options available for the treatment of MRSA Formulate a therapeutic plan for the treatment of MRSA in various situations