1/7/2012. Objectives. New Treatment Guidelines for Methicillin-Resistant Staphylococcus Aureus (MRSA) Classification. Definition

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New Treatment Guidelines for Methicillin-Resistant Staphylococcus Aureus (MRSA) Objectives Review the management of clinical syndromes associated with MRSA disease, including skin and soft tissue

and monitoring Jacqueline Ruiz, BS, PharmD Post Graduate Year One (PGY-1) Pharmacy Resident South Miami Hospital, Miami, Florida JacquelineRu@baptisthealth.

1 New Treatment Guidelines for Methicillin-Resistant Staphylococcus Aureus (MRSA) Objectives Review the management of clinical syndromes associated with MRSA disease, including skin and soft tissue infections, pneumonia, bacteremia, endocarditis, bone and joint infections, and central nervous system infections in adults and children Evaluate guideline recommendations regarding vancomycin dosing and monitoring Jacqueline Ruiz, BS, PharmD Post Graduate Year One (PGY-1) Pharmacy Resident South Miami Hospital, Miami, Florida 1 Describe the role of adjunctive therapies for the treatment of MRSA infections Identify core and supplemental MRSA prevention strategies 2 Definition Methicillin-resistant staphylococcus aureus (MRSA) Gram-positive staphylococcus bacteria resistant to beta-lactam antibiotics Occurs when an isolate carries an altered penicillinbinding protein (PBP2a) The Clinical and Laboratory Standards Institute (CLSI) breakpoint criteria Oxacillin MIC* 4 mcg/ml Oxacillin disk diffusion 10 mm Cefoxitin disk diffusion 21 mm *MIC = minimum inhibitory concentration medscape.com 3 Classification Healthcare-associated MRSA (HA-MRSA) Occurs > 48 hours following hospitalization Occurs outside of the hospital within 12 months of exposure to healthcare Surgery, hospitalization, dialysis, residence in long-term care facility Leading cause of surgical site infection in both tertiary and community hospitals Bacterial strains tend to carry multi-drug resistance Community-associated MRSA (CA-MRSA) Occurs < 48 hours following hospitalization Absence of healthcare exposure Skin and soft tissue infections Leading cause of skin and soft tissue infections in the young, otherwise healthy individual 4 Year Modeled Incidence and Percent Change for All Invasive Hospital-Onset and Healthcare-Associated, Community-Onset MRSA infections, Modeled incidence per 100,000 population Modeled percent change from previous year Total modeled percent change P-value Hospital-onset % % -17.2% 0.01 Healthcare-associated, community-onset % % -11.0% 0.04 Infectious Diseases Society of America-US Public Health Service Grading System for Ranking Recommendations in Clinical Guidelines Strength of Recommendation A Good evidence to support a recommendation for or against use B Moderate evidence to support a recommendation for or against use C Poor evidence to support a recommendation Quality of Evidence I Evidence from 1 properly randomized, controlled trial II Evidence from 1 well-designed clinical trial, without randomization; from cohort or case-controlled analytic studies (preferably from > 1 center); from multiple time-series; or from dramatic results from uncontrolled experiments III Evidence from opinions of respected authorities; based on clinical experience, descriptive studies, or reports of expert committees Kallen AJ SHEA 2009 Khan AR CID

Management of MRSA Clinical Syndromes Skin and soft tissue infections Bacteremia and endocarditis Pneumonia Bone and joint infections Central nervous system infections www.dermimages.med.jhmi.edu www.

org (SSTI) Abscesses Primary treatment: Incision and drainage for simple abscesses or boils () Antibiotic benefit (I) Severe, extensive disease, rapidly progressive with associated cellulitis or

drainage www.themitralvalve.org 7 8 Additional Antimicrobial Benefit?

of clinical cure of MRSA infection Rajendran: cephalexin vs. placebo Duong and Schmitz: vs.

identified in 73% of infections Empiric antimicrobial for β-hemolytic streptococcus () Empiric antimicrobial for CA-MRSA recommended for patients who do not respond to therapy and/or systemic

2 Management of MRSA Clinical Syndromes Skin and soft tissue infections Bacteremia and endocarditis Pneumonia Bone and joint infections Central nervous system infections (SSTI) Abscesses Primary treatment: Incision and drainage for simple abscesses or boils () Antibiotic benefit (I) Severe, extensive disease, rapidly progressive with associated cellulitis or septic phlebitis Signs and symptoms of systemic illness Associated comorbidities or immunosuppression Extremes of age Difficult to drain areas Face, hand, genitalia Failure of prior incision and drainage Additional Antimicrobial Benefit? Multiple observational studies: Microbiology of Skin and Soft Tissue High cure rates without antibiotic Three randomized controlled (RCT) trials of uncomplicated skin abscesses with a primary outcome of clinical cure of MRSA infection Rajendran: cephalexin vs. placebo Duong and Schmitz: vs. placebo Rajendran AAC 2007; Duong Ann Emerg Med 2009; Schmitz Ann Emerg Med Moran NEJM Cellulitis Non-purulent drainage/exudate without drainable abscess β- hemolytic streptococcus identified in 73% of infections Empiric antimicrobial for β-hemolytic streptococcus () Empiric antimicrobial for CA-MRSA recommended for patients who do not respond to therapy and/or systemic toxicity () Cephalexin, Dicloxacillin Amoxicillin* (Cleocin )* 500 mg PO QID 500 mg PO TID mg/kg PO divided TID QID mg PO mg/kg/dose PO Q 6 8 H TID (NTE 40 mg/kg/day) * 600 mg PO BID 10 mg/kg/dose PO Q 8 H (NTE 600 mg/dose) Β-lactam +/- (Bactrim ) or tetracycline NTE= not to exceed; = trimethoprim /sulfamethoxazole * provide coverage for both β-hemolytic strep and CA-MRSA Cellulitis Purulent drainage/exudate without drainable abscess MRSA accounts for nearly 60% of cases followed by MSSA Empiric antimicrobial for CA-MRSA recommended () Empiric antimicrobial for β-hemolytic streptococcus not required () Duration of therapy: 5 10 days 1 2 DS tabs PO BID TMP 4 6 mg/kg/dose, (Bactrim ) SMP mg/kg/dose PO Q 12 H Doxycycline 100 mg PO BID 45 kg: 2 mg/kg/dose PO Q 12 H > 45 kg: adult dose Minocycline 200 mg PO x 1, 4 mg/kg PO x 1, then then 100 mg PO BID 2 mg/kg/dose PO Q 12 H mg PO TID mg/kg/dose PO Q 6 8 H (NTE 40 mg/kg/day) 600 mg PO BID 10 mg/kg/dose PO Q 8 H (NTE 600 mg/dose) DS= double strength; NTE= not to exceed; = trimethoprim /sulfamethoxazole 12 2

3 Complicated SSTI (cssti) cssti deep soft-tissue infections, surgical/traumatic wound infection, major abscesses, cellulitis-infected ulcers/burns Surgical debridement, broad-spectrum antibiotic therapy, and empiric coverage for MRSA pending cultures (Cubicin ) Telavancin (Vibativ ) mg/kg/dose IV NTE= not to exceed; ND= no data available 15 mg/kg/dose IV Q 6 H AI/ 600 mg PO/IV BID < 12 years: 10 mg/kg/dose PO/IV Q 8 H (NTE 600 mg/dose) 4 mg/kg/dose IV daily Ongoing study (5 mg/kg [ages 12-17] 7 mg/kg [ages 7-11] 9 mg/kg [ages 2-6]) AI/ AI/ ND 10 mg/kg/dose IV daily ND AI/ ND 600 mg PO/IV TID mg/kg/dose PO/IV Q 6 8 H (NTE 40 mg/kg/day) BII/ 13 cssti Tigecycline (Tygacil ) consider alternate agent for MRSA SSTI FDA warning: increased risk in all-cause mortality vs. comparator drugs in a pooled analysis of clinical trials Ceftaroline (Teflaro ): β-lactam cephalosporin 600 mg IV Q 12 H, over 1 hour CrCl ml/min: 400 mg IV Q 12 H CrCl ml/min: 300 mg IV Q 12 H End-stage renal disease/hemodialysis: 200 mg IV Q 12 H Duration of therapy: 7 14 days Individualized based on clinical response ; 14 Recurrent MRSA SSTI MRSA Pneumonia Host Personal Hygiene Wound Care (I) Oral antibiotics should not be used as 1 st line therapy for recurrent SSTI Environment Surface Cleaning MRSA Pathogen Decolonization Mupirocin BID x 5-10 days +/- topical skin antiseptic (chlorhexidine) x 5-14 days OR dilute bleach salts Severe, community-acquired pneumonia ICU admission, necrotizing or cavitary infiltrates, or empyema Empirical therapy for MRSA is recommended pending sputum and/or blood cultures (I) NTE= not to exceed mg/kg IV 600 mg PO/IV BID 600 mg PO/IV TID 15 mg/kg/dose IV Q 6 H < 12 years:10 mg/kg/dose PO/IV Q 8 H (NTE 600 mg/dose) mg/kg/dose PO/IV Q 6 8 H (NTE 40 mg/kg/day) BII/ MRSA Pneumonia (Cubicin ) should not be used for pneumonia Inactivated by pulmonary surfactant May be used in patients with hematogenous septic pulmonary emboli MRSA pneumonia + empyema Antimicrobial therapy in conjunction with drainage procedures (I) Empiric treatment for MRSA pneumonia should be discontinued if cultures do not grow MRSA Duration of therapy: 7 21 days Bacteremia Uncomplicated bacteremia Positive blood cultures PLUS Exclusion of endocarditis, no implanted prosthesis, negative follow-up blood cultures at 2 4 days, afebrile within 72 hours of effective therapy, no evidence of metastatic sites of infection Duration of therapy: at least 2 weeks Complicated bacteremia Positive blood cultures not meeting above criteria Duration of therapy: at least 4 6 weeks Infective endocarditis, native valve Duration of therapy: at least 6 weeks

4 Bacteremia and native valve infection Adult Dose Pediatric Dose Class Alternative (Cubicin ) mg/kg IV 15 mg/kg/dose IV Q 6 H Adult Dose Pediatric Dose Class 6 mg/kg/dose IV daily 6 10 mg/kg/dose IV daily AI/CIII 8 10 mg/kg/dose IV daily BIII Addition of gentamicin () or rifampin (AI) to vancomycin is not recommended risk of nephrotoxicity risk of elevated transaminases ( 5x baseline), drug interactions with rifampin, resistance concerns ; Fowler VG NEJM Infective endocarditis, prosthetic valve (BII) IV vancomycin + rifampin 300 mg PO/IV Q 8 H Duration of therapy: at least 6 weeks + Gentamicin 1 mg/kg/dose IV Q 8 H Duration of therapy: 2 weeks Early evaluation for valve replacement surgery is recommended () Pediatric considerations: Insufficient data to support routine use of combination therapy with rifampin or gentamicin in bacteremia or infective endocarditis Echocardiogram evaluation (I) Congenital heart disease, bacteremia > 2 3 days in duration, or other clinical findings suggestive of endocarditis 20 Clinical assessment to identify source and extent of infection () Identify, eliminate, and debride other sites of infection Repeat blood cultures 2 4 days after initial positive cultures; document clearance of bacteremia Echocardiography recommended for all patients with bacteremia (TEE > TTE)* Evaluate for valve replacement surgery: Vegetation > 10 mm, 1 embolic event, severe valvular insufficiency, valvular perforation, decompensated heart failure, perivalvular/myocardial abscess, new heart block *Transesophageal (TEE) Transthoracic (TTE) Echocardiogram 21 MRSA Bone and Joint Bone and joint infections arise from the following: Hematogenous seeding Adjacent focus of infection Direct inoculation (i.e. trauma, medical procedure) Surgical debridement is mainstay of therapy along with antimicrobial therapy () Debridement of necrotic bone or joint space Osteomyelitis Drainage of adjacent abscesses Septic arthritis 22 MRSA Bone and Joint Osteomyelitis/septic arthritis therapy options (Cubicin ) (Bactrim ) mg/kg IV 15 mg/kg dose IV Q 6 H BII/ 6 mg/kg/day IV daily 6 10 mg/kg/day IV daily BII/ CIII 600 mg PO/IV BID 10 mg/kg/dose PO/IV Q 8 H (NTE 600 mg/dose) 600 mg PO/IV TID mg/kg/dose PO/IV Q 6 8 H (NTE 40 mg/kg/day) BII/ CIII BIII/ mg/kg/dose PO/IV BII 600 mg PO daily BII Optimal route of administration not established () 23 MRSA Bone and Joint Some experts recommend adding rifampin 600 mg daily or mg PO/IV BID (BIII) Animal models, small human trials of MSSA osteomyelitis Retrospective study: cure rate of 80%, no added benefit if debridement occurred 1 Duration of therapy Optimal duration is unknown; at least 8 weeks () Hematogenous MSSA vertebral osteomyelitis: 8 weeks vs. < 8 weeks associated with improved outcomes 2,3 Duration of therapy Recurrence Rate 2 6 weeks ~ % 8 weeks ~ 8 % 10 weeks % 1 ; 2 Jensen Arch Intern Med 1998;158:509-17; 3 Priest S Med J 2005;98:

5 MRSA Central Nervous System (CNS) CNS infections occur as a complication of the following: Neurosurgical procedure Associated with adjacent focus of infection Secondary to bacteremia or infective endocarditis Manifestations of CNS infection include: Meningitis Brain abscesses Subdural empyema, spinal epidural abscess Septic thrombosis Cavernous or dural venous sinus MRSA-CNS Treatment is poor due to the blood brain barrier (Bactrim ) Adult Dose mg/kg/dose IV 600 mg PO/IV BID 5 mg/kg/dose PO/IV Pediatric Dose 15 mg/kg/dose IV Q 6 H 10 mg/kg/dose PO/IV Q 8 H ND 600 mg PO/IV daily or mg BID CSF Penetration CSF Concentration Class 1 5% 2 6 mcg/ml BII 66% Peak 7 10 mcg/ml Trough mcg/ml TMP 13 53% SMX 17 63% TMP mcg/ml SMX mcg/ml 22% mcg/ml BII CIII BIII MRSA-CNS CNS shunt infections/meningitis Shunt removal is recommended; replace only when CSF cultures are repeatedly negative () Intraventricular vancomycin or daptomycin may be considered if not responding to systemic therapy Brain abscess, subdural empyema, spinal epidural abscess Neurosurgical evaluation for incision and drainage () Septic cavernous or dural venous sinus thrombosis Debride contiguous sites of infection or abscess () Role of anticoagulation controversial due to risk of intracranial hemorrhage 27 Guideline Recommendations Recommendations based on a consensus statement American Society of Health-System Pharmacists, Infectious Disease Society of America, Society of Infectious Diseases Pharmacists IV vancomycin mg/kg (actual body weight), not to exceed 2 g/dose (BIII) Seriously ill patients with suspected MRSA infection, loading dose of mg/kg may be considered Consider prolonged infusion (2 hours) and pre-medication with antihistamine, given risk of red man syndrome and possible anaphylaxis Limited data to guide vancomycin dosing in pediatrics IV vancomycin 15 mg/kg/dose every 6 H is recommended in serious or invasive disease (BIII) Continuous infusion vancomycin is unlikely to substantially improve patient outcome, compared with intermittent dosing () 28 Therapeutic Monitoring Obtain serum troughs at steady state (before 4 th or 5 th dose) (BII) Monitoring of peak vancomycin concentrations is not recommended (BII) Target trough concentrations: mcg/ml (BII) Serious infections (i.e. severe SSTI, pneumonia, bacteremia, endocarditis, osteomyelitis) For most patients with SSTI, normal renal function, not obese, traditional doses of 1 gram IV Q 12 H is adequate Trough monitoring is not required (BII) Efficacy and safety of targeting trough concentrations of mcg/ml in pediatrics requires additional study Consider in serious infections Pharmacotherapy of Evidence for higher target trough concentrations probability of achieving target area under the curve (AUC)/minimum inhibitory concentration (MIC) ratio AUC/MIC 400 vs. < 400 associated with improved clinical and microbiologic response 1 Mean Trough Mean AUC 9.4 mcg/ml 318 +/- 111 mcg/h/ml 20.4 mcg/ml 418 +/- 152 mcg/h/ml Lower troughs may select for resistance subpopulations [i.e., vancomycin-heteroresistant S. aureus (hvisa)] Clinical outcomes are unclear Few clinical studies Potential for increased nephrotoxicity 29 1 Moise-Broder Clin Pharmacok 2004; 30 5

6 Susceptibility Testing CLSI 2006 Susceptible Intermediate Resistant MIC Breakpoint 2 mcg/ml 4 8 mcg/ml 16 mcg/ml There is a considerable variability in MIC results depending on the method used Acceptable variability for MIC methods is +/- one doubling dilution For isolates with a vancomycin MIC 2 mcg/ml, the clinical response should determine the continued use of vancomycin, independent of MIC ( I) For isolates with a vancomycin MIC > 2 mcg/ml, alternative therapy should be used (I) 31 Treatment Failure Persistent MRSA Bacteremia Consideration factors when contemplating change in therapy (I) Overall clinical response, vancomycin trough concentrations, results of susceptibility testing (i.e., MIC), presence of and ability to remove other foci of infection Antibiotic Considerations (Cubicin ) PLUS Gentamicin (Bactrim ) Adult Dose 10 mg/kg IV daily 1 mg/kg IV Q 8H 600 mg PO/IV daily or mg PO/IV BID 600 mg PO/IV BID 5 mg/kg (TMP) IV BID 32 Reduced Susceptibility to and? Alternative therapeutic options Quinupristin-dalfopristin 7.5 mg/kg/dose IV Q 8 H Low response rates for endocarditis and bacteremia of unknown source 5 mg/kg/dose (TMP component) IV BID 600 mg PO/IV BID Poor outcomes for left-sided endocarditis Telavancin 10 mg/kg/dose IV daily A case report of persistent MRSA bacteremia successfully treated Role of Adjunctive Treatment of MRSA Protein synthesis inhibitors (i.e., clindamycin, linezolid) and intravenous immunoglobulin (IVIG) are not routinely recommended as adjunctive therapy (I) Limited and conflicting in vitro and animal model data Some experts may consider these agents in selected scenarios Toxic shock syndrome Necrotizing/cavitary pneumonia Severe sepsis Center for Disease Control MRSA Prevention Strategies MRSA interventions primarily target two broad areas Preventing transmission from colonized to uncolonized persons Preventing infection in colonized individuals Core Strategies High levels of scientific evidence supporting use Demonstrate high levels of feasibility Supplemental Strategies Variable scientific evidence supporting use Demonstrate variable levels of feasibility 35 Prevention Strategies Core Strategies Assessing hand hygiene practices Implementing contact precautions Recognizing previously colonized patients Rapidly reporting MRSA lab results Providing MRSA education for healthcare providers and family members Supplemental Strategies Active surveillance testing Decolonization Chlorhexidine bathing in high-risk patient population

Antimicrobial Pearls Antimicrobial Pearls Antimicrobial Monitoring & Precautions Bowel movements Abdominal pain Diarrhea Rash Quinupristin- Dalfopristin CBC = complete blood count Liver function

7 Antimicrobial Pearls Antimicrobial Pearls Antimicrobial Monitoring & Precautions Bowel movements Abdominal pain Diarrhea Rash Quinupristin- Dalfopristin CBC = complete blood count Liver function tests Creatinine phosphokinase (weekly) CBC, with differential (weekly) Visual function test Seizure/convulsion activity Drug interactions (Serotonin Syndrome) CBC Bilirubin levels Liver function test Adverse Effects Common Severe Arthralgias/ Myalgias Sore throat and/or pain Nausea/vomiting Diarrhea Headache Tongue discoloration Rash Thrombocytopenia Arthralgias/ Myalgias Nausea Infusion-related reactions Hyperbilirubinemia Pseudomembranous colitis- C. difficile infection (CDI) (Black Box Warning) Osteomyelitis Rhabdomyolysis Toxic optic neuropathy Peripheral neuropathy Hypertension Seizures Myelosuppression Syncope Hepatitis Acidosis 37 Antimicrobial Telavancin Tetracyclines Monitoring & Precautions Liver function test Drug interactions (Q H) Pregnancy test CBC Drug interactions Not recommended in children < 8 years Bowel movements Rash Sulfa allergy Serum potassium Adverse Effects Common Severe Discoloration (tears, urine, sweat, saliva) Heartburn Nausea Nausea/vomiting Metallic taste Children: tooth enamel discoloration and decreased bone growth Photosensitivity Nasopharyngitis Photosensitivity GI disturbances Hyperkalemia Thrombocytopenia Hepatotoxicity Nephrotoxicity Prolonged QT interval Increased serum creatinine Stevens-Johnson syndrome Hepatotoxicity CDI Crystalluria Myelosuppression Stevens-Johnson Syndrome 38 MRSA Performance Measures The management of all MRSA infections should include: Identification, elimination, and/or debridement of the primary source of infection and other sites of infection when possible In patients with MRSA bacteremia, document clearance of bacteremia (follow-up blood cultures 2 4 days after initial positive cultures and as needed thereafter) should be dosed according to actual body weight, mg/kg/dose IV, not to exceed 2 g/dose Target trough mcg/ml in patients with serious infections Document in vitro susceptibility when an alternative to vancomycin is being considered For methicillin-susceptible S. aureus infections, a β-lactam antibiotic is the drug of choice 39 True or False Questions The management of all MRSA infections should include identification, elimination and/or debridement of the primary source and other sites of infection when possible? a. True b. False Tetracyclines should not be used in children less than 8 years of age? a. True b. False To optimize serum trough concentrations in adult patients, vancomycin should be dosed according to ideal body weight (15 20 mg/kg/dose)? a. True b. False y/o F with 3 days of an enlarging, painful lesion on her right thigh. She is afebrile, with a blood pressure of 118/70 and heart rate of 82. PMH: noncontributory Case What is the proper initial management of this patient? A.Incision and drainage alone B.Incision and drainage plus oral anti-mrsa antimicrobial agent C.Oral anti-mrsa antimicrobial agent 41 References Duong M, Markwell S, Peter J. Randomized, controlled trial of antibiotics in the management of communityacquired skin abscesses in the pediatric patient. Ann Emerg Med. 2010;55: Fowler VG, Boucher HW, Corey R. versus Standard for Bacteremia and Caused by Staphylococcus aureus. NEJM 2006; 355: Accessed December 5 th, Jensen AG, Espersen F, Skinhoj P, Frimodt-Moller N. Bacteremic Staphylococcus aureus spondylitis. Arch Intern Med 1998;158: Kallen AJ, Yi Mu, Bulens SN, et al. Changes in the incidence of healthcare-associated invasive MRSA infections and concurrent MRSA control practices in the US, 2005 to 2007 Presented at SHEA Abstract 49. Khan AR, Khan S, Zimmerman V, et al. Quality and strength of evidence of the Infectious Disease Society of America Clinical Practice Guidelines. Clin Infect Dis. 2010; 51 (10): Liu C, Bayer A, Sara E., et al. Clinical Practice Guidelines by the Infectious Diseases Society of America for the Treatment of Methicillin-Resistant Staphylococcus Aureus in Adults and Children Clinical Infectious Diseases 2011;53:1 38. Methicillin-resistant Staphylococcus aureus infections. Accessed on November 15th, Moise-Broder PA, Forrest A, Birmingham MC, Schentag JJ. Pharmacodynamics of vancomycin and other antimicrobials in patients with Staphylococcus aureus lower respiratory tract infections. Clin Pharmacok. 2004;43: Moran GJ, Krishnadasan A, Gorwitz RJ, et al. Methicillin-Resistant S. aureus among Patients in the Emergency Department. N Engl J Med 2006; 355: Priest S, Peacock JE. Hematogenous vertebral osteomyelitis due to Staphylococcus aureus in the adult: clinical features and therapeutic outcomes. South Med J 2005;98: Rajendran PM et al. Randomized, double-blind, placebo-controlled trial of cephalexin for treatment of uncomplicated skin abscesses in a population at risk for community-acquired methicillin-resistant Staphylococcus aureus infection. Antimicrob Agents Chemother. 2007; 51: Schmitz GR, Bruner D, Pitotti R, et al. Randomized controlled trial of trimethoprim-sulfamethoxazole for uncomplicated skin abscesses in patients at risk for community-associated methicillin-resistant Staphylococcus aureus infection. Ann Emerg Med. 2010;56:

Appropriate Antimicrobial Therapy for Treatment of

Appropriate Antimicrobial Therapy for Treatment of Staphylococcus aureus infections ( MRSA ) By : A. Bojdi MD Assistant Professor Inf. Dis. Dep. Imam Reza Hosp. MUMS Antibiotics Still Miracle Drugs Paul