Session 3: New Evidence-Based Clinical Prac ce Guidelines C: Treatment of MRSA Infec ons in Adults and Children 4:15pm - 5:15pm

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1 January 20-22, 2012 Des Moines Marrio, 700 Grand Avenue, Des Moines, IA Session 3: New Evidence-Based Clinical Prac ce Guidelines C: Treatment of MRSA Infec ons in Adults and Children 4:15pm - 5:15pm ACPE UAN L01-P Ac vity Type: Applica on-based 0.1 CEU/1.0 Hr Program Objec ves for Pharmacists: Upon comple on of this CPE ac vity par cipants should be able to: 1. Summarize an microbials used in the treatment of MRSA infec ons 2. Apply knowledge of clinical prac ce guidelines to recommend therapy for MRSA infec ons 3. Use guidelines to provide dosing and monitoring sugges ons for vancomycin 4. Iden fy clinical situa ons where alterna ve therapies may be appropriate 5. Recognize important considera ons for pediatric pa ents Speaker: Erika J. Ernst, PharmD, is an Associate Professor of Pharmacy at the University of Iowa and clinical pharmacy specialist in infec ous diseases at UIHC where she also serves on the pharmacy and therapeu cs and an bio c advisory commi ees. She received her PharmD from the University of Southern California where she also completed a pharmacy prac ce residency. She went on to complete an infec ous diseases fellowship at the University of California, San Francisco prior to joining the faculty at the University of Iowa. Her prac ce and research interests are in an microbial u liza on and resistance. In addi on to having several publica on in the infec ous diseases literature, she is also the President-elect of the Society of Infec ous Diseases Pharmacists. Speaker Disclosure: Erika Ernst does not report any actual or poten al conflicts of interest in rela on to this CPE ac vity. Off-label use of medica ons will be discussed during this presenta on.

2 Treatment of MRSA Infections in Adults and Children Erika J. Ernst, Pharm.D. Associate Professor University of Iowa College of Pharmacy Faculty Disclosure Erika Ernst reports she has no actual or potential conflicts of interest associated with this presentation. Erika Ernst has indicated that off-label use of medication will be discussed during this presentation. Learning Objectives Upon completion of this activity pharmacists will be able to: Summarize antimicrobials used in the treatment of MRSA infections Apply knowledge of clinical practice guidelines to recommend therapy for MRSA infections Use guidelines to provide dosing and monitoring suggestions for vancomycin Identify clinical situations where alternative therapies may be appropriate Recognize important considerations for pediatric patients Pre-Assessment Questions Select the desirable serum level for vancomycin. a b. 15 c. >20 d. None of the above, measuring serum levels is not necessary Which of the following have activity against MRSA? a. Clindamycin (Cleocin) b. TMP/SMX (Bactrim) c. Doxycycline (Vibramycin) d. Vancomycin (Vancocin) e. All of the above I D S A G U I D E L I N E S Clinical Practice Guidelines by the Infectious Diseases Society of America for the Treatment of Methicillin- Resistant Staphylococcus aureus Infections in Adults and Children Catherine Liu,1 Arnold Bayer,3,5 Sara E. Cosgrove,6 Robert S. Daum,7 Scott K. Fridkin,8 Rachel J. Gorwitz,9 Sheldon L. Kaplan,10 Adolf W. Karchmer,11 Donald P. Levine,12 Barbara E. Murray,14 Michael J. Rybak,12,13 David A. Talan,4,5 and Henry F. Chambers1,2 Clinical Infectious Diseases 2011; 52(3):e18-e55 Summary First guideline on treatment of MRSA from IDSA. Primary objective to provide recommendations on management of clinical syndromes caused by MRSA. Address vancomycin dosing and monitoring, susceptibility testing and use of alternate therapies Do not address Surveillance testing or infection-prevention strategies 1

3 Topics Skin and Soft tissue infections (SSTIs) Recurrent SSTIs Bacteremia and Infective Endocarditis Pneumonia Bone and Joint Infections CNS Infections Adjunctive therapies for MRSA Infections Vancomycin dosing and monitoring Susceptibility Testing Persistent Bacteremia & treatment failures Neonates Antimicrobial Therapy Clindamycin Ceftaroline Daptomycin Linezolid Quinupristin-Dalfopristin Telavancin TMP/SMX Vancomycin Doxycycline Minocycline Tigecycline Rifampin in combo Gentamicin in combo 44 year old male with 3 days of enlarging painful area on right forearm. There is an apparent fluctuant collection. The man is afebrile with normal blood pressure and pulse. What is the most important factor in the management of this patient? a. Incision and drainage of the fluid collection. b. Oral antimicrobial therapy. c. I & D plus oral therapy to cover MRSA. SSTIs For abscesses Incision and Drainage is the most important therapy. Antibiotics indicated for abscesses with Severe disease (associated with cellulitis or rapidly progressive) Signs of systemic illness Immune suppressed Extremes of age Difficult to drain (face, hand) Failure of prior I&D Microbiology of Purulent SSTIs non-b-hemolytic strep 4% B-hemolytic strep 3% unknown Column1 9% other 8% MSSA 17% MRSA 59% Oral therapy for purulent cellulitis TMP/SMX 1-2 DS BID <45 kg 2 mg/kg/dose (TMP component) PO every 12 h; >45 kg adult dose Doxycycline/Minocycline 100 mg BID Not recommended Clindamycin TID mg/kg/dose PO every 6-8 h NTE 40 mg/kg/day Linezolid 600 BID 10 mg/kg/dose PO every 8 h NTE 600 mg/dose 2

4 Oral therapy for NON-purulent cellulitis Cephalexin 500 QID mg/kg divided every 6-12 h NTE 4 gm/day Dicloxacillin 500 QID <40 kg: to 6.25 mg/kg every 6 h >40 kg: 125 to 250 mg every 6 h Clindamycin TID mg/kg/dose every 6-8 h NTE 40 mg/kg/day Linezolid 600 BID 10 mg/kg/dose every 8 h NTE 600 mg/dose Complicated SSTI Vancomycin 15 mg/kg IV Q8-12h 15 mg/kg IV Q6h Linezolid 600 mg IV/PO BID 10 mg/kg/dose PO/IV every 8 h NTE 600 mg/dose Daptomycin 4 mg/kg IV QD Study ongoing clincaltrials.gov Telavancin 10 mg/kg IV QD ND Ceftaroline 600 mg IV/PO Q12 h Under study: <75 kg: 8 mg/kg >75 kg: 600 mg Clindamycin 600 mg Q8h mg/kg/dose PO/IV every 6-8 h NTE 40 mg/kg/day A patient asks for advice for her child who is having recurrent MRSA skin infections. She asks if there is anything she can do to help with these recurrent infections. What is an appropriate response for this patient? a. Recommend she see an Infectious Disease Specialist b. Suggest she request oral antibiotics for decolonization c. Suggest she cover draining wounds and emphasize hand hygiene d. Recommend her dogs and cats be tested for MRSA to determine if they are a source of infection Management of Recurrent SSTIs Personal hygiene / Wound Care Cover draining wounds Hand hygiene after touching infected skin Avoid reusing / sharing personal items Environmental hygiene Clean high touch surfaces Decolonization Mupirocin BID for 5-10 days Mupirocin BID for 5-10 days plus topical skin antiseptic (chlorhexidine) x 5-14 days Dilute bleach baths (1 tsp per gallon; ¼ cup per ¼ tub) for 15 min twice weekly for ~ 3 months Oral antibiotics NOT recommended for decolonization MRSA Pneumonia Vancomycin 15 mg/kg IV Q mg/kg IV Q6h Linezolid 600 mg PO/IV BID 10 mg/kg/dose PO/IV every 8 h NTE 600 mg/dose Clindamycin 600 mg PO/IV TID mg/kg/dose PO/IV every 6-8 h NTE 40 mg/kg/day Daptomycin not used for pneumonia inactivated by pulmonary surfactantbut may be use in patients with hematogenous septic pulmonary emboli as a complication of bacteremia/endocarditis. MRSA bacteremia and Endocarditis Vancomycin 15 mg/kg IV Q 8-12 h 15 mg/kg IV Q6h Daptomycin 6 mg/kg IV QD 6 mg/kg IV QD Linezolid not recommended for bacteremia or endocarditis due to increased mortality when organism is not known. Tigecycline not recommended for hospital acquired pneumonia or ventilator associated pneumonia due to increased mortality. 3

5 Vancomycin Treatment Failure Persistent MRSA bacteremia Definition of treatment failure Median time to clearance of bacteremia MSSA with B-lactam 3-4 days MRSA with Vanco 7-9 days Consider Overall clinical response Vancomycin serum concentrations Susceptibility testing results (vanco MIC) Foci of infection Vancomycin Treatment Failure Persistent MRSA bacteremia Search for focus of infection with surgery or drainage Daptomycin (if susceptible) in combination with another agent Gentamicin Rifampin Linezolid TMP/SMX IV 5 mg/kg Q12 h Ceftaroline Prior treatment with vanco and elevated vanco MICs are associated with elevated Dapto MICs Vancomycin Treatment Failure Persistent MRSA bacteremia If reduced susceptibility to vanco and dapto Quinupristin/dalfopristin TMP/SMX IV Linezolid Telavancin Ceftaroline MRSA Bone and Joint Infections Vancomycin 15 mg/kg IV Q 8-12 h 15 mg/kg IV Q6h Daptomycin 6 mg/kg IV QD 6 mg/kg IV QD Linezolid 600 mg PO/IV BID 10 mg/kg/dose PO/IV every 8 h NTE 600 mg/dose Clindamycin 600 mg PO/IV TID mg/kg/dose PO/IV every 6-8 h NTE 40 mg/kg/day TMP/SMX plus rifampin mg/kg/dose PO/IV every 8-12 h 600 mg PO QD ( mg PO BID) No data MRSA CNS infections Vancomycin 15 mg/kg IV Q 8-12 h 15 mg/kg IV Q6h Linezolid 600 mg PO/IV BID 10 mg/kg/dose PO/IV every 8 h NTE 600 mg/dose Adjunctive therapies Protein synthesis inhibitors (eg. Clindamycin or linezolid) and IVIG are not routinely recommended as adjunctive therapy Some limited in vitro and animal model data exist but has some conflicting results 4

6 Vancomycin Dosing and Monitoring Vancomycin 15 mg/kg (total body weight) max 2 gm. Interval Q 8 hours suggested for Age < 40 and Scr < 1.4 Q12 hours suggested for age and Scr < 1.4 Q24 hours suggested for age >65 or Scr >1.4 (regardless of age) Loading dose (25-30 mg) may be considered for seriously ill or obese patients (max 3-4 gm). Measure trough at steady state (prior to 4 th or 5 th dose-when dosing interval selected as above) if patient will remain on vancomycin. Vancomycin Target Trough of 15 estimates an AUC of 400. AUC of > 400 has been associated with improved clinical response Higher troughs (> 20) have been associated with increased nephrotoxicity Elevated vancomycin MICs (> 2 mcg/ml) have been associated with increased likelihood of vancomycin failure What went wrong? A 72 year old 61 kg female with a Scr of 1.3 is started on vancomycin 1 gm Q 12 h for cellulitis that did not respond to oral antibiotics. After the 3 rd dose a vancomycin level is obtained an the level is 14 mcg/ml. She is sent home that evening to continue receiving vancomycin by home care. She will have a Scr 2x/week and vanco level in 1 week. He Scr rises to 1.6. She is feeling poorly and is now confused. She is readmitted and her Scr is 1.7 and her vancomycin level taken 12 hours after a dose is 37 mcg/ml She was not at steady state when the level was taken after the 3 rd dose, she continued to accumulate drug leading to renal insufficiency. Her level was taken too early and she was discharged prematurely A more appropriate starting dose and monitoring plan would have been 15 mg/kg (915 mg) rounded up to 1 gram given every 24 hours. Draw the serum level after the 3 rd dose. Perhaps could have been discharged but the level in the home environment would have occurred the next day. Clindamycin (Cleocin) FDA approved for S. aureus infections Bacteriostatic not recommended for endovascular infections Excellent tissue penetration Limited CSF penetration D-zone test for detection of inducible clindamycin resistance in Erythromycin-resistant, Clindamycin susceptible isolates Diarrhea occurs in up to 20% of patients Oral suspension not well tolerated (may need to add flavoring) Ceftaroline (Teflaro) FDA approved for SSTI and CAP Cephalosporin with MRSA activity (high affinity for penicillin binding protein (PBP) 2a Safety profile similar to ceftriaxone 5

7 Daptomycin (Cubicin) FDA approved for adults with S. aureus bacteremia, right sided endocarditis and cssti. Bactericidal Not used for MRSA pneumonia (inactivated by surfactant) Highly protein bound; renally excreted Elevation of CPK is most common adverse effect (monitor CPK weekly. Eosinophilic pneumonia has been reported Linezolid (Zyvox) FDA approved for SSTI and nosocomial pneumonia caused by MRSA in adults and children Bacteriostatic 100% oral bioavailability; only use IV if patient unable to take oral medication Hematologic toxicity, thrombocytopenia, anemia, neutropenia. Peripheral and optic neuropathy and lactic acidosis Weak non-selective MAOI inhibitor has been associated with serotonin syndrome in pts taking SSRI Quinupristin-Dalfopristin (Synercid) FDA approved for cssti in adults and children > 16 yrs Inhibits protein synthesis but the combo is bactericidal Arthralgias, myalgias, nausea and infusion-related reactions. Telavancin (Vibativ) FDA approved for cssti in adults Bactericidal Nephrotoxicity is more common than vancomycin Monitor Scr, drug level monitoring not available Taste disturbances, nausea, headache, foamy urine Adverse fetal outcomes in animal studies, potential for abnormal fetal development TMP/SMX (Bactrim) Not FDA approved for staphylococcal infections, however % of CA-MRSA strains are susceptible in vitro Hyperkalemia especially in elderly patients on reninangiotension inhibitors or with chronic renal insufficiency. Not recommended in third trimester of pregnancy or in infants under 2 months due to possibility of kernicterus. Vancomycin (Vancocin) FDA approved for the treatment of MRSA infections Slowly bactericidal Possible emergence of resistant strains Tissue penetration is variable (limited penetration into bone, lung epithelial lining fluid and CSF). Renal toxicity at higher doses Monitor Scr, and drug levels 6

8 Doxycycline (Vibramycin)/ Minocycline (Minocin) FDA approved for SSTI due to S. aureus but not specific for MRSA. In vitro activity against MRSA Bacteriostatic Some isolates R to doxycycline may be S to minocycline Not recommended in pregnancy or children < 8 yrs Tigecycline (Tygacil) FDA approved for cssti and intraabdominal infections Glycylcycline, derivative of minocycline Bacteriostatic High tissue concentrations; low serum concentrations FDA warning for serious infections to consider alternative agents due to increased all cause mortality in clinical trials of tigycycline Nausea and vomiting are common adverse effects Not recommended in pregnancy or children Rifampin (Rifadin) Bactericidal activity agains S. aureus, achieves high levels and penetrated biofilm Do not use alone, resistance develops rapidly Do not use until blood cultures are negative Role not clearly defined Drug interactions Gentamicin (Garamycin) Bactericidal Used in combination, not used as primary therapy Nephrotoxicity and ototoxicity Post-Assessment Questions A 6 year old child has cellulitis associated with a recent abrasion. The area is red, swollen, warm to the touch, but there is no apparent fluid collection or pus. She is allergic to ampicillin (rash). Select the most appropriate treatment. a. Doxycycline b. Cephalexin c. Dicloxacillin d. Vancomycin A 26 year old male is admitted for a knee injury sustained playing sports. Following reconstruction he develops an MRSA wound infection. He is otherwise healthy. His Serum creatinine is 0.8 and he weighs 100 kg. He will receive vancomycin 15 mg/kg. You suggest the vancomycin be given a. Every 8 hours b. Every 12 hours c. Every 24 hours d. By continuous infusion 7

9 A 65 year old male is admitted for MRSA bacteremia. His vancomycin MIC is 2 (S); Daptomycin MIC is 0.5 (S) and Linezolid MIC is 0.5 (S). He takes atorvastatin (Lipitor) and lisinopril (Zestril). Select the most appropriate therapy. a. Vancomycin b. Daptomycin c. Linezolid d. Any of the above A 45 year old female is seen for purulent cellulitis that was drained but hasn t healed. She takes sertraline (zoloft) for depression. Select the most appropriate therapy. a. TMP/SMX b. Linezolid c. Mupirocin d. Tigecycline A 38 year old HIV positive male is admitted with signs and symptoms of pneumonia. Sputum grows MRSA. Blood cultures are negative. Which of the following should NOT be used to treat this infection. a. Vancomycin b. Linezolid c. Clindamycin d. Daptomycin Continuing Pharmacy Education Go to click on My Portfolio Scroll down to Take Exam Enter Access Code: (case sensitive) Pharmacists - Technicians - 8

10 2012 Educational Expo Treatment of MRSA Infections in Adults and Children Erika Ernst, PharmD Post Assessment Questions 1. A 6 year old child has cellulitis associated with a recent abrasion. The area is red, swollen, warm to the touch, but there is no apparent fluid collection or pus. She is allergic to ampicillin (rash). Select the most appropriate treatment. A. Doxycycline B. Cephalexin C. Dicloxacillin D. Vancomycin 2. A 26 year old male is admitted for a knee injury sustained playing sports. Following reconstruction he develops an MRSA wound infection. He is otherwise healthy. His Serum creatine is 0.8 and he weighs 100 kg. He will receive vancomycin 15 mg/kg. You suggest the vancomycin be given A. Every 8 hours B. Every 12 hours C. Every 24 hours D. By continuous infusion 3. A 65 year old male is admitted for MRSA bacteremia. His vancomycin MIC is 2 (S); Daptomycin MIC is 0.5 (S) and Linezolid MIC is 0.5 (S). He takes atorvastatin (Lipitor) and lisinopril (Zestril). Select the most appropriate therapy. A. Vancomycin B. Daptomycin C. Linezolid D. Any of the above

11 New vidence-based Clinical Practice Guidelines: Treatment of MRSA Infections in Adults and Children Patient Case A 72 year old 61 kg female with a Scr of 1.3 is started on vancomycin 1 gm Q 12 h for cellulitis that did not respond to oral antibiotics. After the 3 rd dose a vancomycin level is obtained an the level is 14 mcg/ml. She is sent home that evening to continue receiving vancomycin by home care. She will have a Scr 2x/week and vanco level in 1 week. He Scr rises to 1.6. She is feeling poorly and is now confused. She is readmitted and her Scr is 1.7 and her vancomycin level taken 12 hours after a dose is 37 mcg/ml What went wrong? (Assessment) Patient problems: Cellulitis Acute Renal Failure System problems: Her vancomycin level was assessed before reaching steady state and she was discharged home too early/with improper monitoring. Intervention: (Plan) Hold vancomycin. Monitor Scr. Plan to restart vancomycin with prolonged interval.

12 4. A 45 year old female is seen for purulent cellulitis that was drained but hasn t healed. She takes sertraline (zoloft) for depression. Select the most appropriate therapy. A. TMP/SMX (Bactrim) B. Linezolid (Zyvox) C. Mupirocin (Bactoban) D. Tigecycline (Tygacil) 5. A 38 year old HIV positive male is admitted with signs and symptoms of pneumonia. Sputum grows MRSA. Blood cultures are negative. Which of the following should NOT be used to treat this infection. A. Vancomycin B. Linezolid C. Clindamycin D. Daptomycin