ภก.วส นต กาต บ. Use of vancomycin is appropriate or acceptable. FDA Labeled Indication

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1 Quality improvement for DUE: Vancomycin, Linezolid and Daptomycin Vancomycin ภก.วส นต กาต บ Vancomycin. In: DRUGDEX System [Internet database]. Greenwood Village, Colo: Thomson Healthcare. Updated periodically. FDA Labeled Indication Infection of skin AND/OR subcutaneous tissue Infective endocarditis, Lower respiratory tract infection Staphylococcal infectious disease, Methicillin-resistant Clostridium difficile diarrhea(oral only) Vancomycin. In: DRUGDEX System [Internet database]. Use of vancomycin is appropriate or acceptable For treatment of serious infections caused by beta-lactam- resistant gram+ve microorganisms For treatment of infections caused by gram+ve microorganisms in patients who have serious allergies to beta-lactam antimicrobials. When antibiotic-associated colitis fails to respond to metronidazole therapy or is severe and potentially life-threatening. MMWR Recomm Rep Sep 22;44(RR-12):1-13.

2 Use of vancomycin is appropriate or acceptable Prophylaxis, as recommended by the AHA, for endocarditis following certain procedures in patients at high risk for endocarditis Prophylaxis for major surgical procedures involving implantation of prosthetic materials at institutions that have a high rate of infections caused by MRSA/MRSE MMWR Recomm Rep Sep 22;44(RR-12):1-13. Dosing Regimen by indication Bacteremia associated with intravascular line MRSA /MRSE: 15 mg/kg IV q 12 hr ampi-resistant,vse: 15 mg/kg iv q 12 hr ± gentamicin 1 mg/kg iv q 8 hr Bacterial meningitis MRSA-Associated CNS Infections: 15 to 20 mg/kg/dose iv q 8-12 hr Critically ill loading dose mg/kg (actual body weight) Dosing Regimen by indication Infection of skin AND/OR subcutaneous tissue MRSA: 30 mg/kg/day Infective endocarditis MRSA: 15 mg/kg iv q 12 hr trough concentration เ=15-20 mcg/ml Lower respiratory tract infection MRSA:2 g/day iv q 6 or 12 hr Vancomycin Concentration and Killing Activity Relationship between pharmacokinetic/pharmacodynamic indices for vancomycin and bacteriologic efficacy against methicillin-susceptible Staphylococcus aureus.

3 Pharmacodynamics of Vancomycin and Other Antimicrobials in Patients with Staphylococcus aureus Lower Respiratory Tract Infections 100 Culture-pos sitive (%) Treatment day AUC24/MIC <400 (n = 16) AUC24/MIC 400 (n = 18) p = Time (days of therapy) to bacterial eradication vs vancomycin AUC24/MIC <400 and AUC24/MIC 400 illustrated by a Kaplan-Meier survival plot of day of therapy vs the percentage of patients remaining culturepositive on that day. The two AUC24/MIC groups differed significantly (p = ). Moise-Broder et al. Clin Pharmacokinet 2004; 43 (13): Trough serum level = mg/l AUC/MIC > 400 Clin Infect Dis 2009;49: Two Barriers of Penetration Vancomycin Penetration Scheetz MH,et al. Pharmacotherapy. 2006;26(4):

4 Antibiotics in the lung ALVEOLAR MACROPHAGES Alveolar macrophages Edema Alveolar lumen Colonising encapsulated bacteria Alveolar epithelium Neutrophil EPITHELIAL Epithelial LINING lining FLUID fluid Alveolar basement membrane i.v. administration of a single dose of 1,000 mg, CSF vancomycin concentrations were below 0.5 mg/l Capillary lumen Interstitium Infected lung Antibiotics Capillary basement membrane Capillary endothelium Nau, R. Fachbereich Medizin, Universita t Go ttingen,go ttingen, Germany.1992 What are the recommendations for vancomycin dosing & monitoring? For serious infections, such as bacteremia meningitis IE pneumonia osteomyelitis severe SSTI (eg, necrotizing fasciitis) vancomycin trough conc. of mg/l (B-II). Vancomycin level in hemodialysis Pre-HD During HD Rebound Liu C et,al. Clinical Infectious Diseases 2011;52:1 38 Rybak M et,al.am J Health-Syst Pharm. 2009; 66:82-98 Launay-Vacher et al. Critical Care 2002, 6:

5 PK Parameters of vancomycin Parameters Extraction rate Rebound HD 30-46% (high flux membranes) Dialysis duration Filter reuse 37.6 ±13.9% (HEHD) 16-38% (high flux membranes) maximal 3-6 hours after dialysis 37.9 ± 12.9% Klansuwan N.et al. J Med Assoc Thai 2006; 89 (7): Vandecasteele SJ. Et al. Seminars in Dialysis 2011;24(1):50 5. Infect Control Hosp Epidemiol 2010; 31(5): Intraperitoneal Antibiotic Dosing Recommendations for CAPD Patients Intermitent (per exchang, once daily) Continuos (mg/l:all exchanges) Daptomycin LD 100, MD 20 Linezolid Oral mg q.d. Teicoplanin 15 mg/kg LD400,MD 20 Vancomycin 15-30mg/kg q 5-7 day LD1000,MD 25 Contraindications Vancomycin hypersensitivity to vancomycin Precautions thrombophlebitis transient or permanent ototoxicity nephrotoxicity, use with ototoxic agents such as aminoglycosides infusion-related reactions Peritoneal Dialysis International 2010;30: Vancomycin. In: DRUGDEX System [Internet database].

6 Daptomycin Bacteremia or endocarditis caused by MRSA/MRSE in a patient with a serious allergy to vancomycin Therapy for MRSA infections (other than pneumonia) in which the MIC of vancomycin is 1.5 mcg/ml Summary of Reading for Vancomycin Susceptibilities Glycopeptide susceptibility classification Susceptible (VSSA) Intermediate (VISA) Resistant (VRSA) Broth microdilution (µg/ml) CLSI prior to 2006 CLSI after 2006 EUCAST No longer included Howden BP, et al. Clin Microbiol Rev 2010;23: Relationship of MIC to Vancomycin Treatment Failures in MRSA Infections Clinical Significance of Vancomycin MIC Failure Rate (%) 22% 27% 31% 51% MIC (µg/ml) MIC, minimal inhibitory concentration. Moise-Broder PA et al. Clin Infect Dis. 2004;38; van Hal SJ, et al. Clinical Infectious Diseases 2012;54(6):755 71

7 Clinical Significance of Vancomycin MIC Kaplan Meier survival graph of mortality at 90 days according to vancomycin MIC van Hal SJ, et al. Clinical Infectious Diseases 2012;54(6): Cervera C, et al. Clinical Infectious Diseases 2014;58(12): Daptomycin Bacteremia or endocarditis caused by MRSA in a patient failing vancomycin therapy defined as: Clinical decompensation after 3-4 days Failure to clear blood cultures after 7-9 days despite vancomycin troughs of mcg/ml Select cases in which the MIC of vancomycin is 1.5 mcg/ml 236 pts randomized to IV daptomycin 6 mg/kg QD vs. (vancomycin or nafcillin) + gentamicin 1 mg/kg Q8 x 4 days Fowler VG Jr, et al. N Engl J Med. 2006;355(7):

8 MRSA bacteremia & endocarditis Fowler VG NEJM 2006; 355: Among cases of second-line therapy (n=312) the most common reason for switching to daptomycin was failure of the previous regimen (including glycopeptides and penicillins). Clinical outcomes with daptomycin in patients with IE Patients initially treated with 8 mg/kg daptomycin (n=72) had a success rate of 90% overall

9 Daptomycin Daptomycin Salvage therapy for VRE infections other than pneumonia, on a case-by-case basis not effective for the treatment of CAP including infections caused by S. pneumoniae & S. aureus clinical cure rate daptomycin(79.4%) VS ceftriaxone(87.9%) 95% CI diff, -13.8% to -3.2%) Pertel PE, et al.clin Infect Dis. 2008;46(8): Linezolid Documented VISA or VRSA infection Documented MRSA or MRSE infection in a patient with a serious allergy to vancomycin Bacteremia/endocarditis: failure to clear blood cultures after 7-9 days despite vancomycin troughs of mcg/ml Linezolid Pneumonia: worsening infiltrate in a patient with documented MRSA pneumonia after 2-3 days of vancomycin therapy or if the MIC of vancomycin is 1.5 mcg/ml. Documented VRE infection (not colonization)

10 ADD EMPIRIC ANTISTAPHYLOCOCCAL THERAPY IN PRESENCE OF: 2 major risk factors for MRSA ( >7 days in ICU, previous antibiotic exposure, age > 65 yrs, staph nasal carriage, Gram + cocci at gram stain) or severe sepsis Adapted from 1 st line standard therapy: vancomycin LD & MD MSSA Switch to cloxacilin within 48 hrs CULTURE RESPONSE NO STAPH Stop vancomycin Pea F & Viale P. Clin Infect Dis 2006; 42: Pea F & Viale P. Exp Rev Anti Infect Ther 2007; Apr 5: MRSA MIC > 1.5 mg/l MIC < 0.5 mg/l Continue vancomycin and optimize exposure by means of TDM switch to LINEZOLID 600 mg q12h Vancomycin: Adverse Effects Red man syndrome pruritis erythematous rash involving face & neck Proposed mechanism Pseudoallergy Secondary to release of histamine Sivagnanam S,et al. Crit Care 2003; 7: Finch RG,et al. J Antimicrob Chemother 2005; 55(Suppl.S2): ii5 13. Linezolid vs Vancomycin Analysis of Two Double-Blind Studies of Patients With MRSA Nosocomial Pneumonia Clinical Cure Rate: Linezolid vs Vancomycin Survival (Pe ercent of Patie ent) Linezolid( 60 alive, 15 dead) Vancomycin( 54 alive, 31 dead) Time (Days) ITT MRSA(160) P = Wunderink RG,et al. Chest 2003;124; Clinical Cure (percent of Patients) P=0.182 (n=272) Type of Pneumonia P=0.009 (n=123) Wunderink RG,et al. Chest 2003;124;

11 Antihistamine prophylaxis permits rapid vancomycin infusion Results of intravenous antihistamine prophylaxis vs. placebo on the effects of rapid vancomycin infusion Renz,et al.critical Care Medicine 1999;27(9): Vancomycin: Adverse Effects Neutropenia Absolute neutrophil count <1000 cells/mm3 Incidence 2-8% Associated with prolonged therapy (>14 d) Proposed mechanism Immune-mediated destruction of neutrophils Direct suppression of bone marrow Vancomycin: Adverse Effects Ototoxicity Damage to cochlea or auditory nerve Incidence 1-9% True risk low without ototoxic agents Proposed mechanism Affects high frequency sensory hairs in cochlea, then middle and low frequency hairs High-tone deafness occurs before low-tone deafness; permanent hearing loss Pai et al. Ann Pharmacother 2006;40:224-8 Segarra-Newnham et al. Ann Pharmacother 2004;38: Cantu et al. CID 1994;18:533-43, Liu C et al. Antimicrob Agents Chemother 2003;47:3040-5, Brummett et al. Antimicrob Agents Chemother 1989;33:791-6, Waisbren et al. Arch Intern Med 1960;106: Wilhelm et al. Mayo Clinic Proc 1999;74:928-35

12 Vancomycin: Adverse Effects Incidence of vancomycin nephrotoxicity with rising trough levels Nephrotoxicity Incidence 0% to 17% Proposed mechanism in the past manufacturing impurities destruction of glomeruli and necrosis of the proximal tubule due to oxidative stress. Rybak MJ,et al. Am J Health-Syst Pharm. 2009; 66: van Hal SJ,et al. Antimicrob. Agents Chemother. 2013, 57(2):734. Acute & reversible vancomycin nephrotoxicity: case reports Ladino M, et al. JNRT 2008;1(1): 4 10 Vancomycin overuse in Siriraj Hospital prospective observational study inappropriately prescribed 19/222 times (8.6%) inappropriate use was significantly correlated with the type of department Department of Pediatrics, Surgery & Ophthalmology VS. Department of Medicine (p = 0.001) inappropriate use also correlated with topical use (p < 0.001), IV administration (p = 0.012) & no consultation with an ID specialist (p = 0.001) Rattanaumpawan P, et al. J Med Assoc Thai. 2006;89 Suppl 5:S

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