Antimicrobial Handbook 2013

Antimicrobial Handbook 2013 Guidelines, Policies and Treatment Recommendations Content Developed by the Antimicrobial Subcommittee of the Pharmacy & Therapeutics Committee Published by authority of the Medical Advisory Committee Editor Bill Cornish, RPh, BScPhm, ACPR Drug Information Service Department of Pharmacy Associate Editor Sandra A.N. Walker, RPh, BSc, BScPhm, ACPR, PharmD., FCSHP Clinical Coordinator - Infectious Diseases and Antimicrobial Stewardship, Department of Pharmacy Associate Professor (Status), Leslie Dan Faculty of Pharmacy, University of Toronto July 2013 Sunnybrook Health Sciences Centre University of Toronto Toronto, Ontario i

Acknowledgements Development and publication of this handbook was undertaken by the Antimicrobial Subcommittee of the Pharmacy & Therapeutics Committee. The Subcommittee comprises representatives of the Division of Infectious Diseases and the Departments of Microbiology and Pharmacy. Its members include the following individuals: Dr. V. Allen Department of Microbiology and Division of Infectious Diseases W. Cornish Secretary; Pharmacist, Drug Information Dr. N. Daneman Division of Infectious Diseases M. Elligsen Pharmacist, Antimicrobial Stewardship F. Gorenstein Pharmacy Manager, Holland Orthopaedic & Arthritic Centre Dr. S. Mubareka Department of Microbiology and Division of Infectious Diseases L. Palmay Pharmacist, Antimicrobial Stewardship Dr. A. Rachlis Division of Infectious Diseases Dr. A. Simor Chair; Head, Department of Microbiology and Division of Infectious Diseases Dr. S. Walker Pharmacist, Clinical Coordinator - Infectious Diseases and Antimicrobial Stewardship Desktop publishing by Media Source - Graphic Arts. This material has been prepared for use solely at the Sunnybrook Health Sciences Centre (SHSC). SHSC accepts no responsibility for use of this material by any person or institution not associated with the Hospital. Departments of Microbiology and Pharmacy, Sunnybrook Health Sciences Centre. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic, mechanical or otherwise, without permission of the editor. ii

Foreword This Antimicrobial Handbook has been developed by the Antimicrobial Subcommittee of the Pharmacy and Therapeutics Committee, and is intended for use by Attending Physicians, House Staff, Pharmacists and other health care providers at Sunnybrook Health Sciences Centre. It includes practical information about commonly used anti-infective agents and provides suggested guidelines for the management of a variety of infectious diseases. We hope that it addresses frequently asked questions about antimicrobial therapy and serves as a useful aid for the management of hospitalized patients with infections. Your comments regarding the usefulness of this handbook are welcome. Please forward any comments or suggestions to Bill Cornish, Drug Information, Department of Pharmacy, Room EG 03; ext. 4513. E-mail: william.cornish@sunnybrook.ca Dr. A. Simor Head, Department of Microbiology and Division of Infectious Diseases Chair, Antimicrobial Subcommittee July 2013 iii

Page SUBJECT i Title Page ii Acknowledgements iii Foreword iv Table of Contents TABLE OF CONTENTS Microbiology Profiles of Selected Common Pathogens 1 Staphylococcus aureus 2 Streptococcus pneumoniae 2 Enterococcus spp. 3 Pseudomonas aeruginosa 4 Blood Culture Isolates 5 Susceptibility of Blood Culture Isolates, SHSC 6 Susceptibility of Bacterial Isolates, SHSC 7 Susceptibility of Bacterial Isolates, ICUs 8 Antimicrobial Stewardship Policies for Use of Anti-infective Agents 9 Prescribing Restrictions 10 Automatic Substitution Policies 12 Intravenous to Oral Conversion (Step-down Therapy) Treatment Guidelines 14 Clostridium difficile Colitis 15 Febrile Neutropenia 17 Meningitis, Bacterial, Community-acquired 18 Pneumonia, Community-acquired 19 Pneumonia, Hospital-acquired 20 Skin and Skin Structure Infections 21 Urinary Tract Infections, Uncomplicated iv

Drug Use Guidelines 22 Acyclovir and Valacyclovir 24 Aminoglycosides 33 Amphotericin B 35 Ampicillin and Amoxicillin 36 Azithromycin 37 Cefazolin 39 Ceftazidime 40 Ceftriaxone 41 Ciprofloxacin 43 Clindamycin 44 Cloxacillin 45 Co-trimoxazole (TMP/SMX) 50 Fluconazole 51 Levofloxacin 52 Meropenem 54 Metronidazole 55 Penicillin 57 Piperacillin-tazobactam 58 Vancomycin Miscellaneous Guidelines 62 Endocarditis Prophylaxis 66 HIV Post-Exposure Prophylaxis 67 Immunization for Asplenic Patients 69 Penicillin Allergy Recommendations for use of Beta-Lactams 73 Pregnancy and Breastfeeding Safe Use of Anti-infective Agents 91 Renal Insufficiency & Dialysis Drug Dosing Recommendations 105 Surgical Antibiotic Prophylaxis Formulary Anti-infective Agents 122 Systemic Products 131 Ophthalmic / Otic Products 132 Topical / Vaginal Products 134 Cost Comparison for IV and Oral Anti-infective Agents 136 INDEX v

PROFILES OF SELECTED COMMON PATHOGENS Staphylococcus aureus Penicillin-sensitive S. aureus (incidence < 10%) - Drug of choice is penicillin Penicillin-resistant S. aureus (incidence 90%) - Drugs of choice include cloxacillin, cefazolin, cephalexin Methicillin-resistant S. aureus (MRSA) - Incidence < 5% in non-bacteremic, clinically stable patients; 20% in bacteremic patients, including patients who are systemically ill - Resistant to all penicillins, cephalosporins, and carbapenems - Treatment of choice for infection is vancomycin MRSA Colonization & Eradication Patient Selection: - The decision to attempt eradication of MRSA in colonized patients must be individualized - Not all patients are likely to benefit from decolonization, and some may experience adverse reactions - Judicious use of antibiotics, including mupirocin cream, is required in order to avoid development of further MRSA resistance - Infection Prevention & Control can be consulted to assist with decisions regarding management of colonized patients - Eradication is generally not recommended for patients with: active infection treatment with antibiotics chronic skin lesions or ulcers indwelling urinary catheter or other medical device Eradication Regimen: - If a decision is made to attempt to eradicate MRSA, the following regimen is recommended: Chlorhexidine 2% washes once daily x 7 days Rifampin 300 mg PO BID x 7 days Doxycycline 100 mg BID OR Co-trimoxazole DS 1 PO BID x 7 days Mupirocin 2% cream applied to the anterior nares TID x 7 days Don gloves and place 1 cm (1/2 inch) on the tip of a sterile cotton-tipped applicator and apply in one nostril. Using another sterile applicator, repeat the procedure in other nostril. Nostrils should then be pinched together and released repeatedly for about one minute to ensure even application of cream. Follow-up Monitoring: - Follow-up monitoring consists of repeat cultures obtained 7 days following the last day of administration of any of the above oral or topical treatments. 1

Streptococcus pneumoniae Penicillin-sensitive S. pneumoniae ( 85%): - drug of choice is penicillin Penicillin-resistant S. pneumoniae - incidence in Canada (2008) is approximately 16% - initial treatment for meningitis due to these organisms is a combination of ceftriaxone plus vancomycin (see page 17) (vancomycin can be discontinued following confirmation that the organism is sensitive to ceftriaxone) Enterococcus spp. A. Susceptibility Enterococci are intrinsically and predictably resistant to: - cephalosporins, cloxacillin, clindamycin, co-trimoxazole (TMP-SMX), aminoglycosides Agents with activity against Enterococcus include ampicillin, piperacillin-tazobactam, vancomycin (nitrofurantoin for UTI only) Vancomycin-resistant enterococci (VRE): - acquired resistance to vancomycin is increasing - this may be transferable to S. aureus - frequency of VRE increases with increased use of vancomycin (see vancomycin section, page 58, for guidelines on appropriate use) B. Treatment 1) Urinary Tract Infection Treatment: ampicillin 1-2g IV Q6H, or amoxicillin 500 mg po TID Alternatives: vancomycin 1g Q12H, or nitrofurantoin 50-100 mg po QID 2) Bacteremia (without endocarditis) Patients with enterococcal bacteremia should be assessed for possible endocarditis. If present, treat as recommended in Section 3. Treatment: ampicillin 2g IV Q6H ± gentamicin 1mg/kg IV Q8H* Alternative: vancomycin 1g IV Q12H ± gentamicin 1mg/kg IV Q8H* 3) Endocarditis Treatment: ampicillin 2g IV Q4H plus gentamicin 1mg/kg IV Q8H* Alternative: vancomycin 1g IV Q8H plus gentamicin 1mg/kg IV Q8H* * Low-dose gentamicin is appropriate when used for synergistic effect during combination therapy. Once-daily, high-dose regimens against gram positive cocci such as enterococci are not recommended for synergy. (see page 29, section 2). 2

Pseudomonas aeruginosa A. Resistance P. aeruginosa is intrinsically and predictably resistant to: penicillin/ampicillin first/second generation cephalosporins ceftriaxone, cefotaxime erythromycin clindamycin vancomycin co-trimoxazole (TMP/SMX) B. Susceptibility Antimicrobial agents that may be active against P. aeruginosa and may be used to treat infection due to this organism include: aminoglycosides (tobramycin, amikacin) piperacillin/tazobactam ceftazidime meropenem ciprofloxacin (incidence of resistance is 30-40%) Note: prescribing of meropenem and IV ciprofloxacin is restricted (see details, page 9) C. Treatment 1) For uncomplicated P. aeruginosa infections of the urinary tract or skin and skin structure, antimicrobial therapy with a single agent may be used, such as: ciprofloxacin 750 mg po Q12H ceftazidime 2 g IV Q8H tobramycin 7 mg/kg IV Q24H 2) For P. aeruginosa pneumonia or bacteremia or complicated infections, treatment with a combination of antibiotics is generally recommended. Example regimens include: piperacillin-tazobactam 4.5 g IV Q6H plus tobramycin 7 mg/kg IV Q24H or ceftazidime 2 g IV Q8H plus tobramycin 7 mg/kg IV Q24H 3

SUNNYBROOK HEALTH SCIENCES CENTRE BLOOD CULTURE ISOLATES 2012 4 2% Yeast 3% Anaerobes 20% Others 25% Coagulase negative Staphylococci 13% Staphylococcus aureus 27% Coliforms 6% Enterococci 4% Pseudomonas aeruginosa

ANTIMICROBIAL SUSCEPTIBILITY OF BLOOD CULTURE BACTERIAL ISOLATES IN ENTIRE HOSPITAL (% SUSCEPTIBLE) 5 GRAM POSITIVE ORGANISMS PEN CLOX CEF VAN # of isolates S. aureus 0* 87 87 100 109 Coag neg staph 0* 13 13 100 52 GRAM NEGATIVE ORGANISMS AMP CEF CFX GEN TOB SXT CIP TAZ PIP/TAZO MERO # of isolates E.coli 50 84 86 86 85 70 72 86 90 99 182 Klebsiella spp 0 85 90 98 92 90 86 90 91 100 87 Enterobacter spp. 0 0 62 98 95 98 93 62 73 100 40 Other Coliforms 28 28 100 90 90 93 92 100 96 100 39 P. aeruginosa 0 0 0 90 90 0 70 74 76 77 42 AMP=ampicillin; CEF=cefazolin; CFX=ceftriaxone, CIP=ciprofloxacin,CLIN=clindamycin; CLOX=cloxacillin; ERY=erythromycin; GEN=gentamicin; MERO=meropenem; PEN=penicillin; PIP/TAZO=piperacillin/tazobactam; SXT=co-trimoxazole; TOB=tobramycin; TAZ=ceftazidime; VAN=vancomycin * routinely reported as resistant

ANTIMICROBIAL SUSCEPTIBILITY OF BACTERIAL ISOLATES IN ENTIRE HOSPITAL (% SUSCEPTIBLE) 6 GRAM POSITIVE ORGANISMS PEN CLOX CEF CLIN ERY VAN # of isolates S. aureus 0 * 86 86 69 63 100 985 Coag neg staph 0 * 39 39 48 35 100 371 GRAM NEGATIVE ORGANISMS AMP CEF CFX GEN TOB SXT CIP TAZ PIP/TAZO MERO # of isolates E.coli 55 85 90 89 88 75 75 90 88 100 2408 Klebsiella spp 0 88 95 96 95 91 92 95 94 99 738 Enterobacter spp. 0 0 77 99 98 94 95 77 80 98 286 P.mirabilis 83 91 97 95 97 87 85 97 99 99 252 Serratia marcescens 0 0 100 98 93 98 96 100 93 100 95 Other Coliforms 0 1 84 83 86 81 88 84 90 99 250 P. aeruginosa 0 0 0 86 95 0 75 84 80 83 413 AMP=ampicillin; CEF=cefazolin; CFX=ceftriaxone, CIP=ciprofloxacin,CLIN=clindamycin; CLOX=cloxacillin; ERY=erythromycin; GEN=gentamicin; MERO=meropenem; PEN=penicillin; PIP/TAZO=piperacillin/tazobactam; SXT=co-trimoxazole; TOB=tobramycin; TAZ=ceftazidime; VAN=vancomycin * routinely reported as resistant

ANTIMICROBIAL SUSCEPTIBILITY OF BACTERIAL ISOLATES FROM ICUs (CRCU, CVICU, D4ICU, B5ICU, RTBC) (% SUSCEPTIBLE) 7 GRAM POSITIVE ORGANISMS PEN CLOX CEF CLIN ERY VAN # of isolates S. aureus 0* 88 88 79 74 100 178 Coag neg staph 0* 37 37 37 30 100 89 GRAM NEGATIVE ORGANISMS AMP CEF CFX GEN TOB SXT CIP TAZ PIP/TAZO MERO # of isolates E.coli 50 76 86 88 87 77 76 86 76 100 141 Klebsiella spp. 0 79 89 90 88 88 85 89 88 99 82 Enterobacter spp. 0 0 64 97 94 96 93 64 65 97 65 Other Coliforms 24 25 91 91 88 89 87 90 89 98 80 P. aeruginosa 0 0 0 89 93 0 66 72 66 70 107 AMP=ampicillin; CEF=cefazolin; CFX=ceftriaxone, CIP=ciprofloxacin,CLIN=clindamycin; CLOX=cloxacillin; ERY=erythromycin; GEN=gentamicin; MERO=meropenem; PEN=penicillin; PIP/TAZO=piperacillin/tazobactam; SXT=co-trimoxazole; TOB=tobramycin; TAZ=ceftazidime; VAN=vancomycin * routinely reported as resistant

ANTIMICROBIAL SUSCEPTIBILITY OF RESPIRATORY BACTERIAL ISOLATES FROM ICUs (CRCU, CVICU, D4ICU, B5ICU, RTBC) (% SUSCEPTIBLE) 7a a GRAM POSITIVE ORGANISMS PEN CLOX CEF CLIN VAN # of isolates S. aureus 0* 90 90 83 100 110 GRAM NEGATIVE ORGANISMS AMP CEF CFX GEN TOB SXT CIP TAZ PIP/TAZO MERO # of isolates E.coli 50 79 83 75 65 79 79 83 71 100 24 Klebsiella spp. 0 76 94 94 94 94 97 94 92 100 36 Enterobacter spp. 0 0 63 100 100 100 100 63 65 97 37 Other Coliforms 12 15 97 94 89 89 86 97 100 100 34 P. aeruginosa 0 0 0 92 97 0 67 68 64 67 59 AMP=ampicillin; CEF=cefazolin; CFX=ceftriaxone, CIP=ciprofloxacin,CLIN=clindamycin; CLOX=cloxacillin; ERY=erythromycin; GEN=gentamicin; MERO=meropenem; PEN=penicillin;; PIP/TAZO=piperacillin/tazobactam; SXT=co-trimoxazole; TOB=tobramycin; TAZ=ceftazidime; VAN=vancomycin * routinely reported as resistant

ANTIMICROBIAL STEWARDSHIP Antimicrobial stewardship is defined as the limitation of inappropriate antimicrobial use while optimizing antimicrobial selection, dosing, route, and duration of therapy to maximize clinical cure or prevent infection; while limiting unintended consequences, such as the emergence of resistance, adverse drug events, the selection of pathogenic organisms (such as Clostridium difficile) and cost. Sunnybrook s Antimicrobial Stewardship Team (AST) consists of physicians from Infectious Diseases & Microbiology, and Infectious Diseases Pharmacy staff. The activities of the AST focus on optimizing broad-spectrum antibiotic use through a prospective audit and feedback program called Day 3 Reflections. Day 3 Reflections was launched in close collaboration with the level III ICUs in October 2009 with expansion to several medical and surgical services initiated in November 2010. The program involves a formal review of patients who have received 3 or 10 days of a targeted antimicrobial agent. The list of targeted antimicrobial agents for 2012 includes: Carbapenems (meropenem, ertapenem) 3 rd Generation Cephalosporins (ceftriaxone, ceftazidime) Fluoroquinolones (ciprofloxacin, levofloxacin) (IV/PO) Piperacillin-tazobactam Vancomycin (IV) Computer generated progress notes are inserted into the chart of each patient reviewed by the AST and all suggestions for optimization are discussed with the prescribing team. Patients who are being followed by the Infectious Diseases consult service are excluded from the program. Issues to Consider when Prescribing Anti-infective Therapy 1. Does my patient really need to be treated with antibiotics? Treat the patient and not the culture (true infection vs colonization vs contamination). 2. Does my patient really need such a broad-spectrum antibiotic? Make a presumed diagnosis and select empiric management based on the most likely pathogen(s) for that diagnosis. 3. Does my patient really need IV administration of this antibiotic? If the patient is hemodynamically stable, has a functioning gastrointestinal tract, and there is an oral agent with good bioavailability, then use of the oral route is preferred to minimize cost and to avoid IV related complications. 4. Does my patient really need an antibiotic for this long a duration? There are only a few infections that require prolonged therapy (e.g. endocarditis and osteomyelitis). The duration of therapy for other infections should be based on clinical resolution of signs and symptoms. 5. Has my patient changed since yesterday? Re-evaluate your patient daily and ask yourself, is this still the best drug, dosage, and route and is antibiotic therapy still needed? 8

PRESCRIBING RESTRICTIONS DRUG Acyclovir IV Amphotericin B Liposomal (NF) Caspofungin Cefotaxime Colistimethate (NF) Daptomycin (NF) Ertapenem Erythromycin IV Fluconazole IV Ganciclovir Itraconazole Linezolid Meropenem Mupirocin Pentamidine Streptomycin (NF) Ticarcillin-clavulanate (NF) Tigecycline (NF) Voriconazole NF = non-formulary AUTHORIZED SERVICE, INDICATION Critical Care Medicine; Infectious Diseases. Also, Neurology and Neurosurgery may prescribe for herpes encephalitis. Infectious Diseases Infectious Diseases Neonatal ICU Infectious Diseases Infectious Diseases Infectious Diseases Urology may prescribe for prophylaxis prior to transrectal biopsy of the prostate. Obstetrics and Gynecology for PPROM and prevention of GBS disease; Neonatal ICU; GI motility disorders in NPO patients. Critical Care Medicine; Infectious Diseases. Infectious Diseases Infectious Diseases Infectious Diseases Critical Care Medicine; Infectious Diseases For eradication of staphylococcal and MRSA colonization. Nephrology may prescribe for prevention and/or treatment of exit-site infection in peritoneal dialysis patients. Infectious Diseases Infectious Diseases Infectious Diseases for Stenotrophomonas infections Infectious Diseases Infectious Diseases; also Hematology-Oncology (for prophylaxis in patients receiving AML-type chemotherapy) 9

AUTOMATIC SUBSTITUTION POLICIES DOCTOR S ORDER Aminoglycoside Antibiotics Ampicillin Oral Cefazolin Ceftazidime Ceftriaxone Ciprofloxacin IV Clindamycin IV Ear Drops, combination (antibiotic + steroid) Erythromycin oral liquid Fluoroquinolone Eye Drops AUTOMATIC CONVERSION Once-daily therapy (gentamicin or tobramycin 7 mg/kg, or amikacin 15 mg/kg) the prescribed dose will be automatically rounded OFF to the nearest 50 mg. Traditional therapy (gentamicin or tobramycin 2 mg/kg Q8H) the prescribed dose will be automatically rounded UP to the nearest 20 mg. Orders for oral ampicillin Q8H, Q6H, or QID will be automatically converted to amoxicillin PO Q8H. Orders for doses in excess of 3 g per day will be converted to the maximum of 1 g Q8H. Exceptions: Infectious Diseases consultation. A 2 g preop dose is used in surgery. Intrapartum prevention of perinatal group B streptococcal disease in penicillin allergic patients (low risk for anaphylaxis) requires a loading dose of cefazolin 2 g IV, followed by 1 g IV Q8H until delivery. Orders for ceftazidime specifying a dose of less than 2 g be automatically converted to a dose of 2 g at the dosing interval specified in the original order. Exception: dosing must be individualized in renal insufficiency. Orders for doses in excess of 1 g per day will be converted to the maximum of 1 g Q24H. Exceptions: Infectious Diseases consultation. Higher dosages are recommended for endocarditis, meningitis and osteomyelitis (see page 40). Orders for 200 mg IV Q12H in renal insufficiency will be converted to 400 mg IV Q24H. Orders for IV doses in excess of 1800 mg per day will be automatically converted to the standard maximum allowable dosage of 600 mg IV Q8H. Exceptions: Infectious Diseases consultation. 900 mg IV Q8H is recommended for: cerebral toxoplasmosis; pelvic inflammatory disease; postpartum endometritis; intrapartum prevention of perinatal group B streptococcal disease in patients who cannot take penicillin. Orders for combination ear drops containing antibiotics + a corticosteroid (e.g., Cortisporin, Cipro-HC, Garasone ) will be substituted with Ciprodex ear drops at the appropriate dosage. Orders for erythromycin oral liquid 250 mg or 500 mg will be converted to erythromycin ethylsuccinate 400 mg or 800 mg, respectively. Orders for fluoroquinolone eye drops other than moxifloxacin (e.g., ciprofloxacin, gatifloxacin, and ofloxacin eye drops) will be substituted with moxifloxacin (Vigamox ) at the appropriate dosage. 10

AUTOMATIC SUBSTITUTION POLICIES DOCTOR S ORDER Meropenem Metronidazole Mupirocin Nitrofurantoin AUTOMATIC CONVERSION Orders for > 2 g/day will be converted to 500 mg IV Q6H. Exceptions: Infectious Diseases consultation. Meningitis may require 2 g IV Q8H. Orders for > 1 g IV per day will be automatically converted to 500 mg IV Q12H. Exceptions: Brain abscess may require a higher dose; NPO patients with C. difficile colitis may be prescribed 500 mg IV Q8H. Orders for mupirocin (Bactroban ) ointment will be dispensed as the cream formulation. Orders for MacroBID will be automatically converted to nitrofurantoin as indicated in the table. Doctor s Order MacroBID 100 mg BID MacroBID 100 mg Daily or QHS Automatic Conversion Nitrofurantoin 50 mg QID Nitrofurantoin 100 mg Daily or QHS Norfloxacin Nystatin Oral Suspension Oseltamivir Piperacillin- Tazobactam Vaginal Antifungal Products Vancomycin IV Orders for norfloxacin 400 mg po BID will be converted to ciprofloxacin 500 mg po BID. Orders for individual doses < 500,000 Units will be automatically converted to 500,000 Units. Exception: Neonatal Intensive Care Unit. Orders for treatment of influenza will automatically expire after a total of 5 days or therapy. Orders in patients with renal insufficiency for a reduced dose of 2.25 g IV Q6H or Q8H will be automatically converted to 3.375 g IV Q8H or Q12H, respectively. Non-pregnant patients: Orders for any antifungal vaginal inserts will be converted to Canesten 3 Insert Combipak (clotrimazole 200 mg vaginal tablet QHS and topical cream BID for 3 days). Orders for any antifungal vaginal cream will be converted to clotrimazole 2% vaginal cream (Canesten 3 Cream) given QHS for 3 days. Exception: Gynecology may prescribe nystatin vaginal products for resistant candida infection. Pregnant patients: Orders for vaginal antifungal will be converted to miconazole 2% vaginal cream (Monistat 7 Cream) given QHS for 7 days. Orders for irregular doses of vancomycin will be automatically converted to the nearest standard dose (multiple of 250 mg). Example: order for vancomycin 1.2 g Q12H would be converted to 1.25 g Q12H. 11

INTRAVENOUS to ORAL CONVERSION (step-down) Considerable evidence has accumulated indicating that early conversion from intravenous (IV) to oral antibiotic therapy is effective for a variety of infections, including those involving the urinary and respiratory tracts, andskin and soft tissues. This is possible because of the excellent bioavailability of many of the oral antibiotics now available. An early conversion from IV to oral antibiotic therapy in selected patients is an effective way of achieving cost savings in hospital (drug costs and nursing/pharmacy labour costs) while maintaining quality patient care. The switch to oral therapy, however, must be individualized based upon the patient s clinical status. The Medical Advisory Committee has approved the following general guidelines for conversion from IV to oral antibiotic therapy as recommended by the Antimicrobial Subcommittee of the P & T Committee. CRITERIA FOR CONVERSION FROM IV TO ORAL THERAPY The patient has received 48 hours of IV antibiotics, appears to be improving clinically, and has been afebrile for at least 24 hours. The patient is able to take medications orally and there is no evidence of malabsorption. The patient is not being treated for endocarditis, CNS infection, bone or joint infection, bacteremia, or abscess. The patient does not have febrile neutropenia. Examples of IV antibiotics which are available as a well-absorbed oral entity are listed in the Table, page 13. Note, however, that physicians converting from IV to oral therapy should not be limited by those examples. Other conversions may also be appropriate (e.g., from IV aminoglycoside or IV 3rd-generation cephalosporin to oral ciprofloxacin). PHARMACIST-INITIATED AUTOMATIC CONVERSION PROGRAM The Medical Advisory Committee has approved an automatic conversion program whereby the pharmacist will monitor patients receiving selected IV antibiotics (see Table, page 13), determine their eligibility for oral treatment, and initiate where appropriate the conversion from IV to oral therapy. The criteria for the pharmacist-initiated automatic conversion program include those listed above, plus the following: the patient is receiving an IV antibiotic listed in the Table, page 13 the patient is not located in an intensive care unit clinical improvement has been documented by the physician in the progress notes the bacterial pathogen is not known to be resistant to the antibiotic being used. 12

IV to ORAL CONVERSION: Some examples 13 IV Drug 10-day Cost 1 Oral Drug 10-day Cost 1 Savings/10 days Ampicillin 2 g Q6H $100 Amoxicillin 500 mg TID $2 $98 Azithromycin 500 mg Q24H $100 Azithromycin 250-500 mg Daily $25-50 $50-75 Cefazolin 1 g Q8H $90 Cephalexin 500 mg QID $7 $83 Ciprofloxacin 400 mg Q12H $100 Ciprofloxacin 500 mg BID $25 $75 Clindamycin 600 mg Q8H $100 Clindamycin 450 mg QID $50 $50 Co-trimoxazole 160/800 mg Q12H $150 Co-trimoxazole 1 DS BID $2 $148 Fluconazole 400 mg Q24H $220 Fluconazole 400 mg daily $80 $140 Levofloxacin 750 mg Q24H $310 Levofloxacin 750 mg Daily $35 $275 Linezolid 600 mg Q12H 2 $1,900 Linezolid 600 mg BID $1,500 $400 Metronidazole 500 mg Q12H $30 Metronidazole 500 mg BID $1 $29 Voriconazole 200 mg Q12H 3 $2,800 Voriconazole 200 mg BID $960 $1,840 1 Cost of IV therapy includes cost of one minibag ($1.00) per dose. 2 Prescribing of linezolid is restricted to Infectious Diseases. 3 Prescribing of voriconazole is restricted to Infectious Diseases and Haematology-Oncology (see page 9)

Clostridium difficile Colitis C. difficile-associated colitis may develop following disruption of normal bacterial bowel flora, and this normally occurs during or following antimicrobial therapy (within 8 weeks). In addition to diarrhea, the organism can produce severe complications (systemic inflammatory response syndrome, shock, toxic megacolon, bowel perforation) and death (attributable mortality rate > 5%). About 25% of patients experience a relapse within 8 weeks. ALL cases should be managed as follows: Discontinue inciting antibiotics, when possible. Do not start new exacerbating antibiotics, when possible. Avoid antimotility agents and opioids. Treatment depends on disease severity (see table). Severity of Disease Treatment Recommendations Moderate to Severe, Uncomplicated Vancomycin C. difficile in the intensive care unit, 125 mg PO OR Q6H x 10-14 days Presence of pseudomembranes, OR 2 of the following features: Age > 60 years Temperature > 38.3 C WBC > 15,000 x 10 6 /L Albumin 30 g/l Acute renal failure Altered mental status Severe & Complicated Systemic inflammatory response syndrome (SIRS) or sepsis Ileus or toxic megacolon Mild Meeting none of the above criteria Vancomycin 125 mg PO Q6H x 10-14 days Consider ID consult Consider early consultation with General Surgery Consider adding IV metronidazole 500 mg Q8H Consider adding rectal vancomycin (contact Pharmacy) Metronidazole 500 mg PO Q8H x 10-14 days If not responding, consult ID. Vancomycin given IV is ineffective for C. difficile colitis Intravenous metronidazole is an alternative for patients that are NPO Treatment of recurrent disease Consult Infectious Diseases 14

FEBRILE NEUTROPENIA: Empiric Management Temp 38.3 C and ANC 0.5 x 10 9 /L Patient ADMITTED to hospital with FN Respiratory Focus Likely or Confirmed No Patient DEVELOPED FN while in hospital OR was hospitalized for longer than 24 hours in the past month. Yes Begin Piperacillin/tazobactam 4.5g IV q6h + Tobramycin 7mg/kg IVq24h and consult Infectious Diseases. Cefazolin 1g IV q8h + Tobramycin 7mg/kg IVq24h y Regimen provides broad coverage of gram positive and gram negative aerobic bacteria. y BUT, a broad search for a focus of infection must be undertaken in all patients. Some of the infectious foci warranting consideration of expanded coverage include intra-abdominal infection, and colonization with MRSA. Alternate antimicrobial therapy may be indicated in patients with pre-existing renal impairment or those with a severe beta-lactam allergy (e.g. anaphylaxis, urticaria). If uncertain about appropriate empiric treatment for an individual patient, please consider infectious diseases consultation. RE-EVALUATE THERAPY DAY 3 Afebrile (temp < 38.3 C) Persistent fever (temp 38.3 C) See Next Page No Etiology Etiology Low risk (clinically well, no mucositis, non-hematologic malignancy, ANC likely to recover within 1 week) Consider oral antibiotics Options: ciprofloxacin + either cephalexin or amoxicillin/clavulanic acid; if patient has severe beta-lactam allergy then use ciprofloxacin + clindamycin High risk (mucositis, leukemia, bone marrow transplant, severe neutropenia (ANC 0.1) and unlikely to recover within 1 week, or previous history of prolonged neutropenia) Continue Cefazolin + Tobramycin with consideration to convert to oral antibiotics if clinically well. If ANC < 0.5: Treat for a maximum total duration of 2 weeks. If ANC 0.5 x 2 consecutuve days and patient afebrile x 48 hours: Discontinue antibiotics. Modify antibiotics, if necessary, to optimize treatment, while continuing broad spectrum coverage. If ANC < 0.5: Treat for a total duration that is appropriate for type /site of infection and clinical status of the patient. However, ensure that broad spectrum treatment for febrile neutropenia is maintained for a maximum total duration of 2 weeks. If ANC 0.5 x 2 consecutive days: Narrow antibiotic selection to target the specific diagnosed infection. Total duration of therapy should be based on site/ type of infection and clinical status of patient. 15

Continued from previous page Persistent fever day 3 (temp 38.3 C) Discontinue Cefazolin and start Piperacillin/tazobactam 4.5g IV q6h Continue Tobramycin 7mg/kg iv q24h REASSESS DAY 4-5 Afebrile and no new infectious issues (clinically stable) Febrile (Temp 38.3 C) Consult Infectious Diseases Continue Piperacillin/tazobactam and Tobramycin If ANC < 0.5: Treat for a maximum total duration of 2 weeks, in the absence of a documented infection that may require a longer duration. If ANC 0.5 x 2 consecutive days and patient afebrile x 48 hours: Discontinue antibiotics, in the absence of a documented infection that may require a longer duration. Day 7-10 with persistent fever and unresolving neutropenia (ANC < 0.5 x 10 9 /L) If ID has not been consulted, then obtain ID consult for antifungal therapy. Consider CT chest and abdomen to evaluate for invasive fungal infection. 16

MENINGITIS, BACTERIAL, COMMUNITY-ACQUIRED Empiric Treatment The most common pathogens causing adult bacterial meningitis include Streptococcus pneumoniae and Neisseria meningitidis. Listeria monocytogenes should also be considered in the immunocompromised, pregnant or elderly patient. Initiation of empiric therapy for meningitis should never be delayed while awaiting diagnostic procedures (e.g., LP, CT). Empiric treatment should include coverage for penicillin-resistant S. pneumoniae (PRSP) if local prevalence is >5%. In Canada, the prevalence of PRSP is approximately 16%. First-line Empiric Therapy: Ceftriaxone 2 g IV Q12H plus Vancomycin 1 g IV Q8H (target trough levels 15-20 mg/l; see p.58) Alternative for history of life-threatening allergy to penicillins or cephalosporins: Chloramphenicol 1 g IV Q6H plus Vancomycin 1 g IV Q8H (target trough levels 15-20 mg/l; see p.58) Change to more specific therapy once the pathogen is identified and susceptibility results are available. In patients with a serious allergy to a beta-lactam antibiotic, consider desensitization once specific pathogen identified (to avoid prolonged use of Chloramphenicol). Targeted Treatment by Organism Organism First-Line Alternative S. pneumoniae Penicillin-sensitive Penicillin G 4 MU IV Q4H Ceftriaxone 2 g IV Q12H (MIC 0.1mg/L) Intermediate penicillin Ceftriaxone 2g IV Q12H resistance (MIC = 0.1-1.0 mg/l) Meropenem 2 g IV Q8H High-level penicillin Vancomycin 1g IV Q8H Consult Infectious resistance plus Diseases (MIC 2 mg/l) Ceftriaxone 2 g IV Q12H N. meningitidis MIC < 0.1 mg/l Penicillin G 4 MU IV Q4H Ceftriaxone 2 g IV Q12H MIC = 0.1-1.0 mg/l Ceftriaxone 2 g IV Q12H Chloramphenicol 1 g IV Q6H L. monocytogenes Ampicillin 2g IV Q4H Co-trimoxazole Cephalosporins ± (TMP/SMX) are not effective Gentamicin IV 15-20 mg/kg of TMP 1.0-1.5 mg/kg IV Q8H per day divided Q6-8H (see page 45) 17

PNEUMONIA, COMMUNITY-ACQUIRED Guidelines for Empiric Treatment The approach to the management of community-acquired pneumonia (CAP) is dependent on the severity of presentation and individual patient factors (i.e. presence of structural lung disease). The following guidelines are for the empiric management of CAP in adults who require hospitalization and are not significantly immunocompromised. Antimicrobial therapy should be modified based upon Gram stain and culture results and clinical response. Organisms: Streptococcus pneumoniae Haemophilus influenzae Chlamydia pneumoniae Mycoplasma pneumoniae Treatment: Choose one of the two options below Note: If IV route used initially, consider conversion to oral therapy (see guidelines, page 12). Azithromycin 500 mg IV Q24H OR 500 mg po day 1, then 250-500 mg po Q24H PLUS Ceftriaxone 1 g IV Q24H Options for oral step-down therapy from ceftriaxone include: Cefuroxime axetil 500 mg po BID Amoxicillin/calvulanic acid 875 mg po BID or 500 mg po TID Cefixime 400 mg po daily OR Levofloxacin 750 mg IV or PO Q24H (reduce dose in renal insufficiency; see page 51) Suspected Macroaspiration: Ceftriaxone has adequate oral anaerobic coverage and may be used alone. In the setting of severe anaerobic pulmonary infection (e.g. lung abscess, empyema) clindamycin may be added. 18

PNEUMONIA, HOSPITAL-ACQUIRED Hospital-acquired pneumonia (HAP) is defined as pneumonia occurring 48 hours or greater after admission and excludes any infection that may be incubating at the time of admission. The management of HAP is dependent on the severity of illness, time of onset from hospital admission, and individual patient risk factors. The following guidelines are intended for the empiric management of HAP in immunocompetent adults without ventilator-associated pneumonia. Therapy should be tailored once culture & sensitivity results or other diagnostic information becomes available. Usual organisms: Aerobic gram-negative rods (Klebsiella, Enterobacter, Serratia, E. coli, Proteus, Haemophilus influenzae, Pseudomonas) and Staphylococcus aureus Note: Pseudomonas is an infrequent cause of pneumonia in non-critical care areas at SHSC. 1. Initial Treatment: most patients Ceftriaxone 1 g IV once daily 2. Initial Treatment: patients with history of life-threatening allergy to a penicillin Levofloxacin 750 mg PO/IV once daily 3. Step-down Therapy (IV to PO conversion): Cefuroxime axetil 500 mg PO BID OR Levofloxacin 750 mg PO once daily Ceftriaxone use is contraindicated only in patients who have a history of life-threatening allergic reaction to a penicillin. Refer to Guidelines on Penicillin Allergy and Use of Beta-Lactam Antibiotics, page 69. 19

SKIN AND SKIN STRUCTURE INFECTIONS REQUIRING HOSPITALIZATION Guidelines for Empiric Treatment A. Uncomplicated Cellulitis or Erysipelas usually caused by S. aureus or Group A Streptococci streptococcal and staphylococcal cellulitis are clinically indistinguishable; therefore, antistaphylococcal agents are required first-line monotherapy: Cloxacillin 2 g IV Q4-6H or Cefazolin 1 g IV Q8H second-line monotherapy (if allergic or intolerant to above) Vancomycin 1 g IV Q12H or Clindamycin 600 mg IV Q8H or 450 mg PO QID B. Diabetic Foot Infection note: patients with severe infections should be referred to Infectious Diseases often polymicrobic; requires broad spectrum coverage (Gram +ve, Gram -ve, anaerobes) combination therapy: Clindamycin 600 mg IV Q8H or 450 mg PO QID plus Ciprofloxacin 750 mg po Q12H or Co-trimoxazole (TMP/SMX) 10 mg/kg/day (of TMP component) PO or IV in 2-4 divided doses. C. Necrotizing Fasciitis caused by Group A streptococci or mixed aerobic/anaerobic infection combination therapy: Penicillin G 4 MU IV Q4H plus Clindamycin 600 mg IV Q8H for initial 3-5 days Intravenous immune globulin (IVIg) should be administered in a dose of 1 g/kg/day on 2 consecutive days to patients with both necrotizing fasciitis plus streptococcal toxic-shock syndrome (STSS) and those admitted to ICU with necrotizing fasciitis +/- STSS - Detailed information on IVIg is available on SunnyNet (search using keyword IVIg ) - IVIg is prepared and issued by the Blood Bank (requisition required) 20

URINARY TRACT INFECTIONS, UNCOMPLICATED Note: these guidelines are not applicable to complicated UTI s. A. Usual Organisms: E. coli, K. pneumoniae, P. mirabilis, S. saprophyticus, Enterococcus spp. B. Empiric Treatment According to Diagnosis 1) Asymptomatic Bacteriuria Routine screening and/or treatment of asymptomatic bacteriuria are generally not indicated, except in the following situations: during pregnancy prior to urologic surgery 2) Acute Cystitis in Non-Pregnant Women Empiric Therapy: Co-trimoxazole (TMP/SMX) 2 tabs (or 1 DS tab) po Q12H for 3 days or Ciprofloxacin 500mg po Q12H for 3 days 3) Acute Cystitis in Pregnant Women First-line Options Cephalexin 250-500 mg po QID x 7 days Amoxicillin 500 mg po TID x 7 days (use only after susceptibility is confirmed) *Nitrofutantoin 50-100 mg po QID x 5 days Second-line Options *Co-trimoxazole (TMP/SMX) 2 tabs (or 1 DS tab) po BID x 3 days (Consider 7 days for recurrence or relapse) *Trimethoprim 200 mg po once daily x 3 days (Consider 7 days for recurrence or relapse) *Refer to page 73 for safety of anti-infective agents in pregnancy and breastfeeding. 4) Acute Pyelonephritis Inpatient Empiric Therapy: Ampicillin 2g IV Q6H plus Gentamicin 7mg/kg IV Q24H* * Step down to appropriate oral antibiotics when patient afebrile and hemodynamically stable and C&S available) Outpatient Empiric Therapy: Ciprofloxacin 500mg po Q12H for 14 days or Co-trimoxazole (TMP/SMX) 2 tabs (or 1 DS tab) po Q12H for 14 days 21

ACYCLOVIR & VALACYCLOVIR: Guidelines for Use Prescribing of IV acyclovir is Restricted to Infectious Diseases 1. Clinical Uses Herpes simplex virus (HSV) infections Varicella zoster virus (VZV) infections, including varicella and herpes zoster 2. Precautions Acyclovir-resistant HSV: consult Infectious Diseases (prescribing of ganciclovir and foscarnet is restricted) Dosage reductions are required in moderate to severe renal insufficiency (see table, p. 23) Pregnancy and breastfeeding for safety information, see pg 73 3. Adverse Effects Renal failure (crystalline nephropathy) can develop, usually with IV but may occur with PO therapy Risk factors include: dehydration; pre-existing renal impairment; rapid bolus injection of high doses CNS toxicity (malaise, lethargy, confusion, delirium) usually in presence of drug accumulation that results in high serum levels, often due to failure to reduce dose in renal insufficiency Nausea and vomiting Phlebitis at site of IV infusion 4. Dosage in Normal Renal Function Type of Infection and Immune Status of Patient Dosage Recommendations (normal renal function) IV Acyclovir ORAL Acyclovir ORAL Valacyclovir HSV mucocutaneous infection in immunocompetent patient 5 mg/kg Q8H 400 mg Q4H x 5/day ( low-dose ) 1 g Q12H HSV mucocutaneous infection in immunocompromised patient 5 mg/kg Q8H 400 mg Q4H x 5/day ( low-dose ) 1 g Q12H HSV encephalitis 10-15 mg/kg Q8H Not applicable Not applicable VZV infection regardless of immune status 10-15 mg/kg Q8H 800 mg Q4H x 5/day ( high-dose ) 1 g Q8H 22

5. Dosage in Renal Insufficiency: Creatinine Clearance (ml/min) 30 to 49 10 to 29 < 10 (ESRD; PD) Hemodialysis (HD) IV Acyclovir Usual dose Q12H Usual dose Q24H 50 % of usual dose Q24H* 50 % of usual dose Q24H* On dialysis days, give daily dose towards the end of HD. On other days, give dose at same time of day. Dosage Recommendations ORAL Acyclovir Usual dosage Max. 2400 mg/day (800 mg Q8H) Max. 1600 mg/day* (800 mg Q12H) Max. 1600 mg/day* (800 mg Q12H) On dialysis days, give one of the doses after HD ORAL Valacyclovir Max. 2 g per day (1 g Q12H) Max. 1.5 g per day (500 mg Q8H) Max. 1 g Q24H* Max. 1 g Q24H* On dialysis days, give daily dose after HD CRRT Usual dose Q12H Use IV acyclovir Use IV acyclovir * Monitor for CNS toxicity 23

AMINOGLYCOSIDES: Guidelines for Use OUTPATIENT AMINOGLYCOSIDE THERAPY IS DISCOURAGED Based on advice from the Antimicrobial Subcommittee, the Pharmacy & Therapeutics Committee has actively discouraged the practice of discharging SHSC inpatients for the purpose of continuing aminoglycoside treatment at home. Specifically, SHSC inpatients receiving aminoglycoside therapy should not be discharged with the intent of continuing aminoglycoside treatment at home for a period exceeding 3 days, on the basis that the safe management of such treatment (monitoring of renal function, drug levels, and ototoxicity) cannot be ensured. Home aminoglycoside therapy has been proven to pose a serious risk management issue. DOSING TOOLS & CALCULATORS (ONLINE) For dosing tools and calculators, go to Sunnynet, Pharmacy page, click button Alphabetical Index and click on link Aminoglycosides initial dosing recommendations. Parameters calculated include: creatinine clearance, ideal body weight, adjusted body weight, dosing weight, and recommended dose (rounded off as per policy). A. INDICATIONS FOR SPECIFIC AMINOGLYCOSIDES The Formulary aminoglycosides are gentamicin, tobramycin, and amikacin. Indications for their use are as follows: Gentamicin Treatment of infections due to Gram-negative aerobic bacilli (exception: Pseudomonas aeruginosa). Bacterial endocarditis in combination with other agents Surgical prophylaxis in combination with other agents (see page 105) Tobramycin Reserved for treatment of infections known or suspected to be caused by Pseudomonas aeruginosa which may be more likely to occur in patients in intensive care units and those with neutropenia. Use of tobramycin is appropriate in the following situations: i. Documented P. aeruginosa infections (C&S results within the past 7 days) ii. Neutropenia (ANC < 0.5 x 10 9 /L or, if differential not available, WBC < 1.0 x 10 9 /L) iii. Nephrology Service/Consultation (tobramycin may cause less vestibular dysfunction than gentamicin in dialysis patients) Amikacin Reserved for treatment of infections caused by organisms with documented resistance to gentamicin and tobramycin. 24

B. ONCE-DAILY AMINOGLYCOSIDE (ODA) THERAPY Aminoglycosides should generally be prescribed and administered as a single daily dose in most clinical situations according to the SHSC Once-Daily Aminoglycoside Program described below. 1. Rationale for Once-Daily Aminoglycoside (ODA) Therapy Administering aminoglycosides in a single, large dose once daily has several advantages: more rapid bactericidal activity convenience reduced costs for preparation, administration, monitoring 2. Patient Selection for ODA Therapy Once-daily therapy is recommended for treatment of most infection in most patient, with the following exceptions. Traditional multiple daily dosing of aminoglycosides is recommended in the following circumstances, based on lack of published experience with once-daily therapy. See page 29 for guidelines, Septic shock (during initial hemodynamic instability) Renal impairment (estimated creatinine clearance < 40 ml/min) Ascites Burns Endocarditis Meningitis Osteomyelitis Pregnancy Surgical prophylaxis Synergistic therapy (with beta-lactam or vancomycin for enterococci) 3. Initial Dosage for ODA Therapy For dosing tools and calculators, go to Sunnynet, Pharmacy page, click button Alphabetical Index and click on link Aminoglycosides initial dosing recommendations. Parameters calculated include: creatinine clearance, ideal body weight, adjusted body weight, dosing weight, and recommended dose (rounded off as per policy). a) Non-obese Patients Gentamicin - 7 mg/kg total body weight once daily Tobramycin - 7 mg/kg total body weight once daily Amikacin - 15 mg/kg total body weight once daily Dose should be rounded off to nearest 50 mg. If not, pharmacy will automatically convert to nearest 50 mg. 25

b) Obese Patients Dosing based on an adjusted bodyweight, calculated as follows: (i) Determine the patient s actual bodyweight in kilograms (ii) Determine patient s ideal bodyweight (IBW): IBW (male) = 50.0 kg + 2.3 kg (each inch > 5 feet) IBW (female) = 45.5 kg + 2.3 kg (each inch > 5 feet) (1 inch = 2.5 cm) (iii) If patient s weight is 30% above their IBW, then patient is obese and adjusted body weight should be used for dosing. (iv) Adjusted bodyweight (ABW): use dosing tool on Sunnynet or equation below ABW = IBW + 0.4 (actual bodyweight - IBW) c) Initial Schedule Q24H for estimated CrCl 60 ml/min Q36H for estimated CrCl = 40-59 ml/min Estimating CrCl (ml/min): Use formula below, or use tools on Sunnynet (see instructions, page 25, section 3). CrCl(Male) = (140 - age)(actual body wt.kg) x 60 sec/min 50 x Serum Creatinine (µmol/l) CrCl(Female) = 0.85 x CrCl (Male) 4. Monitoring of ODA Therapy a) Renal Function and Nephrotoxicity BUN, creatinine (scr) prior to treatment and twice weekly. If scr rises by 25 mmol/l or by 25% from baseline, reassess need for aminoglycoside. Obtain repeat peak and 8-12h levels at least weekly during therapy. Elevated trough levels are associated with nephrotoxicity (for target ODA trough levels, see table, p. 27). b) Ototoxicity Aminoglycoside therapy may adversely affect cochlear and/or vestibular function. Ototoxicity is not associated with either peak or trough aminoglycoside levels. In order to reduce the risk of ototoxicity, the Medical Advisory Committee has approved a protocol to facilitate monitoring of hearing and balance in patients at the Sunnybrook campus who are alert and deemed to be at high risk for aminoglycoside ototoxicity (testing is currently not available at Holland Orthopaedic & Arthritic Centre). The algorithm on page 31 details the procedure for arranging cochlear and vestibular testing. 26

c) Drug Levels (i) Initial levels Obtain peak level following first dose. Peak levels should be drawn 30 minutes after the completion of the infusion. Obtain a second level 8-12 hours after the first dose. (ii) Further levels Obtain a peak level and 8-12 hour post-dose level on day 7 at the latest and then weekly thereafter. Following a change in dose or frequency, one set of levels (peak and 8 to 12 hr post-dose) may be obtained to document achievement of desired level range. (iii) Target blood levels for ODA Attainment of the target levels in the table below is recommended for all infections except: (1) urinary tract infection; (2) mycobacterial infections being treated with amikacin. Aminoglycoside Desired Peak Desired Trough* Gentamicin 20 mg/l < 0.5 mg/l Tobramycin 20 mg/l < 0.5 mg/l Amikacin 40 mg/l < 1.0 mg/l * Desired Trough levels are for use by pharmacist for avoidance of nephrotoxicity 5. Dosage Adjustment for ODA (Once-Daily Aminoglycoside) Therapy Please consult a pharmacist to determine the optimal dosage regimen to achieve the desired ODA blood levels. a) Dose Amount (based upon peak level) If peak level is less than desired, increase the dose by proportion. For example, if gentamicin 350 mg results in a peak level of 15 mg/l, then 450 mg should yield a peak level of close to 20 mg/l. 27

b) Dosing Interval (based on nomogram) The appropriateness of a Q24H dosing frequency will be assessed by plotting the exact time and value of the 8 to 12 hr post-dose level as instructed on the nomogram below. Amikacin level must be halved prior to using nomogram. Using an object with a right angle at the corner, place it on the nomogram such that the top edge runs horizontally to intersect the y-axis at the value of the 8 to 12 hr post-dose level, and the right edge runs vertically down to intersect the x-axis at the exact time the level was taken. The right upper corner will then fall into one of 5 regions, dictating these responses: - below nomogram (< 2 mg/l) --> give dose once daily - Q24H, Q36H, or Q48H region --> give dose at indicated interval - above nomogram --> discontinue ODA and consult pharmacist (X 2529) for advice. 28

C. TRADITIONAL Multiple Daily Dose (MDD) THERAPY 1. Initial Dosage for Treatment of Gram Negative Bacterial Infections In non-obese patients, the dose is based on total body weight. In obese patients (actual weight > 30% above ideal body weight), the dose is based on an adjusted body weight (ABW) To determine whether patient is obese, follow these steps: Determine actual weight (kg) Calculate ideal body weight (IBW) as follows: - Male IBW = 50 kg + 2.3 kg (each inch > 5 feet) - Female IBW = 45.5 kg + 2.3 kg (each inch > 5 feet) (1 inch = 2.5 cm) Perform the following calculation: (Actual weight IBW) = Z IBW If the value of Z above is 0.3, then patient is obese To determine adjusted body weight, perform the following calculation: - Adjusted body weight = IBW + 0.4 x (Actual weight - IBW) The initial dosage according to renal function is indicated in the table below. Aminoglycoside Creatinine Clearance (ml/min) Dosage Round up to nearest 20 mg for gentamicin / tobramycin * Gentamicin or Tobramycin 70 2 mg/kg Q8H 40-69 2 mg/kg Q12H < 40 2 mg/kg x 1 dose and consult pharmacy 70 8 mg/kg Q12H Amikacin 40-69 8 mg/kg Q12H < 40 8 mg/kg x 1 dose and consult pharmacy * If dose of gentamicin or tobramycin is not rounded up to nearest 20mg Pharmacy will automatically do so (MAC approved auto-sub policy) 2. Dosage of Gentamicin for Synergy with a Beta-lactam or Vancomycin When gentamicin is used in the setting of endocarditis for synergy with a beta-lactam or vancomycin against enterococcus, staphylococcus or streptococcus, use 1mg/kg dosing at interval determined by creatinine clearance and aim for a target peak of 3-5 mg/l and trough < 2 mg/l. 29