Stoplight-Guidelines-Antimicrobial-Use

Appendix 1

ANTIMICROBIAL STEWARDSHIP GUIDELINES FOR ANTIMICROBIAL USE

The Stoplight Formulary System was designed to preserve certain antimicrobials and/or provide alerts for adverse effects. Contained in this document are guidelines for appropriate use and safety precautions for the yellow and red antimicrobials.

Spectrum of Activity* - the listed microorganism are what is expected coverage based on intrinsic properties of the antimicrobial. For specific sensitivities in your areas please see your local antibiograms.

For safety of antimicrobials in pregnancy/breastfeeding or for appropriate use and dosing in pediatrics please refer to the IWK Spectrum app. This is available for free for iPhone and Android devices

Contents Amikacin ...... 4 Amoxicillin-Clavulanate ...... 5 Amphotericin B deoxycholate ...... 6 Amphotericin B Liposomal (Ambisome) ...... 7 Azithromycin ...... 8 Caspofungin ...... 9 Cefepime ...... 10 Cefixime ...... 11 Cefotaxime...... 12 Cefoxitin ...... 13 Ceftazidime ...... 14 Ceftolozane-Tazobactam ...... 15 Ceftriaxone ...... 16 Cephalexin ...... 17 Cidofovir ...... 18 Ciprofloxacin ...... 19 Clarithromycin ...... 20 Clindamycin ...... 21 Colistin ...... 22 Dapsone ...... 23 Daptomycin ...... 24 Ertapenem ...... 25 Erythromycin ...... 26 Fidaxomicin...... 27 Fosfomycin ...... 28 Ganciclovir ...... 29 Gentamicin ...... 30 Imipenem and cilastatin...... 31 Levofloxacin ...... 32 Linezolid ...... 33 Meropenem ...... 34 Neomycin ...... 35 Oseltamivir ...... 36

Pentamidine ...... 37 Piperacillin-Tazobactam ...... 38 Pyrimethamine ...... 39 Tigecycline ...... 40 Tobramycin ...... 41 Trimethoprim ...... 42 Trimethoprim-sulfamethoxazole (co-trimoxazole) ...... 43 Valganciclovir ...... 44 Vancomycin ...... 45 Voriconazole ...... 46

Amikacin Spectrum of Activity* Gram-negative microorganisms, including Pseudomonas

Mycobacteria

Indications Treatment of Gram negatives resistant to other antimicrobials

Treatment of Mycobacterium tuberculosis (TB) and nontuberculous mycobacterial infections (such as M. avium complex (MAC), M. abscessus) in which amikacin is indicated because of lack of response, resistance or adverse reactions to other treatments

Not indicated Anaerobic bacteria are not susceptible to aminoglycosides

Safety Considerations  See aminoglycoside guidelines in handbook  Cranial nerve VIII toxicity: cochlear and vestibular. Audiometry monitoring is recommended for courses longer than 2 weeks.  Nephrotoxicity: increased risk in patients with renal dysfunction, advanced age, dehydration, prolonged therapy, concomitant nephrotoxins  Therapeutic drug monitoring is recommended  Neuromuscular blockade and respiratory paralysis are rare, especially when used concomitantly with anesthetic agents or neuromuscular blockers or in patients with myasthenia gravis or parkinsonism

Renal Dosing Dose adjustments required for renal impairment

Other Considerations

Amoxicillin-Clavulanate Spectrum of Activity* Broad oral antibiotic with activity against Gram-positive microorganisms, including Staphylococcus aureus (MSSA), many Gram-negatives (not Pseudomonas), and anaerobes including Bacteroides.

Indications Primary: Polymicrobial infections with no other oral therapeutic options either alone or in combination.

Infections with microorganisms resistant to first line agents.

Bite prophylaxis (when indicated) or bite infections.

Not indicated

Safety Considerations  Diarrhea is common, less likely with twice daily regimen. C. difficile risk  Hepatotoxicity secondary to clavulanate is rare and usually mild. Renal Dosing Dose adjustments required for renal impairment

Other Considerations

Amphotericin B deoxycholate

Spectrum of Activity* Cryptococcus neoformans Mucormycosis (Mucor, Rhizomucor, Rhizopus) Aspergillus sp. (except A. terreus) Candida sp. (except C. lusitaniae) Blastomyces dermatitidis, Coccidioides, Histoplasma capsulatum, Sporothrix schenckii

Indications Primary:  Primarily used for compounding  Preferred over other amphotericin formulations for neonates

Not indicated

Safety Considerations  Nephrotoxicity, avoid concomitant nephrotoxins  Electrolyte abnormalities, such as hypokalemia, hypomagnesemia, and hyperchloremic acidosis.  Monitor creatinine, potassium and magnesium regularly  Infusion reactions: fever, chills, rigors, chest pain, dyspnea, hypoxia, abdominal, leg, or back pain, flushing, and urticaria. Generally, respond to therapy with diphenhydramine and brief interruption of the infusion.

Renal Dosing Caution: Amphotericin B deoxycholate is more nephrotoxic than the lipid-based formulations of amphotericin B. Can give pre and post infusion of 500mL saline if clinical status allows.

Other Considerations  If fever, chills, headache, nausea, vomiting, myalgias, can premedicate 30 minutes before with acetaminophen 650 mg po, hydrocortisone 25-50 mg IV, and/or diphenhydramine 25-50 mg po/ IV.  Severe chills, rigors (refractory to hydrocortisone): meperidine 25-50 mg IV  No need for test dose  Phlebitis: use central line or rotate peripheral infusion sites

Amphotericin B Liposomal (Ambisome)

Indications Primary indication(s):  Mucormycosis  Cryptococcal infections  Aspergillus infections  Blastomyces, Coccidioides, Histoplasma, Sporothrix

Alternative indication(s): An option for invasive Candida infections, but an echinocandin, fluconazole, or voriconazole is usually preferred.

Not indicated

Safety Considerations  Nephrotoxicity, avoid concomitant nephrotoxins  Infusion reactions: fever, chills, rigors, chest pain, dyspnea, hypoxia, abdominal, leg, or back pain, flushing, and urticaria. Generally, respond to therapy with diphenhydramine and brief interruption of the infusion.  Electrolyte abnormalities, such as hypokalemia, hypomagnesemia, and hyperchloremic acidosis.

Renal Dosing Dosing adjustments required when renal function below 10mL/min

Other Considerations  Lipid-based and conventional formulations are NOT interchangeable and have different dosing recommendations.  For patients who experience a non-anaphylactic infusion-related reaction, premedication 30 to 60 minutes prior to additional doses may be required.

Azithromycin Spectrum of Activity* Chlamydophila pneumoniae, Chlamydia trachomatis Mycoplasma pneumoniae, M. genitalium, M. hominis Legionella Ureaplasma Bordetella pertussis Nontuberculous mycobacteria Haemophilus influenzae, Moraxella catarrhalis Salmonella, Shigella

Increasing resistance: S. pneumoniae, Streptococcus pyogenes, S. agalactiae Indications  Urethritis/cervicitis: Chlamydia and N. gonorrhoeae (in combination with 3rd gen cephalosporin)  Pertussis  Nontuberculous mycobacteria: prophylaxis (advanced HIV infection) and treatment (in combination)  Bartonella infections  Legionella infections

Alternative:  Bacterial COPD exacerbation  Acute otitis media  Bacterial conjunctivitis  Mild – moderate community acquired pneumonia  Pelvic inflammatory disease (in combination)  Salmonella, Shigella, Traveler’s diarrhea  Cesarean section (non-elective) prophylaxis Not indicated

Safety Considerations  Prolonged QT interval and Torsades de Pointes  Diarrhea (5%)  Rare cytopenias, increased liver enzymes  Potential for drug-drug interactions

Renal Dosing Dose adjustments with renal impairment generally not needed. Use with caution when CrCl < 10mL/min

Other Considerations  Increasing resistance to S. pneumoniae. Macrolide resistance to S. pneumoniae has been associated more with azithromycin than clarithromycin use1  Should not be used as monotherapy in individuals with nontuberculous mycobacteria.

1. Vanderkooi OG, Low DE, Green K et al. Toronto Invasive Bacterial Disease Network. Predicting antimicrobial resistance in Invasive pneumococcal infections. Clin Infect Dis. 2005 May 1;40(9):1288‐97. 8

Caspofungin Spectrum of Activity* Candida, including fluconazole resistant species: C. glabrata and C. krusei Aspergillus

Indications Primary indication(s): empiric antifungal for severely ill patients with invasive Candida infection or patients at risk of fluconazole resistance (e.g. receiving fluconazole prophylaxis). Empiric yeast therapy for febrile neutropenia. Fungal endocarditis

Alternative: An option for invasive aspergillosis infections, but amphotericin or voriconazole is usually preferred.

Not indicated The echinocandins have poor urine penetration and should generally not be used for urinary infections. Should not be used for CNS infections.

Safety Considerations Reduce dose if moderate hepatic impairment (Child Pugh B)

Renal Dosing No adjustments required for renal impairment

Other Considerations Higher dose is required for fungal endocarditis (150mg/day)

Cefepime Spectrum of Activity* Broad spectrum activity including S. aureus and Gram- negative microorganisms

Indications Febrile neutropenia in pediatrics: 1) With penicillin allergy or 2) Receiving methotrexate Not indicated MRSA

Safety Considerations C. difficile risk Risk of neurotoxicity and non-convulsive status epilepticus (especially with renal insufficiency) Renal Dosing Dose adjustments may be required in renal impairment

Other Considerations Can cause positive direct Coombs test (without hemolysis)

Cefixime Spectrum of Activity* Gram-negative microorganisms including Neisseria gonorrhoeae

Streptococci, poor activity against S aureus Indications Uncomplicated anogenital gonorrhea infection (urethral, endocervical, vaginal, rectal) in adults and youth > 9 years of age (except infection in men who have sex with men)  Cefixime 800 mg orally PLUS azithromycin 1 gram orally in a single dose1

Can be used for infections resistant to first line agents but susceptible to cefixime

Not indicated Any gonorrhea infection in men who have sex with men OR pharyngeal infection in men or women, preferred therapy is:  Ceftriaxone 250 mg intramuscularly PLUS azithromycin 1 gram orally in a single dose1

Safety Considerations C. difficile risk

Renal Dosing Dose adjustments may be required in renal impairment

Other Considerations

1. Canadian Guidelines on Sexually Transmitted Infections. https://www.canada.ca/en/public- health/services/infectious-diseases/sexual-health-sexually-transmitted-infections/canadian- guidelines.html

Cefotaxime Spectrum of Activity* Similar to ceftriaxone

Gram-negative microorganisms except Pseudomonas

Most penicillin-resistant pneumococci and N. meningitidis are susceptible

Listeria and Enterococcus are resistant

Indications Should be used in place of ceftriaxone for patients with biliary sludging or cholestatic hepatitis.

 EMPIRIC therapy of severely ill patients with suspected Gram-negative infection  Documented Gram-negative infection resistant to 1st and 2nd generation cephalosporins  Meningitis  Spontaneous bacterial peritonitis, community- acquired secondary peritonitis (or hospital acquired with no previous antimicrobial therapy), or intra- abdominal abscess.  Community acquired pneumonia

Not indicated Does not cover Pseudomonas and other resistant Gram- negatives, ESBLs or AmpC producing Enterobacteriaceae.

Safety Considerations C. difficile risk (high risk)

Renal Dosing Dose adjustment required in renal impairment

Other Considerations Dosing for CNS infections: 2 g every 4h

Cefoxitin Spectrum of Activity* Gram negative: Most Enterobacteriaceae, some anaerobes

Listeria and Enterococcus are resistant

Indications  Obstetric and gynecological infections such as pelvic inflammatory disease (PID) and single dose postpartum for 3rd and 4th degree tears

 Surgical prophylaxis for gynecologic procedures

Not indicated Does not cover Pseudomonas and other resistant Gram- negatives, ESBLs or AmpC producing Enterobacteriaceae.

Safety Considerations C. difficile risk (medium risk)

Renal Dosing Dose adjustment required in renal impairment

Other Considerations Increasing anaerobic resistance

Ceftazidime

Spectrum of Activity* Gram-negative bacteria, including Pseudomonas

Indications Treatment or empiric therapy for presumed Pseudomonas infections.

Not indicated  Poor activity for most Gram-positive microorganisms  Does not treat ESBL producing microorganisms

Safety Considerations C. diff risk (high risk)

Renal Dosing Dose adjustment required for renal impairment

Other Considerations Risk of cross-reaction in those allergic to aztreonam (identical side chains)

Ceftolozane-Tazobactam Spectrum of Activity* Gram-negative bacteria, including Pseudomonas. No staphylococcal, enterococcal, or anaerobic activity

Indications Infections caused by multidrug-resistant Gram-negative bacteria, specifically ESBL-producing Enterobacteriaceae and multidrug-resistant P. aeruginosa when other treatment alternatives are not an option

Not indicated

Safety Considerations

Renal Dosing Dosing adjustments required for renal impairment

Other Considerations Laboratory should be asked to perform sensitivity testing.

Higher dosing (3g IV q8h) may be required for pulmonary infections, currently being studied

1. Xiao et al. J Clin Pharmacol. 2016 Jan;56(1):56-66. 10.1002/jcph.566

Ceftriaxone Spectrum of Activity* Streptococci, including most penicillin-resistant pneumococci. All enterococci are resistant. Gram-negative microorganisms except Pseudomonas N. gonorrhoeae Borrelia burgdorferi (Lyme)

Indications  EMPIRIC therapy of severely ill patients with suspected Gram-negative infection  Documented Gram-negative infection resistant to 1st and 2nd generation cephalosporins  Meningitis, brain abscess  Spontaneous bacterial peritonitis, community- acquired secondary peritonitis (or hospital acquired with no previous antimicrobial therapy), or intra- abdominal abscess.  Salmonella  Community acquired pneumonia  Gonorrhea  Pelvic Inflammatory Disease, Epididymitis  Some endocarditis infections  Synergy in some enterococcal endocarditis infections, particularly if gentamicin is contraindicated  Complicated Lyme infections Not indicated Does not cover Listeria, Pseudomonas, ESBLs or AmpC producing Enterobacteriaceae Avoid in patients with biliary sludging or cholestatic hepatitis (see Cefotaxime) Avoid for serious AmpC microorganisms (Citrobacter, Enterobacter infections), even if reported as susceptible.

Safety Considerations  C. difficile risk (high risk)  Pseudocholelithiasis: more likely if on TPN and using  2g/day  Drug induced immune thrombocytopenia  Prolonged QTC with concomitant lansoprazole1

Renal Dosing Does not require dosing adjustments in renal impairment Other Considerations Most infections can be treated with ceftriaxone 1g every 24 hours. Higher dosing recommended for infective endocarditis, CNS infections, bone and joint infections, typhoid Do not co-administer with calcium containing solutions

Cephalexin Spectrum of Activity* Gram-positive and some Gram-negatives such as E.coli, Klebsiella pneumoniae, and Proteus mirabilis

Indications Primary: Cellulitis and erysipelas

Alternative: Uncomplicated urinary infections with cefazolin-sensitive microorganisms

Not indicated DO NOT use in cefazolin-sensitive systemic infections or complicated urinary infections due to E.coli, K. pneumoniae, or P. mirabilis

Safety Considerations

Renal Dosing Dose adjustments required in renal impairment

Other Considerations

Cidofovir Spectrum of Activity* CMV Herpesvirus (HSV, VZV) JC virus

Indications An option for UL97-mutant ganciclovir resistant CMV

Potentially acyclovir resistant HSV

Clinical efficacy has been demonstrated only for CMV. Its clinical utility in infections caused by other viral pathogens remains to be determined

Not indicated

Safety Considerations Administered weekly

High risk of nephrotoxicity (Fanconi-like syndrome): proteinuria, glycosuria, polyuria, acidosis, phosphaturia.

Nausea, fever, alopecia, myalgias, neutropenia, iritis/uveitis.

Prehydration with 1L of normal saline before infusion and, if tolerable, another 1L during or following the infusion.

Probenecid 2 g PO 3h prior and 1 g PO 2h and 8h following each cidofovir infusion

Renal Dosing Contraindicated if CrCl ≤ 55 mL/min or concomitant nephrotoxic agents or proteinuria (2+ or greater)

Other Considerations Close serum creatinine and urine protein monitoring (prior to each dose) with early dose adjustment for kidney injury:  dose reduce for increase of 25-35 µmol/L in serum creatinine  stop if proteinuria (2-3+ or greater) or increase of 44µmol/L above baseline creatinine

Ciprofloxacin Spectrum of Activity* Gram-negatives including Pseudomonas Legionella Indications  treatment of respiratory infections in cystic fibrosis  part of combination empiric therapy of ICU nosocomial pneumonia or severe CAP where Pseudomonas or other resistant Gram-negative infections are suspected;  part of combination therapy of high-risk febrile neutropenia for patients with a severe B-lactam allergy;  treatment of intra-abdominal infections in patients who cannot receive B-lactam or aminoglycoside- containing regimens;  the treatment of a documented Gram-negative infection due to a microorganism resistant to other antibiotics or when another antibiotic is contraindicated; (e.g. UTI)  Pyelonephritis  N. meningitidis prophylaxis Alternative:  bone & joint infections due to susceptible microorganisms  infectious diarrhea when treatment is indicated for susceptible microorganisms Not indicated  first line for uncomplicated UTIs Safety Considerations  Risk of myasthenia gravis exacerbations  Tendinitis and tendon rupture, peripheral neuropathy, and CNS effects  Risk of QT prolongation  Risk of C. difficile infection (high risk) Renal Dosing Dose adjustment required for renal impairment Other Considerations Use higher dose for Pseudomonas infections (po: 750mg bid; IV 400mg q8h) Not generally recommended in children or pregnancy Intravenous ciprofloxacin:  only for patients unable to take oral medication. Bioavailability ~70-80% Oral ciprofloxacin:  Avoid dairy products, antacids, and other sources of divalent cations (Ca, Fe, Mg, Al, Zn) which can chelate ciprofloxacin and prevent absorption  Must hold continuous tube feeding 2 h before and 2 h after administration. Do not use suspension1 1. Wright DH, Pietz SL, Knostantinides FN, Rotschafer JC. Decreased in vitro fluoroquinolone concentrations after mixture with an enteral feeding formulation. JPEN. 2000. 24(1):42-48. Available from: https://www.ncbi.nlm.nih.gov/pubmed/10638471

Clarithromycin Spectrum of Activity* Chlamydophila pneumoniae Mycoplasma, Ureaplasma Legionella Bordetella pertussis Nontuberculous mycobacteria Haemophilus influenzae, Moraxella catarrhalis H. pylori

Increasing resistance: S. pneumoniae, Streptococcus pyogenes, S. agalactiae Indications  Pertussis  Nontuberculous mycobacteria: prophylaxis (advanced HIV infection) and treatment (in combination)  Bartonella infections  Legionella infections  H. pylori (in combination)

Alternative:  Bacterial COPD exacerbation  Acute otitis media  Mild – moderate community acquired pneumonia  Pharyngitis

Not indicated

Safety Considerations  Prolonged QT interval and Torsades de Pointes  Rare cytopenias, increased liver enzymes  Potential for drug-drug interactions o Statins: risk rhabdomyolysis o Calcium channel blockers: hypotension, renal injury o Colchicine: toxicity from colchicine induced pancytopenia  FDA: caution regarding clarithromycin in patients with heart disease because of a potential increased risk of heart problems or death that can occur years later Renal Dosing Dose adjustments with renal impairment

Other Considerations  Increasing resistance to S. pneumoniae.  Should not be used as monotherapy in individuals with nontuberculous mycobacteria.

Clindamycin Spectrum of Activity* S. aureus Streptococci Anaerobes

Indications Primary: For use in combination for treatment of Group A streptococcus (Streptococcus pyogenes) or Staphylococcus aureus infections causing toxic shock syndrome or necrotizing fasciitis

Alternative: -Noninvasive MRSA infections, if susceptible, without alternative option such as TMP/SMX or doxycycline -Part of combination therapy for Pneumocystis, Toxoplasma

Not indicated Increasing resistance of Bacteroides, metronidazole is the drug of choice in such infections.

Safety Considerations Due to high rates of Clostridium difficile with clindamycin use, clindamycin is not recommended for treatment of infections other than those associated with toxic shock syndrome.

Renal Dosing Dosing adjustments not required for renal impairment

Other Considerations Increased rates of surgical infections have been observed with clindamycin prophylaxis.1

1. Blumenthal KG, Ryan EE, Li Y, Lee H, Kuhlen JL, Shenoy ES. The Impact of a Reported Penicillin Allergy on Surgical Site Infection Risk. Clin Infect Dis. 2018 Jan 18;66(3):329-336.

Colistin Spectrum of Activity* Gram-negative bacilli: carbapenem-resistant Enterobacteriaceae (E. coli, Klebsiella pneumoniae, Enterobacter spp), Pseudomonas, and Acinetobacter baumannii

Variable activity for Stenotrophomonas

Indications Used as an alternative in multi-drug resistant infections, primarily carbapenem-resistant microorganisms.

Always use in combination with a carbapenem regardless of in vitro carbapenem susceptibility.

Not indicated Resistant: Burkholderia cepacia, Serratia marcescens, Moraxella catarrhalis, Proteus spp, Providencia spp, and Morganella morganii

Safety Considerations  CNS toxicity: Self-limiting and reversible neurological disturbances may occur: numbness, vertigo, paresthesia, generalized pruritus, tingling and slurred speech. Dose reduction may reduce neurologic symptoms.  Renal toxicity  Respiratory arrest: impaired renal function might increase the risk for neuromuscular blockade

Renal Dosing Dosing adjustments required in renal impairment

Other Considerations Dosage is based on mg of colistin base activity (CBA). Some products are labeled in international units. To convert:1 30mg CBA = 1,000,000 IU CBA 1mg CBA = 2.4 mg colistimethate Calculated doses exceed package insert dosing.

1. Consistent global approach on reporting of colistin doses to promote safe and effective use. Clin Infect Dis. 2014 Jan;58(1):139-41.

Dapsone Spectrum of Activity* Pneumocystis jirovecii Toxoplasma gondii Mycobacterium leprae Indications Primary indication:  Prophylaxis for Pneumocystis jirovecii  Can be used for treatment in combination with trimethoprim for non-acutely ill patients

Toxoplasma gondii prophylaxis in combination with pyrimethamine and leucovorin

May be used for non-infectious diseases, ex: Dermatitis herpetiformis, Immune thrombocytopenia (ITP) Not indicated

Safety Considerations  Hemolysis (dose related) o Enhanced in G6PD-deficient patients  Methemoglobinemia (dose-related; cyanosis, headache, dyspnea, chest pain, and fatigue)  Dapsone hypersensitivity syndrome (fever, rash, eosinophilia, lymphadenopathy, hepatitis, pneumonitis)  Agranulocytosis, anemia, leukopenia, pure red cell aplasia  Neuropathy

Monitoring  Check G6PD levels prior to initiation  CBC (weekly for first month, monthly for 6 months and semiannually thereafter). Use with caution in patients with severe anemia  Reticulocyte counts, liver function tests (baseline and periodic) Renal Dosing

Other Considerations  Discontinue therapy if a significant reduction in leukocytes, platelets, or hemopoiesis  Sulfonamide allergy: Use with caution in patients with hypersensitivity to other sulfonamides. Cross- reactions occur in only 7%–22% of sulfa-allergic patients Fitzpatrick's Dermatology in General Medicine, 8e New York, NY: McGraw-Hill; 2012.

Daptomycin Spectrum of Activity* Gram-positive microorganisms, including MRSA and VRE

Indications VRE

MRSA or other Gram-positive infections in patients who cannot receive 1st line agents

Not indicated DO NOT use for pneumonia, inactivated by pulmonary surfactant

Safety Considerations  Monitor CK weekly during prolonged therapy. Consider stopping statin while on therapy.  Rare eosinophilic pneumonia

Renal Dosing Dosing adjustments required for renal impairment

Other Considerations Can obtain sensitivities on request

Ertapenem Spectrum of Activity* Gram-positive, Gram-negatives (including ESBLs and AmpC producers), and anaerobes No Pseudomonas or enterococcal coverage

Indications Treatment of resistant Gram-negative infections when broad spectrum coverage is needed but not requiring anti- Pseudomonas or enterococcal activity

Treatment of polymicrobial diabetic foot infections when suspected bacteria have a high likelihood of resistance to cefazolin or ceftriaxone.

Not indicated Unlike other carbapenems, does not cover Pseudomonas.

No activity against enterococci or Stenotrophomonas.

Safety Considerations

Renal Dosing Dosing adjustments required for renal impairment

Other Considerations

Erythromycin Spectrum of Activity* Chlamydophila pneumoniae Mycoplasma, Ureaplasma Chlamydia trachomatis Legionella Bartonella Bordetella pertussis Moraxella catarrhalis

Increasing resistance: S. pneumoniae, Streptococcus pyogenes, S. agalactiae Indications In most cases azithromycin or clarithromycin is preferred.

Can be used for gastroparesis (off-label) Not indicated

Safety Considerations  Prolonged QT interval and Torsades de Pointes  Nausea/vomiting (25%)  Diarrhea (8%)  Potential for drug-drug interactions o Statins: risk rhabdomyolysis Renal Dosing

Other Considerations  Increasing resistance to S. pneumoniae.

Fidaxomicin Spectrum of Activity* Clostridium difficile

Indications Primary: none

Alternative: An option for patients with C. difficile infection with a documented allergy or severe adverse drug reaction to vancomycin.

Not indicated Do not use for systemic infections (absorption is negligible)

Safety Considerations Use with caution in patients with a history of macrolide allergy, risk of hypersensitivity cross reaction

Renal Dosing No dosing adjustments required for renal impairment

Other Considerations

Fosfomycin Spectrum of Activity* E. coli, E. faecalis

Indications Uncomplicated acute cystitis

Not indicated Upper urinary infection (pyelonephritis or renal abscess) or systemic infections (bacteremia)

Safety Considerations

Renal Dosing Although the half- life is significantly prolonged in renal impairment there are no specific recommendations for renal dosing.

Other Considerations  Can be used in pregnancy.  Males may require 3g every 2-3 days for 3 doses  Laboratory sensitivity testing available on request

Ganciclovir Spectrum of Activity* Cytomegalovirus (CMV), other herpes viruses

Indications Prophylaxis or therapy for CMV

Not indicated

Safety Considerations Cytopenias (usually responds to G-CSF): monitoring CBC is recommended

May increase creatinine: monitoring is recommended

Renal Dosing Dosing adjustments are required for renal impairment

Other Considerations Resistance can occur, consultation with ID/microbiology if concern.

Gentamicin Spectrum of Activity* Gram-negative microorganisms, including Pseudomonas Synergy against some Gram-positive cocci

Indications Urinary tract infections, including urosepsis

EMPIRIC therapy of severely ill patients with suspected Gram-negative infections (including Pseudomonas)

Synergy for some Gram-positive endocarditis infections

Not indicated Does not cover anaerobes

Safety Considerations  See aminoglycoside guidelines in handbook  Cranial nerve VIII toxicity: cochlear and vestibular. Audiometry monitoring is recommended for courses longer than 2 weeks.  Nephrotoxicity: increased risk in patients with renal dysfunction, advanced age, dehydration, prolonged therapy, concomitant nephrotoxins  Therapeutic drug monitoring is required  Neuromuscular blockade and respiratory paralysis are rare, especially when used concomitantly with anesthetic agents or neuromuscular blockers or in patients with myasthenia gravis or parkinsonism

Renal Dosing Dose adjustments required for renal impairment

Other Considerations

Imipenem and cilastatin Spectrum of Activity* Broad spectrum: -Gram-positive and negative microorganisms -Anaerobes

Enterococcus faecalis if ampicillin susceptible Indications Meropenem should usually be used instead.

However, imipenem can be used in situations in which broad spectrum coverage is required including Enterococcus faecalis (ampicillin susceptible) infections.

Not indicated Stenotrophomonas, MRSA, Enterococcus faecium, or VRE Atypical infections like Legionella

Safety Considerations C. difficile (medium risk) Seizure risk

Renal Dosing Dose adjustments required in renal impairment

Other Considerations

Levofloxacin

Spectrum of Activity* S pneumoniae Gram-negatives including most Enterobacteriaceae, H. influenzae Chlamydophila pneumoniae, Mycoplasma spp. Legionella

Indications Primary - Community Acquired Pneumonia (CAP) requiring ICU admission, Legionella infections

Alternative – CAP (ward admission) if beta-lactam allergy, acute exacerbation of COPD if severe disease, Hospital Acquired Pneumonia (HAP)

Not indicated MRSA or Pseudomonas infections

Safety Considerations  Risk of QT prolongation  Risk of C. difficile infection (high risk)  Tendinitis and tendon rupture, peripheral neuropathy, and CNS effects Renal Dosing Dose adjustments required for renal impairment

Other Considerations Recommended dose 750mg for most indications High oral bioavailability (99%) Oral levofloxacin:  Avoid dairy products, antacids, and other sources of divalent cations (Ca, Fe, Mg, Al, Zn) which can chelate levofloxacin and prevent absorption  Must hold continuous tube feeding 2 h before and 2 h after administration.

Linezolid Spectrum of Activity* Gram-positive microorganisms, including MRSA and VRE

Indications Alternative:  Vancomycin-resistant Enterococcus (VRE) infections when daptomycin cannot be used  MRSA infections in which vancomycin or daptomycin cannot be used

Not indicated

Safety Considerations Inhibits monoamine oxidase. Risk of serotonin syndrome if given to patients taking SSRIs, serotonin norepinephrine reuptake inhibitors or MAOI – check for drug interactions

Predictable cytopenia after 2 weeks of therapy: monitor CBC

Lactic acidosis, peripheral neuropathy, optic neuropathy after 4 weeks of therapy

Renal Dosing No dose adjustments required for renal impairment

Other Considerations Excellent oral bioavailability (100%)

Meropenem Spectrum of Activity* Broad spectrum: -Gram-positive and negative microorganisms -Anaerobes

Indications  Treatment of documented or suspected infections resistant to piperacillin-tazobactam or third- generation cephalosporins  Infections with ESBL or, AMP-C producing bacteria

Not indicated Stenotrophomonas, MRSA, Enterococcus or VRE Atypical infections like Legionella

Safety Considerations C. difficile (medium risk)

Renal Dosing Dose adjustments required in renal impairment

Other Considerations Higher doses (2g IV q8h) should be used to treat CNS infections, cystic fibrosis infections, and endophthalmitis

Neomycin Spectrum of Activity* aerobic gram negative and gram positive bacteria, including the major E. coli species in the colon

Indications For inpatients receiving elective colorectal surgery

Not indicated

Safety Considerations Risk factors for toxicity  Concommitant neurotoxic, ototoxic or renal toxic drugs  Very young and very old  Dehydration

Renal Dosing Dose adjustments required for renal impairment

Other Considerations Not well absorbed orally

Oseltamivir Spectrum of Activity* Influenza A, Influenza B

Indications Primary: Hospitalized patients with influenza or those at high risk of complications even if after 48 hours of symptom onset.  Asthma, chronic lung disease, heart disease, kidney disease, liver disease, diabetes, immunosuppression, aged 65 years or older, pregnant or postpartum (within 2 weeks of delivery), residents of chronic care facilities

Alternative: Consider in adults with uncomplicated influenza presenting within 48 hours of symptom onset (decreases symptom duration by approximately 1 day)

Not indicated Non-hospitalized patients at low risk of complications, particularly if symptoms > 2days

Safety Considerations Nausea, vomiting, confusion

Renal Dosing Dose adjustments required for renal impairment

Other Considerations  Usually treat for 5 days.  No evidence for 150mg BID dosing.

Used for prophylaxis in specific situations, on the guidance of public health or infection prevention and control.

Pentamidine Spectrum of Activity* Pneumocystis pneumonia (Pneumocystis jirovecii) West African trypanosomiasis

Indications Alternative: option for PJP therapy (parenteral) or prophylaxis (aerosolized)

Not indicated

Safety Considerations Parenteral: electrolyte abnormalities, cytopenia, renal injury, QTC prolongation, pancreatitis, hypotension (rapid administration)

Inhaled: bronchospasm/cough

Renal Dosing Dose adjustments required for renal impairment

Other Considerations Systemic infection still possible with inhaled PJP prophylaxis.

Piperacillin-Tazobactam Spectrum of Activity* Gram-positives including MSSA, E. faecalis Gram-negatives including Pseudomonas Anaerobes

Indications Treatment of serious Gram-negative or polymicrobial infections, including mixed aerobic and anaerobic infections, where the use of other agents is not appropriate because of resistance, contraindications or adverse events

Not indicated Does not cover MRSA, most E. faecium, VRE Stenotrophomonas, Atypical pathogens such as Legionella

Avoid in invasive/serious ESBL infections

Avoid for serious AmpC microorganisms (Citrobacter, Enterobacter infections), even if reported as susceptible

Safety Considerations Platelet dysfunction

Renal Dosing Dosing adjustments required for renal impairment

Other Considerations Tazobactam has poor CNS penetration: use alternative agent

Pyrimethamine Spectrum of Activity* Toxoplasma gondii

Indications Primary: In combination with sulfadiazine for toxoplasmosis

Not indicated

Safety Considerations  Use caution in renal and hepatic impairment.  Cytopenia: monitor CBC  Antifolate drug; requires folinic acid replacement

Renal Dosing No dose adjustments required for renal impairment

Other Considerations Access to drug can be difficult, consult infectious diseases.

Tigecycline Spectrum of Activity* Broad spectrum Gram-positive, Gram-negative, and anaerobic activity including some carbapenem resistant microorganisms.

Indications Primary: none

Alternative: multi-drug resistant infections, usually Gram- negatives, in which alternative agents are not available.

Not indicated Pseudomonas and Proteus vulgaris are inherently resistant.

Safety Considerations Lower dosing in severe hepatic impairment (Child Pugh C)

Renal Dosing No dose adjustments required for renal impairment

Other Considerations Higher risk of death compared to other antibacterial drugs, so only use when alternative treatments are not suitable.

Tobramycin Spectrum of Activity* Gram-negative microorganisms, including Pseudomonas

Indications Primary: Urinary infections including urosepsis

EMPIRIC therapy of severely ill patients with suspected Gram-negative (including Pseudomonas) infections

Synergy against some Gram-positive cocci

Not indicated Does not cover Gram-positive, anaerobes or atypical microbes

Safety Considerations  See aminoglycoside guidelines in handbook  Cranial nerve VIII toxicity: cochlear and vestibular. Audiometry monitoring is recommended when treatment for more than 2 weeks is anticipated.  Nephrotoxicity: increased risk in patients with renal dysfunction, advanced age, dehydration, prolonged therapy, concomitant nephrotoxins  Therapeutic drug monitoring is required  Neuromuscular blockade and respiratory paralysis are rare, especially when used concomitantly with anesthetic agents or neuromuscular blockers or in patients with myasthenia gravis or parkinsonism

Renal Dosing Dose adjustments required for renal impairment

Other Considerations

Trimethoprim Spectrum of Activity* Gram-negative microorganisms including Enterobacteriaceae

Staphylococcus aureus, may be resistant Indications Can be used in sulfonamide-allergic or sulfonamide- intolerant patients

Urinary tract infections

Some S. aureus infections

Not indicated Enterococci are resistant (even if reported as sensitive)

S. aureus bacteremia (see S. aureus handbook page)

Safety Considerations Renal injury and hyperkalemia, particularly in older patients (65 or older)

Sudden cardiac death

Higher risk in patients on angiotensin converting enzyme inhibitor (ACEi), angiotensin receptor blocker (ARB), K sparing diuretic (e.g. spironolactone)

Aseptic meningitis is rare

Renal Dosing Dose adjustments required for renal impairment

Other Considerations Regular monitoring of kidney function and electrolytes if prolonged use, over age 65, use of ACEi, ARB, or K- sparing diuretic, baseline renal injury, or other risks for AKI/hyperkalemia

References: Crellin et al. BMJ. 2018 Feb 9;360:k341.

Trimethoprim-sulfamethoxazole (co-trimoxazole) Spectrum of Activity* Gram-negative microorganisms including Enterobacteriaceae, Stenotrophomonas maltophilia

Nocardia Pneumocystis jirovecii Staphylococcus aureus Indications  Urinary tract infections  Stenotrophomonas maltophilia infections  Pneumocystis Pneumonia (PCP)  Nocardiosis  Traveler’s diarrhea  Cyclospora and Shigella infections  Prophylaxis for PCP and Toxoplasma gondii  Some S. aureus infections (MRSA, bone infections) Not indicated Enterococci are resistant (even if reported as sensitive)

Streptococcus pyogenes: clinical failures occur even though may be reported as susceptible

S. aureus bacteremia (see S. aureus handbook page)

Safety Considerations Renal injury and hyperkalemia, particularly in older patients (65 or older)

Sudden cardiac death

Higher risk in patients on angiotensin converting enzyme inhibitor (ACEi), angiotensin receptor blocker (ARB), K sparing diuretic (e.g. spironolactone)

Aseptic meningitis is rare

Renal Dosing Dosing adjustment required for renal impairment

Other Considerations Regular monitoring of kidney function and electrolytes if prolonged use, over age 65, use of ACEi, ARB, or K sparing diuretic, baseline renal injury, or other risks for AKI/hyperkalemia

References:

Fralick, et al. BMJ. 2014 Oct 30;349:g6196

Antoniou, et al. CMAJ. 2015 Mar 3;187(4):E138-43

Crellin et al. BMJ. 2018 Feb 9;360:k341.

Valganciclovir Spectrum of Activity* Cytomegalovirus (CMV), other herpes viruses

Indications Primary: prophylaxis or therapy for CMV

Not indicated

Safety Considerations Cytopenias (may respond to G-CSF): monitoring CBC is recommended. Monitor creatinine.

Renal Dosing Dose adjustments required for renal impairment

Other Considerations Resistance can occur, consultation with ID/microbiology if concern.

Vancomycin Spectrum of Activity* Gram-positive bacteria, including E. faecium and methicillin-resistant staphylococci

Indications  Treatment of suspected MRSA, MRSE, and enterococcus infections  For those with Gram-positive infections susceptible to cloxacillin or cefazolin but have severe allergy to those options.  Oral for C. difficile infection

Not indicated

Safety Considerations Nephrotoxicity, cytopenia, ototoxicity

Renal Dosing Dose adjustments required IV vancomycin for renal impairment

Other Considerations  Less efficacious than beta-lactams for MSSA, beta- lactam is drug of choice  See vancomycin section of handbook for dosing details.  Dosing is based on actual body weight  Therapeutic drug monitoring recommended, trough 15-20 is recommend in most serious infections  Intravenous vancomycin is NOT effective for treating C. difficile diarrhea  There is no oral absorption of vancomycin, making this route ineffective for infections other than C. difficile

Voriconazole Spectrum of Activity* Aspergillus sp., Candida sp. (including krusei), Fusarium sp., various molds. No activity against agents of Mucormycosis.

Indications Primary indication(s): Invasive Aspergillus (including CNS aspergillosis)

Alternative indication(s): Serious Candida infections, prophylaxis in high risk hematologic patients (prolonged neutropenia at high risk of for invasive aspergillosis, GVHD) and some lung transplant patients.

Not indicated For urinary tract infections with fungal microorganisms

Safety Considerations  Check for drug-drug interactions.  Reduce to ½ dose for moderate hepatic insufficiency. Monitor liver function and enzymes (hepatotoxicity).  Rash, photosensitivity, SJS, visual disturbances (flashes, hallucinations), photosensitivity, QT prolongation.

Renal Dosing Parenteral is contraindicated if CrCl < 50 mL/min (accumulation of IV vehicle cyclodextrin).

Other Considerations  See voriconazole section of handbook for dosing details.  Therapeutic drug monitoring is recommended, monitor trough concentrations: o Target 1 – 5.5 μg/mL, 5-7 days after starting therapy.  Not excreted into the urine in active form.