Antimicrobial Treatment Guidelines for Common Infections

March 2019

Published by: The NB Provincial Health Authorities Anti-infective Stewardship Committee under the direction of the Drugs and Therapeutics Committee Introduction: These clinical guidelines have been developed or endorsed by the NB Provincial Health Authorities Anti-infective Stewardship Committee and its Working Group, a sub- committee of the New Brunswick Drugs and Therapeutics Committee. Local antibiotic resistance patterns and input from local infectious disease specialists, medical microbiologists, pharmacists and other physician specialists were considered in their development. These guidelines provide general recommendations for appropriate antibiotic use in specific infectious diseases and are not a substitute for clinical judgment.

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When prescribing antimicrobials: Carefully consider if an antimicrobial is truly warranted in the given clinical situation  Consult local antibiograms when selecting empiric therapy Include a documented indication, appropriate dose, route and the planned duration of therapy in all antimicrobial drug orders Obtain microbiological cultures before the administration of antibiotics (when possible) Reassess therapy after 24-72 hours to determine if antibiotic therapy is still warranted or effective for the given organism or clinical situation. Reassess based on relevant clinical data, microbiologic and/or radiographic information Assess for de-escalation as appropriate based on available microbiology culture and susceptibility results

2 Antimicrobial Treatment Guidelines For Common Infections (Click arrow buttons  to navigate)

Section 1: Anatomical Page Foot Diabetic Foot Infections 4

Gastrointestinal Clostridium difficile Infection 5 Intra-Abdominal Infections 7

Respiratory Acute Bacterial Rhinosinusitis 9 Acute Exacerbation of Chronic Obstructive Pulmonary Disease 10 Community Acquired Pneumonia 11 Hospital Acquired Pneumonia 13 Ventilator Acquired Pneumonia 15

Skin and Soft Tissue Cellulitis/Erysipelas 17

Genitourinary When to Send a Urine for Culture and Urinalysis 18 Positive Urine Culture Assessment Algorithm  19 Urinary Tract Infection Treatment Guideline  20

Drug Use Guidelines Aminoglycoside Dosing and Monitoring Guidelines 21 Antimicrobial Dosing Tool  37 Management of Penicillin and β-Lactam Allergy 49 Antimicrobial Allergy Evaluation Tool 58 IV-to-PO Conversion Criteria 64 Surgical Prophylaxis Guidelines  65 Vancomycin Dosing and Monitoring Guidelines  84 Other Splenectomy Vaccination Kit 91

References 98

3 EMPIRIC ANTIMICROBIAL THERAPY FOR DIABETIC FOOT INFECTION (Endorsed by NB Health Authorities Anti-Infective Stewardship Committee February 2016)

1 1 Infection Severity Preferred Empiric Regimens Alternative Regimens Comments Mild Wound less than 4 weeks duration Wound less than 4 weeks duration • Outpatient management • Cellulitis less than 2 cm • cephalexin 500 mg PO four times daily* • clindamycin 300 – 450 mg PO four times daily (only if recommended and without involvement of Wound greater than 4 weeks duration severe β-lactam allergy) • Tailor regimen based on C&S deeper tissues • sulfamethoxazole/trimethoprim 800/160 mg PO twice daily* + Wound greater than 4 weeks duration results & patient response • Non-limb threatening metroNIDAZOLE 500 mg PO twice daily • amoxicillin/clavulanate 875/125mg PO twice daily* OR • No signs of systemic toxicity • doxycycline 100 mg PO twice daily + metroNIDAZOLE 500 mg PO twice daily Moderate Wound less than 4 weeks duration Wound less than 4 weeks duration • Initial management with • Cellulitis greater than 2 • ceFAZolin 2 g IV q8h* OR • levofloxacin 750mg IV/PO once daily* (only if severe outpatient parenteral therapy cm or involvement of deeper • cefTRIAXone 2 g IV once daily (to facilitate outpatient management when β-lactam allergy) with rapid step-down to oral tissues ambulatory administration of ceFAZolin not possible) Wound greater than 4 weeks duration therapy after 48 to 72 hours • Non-limb threatening based on patient response Wound greater than 4 weeks duration • levofloxacin 750mg IV/PO once daily* + recommended • No signs of systemic toxicity • ceFAZolin 2 g IV q8h* + metroNIDAZOLE 500 mg PO twice daily OR metroNIDAZOLE 500 mg PO twice daily (only if severe β-lactam allergy) • Tailor regimen based on C&S • cefTRIAXone 2 g IV once daily + metroNIDAZOLE 500 mg PO twice daily results & patient response (to facilitate outpatient management when ambulatory administration of ceFAZolin not possible) Severe • piperacillin-tazobactam 3.375 g IV q6h* • imipenem/cilastatin 500 mg IV q6h* OR • Inpatient management • Systemic signs of sepsis • levofloxacin 750 mg IV once daily* + metroNIDAZOLE recommended • Limb or foot threatening 500 mg PO/IV twice daily (only if severe β-lactam • Urgent vascular assessment if • Extensive soft tissue allergy) pulseless foot involvement • Tailor regimen based on C&S • Pulseless foot results & patient response Clinical Pearls: Duration of Therapy 1 If high risk for MRSA, should include sulfamethoxazole/ • Soft tissue only – 2 weeks trimethoprim 800/160 mg PO twice daily * or doxycycline 100 • Bone involvement with complete surgical resection of all infected bone – 2 weeks mg PO twice daily for mild infections and vancomycin weight- • Bone involvement with incomplete surgical debridement of infected bone – 4-6 weeks IV based dosing to a target trough of 15 – 20 mg/L for moderate- severe infections • Bone involvement with no surgical debridement or residual dead bone postoperatively – 6 weeks IV, followed by 6 weeks PO • Debridement, good glycemic control and proper wound care are References: important for the management of diabetic foot infections 1. Bowering K, Embil JM. Canadian Diabetes Association 2013 Clinical Practice Guidelines for the Prevention and Management of Diabetes in • Cultures: prefer tissue specimens post-debridement and Canada: Foot Care. Can J Diabetes 37(2013) S145-S149 cleansing of wound; surface or wound drainage swabs not 2. Lipsky BA, Berendt AR, Cornia PB et al. 2012 Infectious Disease Society of America Clinical Practice Guidelines for the Diagnosis and Treatment recommended of Diabetic Foot Infections. CID 2012:54(12):132-173 • In a clinically infected wound a positive probe-to-bone (PTB) 3. Lipsky BA, Armstrong DG, Citron DM et al. Ertapenem versus piperacillin/tazobactam for diabetic foot infections (SIDESTEP): prospective, test is highly suggestive of osteomyelitis randomized, controlled, double-blinded, multicentre trial. Lancet 2005; 366:1695 – 1703 • Imaging: recommend plain radiography (radionuclide imaging 4. Blond-Hill E, Fryters S. Bugs & Drugs An Antimicrobial/Infectious Diseases Reference. 2012. Alberta Health Services unnecessary)

* Dose adjustment required in renal impairment

9782-10650-04-2016

4 Antimicrobial Therapy for Clostridioides difficile Infection (CDI) (formerly Clostridium difficile) NB Provincial Health Authorities Anti-Infective Stewardship Committee, March 2019

Patient with 3 or more unformed or watery stools in 24 hours (NOT clearly attributable to underlying conditions or laxative use)

Send stool for Clostridioides difficile testing

Colonoscopic or Results pending but high Positive Clostridioides histopathologic findings of clinical suspicion difficile testing results pseudomembranous colitis

 Discontinue therapy with the inciting antimicrobial agent if possible o If discontinuation of antimicrobials is not possible, de-escalate therapy to narrowest effective spectrum of activity  Begin infection control precautions o Accommodate patient in a private room (if possible) o Gowns and gloves (masks unnecessary) o Perform hand hygiene with soap and water at point of care; if not available, use alcohol hand sanitizer at point of care followed immediately with soap and water at the nearest clean sink (alcohol hand sanitizer does NOT effectively remove Clostridioides difficile spores)  Stop all anti-peristaltic and pro-motility agents1 unless clearly indicated  Treat according to severity of CDI (see below)

Mild-to-moderate CDI Severe CDI Fulminant CDI Criteria: WBC lower than 15 x109/L AND Criteria: WBC greater than or equal to 15 9 Criteria: Hypotension/shock OR ileus OR serum creatinine less than 1.5 x baseline x10 /L OR serum creatinine greater than 2 2 megacolon level 1.5 x baseline level

Initial episode Initial episode ANY episode Vancomycin 125 mg PO q6h Vancomycin 125 mg PO q6h Vancomycin 500 mg PO/NG q6h x 10 x 10 days3 x 10 days3 days3 PLUS metroNIDAZOLE 500 mg IV q8h4 If the patient is otherwise healthy and If contraindication to, treatment ambulatory, OR cannot access oral failure6 of or intolerance to oral If contraindication to, treatment vancomycin or fidaxomicin due to vancomycin: failure6 of or intolerance to oral prohibitive cost, may consider: vancomycin: metroNIDAZOLE 500 mg PO q8h Fidaxomicin 200 mg PO Fidaxomicin 200 mg PO q12h x 10 days3 q12h x 10 days PLUS metroNIDAZOLE 500 mg IV q8h4 If contraindication to, treatment failure6 of or intolerance to oral If ileus or vomiting, ADD vancomycin vancomycin: 500 mg in 100 mL NS retention enema q6h5 Fidaxomicin 200 mg PO q12h x 10 days 5 Recurrent CDI Definition: Recurrence of CDI within 8 weeks following the onset of a successfully treated previous episode.

First recurrence:  Vancomycin 125 mg PO q6h x 14 days OR  May consider: Vancomycin Taper-Pulse regimen [Vancomycin 125 mg PO q6h x 14 days, then 125 mg PO q12h x 7 days, then 125 mg PO q24h x 7 days, then 125 mg PO q48h x 21 days, then 125 mg PO q72h x 21 days, then STOP] OR  If contraindication to, treatment failure6 of or intolerance to oral vancomycin: Fidaxomicin 200 mg PO q12h x 10 days

Second recurrence:  Vancomycin Taper-Pulse Regimen [Vancomycin 125 mg PO q6h x 14 days, then 125 mg PO q12h x 7 days, then 125 mg PO q24h x 7 days, then 125 mg PO q48h x 21 days, then 125 mg PO q72h x 21 days, then STOP] OR  Fidaxomicin 200 mg PO q12h x 10 days  Consider fecal microbiota transplant (FMT) for patients who have recurred after receiving treatment with a vancomycin taper-pulse regimen; consult ID specialist or medical-microbiologist

Third or more recurrence:  Initiate vancomycin 125 mg PO q6h and consult an infectious diseases specialist or medical-microbiologist

Note:  Re-treatment with fidaxomicin will only be considered for a relapse occurring within 8 weeks of the completion of the most recent fidaxomicin course  CDI occurring beyond 8 weeks after the completion of the most recent fidaxomicin course will require a trial with vancomycin, unless there is a documented allergy, severe adverse reaction or intolerance to prior oral vancomycin use

Clinical Pearls

 Consider urgent surgical consultation in patients with fulminant CDI who have rising WBC and lactate levels despite appropriate therapy.  Avoid the use of metroNIDAZOLE in pregnant or breastfeeding women  Vancomycin administered intravenously is ineffective for the treatment of CDI  DO NOT test asymptomatic patients (i.e. test of cure); at least 60% of successfully treated patients will continue to test CDI positive, but do not require therapy if they are asymptomatic  Empiric treatment of suspected recurrent CDI without sending confirmatory testing is discouraged – while up to 30% of patients will have a recurrent episode after first diagnosis of CDI, altered bowel habits with recurrent diarrhea is common and up to 35% test negative for CDI  The best method to prevent CDI is to minimize the frequency and duration of exposure to high risk antibiotics (such as clindamycin, fluoroquinolones, 3rd and 4th generation cephalosporins, and carbapenems)  The use of proton pump inhibitors (PPIs) has been associated with CDI, and may increase the risk of recurrent CDI. Evaluate appropriateness of PPI therapy, and discontinue PPI if inappropriately used

1 Examples: loperamide, diphenoxylate, opioids, metoclopramide, domperidone, etc. 2 In patients where the baseline creatinine level is unavailable, use an absolute serum creatinine level of 135 mmol/L as a breakpoint. 3 Consider extending treatment duration to 14 days if clinically improving but without symptom resolution by 10 days of therapy. 4 Continue add-on IV metroNIDAZOLE until the patient is no longer critically ill (usually 5-7 days) 5 In normal circumstances, vancomycin is not absorbed via the GI tract; however, in fulminant CDI, intestinal epithelial integrity may be disrupted, and could lead to systemic drug absorption. Consider monitoring serum vancomycin levels in patients with fulminant CDI who are receiving high dose vancomycin (500 mg q6h) via the oral and rectal routes concomitantly to rule out drug accumulation. 6 Vancomycin treatment failure: defined as 7 days of vancomycin therapy without acceptable clinical improvement and without other identified cause of persistent diarrhea

6 Antimicrobial Therapy for Intra-Abdominal Infections (NB Provincial Health Authorities Anti-Infective Stewardship Committee, September 2018 Origin/Severity of Intra- Probable Preferred Empiric Alternative Empiric Comments Abdominal Infection Pathogens Regimens Regimens f, Community Acquired Core: cefuroxime 1.5 g IV q8h * + ciprofloxacin 400 mg IV OR Duration of Therapy: Enterobacteriaceae metroNIDAZOLE 500 mg IV/PO • 5 – 7 days if optimal source Infection, Mild to a,b 500 mg PO q12h* + (i.e. E.coli, q12h metroNIDAZOLE 500 mg IV/PO control obtained Moderate severity: Klebsiella spp, • • i.e. gastroduodenal Proteus spp, q12h Day of source control intervention a (drainage, surgery, etc.) perforation, cholangitis , Enterobacter spp.) c OR a Intravenous-to-Oral Conversion : cholecystitis , appendicitis, Anaerobes (i.e. B. aminoglycoside (tobramycin OR considered as day 1 of therapy b fragilis, Clostridium amoxicillin/clavulanate 875/125 mg • If intra-abdominal abscess not diverticulitis , primary g, gentamicin) 5 – 7 mg/kg IV q24h* + spp. etc…), po q12h * (spontaneous) bacterial metroNIDAZOLE 500 mg IV/PO resolved after optimal drainage, Streptococcus spp, or if drainage not feasible: peritonitis ± Enterococcus OR q12h • f, antimicrobial therapy may be With no evidence of systemic spp (see below if cefuroxime axetil 500 mg PO q8h * OR isolated) g, prolonged, with duration toxicity (APACHE II score less + metroNIDAZOLE 500 mg PO cefOXitin 2 g IV q6h * than 15) q12h dependant on radiological f resolution (up to 4 to 6 weeks) Community Acquired Core cefTRIAXone 2 g IV q24h + piperacillin/tazobactam 3.375 g IV d,e,g, Infection, Severe: (see above) metroNIDAZOLE 500 mg IV/PO q6h * Stop antimicrobial within 24 hours • As above with APACHE II q12h OR if: score greater than or equal to levoFLOXacin 750 mg IV q24h* + • acute stomach, duodenum &/or 15, signs of systemic toxicity, metroNIDAZOLE 500 mg IV q12h proximal jejunum perforation, if no greater than 70 years old, OR acid-reducing therapy or immunocompromised, malignancy; and source control ampicillin 2 g IV q6hg,* + secondary peritonitis, cancer, achieved OR Intravenous-to-Oral Conversionc: aminoglycoside (tobramycin OR poor nutritional status or • penetrating bowel trauma repaired As for mild to moderate above gentamicin) 5 – 7 mg/kg IV q24h* + incomplete or delayed source within 12 hours OR metroNIDAZOLE 500 mg IV q12h control • intraoperative contamination of a surgical field from enteric contents OR e,f, Healthcare Associated Core Plus: piperacillin/tazobactam 4.5 g IV meropenem 500 mg IV q6h * • acute appendicitis without d,e,g, (preferred if suspected MDR Gram-negative) • Hospitalized greater than 48 Pseudomonas, q6h * perforation, abscess or local Multidrug Resistant peritonitis hours at time of onset, recent OR OR (MDR) Gram • prolonged hospitalization, negative bacteria, patients undergoing post-operative infection, long S aureus ciprofloxacin 400 mg IV q8h* + cholecystectomy for acute term care, rehab, dialysis, metroNIDAZOLE 500 mg IV q12h + cholecystitis unless evidence of nursing home, recent vancomycin 15 mg /kg IV q12hf,* infection outside wall of the antibiotics gallbladder (ex. perforation)

7 Origin/Severity of Intra- Probable Preferred Directed Alternative Directed Comments Abdominal Infection Pathogens Regimens Regimens If MRSA suspected or isolated Add vancomycin 15 mg/kg IV (colonized or history of MRSA q8-12h* (for target trough of 15 – 20 mg/L) infection) • micafungin preferred if Candida krusei or Add fluconazole 800 mg IV/PO then micafungin 100 mg IV q24h Candida glabrata isolated If Candida isolated 400 mg IV/PO q24h* If Enterococcus faecalis isolated: • Enterococcal coverage only necessary if: Add ampicillin 2 g IV q6hg,*  isolated as predominant organism in (not required if on piperacillin/tazobactam or Immediate (IgE-mediated) culture OR imipenem-cilastatin)  If Enterococci isolated penicillin allergy or penicillin healthcare associated infection OR resistant:  patient is immunocompromised OR If Enterococcus faecium isolated: vancomycin 15 mg/kg IV q12h*  Blood culture positive

Add vancomycin 15 mg/kg IV (for target trough of 10 – 20 mg/L) • If vancomycin resistant Entrococcus (VRE) q12h* is isolated, treatment options include h h (for target trough of 10 – 20 mg/L) linezolid or DAPTOmycin . Clinical Pearls: • Antimicrobial therapy does not preclude source control (ex. percutaneous drainage or surgery) • Patients with recent prolonged hospitalization (5 or more days) or recent antimicrobials (2 or more days) within the previous 3 months pose risk for resistance and treatment failure, treat as healthcare associated • Empiric Enterococci coverage is not recommended for mild-moderate severity community-acquired intra-abdominal infections. It should be reserved for patients in whom this pathogen is more frequently found (healthcare-associated infections, particularly those with postoperative infection, presence of severe immunosuppression, recurrent infection, patients who receive long-term cephalosporin treatment, and those with valvular heart disease or prosthetic intravascular materials) • CAUTION: Significant E.coli resistance (greater than 20%) to fluoroquinolones and amoxicillin exist in some areas of the province; check local antibiogram and confirm C&S results when available • Pathogen directed therapy should be used when culture and susceptibility results are available Workup: • Recommend blood, intraoperative and/or abscess fluid cultures in patients with post-operative or healthcare-associated infections; those with treatment failure and/or requiring re-operation; or recently on antimicrobial therapy • Blood cultures recommended if patient has sepsis syndrome • Reassess initial empiric therapy based on clinical state & results of microbiological analysis a Anaerobic coverage not indicated for cholecystitis & cholangitis unless biliary-enteric anastomosis is present or aggravating factors (advanced age, immunosuppression or metabolic instability) b Most cases of diverticulitis can be managed with oral antibiotic therapy c Intravenous-to-Oral conversion: consider if infection well controlled, afebrile x 24 hrs., hemodynamically stable, tolerating oral intake and no clinical, radiographic or surgical sign of intra-abdominal collection from non-optimal drainage d For Pseudomonas aeruginosa infection, piperacillin/tazobactam dosage may be increased to 4.5 gm IV q6h e Anaerobic coverage adequate, addition of metroNIDAZOLE or clindamycin to piperacillin/tazobactam or meropenem not necessary f Appropriate therapy option for patients with an immediate Type-1 (IgE-mediated) hypersensitivity reaction to penicillin (i.e. anaphylaxis, angioedema, laryngeal edema, urticaria) g Avoid in patients with immediate Type-1 (IgE-mediated) hypsensitivity reaction to penicillin, significant risk of cross-reactivity exists. hDiscussion with an Infectious Disease or Microbiology specialist or Internal Medicine Specialist with expertise in infectious disease is required. *Dose adjustment required in renal impairment

8 Antimicrobial Therapy for Acute Uncomplicated Bacterial Rhinosinusitis (ABRS) (NB Provincial Health Authorities Anti-Infective Stewardship Committee, September 2018) Treatment Criteria  Cardinal features of acute rhinosinusitis: Purulent nasal drainage accompanied by nasal obstruction, facial pain-pressure-fullness, or both lasting less than 4 weeks  Clinical diagnosis and differentiation of acute bacterial from viral rhinosinusitis is based on the characteristic patterns of clinical presentations taking into account duration of symptoms, severity of illness, temporal progression and “double-sickening” in the clinical course  The following clinical presentations (any of the 3) are recommended for identifying patients with acute bacterial vs. viral rhinosinusitis: 1. Onset with persistent symptoms or signs compatible with acute rhinosinusitis, lasting for greater than or equal to 10 days without any evidence of clinical improvement 2. Onset with severe symptoms or signs of high fever (greater than or equal to 39 °C) and purulent nasal discharge or facial pain lasting for at least 3 to 4 consecutive days at the beginning of illness 3. Onset with worsening symptoms or signs characterized by the new onset of fever, headache or increased in nasal discharge following a typical viral upper respiratory infection that lasted 5 – 6 days and were initially improving (“double sickening”)  Caution: These guideline recommendations are not intended for patients with complicating factors such as immune deficiency or uncontrolled diabetes; watchful waiting should not be used for patients with complicating factors and they should be started promptly on appropriate antimicrobial therapy Alternative Empiric Presentation Preferred Empiric Regimen Duration Comments Regimen Mild – Moderate Symptomatic therapy only • with or without intranasal corticosteroids and/or Symptoms less than 10 days Consider intranasal saline irrigation analgesics (acetaminophen or ibuprofen) duration Mild – Moderate doxycycline 100 mg po q12h amoxicillin 1000 mg po q8h* • May recommend analgesics (acetaminophen or Symptoms greater than 10 days OR OR OR ibuprofen), topical intranasal corticosteroids and/or nasal saline irrigation for symptomatic relief worsening after 5 to 6 days OR May offer watchful waiting along with amoxicillin/clavulanate 875/125 Severe Symptoms for 3 to 4 • If a patient has been on antibiotic therapy in the past agents for symptom relief if mild symptoms mg po q12h* consecutive days month the antimicrobial therapy chosen should be and follow-up can be completed such that OR based on a different mechanism of action regardless antimicrobial therapy is started if condition of the clinical success fails to improve by day 7 after diagnosis of sulfamethoxazole/trimethoprim ABRS or worsens at any time. 800/160 mg po q12h* 5 – 7 days Failure of Initial Therapy amoxicillin/clavulanate 875/125 mg po levoFLOXacin 750 mg po q24h* • May recommend analgesics (acetaminophen or Symptoms worsening after 48 – 72 q12h* + amoxicillin 1000 mg po q12h* ibuprofen), topical intranasal corticosteroids and/or OR hrs. or failure to improve after 3 – 5 (high-dose amoxicillin with clavulanate) nasal saline irrigation for symptomatic relief days of initial empiric antimicrobial cefuroxime 500 mg po q8-12h* • Patients who fail to respond should be assessed for therapy possible causes including infection with resistant organism, inadequate dosing and noninfectious cause • Select an agent with broader spectrum of activity and from a different antimicrobial class Clinical Pearls • Facial pain-pressure-fullness without purulent nasal discharge is not sufficient for a diagnosis of acute uncomplicated bacterial rhinosinusitis • Majority of cases of acute sinusitis are viral and resolve within 5 to 7 days without the need for antibiotics; only 0.5 – 2% of viral upper respiratory infections are complicated by bacterial infection • Colour of nasal discharge or sputum is related to the presence of neutrophils, not bacteria, and should not be used alone to diagnose bacterial rhinosinusitis • Watchful waiting should be excluded in patients with immune deficiency or coexisting bacterial illness; prescribers should also consider the patient’s age, general health, cardiopulmonary status and comorbid conditions when assessing suitability for watchful waiting • Macrolides are not recommended for empiric therapy due to growing resistance rates for Streptococcus pneumoniae and Haemophilus influenzae within the Province • Respiratory fluoroquinolones (e.g. levoFLOXacin, moxifloxacin) should be reserved for failure of first-line options due to the potential for increasing resistance, risk of Clostridium difficile infection and their importance in the management of other infections • Respiratory fluoroquinolones (e.g. levoFLOXacin, moxifloxacin) have not been found to be superior to β-lactams in the management of ABRS • Antibiotics have not been shown to be beneficial in chronic rhinosinusitis without acute clinical deterioration • Consider ID consultation for refractory nosocomial rhinosinusitis or if immunocompromised • Decongestants (topical or oral) and/or antihistamines are not recommended as adjunctive therapy • Bacteriology of ABRS: S. pneumoniae, H. influenzae, Moraxella catarrhalis and S. aureus (less than 10%) *Dose adjustment required in renal impairment 9 Antimicrobial Therapy for Acute Exacerbation of Chronic Obstructive Pulmonary Disease (NB Provincial Health Authorities Anti-Infective Stewardship Committee, November 2015) Treatment Criteria  The use of antibiotics in acute exacerbations of chronic obstructive pulmonary disease (AECOPD) is controversial  Antimicrobial therapy is only recommended when AECOPD are accompanied by all 3 cardinal symptoms or at least 2 of the 3 cardinal symptoms, if increased sputum purulence is one of the 2 symptoms: 1. Increased dyspnea 2. Increased sputum volume 3. Increased sputum purulence  Patients receiving invasive or non-invasive ventilation for AECOPD should be initiated on intravenous antimicrobial therapy  Antibiotic selection should be based on patient symptoms and risk factors  If infiltrate on chest x-ray or pneumonia suspected then treat as per pneumonia treatment guidelines Probable Preferred Empiric Alternative Empiric Risk Stratification Duration Comments Organism Regimen Regimens Acute Bronchitis Viral in most cases Antimicrobial therapy not recommended • patients presenting with only 1 of Symptomatic therapy only the 3 cardinal symptoms Simple (Low-Risk Patients) Streptococcus doxycycline 100 mg po q12h amoxicillin/clavulanate 875/125 mg po • If a patient has received an antibiotic • Less than 4 exacerbations per year pneumoniae q12h* OR in the last 3 months the therapy Haemophilus sulfamethoxazole/trimethoprim 800/160 chosen should be a regimen based 5 days influenzae mg po q12h* OR on a different mechanism of action Moraxella catarrhalis cefuroxime 500 mg po q12h* OR regardless of the clinical success clarithromycin 500 mg po q12h • Tailor antibiotic therapy for sputum culture results if available Complicated (High Risk As in simple plus: Oral Therapy: Oral Therapy: • If a patient has received an antibiotic Patients) Klebsiella spp and amoxicillin/clavulanate 875/125 mg po cefuroxime 500 mg po q12h* OR in the last 3 months the therapy other Gram- q12h* clarithromycin 500 mg po q12h* OR chosen should be a regimen based At least one of: negatives, levofloxacin 750 mg po q24h* on a different mechanism of action • Forced expiratory volume in 1 5 – 10 days Increased probability regardless of the clinical success second (FEV1) less than 50% of beta-lactam Intravenous Therapy: Intravenous Therapy: • Tailor antibiotic therapy for sputum predicted 5 days resistance cefTRIAXone 1-2 g IV q24h levofloxacin 750 mg IV q24h* (for levofloxacin) culture results if available • Greater than or equal to 4 exacerbations per year • Ischemic heart disease • Use of home oxygen • Chronic steroid use Bronchiectasis/ As in simple and Oral Therapy: Oral Therapy: • Tailor antibiotic therapy for End-stage Lung Disease complicated plus: amoxicillin/clavulanate 875/125 mg po levofloxacin 750 mg po q24h* sputum culture results (past or Pseudomonas q12h* current) aeruginosa, ± Staphylococcus ciprofloxacin 500 -750 mg po q12h* aureus, MRSA (if Pseudomonas aeruginosa is suspected) Intravenous Therapy: 7 – 14 days Other non- Intravenous Therapy: levofloxacin 750 mg IV q24h* fermenting Gram cefTRIAXone 1-2 g IV q24h negative bacilli OR piperacillin/tazobactam 4.5 g IV q6h* (if Pseudomonas aeruginosa is suspected) Clinical Pearls • Macrolides are not recommended as first line empiric therapy due to growing resistance rates for Streptococcus pneumoniae and Haemophilus influenzae • Fluoroquinolones should be reserved for only severe cases, failure of first line options or β-lactam allergy in complicated cases due to the potential for increasing resistance, risk of Clostridium difficile infection and their importance in the management of other infections • Empiric therapy for atypical organisms (Mycoplasma pneumoniae & Chlamydophilia pneumoniae) not recommended • Consider obtaining cultures if not improving after 72 hours of antimicrobial therapy • Consider systemic corticosteroids for moderate to severe exacerbations of COPD (prednisone 40 mg po once daily for 5 days) • Influenza vaccination and pneumococcal vaccination recommended *Dose adjustment required in renal impairment 10 Antimicrobial Therapy for Adult Community Acquired Pneumonia (CAP) (NB Provincial Health Authorities Anti-Infective Stewardship Committee, May 2018) Treatment Considerations: • Having taken antibiotics within the past 3 months significantly increases the risk of resistant S. pneumoniae. Choose an antibiotic from a different class, regardless of clinical success. • Exclusions: immunosuppression, acute exacerbation of COPD, bronchitis, macro-aspiration, chronic pneumonia syndromeβ, cystic fibrosis, bronchiectasis, or MRSA. Determine severity of pneumonia and assess risk of mortality; calculate DS-CRB65 score by adding one point if any of the following criteria are met: History of any of the following comorbid diseases: heart failure, chronic renal disease, chronic liver disease, D  cerebrovascular disease (or other chronic neurological diseases), or active malignancy S Oxygen saturation (SpO2) less than 90% on room air  C Confusion (new onset)  R Respiratory rate greater than or equal to 30 breaths/minute  B Systolic blood pressure less than 90 mmHg OR diastolic blood pressure less than or equal to 60 mmHg  65 Age 65 or older  Total

Site of ∞ Severity DS-CRB65 Mortality Empiric Therapy (start antibiotics as soon as possible) Comments care

amoxicillin 1000 mg PO q8h* Microbiology Tests: None routinely OR Home (unless hospitalized, see below) (unless doxycycline 100 mg PO q12h Less than hospitalized If at risk for Gram-negative bacilli or S. aureus (e.g. post-influenza, alcoholism, COPD, Low 0-1 - Amoxicillin is the oral beta-lactam 1% for reason nursing home): that offers the best coverage other than amoxicillin-clavulanate 875/125 mg PO q12h* against S. pneumoniae. pneumonia) OR cefuroxime axetil 500 mg PO q8h* (if true immediate penicillin allergy⌂) Microbiology Tests: -Blood cultures (2 sets) ampicillin 2 g IV q6h* doxycycline 100 mg PO q12h + [ OR -Sputum culture Macrolide PO (see comments) OR (azithromycin 500 mg IV q24h x 3 days, then STOP)] -Urine antigen for pneumococcus and legionellosis‡ Moderate 2-3 3-9% Hospital If true immediate penicillin allergy▲, OR if at risk for Gram-negative bacilli or S. aureus (e.g. post-influenza, alcoholism, COPD, nursing home): (Depending on clinical context, consider investigation for atypical cefuroxime 1.5 g IV q8h* + [doxycycline 100 mg PO q12h OR pathogens and viruses) Macrolide PO (see comments) OR (azithromycin 500 mg IV q24h x 3 days, then STOP)]

- Macrolide PO: clarithromycin 500 mg PO q12h* OR azithromycin 500 mg PO day 1, then 250 mg PO q24h x 4 days cefTRIAXone 2 g IV q24h + azithromycin 500 mg IV q24h Hospital - If Legionella strongly suspected, OR High 4 or higher 15-29% (consider consider levoFLOXacin or azithromycin ICU) [levoFLOXacin 750 mg IV/PO q24h* or moxifloxacin 400 mg IV/PO q24h] - Exercise caution if using +/- ampicillin 2 g IV q6h* levoFLOXacin or moxifloxacin: (consider adding ampicillin to levofloxacin or moxifloxacin for ICU-based therapy) association with C. difficile and MRSA

Duration of therapy • Treat for a minimum of 5 days, and then until the patient meets all clinical stability criteria (see page 2), then STOP antibiotics. • Longer treatment duration may be required in certain circumstances (e.g. extrapulmonary infections, empyema, infections caused by P. aeruginosa or S. aureus, etc.).

(continued on next page) 11 IV to PO conversion (for more information, please refer to the IV-PO conversion policy and criteria) • Consider oral antibiotics when patients are able to tolerate PO medications and meet all the clinical stability criteria listed below: Clinical stability criteria - community acquired pneumonia Parenteral drug Suggested oral step-down

 Patient is afebrile (e.g. temperature lower than 38°C) for at least 48 hours ampicillin amoxicillin (high dose; 1000 mg PO q8h*)  Heart rate lower than or equal to 100 beats/minute  Respiratory rate lower than or equal to 24 breaths/minute azithromycin azithromycin or clarithromycin  Systolic blood pressure higher than or equal to 90 mmHg amoxicillin + clavulanic acid Cephalosporin (any)  Oxygen saturation (SpO2) higher than or equal to 90% on room air (or return to (or cefuroxime axetil if true penicillin allergy) baseline oxygen level for patients receiving long-term oxygen therapy) levoFLOXacin or moxifloxacin +/- ampicillin levoFLOXacin or moxifloxacin alone +/- amoxicillin  Normal mental state (compared to baseline)  Patient is able to tolerate oral intake Please note: oral monotherapy vs. combined therapy (atypicals) → clinical judgment; see below. Clinical pearls • Within the first 3 days of therapy, as many as 2/3 of patients will satisfy all clinical stability criteria. The majority of the remaining 1/3 of patients will satisfy all criteria by day 7 of therapy. • In low-risk patients, consider adding doxycycline or a macrolide to a beta-lactam regimen if high clinical suspicion of atypical pathogens (beta-lactams DO NOT cover atypicals).Clinical features favouring “atypical” bacteria (Mycoplasma or Chlamydophila): gradual onset and presentation, absence of septic shock, non-lobar pneumonia, family cluster, cough persisting more than 5 days without acute clinical deterioration, absence of sputum production, and normal or minimally elevated white-cell count. • It is important to note that, although Legionella is defined as an “atypical” pathogen, the presentation is similar to “typical” pathogens (i.e. hyperacute and severe presentation). • Azithromycin dosing and duration of therapy depends on the route of administration and its indication for use: 1) When using 500 mg IV once daily in non-critically ill patients, 3 days of therapy is adequate; 2) When using the PO formulation, or in patients that are critically ill, 5 days of therapy is adequate; 3) In patients with infections caused by Legionella, 7 to 10 days of therapy may be required. • Patients at high risk for pneumonia (e.g. age 65 and older, nursing home residents, COPD, etc.) should receive influenza and pneumococcal vaccines if vaccination not up to date. • While MRSA is rarely associated with CAP in New Brunswick, consider adding vancomycin empirically if severe pneumonia (i.e. DS-CRB65 score of 4 or higher) AND presence of one of the following MRSA risk factors: history of MRSA infection or colonization, IV drug use, homelessness, member of First Nations community, incarcerated person, or recent travel to an MRSA endemic region. • Recent literature suggests that corticosteroids could be considered in certain patients with a high inflammatory response due to severe CAP. However, it should be noted that preliminary data suggests patients with influenza pneumonia may not benefit, and could be harmed by adding corticosteroids. • Due to potential QTc prolongation, consider baseline ECG if prescribing macrolides or quinolones to certain patients (e.g. other QTc prolonging drugs, electrolyte abnormalities, etc.). *Dose adjustment required in renal impairment ‡If antigen is positive for Legionella, efforts must be made to obtain sputum and advise laboratory that Legionella culture is required. This is important for epidemiological purposes in case of an outbreak. ∞If microbial cause of infection known, treat accordingly ▲ True, immediate IgE-mediated allergies include, but are not limited to: anaphylaxis, urticaria, angioedema, hypotension, bronchospasm, stridor, and pruritis. β Chronic pneumonia syndrome: pneumonia symptoms lasting more than 3 weeks

12 Antimicrobial Treatment of Hospital Acquired Pneumonia (HAP) (New Brunswick Provincial Health Authorities Anti-Infective Stewardship Committee, May 2018) Definition: Pneumonia that develops 48 hours or more after admission to hospital. ***Note: ventilator-associated pneumonia is excluded; please refer to ventilator-associated pneumonia guidelines.*** Probable pathogens: S. aureus (MSSA or MRSA), Gram-negative bacilli (e.g., E. coli, K. pneumoniae, P. aeruginosa), or S. pneumoniae. Microbiological analyses: Blood cultures x 2 sets (always) + sputum culture +/- S pneumoniae urinary antigen

Patient’s ∞ Risk stratification Empiric therapy Comments condition First-line • Consider adding empiric vancomycin (target cefTRIAXone 2 g IV q24h trough 15-20 mg/L) in patients with a risk factor STABLE If true immediate allergy to a beta-lactam at risk for cross-reactivity with for MRSA: ▲ If NO risk factors cefTRIAXone : o History of MRSA infection or colonization (indicated below) levoFLOXacin 750 mg IV/PO q24h* OR moxifloxacin 400 mg IV/PO q24h o Injection drug use First-line o Homelessness piperacillin-tazobactam 4.5 g IV q6h* o Member of First Nations community UNSTABLE ▲ Incarcerated person Risk factors for MDR If true immediate penicillin allergy o (or requiring higher Recent travel to an MRSA endemic region pathogens or poor outcomes meropenem 500 mg IV q6h* o  Use of IV antibiotics in past 90 level of care) ‡ • days If severe delayed reaction to a beta-lactam: If history of infection or colonization with Gram-  Immunosuppression levoFLOXacin 750 mg IV q24h* + tobramycin 7 mg/kg IV q24h* negative bacilli producing AmpC or ESBL beta-  Chronic lung disease (e.g., lactamases, empiric use of meropenem is bronchiectasis, cystic fibrosis) First-line encouraged (may consider fluoroquinolones if  In intensive care unit (ICU) piperacillin-tazobactam 4.5 g IV q6h* stable and no risk factors). when symptoms appear, or transferred from ICU in last If true immediate penicillin allergy▲ • DO NOT use cefTRIAXone or moxifloxacin if STABLE 48 hours meropenem 500 mg IV q6h* Pseudomonas infection is confirmed or suspected. ‡ If severe delayed reaction to a beta-lactam levoFLOXacin 750 mg IV/PO q24h* + tobramycin 7 mg/kg IV q24h* • If the patient received an antibiotic in the past 3 If presence of at least months, choose an antibiotic from a different one risk factor First-line class, regardless of clinical success. nd (indicated above) piperacillin-tazobactam 4.5 g IV q6h* + 2 anti-pseudomonal agent • Second anti-pseudomonal agents should be (+/- vancomycin 25 mg/kg IV x1 dose, then 15 mg/kg IV q8h*; see from another class, and can include: comments) o tobramycin 7 mg/kg IV q24h* ciprofloxacin 400 mg IV q8h* UNSTABLE If true immediate penicillin allergy ▲: o (or requiring higher meropenem 500 mg IV q6h* + 2nd anti-pseudomonal agent level of care) (+/- vancomycin 25 mg/kg IV x 1 dose, then 15 mg/kg IV q8h*; see comments)

‡ If severe delayed reaction to a beta-lactam levoFLOXcin 750 mg IV q24h* + tobramycin 7 mg/kg IV q24h* + vancomycin 25 mg/kg IV x 1 dose, then 15 mg/kg IV q8h* Duration of therapy

• Treat for no more than 7 days if good clinical response, regardless of bacterial etiology. • Treatment duration could be prolonged for more than 7 days in certain situations (e.g., empyema, extrapulmonary infections, S. aureus bacteremia, immunosuppression, etc.)

(continued on next page) 13 Clinical Pearls

• Recent studies have shown that, compared with standard treatment durations of 10 days or more, 7-day treatment durations were associated with fewer relapses caused by multiresistant pathogens WITHOUT affecting mortality rate. • To avoid prolonged use of broad-spectrum antibiotics, it is essential to de-escalate therapy according to the results of microbiologic analyses. • For patients with HAP requiring intubation, an endotracheal secretions culture is recommended. • Empiric coverage of atypical organisms (e.g., Legionella, Mycoplasma) is generally not recommended. Consider atypical coverage if nosocomial outbreak of Mycoplasma or Legionella. • Empiric double coverage of Pseudomonas aeruginosa is to maximize the likelihood of having at least one active agent (due to increased risk of resistance with Pseudomonas). If Pseudomonas is isolated, step-down to monotherapy (according to susceptibility data). ***Use of aminoglycosides (e.g., tobramycin and gentamicin) as monotherapy for the treatment of pneumonia is NOT recommended (even if susceptibility is confirmed). • DO NOT use DAPTOmycin to treat pneumonia; DAPTOmycin is inactivated by pulmonary surfactant. If MRSA infection, use vancomycin (or linezolid if vancomycin is ineffective or inappropriate). • Serial procalcitonin levels (if available), in combination with clinical evaluation, may assist in the decision to discontinue antibiotics. * Dose adjustment required in renal impairment. ∞ If microbial cause of infection known, treat accordingly. ▲ Immediate, IgE mediated allergies include, but are not limited to, anaphylaxis, urticaria, angiœdema, hypotension, bronchospasm, stridor, and pruritic rash. Refer to the NB-ASC Beta-Lactam Allergy guidelines to determine which beta-lactams share similar side chains. ‡ Severe delayed hypersensitivity reactions to beta-lactams are caused by mechanisms that are not well known and require that subsequent use of beta-lactams be avoided. Severe delayed hypersensitivity reactions can include interstitial nephritis, immune hepatitis, hemolytic anemia, serum sickness, severe cutaneous reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug rash with eosinophilia and systemic symptoms (DRESS).

14 Antimicrobial Treatment of Ventilator-Associated Pneumonia (VAP) (New Brunswick Provincial Health Authorities Anti-Infective Stewardship Committee, May 2018) Definition: Pneumonia that develops 48 hours or more after endotracheal intubation. Probable pathogens: S. aureus (MRSA or MSSA), gram-negative bacilli (e.g., E. coli, K. pneumoniae, P. aeruginosa, A. baumannii) Microbiological analyses (always order): Blood cultures x 2 sets + endotracheal suctioning for culture

Risk stratification Empiric therapy∞ Comments

• Consider adding empiric vancomycin (target trough 15-20 mg/L) in patients with septic shock requiring vasopressors, First-line or with a risk factor for MRSA: piperacillin-tazobactam 4.5 g IV q6h* o History of MRSA infection or colonization If NO risk factors Injection drug use (indicated below) o ▲ Homelessness If true immediate penicillin allergy : o Member of First Nations community meropenem 500 mg IV q6h* o o Incarcerated person o Recent travel to an MRSA endemic region Risk factors for MDR pathogens or poor If severe delayed reaction‡ to a beta-lactam outcomes • If history of infection or colonization with Gram-negative levoFLOXacin 750 mg IV q24h* + tobramycin 7 mg/kg IV q24h*  Septic shock requiring vasopressors bacilli producing AmpC or ESBL beta-lactamases, empiric  Use of IV antibiotics in past 90 days use of meropenem is encouraged.  Immunosuppression • If the patient received an antibiotic in the past 3 months,  Chronic lung disease (e.g., choose an antibiotic from a different class, regardless of bronchiectasis, cystic fibrosis) clinical success.  Acute renal replacement therapy before First-line nd VAP onset piperacillin-tazobactam 4.5 g IV q6h* + 2 anti-pseudomonal agent • Second anti-pseudomonal agents should be from  Hospitalization for at least 5 days before (+/- vancomycin 25 mg/kg IV x 1 dose, then 15 mg/kg IV q8h*; another class, and can include: VAP onset see comments) o tobramycin 7 mg/kg IV q24h*  Acute respiratory distress syndrome o ciprofloxacin 400 mg IV q8h* (ARDS) before VAP onset If true immediate penicillin allergy▲ meropenem 500 mg IV q6h* + 2nd anti-pseudomonal agent (+/- vancomycin 25 mg/kg IV x 1 dose, then 15 mg/kg IV q8h*; If presence of at least see comments) one risk factor (indicated above) If severe delayed reaction‡ to a beta-lactam levoFLOXacin 750 mg IV q24h* + tobramycin 7 mg/kg IV q24h* + vancomycin 25 mg/kg IV x 1 dose, then 15 mg/kg IV q8h*

Duration of therapy

• Treat for no more than 7 days if good clinical response, regardless of bacterial etiology. • Treatment duration could be prolonged for more than 7 days in certain situations (e.g., empyema, extrapulmonary infections, S. aureus bacteremia, immunosuppression, etc.)

(continued on next page) 15 Clinical Pearls

• Recent studies have shown that, compared with standard treatment durations of 10 days or more, 7-day treatment durations were associated with fewer relapses caused by multiresistant pathogens WITHOUT affecting mortality rate. • To avoid prolonged use of broad-spectrum antibiotics, it is essential to de-escalate therapy according to the results of microbiologic analyses. • The role of antimicrobials in the treatment of ventilator-associated tracheobronchitis¶ is controversial. Consider initiating antimicrobial therapy if clinical deterioration (e.g. progressive hypoxemia). • Empiric double coverage of Pseudomonas aeruginosa is to maximize the likelihood of having at least one active agent (due to increased risk of resistance with Pseudomonas). If Pseudomonas is isolated, step-down to monotherapy (according to susceptibility data). ***Use of aminoglycosides (e.g., tobramycin and gentamicin) as monotherapy for the treatment of pneumonia is NOT recommended (even if susceptibility is confirmed). • DO NOT use DAPTOmycin to treat pneumonia; DAPTOmycin is inactivated by pulmonary surfactant. If MRSA infection, use vancomycin (or linezolid if vancomycin is ineffective or inappropriate). • Serial procalcitonin levels (if available), in combination with clinical evaluation, may assist in the decision to discontinue antibiotics. * Dose adjustment required in renal impairment. ∞ If microbial cause of infection known, treat accordingly. ▲ Immediate, IgE mediated allergies include, but are not limited to, anaphylaxis, urticaria, angiœdema, hypotension, bronchospasm, stridor, and pruritic rash. ‡ Severe delayed hypersensitivity reactions to beta-lactams are caused by mechanisms that are not well known and require that subsequent use of beta-lactams be avoided. Severe delayed hypersensitivity reactions can include interstitial nephritis, immune hepatitis, hemolytic anemia, serum sickness, severe cutaneous reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug rash with eosinophilia and systemic symptoms (DRESS). ¶ Ventilator-associated tracheobronchitis: fever with no other identifiable cause with: significant purulent secretions, positive endotracheal aspirate culture, and ABSENCE of pneumonia on a chest X-ray.

16 Treatment of Cellulitis/Skin Infection (NB Provincial Health Authorities Anti-Infective Stewardship Committee, September 2017) Cellulitis/Erysipelas Duration of Preferred Empiric Regimens Comments Severity Therapy Mild cephalexin 500 - 1000 mg PO q6h2 5 days Work-up: None, unless there is (no signs of systemic toxicity) OR (may extend an associated fluctuant pustule cefadroxil 500 - 1000 mg PO q12h2,3 duration if not that can be drained and sent for 1 improved) - Assess for risk factors or 4 culture clinical evidence of MRSA True immediate allergy to a beta-lactam at risk of cross-reactivity with cephalexin or (e.g. purulent boil with cefadroxil: 2 spreading cellulitis, previous cefuroxime 500 mg PO q8-12h MRSA infections or 5 colonization) Severe delayed reaction to a beta-lactam where their future use is not recommended: clindamycin 300 - 450 mg PO q6h MRSA Suspected: sulfamethoxazole/trimethoprim 800/160 mg to 1600/320 mg (1 or 2 DS tablets) PO q12h2,6 OR doxycycline 100 mg PO q12h6 Moderate ceFAZolin 2 g IV q8h2 5 days Work-up: As above plus: (signs of systemic toxicity) (may extend Consider blood cultures (2 sets) Alternative for outpatient management: duration if not 2 OR probenecid 1 g PO followed 30 - 60 min later by ceFAZolin 2 g IV, repeated q24h improved) OR 7 If on IV therapy Progression on oral therapy cefTRIAXone 2 g IV q24h assess every 48 Severe delayed reaction5 where future use of β-lactams not recommended: hours for clindamycin 600-900 mg IV q8h appropriateness for IV to PO MRSA suspected, add: 8 2 conversion (see vancomycin 25 to 30 mg/kg IV x 1 dose then 15 mg/kg IV q8-12h PO options available (adjust based on levels to a trough target of 15 - 20 mg/L) under mild severity) Severe ceFAZolin 2 g IV q8h with or without clindamycin 900 mg IV q8h Consult with Work-up: As above plus: urgent (sepsis syndrome, Necrotizing specialists surgical assessment for Fasciitis [clinical features of NF Risk of mixed bacterial infection: diagnostic biopsy and/or 2 with or without include systemic toxicity, deep piperacillin-tazobactam 3.375 g IV q6h debridement severe pain – more severe than clindamycin 900 mg IV q8h expected for skin findings, violaceous bullae, rapid spread MRSA suspected, add: 2 along fascial planes, gas in soft vancomycin 25 to 30 mg/kg IV x 1 dose then 15 mg/kg IV q8-12h tissues]) (adjust based on levels to a trough target of 15 - 20 mg/L) Clinical pearls:  These guidelines are for basic skin infections only, any complicating features on history may require alternative management (Specific but not exclusive examples include: immunocompromised patients, diabetic foot infections, cellulitis associated with a surgical site, trauma or animal/human bites)  Consider looking for predisposing feature (e.g. Tinea pedis) as source of cellulitis 1 Risk factors for MRSA infection include: known or previous colonization, recent hospitalization, homelessness, injection drug use, member of First Nations community and incarcerated person 2 Dose adjustment required in renal impairment 3 Non-formulary agent not available within hospital 4 True, immediate IgE-mediated allergies include, but are not limited to: anaphylaxis, urticaria, angioedema, hypotension, bronchospasm, stridor, and pruritis. 5 Stevens-Johnson syndrome, toxic epidermal necrolysis, immune hepatitis, DRESS, serum sickness, hemolytic anemia or interstitial nephritis 6 Poor coverage for beta-hemolytic streptococci, consider combining with cephalexin or cefadroxil 7 Assessment of clinical response within 48 hours should be based on pain and fever; mild progression of erythema expected during this timeframe 8 IV to PO conversion appropriate when patient: afebrile, hemodynamically stable, clinically improving, and able to tolerate oral intake (see IV to PO conversion policy for more details) 17 When to Send a Urine for Culture and Urinalysis (NB Provincial Health Authorities Anti-Infective Stewardship Committee, September 2017)

Start UTI Symptoms Cystitis Catheter-Associated UTI Pyelonephritis • Dysuria • Fever • Fever • ↑ frequency • Acute hematuria • Nausea, vomiting • ↑ urgency • Delirium • Costovertebral pain • Suprapubic • Rigors • Flank pain pain • Flank Pain • ± lower tract • ± Lower tract symptoms symptoms if catheter removed Cloudy and/or foul smelling urine are NOT symptoms of UTI

Does the Do NOT send urine for patient have No any UTI culture and/or urinalysis (Unless pregnant or for urologic symptoms? procedure where mucosal bleeding expected)

Yes

Does a non-UTI diagnosis likely Work-up other cause for Yes account for the symptoms symptoms?

No Clinical Pearls • “Changes in cognitive function and declines in activities of daily living REQUIRE careful clinical assessment. DO NOT VCH/ASPIRES 2014 Send urine for culture assume they are secondary to UTI.” • (if patient catheterised send culture Urine culture and susceptibility and urinalysis testing is NOT necessary or beneficial in healthy, non-pregnant, premenopausal, non-diabetic women with from new catheter) acute cystitis (at least 2 of 3 cardinal symptoms – dysuria, urgency or frequency) and NO vaginal discharge without functional or anatomical abnormalities of the urinary tract.

Consider empiric • Always obtain a culture for: pregnant women; patients with sign and symptoms of pyelonephritis; premenopausal adult females with recurrent cystitis; urological antibiotics* procedure; patients with complicated urinary tract infections (i.e. structural abnormality, obstruction, recent urologic procedure, male sex, immunosuppression, poorly controlled diabetes, spinal cord injury or catheterization) Review u rine c ulture *Refer to NB-ASC UTI Treatment Guideline for antibiotic selection results to tailor antibiotic therapy 18 Positive Urine Culture Assessment Algorithm (NB Provincial Health Authorities Anti-Infective Stewardship Committee, September 2017)

Positive Urine Culture

Asymptomatic Bacteriuria Catheter-Associated UTI

Definition Presence of symptoms with greater than 106 CFU/L of ≥ 1 bacterial species in a single catheter urine specimen or in a midstream voided urine after catheter removal for 48 hours, with a positive urinalysis for pyuria Urological Pregnant Possible Signs & Symptoms: Procedure New onset or worsening fever, rigors, altered mental (mucosal bleeding status, malaise, or lethargy with no other identified cause; expected) flank pain; costovertebral tenderness; acute hematuria; pelvic discomfort and in those with catheter removed NO YES dysuria, urgent or frequent urination or suprapubic pain NO or tenderness. · If spinal cord Injury, symptoms may also YES include increased spasticity, autonomic dysreflexia OR a sense of unease

Treat Surgical Do NOT according to Prophylaxis2 Treat urine C&S Was the catheter changed immediately before urine culture was collected? NO YES Symptomatic Bacteriuria

Cystitis (lower UTI) If catheter required, obtain urine culture Dysuria, urgency, frequency, or suprapubic pain with no fever or flank pain; change Treat according to and urinalysis through new catheter prior in cognitive function or activities of daily living REQUIRE careful clinical assessment, urine C&S only if to initiation of antimicrobial therapy never assume these are due to UTI symptoms present OR (adjust according to C&S If catheter is not required, culture voided Pyelonephritis (upper UTI) results) midstream urine prior to initiation of antimicrobial therapy Fever, flank pain, costovertebral tenderness, abdominal/pelvic pain, nausea, vomiting with or without signs/symptoms of lower tract UTI

Treat according to NB-ASC UTI 1 Treatment Guideline1 if See NB-ASC UTI Treatment Guideline for Treatment symptoms present Options (adjust according to C&S results) (Adjust Antimicrobial Therapy According to Urine C&S Results)

1Treatment of Adult Urinary Tract Infections (NB Health Authorities Anti-Infective Stewardship Committee, May 2014) 2Surgical Prophylaxis Guidelines (NB Health Authorities Anti-Infective Stewardship Committee, May 2015) *Urine culture may be contaminated by colonized bacteria. 19 Treatment of Adult Urinary Tract Infections (NB Provincial Health Authorities Anti-Infective Stewardship Committee, September 2017) Empiric Therapy Indication (Tailor regimen based on urine/blood C&S results) Duration Comments Asymptomatic Antibiotic therapy only recommended for: Urological • Asymptomatic bacteriuria with pyuria is NOT an indication for antimicrobial therapy Bacteriuria -Prophylaxis for urological procedures when mucosal bleeding procedures: Pregnancy expected see surgical • Repeat culture and urinalysis 1 week after therapy complete as a test of cure; if positive repeat -Treatment in pregnancy prophylaxis treatment according to urine C&S guideline • Monthly repeat urine cultures recommended for screening until completion of pregnancy • Consider prophylactic/suppressive antibiotic therapy for persistent bacteriuria (Select antimicrobial therapy according to urine C&S) Pregnancy: 3 – 7 days • Intrapartum prophylaxis of early-onset Group B Streptococcal (GBS) disease is recommended if GBS is isolated in urine or vaginal swab Uncomplicated Preferred Regimen: Pregnancy nitrofurantoin monohydrate/macrocrystals 100 mg PO q12h 5 days • (Lower UTI) Repeat culture and urinalysis 1 week after therapy complete as a test of cure; if positive repeat Cystitis (Not recommended if CrCl less than 40 mL/min; in pregnancy, avoid (Female patients with treatment according to urine C&S near term (36-42 weeks) due to risk of haemolytic anemia in the new • Monthly repeat urine cultures recommended for screening until completion of pregnancy dysuria, urgency, born) frequency, or suprapubic • Consider prophylactic/suppressive antibiotic therapy for persistent or recurrent cystitis pain with no fever or flank Alternative Regimens: • Intrapartum prophylaxis of early-onset Group B Streptococcal (GBS) disease is recommended if pain) cefuroxime 500 mg PO q8h OR 7 days GBS is isolated in urine or vaginal swab fosfomycin 3 g PO once4 OR One dose sulfamethoxazole/trimethoprim 800/160 mg PO q12h1,3 3 days (Not recommended in pregnant women) Acute Systemically Well: See Acute Uncomplicated Pyelonephritis Preferred Regimen: Comments • Outpatient management an option if female, not pregnant, no nausea/vomiting, no evidence of Uncomplicated 3 cefixime 400 mg PO q24h dehydration, sepsis or high fever Pyelonephritis • Treat for 14 days (Upper UTI) Alternative Regimens: 3 • May treat for 7 days if female, uncomplicated and using ciprofloxacin (Signs/Sx: fever, flank pain, amoxicillin/clavulanate 875/125 mg PO q12h • For treatment using oral β-lactams, consider an initial single intravenous dose of cefTRIAXone 1 costovertebral tenderness, Additional options if culture confirmed susceptibility: abdominal/pelvic pain, 1,3 g IV and use a 14 day total duration of antimicrobial therapy sulfamethoxazole/trimethoprim 800/160 mg PO q12h nausea, vomiting with or OR ciprofloxacin 500 mg PO q12h1,3 Complicated UTI: without signs/sx of lower • Treat 7 days if prompt response, female and only lower urinary tract infection tract UTI) • Treat 14 days if male, delayed response, structural abnormality, or upper tract symptoms Systemically Unwell/Pregnant: 2 Catheter-Associated UTI: OR cefTRIAXone 1 g IV q24h OR • Pyuria not diagnostic, only treat if symptomatic ampicillin 2 g IV q6h + (tobramycin OR gentamicin) 5 mg/kg IV 2,3,5 • Complicated UTI once daily OR Catheters frequently colonized, obtain culture through new catheter (Complicating Factors: piperacillin/tazobactam 3.375 g IV q6h2,3 • Change catheter if in place for greater than 2 weeks & still required structural abnormality, Pregnancy obstruction, recent • Treat for 10 to 14 days urogenital procedure, male • Prophylactic/suppressive antibiotic therapy recommended for the remainder of the pregnancy sex, immunosuppression, • Repeat culture and urinalysis 1 week after therapy complete as a test of cure; if positive repeat poorly controlled diabetes, spinal cord injury, treatment according to urine C&S catheterization or Signs/Sx • Monthly repeat urine cultures recommended for screening until completion of the pregnancy greater than 7 days) • Intrapartum prophylaxis of early-onset Group B Streptococcal (GBS) disease is recommended if GBS is isolated in urine or vaginal swab Clinical Pearls: • Cloudy and foul smelling urine alone are NOT considered signs of infection and are NOT an indication for a urine culture and sensitivity • Urinalysis interpretation: o Presence of nitrites and leukocytes (leukocyte esterase positive or WBC) and new UTI symptoms: good positive predictive value of UTI o Absence of nitrites and/or leukocytes (negative leukocyte esterase or WBC): good negative predictive value • Therapy should be adjusted according to culture and sensitivity results • Blood cultures should be drawn if febrile, septic, signs and symptoms suggestive of pyelonephritis or immunocompromised • Post-treatment culture not recommended except in case of persistent or recurrent symptoms or pregnancy • nitrofurantoin and fosfomycin are not appropriate for men, complicated UTI or systemic infections 1CAUTION: Significant E.coli resistance (greater than 20%) to fluoroquinolones, sulfamethoxazole/trimethoprim and amoxicillin exist in some areas of the province; check local antibiogram and confirm urine C&S results when available 2De-escalate according to urine/blood C&S and switch IV to PO based on conversion criteria 3Dose adjustment required in renal impairment 4Fosfomycin criteria for use: for multi-drug resistant E.coli or Enterococcus faecalis with limited oral options OR where recommended alternatives are not appropriate due to allergies, drug interactions, poor renal function or other considerations 5Please see aminoglycoside dosing guide for more details on appropriate dosing adjustments and monitoring 20 Approved: September 2018

AMINOGLYCOSIDES DOSING AND MONITORING GUIDELINES

NB Provincial Health Authorities Anti-Infective Stewardship Committee

GENERAL COMMENTS

• Aminoglycosides (AG) include gentamicin, tobramycin, amikacin and streptomycin • AG exert bactericidal activity against gram-negative bacteria • Combination of gentamicin with a cell-wall active agent (i.e. beta-lactam) results in a synergistic effect on certain gram-positive bacteria such as Enterococci and Streptococci in the treatment of endocarditis • Amikacin is generally reserved for infections due to organisms with documented resistance to gentamicin and tobramycin; refer to amikacin section for dosing and monitoring information • Streptomycin is used infrequently to treat drug resistant tuberculosis and nontuberculous mycobacterial infections; its dosage and monitoring are not included in these guidelines • There are three dosing strategies for AG: o Conventional dosing of AG: weight-based dose administered three times a day, or less frequently in decreased renal function o Extended-interval dosing of AG (also called “once daily dosing”): a larger weight-based dose (approximately triple conventional dosing) administered once a day, or less frequently in decreased renal function o Synergistic dosing for gram-positive infections • AG exhibit concentration-dependent killing: higher serum concentrations result in higher rates and extent of bacterial killing • AG demonstrate a post-antibiotic effect: suppression of bacterial growth is continued even after serum concentrations have decreased below the minimum inhibitory concentration (MIC) • AG are nephrotoxic, ototoxic and can produce neuromuscular blockade (in patients with myasthenia gravis, the use of AG is contraindicated) CLINICAL PEARLS • Use care when selecting the dosing interval in patients that are older and/or with multiple co- morbidities (ex. diabetes, heart failure, etc.) or where estimated creatinine clearance would be expected to be an overestimate (ex. low muscle mass in an elderly patient, dysmobility, paraplegia, etc.) • The provided ranges for estimated creatinine clearance are only intended to be a guide for the selection of an empiric dosing interval and should not be used in isolation without considering patient and infection-related factors – especially when estimated creatinine clearance approaches the either end of the range.

21 GENTAMICIN AND TOBRAMYCIN IN ADULT PATIENTS

ADULT EXTENDED INTERVAL DOSING • Use extended interval dosing whenever possible • Takes advantage of concentration-dependent killing and post-antibiotic effect properties of AG with the goals of enhancing efficacy with higher peaks and potentially decreasing toxicity with greater drug-free intervals • Extended interval AG dosing should NOT be used in: o Patients requiring dialysis o Patients with rapid clearance of AG, including burns exceeding 20% of body surface area o Patients with gram-positive infections where AG is used for synergy (i.e. endocarditis) • Extended interval AG dosing should be used with CAUTION in: o Patients with creatinine clearance (CrCl) less than 20 mL/min o Patients with chronic ascites or serious liver disease (altered volume of distribution) o Patients with known auditory or vestibular disease or pre-existing impairment o Pregnant women Initial Dose • 5-7 mg/kg IV o based on ideal body weight or dosing weight (see appendix B) o use 7 mg/kg for serious infections or infections due to Pseudomonas aeruginosa or multidrug resistant organisms o round dose to nearest 20 mg • An initial dosing interval is chosen based on renal function as per the following table Creatinine Clearance Dosing Interval greater than or equal to 60 mL/min q24h 40 to 59 mL/min q36h 20 to 39 mL/min q48h; consider conventional dosing less than 20 mL/min Give first dose then draw serial serum drug levels to determine when to give next dose. Consider conventional dosing.

Levels • Monitoring of trough levels alone is generally sufficient with extended interval dosing • Trough levels verify that AG is being adequately eliminated and is not accumulating • Peak levels are typically NOT required, as the larger doses used are expected to produce concentrations well above those required for clinical efficacy • Peak levels are done in the rare cases where individualized pharmacokinetic monitoring is required Target serum concentrations: • Trough levels: less than 1 mg/L • Peak levels [only if indicated]: 15-25 mg/L o Optimal bactericidal activity for AG is achieved when maximum serum concentrations are approximately 8 to 10 times the MIC Levels recommended are in: • Treatment anticipated to be longer than 3-5 days • Patients more than 65 years of age • Patients with renal dysfunction (CrCl less than 60 mL/min ) or significant changes in renal function from baseline • Patients receiving other nephrotoxic drugs (i.e. vancomycin, NSAIDs, diuretics, ACE-I, ARBs, etc.) • Patients with a large volume of distribution (e.g., ascites, third spacing) • Pregnant women

22 Serum sampling: • Trough levels are taken immediately before a dose (within 30 minutes) • Peak levels are taken 90 minutes after the END of drug infusion, to allow for distribution • The timing and duration of drug administration and sample collection must be carefully documented Timing of serum levels: • The notion of steady state does not apply with extended-interval dosing; therefore levels may be taken prior to the 2nd dose Interpreting serum levels and adjusting dose: • Ensure serum samples were collected at the appropriate time • Trough level result of 1 mg/L or more suggests accumulation; extend dosing interval Hartford Hospital Nomogram (see appendix D): • A random level taken between 8 to 12 hours after the START of drug infusion may be used to determine appropriate dosing interval using the Hartford Hospital nomogram • Only to be used with a 7 mg/kg dose; has not been validated with other doses Monitoring and patient counselling Subsequent serum levels: • After a change in dose • At least once a week for most patients Monitor: • Clinical response • Renal function o Serum creatinine (SCr) at baseline and every 2 to 3 days during therapy o AG can cause renal dysfunction; typically reversible if discontinued in a timely manner; close monitoring is warranted • Ototoxicity o Patients should be advised to watch for and report signs & symptoms of cochlear toxicity (e.g., tinnitus, sense of fullness in ears, loss of hearing) and of vestibular toxicity (e.g., disequilibrium, oscillopsia, cognitive dysfunction, visual sensitivity, nausea/vomiting, vertigo, headache, nystagmus). o AG should be discontinued immediately if any signs/symptoms of toxicity develop; ototoxicity caused by AG may be irreversible. o Audiometry and vestibular testing recommended for patients receiving AG for 7 days or more, or at any time if ototoxicity suspected. Consult Audiology. o If prolonged therapy expected (greater than 7 days) baseline audiometry may be considered o Assess need for continued AG therapy based on microbial susceptibilities, clinical response, side effects, duration of therapy, etc.

23 ADULT CONVENTIONAL DOSING • Use conventional dosing when extended-interval dosing is not indicated Initial Dose Loading dose: • 2 mg/kg IV o based on ideal body weight or dosing weight (see appendix B) o round dose to nearest 20 mg o loading doses DO NOT need to be adjusted in patients with renal dysfunction; only maintenance dosing interval requires adjustment Maintenance dose: • 1.5 to 2 mg/kg IV o based on ideal body weight or dosing weight (see appendix B) o round dose to nearest 20 mg Dosing interval: • Interval depends on patient’s renal function Creatinine Clearance Dosing Interval greater than or equal to 80 mL/min q8h 50 to 79 mL/min q12h 20 to 49 mL/min q24h less than 20 mL/min q48-72h; give first dose and draw serial serum drug levels to determine when to give next dose; close monitoring is recommended

Levels • Therapeutic drug monitoring of AG dosed conventionally is typically done by measuring both peak and trough levels at steady state to confirm that therapeutic concentrations have been achieved and that drug accumulation has not taken place Target serum concentrations: Infection Desired minimal (trough) Desired maximum (peak) plasma concentration plasma concentration (mg/L) (mg/L) Lower urinary tract infection less than 1 4-6 Pelvic inflammatory disease (e.g., less than 2 6-8 endometritis, salpingitis, tubo- ovarian abscess, pelvic peritonitis) Chorioamnionitis Pyelonephritis Peritonitis Soft tissue infections Sepsis less than 2 8-10 Neutropenia Burns Pneumonia Infections due to Pseudomonas (non-urinary) Bone and joint infections Cystic fibrosis less than 2 10-15

Levels are recommended in: • Treatment anticipated to be longer than 3-5 days • Patients more than 65 years of age

24 • Patients with renal dysfunction (CrCl less than 60 mL/min) or significant changes in renal function from baseline • Patients receiving other nephrotoxic drugs (e.g., vancomycin, NSAIDs, diuretics, ACE-I, ARBs, etc.) • Patients with a large volume of distribution (e.g., ascites, third spacing) • Pregnant women Serum sampling: • Trough levels are taken immediately before a dose (within 30 minutes) • Peak levels are taken 30 to 60 minutes after the END of the IV infusion • The timing and duration of drug administration and sample collection must be carefully documented Timing of serum levels: • Levels should be taken at steady state, typically before and after the 3rd dose in patients with normal renal function • Steady state (SS) occurs in 4 to 5 half-lives and can be estimated by the following equations: o Ke (gentamicin) = CrCl x 0.00285 + 0.015 o Ke (tobramycin) = CrCl x 0.0031 + 0.01 o T½ = 0.693/Ke o SS = 4 to 5 T½ Interpreting serum levels and adjusting dose: • Ensure serum samples were collected at the appropriate time and at steady state • Adjust AG dose if serum concentrations are not within the desired range as follows: high trough extend dosing interval high peak decrease dose low peak increase dose • AG exhibit linear kinetics; decreasing or increasing the dose by a specific percentage will result in an equal decrease/increase in percentage of peak levels • Pharmacokinetic calculations may be used determine the dose most likely to produce the desired levels, based on the pre and post levels obtained from the patient. Contact Pharmacy. Monitoring and patient counselling Subsequent serum levels: • After a change in dose, levels should be repeated at new steady state • At least once a week for most patients Monitor: • Clinical response • Renal function o Serum creatinine (SCr) at baseline and every 2 to 3 days during therapy o AG can cause renal dysfunction; typically reversible if discontinued in a timely manner; close monitoring is warranted • Ototoxicity o Patients should be advised to watch for and report signs & symptoms of cochlear toxicity (e.g., tinnitus, sense of fullness in ears, loss of hearing) and of vestibular toxicity (e.g., disequilibrium, oscillopsia, cognitive dysfunction, visual sensitivity, nausea/vomiting, vertigo, headache, nystagmus). o AG should be discontinued immediately if any signs/symptoms of toxicity develop; ototoxicity caused by AG may be irreversible. o Audiometry and vestibular testing recommended for patients receiving AG for 7 days or more, or at any time if ototoxicity suspected. Consult Audiology. o If prolonged therapy expected (greater than 7 days) baseline audiometry may be considered • Assess need for continued AG therapy based on microbial susceptibilities, clinical response, side effects, duration of therapy, etc.

25 ADULT GENTAMICIN SYNERGISTIC DOSING • Used in combination therapy for endocarditis due to Viridans Group Streptococcus, Streptococcus gallolyticus (formerly Streptococcus bovis) or Enterococcus (refer to most recent IDSA/AHA Endocarditis Clinical Practice Guidelines for details) • Only gentamicin is routinely used in this setting • Dose: gentamicin 1 mg/kg q8h or 3 mg/kg q24h, depending on the organism identified o dosing based on IBW (see appendix B) o no initial loading dose o round dose to nearest 20 mg o in patients with renal impairment, consider using 1 mg/kg dosing strategy and lengthening the interval based on the table below Creatinine Clearance Dosing Interval greater than or equal to 80 q8h mL/min 50 to 79 mL/min q12h 20 to 49 mL/min q24h less than 20 mL/min q48-72h; give first dose then draw serial serum drug levels to determine when to give next dose; close monitoring is recommended • Draw gentamicin trough level before the 3rd dose and at least once a week thereafter if patient is stable o Goal of monitoring is to avoid toxicity o Target trough level : less than 1 mg/L o If trough more than 1 mg/L, increase interval • Peaks are NOT routinely recommended o If done, target peak level: 3 to 5 mg/L

26 GENTAMICIN AND TOBRAMYCIN IN PEDIATRIC PATIENTS

DEFINITIONS • Neonate: 0-4 weeks of age o Gestational age: number of weeks from first day of the mother’s last menstrual period until the birth of the baby o Postnatal age: chronological age since birth o Corrected Gestational Age: gestational age plus postnatal age Ex.: baby born at 28 weeks, presently 21 days old corrected gestational age = 31 weeks (28 weeks + 3 weeks) • Infant: 1 month to 1 year of age • Child: 1-12 years of age

PEDIATRIC EXTENDED INTERVAL DOSING • Extended interval AG dosing should NOT be used in pediatric patients who o have renal insufficiency at baseline (CrCl less than 50 mL/min) o require dialysis o have gram-positive infections where AG is used for synergy (use conventional dosing) o have endocarditis (use conventional dosing) o have rapid clearance of drug (e.g., burns exceeding 20% of body surface area) o have altered volume of distribution (e.g., ascites) o have meningitis o are receiving AG for surgical prophylaxis • Use conventional dosing if any of the above exclusion criteria for extended interval dosing are met Neonates Initial dose in neonates (less than 1 month of age): Corrected Gestational Postnatal Age Interval mg/kg/dose IV Age (weeks) (days) (hours) 0-7 5 48 29* or less 8-28 4 36 29 or more 4 24 0-7 4.5 36 30-34 8 or more 4 24 35 or more all 4 24 *or significant asphyxia, Patent Ductus Arteriosus (PDA) or treatment with indomethacin or ibuprofen • round dose to nearest 5 mg Levels Target serum concentrations at 22 hours: • 1.2 mg/L or less Levels recommended in: • Treatment anticipated to be longer than 48h Serum sampling: • A random level (or interval level) should be drawn 22 hours after the first dose regardless of the dosing interval • The timing and duration of drug administration and sample collection must be carefully documented

27 Interpreting serum levels and adjusting dose: Level at 22 hours (mg/L) Suggested dosing interval 1.2 or less q24h 1.3 to 2.6 q36h 2.7 to 3.5 q48h 3.6 or more hold dose and repeat level in 24 hours; base dosing interval on time to achieve a level less than 2 mg/L

Infants and children Initial dose of gentamicin/tobramycin • Infants and children 1 month – up to 9 years: o 7-9 mg/kg IV q24h • Children 9 years and older: o 7 mg/kg IV q24h Initial dose of tobramycin for Febrile Neutropenia • Infants and children 1 month – up to 6 years: o 10 mg/kg IV q24h • Children 6 years and older: o 8 mg/kg IV q24h Dose: • based on actual body weight, unless 20% above IBW, in which case use dosing weight (appendix C) • maximum of 400 mg/24h prior to levels • round dose to nearest 5 mg Levels • Monitoring of trough levels alone are generally sufficient with extended interval dosing of AG o verifies that AG is being adequately eliminated • Peak levels are typically NOT required, as the larger doses used are expected to produce concentrations well above those required for clinical efficacy o may be done in the rare cases where individualized pharmacokinetic monitoring is required Target serum concentrations: • Trough level : less than 1 mg/L • Peak level [only if indicated]: 15-25 mg/L Levels recommended in: • Treatment anticipated to be longer than 48h Serum sampling: • Trough levels are taken immediately before a dose (within 30 minutes) • Peak levels are taken 90 minutes after the END of drug infusion • The timing and duration of drug administration and sample collection must be carefully documented Timing of serum levels: • The notion of steady state does not apply with extended-interval dosing; therefore trough levels may be taken prior to the 2nd dose Interpreting serum levels and adjusting dose: • Trough level of 1 mg/L or more suggests accumulation; extend dosing interval Monitoring • Serum creatinine every 2 to 3 days while on therapy; daily if unstable renal function • Coordinate blood work when possible to minimize the number of times the child has blood drawn

28 PEDIATRIC CONVENTIONAL DOSING Initial dose Neonates (less than 1 month of age): Postnatal Age Interval Weight (kg) mg/kg/dose IV (days) (hours) Less than 1.2 0-28 2.5 18-24 less than 7 2.5 12 1.2 to 2 7 or more 2.5 8 to 12 less than 7 2.5 12 more than 2 7 or more 2.5 8 • round dose to nearest 5 mg

Infants and children: • 1 month to less than 5 years of age: 2.5 mg/kg IV q8h • children 5 years of age and older: 2 to 2.5 mg/kg IV q8h • for treatment of cystic fibrosis: 2.5 to 3.3 mg/kg IV q6-8h • for synergy: 1 mg/kg IV q8h • dose based on actual body weight, unless 20% above IBW, in which case use dosing weight (appendix C) • round dose to nearest 5 mg Levels • Therapeutic drug monitoring of AG dosed conventionally is typically done by measuring both peak and trough levels at steady state to confirm that therapeutic concentrations have been achieved and that drug accumulation has not taken place Target serum concentrations: Infection Desired minimal (trough) Desired maximum (peak) plasma concentration plasma concentration (mg/L) (mg/L) Synergy for gram-positive less than 1 3-5 infections Lower urinary tract infection and less than 2 4-8 mild-moderate infections Severe infections (Pneumonia, less than 2 8-10 Sepsis, etc.) Cystic Fibrosis less than 2 10-15

Levels are recommended in: • Treatment anticipated to be longer than 48h Serum sampling: • Trough levels are taken immediately before a dose (within 30 minutes) • Peak levels are taken 30 to 60 minutes after the END of drug infusion. • The timing and duration of drug administration and sample collection must be carefully documented Timing of serum levels: • Level should be taken at steady state, typically before and after 3rd dose in patients with normal renal function Interpreting serum levels and adjusting dose: • Ensure serum samples were collected at the appropriate time and at steady state • Adjust AG dose if serum concentrations are not within the desired range as follows: high trough extend dosing interval high peak decrease dose low peak increase dose • AG exhibit linear kinetics; decreasing or increasing the dose by a specific percentage will result in an equal decrease/increase in percentage of peak levels.

29 • Pharmacokinetic calculations may be used determine the dose most likely to produce desired levels, based on the pre and post levels obtained from the patient. Contact Pharmacy. Monitoring • Serum creatinine every 2 to 3 days while on therapy; daily if unstable renal function • Coordinate blood work when possible to minimize the number of times the child has blood drawn

30 EXTENDED-INTERVAL TOBRAMYCIN IN CYSTIC FIBROSIS (PEDIATRIC and ADULT)

GENERAL COMMENTS • Patients with Cystic Fibrosis (CF) will have increased AG requirements secondary to increased clearance • Extended interval dosing is as efficacious as conventional dosing of tobramycin in the treatment of CF pulmonary exacerbations in adults and children • Amikacin may also be used to treat CF; data is limited with gentamicin. There are insufficient data in CF patients for guiding extended interval dosing of AG apart from tobramycin. If other AG is needed, use conventional dosing. • For conventional dosing, refer to previous adult and pediatric sections. Target peak levels are 10 to 15 mg/L, while target trough levels are less than 2 mg/L. DOSE AND LEVELS Dose (pediatric and adults; from 1 months of age) • Treatment naïve: Creatinine Clearance Initial tobramycin dose greater than or equal to 50 mL/min 10 mg/kg IV q24h 30-49 mL/min 10 mg/kg IV q36h 20-29 mL/min 10 mg/kg IV q48h less than 20 mL/min avoid maximum tobramycin dose of 600 mg/day prior to levels • Previously treated with tobramycin: dose based on previous therapeutic drug monitoring • Dose based on ideal body weight (see appendix B) Levels: • Monitoring of trough levels alone are generally sufficient with extended interval dosing of AG; trough levels verify that AG is being adequately eliminated • Peak levels are NOT routinely measured, but may be ordered to allow for individualized pharmacokinetic monitoring if concern about clinical progress o Because CF patients have more rapid clearance of AG, extrapolated peaks can be substantially higher than reported values. Target serum concentrations: • Trough levels: less than 1 mg/L • Peak levels [only if indicated]: 20-30 mg/L, peaks NOT to exceed 50 mg/L Serum sampling: • Trough levels are taken immediately before a dose (within 30 minutes) • Peak levels are taken 90 minutes after the END of drug infusion • The timing and duration of drug administration and sample collection must be carefully documented Timing of serum levels: • notion of steady state does not apply in extended-interval dosing; trough levels may be taken before 2nd dose Interpreting serum levels and adjusting dose: • Ensure serum samples were collected at the appropriate time • If tobramycin is being administered via inhalation in addition to IV, absorption of inhaled tobramycin may contribute to tobramycin serum concentrations • If trough is less than 1 mg/L, continue current dose • Adjust AG dose if serum concentrations are not within the desired range as follows: high trough extend dosing interval high peak decrease dose low peak increase dose

Subsequent serum levels: • Trough levels should be monitored every 7 days or sooner if clinically necessary

31 GENTAMICIN AND TOBRAMYCIN IN INTERMITTENT HEMODIALYSIS

GENERAL COMMENTS • Extended interval dosing not indicated for patients on hemodialysis; use conventional dosing • In patients on intermittent hemodialysis, AG is given on dialysis days, typically 3 times a week • AG doses are administered after dialysis • Give the first dose of AG the day it is ordered and subsequent doses on dialysis days • AG are removed by hemodialysis (to a greater extent than vancomycin) o High-flux dialyzers reduce AG serum concentrations by approximately 50% Example: pre-dialysis gentamicin serum concentration is 5 mg/L; following a 4h hemodialysis session, post-dialysis gentamicin serum concentration is approximately 2.5 mg/L DOSE Loading dose: • 1.5-2 mg/kg IV o based on dry weight/dosing weight (see appendix B) o round dose to nearest 20 mg Initial maintenance dose: • 1 mg/kg IV o based on dry weight/dosing weight (see appendix B) o round dose to nearest 20 mg o administered at the end of dialysis session Dosing weight: Patient’s dry weight…. Use as dosing weight is less than ideal body weight dry weight is less than 20% above ideal body weight dry weight is more than 20% above ideal body weight adjusted weight Adjusted weight = 0.4 x (actual body weight – IBW) + IBW LEVELS Trough levels: • Draw trough level within 30 minutes before the start of the hemodialysis session • Target pre-hemodialysis level: 1.5 to 3 mg/L Peak levels: • NOT commonly done • Measure peak level 60 minutes after END of drug infusion, if required • Target peak: 6-10 mg/L, depending on the indication (refer to section “Adults-Conventional Dosing of Gentamicin and Tobramycin”: target serum concentrations)

32 GENTAMICIN AND TOBRAMYCIN IN PREGNANCY CONSIDERATIONS ON THE USE OF AMINOGLYCOSIDES IN PREGNANCY • Glomerular filtration rate can be increased by up to 50% in pregnant and post-partum patients, resulting in a shorter half-life compared to nonpregnant women • Volume of distribution is increased in pregnancy, while the post-partum period is associated with increased mobilization of fluid followed by diuresis as the body eliminates the increased fluid volume of pregnancy • Extended interval dosing o Data limited on extended interval dosing of AG in pregnancy; use with caution o More data on extended-interval dosing of AG is available in post-partum o For pregnant and post-partum patients, the actual body weight should be used. For obese pregnant and post-partum patients, use maximum 500 mg dose prior to levels. o Initial dose and interval . 5 mg/kg IV q24h (if CrCl greater than or equal to 60 mL/min) . dose based on actual body weight . maximum 500 mg/24h prior to levels . dosing interval adjusted based on renal function o Monitoring . Trough levels, taken within 30 minutes before 2nd dose • target less than 1 mg/L • Conventional dosing o Initial dose and interval . 2 mg/kg IV x 1 loading dose, then . 1.5-2 mg/kg IV q8h (if CrCl greater than or equal to 80 mL/min) . dose based on actual body weight . dosing interval adjusted based on renal function o Monitoring . target levels – refer to “Adults-Conventional Dosing of Gentamicin/Tobramycin” section

33 AMIKACIN

GENERAL COMMENTS, DOSING AND MONITORING • Amikacin is a less commonly used AG with similar spectrum of activity and toxicity profile as gentamicin and tobramycin • Dosing and serum concentrations are different compared to gentamicin and tobramycin • Determination of serum concentration is sent to a laboratory outside the province; expect delays in obtaining results • Extended interval dosing o Initial dose . 15 mg/kg IV; dose based on IBW or dosing weight (see appendix B); rounded to nearest 25 mg o Initial interval Creatinine Clearance Dosing Interval greater than or equal to 60 mL/min q24h 40 to 59 mL/min q36h 20 to 39 mL/min q48h; consider conventional dosing less than 20 mL/min Give first dose then draw serial serum drug levels to determine when to give next dose. Consider conventional dosing. • Conventional dosing o Initial dose . 7.5 mg/kg IV x 1 loading dose may be considered, then . 5 to 7.5 mg/kg IV; dose based on IBW or dosing weight; rounded to nearest 25 mg o Initial interval Creatinine Clearance Dosing Interval greater than or equal to 80 mL/min q8h 50 to 79 mL/min q12h 20 to 49 mL/min q24h less than 20 mL/min q48-72h; give first dose then draw serial serum drug levels to determine when to give next dose; close monitoring is recommended • For extended interval dosing of amikacin, o Target trough level: less than 4 mg/L o Target peak level [only if indicated]: 35-50 mg/L o Hartford Hospital nomogram may be used to determine appropriate dosing interval based on a random level taken 8-12h after the first dose, provided a 15 mg/kg dose was used . Divide serum amikacin level obtained in half, then plot on graph (see Appendix D) • For conventional dosing of amikacin, target serum concentrations: Desired minimal Desired maximum (trough) (peak) concentration concentration (mg/L) (mg/L) Moderate infections less than 4 20-25 Severe infections less than 4 25-30

34 APPENDIX A: Calculation of Creatinine Clearance (CrCl)

Women Men CrCl = (140-age) x weight (in kg)† CrCl = (140-age) x weight (in kg)† x 1.2 SCr (in mcmol/L) SCr (in mcmol/L) IBW = 45.5 Kg + (0.92 x cm above 150 cm) or IBW = 50 kg + (0.92 x cm above 150 cm) or 45.5 kg + (2.3 x inches above 60 inches) 50 kg + (2.3 x inches above 60 inches) †use ideal body weight unless actual body weight is more than 20% above ideal body weight (IBW), in such case use dosing weight: Dosing weight = 0.4 x (actual body weight – IBW) + IBW

APPENDIX B: Adult Ideal Body Weight, Dosing Weight and Dry Weight

Patient’s weight…. Use is less than ideal body weight actual body weight is less than 20% above ideal body weight ideal body weight is more than 20% above ideal body weight dosing weight = 0.4 x (actual body weight – IBW) + IBW

Ideal body weight (IBW)

Women Men IBW = 45.5 kg + (0.92 x cm above 150 cm) or IBW = 50 kg + (0.92 x cm above 150 cm) or 45.5 kg + (2.3 x inches above 60 inches) 50 kg + (2.3 x inches above 60 inches)

Dry body weight in hemodialysis: defined as the lowest tolerated post-dialysis weight at which there are minimal signs or symptoms of hypovolemia or hypervolemia

APPENDIX C: Pediatric Ideal Body Weight and Dosing Weight

Child’s weight…. Use is less than 20% above ideal body weight actual body weight is more than 20% above ideal body weight dosing weight = 0.4 x (actual body weight – IBW) + IBW

Ideal body weight (1 to 18 years of age):

• Children less than 5 feet tall: height (cm)2 x 1.65 1000 • Boys 5 feet and taller: 39 kg + (2.3 x inches above 60 inches) • Girls 5 feet and taller: 42.2 kg + (2.3 x inches above 60 inches)

35 APPENDIX D: Hartford Hospital nomogram

• This nomogram is only to be used for a 7 mg/kg dose of gentamicin or tobramycin • This nomogram assumes a Vd of 0.3 L/kg • If interval falls in areas marked as q24h, q36h, q48h, dosing interval should be every 24, 36, or 48 hours respectively. • If the interval level is on one of the sloping lines, choose the longer interval. • If the interval level is above the q48h dosing interval area, stop extended interval dosing and switch to conventional dosing. • If the interval level is below the nomogram (i.e., less than 2 mg/L), AG dosing/therapy should be reassessed if patient not improved. • For amikacin the Hartford Hospital nomogram may be used to determine appropriate amikacin dosing interval based on a random level taken 8-12h after the first dose, provided a 15 mg/kg dose was used o Divide serum amikacin level obtained in half, then plot on graph

36 ADULT ANTIMICROBIAL DOSING TOOL (NB Provincial Health Authorities Anti-Infective Stewardship Committee, September 2017)

Introduction

The dosing recommendations presented here are for adults with moderate-to-severe infections and are based on published literature, the Clinical & Laboratory Standards Institute’s reference dosing for susceptibility interpretation and clinical experience. The recommended doses should only be used as a reference tool. Patient dosing should be individualized and based on pharmacokinetic and clinical evaluation where possible.

Recommendations for renal dose adjustment are made according to estimated creatinine clearance (CrCl) calculated using the Cockroft-Gault equation, which is used in practice. Estimated glomerular filtration rate (eGFR) calculated using the Modification of Diet in Renal Disease 4 (MDRD4) equation, commonly reported with most serum creatinine levels, is NOT interchangeable with CrCl calculated using the Cockroft-Gault equation. The two equations may result in different antimicrobial dosing recommendations in up to 20 to 36% of cases with potential clinical significance.20 Recommendations for renal dose adjustment in the table below are for modifications of the maintenance doses; no adjustments are required for loading doses where applicable.

For patients on intermittent hemodialysis (IHD), antimicrobial dosages and administration times may need to be adjusted. If an antimicrobial is significantly removed by hemodialysis (HD) and recommended to be given post-HD then administration of the dose prior to or during HD should be avoided because drug loss could result in subtherapeutic levels post-HD. The dosing schedule should be adjusted on dialysis days so that the scheduled dose is administered immediately after dialysis. Other strategies may include supplementary doses administered post-HD to replace the amount of antimicrobial removed during HD or intermittent post-HD administration (ex. ceFAZolin 2 g IV post-HD 3 times weekly). Please consult your local pharmacy department for guidance in patients receiving peritoneal dialysis, continuous veno- venous hemofiltration, continuous veno-venous hemodiafiltration or continuous renal replacement therapy. Dosing adjustment may also be necessary in patients with severe liver impairment.

In critically ill patients (ex: sepsis), antimicrobial pharmacokinetics can be significantly altered and unstable potentially resulting in sub-optimal dosing. Critically ill patients may also suffer from acute renal failure (ARF) that can be rapidly reversible; therefore, since the serum creatinine level is not stable, the Cockroft-Gault equation should NOT be used to estimate renal function in ARF. A pharmacy consultation could be considered to optimize antimicrobial doses in this patient population.

37 ADULT ANTIMICROBIAL DOSING TOOL

Usual Adult Dose (CrCl greater CrCl CrCl CrCl less Intermittent Drug General Comments than or equal to 30 - 49 mL/min 10 - 29 mL/min than10 mL /min Hemodialysis (IHD) 50 mL/min)

Penicillins 500 mg q24h; amoxicillin (PO)1,2,3,4,5,6 500 mg – 1 g q8h 500 mg q12h 500 mg q24h administer dose after dialysis on dialysis days - Dose listed as amoxicillin component 500 mg q8h 500 mg q24h; 1,2,7 - Do not use 875 mg tablets if 500 mg q12h 500 mg q24h administer dose after dialysis on amoxicillin/clavulanate (PO) CrCl less than 30 mL/min dialysis days - Less diarrhea with 875 mg 875 mg q12h given q12h vs.500 mg q8h Dose 2 g q4h for 1 – 2 g q12-24h; ampicillin (IV)1,3,5 endocarditis and other deep 1 – 2 g q4-6h 1 – 2 g q6-8h 1 – 2 g q8-12h 1 – 2 g q12-24h administer dose after dialysis ‡ space infections on dialysis days cloxacillin (PO)1,5 500 – 1000 mg q6h Dose 2 g q4h for cloxacillin (IV)1,2,5 endocarditis and deep space 1 – 2 g q4-6h infections‡ Dose 4 million units q4h for 20 – 50% of usual dose q4-6h; 1,5 2 – 4 million units 20 – 50% of usual penicillin G (IV) endocarditis and deep space 75% of usual dose q4-6h administer dose after dialysis on ‡ q4-6h dose q4-6h infections dialysis days penicillin V (PO)2,5,8,9 300 – 600 mg q6h 300 – 600 mg q8h 300 – 600 mg q12h Dose listed as piperacillin 3.375 g q6h 2.25 g q8h 2.25 g q12h; plus tazobactam (CrCl greater than 2.25 g q6h (CrCl 20 – 40 mL/min) (CrCl less than 20 administer supplementary dose components 40 mL/min) mL/min) of 0.75 g after dialysis session piperacillin/tazobactam (IV)1,2,3,5 Hospital acquired 4.5 g q6h 2.25 g q6h 2.25 g q8h; pneumonia, febrile (CrCl greater than 3.375 g q6h (CrCl 20 – 40 mL/min) (CrCl less than 20 administer supplementary dose neutropenia and 40 mL/min) mL/min) of 0.75 g after dialysis session Pseudomonas spp infections 3 – 4 g q6h 2 g q8h; 1,3,5 3 – 4 g q8h 3 – 4 g q12h (CrCl greater than administer supplementary dose piperacillin (IV) (CrCl 20-40mL/min) (CrCl less than 20 mL/min) 40 mL/min) of 1 g after dialysis session Cephalosporins 1 – 2 g q24h; administer dose after dialysis on dialysis days 1,5,19 ceFAZolin (IV) OR 2 g q8h 2 g q12h 1 – 2 g q24h (1st generation) 2 g after dialysis three times weekly if receiving dialysis three times weekly cephalexin (PO)1,3,5 500 mg q12-24h; st 500 mg – 1 g q6h 500 mg q8h 500 mg q12h 500 mg q12-24h administer dose after dialysis on (1 generation) dialysis days

38 ADULT ANTIMICROBIAL DOSING TOOL

Usual Adult Dose (CrCl greater CrCl CrCl CrCl less Intermittent Drug General Comments than or equal to 30 - 49 mL/min 10 - 29 mL/min than10 mL /min Hemodialysis (IHD) 50 mL/min)

£ 1,3,5 500 mg – 1 g three times weekly cefadroxil (PO) Dose 1 g twice daily for 500 mg – 1 g q12h 500 mg – 1 g q24h 500 mg q36h after dialysis if receiving dialysis st complicated UTI (1 generation) three times weekly cefaclor£ (PO)1,3,5 250 mg q8h ; administer nd 250 - 500 mg q8h 250 mg q8h supplementary dose of 250 mg (2 generation) after dialysis session cefuroxime axetil (PO)1,2,3,5, 22, 23 500 mg q24h; nd 500 mg q8-12h 500 mg q12h 500 mg q24h administer dose after dialysis on (2 generation) dialysis days 1,2,5 1.5 g q12h 1.5 g q24h; cefuroxime (IV) 1.5 g q8h (CrCl 10-19 1.5 g q24h administer dose after dialysis on nd (CrCl greater than 20 mL/min) (2 generation) mL/min) dialysis days cefOXitin (IV)1,5,10 Dose 2 g q6h for moderate 1 – 2 g q24h; nd to severe infections such as 1 – 2 g q6-8h 1 – 2 g q8h 1 – 2 g q12h 1 – 2 g q24h administer dose after dialysis on (2 generation) intra-abdominal infections dialysis days cefprozil (PO)1,3,5 250 mg q12h; nd 500 mg q12h 250 mg q12h administer supplementary dose (2 generation) of 250 mg after dialysis session cefixime (PO)2,3 400 mg q24h 200 mg q24h 200 mg q24h (3rd generation) Dose 2 g q12h for CNS 1 cefTRIAXone (IV) infections or Enterococcus 1 – 2 g q24h (3rd generation) faecalis endocarditis in combination with ampicillin

1 – 2 g q24h; 1,2,3 Moderate to severe infection 1 – 2 g q6-8h 1 – 2 g q12h 1 – 2 g q24h administer dose after dialysis on cefotaxime (IV) dialysis days (3rd generation) 2 g q12-24h; CNS infection 2 g q4h 2 g q6h 2 g q8h 2 g q12h administer dose after dialysis on dialysis days cefTAZidime (IV)1,3,5 (3rd generation) 1 g q24h; administer dose after dialysis on dialysis days 2 g 8h 2 g q12h 2 g q24h 1 g q24h OR 2 g after dialysis three times weekly if receiving dialysis three times weekly

1g q24h; £ 1,2 cefepime (IV) Uncomplicated mild to 1 – 2 g q12 – 24h administer dose after dialysis on 1 – 2 g q8-12h 1 – 2 g q24h 1 g q24h (4th generation) moderate infections (ClCr 30-59 mL/min dialysis days OR

39 ADULT ANTIMICROBIAL DOSING TOOL

Usual Adult Dose (CrCl greater CrCl CrCl CrCl less Intermittent Drug General Comments than or equal to 30 - 49 mL/min 10 - 29 mL/min than10 mL /min Hemodialysis (IHD) 50 mL/min)

Severe infections including 2 g after dialysis three times febrile neutropenia, hospital £ 1,2 weekly if receiving dialysis three cefepime (IV) acquired pneumonia, deep 2 g q12h 2 g q24h th 2 g q8h 1 g q24h times weekly (4 generation) space infections‡ or (ClCr 30-59 mL/min coverage for Pseudomonas aeruginosa Carbapenems 500 mg q24h; administer supplementary dose ertapenem£ (IV/IM)13,5 1 g q24h 500 mg q24h of 150 mg after dialysis session if daily dose given less than 6 hr before start of HD 500 mg q8-12h 250 – 500 mg q12h 250 – 500 mg q12h; Meropenem preferred for 500 – 1000 mg q6h 500 mg q6-8h R 1,11 (CrCl 21 – 30 (CrCl less than 20 administer dose after dialysis on CNS infections and when (CrCl greater than (CrCl 31 – 70 imipenem/cilastatin (IV) mL/min) mL/min) dialysis days CrCl less than 30 mL/min 70 mL/min) mL/min)

q6h dosing regimen: 500 mg q8h 500 mg q12h 500 mg q24h; Caution: do NOT use this 500 mg q6h (CrCl 26 – 50 (CrCl 10 – 25 500 mg q24h administer dose after dialysis on regimen for CNS infections mL/min) mL/min) dialysis days meropenemR (IV)1,2,3,5 q8h dosing regimen: 500 mg – 1000 mg q24h; 500 mg – 1000 mg Dose 2 g q8h for CNS 1000 – 2000 mg q8h 1000– 2000 mg q12h administer dose after dialysis on q24h infections dialysis days Aminoglycosides – Adjust dose for serum drug levels where applicable. For prolonged therapies consider pharmacy consult for appropriate dosing and monitoring

- 7 mg/kg for serious 5 – 7 mg/kg IV to 5 – 7 mg/kg q48h infections start then use serial (CrCl 20 – 39 serum drug levels to 5 – 7 mg/kg q24h 5 – 7 mg/kg q36h mL/min) gentamicin/tobramycin (IV) - Dosing based on IBW, adjust (CrCl less (CrCl greater than or (CrCl 40 – 59 OR 2,4,14 unless actual body weight than 20 mL/min) 1.5 – 2 mg/kg loading dose Extended Interval Dosing equal to 60 mL/min) mL/min) Consider greater than 20% above OR followed by 1 mg/kg conventional IBW, then use dosing weight Consider maintenance dose at the end of dosing conventional dosing each dialysis session; dose adjustments based on pre-dialysis levels - Dosing based on IBW, 1.5 – 2 mg/kg q8h (dosing based on patient’s dry unless actual body weight (CrCl greater than or 1.5 – 2 mg/kg q48-72hrs weight if not obese; if dry weight greater than 20% above equal to 80 mL/min) 1.5 – 2 mg/kg q24h OR is greater than 20% above IBW gentamicin/tobramycin (IV) then use dosing weight) 2,4,14 IBW, then use dosing weight (CrCl 20 – 49 Single dose, then use serial drug levels to Conventional Dosing 1.5 – 2 mg/kg q12h mL/min) adjust; close monitoring recommended - Consider a loading dose of (CrCl 50 – 79 (CrCl less than 20 mL/min) 2 mg/kg to start mL/min)

40 ADULT ANTIMICROBIAL DOSING TOOL

Usual Adult Dose (CrCl greater CrCl CrCl CrCl less Intermittent Drug General Comments than or equal to 30 - 49 mL/min 10 - 29 mL/min than10 mL /min Hemodialysis (IHD) 50 mL/min)

- For Gram positive infections only; tobramycin not for 1 mg/kg at the end of each synergy against 1 mg/kg q8h (CrCl dialysis session; 1 mg/kg q48-72hrs Enterococcus spp infections greater than or dose adjustments based on gentamicin/tobramycin (IV) 1 mg/kg q24h OR 2,3,14 equal to 80 mL/min) pre-dialysis levels (CrCl 20 – 49 Single dose, then use serial drug levels to Synergy Dosing - Dosing based on IBW, (dosing based on patient’s dry mL/min) adjust; close monitoring recommended unless actual body weight 1 mg/kg q12h (CrCl weight if not obese; if dry weight (CrCl less than 20 mL/min) greater than 20% above 50 – 79 mL/min) is greater than 20% above IBW IBW, then use dosing then use dosing weight) weight

15 mg/kg to start 15 mg/kg q48h then use serial Dosing based on IBW, (CrCl 20 – 39 serum drug levels to unless actual body weight 15 mg/kg q24h (CrCl mL/min) amikacin (IV) 15 mg/kg q36h (CrCl adjust (CrCl less greater than 20% above greater than or OR 1,2,4 40 – 59 mL/min) than 20 mL/min) 5 – 7.5 mg/kg at the end of each Extended Interval Dosing IBW, then use dosing weight equal to 60 mL/min) Consider OR dialysis session; conventional Consider dose adjustments based on dosing conventional dosing pre-dialysis levels (dosing based on patient’s dry - Dosing based on IBW, 5 – 7.5 mg/kg q8h weight if not obese; if dry weight unless actual body weight (CrCl greater than or 5 – 7.5 mg/kg q48-72hrs is greater than 20% above IBW greater than 20% above equal to 80 mL/min) 5 – 7.5 mg/kg q24h OR amikacin (IV) then use dosing weight) 1,2,4 IBW, then use dosing weight (CrCl 20 – 49 use serial serum drug levels to adjust; Conventional Dosing 5 – 7.5 mg/kg q12h mL/min) close monitoring recommended - Consider a loading dose of (CrCl 50 – 79 (CrCl less than 20 mL/min) 7.5 mg/kg to start mL/min) Macrolides erythromycin (IV)1,2 500 – 1000 mg q6h 50 – 75% dose q6h

Formulary product: •erythromycin 250 mg erythromycin (PO)1,2,3 capsules containing EC 250 – 500 mg q6h 50 – 75% dose q6h pellets azithromycin (IV)1 500 mg q24h x 3-5 days 500 mg q24h x 3 days Use with caution – No dose adjustment provided azithromycin (PO)1 OR 500 mg on day one, then 250 mg daily for days 2 to 5 500 mg q24h; clarithromycin (PO)1,3,4 500 mg q12h 500 mg q24h administer dose after dialysis on dialysis days 500 mg q24h; clarithromycin XL£ (PO)1,3 1000 mg q24h 500 mg q24h administer dose after dialysis on dialysis days

41 ADULT ANTIMICROBIAL DOSING TOOL

Usual Adult Dose (CrCl greater CrCl CrCl CrCl less Intermittent Drug General Comments than or equal to 30 - 49 mL/min 10 - 29 mL/min than10 mL /min Hemodialysis (IHD) 50 mL/min)

Quinolones

400 mg q12h 400 mg q24h; ciprofloxacin (IV)1,2,8 400 mg q24h administer dose after dialysis on Severe infections; infections dialysis days due to Pseudomonas 400 mg q8h 400 mg q12h aeruginosa

500 mg q12h ciprofloxacin (PO) 250 – 500 mg q24h; 1,2,9 Infection of the bone or skin, 500 mg q24h administer dose after dialysis on (regular release oral solid ) infections due to dialysis days 750 mg q12h 500 mg q12h Pseudomonas spp or severe infections

500 mg once then 250 mg q24h 500 mg q24h 500 mg once then 250 mg q48h (CrCl less than 20 mL/min or IHD) (CrCl 20 – 49 mL/min)

1 High dose for bacteremia, levofloxacin (PO/IV) complicated UTI, pyelonephritis, complicated 750 mg q48h skin infection, nosocomial 750 mg q24h (CrCl 20 – 49 750 mg once then 500 mg q48h (CrCl less than 20 mL/min or IHD) pneumonia, intra-abdominal mL/min) infections, infections due to Pseudomonas spp moxifloxacin(PO/IV)1 400 mg q24h norfloxacin£ (PO)1,3 400 mg q12h 400 mg q24h Tetracyclines doxycycline (PO)1 100 mg q12h £ 1,3,5 200 mg then 100 mg Usual dose (Doxycycline preferred) minocycline (PO) q12h 250 – 500 mg q6h (CrCl greater than 80 mL/min) 250 – 500 mg q24h 1,3,5 250 – 500 mg q12 – 24h (doxycycline Use not recommended tetracycline (PO) 250 – 500 mg q8- (doxycycline preferred) preferred) 12h (CrCl 50 to 80 mL/min) tigecyclineR (IV)1 100 mg initially, then 50 mg q12h

42 ADULT ANTIMICROBIAL DOSING TOOL

Usual Adult Dose (CrCl greater CrCl CrCl CrCl less Intermittent Drug General Comments than or equal to 30 - 49 mL/min 10 - 29 mL/min than10 mL /min Hemodialysis (IHD) 50 mL/min)

Other clindamycin (IV)1 600 – 900 mg q8h clindamycin (PO)1,12 300 – 450 mg q6-8h

Skin and soft tissue infections: 4 mg/kg q24h Usual dose q48h R 1,3 Usual dose q48h if CrCl less than 30 6 – 8 mg/kg q24h Administer dose after dialysis on DAPTOmycin (IV) Severe infections: mL/min 8-10 mg/kg q24h dialysis days

Monitor baseline and weekly creatine kinase levels fosfomycin (PO) Uncomplicated UTI 3 g ONCE

600 mg q12h linezolidR (PO/IV)1,2,3 600 mg q12h Administer dose after dialysis on dialysis days 500 mg q12h Dose 500 mg q8h for Consider a supplemental dose 1,2 500 mg q12h metroNIDAZOLE (PO/IV) Clostridium difficile infection after dialysis if administration or CNS infection cannot be separated from the dialysis session nitrofurantoin monohydrate/macrocrystal 100 mg q12h sustained release capsules 1 (MACROBID) (PO) Contraindicated if CrCl less than 40 mL/min (will NOT be effective in these patients) nitrofurantoin regular release oral solidR,1 50 – 100 mg q6h

43 ADULT ANTIMICROBIAL DOSING TOOL

Usual Adult Dose (CrCl greater CrCl CrCl CrCl less Intermittent Drug General Comments than or equal to 30 - 49 mL/min 10 - 29 mL/min than10 mL /min Hemodialysis (IHD) 50 mL/min)

sulfamethoxazole + trimethoprim 8 – 20 mg TMP/kg/day divided q6-12h (IV) 50% of usual dose Generally not 2.5 – 10 mg/kg q24h; administer •Each mL of injectable contains (CrCl 15 – 29 recommended, but if dose after dialysis on dialysis sulfamethoxazole 80 mg and - Dose listed as trimethoprim Pneumocystis jiroveci Treatment: mL/min) required: 4 – 6 days 1,2,8 (TMP) component 15 – 20 mg/kg/day divided q6-8h mg/kg/day divided OR trimethoprim 16 mg q12-24h 4-6 mg/kg 3 times weekly after (CrCl less than 15 dialysis if receiving dialysis three - Use of sulfamethoxazole + mL/min) times weekly sulfamethoxazole + trimethoprim trimethoprim in moderate to Pneumocystis (PO) severe renal dysfunction has jiroveci not been not adequately Treatment (CrCl • Each regular strength tablet studied, close monitoring of 15 – 30 mL/min): Pneumocystis contains sulfamethoxazole 400 sulfamethoxazole/trimethoprim 800/160 to patient response, 1600/320 mg q12h 15 – 20 mg/kg/day jiroveci Treatment Pneumocystis jiroveci mg and trimethoprim 80 mg electrolytes and serum divided q6-8h for (CrCl less than15 Treatment: • Each double-strength (DS) tablet creatinine recommended 48 hr then 7 – 10 mL/min): 7 – 10 mg/kg after dialysis three mg/kg/day divided 7 – 10 mg/kg/day times weekly if receiving dialysis contains sulfamethoxazole 800 Pneumocystis jiroveci Treatment: mg and trimethoprim 160 mg 15 – 20 mg/kg/day divided q6-8h q12h divided q12-24h three times weekly • Each mL of oral suspension contains sulfamethoxazole 40 mg and trimethoprim 8 mg1,2,8 Generally not recommended if 50 mg q12h 50 mg q24h 2 CrCl less than 15 100 mg q12h (CrCl 15 – 29 Administer dose after dialysis on trimethoprim (PO) mL/min, but if mL/min) dialysis days required: 50 mg q24h Target Trough - Consider a loading dose of Less than 70 kg: 10 – 15 mg/L 25-30 mg/kg if severe Target Trough 1000 mg loading dose then 500 Target Trough infection, adjusting 10 – 15 mg/L mg maintenance dose infused 15 mg/kg q12h 10 – 15 mg/L maintenance doses based after dialysis on dialysis days; (CrCl greater than on renal function 15 mg/kg 80 mL/min) 15 mg/kg q48h q36h 70-100 kg: (CrCl 10 –19 - Dosing based on actual (CrCl 20 – 39 1250 mg loading dose then 750 15 mg/kg q24h mL/min) body weight mL/min) Consider loading mg maintenance dose infused (CrCl 40 – 80 dose of 25 – 30 after dialysis on dialysis days; mL/min) vancomycin (IV)2,8,13 mg/kg; then use Target Trough - Maximum of 2 g per dose for serial serum drug Greater than 100 kg: 15 – 20 mg/L maintenance doses levels to adjust 1500 mg loading dose then Target Trough Target Trough 1000 mg maintenance dose 15 mg/kg q8h 15 – 20 mg/L 15 – 20 mg/L - Adjust dose for serum drug infused after dialysis on dialysis (CrCl greater than levels where applicable. For days 80 mL/min) 15 mg/kg q24h 15 mg/kg q48h prolonged therapies (CrCl 20 – 39 (CrCl 10 – 19 consider pharmacy consult (Adjust maintenance doses 15 mg/kg q12h mL/min) mL/min) for appropriate dosing and based on pre-dialysis (CrCl 40 – 80 monitoring vancomycin trough levels) mL/min)

44 ADULT ANTIMICROBIAL DOSING TOOL

Usual Adult Dose (CrCl greater CrCl CrCl CrCl less Intermittent Drug General Comments than or equal to 30 - 49 mL/min 10 - 29 mL/min than10 mL /min Hemodialysis (IHD) 50 mL/min)

C. difficile infection ONLY 1 See NB-ASC Clostridium 125 – 500 mg q6h vancomycin (PO) difficile Infection treatment guidelines for more details Antivirals Dose based on ideal or dosing body weight Herpes zoster (shingles)/ Herpes simplex/ Varicella- 5 – 10 mg/kg q12h 5 – 10 mg/kg q24h 2.5 – 5 mg/kg q24h acyclovir (IV)1,2,3,9 zoster (chickenpox) in an 5 – 10 mg/kg q8h (CrCl 25 – 49 (CrCl 10 – 24 2.5 – 5 mg/kg q24h Administer after dialysis on immunocompromised host mL/min) mL/min) dialysis days or patient with severe disease or encephalitis: 10 - 15 mg/kg q8h Herpes zoster, and Varicella 200 - 800 mg q12h acyclovir (PO)1 zoster: 800 mg five times a 400 – 800 mg q8h to five times a day 400 – 800 mg q8h 200 – 800 mg q12h Administer dose after dialysis on day dialysis days 500 mg q8h 500 mg q12h 500 mg q24h 250 mg q24h 250 mg after each dialysis Herpes zoster (shingles) (CrCl greater than or (CrCl 40 – 59 (CrCl 20 – 39 (CrCl less than 20 session equal to 60 mL/min) mL/min) mL/min) mL/min)

250 mg q8h 250 mg q24h 250 mg q12h 250 mg after each dialysis £ 1,2,3,8 Primary genital herpes (CrCl greater than (CrCl less than 20 famciclovir (PO) (CrCl 20 – 40 mL/min) session 40 mL/min) mL/min) 1000 mg q12h 500 mg q12h x 1 500 mg as a single 250 mg as a single x 1 day day dose 250 mg as a single dose after a Recurrent Genital herpes dose (CrCl <20 (CrCl greater than (CrCl 40 – 59 (CrCl 20 – 39 dialysis session mL/min) 40 mL/min) mL/min) mL/min) 5 mg/kg q12h or 2.5 mg/kg q12h if 1.25 mg/kg 3 times weekly (following dialysis, if Induction 2.5 mg/kg q24h 1.25 mg/kg q24h (CrCl 50 – 69 receiving dialysis three times weekly) mL/min) ganciclovir (IV)1,8 5 mg/kg q24h or 2.5 mg/kg q24 h if 0.625 mg/kg three times weekly (following dialysis, if Maintenance 1.25 mg/kg q24h 0.625 mg/kg q24h (CrCl 50 – 69 receiving dialysis three times weekly) mL/min)

75 mg q12h 30 mg q12h Use with caution: 75 mg after each dialysis Treatment (CrCl greater than (CrCl 30 – 60 30 mg q24h 75 mg ONCE session over a period of 5 days (for 5 days) 60 mL/min) mL/min)

1,2,15 An initial 30 mg dose may be oseltamivir (PO) given prior to HD if exposed 75 mg q24h 30 mg q24h during the 48 hours between Prophylaxis Use with caution: (CrCl greater than (CrCl 30 – 60 30 mg q2days dialysis sessions. Then (for 10 to 14 days) 30 mg ONCE 60 mL/min) mL/min) administer 30 mg after alternate dialysis sessions over a period of 10-14 days

45 ADULT ANTIMICROBIAL DOSING TOOL

Usual Adult Dose (CrCl greater CrCl CrCl CrCl less Intermittent Drug General Comments than or equal to 30 - 49 mL/min 10 - 29 mL/min than10 mL /min Hemodialysis (IHD) 50 mL/min)

1 g three times weekly after Herpes zoster (shingles) 1 g q8h 1 g q12h 1 g q24h 500 mg q24h dialysis, if receiving dialysis three times weekly 500 mg as a single dose 500 mg q12h x 2 500 mg as a single Herpes labialis 2g q12h x 2 doses 1 g q12h x 2 doses Administer dose after a dialysis doses dose session 500 mg PO q24h Primary genital herpes 1g q12h 1g q24h 500 mg q24h Administer dose after dialysis on dialysis days 1,2,16 valACYclovir (PO) 500 mg PO q24h 500 mg q12h x 3 days or Recurrent genital herpes 500 mg q24h Administer dose after dialysis on 1g q24h x 5 days dialysis days Herpes simplex/ Varicella 1 g three times weekly after zoster treatment in oncology 1 g q8h 1 g q12h 1 g q24h 500 mg q24h dialysis, if receiving dialysis patients three times weekly Herpes simplex/ Varicella 500 mg PO q24h zoster prophylaxis in 500 mg q8-12h 500 mg q12h 500 mg q24h Administer dose after dialysis on oncology patients dialysis days 450 mg q12h 900 mg q12h (CrCl 40 – 59 450 mg q48h (CrCl greater than or mL/min) Induction (CrCl 10 – 24 Consider ID or Transplant consult equal to 60 mL/min) 450 mg q24h ml/min) (CrCl 25 – 39 valGANciclovir (PO)1,2,8 mL/min) 450 mg q24h 900 mg q24h (CrCl 40 – 59 450 mg 2x/week (CrCl greater than or Maintenance mL/min) (CrCl 10 – 24 Consider ID or Transplant consult equal to 60 mL/min) 450 mg q2days ml/min) (CrCl 25-39 mL/min) Treatment 10 mg inhaled orally q12h zanamivir£ (inhaled)1,15 Prophylaxis 10 mg inhaled orally q24h Antifungals 1,2,4,8 amphotericin B (IV) 0.5-1 mg/kg q24h (FUNGIZONE) amphotericin B, lipid complex£ (IV)1,4,8 5 mg/kg q24h (ABELCET) 1,8 amphotericin B, liposomal (IV) 3 – 6 mg/kg q24h (AMBISOME)

£ 1 200 mg once then 100 mg q24h anidulafungin (IV) caspofungin£ (IV)1 70 mg once, then 50 mg q24h

46 ADULT ANTIMICROBIAL DOSING TOOL

Usual Adult Dose (CrCl greater CrCl CrCl CrCl less Intermittent Drug General Comments than or equal to 30 - 49 mL/min 10 - 29 mL/min than10 mL /min Hemodialysis (IHD) 50 mL/min)

100 mg q24h Esophageal candidiasis OR 150 mg q24h micafungin (IV)1,17 invasive aspergillosis Prophylaxis of Candida infection in hematopoietic 50 mg q24h stem cell transplantation Administer usual dose after Candidemia: 800 mg loading 1 dialysis on dialysis days; on dose on day 1 then 400 mg 200 – 800 mg q24h 50% of the dose if CrCl 50 mL/min or less fluconazole (PO/IV) non-dialysis days, reduce dose daily by 50 % itraconazole (PO)1 Aspergillosis: Consider *Capsules and oral solution are NOT loading dose of 200 mg q8h 100 – 200 mg q24h bioequivalent; favor the oral solution x 3 days; then 200 mg q12h

Loading dose, 300 mg IV infusion q12h 1,8,9 on day 1, followed Accumulation & resultant toxicity of the diluent can occur if CrCl less than 50 mL/min. posaconazole (IV) by 300 mg IV infusion q24h starting on day 2 Delayed-Release Tablet Loading dose of 300 mg q12h on day 1 followed by 300 mg q24h starting on day 2 posaconazole (PO)1,8,9 Delayed release tablet and oral suspension are NOT bioequivalent; Prophylaxis: 200 mg three times daily favor the delayed release tablet. Oral Suspension Treatment of invasive fungal infections: 400 mg q12h or 200 mg four times daily for patients unable to tolerate a meal or nutritional supplement Therapeutic drug 6 mg/kg q12h x 2 1 monitoring may be Accumulation & resultant toxicity of the diluent can occur if CrCl less than 50 mL/min. doses then 4 mg/kg voriconazole (IV) Use oral voriconazole at normal doses considered q12h thereafter

For patients weighing greater than or equal to 40 kg: 400 mg q12h x 2 doses then 200 mg q12h ; OR for patients less than 40 Therapeutic drug kg: 200 mg q12h x 2 doses then 100 mg q12h 1,18 voriconazole (PO) monitoring may be IDSA recommendations for invasive aspergillosis: may consider oral therapy in place of IV with dosing of 4 mg/kg rounded up considered to convenient tablet dosage form every 12 hours. IV administration preferred in serious infections as comparative efficacy with the oral route has not been established.

47 ADULT ANTIMICROBIAL DOSING TOOL (NB Provincial Health Authorities Anti-Infective Stewardship Committee, September 2017)

Legend: R: restricted antimicrobial £: antimicrobial not listed on NB Hospital Formulary ‡: deep space infections include meningitis, septic arthritis,complicated abscesses, etc IBW: ideal body weight Dry body weight in hemodialysis: defined as the lowest tolerated post-dialysis weight at which there are minimal signs or symptoms of hypovolemia or hypervolemia.21 Obesity: defined as an actual body weight greater than 20% above patient’s calculated ideal body weight.

Cockcroft-Gault equation for estimated creatinine clearance (mL/min): CrCL (females) = (140 – age) x weight (kg)* serum creatinine (mcmol/L)

CrCl (males) = CrCl (females) x 1.2

*For weight, use ideal body weight unless actual body weight is greater than 20% of ideal body weight, in which case use dosing body weight. Ideal body weight (IBW): IBW (females) = 45.5 kg + 0.92 x (height in cm – 150 cm) OR 45.5 kg + 2.3 × (height in inches – 60 inches) IBW (males) = 50 kg + 0.92 x (height in cm – 150 cm) OR 50 kg + 2.3 × (height in inches – 60 inches) Dosing weight (kg) = IBW + 0.4 × (actual body weight – IBW)

48 Management of Penicillin and Beta-Lactam Allergy (NB Provincial Health Authorities Anti-Infective Stewardship Committee, September 2017) Key Points • Beta-lactams are generally safe; allergic and adverse drug reactions are over diagnosed and over reported • Nonpruritic, nonurticarial rashes occur in up to 10% of patients receiving penicillins. These rashes are usually not allergic and are not a contraindication to the use of a different beta-lactam • The frequently cited risk of 8 to 10% cross-reactivity between penicillins and cephalosporins is an overestimate based on studies from the 1970’s that are now considered flawed • Expect new intolerances (i.e. any allergy or adverse reaction reported in a drug allergy field) to be reported after 0.5 to 4% of all antimicrobial courses depending on the gender and specific antimicrobial. Expect a higher incidence of new intolerances in patients with three or more prior medication intolerances1 • For type-1 immediate hypersensitivity reactions (IgE-mediated), cross-reactivity among penicillins (table 1) is expected due to similar core structure and/or major/minor antigenic determinants, use not recommended without desensitization • For type-1 immediate hypersensitivity reactions, cross-reactivity between penicillins (table 1) and cephalosporins is due to similarities in the side chains; risk of cross-reactivity will only be significant between penicillins and cephalosporins with similar side chains • Only type-1 immediate hypersensitivity to a penicillin manifesting as anaphylaxis, bronchospasm, angioedema, hypotension, urticaria or pruritic rash warrant the avoidance of cephalosporins with similar side chains and other penicillins • Patients with type-1 immediate hypersensitivity to a penicillin may be safely given cephalosporins with side chains unrelated to the offending agent (See figure 1 & 2 below) o For example, ceFAZolin does not share a side chain with any beta-lactam and is not expected to cross react with other agents • Cross-reactivity between cephalosporins is low due to the heterogeneity between side chains; therefore, a patient with a cephalosporin allergy may be prescribed another cephalosporin with a dissimilar side chain • Cross-reactivity between penicillins and carbapenems is low. Carbapenems would be a reasonable option when antibiotics are required in patients with type-1 immediate hypersensitivity reaction to penicillins • Patients with reported Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, immune hepatitis, hemolytic anemia, serum sickness or interstitial nephritis secondary to beta-lactam use should avoid beta-lactams and not receive beta-lactam skin testing, re-challenging or desensitization • Penicillin skin tests can be used to predict penicillin sensitivity and have a 97-99% negative predictive value • Any patient with possibility of type-1 immediate hypersensitivity to a beta-lactam should be referred for allergy confirmation

Management of the Beta-Lactam Allergy (Figure 1 & Figure 2) 1,2,3,4 1. Avoid the unnecessary use of antimicrobials, particularly in the setting of viral infections. 2. Complete a thorough investigation of the patient’s allergies, including, but not limited to: the specific drug the patient received, a detailed description of the reaction, temporal relationship of the onset of the reaction with respect to when the drug was given, concomitant drugs received when the reaction occurred, the time elapsed since the reaction occurred and tolerability of any structurally related compounds. If the patient: a. reports intolerance (e.g. nausea, vomiting, diarrhea, headache) – likely not allergic, attempt beta-lactam therapy b. has a documented severe non-IgE mediated hypersensitivity reaction to a beta-lactam (e.g. interstitial nephritis, immune hepatitis, hemolytic anemia, serum sickness, severe cutaneous reactions such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug rash with eosinophilia and systemic symptoms (DRESS), etc…) – avoid all beta-lactam antibiotics including their use for allergy testing, desensitization and re-challenge. . Treatment options include non-beta-lactam antibiotics c. has a documented severe type-1 immediate (IgE-mediated) hypersensitivity reaction to a penicillin (e.g. anaphylaxis, urticaria, angioedema, hypotension, bronchospasm, stridor, pruritis) – avoid other penicillins and cephalosporins with similar side chain, unless patient undergoes desensitization. . Treatment options include cephalosporins with dissimilar side chains or carbapenems or non- beta-lactam antibiotics – Note: ceFAZolin does not share a side chain with any beta-lactam agent. d. has a documented severe type-1 immediate (Ige-mediated) hypersensitivity reaction to a cephalosporin (e.g. anaphylaxis, urticaria, angioedema, hypotension, bronchospasm, stridor, pruritis) – avoid cephalosporins with similar side chains and penicillins with similar side chains (see figure 2) unless desensitization is performed. . Treatment options include penicillins with dissimilar side chains, cephalosporins with dissimilar side chains, carbapenems or non-beta-lactam antibiotics.

49 Figure 1: Management Diagram

Reported Penicillin Allergy

Assess the nature of the allergy

Onset after more Onset within 1-72 hours of administration than 72 hours of administration of: of: Intolerance such as: Onset after more Stevens-Johnson Anaphylaxis, Diarrhea, than 72 hours of hypotension, syndrome, toxic Nausea, administration of: bronchoconstriction, Vomiting, non-pruritic epidermal necrolysis, allergic rhinitis, immune hepatitis, early onset urticaria, Headache morbiliform rash, DRESS, serum stridor, maculopapular rash angioedema sickness, hemolytic anemia or interstitial nephritis

Further assess the Ok to attempt Ok to attempt Avoid testing, allergy beta-lactam therapy with a desensitizing and re- How long ago? therapy different beta- challenging with all What specific agent? lactam beta-lactam antibiotics Re-challenged? Penicillin skin testing available?

Yes No

Positive Penicillin Negative Penicillin Convincing history of Skin Test Skin test an IgE-mediated Avoid all penicillins as Consider oral reaction: well as beta-lactams challenge in a Avoid all penicillins as with a similar side monitored setting; if well as beta-lactams chain (see figure 2) or negative, penicillin with a similar side consider class antibiotics may chain (see figure 2) or desensitization or be used consider select a non-beta- desensitization or lactam antibiotic select a non-beta- lactam antibiotic.

50 Figure 2: Matrix of Beta-Lactam Cross Allergy (based on similar core and/or side chains) 5,6,7,8,9:

Each ‘X’ in the matrix indicates side-chain and/or major/minor antigenic similarity between two antibiotics. For type-1 immediate hypersensitivity there is a risk of cross-allergenicity between pairs due to similar side-chains and/or major/minor antigenic determinants, use NOT recommended without desensitization. For example: a patient allergic to amoxicillin would likely manifest a reaction to ampicillin, cloxacillin, piperacillin, ticarcillin, cefadroxil, cephalexin, cefaclor and cefprozil but NOT to ceFAZolin, cefuroxime or cefTRIAXone, etc.

Beta-lactam cross-allergy penicillin amoxicillin ampicillin cloxacillin piperacillin ticarcillin cefadroxil ceFAZolin cephalexin cephalothin cefaclor cefprozil cefuroxime cefOXitin cefixime cefotaxime cefTAZidime cefTRIAXone cefepime meropenem imipenem ertapenem aztreonam penicillin X X X X X X X amoxicillin X X X X X X X X X ampicillin X X X X X X X X X PENICILLINS cloxacillin X X X X X piperacillin X X X X X ticarcillin X X X X X cefadroxil X X X X X 1ST ceFAZolin GENERATION cephalexin X X X X X CEPHALOSPORION cephalothin X X X cefaclor X X X X X 2ND cefprozil X X X X X GENERATION cefuroxime X CEPHALOSPORIN cefOXitin X X X cefixime 3RD cefotaxime X X X GENERATION cefTAZidime X CEPHALOSPORIN cefTRIAXone X X 4TH GEN CEPH cefepime X X meropenem X X CARBAPENEMS imipenem X X ertapenem X X Monobactam aztreonam X

*Please note that the Matrix of Beta-Lactam Cross Allergy should only be used to evaluate the risk of cross-reactivity in patients with type 1 immediate (IgE-mediated) hypersensitivity reactions to a beta- lactam (e.g. anaphylaxis, urticaria, angioedema, hypotension, bronchospasm, stridor, pruritis). Please refer to figure 1 for all other types of reactions.

51 Therapeutic Review

Beta-lactam antibiotics are the most commonly prescribed class of antimicrobials and include penicillins, cephalosporins, carbapenems and monobactams (table 1).9 Due to similarities in their beta-lactam ring structure it has been widely accepted that penicillins, cephalosporins and carbapenems have significant cross-reactivity with other classes of beta-lactams.5,9,10,11 Historically it has been reported that approximately 10% of patients allergic to penicillins are also allergic to cephalosporins and up to 50% cross-reactivity has been reported between penicillins and carbapenems.4,5,9,10,11 Therefore, it has been commonly recommended that patients with a severe allergic reaction to one class of beta-lactam antibiotic should not receive any beta-lactam antibiotic.9 This historic over-estimation of cross-sensitivity between classes of beta-lactams is inaccurate and based on flawed methodologies.12

Studies have shown that physicians are more likely to prescribe antimicrobials from other classes when patients have a documented penicillin or cephalosporin allergy.13,14 Non beta-lactam alternatives may be: less effective, more toxic, broader spectrum, more expensive and more likely to lead to infection or colonization with resistant organisms.4,13,15,16,17 The inaccurate documentation of a penicillin allergy can lead to undesirable patient outcomes. For example, one study showed that patients with a documented penicillin allergy at admission spend more time in hospital and are more likely to be exposed to antibiotics associated with C.difficile and vancomycin resistant Enterococcus.18 In addition they had increased prevalence rates for infections secondary to C.difficile, vancomycin- resistant Enterococcus and methicillin-resistant Staphylococcus aureus.18 Another study showed that patients with an “allergy” label (to any antimicrobial) in their medical record were more likely to have longer hospital stays, to be admitted to an intensive care unit, to receive more than one antibiotic during their hospitalisation, and to die during hospitalisation.36

Practice however is changing because allergies have been better defined and the role of the chemical structure on the likelihood of cross-reactivity is now better understood. Recent data shows that the rate of allergic cross-reactivity between penicillins and other beta-lactams is much lower than previous estimates.4,5,9,11

Determining the nature of the patient’s reaction is an important step in differentiating between an allergic reaction and an adverse drug reaction such as nausea, vomiting, diarrhea and headache.5,9 Immunologic reactions to medications are generally classified according to the Coombs and Gell classification of hypersensitivity reactions (see table 2).5,9 The onset and presentation of the reaction can be used to help classify the reaction and determine whether or not a beta-lactam antibiotic may be used (table 2).5,9 Type-1, immediate hypersensitivity reactions, are immunoglobulin (Ig) E-mediated reactions and are the only true allergic reactions where the potential risk of cross-reactivity between beta-lactams should be considered.5,9 Type-1 immediate hypersensitivity reactions usually occur within 1 hour of exposure and typically manifest as anaphylaxis, bronchospasm, angioedema, stridor, wheezing, hypotension, urticaria or a pruritic rash.5 The incidence of these reactions is very low.19 Nonurticarial and nonpruritic rashes are almost certainly not IgE-mediated.5

Penicillins

Penicillin is the most frequently reported drug allergy and is reported in 5-10% of the population.20,21,22 Studies have shown that between 80 and 95% or more of those patients reporting a penicillin allergy 52 do not in fact have true hypersensitivity reactions and the vast majority of these patients can tolerate beta-lactams.1,10,21,22,23,24,25

The use of penicillins can be associated with a nonimmediate, nonpruritic, nonurticarial rash in up to 10% of patients that is unlikely to be IgE-mediated and most often idiopathic or T-cell mediated.5,26 While inconvenient, these reactions have not been associated with anaphylaxis and pose no risk of cross reactivity with other beta-lactams.26 An example is the nonpruritic maculopapular rash commonly seen after the administration of ampicillin or amoxicillin to children suffering from infectious mononucleosis secondary to the Epstein-Barr virus.27

Only a type-1 immediate (IgE-mediated) hypersensitivity reaction to a penicillin manifesting as: anaphylaxis, bronchospasm, angioedema, hypotension, urticaria or pruritic rash warrants the avoidance of other penicillins and cephalosporins with similar side chains.4,5,9,11 Cross-reactivity between penicillins (figure 2) may be due to shared common antigenic determinants based on similarities in their core ring structure that is common to all penicillins and/or the side chains that distinguish different penicillins from one another; therefore, cross-reactivity cannot be based on side chain similarities alone.

Currently, there is one Health Canada-approved standardized penicillin skin test. PRE-PEN contains the major antigenic determinant of penicillin and is used to rule out a type-1 immediate (IgE-mediated) penicillin allergy. Available literature suggests that the skin test using both major and minor antigenic determinants are roughly 50-60% predictive of penicillin hypersensitivity with a 97-99% negative predictive value.4 When penicillin skin testing is not available, the approach to penicillin allergic patients is based on their reaction history and the need for treatment with a penicillin.28 While patients with a convincing reaction history are more likely to be allergic, those with vague histories cannot be discounted as they may also be penicillin allergic.28 The time passed since the reaction is useful because 50-80% of penicillin allergic patients lose their sensitivity after 5 and 10 years respectively.2,29,30

Skin testing, desensitization or re-challenge with a beta-lactam should not be performed in those patients with a history of Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS, serum sickness, immune hepatitis, hemolytic anemia or interstitial nephritis.5

Cephalosporins

Cephalosporin-induced skin reactions, described as urticarial, rash, exanthema and pruritus, occur in approximately 1 to 3% of patients.31

Early analysis of cephalosporin use in penicillin allergic patients was complicated by the uncritical evaluation of “allergic reaction”.5,9,11 Any adverse reaction to cephalosporins was often classified as “allergic”.5,9,11 This, accompanied with possible penicillin contamination in early cephalosporin production, resulted in overestimations of cross-sensitivity.5,9 In addition, penicillin allergic patients are more likely to have an allergy to any drug when compared to other patients.4,5,9,10,11 Investigations have shown that individuals with a penicillin allergy are three times more likely to develop new allergies to unrelated compounds, leading to further overestimations of cross-reactivity.5,9,10

Cross-reactivity between penicillins and cephalosporins is due to similarities in side chains at the C-3 or C-7 position as shown in table 3 and not similarities in beta-lactam ring structure as previously speculated.4,5,9,11 The American Academy of Pediatrics states that the likelihood of a penicillin allergic 53 patient reacting to a cephalosporin with a different side chain is similar to that of a non-penicillin allergic patient.5 A prospective study with skin test or challenge dose confirmed penicillin allergy demonstrated a 0% cross-reactivity to ceFAZolin, cefuroxime and cefTRIAXone. None of these agents share a side chain with penicillin.32 Meanwhile the risk of cross-reactivity may be up to 40% between penicillins and cephalosporins with the similar R-group side chains.3,33 A retrospective population based analysis of 3.9 million patients revealed that there was no significant difference between the rates of anaphylaxis to a cephalosporin in patients with and without documented penicillin “allergy”. This study also highlighted that the practice of avoiding 1st and 2nd generation cephalosporins and using 3rd or 4th generation cephalosporins instead was associated with higher rates of C. difficile infection. The authors go on to say: “Warnings against the administration of cephalosporins to patients with unconfirmed penicillin allergy should be removed from electronic medical record systems.The public would be better served by warnings that the use of cephalosporins, particularly third- or higher generation parenteral cephalosporins, is associated with an increased risk of C difficile infection within 90 days.”38

Cross-reactivity between cephalosporins is low because of the significant heterogeneity of the side chains at the C-3 and C-7 positions.9,34 Therefore, if a patient has a cephalosporin allergy, one can safely prescribe another cephalosporin that has dissimilar side chains at both C-3 and C-7 positions.34 A prospective study evaluating the possibility of using alternative cephalosporins in patients with confirmed cephalosporin allergy demonstrated that cephalosporin allergies are not a class effect, and that patients with confirmed cephalosporin allergy can safely receive cephalosporins with dissimilar side chains.37

CeFAZolin is not expected to cross react with any penicillin or cephalosporin as it does not share a side chain with any beta-lactam.4,34

Carbapenems

Early studies evaluating the risk of cross-reactivity between penicillin and carbapenems found rates upwards of 47%. However, these studies had poor definitions of allergy and variable methods for determining allergy status.9 A more recent systematic review was completed to collect and combine all published data on pediatric and adult patients reported to have a clinical history of type-1 immediate hypersensitivity (IgE-mediated) to a penicillin and/or cephalosporin who were then given a carbapenem.35 Within the study allergic reactions were classified as proven, suspected or possible IgE-mediated and non-IgE-mediated.35 Overall, for patients with a history of proven, suspected or possible IgE-mediated reaction to a penicillin; 4.3% (36/838) had a suspected hypersensitivity reaction to a carbapenems but only 20 were compatible with an IgE-mediated reaction and only one was considered to be proven.35 The authors concluded that carbapenems would be a reasonable option when antibiotics are required in patients with IgE-mediated reactions to penicillins.35 They advise that clinicians proceed with caution by administering the first dose of carbapenem in a setting where anaphylaxis can be managed and to consider giving via a graduated challenge.35 If at any stage the patient reacts then the options are to use a carbapenem desensitization protocol or switch to a non- beta-lactam antibiotic.35

54 Desensitization

Desensitization, or temporary induction of drug tolerance, is used for patients with a documented or convincing history of type-1 immediate (IgE-mediated) beta-lactam allergy and/or positive skin test and a serious infection where non-cross-reacting alternatives are not appropriate.2,28 The goal of desensitization is to modify a patient’s immune response to allow safe treatment with the allergenic drug.28

Desensitization will not prevent non-IgE mediated reactions and should never be attempted in patients with reactions involving major organs or severe cutaneous reactions (e.g. interstitial nephritis, SJS, TEN, DRESS, etc.).2

Desensitization is performed by administering incremental doses of the allergenic drug.3 Usually the procedure is complete within hours and starts in the microgram range.28 Dosages are usually doubled every 15 to 30 minutes until therapeutic doses are achieved.28 When the desensitization process is complete, treatment with the select beta-lactam should be started immediately and must not be interrupted during the treatment course.2,28 Desensitization is usually lost within two days of cessation and must be repeated if the beta-lactam is required in the future.2,28

Graduated Challenge

Graduated challenges are used when there is a low likelihood of drug allergy and differ from desensitization in that they do not alter the patient’s underlying immune response to the drug in question.28 Their purpose is to allow cautious administration in patients unlikely to be allergic when there is no intention to alter the patient’s immune response.28 If the graduated challenge is tolerated the patient is then considered not to be allergic and not at increased risk for future reactions.28 Graduated challenges should never be performed in patients with reactions involving major organs or non-IgE mediated severe cutaneous reactions (e.g. interstitial nephritis, SJS, TEN, DRESS, etc…).28

The starting dose of a graduated challenge is often higher than that used for desensitization and usually only involves 2 to 3 steps and completed within hours.28 For a graduated challenge for an intravenous antibiotic, 1% of the full dose is administered, then 10 % of the full dose, then the full dose, separated by 30 minutes to 1 hour each and under careful observation.2,3 If at any point a reaction occurs the graduated challenge is stopped.

The decision to use a graduated challenge is based on the risk of cross-reactivity and the description and remoteness of the allergic reaction in question. Treatment options requiring desensitization or graduated challenge should be avoided in severe infections (ex. febrile neutropenia, sepsis, meningitis, etc.) where delays in appropriate drug therapy are associated with poor patient outcome, in these scenarios a non-beta lactam treatment option should be considered for empiric therapy.

Allergy assessment

Allergy evaluation and “de-labelling” is emerging as a new antimicrobial stewardship intervention. Recent IDSA guidelines recommend that antimicrobial stewardship programs promote allergy assessments and penicillin skin testing when appropriate, as these may enhance the use of first-line agents.39 A multicenter prospective trial demonstrated that antimicrobial stewardship pharmacists performing beta-lactam allergy skin testing and graduated challenge at the point of care was 55 associated with greater use of preferred beta-lactam therapy without increasing the risk of adverse drug reactions.40

Table 1: Classification of Beta-Lactams Cephalosporins Penicillins First Second Third Fourth Carbapenems Monobactam Generation Generation Generation Generation penicillin cefadroxil cefaclor cefTAZidime cefepime ertapenem aztreonam ampicillin ceFAZolin cefOXitin cefixime imipenem amoxicillin cephalexin cefprozil cefTRIAXone meropenem cloxacillin cefuroxime cefotaxime piperacillin ticarcillin

Table 2: Coombs and Gell Classification of Hypersensitivity Reactions4,5,31,38,41,42,43,44 Type Mediator Onset Clinical Reaction Comments I - Immediate and IgE antibodies Less than 1hr Anaphylaxis, Anaphylaxis: Acute hypersensitivity (Rarely up to 72 urticaria, Penicillins hours) angioedema, 0.015 – 0.2% hypotension, bronchospasm, Cephalosporins stridor, pruritis 0.0001 – 0.1%

Avoid the offending agent and side chain related agents (See Figure 2) II – Delayed cytotoxic IgG and IgM Greater than Hemolytic anemia, Drug specific, avoid antibody-mediated antibodies 72 hours thrombocytopenia, the offending agent hypersensitivity neutropenia III – Antibody complex- IgG and IgM Greater than Serum sickness, Antibody-antigen mediated complexes 72 hours glomerulonephritis, complexes precipitate hypersensitivity small vessel in tissues and vasculitis, drug potentially affect any fever end organ IV – Delayed type T-Cells Greater than Contact dermatitis, Incidence is low. hypersensitivity 72 hours pustulosis Ex: Eosinophilia, bullous exanthems, severe exfoliative dermatoses (ex. SJS/TEN), interstitial nephritis, immune hepatitis and some morbilliform or maculopapular rashes

Idiopathic Reactions Unknown Usually greater Maculopapular or 1 – 4% of patients than 72 hours morbilliform rashes receiving beta-lactams Not a contraindication to future use of beta- lactam antibiotics *Anaphylaxis: defined as serious hypersensitivity reaction that is rapid in onset and may cause death, typically involving the skin, mucosal tissue or both and either respiratory compromise (e.g. dyspnea, wheeze-bronchospasm, stridor, reduced peak expiratory flow, hypoxemia) or reduced blood pressure or the associated symptoms and signs of end-organ dysfunction. 56 Table 3: Beta-Lactam Groups with Similar Side-Chains Similar C-7 Side Chain Similar C-3 Side Chain (Cross Reactions between agents (Cross reactions between agents within one group is possible) within one group is possible) Group 1 Group 2 Group 3 Group 1 Group 2 Group 3 Group 4 Group 5 Group 6 Group 7 penicillin amoxicillin cefepime cefadroxil cefotaxime cefuroxime cefixime cefTAZidime cefOXitin ampicillin cefotaxime cephalexin cephalothin cefOXitin aztreonam cefaclor cefTRIAXone cephalexin cefadroxil cefprozil Note: • CeFAZolin does not share a side chain with any beta-lactam and is not expected to cross react with other agents • Amoxicillin, ampicillin, penicillin, cloxacillin, piperacillin and ticarcillin share common major allergic determinants based on similarities in their core structure and/or side chains; therefore, cross-reactivity cannot be based on side chain similarities alone

57 Antimicrobial Allergy Evaluation Tool (NB Provincial Health Authorities Anti-Infective Stewardship Committee, May 2016)

Reaction (as indicated in the patient’s chart  or described by the patient )

Personal history Asthma Autoimmune disease Atopic dermatitis Latex allergy Prior anaphylaxis  Multiple drug intolerance syndrome  Multiple drug allergy syndrome Food allergy: ______Other:______Patient questionnaire 1. When did the reaction take place? ______

2. How old was the patient at the time of the reaction? ______

3. Does the patient recall the reaction? If not, who informed them of the reaction? ______

4. Does the patient remember which medication? ______

5. What was the medication prescribed for? ______

6. What was the route of administration? ______

7. How long after starting the medication did the reaction begin? ______

8. Describe the reaction: ______

9. Did the patient seek medical care due to the reaction? ______

10. Was the medication discontinued? If so, what happened after it was discontinued? ______

11. Did the patient have any other ongoing medical problem at the time of the reaction? ______

12. What other medications was the patient taking? Why and when were they prescribed? ______

13. Has the patient taken any similar medications before or after the reaction? If so, what was the result? ______

14. Has the patient ever experienced this reaction without intake of the suspected medication? ______Assessment  Probable non-severe delayed hypersensitivity  Probable type 1 immediate hypersensitivity reaction reaction (non-IgE mediated) (IgE mediated)  Probable non-allergic adverse reaction or  Probable severe delayed hypersensitivity reaction intolerance (non-IgE mediated)

Completed by:______Date/time:______58 Table 1: Patient questionnaire1,2,4,5,6,7,12,13,14

Question Comments When did the reaction take place? Patients with type 1 immediate (IgE-mediated) hypersensitivity reactions to penicillin may lose their sensitivity over time (50% after 5 years, and 80% after 10 years)

How old was the patient at the time of the Certain confounding factors may be more common depending on the reaction? patient’s age. (Example: viral exanthems in pediatric patients)

Does the patient recall the reaction? If not, Vague histories do not rule out serious reactions. However, it is less who informed them of the reaction? likely to be a serious hypersensitivity reaction if the patient or family cannot recall the specifics of the reaction.

Does the patient remember which medication? Knowing the specific antimicrobial which caused the reaction can help in determining safe alternatives.

What was the medication prescribed for? Sometimes patients confuse symptoms of the condition with adverse reactions of the medication. (e.g.: Strep. pyogenes scarlet fever rash being confused as a drug-reaction)

What was the route of administration? Hypersensitivity reactions can be more common when medications are administered intravenously compared to orally.

How long after starting the medication did the Timeframe is essential to distinguish between an IgE-mediated reaction begin? immediate hypersensitivity reaction or non-IgE mediated delayed reaction.

Describe the reaction. Obtain specific information from the patient. (Ex: if a rash; determine location, morphology, etc.)

Did the patient seek medical care due to the Can be of value to stratify how severe the reaction was. reaction?

Was the medication discontinued? If so, what Discontinuing the medication will have varying results. (e.g.: depending happened after it was discontinued? on the type of skin reaction, symptoms may or may not improve after discontinuation)

Did the patient have any other ongoing Certain viral infections [e.g. Epstein-Barr virus (EBV), Herpes simplex medical problem at the time of the reaction? virus (HSV), Human immunodeficiency virus (HIV), Cytomegalovirus (CMV)] are associated with non-IgE mediated cutaneous drug reactions that are often misdiagnosed as “allergic reactions”.

What other medications was the patient Concomitant medications could cause or contribute to the reaction. taking? Why and when were they prescribed?

Has the patient taken any similar medications Tolerance of structurally similar medications is not always indicative of before or after the reaction? If so, what was tolerance of the suspected medication; however, it can assist in the result? determining safe alternatives.

Has the patient ever experienced this reaction If the same reaction has occurred without exposure to the suspected without intake of the suspected medication? medication, it may be caused by other factors.

59 Therapeutic review

Allergy evaluation is an essential component of patient care. Beta-lactams, as a class, are generally safe; allergic and adverse reactions are over diagnosed and over reported. For example, up to 10% of the population will report a penicillin allergy; but up to 95% (or more) of these patients do not have a true allergy.4,6,11

Fearing a potential anaphylaxis secondary to beta-lactam use, many clinicians will over diagnose penicillin allergy or simply accept a diagnosis of penicillin allergy from patients without a proper history of the reaction.2 Studies have shown that physicians are more likely to prescribe antimicrobials from other classes when patients have a documented penicillin or cephalosporin allergy.2,9 Non beta-lactam alternatives may be: less effective, more toxic, broader spectrum, more expensive and more likely to lead to infection or colonization with resistant organisms.6,9 Unfortunately, a penicillin allergy label is not benign. Simply being labelled as having an allergy to penicillin increases the likelihood of prolonged hospital stay and increases the risk of infections due to Clostridium difficile, vancomycin-resistant Enterococcus (VRE), and methicillin-resistant Staphylococcus Aureus (MRSA).10

Most patients have no current physical findings that can either prove or disprove their allergy label.2 The initial probability of a true allergy is almost always determined by the allergy history.2 The included patient questionnaire can assist clinicians in obtaining a detailed allergy history.

A detailed investigation of the patient’s allergy history is necessary to differentiate between true type 1 (IgE-mediated) immediate hypersensitivity reactions (true allergic reactions) and non IgE-mediated hypersensitivity reactions or intolerances/adverse reactions. While some of the non IgE-mediated reactions are minor, other types of reactions can be severe (e.g. interstitial nephritis, immune hepatitis, hemolytic anemia, serum sickness, Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS, etc.). Table 2 below subdivides the reactions based on the Coombs and Gell classification of hypersensitivity reactions:

Table 2: Coombs and Gell Classification of Hypersensitivity Reactions 6,7

Type Mediator Onset Clinical Reaction Comments I - Immediate and Acute IgE antibodies Within 1hr Anaphylaxis, urticaria, Anaphylaxis: Penicillins hypersensitivity (Rarely up to 72 angioedema, 0.01-0.05% hours) hypotension, bronchospasm, stridor, Cephalosporins 0.0001- pruritis 0.1%

II – Delayed cytotoxic IgG and IgM Greater than 72 Hemolytic anemia, Drug specific antibody-mediated antibodies hours thrombocytopenia, hypersensitivity neutropenia III – Antibody complex- IgG and IgM Greater than 72 Serum sickness, Antibody-antigen complexes mediated hypersensitivity complexes hours glomerulonephritis, precipitate in tissues and small vessel vasculitis, potentially affect any end drug fever organ IV – Delayed type T-Cells Greater than 72 Contact dermatitis, Incidence is low. hypersensitivity hours pustulosis Ex: Eosinophilia, bullous exanthems, severe exfoliative dermatoses (ex. SJS/TEN), interstitial nephritis, immune hepatitis and some morbilliform or maculopapular rashes

Idiopathic Reactions Unknown Usually greater than Maculopapular or 1 – 4% of patients receiving 72 hours morbilliform rashes beta-lactams

The time to onset of the reaction can be a helpful tool in determining if the reaction was in fact a true type 1 immediate (IgE-mediated) hypersensitivity reaction. Type 1 reactions usually occur within an hour of exposure, with the possibility of occurring up to 72 hours post-exposure, and can include anaphylaxis, urticaria, angioedema, hypotension, bronchospasm, stridor and pruritis.5,6,7 60 Cutaneous reactions

Many patients may report a “rash” as an allergic reaction; however more information should be sought to assist in defining the true nature of the reaction. Cutaneous reactions can range from non-severe delayed maculopapular rashes to life- threatening toxic epidermal necrolysis; therefore it is essential to further question the patient.

Certain infections can either cause cutaneous reactions or predispose patients to reacting to antimicrobials. Patients suffering from certain bacterial infections (e.g. Streptococcus pyogenes, Mycoplasma pneumoniae) can develop cutaneous symptoms, irrespective of which antibiotic is used.18,22 Certain viral infections [e.g. Epstein-Barr virus (EBV), Herpes simplex virus (HSV), Human immunodeficiency virus (HIV), Cytomegalovirus (CMV)] can also directly cause cutaneous symptoms.14,18,22 Patients suffering from these viral infections may also be at a higher risk to react to certain antimicrobials.2,4,12,13 A notable example is the delayed morbilliform rash that often develops when patients suffering from EBV are treated with an aminopenicillin, such as amoxicillin.4,18

Please see table 3 below for a brief description of certain cutaneous reactions.

Table 3 – Cutaneous reactions 1,2,15,16,18,19,20,21 Type of skin reaction Chronology Description Angioedema Onset: Usually Region(s) affected: Lips, eyelids, earlobes, tongue, mouth, larynx, immediate genitalia (0-6 hours) Morphology: Skin-coloured circumscribed edema involving the Duration: subcutaneous tissues. (can be asymmetrical/unilateral) Resolution within 24-72 hours More details: Non-pruritic; often very frightening for patients; can be painful

DRESS syndrome Onset: 1-8 weeks Region(s) affected: Classic distribution: Face, upper trunk, (Drug Rash with after exposure extremities (but can progress anywhere on the surface of the skin Eosinophilia and Systemic and can sometimes have mucosal involvement) Symptoms) Duration: Weeks- months (even after Morphology: Most commonly begins as an erythematous, pruritic, discontinuing the morbilliform rash suspected medication) More details: Pruritis and fever usually precede cutaneous eruptions. Can cause facial edema, which can be mistaken for angioedema.

Systemic systems involved: - Lymphatic: lymphadenopathy is very common - Hematologic: leukocytosis, eosinophilia, lymphocytosis - Hepatic: hepatosplenomegaly, hepatitis, elevated liver transaminases, elevated alkaline phosphatase - Renal: hematuria, proteinuria, elevated BUN and creatinine - Other: pulmonary, cardiac, neurologic

Erythema multiforme Onset: Within 3-5 Region(s) affected: Often appear on the extremities (hands, palms, days extensor of the forearms, soles of the feet, etc.) and can spread (May include inwards towards the trunk. May involve mucous membranes of the prodromal mouth and genitalia. symptoms of an upper respiratory Morphology: Well-demarcated, circular, erythematous papules; infection) often “target” or “iris”-like.

Duration: More details: Approximately 2 - Can be difficult to discern from Stevens-Johnson Syndrome weeks - Often associated with HSV or mycoplasma infections - Fever, if present, is usually mild 61 Type of skin reaction Chronology Description Maculopapular rash / Onset: Delayed Region(s) affected: Commonly begin on head, neck or upper torso, Morbilliform rash / (often more than 72 and progress downward to the extremities. Exanthems hours), within the first 2-4 weeks Morphology: Often bilateral and symmetrical. Usually flat, barely following the initial raised, erythematous patches (one to several mm in diameter). Can dose also include papules.

Duration: Usually More details: fades within 2 - With or without pruritis weeks - Can develop into confluent areas - Can be the result of several mechanisms (ex: viral infection, idiopathic, etc.) - Mild eosinophilia is possible, but not common - Fever rarely associated; but is mild if present

Photosensitivity / Onset: 5-20 hours Region(s) affected: Areas most often exposed to the sun (ex: face, Phototoxicity after drug + UV back of the hands, back and sides of the neck, extensor surfaces of light exposure the forearm, etc.). Classical presentation spares shaded areas, such as under the chin, under the nose, behind the ears. Duration: N/A Morphology: Often resembles exaggerated sunburn, sometimes with blisters. Sharp demarcation at sites where clothing or jewelry were present during light exposure.

More details: Not common with beta-lactam antibiotics

Pruritis Onset: N/A Region(s) affected: Localized or generalized itching; more often generalized when drug induced. Duration: N/A Morphology: Does not require visible cutaneous signs of a reaction.

More details: Mechanism not always clear

Stevens-Johnson Onset: Delayed Region(s) affected: Less than 10% of the body surface is affected. syndrome (within 8 weeks of Can affect the skin, eyes, and mucous membranes; such as the first exposure), but lips, mouth, and genital mucous membranes. with abrupt onset of symptoms. Morphology: Often begins with dusky red, flat lesions (sometimes target-like, similar to erythema multiforme), progressing to bullae Duration: Up to 6 and necrotic lesions. Leads to blisters and dislodgement of the weeks epidermis.

More details: - Is accompanied by any (or all) of: high fever, malaise, myalgia, arthralgia, headache, ocular involvement, painful stomatitis - A medical emergency; in-hospital mortality = 5-12 %

Toxic epidermal necrolysis Onset: Delayed Region(s) affected: Greater than 30% of the body surface is (within 8 weeks of affected. Can affect the skin, eyes, and mucous membranes; such first exposure), but as the lips, mouth, and genital mucous membranes. Hairy regions with abrupt onset of of the skin are often spared. symptoms. Morphology: See Stevens-Johnson Syndrome; eventually can Duration: Up to 6 resemble extensive second degree burns weeks More details: - Is accompanied by any (or all) of: high fever, fatigue, vomiting, diarrhea, malaise, myalgia, angina, arthralgia, headache, ocular involvement, painful stomatitis - A medical emergency; in-hospital mortality more than 30%

62 Type of skin reaction Chronology Description Urticaria Onset: Immediate, Region(s) affected: Can occur in any location. Involves the usually within 36 superficial portion of the dermis, and not subcutaneous tissues. hours Morphology: Raised, erythematous areas of edema (wheals), Duration: Rarely sometimes with central pallor. Will often blanch with pressure. persist for more than 24 hours More details: - Often pruritic - May or may not be accompanied by angioedema, can progress to anaphylaxis

For more information, please see the Management of Penicillin and Beta-Lactam Allergy guideline prepared by the NB Provincial Health Authorities Anti-Infective Stewardship Committee.

63 Antimicrobial Route of Administration (IV to PO) Therapeutic Conversion

Patients on the targeted IV antimicrobials should be assessed within 72 hours of the start of IV therapy and regularly thereafter for the appropriateness of IV to PO conversion based on the following criteria (see below for list of targeted antimicrobials and their renal dose adjustments).

GENERAL CRITERIA The patient: is tolerating food, enteral feeds and/or other oral medications AND is not showing evidence of malabsorption (e.g.diarrhea/vomiting) AND does not have continuous nasogastric suctioning, gastrectomy, malabsorption syndrome, GI obstruction or ileostomy

ANTIMICROBIAL CRITERIA The patient: is clinically improving (which may include documented improved clinical signs and symptoms of infection, normalizing white blood cell count, etc…) AND is hemodynamically stable AND has been afebrile for at least 48 hours (i.e. temperature less than 38°C) AND is not being treated for a condition where parenteral therapy is clinically indicated, including but not limited to: endocarditis, CNS infection, osteomyelitis, S. aureus bacteremia, undrained or complicated abscess, cystic fibrosis, febrile neutropenia AND doesn’t have a pathogenic isolate showing resistance to the suggested antibiotic

Table 1: Route of Administration (IV to PO) Conversion Protocol for Targeted Antimicrobials Drug IV dose PO drug/dose Interval azithromycin 250 or 500 mg q24h azithromycin 250 mg q24h 1 1000 mg q8h 1,2 ceFAZolin cephalexin 500 mg q6h 2000 mg q8h cefTRIAXone 1000 mg q24h 1,2 amoxicillin/clavulanate (For community-acquired pneumonia q12h 2000 mg q24h 875/125 mg or acute exacerbation of COPD) 1 1 400 mg q12h or q24h ciprofloxacin 500 mg Same as IV ciprofloxacin 400 mg q8h ciprofloxacin1 750 mg q12h clindamycin 600-900 mg q8h or q12h clindamycin 450 mg q6h metroNIDAZOLE1 500 mg q8h or q12h metroNIDAZOLE1 500 mg Same as IV moxifloxacin 400 mg q24h moxifloxacin 400 mg q24h levofloxacin1 500-750 mg q24h levofloxacin1 (dose same as IV) Same as IV 1Dose adjustment required in renal impairment 2Assess for true penicillin allergy

Table 2: Antimicrobial Dosing in Renal Impairment Usual adult dose CrCl 30 - 49 Drug (CrCl equal to or greater CrCl 10 - 29 mL/min CrCl less than 10 mL/min mL/min than 50 mL/min) amoxicillin + clavulanate 875/125 mg q12h no adjustment 500/125 mg q12h 500/125 mg q24h cephalexin 500 mg q6h 500 mg q8h 500 mg q12h 500 mg q24h 1000 mg q8h no adjustment 1000 mg q12h 1000 mg q24h ceFAZolin 2000 mg q8h no adjustment 2000 mg q12h 2000 mg q24h 250–500 mg q12h no adjustment extend interval to q24h extend interval to q24h ciprofloxacin PO 750 mg q12h 500 mg q12h 500 mg q24h 500 mg q24h 400 mg IV q12h no adjustment 400 mg q24h 400 mg q24h ciprofloxacin IV 400 mg IV q8h 400 mg q12h 400 mg q24h 400 mg q24h metroNIDAZOLE 500 mg q8h or q12h no adjustment no adjustment 500 mg q12h CrCl 20-49 mL/min CrCl less than 20 mL/min 750 mg q24h 750 mg q48h 500 mg q48h levofloxacin CrCl 20-49 mL/min CrCl less than 20 mL/min 500 mg q24h 250 mg q24h 250 mg q48h Version: 20160317

64 Surgical Prophylaxis Guidelines

Prepared by:

NB Provincial Health Authorities Anti-Infective Stewardship Committee

2018

65 Surgical Prophylaxis Guidelines

Section 1: General Principles Page General Principles 67 Timing of Prophylaxis 67 Duration of Antibiotic 67 Choice of Prophylactic Antibiotic 68 Antibiotic Dosing 69 • Intra-operative Dosing 69 • Renal or Hepatic Impairment 69 • Aminoglycoside Dosing 69 • Vancomycin Dosing 70 • Dosing in Obesity 70 • Pediatric Dosing: 70 Section 2: Surgical Prophylaxis Recommendations Cardiac 70 Gastrointestinal • Appendectomy 71 • Colorectal 71 • Small Intestinal 71 • Gastroduodenal 72 • Hernia Repair 72 • Hepatic/Pancreatic/Biliary 72 Head and Neck 74 Neurosurgery 74 Obstetrics and Gynecology 75 Ophthalmology 76 Oral and Maxillofacial 76 Orthopedics 77 Plastic Surgery 77 Spine 79 Thoracic 79 Trauma 80 Urology 81 Vascular 82 References 109

66 These guidelines provide general recommendations for appropriate prophylactic antibiotic use for common surgical procedures; the list of surgical procedures is not all inclusive. SECTION 1: GENERAL PRINCIPLES OF ANTIMICROBIAL PROPHYLAXIS1,2,3,4,6,7,8,10,11 • Antimicrobial prophylaxis should be provided for surgical procedures for which it has been demonstrated to be beneficial. • Antimicrobial surgical prophylaxis is administered to achieve serum and tissue antibiotic concentrations that exceed the minium inhibitory concentration of the majority of organisms likely to be encountered, at the time of the incision and for the duration of the procedure. Key to achieving this goal is: . appropriate dosing . timely administration of first dose antimicrobial within 60 to 120 minutes of surigical incision . repeat dosing for prolonged procedures or in the event of major blood loss.

• It is estimated that 50% of surgical site infections are preventable by application of evidence- based strategies.

• General patient-related risk factors for surgical site infection include extremes of age, compromised nutritional status, obesity, diabetes mellitus, tobacco use, co-existent remote body site infection, altered immune response, corticosteroid therapy, recent surgical procedure, length of preoperative hospitalization and colonization withmicroorganisms

TIMING OF PROPHYLACTIC ANTIMICROBIAL DOSE: • Preoperative doses of antimicrobials must be given in the 60 minutes before the first surgical incision. Some agents, such as fluoroquinolones and vancomycin, require administration over one to two hours; therefore, the administration of these agents should begin within 120 minutes before surgical incision. • Patients receiving therapeutic antimicrobials for an infection before surgery should be given additional antimicrobial prophylaxis before surgery.

DURATION OF PROPHYLACTIC ANTIBIOTIC:

• Post-operative doses of prophylactic antibiotics are generally unnecessary.

• If antimicrobial prophylaxis is continued post-operatively, the duration should be less than 24 hours, regardless of the presence of intravascular catheters or indwelling drains.

• If the surgery is contaminated, it should be indicated that the post-operative antibiotic orders are for treatment.

67 CHOICE OF PROPHYLACTIC ANTIMICROBIAL:

• Antimicrobial prophylaxis is generally unnecessary for “clean” surgical procedures.

• For the majority of surgical procedures in which antimicrobial prophylaxis is indicated, a single dose of ceFAZolin 2 g IV given within the 60 minutes before the first surgical incision is appropriate.

• Beta-lactam allergy: Obtain a reliable history and document exact nature of the reaction. Approximately 10% of the population report having a penicillin allergy; however, greater then 90% of these individuals are not truly allergic. Non-beta-lactam options may be more toxic and less effective. For example, there is an increasing rate of gram-positive resistance to clindamycin. In addition, a study by Blumenthal et al. found that patients with a reported pencillin allergy had a 51% increased risk of surgical site infection that was primarily related to receiving a non-beta-lactam antibiotic.17

o For immediate or Type 1 (IgE-mediated) hypersensitivity reactions (e.g. anaphylaxis, urticaria, angioedema, hypotension, bronchospasm, stridor, pruritus), cross-reactivity between cephalosporins and penicillins is due to similarity in side-chains and was overestimated in the past. There is only significant risk of cross-reactivity among penicillins and between penicillins and cephalosporins with similar side-chains.

o Immediate or Type 1 (IgE-mediated) hypersensitivity reaction to penicillin warrants the avoidance of cephalosporins with similar side chains and other penicillins.

o Cross-reactivity among cephalosporins is low due to heterogeneity among side chains. Cephalosporin allergic patients may safely receive another cephalosporin with dissimilar side chains.

o CeFAZolin does not share a side chain with any beta-lactam and is not expected to cross react with other beta-lactams. CeFAZolin is the only systemic beta-lactam included in this guide and may safely be given to patients with immediate or Type 1 (IgE-mediated) hypersensitivity reactions to penicillins or other cephalosporins. It should only be avoided in patients allergic to ceFAZolin or who have a severe non-IgE mediated reaction to a beta- lactam antibiotic (see below).

o Severe non-IgE mediated hypersensitivity reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, immune hepatitis, hemolytic anemia, serum sickness, interstitial nephritis, small vessel vasculitis)- warrant the avoidance of all beta-lactams.

o Idiopathic reactions are not clearly immune-mediated (non-pruritic morbilliform rash) and are not a contraindication to taking a different beta-lactam such as ceFAZolin.

o For more information on assessing beta-lactam allergies, please see the “Management of Penicillin and Beta-Lactam Allergy” Guide on the NB-ASC website.

68 • Known MRSA colonization: • Consider administration of pre-op vancomycin prophylaxis in addition to recommended routine surgical prophylaxis regimen. Vancomycin ALONE is less effective than ceFAZolin for preventing surgical site infections due to MSSA.

o Consider pre-procedural MRSA decolonization o Consider consult to infectious diseases/medical microbiology for recommendations

DRUG DOSING

Intra-operative dosing: • For antimicrobials with short half-lives, intra-operative dosing recommended for patients with normal renal function if: prolonged surgical procedure (> 2 half-lives of the antimicrobial) OR major blood loss (>1.5L). If massive blood loss occurs, a second dose should be given promptly. See Table 1.

Table 1. Intra-operative Antibiotic Prophylaxis

Recommended re-dosing interval Prophylactic Antibiotic Half-life (hours) (from time of administration of the pre-op dose) ceFAZolin 1.2–2.2 Q4h clindamycin 2-4 Q6h aminoglycoside 2-3 N/A* metroNIDAZOLE 6-8 N/A* vancomycin 4-8 N/A* *Recommended redosing intervals marked as “not applicable” (N/A) are based on typical case length; for unusually long procedures, redosing may be needed except for aminoglycoside dosed at 5 mg/kg.

Renal or Hepatic Impairment: • Antimicrobial prophylaxis for patients with renal or hepatic dysfunction often does not need to be modified when given as a single dose pre-operatively.

Aminoglycoside dosing: • Aminoglycoside 5 mg/kg (extended interval dose) provides at least 24 hours of antimicrobial coverage. • Tobramycin is an acceptable alternative for the indication of surgical prophylaxis in the event that gentamicin is not available. Dose based on ideal body weight (IBW), unless actual body weight (ABW) is greater than 20% above IBW, then use dosing body weight, calculated as follows:

69 • Ideal body weight (males) = 50 kg + (0.92 x cm above 150 cm) OR 50 kg + (2.3 kg x inches above 60 inches) • Ideal body weight (females) = 45.5 kg + (0.92 x cm above 150 cm) OR 45.5 kg + (2.3 kg x inches above 60 inches) • Dosing body weight = IBW + 0.4 (ABW –IDW)

Vancomycin Dosing: • Vancomycin 15 mg/kg based on patient’s ABW and rounded to the nearest 250 mg.

Drug dosing in obesity: • Conclusive recommendations for weight-based dosing for antimicrobial prophylaxis in obese patients cannot be made because data demonstrating clinically relevant decreases in SSI rates from the use of such dosing strategies instead of standard doses are not available in the published literature. • Considering the low cost and favourable safety profile of ceFAZolin, the minimum dose should be 2 g. Increasing the dose to 3 g for those weighing 120 kg or more can easily be justified. For simplification, these guidelines recommend 2 g ceFAZolin doses for all adult patients.

Pediatric Dosing: • Note: This guideline is intended for adults only. Pediatric dosing provided in Table 2.

Table 2. Pediatric Prophylactic Antibiotic Dosing a,b,c, Antibiotic Recommended Dose ampicillin 50 mg/kg ceFAZolin 30 mg/kg cefTRIAXone 50-70 mg/kg ciprofloxacin 10 mg/kg clindamycin 10 mg/kg aminoglycoside 2.5 mg/kg based on dosing weight metroNIDAZOLE 15 mg/kg piperacillin- Infants 2 – 9 months: 80 mg/kg of the piperacillin component tazobactam Children greater than 9 months and less than or equal to 40kg: 100mg/kg of the piperacillin component vancomycin 15 mg/kg aThis table applies only to pediatric patients weighing 40kg or less bThe maximum pediatric dose should not exceed the usual adult dose cThis table does not specifically address new born infants

70 SECTION 2: SURGICAL PROPHYLAXIS RECOMMENDATIONS Pre-Operative Antibiotic Recommendation Post-Operative IV Patient Selection Alternate Preferred Antibiotic Duration (See Principles) CARDIAC1,2,3,7,9,12 • Cardiac device insertion ceFAZolin 2 g* vancomycin No Antibiotics (pacemaker implantation) 15 mg/kg • Ventricular assist devices OR clindamycin 900 mg • CABG ceFAZolin 2 g* vancomycin Less than 24 hours • Prosthetic valve 15 mg/kg • Open heart surgery OR • Other cardiac procedures clindamycin 900 mg • Cardiac catheterization +/- No Antibiotics N/A N/A stenting

APPENDECTOMY1,2,7,12 Appendectomy for metroNIDAZOLE metroNIDAZOLE • No Antibiotic uncomplicated appendicitis 500 mg 500 mg • If gangrenous or Plus Plus perforated ceFAZolin 2 g* aminoglycoside 5 appendicitis or mg/kg intestine, initiate treatment course COLORECTAL1,2,3,7,9,12 All patients metroNIDAZOLE [metroNIDAZOLE No Antibiotics 500 mg 500 mg Plus Plus ceFAZolin 2 g* aminoglycoside 5 mg/kg

SMALL INTESTINE SURGERY 1,3 Non-obstructed ceFAZolin 2 g* clindamycin 900 mg Less than 24 hours Plus aminoglycoside 5 mg/kg

Obstructed or emergency surgery ceFAZolin 2 g* [metroNIDAZOLE Less than 24 hours Plus 500 mg metroNIDAZOLE OR 500 mg clindamycin 900 mg] Plus aminoglycoside 5 mg/kg

*May consider ceFAZolin 3 g for patients weighing greater than or equal to 120 kg 71 Pre-Operative Antibiotic Recommendation Post-Operative IV Patient Selection Alternate Preferred Antibiotic Duration (See Principles) GASTRODUODENAL 1,2,3,7,9,12 • Procedures involving entry ceFAZolin 2 g* clindamycin 900 mg No Antibiotics into lumen of GI tract Plus (including bariatric surgery, aminoglycoside 5 pancreaticduodenectomy, mg/kg gastric carcinoma, perforated ulcer, and percutaneous endoscopic gastrostomy) • Procedures not involving incision in GI tract (ex. antireflux, highly selective vagotomy), High risk patients only • Decreased gastric acidity • Decreased GI motility • Obstruction • Hemorrhage • Gastric ulcer or malignancy • morbid obesity • Gastroduodenal perforation • ASA classification of ≥3 High risk gastroesophageal ceFAZolin 2 g* clindamycin 900 mg No Antibiotics endoscopy Plus • esophageal dilation aminoglycoside 5 • variceal sclerotherapy mg/kg

HERNIA REPAIR1,2,3,9,12 All patients ceFAZolin 2 g* vancomycin No Antibiotics • Herniorraphy 15 mg/kg • Hernioplasty OR clindamycin 900 mg

HEPATIC PANCREATIC BILIARY TRACT (HPB) – Major Procedures2,3,7 Major Procedures metroNIDAZOLE metroNIDAZOLE 500 No Antibiotics 500 mg mg Plus Plus ceFAZolin 2 g* aminoglycoside 5 mg/kg

*May consider ceFAZolin 3 g for patients weighing greater than or equal to 120 kg 72 Pre-Operative Antibiotic Recommendation Post-Operative IV Patient Selection Alternate Preferred Antibiotic Duration (See Principles) HEPATIC PANCREATIC BILIARY TRACT (HPB) – Minor Procedures1,2,3,7,9,12 Low Risk Procedures No Antibiotics N/A N/A • Elective laparoscopic (Note: many risk cholecystectomy without risk factors may not be factors (see below for risk factors) known until intra- operatively, so may be • Liver biopsy reasonable to give every patient a single pre-op dose of antibiotic)

High risk Procedures ceFAZolin 2 g* clindamycin 900 mg No antibiotics for most • Laparoscopic Plus patients except cholecystectomy with risk aminoglycoside 5 • Acute cholecystitis: factors which include: mg/kg • 2 – 5 days (emergency procedures, diabetes, • Emphysematous anticipated procedure duration cholecystitis: exceeding 120 minutes, intra- operative gallbladder rupture, age • 5 – 7 days greater than 70 years, open • Gangrene or cholecystectomy, risk of conversion perforated gall from laparoscopic to open bladder: cholecystectomy, American Society of Anesthesiologists Physical Status • change to broad Classification System (ASA) of 3 or spectrum antibiotic more, episode of colic within 30 for treatment days before the procedure, re- intervention in less than a month for non-infectious complications of prior biliary operation, acute cholecystitis, anticipated bile spillage, jaundice, pregnancy, non- functioning gallbladder, biliary obstruction, obstructive jaundice or common bile duct stones and immunosuppression) • Open cholecystectomy • Insertion of prosthetic device • ERCP (if biliary obstruction, known pancreatic pseudocyst, or if complete biliary drainage is unlikely) • Liver Resection

*May consider ceFAZolin 3 g for patients weighing greater than or equal to 120 kg 73 Pre-Operative Antibiotic Recommendation Post-Operative IV Patient Selection Alternate Preferred Antibiotic Duration (See Principles) HEAD AND NECK (MAJOR)1,2,3,7,9,12 Clean procedures: No Antibiotics N/A N/A • No incision of the oral or pharyngeal mucosa • No implantation of prosthetic material • Lymph node excisions • Exceptions (no antibiotics): o Thyroidectomy o Parotidectomy o Submandibular gland excision o all of above with no neck dissections and/or skull base involvement

Clean procedures: ceFAZolin 2 g* clindamycin 900 mg 24 hours • Cancer surgery • Placement of prosthesis (except tympanostomy tubes)

Clean-contaminated procedures: ceFAZolin 2 g* clindamycin 900 mg 24 hours • Require penetration of the Plus Plus oral/nasal/pharyngeal mucosa metroNIDAZOLE aminoglycoside 5 • Complex resection with 500 mg mg/kg reconstruction procedures • Revision and salvage surgeries • Cancer surgery • Mandibular surgery (if tobacco/alcohol/drug use)

• Tonsillectomy No Antibiotics N/A N/A • Functional endoscopic sinus procedure • Nasal Septoplasty

NEUROSURGERY1,2,3,7,9,12 • Craniotomy (elective, clean, ceFAZolin 2 g* vancomycin No Antibiotics non-implant) 15 mg/kg • Elective implantation of OR intrathecal pump clindamycin 900 mg

*May consider ceFAZolin 3 g for patients weighing greater than or equal to 120 kg

74 Pre-Operative Antibiotic Recommendation Post-Operative IV Patient Selection Alternate Preferred Antibiotic Duration (See Principles) Craniotomy ceFAZolin 2 g* vancomycin No Antibiotics • clean-contaminated Plus 15 mg/kg • crosses sinuses or metroNIDAZOLE Plus naso/oropharynx 500 mg metroNIDAZOLE 500 • emergency surgery mg • operation ≥2 hours • CSF leakage • Subsequent operation • Transsphenoidal surgery (All patients) CSF Shunting Procedures ceFAZolin 2 g* clindamycin 900 mg Less than 24 hours OR vancomycin 15 mg/kg OBSTETRICS AND GYNAECOLOGY 1,2,3,5,7,9,12,13,14,15 Therapeutic termination of doxycycline 100 mg azithromycin 1 g PO If doxycycline used pre- pregnancy PO 1 hr pre-op op: doxycycline 200 mg PO 30 min post-op

Caesarean section Elective Procedure: Elective Procedure: No Antibiotics • Administer antibiotics prior ceFAZolin 2 g* clindamycin 900 mg to skin incision NOT after Plus cord clamping aminoglycoside 5 mg/kg

Nonelective Nonelective No Antibiotics Procedure: Procedure : ceFAZolin 2 g* clindamycin 900 mg Plus Plus azithromycin 500 mg aminoglycoside 5 mg/kg Plus azithromycin 500 mg

• Radical and total ceFAZolin 2 g* [clindamycin 900 mg No Antibiotics hysterectomy (abdominal, OR laparoscopic or vaginal) metroNIDAZOLE • Vulvectomy with or without 500 mg] lymphadenectomy Plus • Vaginectomy aminoglycoside 5 • Urogynecological procedures mg/kg o Laparoscopic Burch o 2-Team sling

*May consider ceFAZolin 3 g for patients weighing greater than or equal to 120 kg 75 Pre-Operative Antibiotic Recommendation Post-Operative IV Patient Selection Alternate Preferred Antibiotic Duration (See Principles) • Endometrial ablation No antibiotics N/A N/A • Dilatation and curettage • Laparoscopic procedures that do not enter uterus and/or vagina Endometriosis (laparoscopic and metroNIDAZOLE metroNIDAZOLE No antibiotics open) 500 mg 500 mg Plus Plus ceFAZolin 2 g* aminoglycoside 5 mg/kg OPHTHALMIC1,3,12 Ophthalmic Procedures: 4th generation topical fluoroquinolones (moxifloxacin) given as 1 drop • Cataract extractions every 5-15 min for 5 doses within the hour before the start of the • Vitrectomy procedure • Keratoplasty • Intraocular lens implantation Addition of ceFAZolin 100 mg by subconjunctival injection or intracameral • Glaucoma procedures ceFAZolin 1 – 2.5 mg or cefuroxime 1 mg at the end of the procedure is • Strabotomy optional • Retinal detachment repair • Laser in situ keratomileusis • Laser-assisted subepithelial keratectomy • Corneal transplant • Eyelid surgery • Dacryocystorhinostomy • Enucleation ORAL AND MAXILLOFACIAL2,7 • No oral or sinus cavity ceFAZolin 2 g* clindamycin 900 mg No Antibiotics involvement

• Oral cavity or sinus cavity ceFAZolin 2 g* clindamycin 900 mg No Antibiotics involvement Plus • Comminuted and metroNIDAZOLE compounded fractures 500 mg • Implants/prosthesis; bone graft • Orthognathic • Gunshot wound ceFAZolin 2 g* clindamycin 900 mg • 24 hours • Animal or human bite injuries Plus Plus • For grossly • Grossly contaminated and aminoglycoside 5 aminoglycoside 5 contaminated/dirty dirty injury mg/kg mg/kg wounds, consider a Plus course of treatment metroNIDAZOLE with broad spectrum 500 mg antibiotics *May consider ceFAZolin 3 g for patients weighing greater than or equal to 120 kg 76 Pre-Operative Antibiotic Recommendation Post-Operative IV Patient Selection Alternate Preferred Antibiotic Duration (See Principles) ORTHOPEDIC1,2,3,7,9,12 Major procedures: ceFAZolin 2 g* clindamycin 900 mg 24 hours or less • Difficult fracture OR reconstruction vancomycin • Closed fracture with internal 15 mg/kg fixation • Total hip and knee replacement • Other procedures requiring prophylaxis • Total joint replacement • Implantation of internal fixation devices • Hip fracture repair Fasciotomy

Minor procedures: No antibiotics N/A N/A • Arthroscopy • Procedures not involving implantation of prosthetic material • Clean operations involving foot, hand, or knee

PLASTIC SURGERY1,2,3,7 Clean Procedures (Low Risk) No Antibiotics N/A N/A • Dermatologic • Facial bone fracture • Tumor excision • Simple rhinoplasty or septoplasty • Simple lacerations • Flexor tendon injuries • Hand surgery (simple)

Clean Procedures (High Risk) ceFAZolin 2 g* clindamycin 900 mg No Antibiotics • Placement of prosthetic OR material vancomycin • Skin irradiation 15 mg/kg • Procedures below waist

*May consider ceFAZolin 3 g for patients weighing greater than or equal to 120 kg

77 Pre-Operative Antibiotic Recommendation Post-Operative IV Patient Selection Alternate Preferred Antibiotic Duration (See Principles) Clean Contaminated Procedures ceFAZolin 2 g* clindamycin 900 mg No Antibiotics • Contaminated OR skin/mucosa/intertriginous vancomycin areas (oral cavity, upper 15 mg/kg respiratory tract, axilla, groin, perineum) • Wedge excision lip/ear • Flaps on nose/head/neck • Grafts Breast: ceFAZolin 2 g* vancomycin No Antibiotics High risk patients only14,15 15 mg/kg Except • Breast cancer procedures OR Autologous breast • Recent neoadjuvant clindamycin 900 mg reconstruction: Consider chemotherapy or radiation 24 hours or less therapy • Prosthetic material or mesh • Re-operation or recent prior breast surgery • Reconstruction surgeries • Operation duration ≥2 hours • Immunocompromised patients (diabetics, steroids, etc) • Morbid obesity (> 100 kg) • Skin irradiation Hand: ceFAZolin 2 g* vancomycin 24 hours Complex Clean Procedures: 15 mg/kg • Mutilating and crushing OR injuries from home & clindamycin 900 mg industrial source • Bone, joint, tendon (except open flexor tendon injuries – see below) and nerve involvements • Implants/ prosthesis • Flap reconstruction • Injuries require amputations • High risk patients with medical comorbidities and/or immunosuppressive drugs

*May consider ceFAZolin 3 g for patients weighing greater than or equal to 120 kg

78 Pre-Operative Antibiotic Recommendation Post-Operative IV Patient Selection Alternate Preferred Antibiotic Duration (See Principles) Hand: ceFAZolin 2 g* clindamycin 900 mg • 24 hours Clean-contaminated and Plus Plus • For grossly Contaminated Procedures: aminoglycoside aminoglycoside contaminated/ dirty • Mutilating and crushing 5 mg/kg 5 mg/kg wounds and injuries injuries from farm Plus longer than 6 hours environment metroNIDAZOLE consider a course of • Grossly contaminated and 500 mg treatment with broad dirty injuries spectrum antibiotics • Animal and human bites • Open fractures • Use of leeches

SPINE1,2,3,7,12 • Fusion ceFAZolin 2 g* vancomycin Less than 24hours • Decompression 15 mg/kg • Laminectomy OR • Microdiscectomy clindamycin 900 mg • Insertion of foreign material • Instrumentation

THORACIC1,2,3,7,12 • Thoracentesis No antibiotics N/A N/A • Chest tube insertion for spontaneous pneumothorax

Non-cardiac procedures: ceFAZolin 2 g* vancomycin Less than 24 hours • Lobectomy 15 mg/kg • Pneumonectomy OR • Lung resection clindamycin 900 mg] • Thoracotomy • VATS (video assisted thorascopic surgery) • Chest tube insertion for chest trauma with hemo/pneumothorax

Esophageal resection ceFAZolin 2 g* clindamycin 900 mg 24 hours Plus Plus metroNIDAZOLE aminoglycoside 5 500 mg mg/kg

*May consider ceFAZolin 3 g for patients weighing greater than or equal to 120 kg 79 Pre-Operative Antibiotic Recommendation Post-Operative IV Patient Selection Alternate Preferred Antibiotic Duration (See Principles) TRAUMA – Gunshot2,7 Gunshot fracture wound ceFAZolin 2 g* vancomycin 48 hours 15 mg/kg

Gunshot fracture wound with ceFAZolin 2 g* vancomycin 48 hours • Large soft tissue defects or Plus 15 mg/kg cavitary lesions aminoglycoside 5 Plus AND/OR mg/kg aminoglycoside 5 • Fracture of the extremities mg/kg (in area of the hand, foot and ankle)

Gunshot fracture wound with ceFAZolin 2 g* vancomycin 48 hours • Large soft tissue defects or Plus 15 mg/kg For grossly cavitary lesions aminoglycoside 5 Plus contaminated/dirty AND/OR mg/kg aminoglycoside 5 wounds and injuries • Fracture of the extremities Plus mg/kg longer than 6 hours (in area of the hand, foot and metroNIDAZOLE Plus consider a course of ankle) 500 mg metroNIDAZOLE 500 treatment with broad PLUS mg spectrum antibiotics. • Gross contamination of the wound and environment: o Occurred in rural/wooded area o Grossly dirty skin and clothes o Bowel communication

TRAUMA – Abdomen2,7 Penetrating abdominal trauma metroNIDAZOLE metroNIDAZOLE 500 24 hours • Hollow viscus injury 500 mg mg Plus Plus ceFAZolin 2 g* aminoglycoside 5 mg/kg

Penetrating abdominal trauma metroNIDAZOLE metroNIDAZOLE 500 No Antibiotics • Non-hollow viscus injury 500 mg mg Plus Plus ceFAZolin 2 g* aminoglycoside 5 mg/kg

TRAUMA – Orthopedic3,18,19,20 Closed Fractures with internal ceFAZolin 2 g* Vancomycin 15 No Antibiotics fixation mg/kg

*May consider ceFAZolin 3 g for patients weighing greater than or equal to 120 kg 80 Pre-Operative Antibiotic Recommendation Post-Operative IV Patient Selection Alternate Preferred Antibiotic Duration (See Principles) Open/Compound Fractures ceFAZolin 2 g* Vancomycin 15 24 to 48 hours post-op • Administer parenteral mg/kg antibiotics as soon as If heavily soiled or possible after injury. contaminated If heavily soiled or Consider time of first dose complex open contaminated and delay to surgical fracture: ADD complex open intervention when aminoglycoside 5 fracture: ADD determining appropriate mg/kg aminoglycoside 5 repeat dosing schedule mg/kg

URINARY DIVERSION PROCEDURES INVOLVING BOWEL SEGMENTS2,3,7,12 (assuming all patients have urine culture performed and all positive urine culture patients are treated before surgery) • Ileal conduit procedures or metroNIDAZOLE [metroNIDAZOLE Less than 24 hours procedures involving bowel 500 mg 500 mg segments Plus Plus ceFAZolin 2 g* aminoglycoside 5 mg/kg

UROLOGY1,2,3,7,12,16 (assuming all patients have urine culture performed and all positive urine culture patients are treated before surgery) • Lower tract instrumentation, ciprofloxacin 500 mg aminoglycoside 5 Less than 24 hours including transrectal prostate PO mg/kg biopsy, cystoscop, etc. OR with or without High Risk only sulfamethoxazole/ clindamycin 900 mg o Advanced age trimethoprim o Poor nutritional status 800/160mg PO o Diabetes mellitus OR o Smoking ceFAZolin 2 g* IM/IV o Obesity OR o Coexisting infection at a aminoglycoside 5 remote body site mg/kg o Colonization with microorganisms Note: PO regimens, o Anatomical anomalies of give 1 – 2 hours pre- the urinary tract op o Urinary obstruction or stone o Chronic steroid use o Immunodeficiency o Externalised catheters o Colonized endogenous/exogenous material o Prolonged hospitalization

*May consider ceFAZolin 3 g for patients weighing greater than or equal to 120 kg 81 Pre-Operative Antibiotic Recommendation Post-Operative IV Patient Selection Alternate Preferred Antibiotic Duration (See Principles) Clean without entry into urinary ceFAZolin 2 g* clindamycin 900 mg Less than 24 hours tract OR vancomycin 15 mg/kg

Clean without entry into urinary ceFAZolin 2 g* (clindamycin Less than 24 hours tract + prosthesis with or without 900 mg aminoglycoside 5 OR mg/kg vancomycin 15 mg/kg) with or without aminoglycoside 5 mg/kg Clean with entry into urinary ceFAZolin 2 g* ciprofloxacin Less than 24 hours tract with or without 500 mg aminoglycoside 5 OR mg/kg (only if (aminoglycoside prosthesis involved) 5 mg/kg with or without clindamycin 900 mg) Clean Contaminated ceFAZolin 2 g* ciprofloxacin Less than 24 hours Plus 500 mg metroNIDAZOLE OR 500 mg (aminoglycoside 5 mg/kg Plus metroNIDAZOLE 500 mg)

VASCULAR 1,2,3,7,12 • Lower limb amputation ceFAZolin 2 g* vancomycin 24 hours or less • Abdominal and lower limb 15 mg/kg vascular surgery OR • Procedures involving groin clindamycin 900 mg incision or insertion of prosthetic material • Carotid endarterectomy and brachial arterial repair with prosthetic graft only

• Native AV fistula ceFAZolin 2 g* vancomycin No antibiotics • Peritoneal dialysis catheter 15 mg/kg placement OR • Artificial AV graft clindamycin 900 mg

*May consider ceFAZolin 3 g for patients weighing greater than or equal to 120 kg 82 Pre-Operative Antibiotic Recommendation Post-Operative IV Patient Selection Alternate Preferred Antibiotic Duration (See Principles) Low risk carotid endarterectomy, No Antibiotics N/A N/A brachial artery repair, endovascular stenting without implantation of prosthetic graft material

83 Approved: September 2018

VANCOMYCIN DOSING AND MONITORING GUIDELINES (NB Provincial Health Authorities Anti-Infective Stewardship Committee)

GENERAL COMMENTS • Vancomycin is a glycopeptide antibiotic with bactericidal activity • It is active against gram-positive bacteria, including methicillin-resistant staphylococcus (MRSA) • Vancomycin is less effective than beta-lactams against Staphylococcus aureus that is susceptible to cloxacillin/methicillin • Vancomycin exhibits time-dependent killing: its effect depends primarily upon the time the concentration exceeds the organism’s Minimum Inhibitory Concentration (MIC) • These guidelines pertain to IV vancomycin only; they do not apply to PO vancomycin, which is not absorbed • Ensure that an adequate mg/kg dose and appropriate interval are ordered initially. Adjust the dose if necessary immediately; do not wait for a confirmatory trough level. • When managing a severe Staphylococcus aureus infection (e.g., bacteremia), an Infectious Diseases consultation is strongly encouraged.

VANCOMYCIN IN ADULT PATIENTS

ADULT INITIAL DOSE Loading dose: • Consider using a loading dose in patients with: o severe infections where rapid attainment of target level of 15-20 mg/mL is desired o significant renal dysfunction in order to decrease the time required to attain steady state • Recommended dose: 25-30 mg/kg IV o based on actual body weight, for 1 dose, followed by maintenance dose separated by recommended dosing interval o consider capping the loading dose at a maximum of 3.5 g o loading doses DO NOT need to be adjusted in patients with renal dysfunction; only maintenance dosing interval requires adjustment • If loading dose not used then proceed with administration of a maintenance dose at recommended dosing interval Maintenance dose: • 15-20 mg/kg IV o based on actual body weight; maximum of 2g/dose for initial maintenance doses (prior to vancomycin levels) o doses greater than 500 mg – round to the nearest 250 mg o doses less than 500 mg – round to the nearest 50 mg

84 Dosing interval: • Interval depends on patient’s renal function and targeted serum vancomycin concentration Target trough of 15 to 20 mg/L Target trough of 10 to 15 mg/L Creatinine Clearance Dosing Interval Creatinine Clearance Dosing Interval greater than 80 mL/min q8 – 12h greater than 80 mL/min q12h 40 to 80 mL/min q12h 40 to 80 mL/min q24h 20 to 39 mL/min q24h 20 to 39 mL/min q36h 10 to 19 mL/min q48h 10 to 19 mL/min q48h less than 10 mL/min consider a loading dose, less than 10 mL/min consider a loading dose, then adjust maintenance then adjust dose based on serial maintenance dose serum drug levels to based on serial serum target trough drug levels to target trough • Estimated creatinine clearance (CrCl) Women Men CrCl = (140-age) x weight (in kg)† CrCl = (140-age) x weight (in kg)† x 1.2 SCr (in mcmol/L) SCr (in mcmol/L) IBW = 45.5 kg + (0.92 x cm above 150 cm) or IBW = 50 kg + (0.92 x cm above 150 cm) or 45.5 kg + (2.3 x inches above 60 inches) 50 kg + (2.3 x inches above 60 inches) †Use ideal body weight unless actual weight is 20% above ideal body weight (IBW), in such case use adjusted body weight. Adjusted body weight = 0.4 x (actual body weight – IBW) + IBW If actual weight is less than ideal body weight, use actual weight.

Clinical Pearls: • Use care when selecting patients for q8h dosing – recommend to avoid in patients that are older and/or with multiple co-morbidities (ex. diabetes, heart failure, etc.) or where estimated creatinine clearance would be expected to be an overestimate (ex. low muscle mass in an elderly patient, dysmobility, paraplegia, etc.) • Consider q8h dosing for patients who are younger and otherwise well with few medical co-morbidities • The provided ranges for estimated creatinine clearance are only intended to be a guide for the selection of an empiric dosing interval and should not be used in isolation without considering patient and infection-related factors – especially when estimated creatinine clearance approaches either end of the range

LEVELS • The ratio of Area Under the Curve to Minimum Inhibitory Concentration (AUC/MIC) is thought to be the best pharmacokinetic parameter associated with a clinical and bacterial response to vancomycin; however, because of its relative impracticality to determine in clinical practice, trough levels are used as a surrogate for efficacy. • Peak (post) levels are generally NOT recommended because they are not correlated with improved clinical outcome; they should only be ordered in rare circumstances to facilitate individualized patient pharmacokinetic analysis. • Vancomycin’s efficacy depends primarily upon the time above the MIC

85 Target serum concentrations: Desired minimal (trough) Infection plasma concentration -All MRSA infections -Invasive and/or deep space infections, including but not limited to: o Osteomyelitis o Pneumonia 15-20 mg/L o CNS infection o Endocarditis o Bacteremia o Prosthetic joint infection Uncomplicated skin and soft tissue infections 10-15 mg/L Urinary tract infections vancomycin levels should always be maintained above 10 mg/L to avoid development of resistance

Levels are recommended in: o patients who are severely ill and/or require target trough of 15-20 mg/L o patients with anticipated therapy duration of 7 days or greater o patients with impaired renal function (CrCl 50 mL/min or less) or unstable renal function (change in baseline serum creatinine (SCr) of 40 mcmol/L or greater, or change of 50% or more from baseline) o patients on dialysis o concomitant use of other nephrotoxic drugs (i.e. aminoglycoside, NSAID, diuretics, ACEI, ARB, etc.) o patients with altered volume of distribution or clearance of vancomycin, including . morbidly obese patients (190% or greater of ideal body weight or BMI 40 kg/m2 or greater) . cystic fibrosis . burns more than 20% BSA . pregnancy • Routine trough (pre) levels are generally not necessary when: o vancomycin is used for empiric therapy as it may be discontinued once final culture results are available Serum sampling: • Trough (pre) levels are taken immediately before a dose (within 30 minutes) • The timing of drug administration and sample collection must be carefully documented • Do not hold next vancomycin dose while waiting for results of vancomycin levels unless there is a specific reason to do so, e.g. significant decline in renal function Timing of serum levels: • First trough level should be taken at steady state, typically prior to 4th dose if q12h interval o th o prior to the 5 dose if q8h interval • Steady state (SS) occurs in 4 to 5 half-lives and can be estimated for vancomycin by the following equations: o Ke = CrCl x 0.00083 + 0.0044 o T½ = 0.693/Ke o SS = 4 to 5 T½ • Vancomycin clearance is enhanced in obesity. Consider drawing first level sooner (i.e. before the 3rd dose if normal renal function) in morbidly obese patients

86 INTERPRETING TROUGH LEVELS AND ADJUSTING DOSE • Verify the timing of the trough in relations to the dose that preceded it and the dose that followed • Verify if the trough was taken at steady state • Verify for changes in renal function since the trough was drawn • Consider alternate sources of vancomycin that may be contributing to measured serum concentrations (e.g., vancomycin instilled intra-operatively, or added to cement during orthopedic surgery) • If the trough is below the target level, ensure the dose is 15-20 mg per kg actual body weight, and consider shortening the dosing interval (e.g., if was dosed q12h, change to q8h) • If the trough is above 20-25 mg/L, consider decreasing the dose and/or lengthening the dosing interval • If trough level is significantly elevated (i.e. greater than 30 mg/L) hold vancomycin and use repeat levels to determine when to restart vancomycin and new dosing regimen MONITORING Subsequent serum levels: • With dosage change: trough should be repeated at new steady state as described in “Levels” section • Once target trough achieved: trough should be taken approximately every 7 days in hemodynamically stable patients; more frequently if hemodynamically unstable, renal function changing, if concurrent nephrotoxic drugs, or underlying renal dysfunction Monitor: • patient’s clinical response to vancomycin • CBC at least weekly on long-term vancomycin therapy • SCr at least twice a week initially, then at least weekly on long-term therapy; more frequent monitoring should be considered if renal function changing, if concurrent nephrotoxic drug, underlying renal dysfunction or age greater than 60. o If SCr increases significantly (i.e. greater than 15 – 20% from baseline), draw trough level to assess for need for dosage adjustment as vancomycin accumulation may occur Adverse effects of vancomycin include: • Nephrotoxicity: 5-43%; more common with higher trough levels, longer durations, critically ill patients, concomitant nephrotoxic drugs, elderly patients or pre-existing renal dysfunction; rise in SCr usually reversible upon discontinuation of vancomycin • Red Man Syndrome: 5-10%; ensure appropriate duration of infusion to minimize risk (refer to Parenteral Drug Manual) • Neutropenia: less than 2%, delayed onset (15-40 days), reversible

87 VANCOMYCIN IN PEDIATRIC PATIENTS DEFINITIONS • Neonate: 0-4 weeks of age o Gestational age: number of weeks from first day of the mother’s last menstrual period until the birth of the baby o Postnatal age: chronological age since birth o Corrected Gestational Age: gestational age plus postnatal age Ex.: baby born at 28 weeks, presently 21 days old corrected gestational age = 31 weeks (28 weeks + 3 weeks) • Infant: 1 month to 1 year of age • Child: 1-12 years of age PEDIATRIC INITIAL DOSE Initial dose in neonates (less than 1 month of age): Corrected Gestational Postnatal Age Interval mg/kg/dose IV Age (weeks) (days) (hours) 0-14 10 - 15 18 29 or less 15 or more 10 - 15 12 0-14 10 - 15 12 30-36 15 or more 10 - 15 8 0-7 10 - 15 12 37-44 8 or more 10 - 15 8 45 or more all 10 - 15 6

Initial dose in infants and children (1 month to 12 years of age): • Traditional: o 40-60 mg/kg/day, divided in q6h-8h o max dose of 2g/day prior to levels • Alternative (for more severe infections): o 15 mg/kg/dose IV q6h o max dose of 4g/day prior to levels LEVELS • Trough levels are taken 30 minutes or less prior to the next dose • Peak levels are generally NOT recommended Target trough levels in neonates (less than 1 month of age): o 5-15 mg/L o up to 20 mg/L for severe infections where vancomycin penetration to the site may be poor or high MIC is suspected (osteomyelitis, meningitis and endocarditis or infection with MRSA) Target trough levels in infants and children (1 month to 12 years of age): o 15-20 mg/L for most infections o 10-15 mg/L for less severe infections • First trough level should be taken at steady state, typically prior to 4th dose INTERPRETING TROUGH LEVELS AND ADJUSTING DOSE • Verify the timing of the trough in relations to the dose that preceded it and the dose that followed • Verify if the trough was taken at steady state • Verify for changes in renal function since the trough was drawn • If the trough is below the target level, consider shortening the dosing interval • If the trough is high, consider lengthening the dosing interval SUBSEQUENT TROUGH LEVELS AND MONITORING • See Adults section for guidance

88 VANCOMYCIN IN INTERMITTENT HEMODIALYSIS

GENERAL COMMENTS • In patients undergoing intermittent hemodialysis, vancomycin IV is given on dialysis days, typically 3 times a week • Give the first dose of vancomycin the day it is ordered and subsequent doses on dialysis days • Vancomycin doses are administered during the last portion of the hemodialysis session (intradialytic administration) or after hemodialysis DOSE • Patient with weight less than 70 kg: vancomycin 1000 mg IV for the first dose, then 500 mg IV for subsequent doses • Patient with weight 70 to 100 kg: vancomycin 1250 mg IV for the first dose, then 750 mg IV for subsequent doses • Patient with weight above 100 kg: vancomycin 1500 mg IV for the first dose, then 1g IV for subsequent doses LEVELS Target pre-dialysis vancomycin levels: o 15-20 mg/L o 10-15 mg/L may be acceptable for uncomplicated skin and soft tissue infections and urinary tract infections; see Adults section for more information • Vancomycin levels are drawn before the beginning of the hemodialysis session • Do not hold post-dialysis vancomycin dose while waiting for results of pre-dialysis vancomycin levels unless there is a specific reason to do so • If the trough is below the target level, consider a top-up dose and increase the next maintenance dose accordingly • If the trough is high, consider decreasing the next maintenance dose • Vancomycin trough levels should be obtained before each dialysis until desired trough is attained. After that, vancomycin trough levels should be obtained once a week before dialysis.

89 VANCOMYCIN IN PREGNANCY CONSIDERATIONS ON THE USE OF VANCOMYCIN IN PREGNANCY • Pregnancy is associated with accelerated renal clearance of vancomycin due to increased renal blood flow • Pregnancy is associated with higher volumes of distribution • Pharmacokinetic changes become more pronounced in the later stages of pregnancy and gradually return to pre-pregnancy values a few days following delivery • Dose and target trough levels same as other adults • Will likely achieve steady state sooner • May require higher dosage and shorter dosing intervals to achieve target levels compared to non-pregnant individuals • Recommend routine trough levels in pregnant patients • If target levels difficult to achieve, consider drawing two levels (trough and peak) to enable individualized pharmacokinetic calculations

OUTPATIENT VANCOMYCIN IV THERAPY

NOTES FOR TRANSITIONS TO OUTPATIENT IV VANCOMYCIN THERAPY • Prior to discharge on outpatient IV vancomycin therapy, the healthcare team should: o Review the treatment plan to confirm that oral alternatives are not available or appropriate for patient management o Review the feasibility and safety of the treatment and care plan o Review the patient’s concomitant medications to identify any nephrotoxic agents (e.g. aminoglycoside, NSAID, diuretic, ACEI, ARB, etc.) and evaluate whether any should be held for the duration of treatment o Communicate the treatment and care plan to the patient and/or care givers and community healthcare providers; including necessary blood work, target levels and duration of therapy o Communicate the importance of proper timing of blood work in relation to administration of the vancomycin dose to allow interpretation of vancomycin serum concentrations o Educate and inform the patient and their caregivers on the signs and symptoms of potential adverse reactions to report or act on o Arrange all necessary monitoring test and follow-up appointments o Avoid scheduling blood work on Fridays because interpretation may be delayed

90 Prevention of Overwhelming Postsplenectomy Infection in Adults

Introduction The spleen is the largest lymphatic organ in the body and its primary functions are to filter damaged red blood cells and micro-organisms from the blood and to aid in the production of antibodies to enhance the immune response.1 Asplenic patients or patients who suffer from functional asplenia have an increased risk of infection and are at risk of contracting a syndrome known as overwhelming postsplenectomy infection (OPSI).2 Overwhelming postsplenectomy infection has been defined as ”septicaemia and/or meningitis, usually fulminant but not necessarily fatal, occurring at any time after removal of the spleen”.3 The incidence of OPSI has been difficult to establish due to a wide variation in occurrence rates among different groups of patients, but lifetime risk has been estimated at 5%.2 Risk of OPSI has been found to be dependent on age at which splenectomy occurs, time interval from splenectomy, cause for asplenia and immune status of the patient.4 Although the incidence of OPSI is low, the estimated mortality is high (38 – 69%).2 Therefore, prevention and early identification of OPSI have been identified as key strategies to improve patient outcome.2 Some of the current strategies being used and recommended to decrease a patient’s risk of OPSI include vaccination, communication of hyposplenic state to other healthcare providers and patient education.1,2,5 In addition, some groups recommend either short term or lifelong prophylactic antibiotics to reduce the risk of OPSI.8 However, the use of antibiotics for the prevention of OPSI is often limited by poor compliance and antibiotic resistance; therefore, its use should be assessed on a case-by-case basis.8 Recommendations from the Canadian Pediatric Society include the administration of prophylactic antibiotics until the patient is 60 months of age with consideration to be given for lifelong prophylaxis.14 Experts and some guidelines also recommend that patients have a home supply of antibiotics for urgent use.15,16

The Provincial Anti-infective Stewardship Committee (ASC) has prepared resources to facilitate recommended vaccination orders, vaccine distribution, patient education and communication to the primary care provider. Recommendations regarding the prophylactic or as needed use of antibiotics are beyond the scope of these guidelines, please consult a local infectious disease specialist for recommendations.

Vaccinations Asplenic patients are at risk of OPSI with any micro-organism but particularly encapsulated bacteria such as Streptococcus pneumoniae, Haemophilus influenzae and Neisseria meningitidis.2,4 Encapsulated bacteria are more difficult for the body to clear because they resist antibody binding and their clearance is primarily completed by the spleen.4 Therefore, it is important that attention be paid to providing optimal protection against encapsulated bacteria using appropriate immunizations.6 The National Advisory Committee on Immunization (NACI) and the Canadian Immunization Guideline currently recommend the following vaccines for adult asplenic or hyposplenic patients: pneumococcal 13-valent conjugate vaccine (PNEU-C-13), pneumococcal 23-valent polysaccharide vaccine (PNEU-P-23), Haemophilus influenzae type b conjugate (Hib) vaccine, meningococcal ACYW-135 conjugate (Men-C-ACYW) vaccine, all routine immunizations and yearly influenza vaccine.6,7 NACI also recommends multi-component meningococcal serogroup B (4CMenB) vaccination for active immunization of patients with anatomical or functional asplenia who are greater than 2 months of age.11

Streptococcus pneumoniae is responsible for 50 – 90% of all cases of OPSI. 4 Pneumococcal polysaccharide vaccine (PNEUMOVAX 23) provides protection against 23 serotypes of Streptococcus pneumoniae and is the vaccine of choice for adult patients at high risk of invasive pneumococcal disease (IPD). 6 The pneumococcal polysaccharide vaccine has been found to have an efficacy of 50 to 80% against IPD among the elderly and high risk groups.6 However, after immunization with PNEU-P-23 vaccine, antibody levels begin to decline after 5 to 10 years and the duration of immunity is unknown.6 In an effort to improve the duration of immunity the current NACI guidelines recommend for adults with asplenia or hyposplenia one dose of PNEU-C-13 6 vaccine (PREVNAR 13) followed at least 2 months later by one dose of PNEU-P-23 vaccine. If PNEU-P-23 vaccine has been previously received, then wait 1 year before giving PNEU-C-13 vaccine. 10 In the case where only one vaccine can be given then it should be the PNEU-P-23 vaccine. A single booster of PNEU-P-

91 23 vaccine is recommended 5 years after the initial dose.6 Due the increased risk of invasive pneumococcal disease and rapid decline in antibodies following PNEU-P-23 vaccination, patients age 65 years and over, regardless of previous vaccination history, should receive one dose of PNEU-P-23 vaccine as long as 5 years have passed since the previous PNEU-P-23 vaccine dose.12 The Center for Disease Control and Prevention’s Advisory Committee on Immunization Practices released a statement in October 2012 with similar recommendations for all adult patients 19 years of age or greater.10

A single dose of Haemophilus influenzae type b (HiB) conjugate vaccine is recommended in all patients who are functionally or anatomically asplenic and greater than 5 years of age regardless of previous Hib immunization.5,6 Current Hib vaccine should be given at least one year after any previous dose.6 This is despite limited efficacy data and a low overall risk of Haemophilus influenzae sepsis in patients greater than 5 years of age.6

Meningococcal ACYW-135 conjugate vaccine, NIMENRIX, MENACTRA or MENVEO, is recommended for all 6,7 groups at high risk of invasive meningococcal infection when long-term protection is required. MENVEO (Men- 6,13 C-ACYW-CRM) has the A, C, Y and W-135 serogroup oligosaccharides conjugated to the CRM197 protein. Men-C-ACYW-CRM (MENVEO) can be administered concomitantly with routine childhood vaccines but further studies are needed with respect to concomitant administration with other CRM197 conjugate vaccines such as the pneumococcal 13-valent conjugate vaccine (PREVNAR); therefore, Men-C-ACYW-CRM vaccine has been left off the clinical order set to avoid this concomitant administration.6,13 Recommendations are to give 2 doses of meningococcal ACYW-135 conjugate vaccine at least 8 weeks apart for patients with anatomic or functional asplenia between the ages of 1 – 55.6 Based on limited evidence and expert opinion, current NACI guidelines recommend that 2 doses of meningococcal ACYW-135 conjugate vaccine given 8 weeks apart is also appropriate for individuals greater than 55 years of age, despite lacking authorization for use in this age group.6,7 Booster doses are recommended every 3 - 5 years in individuals vaccinated at 6 years of age or younger and every 5 years for individuals vaccinated at greater than 6 years of age.6 Multi-component meningococcal serogroup B (4CMenB) vaccine (BEXSERO) given as a 2 dose series 4 weeks apart is also recommended.11

In addition, all routine immunizations and yearly influenza vaccination should be given as there are no contraindications to the use of any vaccine in patients with functional or anatomical hyposplenia. 6 When an elective splenectomy is planned, the necessary vaccines are recommended to be given two weeks before removal of the spleen. 6 In the case of an emergent splenectomy, vaccines should be given two weeks post- splenectomy or prior to hospital discharge if there is a concern that the patient may not return for vaccination. 6

Asplenic patients are at increased risk of travel related infectious diseases, including malaria and babesiosis.9 Expert advice should be sought prior to travel to endemic areas.

Patient Education Education has also been cited as an essential component for successful prevention of OPSI. 2 Patients should be educated regarding their increased risk of developing life threatening sepsis, what to do at the first sign of infection, to inform all healthcare providers of their hyposplenic state and to take appropriate precautions to prevent OPSI.2 Education may be provided through thorough discussion and provision of appropriate reading materials.2

Document Updated by: Tim MacLaggan, BSc(Pharm), ACPR Document reviewed and approved by: New Brunswick Anti-infective Stewardship Committee – May 2018

92 **The following clinical order set is provided as a sample only and would have to be modified to an individual zone’s format for local use** Clinical Order Set Post-Splenectomy Vaccinations – Adult Provincial Anti-infective Stewardship Committee Patient: Allergies: INSTRUCTIONS 1. The following orders will be carried out by a nurse only on the authority of a physician/nurse practitioner. 2. A bullet preceding an order indicates the order is standard and should always be implemented. 3. A check box preceding an order indicates the order is optional and must be checked off to be implemented. 4. Applicable boxes to the right of an order must be checked off and initialed by the person implementing the order. 5. Date and time of administration must be recorded

Contraindications • Hypersensitivity to any vaccine component • Anaphylactic reaction to previous dose of any of the vaccines listed below Vaccinations (if not received pre-operatively for elective surgeries or if not received previously)

• Haemophilus influenzae type b conjugate vaccine (ACT-HIB) 0.5 mL intramuscularly in deltoid

• Meningococcal ACYW-135 conjugate vaccine (NIMENRIX, MENACTRA) 0.5 mL intramuscularly in deltoid (additional dose of meningococcal ACYW-135 conjugate vaccine required in 2 months followed by a booster every 5 years)

• Multicomponent Meningococcal Serogroup B (4CMenB) Vaccine (BEXSERO) 0.5 mL intramuscularly in the deltoid (additional dose of Multicomponent Meningococcal Serogroup B (4CMenB) Vaccine required in 1 month)

Pneumococcal Vaccination: If pneumococcal 23-valent polysaccharide vaccine (PNEUMOVAX 23) not previously received or received greater than one year ago then give Pneumococcal 13-valent conjugate vaccine (PREVNAR 13) 0.5 mL intramuscularly in deltoid (Pneumococcal 23- valent polysaccharide vaccine (PNEUMOVAX 23) required 8 weeks later if not previously received. Single lifetime booster of Pneumococcal 23-valent polysaccharide (PNEUMOVAX 23) required 5 years after first dose.) OR If Pneumococcal 23-valent polysaccharide vaccine (PNEUMOVAX 23) previously received but less than one year ago then wait 1 year from that date to give Pneumococcal 13-valent conjugate vaccine (PREVNAR 13). Single lifetime booster of Pneumococcal 23-valent polysaccharide (PNEUMOVAX 23) required 5 years after first dose.

• Seasonal Influenza Vaccine (if not already received) Notes -Vaccinations should be given two weeks post-operatively or on hospital discharge if there is a concern that he or she might not return for vaccination. -All vaccinations may be administered simultaneously. Separate syringes and separate injection sites should be used if more than one vaccine is administered on the same day. Adapted with permission from Antimicrobial Handbook-2010 Capital Health, Nova Scotia Revised and Approved May 2018

93 Adult Splenectomy Vaccines Documentation for Primary Care Provider and Public Health Please complete and forward to patient’s primary care provider and local Public Health office on discharge. From:

Phone: Fax:

To: Local Public Health Office

Fax #:

Re. Patient Name:

HCN:

D.O.B:

Asplenic patients are known to be at risk of infection, and are particularly susceptible to encapsulated organisms. Vaccinations are recommended to reduce the risk of infection in this patient population.

Your patient received the following vaccinations while in hospital after splenectomy. Please update your records, and note the patient’s need for future vaccinations.

Meningococcal ACYW-135 conjugate vaccine (NIMENRIX, MENACTRA) (2 doses, 2 months apart) Date 1st dose given: Lot#: Dose: Administration Site: Date 2nd dose given: Lot#: Dose: Administration Site: A booster is recommended every 5 years

Multicomponent Meningococcal Serogroup B (4CMenB) Vaccine (BEXSERO) (2 doses, 1 month apart) Date 1st dose given: Lot#: Dose: Administration Site: Date 2nd dose given: Lot#: Dose: Administration Site:

Haemophilus influenzae type b conjugate vaccine (ACT-HIB) Date given: Lot#: Dose: Administration Site:

Pneumococcal 13-valent conjugate vaccine (PREVNAR 13) Date given: Lot#: Dose: Administration Site:

Pneumoccocal polysaccharide vaccine (PNEUMOVAX 23) due 8 weeks after pneumococcal 13-valent conjugate vaccine (PREVNAR 13) Date given: Lot#: Dose: Administration Site: A single booster dose of pneumococcal polysaccharide vaccine is recommended after 5 years.

- Yearly influenza vaccine recommended.

If you have any questions regarding these vaccinations please call the numbers above, or contact the Department of Public Health for further information.

Thank you. This message is CONFIDENTIAL. If you received this fax by mistake, please notify us immediately. Adapted with permission from Antimicrobial Handbook-2010 Capital Health, Nova Scotia Revised and Approved May 2018

94 Splenectomy Information for Patients

Role of the spleen: • The spleen has many functions, including removal of damaged blood cells. It also plays an important role in removal of certain types of bacteria. • The spleen may be removed (splenectomy) if it becomes overactive, stops working or is ruptured in an accident. Life without a spleen: • Adults can live a normal life without a spleen. However, you may be at risk of developing infections caused by certain types of bacteria which are normally removed by the spleen. • The most serious possible infection is called overwhelming post-splenectomy infection (OPSI). This infection is rare, but can progress rapidly and may result in the loss of limbs or death. How to reduce the risk of infection: • Inform all doctors, dentists and other health care professionals that you do not have a spleen. • A series of vaccinations is recommended for patients who have their spleen removed. These vaccines are two doses of meningococcal quadrivalent conjugate vaccine, pneumococcal conjugate vaccine, pneumococcal polysaccharide vaccine (due 2 months after pneumococcal conjugate vaccine), two doses of multi-component meningococcal serogroup B vaccine and Haemophilus influenzae type b conjugate vaccine. • You should receive a single booster of pneumococcal polysaccharide vaccine in 5 years. • You should receive a booster dose of meningococcal conjugate vaccine every 5 years. • You should receive a yearly flu shot. • Your primary care provider will receive a letter explaining the vaccinations you received in hospital, as well as recommendations for future vaccinations. • Seek expert medical advice before travel. Patients without a spleen are at increased risk of travel-related infectious diseases, including severe malaria. Additional vaccines and/or one or more medications may be recommended to prevent or treat travel-related infectious diseases. Where malaria is endemic, preventative measures including antimalarial medications, insect repellent and barrier precautions should be used. Identification: • Wallet card (included with this information) includes information on vaccinations you have received. • Medic-Alert™ bracelet should be worn. It should indicate that you had your spleen removed. When to seek medical attention: • If you receive a tick or animal bites/scratches. You may be at risk of developing a serious infection. • Fever, shakes and/or chills may be a sign of a serious infection. Proceed immediately to the nearest emergency department for further evaluation and care. If you have been provided antibiotics to use on an as needed basis for infection, take one dose immediately and then proceed to the nearest emergency department.

Adapted with permission from Antimicrobial Handbook-2010 Capital Health, Nova Scotia Approved May 2018

95 Wallet card for Asplenic Patients Please complete card and give to patient on hospital discharge.

Medical Alert Asplenic Patient

Patient Name: Name: Phone: Patient is at risk of potentially fatal, overwhelming infections. Medical attention required for: Signs of infection- fever > 38ºC, sore throat, chills, unexplained cough. Tick and animal bites/scratches.

Vaccination Record Patient has received the following vaccinations: Meningococcal ACYW-135 conjugate vaccine (NIMENRIX, MENACTRA) 2 doses 8 weeks apart Date 1st dose given: Date 2nd dose given: Meningococcal ACYW-135 conjugate vaccine booster (NIMENRIX, MENACTRA or MENVEO) Dates due: every 5 years Dates given: Multicomponent Meningococcal Serogroup B (4CMenB) Vaccine (BEXSERO) 2 doses 4 weeks apart Date 1st dose given: Date 2nd dose given: Pneumococcal 13-valent conjugate vaccine (PREVNAR 13) Date given: Pneumococcal polysaccharide vaccine (PNEUMOVAX 23) Date due: 8 weeks after pneumococcal 13-valent conjugate vaccine (PREVNAR 13) Date given: Pneumococcal polysaccharide booster (PNEUMOVAX 23) Date due: single dose 5 years after initial vaccine Date given: Haemophilus influenzae type b conjugate vaccine (ACT-HIB) Date given:

Adapted with permission from Antimicrobial Handbook-2010 Capital Health, Nova Scotia Approved May 2018

96 Splenectomy Vaccine Checklist

1) Post-Splenectomy Vaccinations Clinical Order Set

2) Vaccines as per clinical order set plus package inserts

3) Splenectomy Vaccines – Documentation for Primary Care Provider and Public Health Form

4) Splenectomy – Information for Patients Sheet

5) Wallet Card for Asplenic Patients Sheet

Adapted with permission from Antimicrobial Handbook-2010 Capital Health, Nova Scotia Approved May 2018

97 References Clostridium difficile Infection McDonald LC, Gerding DN, Johnson S, Bakken JS, Carroll KC, Coffin SE, Dubberke ER, Garey KW, Gould CV, Kelly C, Loo V, Sammons JS, Sandora TJ, Wilcox MH. Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA), Clinical Infectious Diseases. 2018. cix1085, https://doi.org/10.1093/cid/cix1085

Sirbu BD et al. Vancomycin Taper and Pulse Regimen with Careful Follow-up for Patients With Recurrent Clostridium difficile Infection. Clinical Infectious Diseases. 2017;65(8):1396–9

Loo VG, Davis I, Embil J, et al. Association of Medical Microbiology and Infectious Disease Canada treatment practice guidelines for Clostridium difficile infection. Official Journal of the Association of Medical Microbiology and Infectious Disease Canada 3.2, 2018. doi:10.3138/jammi.2018.02.13

Adapted from Vancouver Coastal Health Antimicrobial Stewardship Treatment Guidelines for Common Infections (2011)

Intra-Abdominal Infections Ball, C., Hansen, G., Harding, G., Kirkpatrick, A., Weiss, K. & Zhanel, G. (2010). Canadian practice guidelines for surgical intra-abdominal infections. Canadian Journal of Infectious Disease and Medical Microbiology, 21(1), 11-37.

Doyle, J., Nathens, A., Morris, A., Nelson, S., & McLeod, R. (2011). Best practice in general surgery guideline #4: Management of Intra- abdominal infections. Toronto, ON: University of Toronto, Faculty of Medicine.

INESSS. Antibiotic Treatment Guide: Intra-abdominal Infections in Adults. June 2012

So, M. (2010). Intra-abdominal infections education module. Toronto, ON: Mount Sinai Hospital and University Health Network.

Solomkin, J., Mazuski, J., Bradley, J, et al. (2010). Diagnosis and management of complicated intra-abdominal infections in adults and children: Guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. Clinical Infectious Disease, 50 (15 January)., 133-163.

Blondel-Hill E. & Fryters S. (2012). Bugs & Drugs. An Antimicrobial/Infectious Diseases Reference. Alberta Health Services.

Young-FAdok, T., & Pemberton, J. (2014). Treatment of acute diverticulitis. UpToDate. Retrieved from www.uptodate.com.

Antimicrobial Stewardship Treatment Guidelines for Common Infections. 1st Edition Vancouver Coastal Health. March 2011

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Sawyer RG, Claridge JA, Nathens AB, Rotstein OD, Duane TM et al. Trial of Short-Course Antimicrobial Therapy for Intraabdominal Infection. N Engl J Med 2015;372(21):1996

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