Module 2: Antimicrobial Stewardship and Respiratory Tract Infections Benjamin P Westley MD FAAP FACP 4120 Laurel St Suite 204 Anchorage, AK 99508

Objectives Recognize that respiratory tract infection is the most frequent indication for antimicrobial use in the hospital Identify categories of pneumonia that inform empiric antimicrobial selection Community-acquired Pneumonia Hospital-acquired Pneumonia Ventilator-associated Pneumonia Healthcare-associated Pneumonia Discuss data that drives regimen optimization and duration Review best practice regarding antimicrobial use for acute exacerbation of chronic bronchitis Understand that antibiotics are NOT indicated for acute bronchitis in immune-competent hosts nor for prophylaxis of COPD exacerbations

AMS at PAMC 6,900 interventions since program inception 1,900 of 6,900 (28%) relate to respiratory infections By far the most common type of intervention Types of interventions Medication class change Duration of therapy IV to PO Respiratory-related AMS interventions represent “low- hanging fruit” and are “bread-n-butter” to an active AMS program

Community-acquired Pneumonia1 Pneumonia in patients WITHOUT risk factors for nosocomial organisms Subcategories Outpatient Severe (ICU) vs. non-severe Structural lung disease that increases Pseudomonas risk Aspiration pneumonia and lung abscess Organisms Pneumococcus, Haemophilus, Moraxella Legionella, Mycoplasma, Chlamydia Structural lung disease: above plus Pseudomonas Alcoholic with bloody sputum: above plus enteric GNR (Klebsiella) Lung abscess or empyema: above plus oral anaerobes

CAP Empiric Rx1 Outpatients: Amox/clav 875/125mg plus azithromycin 500mg No monotherapy with doxycycline or azithromycin (pneumococcus sensitivity <90%) Ceftriaxone 1-2g plus Azithromycin 500 mg regardless of severity If anaphylactic PCN Allergy: Levofloxacin 750mg (add aztreonam if ICU) Structural lung disease: Pip/tazo or cefepime PLUS atypical Rx (use quinolone if empiric pseudomonas coverage <90% with monotherapy) Lung abscess and aspiration “pleuropulmonary syndrome”: (Ceftriaxone plus metronidazole) OR amp/sulbactam Aspiration at time of intubation/suctioning or from vomiting does NOT require anaerobic coverage

Azithromycin 500mg PO or IV x 3 days2,3 Multiple studies and meta-analysis support short course 500 mg dosing Azithromycin is the preferred form of atypical coverage in severe illness Combination therapy decreases mortality in bacteremic pneumococcal illness4 Azithromycin plus beta-lactam is associated with decreased mortality in ICU-severity CAP vs. quinolone plus beta- lactam5 Small increased MI risk (OR 1.17) outweighed by survival benefit in elderly veterans (HR 0.73) 14

Intensive Care Med (2010) 36:612–620

Duration of therapy 1,6,7 Switch to PO as soon as hemodynamically stable and taking PO Stop after the following durations assuming afebrile >24h and hemodynamically stable: 5 days if no immune-compromise* or structural lung disease 7 days if moderate immune compromise or structural lung disease 10-14 days if poor clinical response, inappropriate initial therapy, or severe immune compromise Duration for pneumonia with uncomplicated pneumococcal bacteremia is the SAME!! (i.e. 5 days ok if adequate response, ok to swap to PO as per usual protocol) *Organ transplant, HIV, chemotherapy, chronic prednisone >10mg, immune-suppressing medications

Clinical Infectious Diseases 2012;54(11):1581–7

Levofloxacin 750 mg (7) Levofloxacin 750 mg x 5d duration EQUIVALENT cure rates to 500mg x 10d

Is atypical coverage really necessary?

Netherlands, 2283 patients conducted 2011 to 2013 CAP START study, NEJM 201515 Randomized trial of Beta-lactam vs. Beta-lactam plus azithromycin vs. quinolone monotherapy in non-severe inpatient CAP Therapy could be altered for medical reasons Netherlands, 2283 patients conducted 2011 to 2013 No difference in 90 day mortality, length of stay, or complication rate N Engl J Med 2015;372:1312-23.

Is Atypical Rx Needed?9 BMJ Open 2015;5:e006892

HAP, VAP, and HCAP10 Pneumonias associated with hospital stay, antibiotic exposure, and/or colonization with resistant organisms Early onset HAP <5d from admit is treated like CAP but WITHOUT atypical coverage VAP and HCAP are assumed to be at risk for resistant organisms including MRSA and resistant gram-negative rods Data supporting this conclusion is high quality in VAP but weak in HAP and especially HCAP which was extrapolated from other types of infections in patients with specific risk factors “The guideline recognizes the variability of bacteriology from one hospital to another and from one time period to another and recommends taking local microbiologic data into account when adapting treatment recommendations to any specific clinical setting”

Healthcare-associated Pneumonia New category in 2005 IDSA/ATS guidelines10

HAP, VAP, HCAP Algorithm10 Lower respiratory tract cultures should be obtained from all patients prior to antibiotic start or change Do not unduly delay abx while awaiting cultures Empiric regimen to cover MRSA and Pseudomonas in addition to early HAP organisms guided by institutional epidemiologic data Is MRSA common in the community? Does mono-therapy against Pseudomonas cover >90% of isolates or is double-Pseudomonas therapy required until sensitivities are known? Once cultures return, narrow to single drug and treat for 7 days UNLESS non-lactose fermenting gram negative rod (Pseudomonas, Acinetobacter, Stenotrophomonas)11 ,13 Duration 14 days for NLF GNR due to increased relapse risk If high quality lower respiratory tract cultures were obtained prior to antibiotics, are negative at 48-72h, and the patient is improved antibiotics should usually be STOPPED!!10, 12

Approach in Anchorage Make sure lower respiratory tract cultures are ordered! Early onset HAP Ceftriaxone Late onset HAP or VAP/HCAP: Vancomycin dosed to goal trough 15-20 Cefepime 1g q8h (or 2g q12h) Cefepime is active against >90% of our enteric GNRs and Pseudomonas, is less nephrotoxic than pip/tazo when combined with vancomycin, has no unnecessary anaerobic coverage, and is in adequate supply Above dosing determined by examining probability of target attainment (PTA) based on the MIC 90 at our institutions Aggressively narrow/stop once cultures back No atypical or anaerobic coverage required

IDSA/ATS HCAP Definition is probably overly inclusive Current thinking is that a large amount of present abx overuse/misuse in the US is due to HCAP since 2005 Clinical Infectious Diseases 2013;57(10):1373–83

Novel HCAP Definition16 IDSA guideline update pending. We are pulling our own data at ANMC to sort this out.

Acute Exacerbation of COPD Chronic bronchitis or emphysema with worsening respiratory symptoms GOLD 2015 guidelines form management standards17 Data supports antibiotic use for moderate to severe exacerbation only and is based on limited placebo controlled data and meta-analysis that suggest near-term mortality benefit18,19 To qualify for antibiotics, patient must have: Increased dyspnea and sputum PURULENCE, or Require mechanical ventilation (ETT or BiPAP)

Antibiotic choice for AECOPD “The choice of the antibiotic should be based on the local bacterial resistance pattern.”17 “…aminopenicillin with or without clavulanic acid, macrolide, or tetracycline…usually 5 – 10 days.”17 There is no compelling data to drive empiric selection. Weak quality data suggests that augmentin, macrolide, and quinolones perform equally poorly, but that quinolones might decrease risk of near-term recurrent exacerbation17-21 At ANMC we pulled our own data Large % not getting cultures Bugs mirror CAP organisms but occasionally include S aureus or Pseudomonas We encourage obtaining cultures and use usual CAP regimens for 5 days (guided by culture data when available) for inpatients. Outpatients with mild exacerbation do not require sputum cultures or antibiotics.

Azithromycin vs Levofloxacin for AECOPD Retrospective review of 19,608 patient given either quinolone or macrolide for AECOPD20

Daily prophylactic azithromycin for COPD? Taken daily for 1 year, exacerbation averaged 1.48 vs. 1.83 (HR 0.73) in patients on daily azithromycin 250 mg22 Hearing loss over 1 year higher in treatment group and more resistant organisms developed “…treatment is not recommended because of an unfavorable balance between benefits and side effects…the use of antibiotics, other than for treating infectious exacerbations of COPD and other bacterial infections, is currently not indicated.”17

Antibiotics are NOT indicated for acute bronchitis Period!!!23-25 No improvement in symptoms Increase in side effects vs. placebo

References Clinical Infectious Diseases 2007; 44:S27–72 Eur Respir J, 1995, 8, 398–402 Journal of Antimicrobial Chemotherapy (2001) 48 ,691-703 Am J Respir Crit Care Med Vol 170. pp 440– 444, 2004 Intensive Care Med (2010) 36:612–620 Clinical Infectious Diseases 2012;54(11):1581– 7 Drugs 2008; 68 (13): 1841-1854 Clinical Infectious Diseases 2003; 37:752–60 BMJ Open 2015;5:e006892 Am J Respir Crit Care Med Vol 171. pp 388– 416, 2005 JAMA. 2003 Nov 19;290(19):2588-98. Am J Respir Crit Care Med 2000;162:505–511. Cochrane Database Syst Rev. 2015 Aug 24;8:CD007577. JAMA. 2014 June 4; 311(21): 2199–2208 N Engl J Med 2015;372:1312-23. Clinical Infectious Diseases 2013;57(10):1373– 83 http://www.goldcopd.org/uploads/users/files/ GOLD_Report_2015.pdf Accessed 3/28/16 Cochrane Database Syst Rev 2006: CD004403

References (2) Chest 2008: 133;756-66 Journal of Hospital Medicine 2010;5:261–267 Eur Respir J 2007; 29: 1127–1137 N Engl J Med 2011;365:689-98. Ann Intern Med. 2016;164:425-434 Cochrane Database Syst Rev. 2014;3:CD000245 BMJ. 2013;347:f5762.