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

2. 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

3. 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

4. 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

5. 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

6. 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

7. Intensive Care Med (2010) 36:612–620

8. 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

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

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

11. Is atypical coverage really necessary?

12. Netherlands, 2283 patients conducted 2011 to 2013
CAP START study, NEJM
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:

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

14. 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”

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

16. 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

17. 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

18. 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

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

20. 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)

21. 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.

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

23. Daily prophylactic azithromycin for COPD?
Taken daily for 1 year, exacerbation averaged 1.48 vs (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

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

25. References Clinical Infectious Diseases 2007; 44:S27–72
Eur Respir J, 1995, 8, 398–402
Journal of Antimicrobial Chemotherapy (2001) 48 ,
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):
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 Nov 19;290(19):
Am J Respir Crit Care Med 2000;162:505–511.
Cochrane Database Syst Rev Aug 24;8:CD
JAMA June 4; 311(21): 2199–2208
N Engl J Med 2015;372:
Clinical Infectious Diseases 2013;57(10):1373– 83
GOLD_Report_2015.pdf Accessed 3/28/16
Cochrane Database Syst Rev 2006: CD004403

26. 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:
Ann Intern Med. 2016;164:
Cochrane Database Syst Rev ;3:CD000245
BMJ. 2013;347:f5762.