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… ? Or different term?

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 in first 2.5 years of program

1,900 of 6,900 (28%) related 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 nosocomialorganisms

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: Amoxicillin 1g TID x5-7d plus azithromycin 500mg x3d 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?

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

2016 IDSA HAP/VAP Guidelines26

Removed concept of HCAP

Defined risk for MDR VAP: IV abx within 90 days Septic shock or ARDS at diagnosis >5d hospitalization prior to VAP Acute dialysis prior to VAP

Defined risk for MDR HAP: IV abx within 90 days

Defined risk for MRSA HAP or VAP: IV abx within 90 days

Define risk for MDR Pseudomonas HAP or VAP: IV abx within 90 days

Endorsed non-invasive lower respiratory tract cultures

Recommend empiric regimens based on local susceptibility data

Vancomycin or linezolid for empiric MRSA coverage

2 agents for pseudomonas if ongoing septic shock or high risk of death

Recommend 7d duration for HAP and VAP

HAP, VAP 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 NT suction of uncooperative patients is reasonable

Empiric regimen based on 2016 IDSA HAP/VAP guidelines

Once cultures return, narrow to single drug and treat for 7 days

If invasive 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 and non-severe VAP: Ceftriaxone or ampicillin/sulbactam

Late onset HAP or VAP: Vancomycin dosed to goal trough 15-20 OR linezolid 600 mg PO/IV

q12h Cefepime 1g q6h (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

Aggressively narrow/stop once cultures back

No atypical or anaerobic coverage required

Acute Exacerbation of COPD Chronic bronchitis or emphysema with worsening

respiratory symptoms

GOLD 2018 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)

Procalcitonin in COPD ProHOSP study JAMA 200927. 228 patients with AECOPD.

49% received abx when PCT used vs 70% without No difference in outcomes

Stolz, Chest, 200728. 208 patient randomized to PCT algorithm with AECOPD. 40% vs 72% received abx, no difference in outcomes.

Christ-Crain, Lancet 200429. 243 patients with LRTI randomized to PCT. 25% with AECOPD. Abx given in 38% of PCT group vs87% of control group, no difference in outcomes.

Schuetz, Cochrane review 201230. ~300 COPD patients/arm, 48% in PCT vs 73% in control arm received abx. Treatment failure and mortality similar in both arms.

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 – 7 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 with elevated PCT (>0.25) or those requiring mechanical ventilation (invasive or non-invasive).

Outpatients with mild exacerbation do not require sputum cultures or antibiotics.

Azithromycin vs Levofloxacinfor AECOPD

Retrospective review of 19,608 patient given either quinolone or macrolide for AECOPD20

Daily prophylactic azithromycinfor 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

Gold guidelines now summarize the data, do not make statement for or against azithromycin prophylaxis

Antibiotics are NOT indicated for acute bronchitis

Period!!!23-25

No improvement in symptoms

Increase in side effects vs. placebo

References1. Clinical Infectious Diseases 2007; 44:S27–72

2. Eur Respir J, 1995, 8, 398–402

3. Journal of Antimicrobial Chemotherapy (2001) 48 ,691-703

4. Am J Respir Crit Care Med Vol 170. pp 440–444, 2004

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

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

7. Drugs 2008; 68 (13): 1841-1854

8. Clinical Infectious Diseases 2003; 37:752–60

9. BMJ Open 2015;5:e006892

10. Am J Respir Crit Care Med Vol 171. pp 388–416, 2005

11. JAMA. 2003 Nov 19;290(19):2588-98.

12. Am J Respir Crit Care Med 2000;162:505–511.

13. Cochrane Database Syst Rev. 2015 Aug 24;8:CD007577.

14. JAMA. 2014 June 4; 311(21): 2199–2208

15. N Engl J Med 2015;372:1312-23.

16. Clinical Infectious Diseases 2013;57(10):1373–83

17. http://goldcopd.org/wp-content/uploads/2017/11/GOLD-2018-v6.0-FINAL-revised-20-Nov_WMS.pdf Accessed 3/20/2018

18. Cochrane Database Syst Rev 2006: CD004403

References (2)19. Chest 2008: 133;756-66

20. Journal of Hospital Medicine 2010;5:261–267

21. Eur Respir J 2007; 29: 1127–1137

22. N Engl J Med 2011;365:689-98.

23. Ann Intern Med. 2016;164:425-434

24. Cochrane Database Syst Rev. 2014;3:CD000245

25. BMJ. 2013;347:f5762.

26. Clinical Infectious Diseases, 2016, 63(5), e61–e111

27. JAMA 2009 302(10) 1059-1066.

28. Stolz Chest 2007 131:9-19.

29. Christ-crain Lancet 2004 363:600-607

30. Schuetz Cochrane Review 2012 Issue 9.