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Home , Aspiration pneumonia, Lung abscess, Pneumonia

Community-Acquired – Frequently Asked Questions

In outpatient CAP in healthy patients without comorbidities, why are and monotherapy no longer recommended?

Per the 2019 SHC Antibiogram, and tetracycline resistance in S. pneumoniae is 44% and 42%, respectively.1 Negative clinical outcomes like breakthrough bacteremia have been shown in patients with -resistant receiving macrolide therapy.2,3 The 2019 ATS/IDSA CAP Guidelines recommend avoidance of macrolide monotherapy when local pneumococcal resistance rates exceed 25%.4 While the guidelines do not address a local threshold for S. pneumoniae tetracycline (doxycycline) resistance directly, the SHC resistance rate (42%) varies so substantially from the 2017 U.S. national average (11%) that an empiric recommendation cannot be justified.1,4,5

In outpatient CAP in healthy patients without comorbidities, why is monotherapy recommended, which does not have “atypical” coverage?

Multiple prospective, randomized studies have demonstrated equivalent efficacy of high dose amoxicillin to antimicrobials with atypical coverage including fluoroquinolones and ketolides in patients with CAP.6–8 Meta-analyses of these and other studies comparing beta lactams with or fluoroquinolones also demonstrated no differences in clinical success and mortality, particularly in healthy outpatients with CAP.9 Additionally, per the 2018 SHC Antibiogram, using as a surrogate, amoxicillin susceptibility amongst S. pneumoniae is very high at 98%.1

Why is Healthcare Associated Pneumonia (HCAP) no longer a recognized clinical entity?

The term ‘HCAP’ was initially coined based on studies showing a higher prevalence of organisms like MRSA and P. aeruginosa in certain subsets of patient with CAP (e.g. , residence, recent hospitalization, home infusion therapy, home wound care). In prior pneumonia guidelines, broader spectrum therapy was recommended in patients who met any of these HCAP criteria. However, more recent meta-analyses of subsequent studies showed poor discriminatory ability of the HCAP criteria to detect MRSA and P. aeruginosa, no increase in mortality of HCAP, and significant publication bias and low study quality.10 Numerous studies have also shown no difference in outcomes when using standard CAP therapy compared with broader spectrum therapy with anti-pseudomonal and MRSA activity in aggregate11,12, as well as subsets of non-severe disease or non-ICU patients13,14 and critically ill patients15. See below for when empiric MRSA or P. aeruginosa-directed therapy should be considered.

What is the evidence behind when empiric MRSA or Pseudomonas coverage should be considered?

Overall, incidence of MRSA and P. aeruginosa in CAP is low.16–19 The strongest predictor of MRSA or P. aeruginosa is prior isolation of these organisms from respiratory culture.16,18,19 The 2019 ATS/IDSA CAP guidelines recommend empirically covering MRSA or P. aeruginosa, respectively, if these organisms have been isolated from respiratory cultures in the past 12 months.4 Receipt of broad spectrum intravenous during hospitalization was also identified as a predictor of MRSA and P. aeruginosa but its association is weaker, thus the 2019 ATS/IDSA CAP guidelines recommend only empirically covering these organisms in severe CAP, otherwise respiratory cultures should be obtained and MRSA or P. aeruginosa coverage added only if these organisms are isolated.4,19 Other less strongly associated risk factors for MRSA include recurrent skin infections18 and severe disease.18 For P. aeruginosa they include tracheostomy16, bronchiectasis16, severe COPD16, and invasive respiratory or vasopressor support16. If antimicrobials for MRSA and/or P. aeruginosa are initiated, blood and respiratory cultures as well as nasal MRSA PCR screen should be performed and if these assays do not identify these , therapy can be narrowed.4

Why do patients with suspected (without radiographic evidence of or ) no longer need additional anaerobic coverage?

While more definitive research is needed in this area, the origins of needing anaerobic coverage (e.g. adding ) were based on studies of aspiration pneumonia using trans-tracheal aspiration in patients late in their disease course finding high rates of anaerobic organisms.20,21 More recent studies have found that gram negative aerobic organisms are more common and anaerobes play less of a role.22,23 Additionally, what may initially be diagnosed as aspiration pneumonia could instead be aspiration , a non-infectious syndrome, in which patients improve rapidly and antimicrobials do not affect outcome.24,25 Thus, the 2019 ATS/IDSA CAP Guidelines do not recommend adding anaerobic coverage for aspiration pneumonia unless radiographic evidence of or empyema exist.4

When discharging a patient with CAP, given potential insurance formulary challenges, can other like or be substituted?

The 2019 ATS/IDSA CAP Guidelines only recommend cefpodoxime and as oral options in the treatment of CAP along with amoxicillin/clavulanate.4 Cefdinir does carry an FDA indication for CAP and its use is supported by a prospective randomized controlled trial at a dosage of 300 mg PO BID, where it achieved 89% clinical cure.26,27 While inclusion criteria were not as stringent as modern CAP trials and duration of therapy was 10 days, on subgroup analysis, cefdinir did demonstrate high cure rates (85-100%) in culture-positive pneumonia with S. pneumoniae, M. catarrhalis, H. influenzae, and H. parainfluenzae supporting its efficacy.27 Cefixime is another commonly used oral 3rd generation cephalosporin, however, it does not carry an FDA indication for pneumonia and clinical studies supporting its use are of poor quality.28

What is the appropriate treatment duration of CAP?

Several randomized controlled trials have demonstrated similar efficacy with 5 days (or less) of therapy to longer courses (8-10 days).29–31 The 2019 ATS/IDSA CAP Guidelines recommend that in patients with CAP with clinical improvement (i.e. resolution of vital sign abnormalities, normal mentation, ability to eat), treatment should be no less than 5 days. In patients who do not stabilize by day 5 of treatment should be evaluated for drug-resistant pathogens, complications of pneumonia, or other sources of /inflammatory response. Duration of therapy should be extended to 7 days in patients with documented MRSA or P. aeruginosa pneumonia and duration should be extended appropriately if pneumonia is complicated by meningitis, endocarditis, or other deep-seated infection or caused by other less common pathogens (e.g. M or endemic fungi).4

Can azithromycin be discontinued after 3 days of therapy at 500 mg daily?

Multiple randomized studies of and CAP, demonstrated similar treatment efficacy between 3 days of azithromycin (500 mg PO daily) compared with both 5 days of azithromycin (500 mg PO on day 1 followed by 250 mg PO on days 2-5)32 and 8 days of clarithromycin33. In patients with CAP and rapid clinical improvement on therapy with a beta lactam and azithromycin 500 mg daily, azithromycin can be safety discontinued after 3 doses, while the beta lactam can be continued for at least 5 total days of therapy as above.

1. Banaei N, Watz N, Getsinger D, Ghafghaichi L. Stanford Antibiogram 2019. 2019.

2. Lonks JR, Garau J, Gomez L, et al. Failure of Macrolide Antibiotic Treatment in Patients with Bacteremia Due to Erythromycin-Resistant pneumoniae. Clin Infect Dis. 2002;35(5):556-564.

3. Daneman N, McGeer A, Green K, Low DE. Macrolide Resistance in Bacteremic Pneumococcal Disease: Implications for Patient Management. Clin Infect Dis. 2006;43(4):432-438.

4. Metlay JP, Waterer GW, Long AC, et al. Diagnosis and Treatment of Adults with Community- acquired Pneumonia. An Official Clinical Practice Guideline of the American Thoracic Society and Infectious Diseases Society of America. Am J Respir Crit Care Med. 2019;200(7):e45-e67. doi:10.1164/rccm.201908-1581ST

5. ABCs 2017 Strep Pneumoniae Report | CDC. https://www.cdc.gov/abcs/reports- findings/survreports/spneu17.html. Published April 5, 2019. Accessed February 27, 2020.

6. Aubier M, Verster R, Regamey C, Geslin P, Vercken J-B, Group TSES. Once-Daily Sparfloxacin versus High-Dosage Amoxicillin in the Treatment of Community-Acquired, Suspected Pneumococcal Pneumonia in Adults. Clin Infect Dis. 1998;26(6):1312-1320.

7. Petitpretz P, Arvis P, Marel M, Moita J, Urueta J. Oral vs High-Dosage Amoxicillin in the Treatment of Mild-to-Moderate, Community-Acquired, Suspected Pneumococcal Pneumonia in Adults. Chest. 2001;119(1):185-195. doi:10.1378/chest.119.1.185

8. Hagberg L, Torres A, van Rensburg D, Leroy B, Rangaraju M, Ruuth E. Efficacy and Tolerability of Once-Daily Telithromycin Compared with High-Dose Amoxicillin for Treatment of Community- Acquired Pneumonia. Infection. 2002;30(6):378-386. doi:10.1007/s15010-002-2096-z 9. Maimon N, Nopmaneejumruslers C, Marras TK. Antibacterial class is not obviously important in outpatient pneumonia: a meta-analysis. Eur Respir J. 2008;31(5):1068-1076. doi:10.1183/09031936.00109007

10. Chalmers JD, Rother C, Salih W, Ewig S. Healthcare-Associated Pneumonia Does Not Accurately Identify Potentially Resistant Pathogens: A Systematic Review and Meta-Analysis. Clin Infect Dis. 2014;58(3):330-339. doi:10.1093/cid/cit734

11. Grenier C, Pépin J, Nault V, et al. Impact of guideline-consistent therapy on outcome of patients with healthcare-associated and community-acquired pneumonia. J Antimicrob Chemother. 2011;66(7):1617-1624. doi:10.1093/jac/dkr176

12. Rothberg MB, Zilberberg MD, Pekow PS, et al. Association of guideline-based antimicrobial therapy and outcomes in healthcare-associated pneumonia. J Antimicrob Chemother. 2015;70(5):1573- 1579. doi:10.1093/jac/dku533

13. Attridge RT, Frei CR, Restrepo MI, et al. Guideline-concordant therapy and outcomes in healthcare- associated pneumonia. Eur Respir J. 2011;38(4):878-887. doi:10.1183/09031936.00141110

14. Chen JI, Slater LN, Kurdgelashvili G, Husain KO, Gentry CA. Outcomes of Health Care–Associated Pneumonia Empirically Treated with Guideline-Concordant Regimens Versus Community-Acquired Pneumonia Guideline–Concordant Regimens for Patients Admitted to Care Wards from Home. Ann Pharmacother. 2013;47(1):9-19. doi:10.1345/aph.1R322

15. Attridge RT, Frei CR, Pugh MJV, et al. Health care–associated pneumonia in the : Guideline-concordant antibiotics and outcomes. J Crit Care. 2016;36:265-271. doi:10.1016/j.jcrc.2016.08.004

16. Restrepo MI, Babu BL, Reyes LF, et al. Burden and risk factors for community-acquired pneumonia: a multinational point prevalence study of hospitalised patients. Eur Respir J. 2018;52(2). doi:10.1183/13993003.01190-2017

17. Jain S, Self WH, Wunderink RG, et al. Community-Acquired Pneumonia Requiring Hospitalization among U.S. Adults. N Engl J Med. 2015;373(5):415-427. doi:10.1056/NEJMoa1500245

18. Global initiative for meticillin-resistant pneumonia (GLIMP): an international, observational cohort study- ClinicalKey. https://www-clinicalkey- com.laneproxy.stanford.edu/#!/content/playContent/1-s2.0- S1473309916302675?returnurl=null&referrer=null. Accessed February 27, 2020.

19. Gross AE, Schooneveld TCV, Olsen KM, et al. Epidemiology and Predictors of Multidrug-Resistant Community-Acquired and Health Care-Associated Pneumonia. Antimicrob Agents Chemother. 2014;58(9):5262-5268. doi:10.1128/AAC.02582-14

20. Gonzalez-C CL, Calia FM. Bacteriologic Flora of Aspiration-Induced Pulmonary . Arch Intern Med. 1975;135(5):711-714. doi:10.1001/archinte.1975.00330050085014

21. Bartlett JG, Gorbach SL. Treatment of Aspiration Pneumonia and Primary Lung Abscess: Penicillin G vs . JAMA. 1975;234(9):935-937. doi:10.1001/jama.1975.03260220039016 22. Marik PE, Careau P. The Role of Anaerobes in Patients With Ventilator-associated Pneumonia and Aspiration Pneumonia: A Prospective Study. Chest. 1999;115(1):178-183. doi:10.1378/chest.115.1.178

23. El-Solh AA, Pietrantoni C, Bhat A, et al. Microbiology of Severe Aspiration Pneumonia in Institutionalized Elderly. Am J Respir Crit Care Med. 2003;167(12):1650-1654. doi:10.1164/rccm.200212-1543OC

24. Jaoude P, Badlam J, Anandam A, El-Solh AA. A comparison between time to clinical stability in community-acquired aspiration pneumonia and community-acquired pneumonia. Intern Emerg Med. 2014;9(2):143-150. doi:10.1007/s11739-012-0764-2

25. Aspiration pneumonia: A review of modern trends- ClinicalKey. https://www-clinicalkey- com.laneproxy.stanford.edu/#!/content/playContent/1-s2.0- S0883944114002871?returnurl=null&referrer=null. Accessed February 27, 2020.

26. 50739S2LBL.pdf. https://www.accessdata.fda.gov/drugsatfda_docs/label/1999/50739S2LBL.PDF. Accessed February 27, 2020.

27. Drehobl M, Bianchi P, Keyserling CH, Tack KJ, Griffin TJ. Comparison of cefdinir and in treatment of community-acquired pneumonia. Antimicrob Agents Chemother. 1997;41(7):1579- 1583. doi:10.1128/AAC.41.7.1579

28. 203195s000lbl.pdf. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203195s000lbl.pdf. Accessed February 27, 2020.

29. Uranga A, España PP, Bilbao A, et al. Duration of Antibiotic Treatment in Community-Acquired Pneumonia: A Multicenter Randomized Clinical Trial. JAMA Intern Med. 2016;176(9):1257-1265. doi:10.1001/jamainternmed.2016.3633

30. el Moussaoui R, de Borgie CAJM, van den Broek P, et al. Effectiveness of discontinuing antibiotic treatment after three days versus eight days in mild to moderate-severe community acquired pneumonia: randomised, double blind study. BMJ. 2006;332(7554):1355.

31. Dunbar LM, Wunderink RG, Habib MP, et al. High-Dose, Short-Course for Community- Acquired Pneumonia: A New Treatment Paradigm. Clin Infect Dis. 2003;37(6):752-760.

32. Schönwald S, Skerk V, Petricevic I, Car V, Majerus-Misic L, Gunjaca M. Comparison of three-day and five-day courses of azithromycin in the treatment of atypical pneumonia. Eur J Clin Microbiol Infect Dis Off Publ Eur Soc Clin Microbiol. 1991;10(10):877-880. doi:10.1007/bf01975847

33. Rizzato G, Montemurro L, Fraioli P, et al. Efficacy of a three day course of azithromycin in moderately severe community-acquired pneumonia. Eur Respir J. 1995;8(3):398-402. doi:10.1183/09031936.95.08030398