Duration of therapy in Community Acquired Pneumonia

18 Nov

While up on the medical unit I was asked by one of our hospitalists what the ideal duration of therapy for CAP is these days.  Is it 10-14 days?

Community –acquired pneumonia (CAP) is the most common infectious disease requiring hospitalization.  The optimal duration of antibiotic therapy for CAP has not been clearly defined.  Previous treatment recommendations for uncomplicated pneumonia ranged from 7 to 14 days and were mostly opinion-based.  I have been unable to find where or why the 7 -14 day durations were chosen.

A recent audit of 2003 patients found that the duration of antibiotic use had little relationship with patients response to treatment or initial severity.  Not surprisingly it also found that prolonged courses of antibiotics for CAP are common (1).

Shortening the duration of antibiotic therapy can potentially reduce antimicrobial use without putting the patient at risk.

A meta-analysis, performed by Li et al. (2), compared short-course antibiotic therapy (<7 days) versus extended-course regimens (>7 days).  The meta-analysis included 15 randomized control trials in adults (both in and outpatients).  The primary outcome measure was failure to achieve clinical improvement or cure as defined by the investigators of each individual study.  The analysis found no difference in the risk of treatment failure between short course and extended-course antibiotics.  Of note, the majority of the trials in the analysis used azithromycin as the short-course comparator…more on that later.

A randomized, double-blind, placebo controlled non-inferiority trial performed by Moussaoui et al. (3).   The trial, which took place in the Netherlands, looked at adults with mild to moderate-severe pneumonia (PSI =< 110).  Patients were treated with 3 days of IV amoxicillin (standard of care in Netherlands).  If they had substantially improved after three days patients were randomized to receive either oral amoxicillin (n= 63) or placebo (n=56) three times daily for five days.  The trial found that the 3 day course was non-inferior to the total course of 8 days.

Yes that’s correct…3 days of antibiotics for CAP! FYI, amoxicillin exhibits time-dependant killing and has a short half-life of 71 minutes (4).

In another randomized, double-blinded investigation Dunbar et. al (5) compared high dose (750 mg) levofloxacin for 5 days with levofloxacin (500 mg) for 10 days in 528 adults with mild to severe CAP.   The study found that the shorter 5 day course was at least as effective as the 10 day treatment.

Most of the trials that examined short course therapy generally excluded patients with severe cases of pneumonia.  A recent prospective observational study by Choudury et. al (6) aimed to guide in the duration of therapy for severe pneumonia.  The English study included patient’s with CURB-65 scores of 3-5 and presented with signs and symptoms consistent with an acute lower respiratory tract infection (new chest X-ray shadowing with no other explanation).   The study compared patients treated for 7 days and those treated for greater than 7 days.  The study found no significant difference on 30-day mortality between the two groups.

A brief word about azithromycin; per Lexi-Comp the half-life elimination is 68-72 hours.  In a 29 patient open investigation, a single 500 mg dose of azithromycin orally was shown to have concentrations in the pulmonary tissue up to 5 days after the dose! (7)

For inpatients you might say that these patients have more severe pneumonia, thus require longer durations.  However, the majority of patients seen in hospital have moderate-severe pneumonia (PSI < 130) (8). 

Insert the frequently used “more studies are needed” line here.  It’s true, there aren’t many studies and they’re with their flaws. However, giving antibiotics can cause harm.  By treating for the shortest duration possible we have much to gain.

To answer the hospitalist’s question.  

If the patient improves significantly after 3 days of antibiotics we generally recommend a short course of therapy (5 days).  Patients with more severe pneumonia may require longer courses.  As you may know, the IDSA’s current CAP guidelines suggest at least 5 days of therapy (Level 1 evidence) (9).

This contradicts the old adage, “Take all your antibiotics until they’re finished, even if you feel better.” 

It does, but that topic is for another blog post.

References

1) Aliberti, S., Blasi, F., Zanaboni, A. M., Peyrani, P., Tarsia, P., Gaito, S., & Ramirez, J. A. (2010). Duration of antibiotic therapy in hospitalised patients with community-acquired pneumonia. The European respiratory journal official journal of the European Society for Clinical Respiratory Physiology, 36(1), 128-134. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/19926738

2) Li, J. Z., Winston, L. G., Moore, D. H., & Bent, S. (2007). Efficacy of short-course antibiotic regimens for community-acquired pneumonia: a meta-analysis. The American Journal of Medicine, 120(9), 783-790. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/17765048

3) El Moussaoui, R., De Borgie, C. A. J. M., Van Den Broek, P., Hustinx, W. N., Bresser, P., Van Den Berk, G. E. L., Poley, J.-W., et al. (2006). Effectiveness of discontinuing antibiotic treatment after three days versus eight days in mild to moderate-severe community acquired pneumonia: randomised, double blind study. BMJ British Medical Journal, 332(7554), 1355.. Retrieved from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1479094&tool=pmcentrez&rendertype=abstract

4) Humbert, G., Spyker, D. A., Fillastre, J. P., & Leroy, A. (1979). Pharmacokinetics of Amoxicillin: Dosage Nomogram for Patients with Impaired Renal Function. Antimicrobial Agents and Chemotherapy, 15(1), 28-33 Retrieved from http://aac.asm.org/content/15/1/28.full.pdf

5) Dunbar, L. M., Wunderink, R. G., Habib, M. P., Smith, L. G., Tennenberg, A. M., Khashab, M. M., Wiesinger, B. A., et al. (2003). High-dose, short-course levofloxacin for community-acquired pneumonia: a new treatment paradigm. Clinical Infectious Diseases. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/12955634

6) Choudhury, G., Mandal, P., Singanayagam, A., Akram, A. R., Chalmers, J. D. and Hill, A. T. (2011), Seven-day antibiotic courses have similar efficacy to prolonged courses in severe community-acquired pneumonia—a propensity-adjusted analysis. Clinical Microbiology and Infection, 17: 1852–1858 Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/21919994

7) Morris, D. L., De Souza, A., Jones, J. A., & Morgan, W. E. (1991). High and prolonged pulmonary tissue concentrations of azithromycin following a single oral dose. European journal of clinical microbiology infectious diseases official publication of the European Society of Clinical Microbiology. Retrieved from www.ncbi.nlm.nih.gov/pubmed/1662633

8) Fine, M. J., Auble, T. E., Yealy, D. M., Hanusa, B. H., Weissfeld, L. A., Singer, D. E., Coley, C. M., et al. (1997). A prediction rule to identify low-risk patients with community-acquired pneumonia. The New England Journal of Medicine, 336(4), 243-250. Mass Medical Soc. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/8995086

9) Mandell, L. A., Wunderink, R. G., Anzueto, A., Bartlett, J. G., Campbell, G. D., Dean, N. C., Dowell, S. F., et al. (2007). Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clinical Infectious Diseases, 44 Suppl 2(Suppl 2), S27-72. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/17278083

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