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Clinician Article

Azithromycin for acute lower respiratory tract infections.



  • Laopaiboon M
  • Panpanich R
  • Swa Mya K
Cochrane Database Syst Rev. 2015 Mar 8;(3):CD001954. doi: 10.1002/14651858.CD001954.pub4. (Review)
PMID: 25749735
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Disciplines
  • Emergency Medicine
    Relevance - 6/7
    Newsworthiness - 5/7
  • Family Medicine (FM)/General Practice (GP)
    Relevance - 6/7
    Newsworthiness - 5/7
  • General Internal Medicine-Primary Care(US)
    Relevance - 6/7
    Newsworthiness - 5/7
  • Hospital Doctor/Hospitalists
    Relevance - 6/7
    Newsworthiness - 5/7
  • Infectious Disease
    Relevance - 6/7
    Newsworthiness - 5/7
  • Internal Medicine
    Relevance - 6/7
    Newsworthiness - 5/7
  • Pediatric Hospital Medicine
    Relevance - 6/7
    Newsworthiness - 4/7
  • Pediatric Emergency Medicine
    Relevance - 5/7
    Newsworthiness - 5/7
  • Pediatrics (General)
    Relevance - 5/7
    Newsworthiness - 5/7
  • Respirology/Pulmonology
    Relevance - 5/7
    Newsworthiness - 5/7

Abstract

BACKGROUND: Acute lower respiratory tract infections (LRTI) range from acute bronchitis and acute exacerbations of chronic bronchitis to pneumonia. Approximately five million people die from acute respiratory tract infections annually. Among these, pneumonia represents the most frequent cause of mortality, hospitalisation and medical consultation. Azithromycin is a macrolide antibiotic, structurally modified from erythromycin and noted for its activity against some gram-negative organisms associated with respiratory tract infections, particularly Haemophilus influenzae (H. influenzae).

OBJECTIVES: To compare the effectiveness of azithromycin to amoxycillin or amoxycillin/clavulanic acid (amoxyclav) in the treatment of LRTI, in terms of clinical failure, incidence of adverse events and microbial eradication.

SEARCH METHODS: We searched CENTRAL (2014, Issue 10), MEDLINE (January 1966 to October week 4, 2014) and EMBASE (January 1974 to November 2014).

SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs, comparing azithromycin to amoxycillin or amoxycillin/clavulanic acid in participants with clinical evidence of an acute LRTI, such as acute bronchitis, pneumonia and acute exacerbation of chronic bronchitis.

DATA COLLECTION AND ANALYSIS: The review authors independently assessed all potential studies identified from the searches for methodological quality. We extracted and analysed relevant data separately. We resolved discrepancies through discussion. We initially pooled all types of acute LRTI in the meta-analyses. We investigated the heterogeneity of results using the forest plot and Chi(2) test. We also used the index of the I(2) statistic to measure inconsistent results among trials. We conducted subgroup and sensitivity analyses.

MAIN RESULTS: We included 16 trials involving 2648 participants. We were able to analyse 15 of the trials with 2496 participants. The pooled analysis of all the trials showed that there was no significant difference in the incidence of clinical failure on about days 10 to 14 between the two groups (risk ratio (RR), random-effects 1.09; 95% confidence interval (CI) 0.64 to 1.85). A subgroup analysis in trials with acute bronchitis participants showed significantly lower clinical failure in the azithromycin group compared to amoxycillin or amoxyclav (RR random-effects 0.63; 95% CI 0.45 to 0.88). A sensitivity analysis showed a non-significant reduction in clinical failure in azithromycin-treated participants (RR 0.55; 95% CI 0.25 to 1.21) in three adequately concealed studies, compared to RR 1.32; 95% CI 0.70 to 2.49 in 12 studies with inadequate concealment. Twelve trials reported the incidence of microbial eradication and there was no significant difference between the two groups (RR 0.95; 95% CI 0.87 to 1.03). The reduction of adverse events in the azithromycin group was RR 0.76 (95% CI 0.57 to 1.00).

AUTHORS' CONCLUSIONS: There is unclear evidence that azithromycin is superior to amoxycillin or amoxyclav in treating acute LRTI. In patients with acute bronchitis of a suspected bacterial cause, azithromycin tends to be more effective in terms of lower incidence of treatment failure and adverse events than amoxycillin or amoxyclav. However, most studies were of unclear methodological quality and had small sample sizes; future trials of high methodological quality and adequate sizes are needed.


Clinical Comments

Emergency Medicine

Important implications to provide clinical alternatives in an era of frequent drug shortages.

Emergency Medicine

The meta-analysis comparing azithromycin vs amoxicillin +/- clavulante for treating lower respiratory infections (acute bronchitis, exacerbation of chronic bronchitis and pneumonia) is well done. However, most of the original articles are small and have significant risk of bias. Although the authors report that the funnel plot shows no publication bias, visual inspection of the plot seems to indicate that small studies that showed a large treatment benefit for azithromycin are missing, a finding with uncertain implications. Overall, effectiveness of azithromycin is similar to that of amoxicillin-containing antibiotics. However, for acute bronchitis (not exacerbation of chronic bronchitis or pneumonia), azithromycin is superior. Azithromycin shows borderline increased adverse events (risk ratio 0.76, CI 0.57, 1.00). The authors conclude that future trials of high methodological quality and adequate sizes are needed to more definitely answer the clinical question posed.

Family Medicine (FM)/General Practice (GP)

The level of the evidence from the studies included in the review is low and one major theme - the potential for antibiotic resistance - is not covered in this review.

General Internal Medicine-Primary Care(US)

The results are not surprising or particularly helpful. Sputum cultures in LRTIs are infrequent and misleading, not to mention the fact that many episodes of bronchitis are viral. It probably makes no difference which antibiotic you choose; unfortunately, everyone gets treated.

Infectious Disease

It's nice to know that good old amoxicillin is just as effective as the macrolide. The subgroup analysis of presumed bacterial bronchitis patients is interesting in showing a trend for azithromycin, presumably due to Chlamydia and Pertussis infections in that group.

Pediatric Emergency Medicine

I was hopeful that this Cochrane review would look into the question of whether the addition of azithromycin to standard anti-pneumococcal therapy would be helpful in community-acquired pneumonia. Unfortunately, most of the studies included were in adults with bronchitis, not a particularly relevant population for the PEM practitioner, and those studies including children randomized children with CAP to either azithromycin alone or standard care (which in many cases included erythromycin - uncertain whether this is really a different treatment than azithromycin). Overall, this is not particularly relevant to today`s CAP treatment, as current guidelines recommend monotherapy with beta lactam antibiotics to cover pneumococcus, which is the most prevalent pathogen in children.

Pediatric Emergency Medicine

Emergency physicians commonly evaluate and treat patients with acute lower respiratory tract infections, and many receive antibiotic therapy. Amoxicillin, amoxyclav, and azithromycin are common drugs prescribed by physicians. This review shows that evidence is insufficient to state conclusively that azithromycin is superior to amoxycillin or amoxyclav in treating acute LRTI.

Pediatric Emergency Medicine

The review findings are interesting, particularly given the swing towards azithromycin use that appears to be happening. There is no separation of paediatric cases, however, which limits its applicability to paediatric LRTIs.

Respirology/Pulmonology

Cochrane review of available literature finds that azithromycin is as effective as amoxicillin and amoxicillin/clavulante for treating lower respiratory tract infections, with perhaps fewer adverse effects. The quality of the data was poor so it`s not clear to me that the review provides any meaningful results nor should it have any impact on clinical practice.

Respirology/Pulmonology

Cochrane meta-analysis finding that azithromycin did not differ from amoxicillin or amoxicillin-clavulanate for LRTI, but did reduce risk for clinical failure in acute bronchitis specifically. The Outcome lumps 3 different diagnoses (acute bronchitis, AECB, and pneumonia) with different patterns of microbial ethology and different natural histories together. Why did they do this in the first place? Not surprising that diagnosis partly explained high heterogeneity, which remained unexplained in the AECB subgroup, precluding any meaningful interpretation in that subgroup. Individual trials are small and mostly non-significant, so meta-analysis adds new information.

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