Azithromycin for treating uncomplicated typhoid and paratyphoid fever (enteric fever)

Typhoid or paratyphoid fevers (known as enteric fever) are infectious diseases caused by Salmonella bacteria. There were over 25 million new cases worldwide in 2000. Infections are mostly in the middle- and low-income countries where sanitation and water supplies are poor. The diseases are common in the Indian subcontinent, South-East and Far East Asia, Africa, Central and South America, and the Mediterranean region. Enteric fever occurs mainly in young people between five and 19 years and in some areas it is common among children less than five years' old. The infection is usually transmitted by ingestion of food or water contaminated with faeces from people who have the infection. Symptoms include intermittent fever, severe headaches, abdominal discomfort, loss of appetite, malaise, vague abdominal tenderness, and enlarged liver and/or spleen. About 10% to 15% of people get complications, which include bleeding, shock, and inflammation of the pancreas, heart muscles, and the brain. For many years, antibiotics such as chloramphenicol, ampicillin, and cotrimoxazole were used for treating enteric fever. However, multiple-drug resistant strains of the bacteria have now emerged. Other antibiotics like the fluoroquinolones, cephalosporins, and azithromycin are used as well. This review of trials looked at azithromycin as a treatment for uncomplicated enteric fever. There were seven trials (from Egypt, Vietman, and India) involving 773 people, all treated in hospital. There was limited evidence showing azithromycin is effective for treating typhoid or paratyphoid fevers. This is especially important where there are multiple-drug resistant strains. Azithromycin was better than some of the other drugs used. However, care will need to be taken to prevent strains becoming resistant to azithromycin too. More large trials, preferably multicentred and involving outpatients in areas endemic for enteric fever, are needed.

Authors' conclusions: 

Azithromycin appears better than fluoroquinolone drugs in populations that included participants with drug-resistant strains. Azithromycin may perform better than ceftriaxone.

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Background: 

Review status: Current question – no update intended. Azithromycin treatments are included in the review: Fluoroquinolones for treating typhoid and paratyphoid fever (enteric fever). (Thaver D, Zaidi AKM, Critchley JA, Azmatullah A, Madni SA, Bhutta ZA. Fluoroquinolones for treating typhoid and paratyphoid fever (enteric fever). Cochrane Database of Systematic Reviews 2008, Issue 4. Art. No.: CD004530. DOI: 10.1002/14651858.CD004530.pub3.)   This latter review is being updated, and will be published in late 2011.

Enteric fever (typhoid and paratyphoid fever) is potentially fatal. Infection with drug-resistant strains of the causative organism Salmonella enterica serovar Typhi or Paratyphi increases morbidity and mortality. Azithromycin may have better outcomes in people with uncomplicated forms of the disease.

Objectives: 

To compare azithromycin with other antibiotics for treating uncomplicated enteric fever.

Search strategy: 

In August 2008, we searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (The Cochrane Library 2008, Issue 3), MEDLINE, EMBASE, LILACS, and mRCT. We also searched conference proceedings, reference lists, and contacted researchers and a pharmaceutical company.

Selection criteria: 

Randomized controlled trials comparing azithromycin with other antibiotics for treating children and adults with uncomplicated enteric fever confirmed by cultures of S. Typhi or Paratyphi in blood and/or stool.

Data collection and analysis: 

Both authors independently extracted data and assessed the risk of bias. Dichotomous data were presented and compared using the odds ratio, and continuous data were reported as arithmetic means with standard deviations and were combined using the mean difference (MD). Both were presented with 95% confidence intervals (CI).

Main results: 

Seven trials involving 773 participants met the inclusion criteria. The trials used adequate methods to generate the allocation sequence and conceal allocation, and were open label. Three trials exclusively included adults, two included children, and two included both adults and children; all were hospital inpatients. One trial evaluated azithromycin against chloramphenicol and did not demonstrate a difference for any outcome (77 participants, 1 trial). When compared with fluoroquinolones in four trials, azithromycin significantly reduced clinical failure (OR 0.48, 95% CI 0.26 to 0.89; 564 participants, 4 trials) and duration of hospital stay (MD -1.04 days, 95% CI -1.73 to -0.34 days; 213 participants, 2 trials); all four trials included people with multiple-drug-resistant or nalidixic acid-resistant strains of S. Typhi or S. Paratyphi. We detected no statistically significant difference in the other outcomes. Compared with ceftriaxone, azithromycin significantly reduced relapse (OR 0.09, 95% CI 0.01 to 0.70; 132 participants, 2 trials) and not other outcome measures. Few adverse events were reported, and most were mild and self limiting.

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