Antibiotics for the treatment of leptospirosis

Leptospirosis is a common disease both in the developed and developing world. It is caused by a bacteria spread by the urine of animals. People travelling, agricultural field workers, hunters, homeless, and others with close animal contact are groups that, in particular, can get leptospirosis. Like many common infections, most people infected with this disease do not feel sick. When people do feel sick, in some instances up to 1 out of every 10 people have died. Whether or not antibiotics should be used, and if used which antibiotic should be used have been matters for debate for many years. This review identified and assessed seven clinical trials that tested antibiotics in patients sick with leptospirosis. Four of these trials compared intravenous penicillin to a placebo. Three of the trials looked at differences between different antibiotics. All trials had high risk of systematic errors (bias) and of random errors (play of chance). When looked at together, these trials do not answer the basic questions about whether or not antibiotics should be used. Part of the reason for this is that there is a wide range of severity among people ill with the disease. Additional randomised clinical trials are needed. Nonetheless, these trials suggest that antibiotics administered to patients who are sick with leptospirosis may make patients feel better two days earlier than they otherwise would have improved. However, it is also possible that when patients are severely ill, penicillin therapy might increase the risk of death or dialysis in comparison to those who receive no antibiotics. Other antibiotics have not been tested in this way. Despite the lack of evidence, if a clinician chooses to treat leptospirosis with an antibiotic, there does not seem to be any difference between the appropriate use of intravenous penicillin, intravenous cephalosporin, doxycyline, or azithromycin. But, for this they have not been tested to the same extent as intravenous penicillin.

Authors' conclusions: 

Insufficient evidence is available to advocate for or against the use of antibiotics in the therapy for leptospirosis. Among survivors who were hospitalised for leptospirosis, use of antibiotics for leptospirosis may have decreased the duration of clinical illness by two to four days, though this result was not statistically significant. When electing to treat with an antibiotic, selection of penicillin, doxycycline, or cephalosporin does not seem to impact mortality nor duration of fever. The benefit of antibiotic therapy in the treatment of leptospirosis remains unclear, particularly for severe disease. Further clinical research is needed to include broader panels of therapy tested against placebo.

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Background: 

Leptospirosis has a wide-ranging clinical and public health impact. Leptospira are globally distributed. Case attack rates are as high as 1:4 to 2:5 persons in exposed populations. In some settings mortality has exceeded 10% of infected people. The benefit of antibiotic therapy in the disease has been unclear.

Objectives: 

We sought to characterise the risks and benefits associated with use of antibiotic therapy in the management of leptospirosis.

Search strategy: 

We searched the The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded regardless of study language. This was augmented by a manual search. The last date of search was November, 2011.

Selection criteria: 

To be included in assessment of benefits, trials had to specifically assess the use of antibiotics in a randomised clinical trial. A broad range of study types were incorporated to seek potential harms.

Data collection and analysis: 

Included trials were systematically abstracted, as were excluded studies for the purposes of assessing harms. Analyses were conducted in accordance with The Cochrane Handbook and practices of The Cochrane Hepato-Biliary Group.

Main results: 

Seven randomised trials were included.  Four trials with 403 patients compared an antibiotic with placebo or no intervention. Three trials compared at least one antibiotic regimen with another antibiotic regimen. The trials all had high risk of bias. The trials varied in the severity of leptospirosis among trial patients. The ability to group data for meta-analysis was limited. While all four trials that compared antibiotics with placebo reported mortality and used parenteral penicillin, there were no deaths in two of them. Since odds ratio calculations cannot employ zero-event trials, only two trials contributed to this estimate. The number of deaths were 16/200 (8.0%) in the antibiotic arm versus 11/203 (5.4%) in the placebo arm giving a fixed-effect OR 1.56 (95% CI 0.70 to 3.46). The random-effects OR is 1.16 (95% CI 0.23 to 5.95). The heterogeneity among these four trials for the mortality outcome was moderate (I2= 50%). Only one trial (253 patients) reported days of hospitalisation. It compared parenteral penicillin to placebo without significant effect of therapy (8.9 versus 8.8 days; mean difference (MD) 0.10 days, 95% CI -0.83 to 1.03). The difference in days of clinical illness was reported in two of these trials (71 patients). While parenteral penicillin therapy conferred 4.7 to 5.6 days of clinical illness in contrast to 7.7 to 11.6 days in the placebo arm, the size of the estimate of effect increased but statistical significance was lost under the random-effect model (fixed-effect: MD -2.13 days, 95% CI -2.46 to -1.80; random-effects: MD -4.04, 95% CI -8.66 to 0.58). I2 for this outcome was high (81%). When duration of fever alone was assessed between antibiotics and placebo in a single trial (79 patients), no significant difference existed (6.9 versus 6.6 days; MD 0.30, 95% CI -1.26 to 1.86). Two trials with 332 patients in relatively severe and possibly late leptospirosis, resulted in trends towards increased dialysis when penicillin was used rather than placebo, but the estimate of effect was small and did not reach statistical significance (42/163 (25.8%) versus 31/169 (18.4%); OR 1.54, 95% CI 0.91 to 2.60). When one antibiotic was assessed against another antibiotic, there were no statistically significant results. For mortality in particular, these comparisons included cephalosporin versus penicillin (2 trials, 6/176 (3.4%) versus 9/175 (5.2%); fixed-effect: OR 0.65, 95% CI 0.23 to 1.87, I2= 16%), doxycycline versus penicillin (1 trial, 2/81 (2.5%) versus 4/89 (4.5); OR 0.54, 95% CI 0.10 to 3.02), cephalosporin versus doxycycline (1 trial, 1/88 (1.1%) versus 2/81 (2.5%); OR 0.45, 95% CI 0.04 to 5.10). There were no adverse events of therapy which reached statistical significance.

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