Brett-Major David M, Coldren Rodney
U.S. Military Tropical Medicine, Navy Medicine Manpower, Personnel, Training and Education Command (NAVMED MPT&E),Bethesda, MD, USA.
Cochrane Database Syst Rev. 2012 Feb 15;2012(2):CD008264. doi: 10.1002/14651858.CD008264.pub2.
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.
We sought to characterise the risks and benefits associated with use of antibiotic therapy in the management of leptospirosis.
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.
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.
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.
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 (I(2)= 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). I(2) 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, I(2)= 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.
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.
钩端螺旋体病对临床和公共卫生有着广泛影响。钩端螺旋体在全球范围内分布。在暴露人群中，病例罹患率高达1:4至2:5。在某些情况下，死亡率超过感染人群的10%。抗生素治疗在该病中的益处尚不清楚。
我们试图明确抗生素治疗在钩端螺旋体病管理中的风险和益处。
我们检索了Cochrane肝胆组对照试验注册库、Cochrane图书馆中的Cochrane对照试验中心注册库（CENTRAL）、MEDLINE、EMBASE和科学引文索引扩展版，检索不限研究语言。此外还进行了手工检索。最后检索日期为2011年11月。
纳入益处评估的试验必须在随机临床试验中专门评估抗生素的使用。纳入了广泛的研究类型以探寻潜在危害。
对纳入的试验进行系统摘要，对排除的试验也进行摘要以评估危害。分析按照Cochrane手册和Cochrane肝胆组的方法进行。
纳入了7项随机试验。4项试验共403例患者，比较了抗生素与安慰剂或不干预。3项试验比较了至少一种抗生素方案与另一种抗生素方案。这些试验均存在高偏倚风险。试验患者的钩端螺旋体病严重程度各异。进行荟萃分析时的数据分组能力有限。虽然所有4项比较抗生素与安慰剂的试验均报告了死亡率且使用了静脉注射青霉素，但其中两项试验中无死亡病例。由于比值比计算不能采用零事件试验，仅有两项试验用于此估计。抗生素组死亡人数为16/200（8.0%），安慰剂组为11/203（5.4%），固定效应比值比为1.56（95%可信区间0.70至3.46）。随机效应比值比为1.16（95%可信区间0.23至5.95）。这4项试验中死亡率结局的异质性为中度（I² = 50%）。仅有一项试验（253例患者）报告了住院天数。该试验比较了静脉注射青霉素与安慰剂，治疗无显著效果（8.9天对8.8天；平均差值（MD）0.10天，95%可信区间 -0.83至1.03）。其中两项试验（71例患者）报告了临床疾病天数。静脉注射青霉素治疗的临床疾病天数为4.7至5.6天，而安慰剂组为7.7至11.6天，效应估计值增大，但在随机效应模型下失去统计学意义（固定效应：MD -2.13天，95%可信区间 -2.46至 -1.80；随机效应：MD -4.04，95%可信区间 -8.66至'0.58）。此结局的I²较高（81%）。在一项试验（79例患者）中，仅评估抗生素与安慰剂之间的发热持续时间时，无显著差异（6.9天对6.6天；MD 0.30，95%可信区间 -1.26至1.86）。两项试验共332例患者，处于相对严重且可能为晚期的钩端螺旋体病，使用青霉素而非安慰剂时透析有增加趋势，但效应估计值较小且未达到统计学意义（42/163（25.8%）对31/169（18.4%）；比值比1.54，95%可信区间0.91至2.60）。当一种抗生素与另一种抗生素比较时，无统计学显著结果。特别是对于死亡率，这些比较包括头孢菌素与青霉素（2项试验，6/176（3.4%）对9/175（5.2%）；固定效应：比值比0.65，95%可信区间0.23至1.87，I² = 16%），多西环素与青霉素（1项试验，2/81（2.5%）对4/89（4.5%）；比值比0.54，95%可信区间0.10至3.02），头孢菌素与多西环素（1项试验，1/88（1.1%）对2/81（2.5%）；比值比0.45，95%可信区间0.04至5.10）。治疗无不良事件达到统计学意义。
没有足够证据支持或反对在钩端螺旋体病治疗中使用抗生素。在因钩端螺旋体病住院的幸存者中，使用抗生素治疗可能使临床疾病持续时间缩短两至四天，尽管该结果无统计学意义。选择使用抗生素时，选择青霉素、多西环素或头孢菌素似乎对死亡率和发热持续时间无影响。抗生素治疗在钩端螺旋体病治疗中的益处仍不明确，尤其是对于严重疾病。需要进一步的临床研究，纳入更广泛的与安慰剂对照的治疗方案。
