Broad-spectrum antibiotics to cover bacteria are usually required while a definite diagnosis of leptospirosis is pending [34]. However, no exact guidelines on the type of antibiotic that should be prescribed exist, and the effectiveness of this approach has yet to be demonstrated. Improper use of antibiotics may lead to the emergence of resistant strains, adverse side effects, and increased medical costs [8]. Thus, this meta-study evaluating the effectiveness of antibiotics for Leptospira was needed. We aimed to identify the best antibiotic option to treat leptospirosis through a comprehensive meta-analysis, searching the literature in English using various related terms.

Despite the worldwide distribution of leptospirosis, only a small number of RCTs evaluating treatments have been performed [27,28,29,30, 32,33,34,35]. Unfortunately, the existing findings are conflicting, with some studies concluding that antibiotic treatment for spirochetes is beneficial [25, 27,28,29, 31, 34,35,36,37], while others have indicated that it is not effective [26, 30, 32, 33]. Some studies have recommended penicillin as the standard antibacterial drug for the treatment of moderate to severe leptospirosis [25, 29], but others found poor efficacy for patients with advanced severe leptospirosis [30, 32, 33]. Cefotaxime and ceftriaxone are third-generation cephalosporins with potential efficacy against leptospirosis. They can effectively inhibit the growth of Leptospira and shorten the duration of leptospirosis [34, 35]. Cephalosporins are preferred over penicillin because they are simpler to administer (ceftriaxone once a day given either intravenously or intramuscularly vs. penicillin four times per day given only intravenously) and more readily available. Also, in many cases of penicillin allergy, it is possible to safely administer a cephalosporin [38, 39]. Another favored antibiotic is doxycycline, which shortens the duration of the disease and has favorable effects on fever, malaise, headache, and myalgia [28, 36]. Doxycycline, which has been recommended and used widely for the prophylaxis and treatment of leptospirosis of mild severity [38, 40, 41], is also active against Rickettsia organisms. Azithromycin, although expensive, may be a good alternative for the treatment of leptospirosis, especially when drug resistance is suspected [36]. Clinical studies suggest that oxytetracycline may have good efficacy in the treatment of leptospirosis and that chloramphenicol has no efficacy [26, 27]. The tissue localization stages of leptospirosis have been identified and organ damage has been observed, but antibiotics may be of little value in regulating the disease process [30]. We found that the studies reporting limited significance for antibiotic treatment of leptospirosis were conducted in patients with severe, jaundiced, and acute renal failure leptospirosis, and we cannot exclude that our results were affected by this selection of patients [26, 30, 32, 33].

Fever is one of the most common symptoms of leptospirosis, and we evaluated the time to fever reduction with antibiotics. Six types of medications (cefotaxime, azithromycin, doxycycline, ceftriaxone, penicillin, and penicillin or ampicillin group) significantly reduced the defervescence time. However, the antibiotics were not effective in reducing the mortality and hospital stay lengths. We speculate that the smaller number of included studies and larger number of included severe leptospirosis cases have an impact on the evaluation of mortality and hospital stay lengths. The main adverse reactions after antibiotic use included Jarisch–Herxheimer reactions, rash, headache, and digestive reactions (nausea, vomiting, diarrhea, and abdominal pain). We found that most of the included articles discussed severe or jaundiced leptospirosis, so we performed a subgroup study on the defervescence time for these patients. Antibiotics were ineffective for treating severe or jaundiced leptospirosis, with the exception of the penicillin or ampicillin group, which showed some efficacy. Severe or advanced disease reflects the second stage of leptospirosis, which is largely considered an immune-mediated event [42, 43]. The use of antibiotic potency at this stage is controversial. The limited number of studies included in our analysis prevents us from drawing definitive conclusions regarding the efficacy of antibiotics in severe/late leptospirosis.

Evaluating antibiotic therapies for leptospirosis is difficult due to the wide range of severity and complications associated with the disease. Mild clinical symptoms may not require antibiotic treatment and may resolve on their own [44]. However, as the disease can potentially evolve to a more severe stage, with life-threatening complications, we recommend that the patient be treated with antibiotics in time after diagnosis. Although antibiotics have no meaningful impact on the lethality of the infection, they can accelerate the defervescence, thereby alleviating the patient’s discomfort and buying time for treatment. Therefore, we recommend the use of cephalosporins, doxycycline, or penicillin for the treatment of leptospirosis. Azithromycin is a potential drug-resistance alternative.

The management of antibiotic therapy for leptospirosis is fraught with problems: (i) the lack of experimental and clinical data, as well as the lack of understanding of the pathophysiology of the disease, has hindered progress in the field of antibiotic treatment of leptospirosis. (ii) The leptospirosis diagnoses are commonly delayed, and some experts recommend that medication should be administered as soon as leptospirosis is suspected [44, 45]. (iii) The use of antibiotics in severe or advanced leptospirosis is controversial, and the terms “severe” and “late” have been used interchangeably with differing definitions. This is probably due to the notion that protracted clinical disease is de facto severe or prone to progressing to severe complications [44,45,46] and has implications for treatment. Prompt diagnoses and initiation of appropriate therapy are important for managing leptospirosis.

The sources of infection included in this paper were from Australia, Malaya, Malaysia, Panama, the Philippines, the West Indies, Brazil, and Thailand. Most of these places are tropical developing countries with a high incidence of leptospirosis. High temperatures, stagnant water, and poor sanitation all contribute to the high incidence of leptospirosis in the tropics. There are more Leptospira serotypes in the tropics and there is no literature on the relationship of these serotypes to treatment and drug resistance. Clinical trials of antibiotic treatment for leptospirosis are few and old, and it is difficult to discern differences in antibiotic treatment and resistance in different regions from the available data. It is hoped that more studies will supplement these deficiencies at a later stage.

This study has limitations. First, while we only included clinical control trials, some of these were not randomized control trials, which may lead to variable results. We did a bias analysis and did not find any bias in the results due to non-RCT data. Second, we did not have access to high-quality data on all drugs and mortality, which may affect efficacy and safety to some extent. Third, there is insufficient RCT data to produce results on the duration of drug treatment, dosage, etc. Lastly, we did find evidence of inconsistency in the results from our indirect comparison analysis. These findings should be interpreted with caution as the low number of pairwise comparisons suggests that there may be significant differences in drug efficacy from a clinical perspective.