Version May 2024
INTRODUCTION — Leptospirosis is a zoonosis of the genus Leptospira. Synonyms include Weil's disease, Weil-Vasiliev disease, Swineherd's disease, rice-field fever, waterborne fever, nanukayami fever, cane-cutter fever, swamp fever, mud fever, Stuttgart disease, and Canicola fever.
The treatment and prevention of leptospirosis will be presented here. The epidemiology, microbiology, clinical manifestations, and diagnosis of this disease are discussed separately. (See "Leptospirosis: Epidemiology, microbiology, clinical manifestations, and diagnosis".)
TREATMENT
Supportive care — In the setting of severe illness due to leptospirosis, supportive care with renal replacement therapy, ventilatory support, and blood products may also be required [1]. In general, such management is the same as organ failure due to other causes of sepsis.
In one Brazilian study of patients with complications of leptospirosis including acute respiratory distress syndrome (ARDS) and acute kidney injury (AKI), daily hemodialysis was associated with lower mortality than alternate-day dialysis [2]. Hypokalemia is common in non-oliguric AKI associated with leptospirosis and should be corrected [3]. Recovery of renal function after the acute period is generally rapid and complete [4-6]. (See "Kidney replacement therapy (dialysis) in acute kidney injury in adults: Indications, timing, and dialysis dose".)
For patients with ARDS, low net fluid intake to prevent pulmonary hemorrhage and lung-protective ventilation practices are appropriate. Extracorporeal membrane oxygenation has been used successfully in cases of leptospirosis with severe pulmonary hemorrhage, though there is no randomized evidence supporting routine use [7]. (See "Acute respiratory distress syndrome: Ventilator management strategies for adults".)
Antimicrobial therapy
Clinical approach
General principles — Most cases of leptospirosis are self-limited in the absence of antimicrobial therapy; however, some patients do develop complications with significant morbidity and mortality. In general, if the illness is severe enough to come to clinical attention and the diagnosis is recognized, antibiotic therapy should be administered to shorten the duration of illness and reduce shedding of organisms in the urine. The approach varies with the clinical presentation.
A Jarisch-Herxheimer reaction may occur following antimicrobial therapy for leptospirosis; this is an acute inflammatory response to clearance of spirochetes from the circulation and is characterized clinically by fever, rigors, and hypotension [8-10]. In one series including 262 patients with leptospirosis, a Jarisch-Herxheimer reaction occurred in 21 percent of cases; risk factors included infection with the L. interrogans serogroup Australis strain and <3 days between symptom onset and antibiotic therapy [11]. (See "Syphilis: Treatment and monitoring", section on 'Jarisch-Herxheimer reaction'.)
Mild disease — For outpatients with mild disease, we favor treatment with doxycycline (adults: 100 mg orally twice daily for 7 days; children: 2 mg/kg per day in two equally divided doses [not to exceed 200 mg daily] for 7 days) or azithromycin (adults: 500 mg orally once daily for three days; children: 10 mg/kg orally on day 1 [maximum dose 500 mg/day] followed by 5 mg/kg/day orally once daily on subsequent days [maximum dose 250 mg/day]). These agents also have activity against rickettsial disease, which can be confused with leptospirosis.
For pregnant women, we favor treatment with either azithromycin (500 mg orally once daily for three days) or amoxicillin (25 to 50 mg/kg in three equally divided doses [maximum 500 mg/dose] for seven days). Azithromycin is preferred over amoxicillin if the differential diagnosis includes rickettsial infection.
Severe disease — For hospitalized adults with severe disease, we favor treatment with penicillin (1.5 million units intravenously [IV] every six hours), doxycycline (100 mg IV twice daily), ceftriaxone (1 to 2 g IV once daily), or cefotaxime (1 g IV every six hours). The duration of treatment in severe disease is usually seven days.
For hospitalized children with severe disease, we favor treatment with penicillin (250,000 to 400,000 units/kg IV per day in four to six divided doses [maximum dose 6 to 12 million units daily]), doxycycline (4 mg/kg IV per day in two equally divided doses [maximum dose 200 mg/day]), ceftriaxone (80 to 100 mg/kg IV once daily [maximum dose 2 g daily]), or cefotaxime (100 to 150 mg/kg IV per day in three to four equally divided doses). For children who cannot tolerate the above agents, azithromycin is an acceptable alternative agent (10 mg/kg IV on day 1 [maximum dose 500 mg/day], followed by 5 mg/kg/day IV once daily on subsequent days [maximum dose 250 mg/day]). The duration of treatment in severe disease is usually seven days.
Tetracycline antibiotics may cause permanent tooth discoloration for children <8 years if used repeatedly. However, doxycycline binds less readily to calcium than other tetracyclines and may be used for ≤21 days in children of all ages [12].
Pregnant women with severe leptospirosis may be treated with penicillin, ceftriaxone, cefotaxime, or azithromycin. Doxycycline appears to be safer in pregnancy than other tetracyclines; it should be considered if the diagnosis of leptospirosis is not certain and murine typhus is a possible alternative diagnosis (since murine typhus does not respond as well to azithromycin as to doxycycline) [13].
Penicillin and cephalosporins lack activity against rickettsiaceae and so should be avoided in circumstances in which leptospirosis cannot be definitively distinguished from rickettsial infection [14]. Intravenous doxycycline is an appropriate therapy for treatment of severely ill patients in areas endemic for both leptospirosis and rickettsial infection.
Efficacy — Whether antimicrobials produce a beneficial effect in leptospirosis remains unclear, mainly due to the paucity of clinical trial evidence in the disease. A recent meta-analysis of 10 clinical trials (the most recent from 2007) found that antimicrobial therapy did not affect mortality, the incidence of oliguria/anuria, the need for dialysis treatment, time to creatinine normalization, incidence of jaundice, or liver function normalization time [15]. In a retrospective case-control study from New Caledonia, risk factors for the development of severe leptospirosis included a delay of >2 days following the start of symptoms in the initiation of antibiotic treatment, suggesting that antibiotics may reduce the likelihood of progression to severe disease in some cases [16].
Activity against leptospires has been observed in vitro and in animal models for penicillins, cephalosporins, tetracyclines, chloramphenicol, fluoroquinolones, macrolides, and telithromycin, and in vitro studies have demonstrated that carbapenems and aztreonam also have excellent activity against leptospires [17-21]. Antibiotic susceptibility testing is not done routinely as it is difficult to do and, thus far, resistance does not appear to be a problem, based on susceptibility studies that have been done as well as favorable clinical response to the antibiotics generally used for treatment. The development of a new solid media (LVW agar) for leptospirosis may facilitate more routine testing, which will enable quicker identification of drug resistance should it arise in the setting of inadequate clinical response [22].
Studies from Thailand have noted comparable efficacy for penicillin, ceftriaxone, cefotaxime, and doxycycline for treatment of leptospirosis. In one study of 173 patients with severe leptospirosis, penicillin G (1.5 million units IV every six hours for seven days) was compared with ceftriaxone (1 g IV every 24 hours for seven days) [23]. In another study, 540 patients with suspected severe leptospirosis (264 serologically confirmed) were randomized to treatment with cefotaxime (1 g IV every six hours for seven days), penicillin G (1.5 million units IV every six hours for seven days), or doxycycline (200 mg initially followed by 100 mg IV every 12 hours for seven days) [14]. In both studies, all regimens had similar efficacy for leptospirosis but did not include a placebo arm [24].
In another study, 296 patients in Thailand with suspected leptospirosis or scrub typhus were randomized to receive doxycycline (200 mg initially followed by 100 mg orally every 12 hours for seven days) or azithromycin (2 g on day 1 followed by 1 g daily for two more days) [25]. There was no difference in fever clearance times; oral azithromycin was better tolerated than doxycycline.
Role of corticosteroids and plasmapheresis — Use of intravenous corticosteroid therapy has been proposed given the vasculitic nature of severe leptospirosis, particularly in the setting of pulmonary involvement; thus far, there is insufficient evidence for routine use of corticosteroids. Some reports have suggested a possible benefit to use of steroids as an adjunct to antibiotic therapy in severe disease [26-30]; further study is needed.
Plasmapheresis has also been used in severe leptospirosis and there is some nonrandomized evidence suggesting benefit [31,32], but there is no high-quality randomized evidence to justify routine use [7].
PREVENTION — Several human vaccines have been developed; all are serovar specific, developed for specific epidemiologic circumstances. None is widely available. Prevention measures include avoiding potential sources of infection, administration of prophylaxis for individuals at high risk of exposure, and animal vaccination.
The most important control measures for preventing human leptospirosis include avoiding potential sources of infection such as stagnant water and animal farm water runoff, rodent control, and protection of food from animal contamination.
Antimicrobial prophylaxis for individuals at high risk of exposure may be useful in some settings, although the evidence for this is weak as clinical studies have been heterogenous in design and mostly underpowered [15]. Among more than 700 individuals in the Andaman Islands (a highly endemic setting in Southeast Asia where outbreaks of leptospirosis related to flooding are common) randomized to prophylaxis with doxycycline 200 mg orally weekly or placebo, clinical infection rates were lower among those who received doxycycline (3.1 versus 6.8 percent), although there was no difference in seroconversion rates [33]. In another study including more than 900 soldiers deployed for jungle training in Panama, fewer cases of leptospirosis were observed among those who received doxycycline prophylaxis (200 mg orally every week for two to three weeks and at the end of exposure) compared with placebo (1 versus 20 cases) [34].
Vaccination of domestic and farm animals against leptospirosis can provide variable levels of protection [35-38]. Some immunized animals become infected and excrete leptospires in their urine.
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Leptospirosis (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Clinical approach – The majority of leptospirosis infections are self-limiting. Antimicrobial therapy shortens the duration of illness and reduces shedding of the organism in the urine. (See 'Clinical approach' above.)
●Mild leptospirosis – We suggest administration of antimicrobial therapy for treatment of patients with mild leptospirosis (Grade 2B). We favor treatment with oral doxycycline or oral azithromycin; these agents are also effective for rickettsial infections, which can be difficult to distinguish from leptospirosis. Doxycycline should be avoided in pregnant women; reasonable alternatives include azithromycin or amoxicillin. (See 'Clinical approach' above.)
●Severe leptospirosis – We recommend administration of antimicrobial therapy for treatment of patients with severe leptospirosis (Grade 1B). Parenteral penicillin, doxycycline, and third-generation cephalosporins are all acceptable options. Penicillin and cephalosporins lack activity against rickettsiaceae and so should not be used for circumstances in which leptospirosis cannot be definitively distinguished from rickettsial infection. (See 'Antimicrobial therapy' above.)
●Prevention – There is no human vaccine widely available. Prevention measures include avoiding potential sources of infection, administration of prophylaxis for individuals at high risk of exposure, and animal vaccination. Prophylaxis with doxycycline is reasonable for individuals with high likelihood for exposure to leptospires in endemic environments over a defined period. (See 'Prevention' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Dr. E Dale Everett, who contributed to an earlier version of this topic review.
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