Treatment and prevention of leptospirosis

Author:Nick Day, DM, FRCPSection Editors:Stephen B Calderwood, MDMorven S

Edwards, MDDeputy Editor:Elinor L Baron, MD, DTMH
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Apr 2017. | This topic last updated: Mar 22,
2017.
INTRODUCTION Leptospirosis is a zoonosis caused by the spirochetes 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 "Epidemiology, microbiology, clinical manifestations, and diagnosis of
leptospirosis".)
TREATMENT Most cases of leptospirosis are self-limited in the absence of
antimicrobial therapy, although a proportion of patients do develop severe 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.
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 significantly 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].
For patients with ARDS, low net fluid intake to prevent pulmonary hemorrhage and lung-
protective ventilation practices are appropriate. (See "Renal replacement therapy
(dialysis) in acute kidney injury in adults: Indications, timing, and dialysis dose" and
"Mechanical ventilation of adults in acute respiratory distress syndrome".)
Antimicrobial therapy
Clinical approach Symptomatic patients presenting for medical attention should
receive antimicrobial therapy to shorten the duration of illness and reduce shedding of
organisms in the urine. We suggest the following approach, which varies with the clinical
presentation.
For outpatients with mild disease, we favor treatment with doxycycline (adults: 100 mg
orally twice daily for 7 days; children 8 years of age: 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 children <8 years and pregnant women, we favor
treatment with either azithromycin or amoxicillin (25 to 50 mg/kg in three equally
divided doses [maximum 500 mg/dose] for 7 days).
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). Doxycycline should be avoided in children <8 years of age unless there
are no other treatment options. The duration of treatment in severe disease is usually
seven days.
For hospitalized children <8 years of age with severe disease and beta-lactam
hypersensitivity, we favor therapy with azithromycin (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]).
Pregnant women with severe leptospirosis may be treated with penicillin, ceftriaxone,
cefotaxime, or azithromycin; doxycycline should not be used.
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 [7-9]. 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. [10].
Penicillin and cephalosporins lack activity against rickettsiae and so should be avoided in
circumstances in which leptospirosis cannot be definitively distinguished from rickettsial
infection [11]. 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 mild illness remains
controversial [12-15]. A Cochrane review noted that antimicrobial therapy does not affect
mortality, though there was a nonsignificant trend toward quicker resolution of clinical
illness (by two to four days) with treatment [16]. 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 [17].
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 [18-22]. 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 [23].
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) [24]. 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)
[11]. In both studies, all regimens had similar efficacy for leptospirosis [16].
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 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.
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. 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 weekly doxycycline 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 [31]. 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) [32].
Vaccination of domestic and farm animals against leptospirosis can provide variable
levels of protection [33-36]. Some immunized animals become infected and excrete
leptospires in their urine.
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Basics topic (see "Patient education: Leptospirosis (The Basics)")

SUMMARY AND RECOMMENDATIONS

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.)

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 disease, which can be difficult
to distinguish from leptospirosis. Doxycycline should be avoided in children <8 years of
age unless no other treatment options are available and in pregnant women; reasonable
alternatives include azithromycin or amoxicillin. (See 'Clinical approach' above.)

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 rickettsiae and so should not be used for circumstances in which leptospirosis
cannot be definitively distinguished from rickettsial infection. Doxycycline should be
avoided in children <8 years of age (unless no other treatment options are available) and
in pregnant women. (See 'Antimicrobial therapy' above.)

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 editorial staff at UpToDate would like to acknowledge

Dr. E Dale Everett, who contributed to an earlier version of this topic review.
Use of UpToDate is subject to the Subscription and License Agreement.
REFERENCES
1 Wiwanitkit V. Comparison between blood exchange and classical therapy for acute
renal failure in Weil's disease: appraisal on Thai reports. Nephrology (Carlton)
2006; 11:481.
2 Andrade L, Cleto S, Seguro AC. Door-to-dialysis time and daily hemodialysis in
patients with leptospirosis: impact on mortality. Clin J Am Soc Nephrol 2007;
2:739.
3 Abdulkader RC, Seguro AC, Malheiro PS, et al. Peculiar electrolytic and hormonal
abnormalities in acute renal failure due to leptospirosis. Am J Trop Med Hyg
1996; 54:1.
4 Daher Ede F, Zanetta DM, Abdulkader RC. Pattern of renal function recovery after
leptospirosis acute renal failure. Nephron Clin Pract 2004; 98:c8.
5 Herath NJ, Kularatne SA, Weerakoon KG, et al. Long term outcome of acute kidney
injury due to leptospirosis? A longitudinal study in Sri Lanka. BMC Res Notes
2014; 7:398.
6 Andrade L, de Francesco Daher E, Seguro AC. Leptospiral nephropathy. Semin
Nephrol 2008; 28:383.
7 Guerrier G, D'Ortenzio E. The Jarisch-Herxheimer reaction in leptospirosis: a
systematic review. PLoS One 2013; 8:e59266.
8 Tunbridge AJ, Dockrell DH, Channer KS, McKendrick MW. A breathless triathlete.
Lancet 2002; 359:130.
9 Takamizawa S, Gomi H, Shimizu Y, et al. Leptospirosis and Jarisch-Herxheimer
reaction. QJM 2015; 108:967.
10 Guerrier G, Lefvre P, Chouvin C, D'Ortenzio E. Jarisch-Herxheimer Reaction
Among Patients with Leptospirosis: Incidence and Risk Factors. Am J Trop Med
Hyg 2017.
11 Suputtamongkol Y, Niwattayakul K, Suttinont C, et al. An open, randomized,
controlled trial of penicillin, doxycycline, and cefotaxime for patients with severe
leptospirosis. Clin Infect Dis 2004; 39:1417.
12 McClain JB, Ballou WR, Harrison SM, Steinweg DL. Doxycycline therapy for
leptospirosis. Ann Intern Med 1984; 100:696.
13 Watt G, Padre LP, Tuazon ML, et al. Placebo-controlled trial of intravenous
penicillin for severe and late leptospirosis. Lancet 1988; 1:433.
14 Edwards CN, Nicholson GD, Hassell TA, et al. Penicillin therapy in icteric
leptospirosis. Am J Trop Med Hyg 1988; 39:388.
15 Costa E, Lopes AA, Sacramento E, et al. Penicillin at the late stage of
leptospirosis: a randomized controlled trial. Rev Inst Med Trop Sao Paulo 2003;
45:141.
16 Brett-Major DM, Coldren R. Antibiotics for leptospirosis. Cochrane Database
Syst Rev 2012; :CD008264.
17 Tubiana S, Mikulski M, Becam J, et al. Risk factors and predictors of severe
leptospirosis in New Caledonia. PLoS Negl Trop Dis 2013; 7:e1991.
18 Murray CK, Hospenthal DR. Determination of susceptibilities of 26 Leptospira
sp. serovars to 24 antimicrobial agents by a broth microdilution technique.
Antimicrob Agents Chemother 2004; 48:4002.
19 Moon JE, Ellis MW, Griffith ME, et al. Efficacy of macrolides and telithromycin
against leptospirosis in a hamster model. Antimicrob Agents Chemother 2006;
50:1989.
20 Alt DP, Zuerner RL, Bolin CA. Evaluation of antibiotics for treatment of cattle
infected with Leptospira borgpetersenii serovar hardjo. J Am Vet Med Assoc
 2001; 219:636.
21 Griffith ME, Moon JE, Johnson EN, et al. Efficacy of fluoroquinolones against
Leptospira interrogans in a hamster model. Antimicrob Agents Chemother 2007;
51:2615.
22 Ressner RA, Griffith ME, Beckius ML, et al. Antimicrobial susceptibilities of
geographically diverse clinical human isolates of Leptospira. Antimicrob Agents
Chemother 2008; 52:2750.
23 Wuthiekanun V, Amornchai P, Paris DH, et al. Rapid isolation and susceptibility
testing of Leptospira spp. using a new solid medium, LVW agar. Antimicrob
Agents Chemother 2013; 57:297.
24 Panaphut T, Domrongkitchaiporn S, Vibhagool A, et al. Ceftriaxone compared
with sodium penicillin g for treatment of severe leptospirosis. Clin Infect Dis
2003; 36:1507.
25 Phimda K, Hoontrakul S, Suttinont C, et al. Doxycycline versus azithromycin for
treatment of leptospirosis and scrub typhus. Antimicrob Agents Chemother 2007;
51:3259.
26 Kularatne SA, Budagoda BD, de Alwis VK, et al. High efficacy of bolus
methylprednisolone in severe leptospirosis: a descriptive study in Sri Lanka.
Postgrad Med J 2011; 87:13.
27 Thunga G, John J, Sam KG, et al. Role of high-dose corticosteroid for the
treatment of leptospirosis-induced pulmonary hemorrhage. J Clin Pharmacol
2012; 52:114.
28 Minor K, Mohan A. Severe leptospirosis: treatment with intravenous
corticosteroids and supportive care. Am J Emerg Med 2013; 31:449.e1.
29 Azevedo AF, Miranda-Filho Dde B, Henriques-Filho GT, et al. Randomized
controlled trial of pulse methyl prednisolone placebo in treatment of pulmonary
involvement associated with severe leptospirosis. [ISRCTN74625030]. BMC
Infect Dis 2011; 11:186.
30 Rodrigo C, Lakshitha de Silva N, Goonaratne R, et al. High dose corticosteroids
in severe leptospirosis: a systematic review. Trans R Soc Trop Med Hyg 2014;
108:743.
31 Sehgal SC, Sugunan AP, Murhekar MV, et al. Randomized controlled trial of
doxycycline prophylaxis against leptospirosis in an endemic area. Int J
Antimicrob Agents 2000; 13:249.
32 Takafuji ET, Kirkpatrick JW, Miller RN, et al. An efficacy trial of doxycycline
chemoprophylaxis against leptospirosis. N Engl J Med 1984; 310:497.
33 Andr-Fontaine G, Branger C, Gray AW, Klaasen HL. Comparison of the
efficacy of three commercial bacterins in preventing canine leptospirosis. Vet Rec
2003; 153:165.
34 Hancock GA, Wilks CR, Kotiw M, Allen JD. The long term efficacy of a hardjo-
pomona vaccine in preventing leptospiruria in cattle exposed to natural challenge
with Leptospira interrogans serovar hardjo. Aust Vet J 1984; 61:54.
35 Rinehart CL, Zimmerman AD, Buterbaugh RE, et al. Efficacy of vaccination of
cattle with the Leptospira interrogans serovar hardjo type hardjoprajitno
component of a pentavalent Leptospira bacterin against experimental challenge
with Leptospira borgpetersenii serovar hardjo type hardjo-bovis. Am J Vet Res
 2012; 73:735.
36 Sykes JE, Hartmann K, Lunn KF, et al. 2010 ACVIM small animal consensus
statement on leptospirosis: diagnosis, epidemiology, treatment, and prevention. J
Vet Intern Med 2011; 25:1.