Medscape Leptospirosis

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emedicine.medscape.com
Leptospirosis
Updated: Jun 13, 2018
Author: Sandra G Gompf, MD, FACP, FIDSA; Chief Editor: Michael Stuart Bronze, MD
Overview
Practice Essentials
Leptospirosis is an infectious disease of humans and animals that is caused by pathogenic spirochetes of the genus Leptospira
(see the image below). It is considered the most common zoonosis in the world and is associated with rodents in settings of
poor sanitation, agricultural occupations, and increasingly "adventure" sports or races involving fresh water, mud, or soil
exposure. Leptospirosis is endemic in most areas where dengue virus is transmitted and may be mistaken for dengue, which is
typically more common. It is important to consider leptospirosis when dengue is diagnosed in a severely ill patient, because
early antibiotics are beneficial in the treatment of leptospirosis and are not given for dengue virus infection. Co-infection occurs
in up to 8% of cases.
A scanning electron micrograph depicting Leptospira atop a 0.1-µm polycarbonate filter. (This image is in the public domain
and thus free of any copyright restrictions. Courtesy of the Centers for Disease Control/Rob Weyant)
Signs and symptoms

Leptospirosis ranges in severity from a mild illness suggesting a viral infection to a multisystemic syndrome with unique
features. It is characterized by sudden onset of the following:
Fever (38-40°C)
Rigors
Headache, retro-orbital pain, photophobia
Muscle pain localized to the calf and lumbar areas
Conjunctival suffusion
Dry cough
Nausea and vomiting, diarrhea
More severe disease manifests as icteric leptospirosis, also known as Weil disease, with the following features:
Icterus or frank jaundice
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Renal failure with oliguria
Hemorrhagic features
Systemic inflammatory syndrome or shock
See Clinical Presentation for more detail.
Diagnosis
Laboratory studies used to screen for the diagnosis of leptospirosis include the following:
Leptospira immunoglobulin M (IgM) ELISA or IgM/immunoglobulin G (IgG) enzyme-linked immunoabsorbent assay

(ELISA), including rapid diagnostic kits usable in the field
Real-time DNA polymerase chain reaction (PCR) of blood, urine, and cerebrospinal fluid (CSF)
Laboratory studies used to confirm the diagnosis of leptospirosis include the following:
Microscopic agglutination testing (MAT; criterion standard for serologic identification of leptospires, available at reference
laboratories)
Single titer ≥1:200 or 4-fold rise in serum drawn between the first and fourth week of illness is considered diagnostic
DNA PCR of blood, urine, CSF, tissue
Culture of leptospires from body fluids or tissue (criterion standard, but requires specific media and several weeks’
incubation, thus usually limited to reference laboratory)
Studies to determine the extent of organ involvement and severity of complications may include the following, depending on the
clinical presentation:
Complete blood cell (CBC) count

Renal function studies
Coagulation studies
Liver function studies
CSF analysis
Chest radiography
Biliary tract ultrasonography
Electrocardiography (ECG)
See Workup for more detail.
Management
Antibiotic therapy in the treatment of mild leptospirosis is typically unnecessary, since it is often self-limited, and most cases
resolve without medical attention. Oral antibiotics shorten the course of illness and, perhaps most importantly, reduce and
shorten urinary excretion of leptospires. Prophylaxis may be used in the setting of epidemics. If used, antibiotic treatment may
include the following:
Doxycycline
Ampicillin or amoxicillin
Azithromycin or clarithromycin
Fluoroquinolone such as ciprofloxacin or levofloxacin
Antibiotics for leptospirosis requiring hospitalization include the following:
Intravenous penicillin G
Intravenous third-generation cephalosporins (cefotaxime and ceftriaxone)
Intravenous ampicillin or amoxicillin (second-line agents)
Intravenous erythromycin (in penicillin-allergic pregnant women)
Patients with severe cases of leptospirosis also require supportive therapy and careful management of renal, hepatic,
hematologic, and central nervous system complications. If renal failure ensues, early initiation of hemodialysis or peritoneal
dialysis may reduce mortality by nearly two-thirds. Additional supportive care may include inotropic agents, diuretics, or
ophthalmic drops.
See Treatment and Medication for more detail.
Background
Leptospirosis is an infectious disease of humans and animals that is caused by pathogenic spirochetes of the genus Leptospira.
It is considered the most common zoonosis in the world.[1] Leptospirosis is distributed worldwide (sparing the polar regions) but
is most common in the tropics.
Leptospirosis has been recognized as a re-emerging infectious disease among animals and humans[2] and has the potential to
become even more prevalent with advancing climate change and related trends.[3] By 2100, various climate models project that
global temperatures will rise by 2°F to 11.5°F, depending on trends in future greenhouse gas emissions.[4]
Leptospira species infect a wide range of animals, including mammals, birds, amphibians, and reptiles. Part of its life cycle is a
chronic carrier state in some animals, in which the leptospires spread hematogenously, colonize the proximal renal tubules, and
are shed via urine into the environment. This may be fairly asymptomatic such that the animal becomes a chronic carrier and
environmental reservoir. Humans can shed leptospires for only a limited time and are therefore considered accidental hosts
Rats, dogs, and ungulates, however, can chronically shed leptospires. The organism is typically transmitted via exposure of
mucous membranes or abraded skin to the body fluid of an acutely infected animal or by exposure to soil or fresh water
contaminated with the urine of a chronic carrier.
Occupational exposure probably accounts for 30-50% of human cases of leptospirosis. The main occupational groups at risk
include farm workers, veterinarians, pet shop owners, field agricultural workers, abattoir workers, plumbers, meat handlers and
slaughterhouse workers, coal miners, workers in the fishing industry, military troops, milkers, and sewer workers.
Although leptospirosis continues to be predominantly an occupational disease, in recent decades it has also increasingly been
recognized as a disease of recreation. The disease may be acquired during "adventure racing," travel, or sporting events that
involve fresh water or hiking (eg, "mud runs").[5, 6, 7, 8, 54] Urban dwellers in economically deprived areas may contract the
disease through exposure to rat urine.[11]
The incidence of leptospirosis is rising in domestic dogs, especially those that live on dairy farms or roam in rural areas.
Leptospirosis in a pet increases the risk of human transmission if there is contact with the urine, feces, birth products, or tissues
of the animal. Other routine types of contact and care pose little risk. More exotic pets such as rodents have transmitted
leptospirosis to owners, and reptiles can also act as chronic carriers.
Widespread flooding may lead to epidemic spread of leptospirosis in large populations.[9] Hurricanes in subtropical and tropical
areas pose a risk of leptospirosis outbreaks. Flooding on a smaller scale may also lead to individuals contracting the disease.
[10]
In 90% of cases, leptospirosis manifests as an acute febrile illness with a biphasic course and an excellent prognosis.
Nonspecific signs and symptoms of leptospirosis (eg, fever, headache, nausea, vomiting) are often confused with viral illness.
In 10% of cases, the presentation is more dramatic, and the infection has an overall case fatality rate of 5%-10%. Known as
Weil disease or icteric leptospirosis, the classic definition of this form of leptospirosis includes fever, jaundice, renal failure, and
hemorrhage. Other organ systems (ie, pulmonary system, cardiac system, central nervous system) are also frequently involved.
Risk factors associated with higher mortality risk include old age, alteration of mental status, and pulmonary alveolar
hemorrhage. (See Clinical Presentation.)
Treatment of leptospirosis should be started as soon as possible. Treatment is begun empirically in patients with a plausible
exposure history and compatible symptoms, as culture times for Leptospira are long and recovery rates are low. The criterion
standard for serologic identification of leptospires, microscopic agglutination testing (MAT), is available only at reference
laboratories. Paired acute and convalescent serum specimens can provide delayed confirmation of the diagnosis.
In uncomplicated infections that do not require hospitalization, oral doxycycline has been shown to decrease duration of fever
and most symptoms. In hospitalized patients, intravenous penicillin G has been the treatment of choice. Patients with severe
leptospirosis (Weil disease) require supportive therapy and careful management of renal, hepatic, hematologic, and central
nervous system complications. (See Treatment.)
Historical background
In ancient China, a disease that was certainly leptospirosis was recognized as an occupational hazard of rice harvesters. In
Japan, leptospirosis was called akiyami, or autumn fever, a term still used for this disease.[12]
In the West, leptospirosis was described by Larrey in 1812 as fièvre jaune among Napoleon's troops at the siege of Cairo. The
disease was initially believed to be related to the plague but not as contagious. Throughout the remainder of the 19th century,
leptospirosis was known in Europe as bilious typhoid.
Leptospirosis was recognized as an occupational disease of sewer workers in 1883. In 1886, Adolph Weil published his historic
paper describing the most severe form of leptospirosis that would be later known as Weil disease. Weil described the clinical
manifestations in 4 men who had severe jaundice, fever, and hemorrhage with renal involvement.[13]
In 1907, Stimson used special staining techniques in the postmortem examination of a kidney from a person with Weil disease
and found a spiral organism with hooked ends, which was named Spirochaeta interrogans because its shape resembled that of
a question mark. Inada et al identified the causal agent of infectious jaundice in Japan in 1916, naming the organism
Spirochaeta icterohaemorrhagiae.[13]
Pathophysiology
Leptospires are thin, coiled, gram-negative, aerobic organisms 6-20 µm in length (see the image below). They are motile, with
hooked ends and paired axial flagella (one on each end), enabling them to burrow into tissue. Motion is marked by continual
spinning on the long axis. They are unique among the spirochetes in that they can be isolated on artificial media.
A scanning electron micrograph depicting Leptospira atop a 0.1-µm polycarbonate filter. (This image is in the public domain
and thus free of any copyright restrictions. Courtesy of the Centers for Disease Control/Rob Weyant)
Leptospires belong to the order Spirochaetales and the family Leptospiraceae. Traditionally, the organisms are classified based
on antigenic differences in the lipopolysaccharide envelopes that surround the cell wall. Serologic detection of these differences,
therefore, is based on identifying serovars within each species. Based on this system, the genus Leptospira contains two
species: the pathogenic Leptospira interrogans, with at least 218 serovars; and the nonpathogenic, free-living, saprophytic
Leptospira biflexa, which has at least 60 serovars.
Current studies that classify the organisms based on DNA relatedness identify at least 7 pathogenic species of leptospires.
However, organisms that are identical serologically may be different genetically, and organisms with the same genetic makeup
may differ serologically. Therefore, some authors feel that the traditional serologic system is the most useful from a diagnostic
and epidemiologic standpoint.
Animal reservoirs
Most leptospiral serovars have a primary reservoir in wild mammals, which continually reinfect domestic populations. The
organism affects at least 160 mammalian species and has been recovered from rats, swine, dogs, cats, raccoons, cattle,
mongooses, and bandicoots.[14, 15] The most important reservoirs are rodents, and rats are the most common source
worldwide. In the United States, important leptospiral sources include dogs, livestock, rodents, and wild animals.
Many serovars are associated with particular animals. For example, L pomona and L interrogans are seen in cattle and pigs; L
grippotyphosa is seen in cattle, sheep, goats, and voles; L ballum and L icterohaemorrhagiae are associated with rats and mice;
and L canicola is associated with dogs. Other important serotypes include L autumnalis, L hebdomidis, and L australis.
Leptospiral species' and serogroups' host animals vary from region to region. Individual animals may carry several serovars.
Leptospirosis in animals is often subclinical. Leptospires may persist for long periods in the renal tubules of animals by
establishing a symbiotic relationship with little or no evidence of disease or pathological changes in the kidney. As a result,
animals that serve as reservoirs of host-adapted serovars can shed high concentrations of the organism in their urine without
showing clinical evidence of disease.
This leptospiruria in animals often occurs for months after the initial infection. Leptospiruria also has been found to occur in
healthy immunized dogs. Leptospiruria in humans is more transient, rarely lasting more than 60 days. Humans and nonadapted
animals are incidental hosts. With rare exceptions, man represents a dead end in the chain of infection because person-to-
person spread of the disease is rare.
Transmission and incubation
Urinary shedding of organisms from infected animals is the most important source of these bacterial pathogens. Contact with
the organism via infected urine or urine-contaminated media results in human infection. Such media include contaminated water
and food, as well as animal bedding, soil, mud, and aborted tissue. Under favorable conditions, leptospires can survive in fresh
water for as many as 16 days and in soil for as many as 24 days.[16]
Leptospires are believed to enter the host through the following:
Abrasions in healthy skin
Animal and rodent bites
Sodden and waterlogged skin
Mucous membranes or conjunctiva
Lungs (after inhalation of aerosolized body fluid)[17]
The placenta during pregnancy
Virulent organisms in a susceptible host gain rapid access to the bloodstream through the lymphatics, resulting in leptospiremia
and spread to all organs, but particularly the liver and kidney. The incubation period is usually 5-14 days but has been described
from 72 hours to a month or more.
Pathologic effects
Although direct invasion of tissue may cause some pathologic effects, researchers note that the marked degree of multiorgan
tissue injury appears inconsistent with the number of leptospires found on microscopic examination of tissue. Other mediators
induced by the leptospire are the suspected causes of the disease's various manifestations. Research has suggested endotoxin,
hemolysin, and lipase as possible sources of pathogenicity. However, the true mechanism of host tissue injury remains unclear
and likely involves a complex set of interactions.
The most consistent pathologic finding in leptospirosis is vasculitis of capillaries, manifested by endothelial edema, necrosis,
and lymphocytic infiltration. Capillary vasculitis is found in every affected organ system. The resulting loss of red blood cells and
fluid through enlarged junctions and fenestrae, which cause secondary tissue injury, probably accounts for many of the clinical
findings.
In the kidneys, leptospires migrate to the interstitium, renal tubules, and tubular lumen, causing interstitial nephritis and tubular
necrosis. Capillary vasculitis is readily identified. Although the glomeruli are spared, the progression from normal renal function
to decreased glomerular filtration rate to renal failure requiring dialysis can be rapid. Renal failure is usually due to tubular
damage, but hypovolemia from dehydration and from altered capillary permeability can also contribute to renal failure.
Liver involvement is marked by centrilobular necrosis and Kupffer cell proliferation. Jaundice may occur as a result of
hepatocellular dysfunction.
Pulmonary involvement is secondary to alveolar and interstitial vascular damage resulting in hemorrhage. This complication is
considered to be the major cause of leptospirosis-associated death.
Cardiac lesions have been identified in postmortem examinations. In an autopsy series of fatal cases of leptospirosis in Mumbai,
India in 2005, involvement of the cardiovascular system was found in 41 of 44 cases. Interstitial myocarditis was the
predominant feature on histopathological examination. These authors suggested that leptospirosis be viewed as an infective
systemic vasculitis.[18]
Hemorrhage, focal necrosis, and inflammatory infiltration have been documented within the adrenal gland. Although these
complications do not appear clinically, some researchers speculate that adrenal insufficiency may mediate, in part, the final
vascular collapse associated with fatal leptospirosis.
The skin is affected by epithelial vascular insult. Skeletal muscle involvement is secondary to edema, myofibril vacuolization,
and vessel damage. Muscular microcirculation is impaired and capillary permeability is increased, with resultant fluid leakage
and circulatory hypovolemia.
The damage to the vascular system as a whole can result in capillary leakage, hypovolemia, and shock. Patients with
leptospirosis may develop disseminated intravascular coagulation (DIC), hemolytic uremic syndrome (HUS), or thrombotic
thrombocytopenic purpura (TTP). Thrombocytopenia indicates severe disease and should raise suspicion for a risk of bleeding.
[19, 20]
If the host survives the acute infection, septicemia and multiplication of the organism persist until the development of opsonizing
immunoglobulin in the plasma, followed by rapid immune clearance. Although the systemic immune response may eliminate the
organism from the body, it may also lead to a symptomatic inflammatory reaction that can produce secondary end-organ injury.
Despite clearance from the blood, leptospires may remain in immunologically privileged sites, including the renal tubules, brain,
and aqueous humor of the eye, for weeks to months. Persistent leptospires in the eye occasionally lead to chronic or recurrent
uveitis. In humans, leptospires in the renal tubules and resulting leptospiruria rarely persist longer than 60 days.
Etiology
Leptospirosis is caused by spiral bacteria that belong to the genus Leptospira, the family Leptospiraceae, and the order
Spirochaetales. These spirochetes are finely coiled, thin, motile, obligate, slow-growing aerobes.
The nomenclature system used to organize leptospires has been revised, making review of the literature often confusing. The
traditional system divided the genus into 2 species: the pathogenic Leptospira interrogans and the nonpathogenic Leptospira
biflexa. These species were divided further into serogroups, serovars, and strains based on shared antigens. L interrogans
included more than 250 serovars.
The current classification system is based on DNA homology and recognizes the heterogeneity of the classic leptospires,
dividing L interrogans and L biflexa into 20 named species.[21] Within these species, leptospires are further grouped by
serogroups, serovars, and strains on the basis of microscopic agglutination testing (MAT).
Serologic grouping may, however, cross DNA-based species boundaries, and both pathogenic and nonpathogenic serovars may
be found within the same species. Although certain species (eg, L interrogans) have a classic association with Weil disease,
knowledge of the species type does not necessarily help predict disease severity.
Particular serovars may be associated with specific clinical manifestations. For example, a characteristic pretibial erythematous
rash is seen in patients with L autumnalis infection, and gastrointestinal symptoms predominate in patients infected with L
grippotyphosa.
Nevertheless, any leptospiral serovar can lead to the signs and symptoms seen with this disease. For example, jaundice occurs
in 83% of patients with L icterohaemorrhagiae infection and in 30% of patients infected with L pomona. Aseptic meningitis
commonly occurs in those infected with L pomona or L canicola.
Transmission of leptospires to humans typically occurs by invasion across mucosal surfaces or nonintact skin. Infection may
occur via direct contact with infected animals or their tissues or urine or through contact with contaminated water and soil.
Epidemiology
United States statistics
Leptospirosis, as a clinical entity, is underdiagnosed and underreported. From 1985-1994, the reported annual incidence ranged
from 0.02-0.04 cases per 100,000 persons. In 1994, 38 leptospirosis cases were reported nationwide, and the Council of State
and Territorial Epidemiologists recommended removing leptospirosis from the list of notifiable diseases.[22]
Because reliable diagnostic testing was not readily available and organized reporting had not resulted in implementation of
methods to control the disease, many states stopped reporting leptospirosis. Nevertheless, numerous states, including Hawaii,
continued to report. In 2013, leptospirosis was reinstated as a nationally notifiable disease.
In Hawaii, which reports the highest annual occurrence rate, 405 suspected cases of leptospirosis were reported between June
1998 and February 1999; 61 of those cases were confirmed.[23] Case numbers widely varied from island to island within the
state. Incidence rates ranged from 2.3-40.2 cases per 100,000 persons, with the highest numbers of cases on Kauai and
Hawaii.
These reported cases starkly contrast with the prevalence rates found under active surveillance.[24] Using active surveillance
measures, Hawaiian researchers projected the state's true local incidence at approximately 128 cases per 100,000 persons.
Major risk factors identified in Hawaii include the use of water catchment systems, wild pig hunting, and the presence of skin
wounds.
An estimated 100-200 cases are identified annually in the United States, with about 50% of cases occurring in Hawaii. Endemic
canine leptospirosis is becoming more common in the United States, and California has seen a re-emergence of disease since
2000. Over the past 20 years, epidemiology has begun to shift from primarily recreational water exposures to an increasing
number of occupational exposures related to farm and agricultural activities.[25]
Although less dramatic and often unrecognized, people with no obvious risk factor have significantly higher background infection
rates than reports often indicate. Approximately 30% of children in urban Detroit[26] and 16% of adults in Baltimore[27]
demonstrated serologic evidence of past infection. The Detroit study also showed correlation between degree of rat infestation
and seropositivity rates. This finding suggests rats are major, if not the most important, vectors for human leptospirosis in the
mainland United States.
Leptospirosis has a seasonal incidence. Most cases occur during the rainy season in the tropics and during the late summer or
early fall in Western countries, when the soil is moist and alkaline. The leptospires from infected animals survive best in fresh
water, damp alkaline soil, vegetation, and mud with temperatures higher than 22°C.
International statistics
Leptospirosis is a ubiquitous disease found throughout the world. Specific serovars vary with locality. The incidence varies from
sporadic in temperate zones to endemic in a few tropical countries. Up to 80% of individuals in tropical areas are estimated to
have positive seroconversion rates, indicating either past or present infection. Although leptospirosis is generally associated with
tropical countries and heavy rainfall, most cases actually occur in temperate climates, probably because of underreporting in
some countries.
High-risk areas include the Caribbean islands, Central and South America, Southeast Asia, and the Pacific islands. Frequently,
the disease gains public attention when outbreaks occur in association with natural disasters, such as flooding in Nicaragua in
1995[9] or among foreign travelers, as with extreme athletes competing in tropical rainforests.
Sex- and age-related differences in incidence
No evidence suggests that leptospirosis affects persons of various races, ages, or sexes differently. However, because
occupational exposure constitutes a major risk for development of disease, a disproportionate number of working-aged males
seem to be affected.
On the other hand, the rates may be different because some practitioners are more likely to look for and, hence, diagnose the
disease in patients who have obvious risk factors. When population groups other than adult males are actively surveyed, their
rates are higher than those previously reported.
In addition, outbreaks have been reported in which more than 40% of patients were younger than 15 years, a reversal of
traditional prevalence rates. Potential explanations in such cases include childhood predilections to play with suspected vectors
(eg, dogs) or indiscriminate contact with water. Active surveillance measures have detected leptospire antibodies in as many as
30% of children in some urban American populations.
Seasonal variation in incidence
Leptospirosis has a seasonal incidence. Most cases occur during the rainy season in the tropics and during the late summer or
early fall in Western countries, as leptospires survive best in fresh water, damp alkaline soil, vegetation, and mud with
temperatures higher than 22°C.
Seasonal outbreaks associated with changes in local water levels have been described. Flood conditions increase risk of
exposure to the population at large, and drought causes leptospire concentrations to peak in isolated pools.[28, 29]
Seasonal variation also correlates with participation in activities that increase exposure to leptospires. For example, outbreaks
have been reported in triathlon athletes and white-water rafters.[6, 7, 8, 54]
Prognosis
The mild form of leptospirosis is rarely fatal, and an estimated 90% of cases fall into this category. The mortality rate in severe
leptospirosis averages approximately 10%, but has been described as ranging from 5-40%. Elderly and immunocompromised
people are at the highest risk of mortality overall. Most deaths occur from renal failure, massive hemorrhage, or acute
respiratory distress syndrome (ARDS).
The incidence of pulmonary involvement has increased over the past few years, affecting up to 70% patients. Pulmonary
involvement has emerged as a serious cause of mortality, becoming the main cause of leptospirosis-associated death in some
countries.[30, 31]
Leptospirosis occurring during pregnancy is ominous. In a review of 16 cases, spontaneous abortion was likely during the first 2
trimesters.[32] When disease occurred in the third trimester, a third of pregnancies ended in abortion or perinatal death.
In general, survivors of leptospirosis experience little long-term morbidity, regardless of disease severity. Hepatic and renal
functions return to normal, despite severe dysfunction during acute illness, even among patients who required dialysis.
Approximately a third of patients with documented aseptic meningitis may continue to complain of periodic headaches of varying
severities. Patients who have had leptospiral uveitis may experience persistent visual acuity loss (caused by lens pigmentation
following anterior uveitis) and blurry vision (associated with keratic precipitates in the anterior chamber).
Patient Education
Women who are pregnant or who are trying to become pregnant should avoid exposure to leptospirosis or may consider
avoiding pregnancy during periods of high-risk exposure. While there are little data on congenital infection in humans,
leptospirosis has been documented to cause spontaneous abortion and stillbirth during the first and second trimesters in over
60% of cases, probably in patients with more severe disease.[32] Women who become ill during the last trimester of pregnancy
and have had high-risk exposure should present promptly for treatment to prevent in utero infection. Newborns of ill mothers can
also be treated. Leptospires may be shed in breastmilk for an unknown duration.
Travelers and participants in "adventure racing" or other freshwater sports who may be hiking and may otherwise be exposed to
fresh water, soil, mud, and vegetation are at higher risk, especially those older than 60 years or those who are
immunosuppressed. These individuals in particular should seek information concerning the risk of leptospirosis (and other
infectious diseases) at their destinations before they travel and take appropriate precautions.[54]
Patients should be advised to do the following:
Avoid contact with environments potentially contaminated with animal urine, especially rodent-infested areas.
Avoid swallowing or inhaling water from lakes, rivers, or swamps while swimming.
Shower promptly after swimming in fresh water and treat any cuts or abrasions with topical antibacterial medication and
bandages.
Avoid participation in adventure racing activities with any cuts or abrasion of the skin.
Wear protective clothing and shoes.
Individuals who own dogs in warm climates with high rainfall may discuss vaccination with their veterinarian. At-risk animals are
those that frequent areas where there are cattle, swine, rodents, or wild animals or that may drink from lakes, rivers, or streams
in rural areas. Vaccination is repeated yearly.
Several polyvalent vaccines are available for immunization of livestock. Leptospirosis is a significant cause of stillbirths and
reduced productivity in agriculture.
Presentation
History
A good clinical history is often the key to accurate diagnosis in leptospirosis. Important features include a plausible exposure
history and a clinical picture consistent with the disease.
The exposure history may reveal direct contact with body fluids or organs of infected animals, or indirectly (eg, via contaminated
soil or water). Direct exposure often occurs in occupational cases, while indirect exposure is more typical of cases contracted
during travel or recreational activities rivers (eg, white-water rafting). Onset of clinical illness occurs abruptly, after an incubation
period of 2-30 days (typically 5-14 d).
Expert consensus is that leptospirosis occurs as two recognizable clinical syndromes: anicteric and icteric (the existence of a
third syndrome of asymptomatic infection is more controversial). Anicteric leptospirosis is a self-limited, mild flulike illness. Icteric
leptospirosis, also known as Weil disease, is a severe illness characterized by multiorgan involvement or even failure.
Two distinct phases of illness are observed in the mild form: the septicemic (acute) phase and the immune (delayed) phase. In
icteric leptospirosis, the 2 phases of illness are often continuous and indistinguishable. At disease onset, clinically predicting the
severity of disease is not possible.
An acute illness follows infection with any serovar of leptospirosis. Most of the following signs and symptoms may develop in
varying degrees:
Headache
Fever (38-40°C)
Rigors
Muscle pain (typically localized to the calf and lumbar areas)
Nausea and vomiting
Anorexia
Diarrhea
Dry cough
Pharyngitis
Conjunctival suffusion
Nonpruritic skin rash
Despite reports of fever as a cardinal symptom, research by the Hawaii Department of Health found that the presence of fever
varied.[24, 33] In serologically confirmed cases, 5% of patients gave no history of fever, and 55% were afebrile at the time of
presentation. Myalgias and headache were universally reported at the time of presentation and were the chief complaint in 25%
of patients.
The natural course of leptospirosis falls into 2 distinct phases. The acute phase of illness lasts 5-7 days and is followed by a 1-3
day period of improvement in which the temperature curve falls and the patient may become afebrile and relatively
asymptomatic. Subsequently, leptospirosis either regresses to a relatively asymptomatic illness or progresses to a more severe
illness.
Recurrence of fever indicates the onset of the second, immune stage. Nonspecific symptoms, such as fever and myalgia, may
be less severe than in the first stage and last a few days to a few weeks. Many patients (77%) experience headache that is
intense and poorly controlled by analgesics; this often heralds the onset of meningitis.
Aseptic meningitis is the most important clinical syndrome observed in the immune anicteric stage. Meningeal symptoms
develop in 50% of patients. Cranial nerve palsies, peripheral facial palsy,[34] encephalitis, and changes in consciousness are
less common. Mild delirium may also be seen. Meningitis usually lasts a few days but occasionally lasts 1-2 weeks. Death is
extremely rare in anicteric cases.
Abdominal pain with diarrhea or constipation (30%), hepatosplenomegaly, nausea, vomiting, and anorexia are also seen.
Acalculous cholecystitis may be seen rarely but is clinically significant.[35]
Uveitis (2-10%) can develop early or late in the disease and has been reported to occur as late as one year after initial illness.
Iridocyclitis and chorioretinitis are other late complications that may persist for years. These symptoms first manifest 3 weeks to
1 month after exposure. Subconjunctival hemorrhage is the most common ocular complication of leptospirosis, occurring in as
many as 92% of patients.
Renal manifestations include hematuria. Oliguric or anuric acute tubular necrosis may occur during the second week due to
hypovolemia and decreased renal perfusion.
Weil syndrome, the severe form of leptospirosis, primarily manifests as profound jaundice, renal dysfunction, hepatic necrosis,
pulmonary dysfunction, and hemorrhagic diathesis. Pulmonary manifestations include cough, dyspnea, chest pain, bloodstained
sputum, hemoptysis, and respiratory failure.
Physical Examination
The physical examination findings differ depending on the severity of disease and the time from onset of symptoms. Patients
may appear mildly ill or toxic. Early in the disease, temperatures as high as 40°C and tachycardia are common. Hypotension,
oliguria, and abnormal chest auscultation findings at presentation may portend severe illness. When fever is severe and
prolonged, hypotension and shock due to volume depletion may also occur. The fever typically subsides within 7 days.
Early in the disease, the skin is warm and flushed. Additional skin findings include a transient petechial eruption that can involve
the palate. Later in severe disease, jaundice and purpura can develop. The classic ocular finding of conjunctival suffusion
occurs early irrespective of disease severity. Conjunctival suffusion is characterized by redness of the conjunctiva that
resembles conjunctivitis but that does not involve inflammatory exudates.
Uveitis is a common feature following acute leptospirosis. However, patients who receive antibiotics during the acute phase of
illness may develop only mild uveitis.[36]
Muscle tenderness can occur with the myositis of early infection. This can be particularly prominent in the paraspinal and calf
muscles but can involve any muscle.
Neurologic examination can reveal signs of meningitis, including neck stiffness and rigidity and photophobia. Early in the
disease, the stiffness on neck examination can be confused as muscular in origin; however, this symptom may actually
represent early meningismus.
Lung examination results may be normal in early or mild illness. In severe illness, signs of consolidation due to alveolar
hemorrhage may be found. In patients with cardiac-related pulmonary edema, rales and wheezes can be heard.
Abdominal examination may reveal liver enlargement and tenderness due to hepatitis. Acalculous cholecystitis, which may be
suggested by a positive Murphy sign, is a finding of profound systemic illness. Pancreatitis has also been described in severe
cases.[37, 38, 39] Heme-positive stool and even gross blood can be found on rectal examination in patients with DIC and
bleeding.
In severe disease, delirium may develop either as a consequence of shock or independent of it. Delirium may be an early finding
in severe disease. Late in disease and into convalescence, prolonged mental symptoms may persist, including depression,
anxiety, irritability, psychosis, and even dementia.
Rash may present as a macular or maculopapular eruption with erythematous, urticarial, petechial, or desquamative lesions.
Adenopathy may be noted.
Complications
The infection may progress to severe systemic inflammatory syndrome with hemorrhagic features. Findings of disseminated
intravascular coagulation may occur with bleeding.
The onset of mental status alterations indicates progression to parenchymal involvement of the cerebral cortex with meningo-
encephalitis, heralding a high mortality risk.
Severe and diffuse alveolar hemorrhage with massive hemoptysis can occur in the absence of typical Weil disease.
Myocarditis may occur in severe disease. All of the physical findings of biventricular heart failure can be found, including
elevated jugular venous pulsations; a new S3 gallop; and dysrhythmias, including atrial fibrillation, heart blocks of varying
severity, and ventricular ectopy.
Acalculous cholecystitis is a finding of profound systemic illness. Pancreatitis has also been described in severe cases.[37, 38,
39]
Uveitis, iridocyclitis, and chorioretinitis may occur late into illness and may persist for years.
DDx
Diagnostic Considerations
The differential diagnosis of leptospirosis is confoundingly broad. The flulike illness that characterizes mild cases may resemble
a benign viral syndrome, while more severe cases may resemble meningitis or sepsis. Dengue, in particular, and chikungunya
often overlap in territory with leptospirosis, and more than one infection may be present.
Recognizing and addressing the differential diagnoses when evaluating a patient suspected of having leptospirosis is critical.
Missing other life-threatening illnesses, such as bacterial meningitis, acute toxin-induced hepatitis, pancreatitis, cholangitis, or
Goodpasture disease, can be devastating, particularly because each of those diseases has a specific and entirely different
necessary therapy. In addition, delayed treatment for severe leptospirosis may negatively affect patient outcome.
A possible key to correct diagnosis is a thorough history focusing on the patient's travel history, activities, and exposure to
animals. Case clusters, if present, may suggest a common exposure.
Other problems to be considered may include the following:
Enteric fever
Infantile polyarteritis nodosa
Kawasaki disease
Primary HIV infection
Typhoid fever
Yellow fever
Mononucleosis
Cholecystitis
Pancreatitis and pancreatic pseudocyst
Differentials
Brucellosis
Dengue
Chikungunya
Enteroviral Infections
Hantavirus Pulmonary Syndrome
Hepatitis A
Malaria
Meningitis
Q Fever
Rickettsial Infection
Viral Hemorrhagic Fevers
Measles
Rubella
Workup
Workup
Approach Considerations
Leptospires grow slowly in culture, and recovery rates are low. Serologic tests are available only in specialized laboratories, and
the sensitivity of acute serologic tests is low. Consequently, those tests should not be the basis on which treatment is initiated. In
a patient with compatible symptoms and a plausible exposure history, empiric therapy should be started.
Laboratory studies are used for two purposes: to confirm the diagnosis and to determine the extent of organ involvement and
severity of complications. Laboratory confirmation of leptospirosis can be accomplished through isolation of the pathogen or by
serologic testing.
Isolation of the leptospires from human tissue or body fluids is the criterion standard, but culture is not routinely available; thus,
molecular assays such as DNA PCR are more commonly used, if available. Consultation with the local microbiology laboratory
is essential, because processing requires specialized techniques. Urine is the most reliable body fluid to study because the
urine contains leptospires from the onset of clinical symptoms until at least the third week of infection.
Other body fluids contain the organism, but the window of opportunity to isolate them is shorter. Blood and CSF may produce
positive PCR or cultures during the first 7-10 days of symptoms.
Tissues (ie, liver, muscle, kidney, skin, eyes) are also sources of identification of the leptospires but are obviously more
complicated to acquire.
Most often, paired acute and convalescent serum specimens are used to confirm the diagnosis. Again, this is a delayed means
of confirmation because the acute sera are collected 1-2 weeks after onset of symptoms, and the convalescent sera are
collected 2 weeks afterward.
Antileptospire antibodies in these samples are detected using the microscopic agglutination test (MAT). The Centers for Disease
Control and Prevention (CDC) laboratory in Atlanta, Georgia, performs the MAT using 23 leptospire antigens. A 4-fold rise in
MAT titer between acute and convalescent sera with any of these antigens confirms the diagnosis of leptospirosis.
Faster laboratory methods may strongly suggest the diagnosis of leptospirosis, but they may be no more readily available than
the CDC laboratory in Atlanta. A single MAT titer of 1:200 on any sera or identification of spirochetes on dark-field microscopy,
when accompanied by the appropriate clinical scenario, is strongly suggestive.
In suspected leptospirosis, further laboratory studies should be routinely performed to determine the extent and severity of
organ involvement after the acute phase of illness. A complete blood cell count (CBC) is necessary. Findings on general
laboratory studies are as follows:
In patients with mild disease, elevated erythrocyte sedimentation rates and peripheral leukocytosis (3,000-26,000 x
109/L) with a left shift are noted
Significant anemia due to pulmonary and gastrointestinal hemorrhage can occur
The platelet count may be diminished as a component of disseminated intravascular coagulation (DIC)
levels of blood urea nitrogen and serum creatinine may be profoundly elevated in the anuric or oliguric phase
Serum creatine kinase levels (MM fraction) are often elevated in patients with muscular involvement.
Coagulation times may be prolonged in patients with hepatic dysfunction and/or DIC On liver function testing, serum
bilirubin levels elevate as part of the obstructive disease due to capillaritis in the liver. Levels of hepatocellular
transaminases are elevated less often and less significantly (usually < 200 U/L). Jaundice and bilirubinemia
disproportional to hepatocellular damage is common in leptospirosis; alkaline phosphatase levels may be elevated 10-
fold.
On urinalysis, proteinuria may be present. Leukocytes, erythrocytes, hyaline casts, and granular casts may be present in the
urinary sediment.
Analysis of the CSF is useful only in excluding other causes of bacterial meningitis. When the CNS becomes involved in
leptospirosis, polymorphonuclear leukocytes initially predominate and are later replaced by monocytes. CSF protein may be
normal or elevated, whereas glucose levels remain normal. CSF pressure is normal, but a lumbar puncture can relieve the
headache. Leptospires are routinely isolated from the CSF, but this finding does not change management of the disease.
Imaging studies are useful in determining the extent and severity of organ involvement. This may include chest radiography to
evaluate lung disease and biliary tract ultrasonography in suspected acalculous cholecystitis.
Electrocardiographic (ECG) abnormalities are common during the leptospiremic phase of Weil syndrome. In severe cases,
congestive heart failure and cardiogenic shock may occur.
Culture
Isolating the organism by culture allows definitive diagnosis. Leptospires remain viable in anticoagulated blood for as long as 11
days; hence, specimens can be mailed to a reference laboratory for culture. The infecting serovar can be isolated only by
culture.
Blood cultures may be negative if drawn too early or too late. Leptospires may not be detected in the blood until 4 days after the
onset of symptoms (7-14 d after exposure). Once the immune system is activated, blood cultures may again become negative.
Leptospires may be isolated from the cerebrospinal fluid (CSF) within the first 10 days.
Leptospires may be isolated from the urine for several weeks after the initial infection. In some patients, urine cultures may
remain positive for months or years after the onset of illness. Positive urine cultures may take as long as 8 weeks to grow.
Microscopic Agglutination Testing

Microscopic agglutination testing (MAT) uses a battery of antigens taken from common (frequently locally endemic) leptospire
serovars. MAT is available only at reference laboratories, such as the Centers for Disease Control and Prevention (CDC).
In a patient with clinical findings consistent with the disease, a single titer exceeding 1:200 or serial titers exceeding 1:100
suggest leptospirosis; however, neither is diagnostic. A 4-fold rise in titer between acute and convalescent specimens is
considered a positive result. The antibody response does not reach detectable levels until the second week of illness, and it can
be affected by treatment.
False-negative MAT findings may result from testing a single specimen obtained before the immune phase of disease. Test
accuracy is also affected by appropriate selection of antigens for the battery, necessitating discussion with the laboratory about
which serovars are suspected or predominate in the region where the case originated. False-positive MAT results may occur
with cases of Legionella infection, Lyme disease, and syphilis.
Other Tests
Screening tests for leptospirosis, which are easy to perform and provide results relatively rapidly, include the macroscopic slide
agglutination test, the Patoc-slide agglutination test, the microcapsule agglutination test, latex agglutination tests, dipstick tests,
and the indirect hemagglutination test. Confirmation of screening test results (positive or negative) is advisable, however,
preferably with MAT.[40]
An immunoglobulin M (IgM) enzyme-linked immunoabsorbent assay (ELISA) has been developed. The ELISA uses a broadly
reactive antigen and is a standard serologic procedure, as is the MAT.[41] Because it detects IgM, it may be useful for diagnosis
of new infections within 3-5 days. Positive results should be referred for confirmatory testing.
Nucleic acid amplification (polymerase chain reaction [PCR])–based techniques have been developed to diagnose leptospirosis.
PCR can confirm the diagnosis rapidly during the early phase of the disease, when leptospires may be present and before
antibody titers are detectable, but it requires adequate infrastructure such as appropriate equipment, laboratory space, and
skilled personnel. In addition, PCR-based techniques are unable to identify the infecting serovar, which reduce their
epidemiologic and public health value.
Dark-field examination of blood or urine has been used to identify leptospires. However, this technique cannot be
recommended, as it frequently leads to misdiagnosis.
Chest Radiography
The most common abnormality on chest radiography is bilateral diffuse airspace disease. Chest radiography may also reveal
cardiomegaly and pulmonary edema due to myocarditis. In patients with alveolar hemorrhage due to pulmonary capillaritis, the
lung parenchyma may contain multiple patchy infiltrates.
Histologic Findings
Shortly after inoculation and during the incubation period, leptospires actively replicate in the liver. The leptospires then
disseminate throughout the body and infect multiple tissues.
Silver staining and immunofluorescence can identify leptospires in the liver, spleen, kidney, CNS, muscles, and heart. During the
acute phase of leptospirosis, histology reveals these organisms without much inflammatory infiltrate. In addition to the finding of
leptospires during histologic examination, the pathologic effects of leptospiral toxins are also apparent. See the image below.
Silver stain, liver, fatal human leptospirosis. (This image is in the public domain and thus free of any copyright restrictions.
Courtesy of the Centers for Disease Control/Dr. Martin Hicklin)
Leptospirosis may be seen as an infective systemic vasculitis.[18] Leptospiral toxins break down endothelial cell membranes of
capillaries. This toxin-mediated process allows for extravasation of blood and leptospires from blood vessels into the supported
parenchyma. Secondarily, because the capillaries are no longer functional, ischemia and cell death can occur. Later in infection,
mononuclear cells predominate in the areas of this focal cell necrosis.
Leptospires can be identified in immunologically privileged sites, such as renal tubules, CNS, and the anterior chamber of the
eyes, for weeks to months after the initial infection. In nonhuman animals, the intended hosts of infection, the leptospires
establish residence in these immunologically privileged sites. Provided that the animal survives the initial infection, a chronic
carrier state is then established, and histology reveals leptospires at these sites for years after initial infection.
Treatment
Approach Considerations
Antimicrobial therapy is indicated for the severe form of leptospirosis, but its use is controversial for the mild form of
leptospirosis. A Cochrane Review found insufficient evidence to advocate for or against the use of antibiotics in the therapy for
leptospirosis.[42]
If antibiotics are used, they should be initiated as soon as the diagnosis of leptospirosis is considered and should be continued
for a full course despite initial serologic results, because most patients are diagnosed only through acute and convalescent
testing. Early treatment has been shown to offer the best clinical outcomes; results from controlled studies of treatment during
the immune phase have yielded mixed results.[43, 44]
Mild leptospirosis is treated with doxycycline, ampicillin, or amoxicillin. For severe leptospirosis, intravenous penicillin G has long
been the drug of choice, although the third-generation cephalosporins cefotaxime and ceftriaxone have become widely used.
Alternative regimens are ampicillin, amoxicillin, or erythromycin. Several other antibiotics may be useful—for example, broth
microdilution testing has shown sensitivity to macrolides, fluoroquinolones, and carbapenems[45] —but clinical experience with
these agents is more limited.
Severe cases of leptospirosis can affect any organ system and can lead to multiorgan failure. Supportive therapy and careful
management of renal, hepatic, hematologic, and central nervous system complications are important.
Patients should be managed in a monitored setting because their condition can rapidly progress to cardiovascular collapse and
shock. Access to mechanical ventilation and airway protection should be available in the event of respiratory compromise.
Continuous cardiac monitoring should be attained; arrhythmias, including ventricular tachycardia and premature ventricular
contractions, as well as atrial fibrillation, flutter, and tachycardia, can occur.
Renal function should be evaluated carefully and dialysis considered in cases of renal failure. In most cases, the renal damage
is reversible if the patient survives the acute illness. Early initiation of hemodialysis or peritoneal dialysis considerably reduces
mortality risk. A few cases in the literature have reported that plasma exchange, corticosteroids, and intravenous
immunoglobulin may be beneficial in selected patients in whom conventional therapy does not elicit a response.[46, 47, 48]
Corticosteroid therapy is controversial. A 2014 review suggests lack of benefit and possible increased risk of nosocomial
infection.[49] As with severity of illness, response may vary depending on host immune factors or the particular virulence of the
leptospire. Treatment with high-dose pulsed methylprednisolone (30 mg/kg/d, not to exceed 1500 mg) has been used
successfully to treat patients with leptospiral renal failure without dialysis. This approach may have be beneficial in resource-
poor areas where dialysis is unavailable and would involve lengthy medical transport. The use of renal-dose dopamine in
conjunction with steroids or diuretics has also been described.[23]
Pulse-dose steroids may also play a role early in the management of severe pulmonary disease.[50, 47] Patients with Weil
syndrome may need transfusions of whole blood, platelets, or both. Ophthalmic drops of mydriatics and corticosteroids have
been used for relief of ocular symptoms.[51]
Patients with severe disease should remain hospitalized until adequate resolution of organ failure and clinical infection.
Outpatient follow-up may include an assessment of renal function to ensure ongoing reversal of any damage. A cardiac
assessment may be indicated in patients with symptoms suggestive of heart involvement.
Diet and Activity

In mild cases, patients should be encouraged to maintain adequate fluid intake to avoid volume depletion. In more severe
cases, diets appropriate for the clinical picture should be ordered (eg, electrolyte and protein restriction in cases of renal
insufficiency). Patients with hypotension or clinical shock should not be fed enterally until adequate perfusion is restored.
Patients with severe disease should be placed on bed rest until adequately resuscitated and treated. Those with mild disease
can pursue activity as tolerated.
Transfer
Transfer to a facility with an appropriate level of care should be considered in patients with severe disease. Leptospirosis has a
regional epidemiology with high incidence of cases in remote regions that offer limited medical care. Although transporting
patients with severe disease to appropriate medical centers is preferred, military physicians who have treated patients from
Western Pacific islands averted the need for transoceanic transport for dialysis by administering high-dose steroids.[38, 37]
Consultations
In severe cases of leptospirosis, several specialty consultations may aid in proper patient management. An infectious disease
specialist may assist in differentiating leptospirosis from diseases with similar presentations but that may have significantly
different treatments and in treating co-infections such as malaria, dengue, or others, depending on exposure history. A
nephrologist should be alerted early in the course because the need for dialysis may develop rapidly. If available, critical care
specialists may be best prepared to manage patients with affected multiple systems.
For assistance with laboratory diagnosis, the Centers for Disease Control and Prevention (CDC) or the World Health
Organization (WHO) can aid the clinician in obtaining samples and ordering tests.
Deterrence/Prevention
Prevention of leptospirosis is difficult because the organism cannot be eradicated from wild animal reservoirs, which constantly
infect domestic animals. Important control measures include control of livestock infection with good sanitation, immunization,
and proper veterinary care.
Preventing infected animals from urinating in waters where humans have contact, disinfecting contaminated work areas,
providing worker education, practicing good personal hygiene, and using personal protective equipment (PPE) when handling
infected animals or tissues are important actions for prevention of the disease. Examples of PPE include gloves and face
shields for veterinarians and rubber boots for sewer workers and agricultural workers who wade in rodent urine- contaminated
water.
Public health measures include investigation of cases in an effort to detect common source outbreaks and implementation of
appropriate control measures to prevent further cases. Leptospirosis was reinstated as a Nationally Notifiable Disease in 2013.
Other public health measures include identification of contaminated water supplies, rodent control, prohibition of swimming in
lakes or streams where risk of infection may be high, and informing people of risk when they are involved in recreational
activities.
Vaccines exist for animals and humans but are not necessarily available in all areas. For example, vaccines may be offered to
high-risk workers in some European and Asian countries (eg, rice workers in Italy) but are not available to US short-term
travelers to endemic areas. No leptospirosis vaccine is available for human use in the United States, but there are vaccines for
animals (pets and agricultural). Because of the heterogeneity in Leptospira serovars that cause disease in different host species,
different polyvalent vaccines are given depending on exposure type and geography. They may not protect against all the
serovars that may be prevalent, and new serovars may be introduced over time.
Leptospirosis vaccines are also associated with significant adverse effects. Live attenuated vaccines for dogs have been
associated with reversion of the attenuated strain to virulence, with associated chronic shedding of infectious leptospires and
transmission to humans. Most vaccines in use for several decades are thus killed whole-cell bacterin vaccines. Depending on
the vaccine, duration may range from 1-3 years, with variable efficacy. Recombinant protein vaccines and DNA vaccines that
introduce chronic antigen production into the host via plasmid offer hope for effective immunization across multiple serovars.
Doxycycline, in the dose of 200 mg every week, has demonstrated efficacy of 95% against leptospirosis and may help prevent
the disease in exposed adults.[52, 53] This regimen is recommended for those with short-term exposure and is not for repeated
or long-term exposure. The role of prophylaxis in children has not been adequately studied.
Medication
Medication Summary
Treatment for leptospirosis consists of empiric antibiotic therapy. In general, antibiotic therapy should be effective against
leptospirosis and against the other pathogens considered in the differential diagnoses. If renal failure ensues, corticosteroids
may be considered. Additional supportive care may include inotropic agents, diuretics, or ophthalmic drops. Currently, no human
vaccine against leptospirosis is available.
Antibiotics
Class Summary
For severe leptospirosis, intravenous penicillin G has long been considered the drug of choice. Doxycycline is used for the
treatment of mild leptospirosis. Ampicillin or amoxicillin are alternatives for the treatment of mild leptospirosis. Erythromycin is
the therapy of choice in pregnant patients who are allergic to penicillin. Third-generation cephalosporins have become widely
used for intravenous antibiotic treatment in patients with severe leptospirosis.
Penicillin G aqueous (Pfizerpen-G)

Intravenous penicillin is first-line antibiotic therapy for severe leptospirosis. Penicillin interferes with synthesis of cell wall
mucopeptide during active multiplication, resulting in bactericidal activity against susceptible microorganisms.
Doxycycline (Vibramycin, Doryx, Adoxa, Morgidox, Mondoxyne NL)

Doxycycline inhibits protein synthesis, and thus bacterial growth, by binding to 30S and possibly 50S ribosomal subunits of
susceptible bacteria. Excretion is hepatobiliary and renal.
Ampicillin
Ampicillin is a second-line agent or for patients younger than 8 years of age, in whom doxycycline is contraindicated. This agent
interferes with synthesis of cell-wall mucopeptides during active multiplication, resulting in bactericidal activity. Excretion is
primarily renal, although some ampicillin is metabolized by the liver.
Amoxicillin (Moxatag)
Amoxicillin is a second-line agent or for patients younger than 8 years of age, in whom doxycycline is contraindicated. This
agent interferes with synthesis of cell wall mucopeptides during active multiplication, resulting in bactericidal activity against
susceptible bacteria.
Erythromycin ethylsuccinate (E.E.S., EryPed, Erythrocin, PCE, Ery-Tab)

Erythromycin inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-
dependent protein synthesis to arrest. In pregnant patients who are allergic to penicillin, erythromycin is the therapy of choice.
Cefotaxime (Claforan)
A third-generation cephalosporin with broad gram-negative spectrum, cefotaxime has lower efficacy against gram-positive
organisms and higher efficacy against resistant organisms. This agent arrests bacterial cell wall synthesis by binding to one or
more of the penicillin-binding proteins, which in turn inhibits bacterial growth.
Ceftriaxone (Rocephin)
Ceftriaxone is a third-generation cephalosporin with broad-spectrum, gram-negative activity. It has lower efficacy against gram-
positive organisms and higher efficacy against resistant organisms.
Ceftriaxone exerts its bactericidal effect by interfering with the synthesis of peptidoglycan, a major structural component of
bacterial cell walls. Bacteria eventually lyse owing to the ongoing activity of cell wall autolytic enzymes while cell wall assembly
is arrested.
Ceftriaxone is highly stable in presence of beta-lactamases, both penicillinase and cephalosporinase, produced by gram-
negative and gram-positive bacteria. Approximately 33-67% of the dose is excreted unchanged in urine; the remainder is
secreted in bile and ultimately in feces as microbiologically inactive compounds.
This agent reversibly binds to human plasma proteins. Binding has been reported to decrease with increasing plasma
concentrations of the drug, from 95% bound at plasma concentrations < 25 mcg/mL to 85% bound at 300 mcg/mL.
Corticosteroids
Class Summary
In patients with leptospirosis, corticosteroids are indicated to improve renal failure outcome.
Methylprednisolone (A-Methapred, Medrol, Depo-Medrol, Solu-Medrol)

Methylprednisolone decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and reversing
increased capillary permeability. High-dose pulsed methylprednisolone (30 mg/kg/d, not to exceed 1500 mg) has been used
successfully to treat patients with leptospiral renal failure without dialysis.
Questions & Answers

Overview
What is leptospirosis?
What are the signs and symptoms of leptospirosis?
Which lab studies are performed to screen for and diagnosis leptospirosis?
Which studies are used to determine the severity of organ complications caused by leptospirosis?
What are the treatment options for leptospirosis?
What is leptospirosis?
How is leptospirosis transmitted?
What are the risk factors for Leptospira exposure?
What is the initial presentation of leptospirosis?
How is leptospirosis treated?
What is the historical background on leptospirosis?
What are leptospires and how are they classified?
What is the primary reservoir of leptospiral serovars?
What are the clinical manifestations of leptospirosis in animals?
What is the pathogenesis of leptospirosis?
What are the pathologic effects of leptospirosis?
What is the effect of leptospirosis on the kidneys?
What is the effect of leptospirosis on the liver?
What is the effect of leptospirosis on the lungs?
What is the effect of leptospirosis on the heart?
What is the effect of leptospirosis on the adrenal gland?
What is the effect of leptospirosis on the skin and muscles?
What is the effect of leptospirosis on the vascular system?
What is the pathogenesis of leptospirosis if left untreated?
What causes leptospirosis?
How are Leptospira classified?
What are the clinical manifestations of leptospirosis?
How is leptospirosis transmitted to humans?
What is the incidence of leptospirosis in the US?
Which US state has the highest annual case reports of leptospirosis?
Which animal is a major vector of leptospirosis in the US?
What is the seasonal incidence of leptospirosis in the US?
What are the global incidence rates and environmental associations of leptospirosis?
How does the incidence for leptospirosis vary among different demographic groups?
What is the seasonal variation in incidence for leptospirosis?
What are the mortality rates for leptospirosis?
What is the incidence of pulmonary involvement in leptospirosis?
What is the prognosis of leptospirosis during pregnancy?
What are the long-term morbidities of leptospirosis?
What are the risks of leptospirosis during pregnancy?
Who is at a higher risk of contracting leptospirosis?
What information about leptospirosis prevention should patients receive?
Presentation
What is the focus of history in suspected leptospirosis?
What are the clinical syndromes of leptospirosis?
What are the phases of illness for leptospirosis?
What are the signs and symptoms of acute phase leptospirosis?
What is the disease course of leptospirosis?
How do the physical findings vary by severity of leptospirosis?
What are the ocular symptoms of leptospirosis?
Which physical findings are characteristic of leptospirosis?
What are complications of leptospirosis?
What are the cardiac complications of severe leptospirosis?
What complications may occur late in the disease course of leptospirosis?
DDX
Which conditions should be included in the differential diagnoses of leptospirosis?
How can history be used to narrow the differential diagnoses of leptospirosis?
Workup
What is the role of serologic testing in the diagnosis and treatment of leptospirosis?
What is the role of lab testing in the evaluation of leptospirosis?
Which lab tests are used to confirm a diagnosis of leptospirosis?
What are the limitations of lab confirmation of leptospirosis?
What is the role of microscopic agglutination test (MAT) in the diagnosis of leptospirosis?
Following acute phase of leptospirosis, which tests are performed to determine the extent and severity of organ involvement?
What is the role of urinalysis in the diagnosis of leptospirosis?
What is the role of CSF analysis in the diagnosis of leptospirosis?
What is the role of imaging studies in the diagnosis of leptospirosis?
What is the role of blood culture in the evaluation of leptospirosis?
What is microscopic agglutination testing (MAT) and how is it used in the diagnosis of leptospirosis?
Which factors affect microscopic agglutination test (MAT) accuracy in diagnosing leptospirosis?
Which tests are used to screen for leptospirosis?
What is the role of immunoglobulin M (IgM) ELISA in the evaluation of leptospirosis?
What is the role of PCR in the diagnosis of leptospirosis?
Which is the role of dark-field exam of blood or urine in the diagnosis of leptospirosis?
What is the role of chest radiography in the evaluation of leptospirosis?
Which histological findings are characteristic of leptospirosis?
What are the histological findings of infective systemic vasculitis that indicate leptospirosis?
Where in the body are leptospires identified after the initial infection?
Treatment
What is the role of antimicrobial therapy for the treatment of leptospirosis?
When should antibiotics be administered for the treatment of leptospirosis?
Which antibiotics are used for the treatment of mild leptospirosis?
What is the focus of treatment of severe leptospirosis?
What is the approach to disease management for leptospirosis?
What is the role of corticosteroid therapy for leptospirosis?
How are the complications of leptospirosis managed?
What diet modifications are needed during the treatment of leptospirosis?
What activity modifications are needed during the treatment of leptospirosis?
When is transfer of patients with leptospirosis indicated?
Which specialist consultations are necessary in the management of leptospirosis?
Where can assistance with lab diagnosis of leptospirosis be obtained?
How is leptospirosis prevented?
Which public health measures are employed in the prevention of leptospirosis?
What is the role of vaccines in the prevention of leptospirosis in humans and animals?
What is the role of doxycycline in the treatment of leptospirosis?
Medications
What are the medical treatments for leptospirosis?
Which medications in the drug class Corticosteroids are used in the treatment of Leptospirosis?
Which medications in the drug class Antibiotics are used in the treatment of Leptospirosis?
Contributor Information and Disclosures
Author
Sandra G Gompf, MD, FACP, FIDSA Associate Professor of Infectious Diseases and International Medicine, University of
South Florida College of Medicine; Chief, Infectious Diseases Section, Director, Occupational Health and Infection Control
Programs, James A Haley Veterans Hospital
Sandra G Gompf, MD, FACP, FIDSA is a member of the following medical societies: American College of Physicians, Infectious
Diseases Society of America
Disclosure: Nothing to disclose.
Coauthor(s)
Ana Paula Velez, MD Assistant Professor of Medicine, Division of Infectious Disease and International Medicine, University of
South Florida College of Medicine and James A Haley Veterans Affairs Medical Center; Attending Physician, Moffitt Cancer
Center
Ana Paula Velez, MD is a member of the following medical societies: American College of Physicians-American Society of
Internal Medicine, American Medical Association, Infectious Diseases Society of America
Judith Green-McKenzie, MD, MPH, FACP, FACOEM Associate Professor, Director of Clinical Practice, Occupational Medicine
Residency Director, University of Pennsylvania School of Medicine
Judith Green-McKenzie, MD, MPH, FACP, FACOEM is a member of the following medical societies: American College of
Physicians, American College of Preventive Medicine, National Medical Association, American College of Occupational and
Environmental Medicine
Specialty Editor Board
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy;
Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Chief Editor
Michael Stuart Bronze, MD David Ross Boyd Professor and Chairman, Department of Medicine, Stewart G Wolf Endowed
Chair in Internal Medicine, Department of Medicine, University of Oklahoma Health Science Center; Master of the American
College of Physicians; Fellow, Infectious Diseases Society of America; Fellow of the Royal College of Physicians, London
Michael Stuart Bronze, MD is a member of the following medical societies: Alpha Omega Alpha, American College of
Physicians, American Medical Association, Association of Professors of Medicine, Infectious Diseases Society of America,
Oklahoma State Medical Association, Southern Society for Clinical Investigation
Acknowledgements
Denise Demers, MD, FAAP Assistant Professor of Pediatrics, Uniformed Services University of the Health Sciences; Attending
Physician, Division of Pediatric Infectious Diseases, Department of Pediatrics, Tripler Army Medical Center
Juan D Diaz, DO Fellow in Infectious Diseases, University of South Florida College of Medicine, Tampa General Hospital, and
James A Haley Veterans Hospital
Joseph Domachowske, MD Professor of Pediatrics, Microbiology and Immunology, Department of Pediatrics, Division of
Infectious Diseases, State University of New York Upstate Medical University
Joseph Domachowske, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of
Pediatrics, American Society for Microbiology, Infectious Diseases Society of America, Pediatric Infectious Diseases Society,
and Phi Beta Kappa
Patrick W Hickey, MD, FAAP Assistant Professor of Pediatrics and Preventive Medicine, Uniformed Services University of the
Health Sciences; Consulting Staff, Department of Pediatrics, Division of Pediatric Infectious Disease, Walter Reed Army Medical
Center
Patrick W Hickey, MD, FAAP is a member of the following medical societies: Alpha Omega Alpha, American Academy of
Pediatrics, American Society of Tropical Medicine and Hygiene, Infectious Diseases Society of America, International Society of
Travel Medicine, and Pediatric Infectious Diseases Society
Edmond A Hooker II, MD, DrPH, FAAEM Assistant Professor, Department of Emergency Medicine, University of Cincinnati
College of Medicine; Associate Professor, Department of Health Services Administration, Xavier University
Edmond A Hooker II, MD, DrPH, FAAEM is a member of the following medical societies: American Academy of Emergency
Medicine, American Public Health Association, Society for Academic Emergency Medicine, and Southern Medical Association
Matthew R Jezior, MD Fellow, Department of Cardiology, Walter Reed Medical Center
Maria D Mileno, MD Associate Professor of Medicine, Division of Infectious Diseases, The Warren Alpert Medical School of
Brown University
Maria D Mileno, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians,
American Society of Tropical Medicine and Hygiene, Infectious Diseases Society of America, International Society of Travel
Medicine, and Sigma Xi
Joseph T Morris, MD Chief of Infectious Disease Service, Madigan Army Medical Center; Assistant Professor, Department of
Internal Medicine, Uniformed Services University of the Health Sciences
Gary J Noel, MD Professor, Department of Pediatrics, Weill Cornell Medical College; Attending Pediatrician, New York-
Presbyterian Hospital
Gary J Noel, MD is a member of the following medical societies: Pediatric Infectious Diseases Society
Cecily K Peterson, MD Program Director, Clinical Faculty, Department of Medicine, Madigan Army Medical Center
Charles V Sanders, MD Edgar Hull Professor and Chairman, Department of Internal Medicine, Professor of Microbiology,
Immunology and Parasitology, Louisiana State University School of Medicine at New Orleans; Medical Director, Medicine
Hospital Center, Charity Hospital and Medical Center of Louisiana at New Orleans; Consulting Staff, Ochsner Medical Center
Charles V Sanders, MD is a member of the following medical societies: Alliance for the Prudent Use of Antibiotics, Alpha
Omega Alpha, American Association for the Advancement of Science, American Association of University Professors, American
Clinical and Climatological Association, American College of Physician Executives, American College of Physicians, American
Federation for Medical Research, American Foundation for AIDS Research, AmericanGeriatricsSociety, American Lung
Association, American Medical Association, American Society for Microbiology, American Thoracic Society, American Venereal
Disease Association, Association for Professionals in Infection Control and Epidemiology, Association of American Medical
Colleges, Association of American Physicians, Association of Professors of Medicine, Infectious Disease Society for Obstetrics
and Gynecology, InfectiousDiseases Societyof America, Louisiana State Medical Society, Orleans Parish Medical Society, Royal
Society of Medicine, Sigma Xi, Society of General Internal Medicine, Southeastern Clinical Club, Southern Medical Association,
Southern Society for Clinical Investigation, and Southwestern Association of Clinical Microbiology
William H Shoff, MD, DTM&H Director, PENN Travel Medicine; Associate Professor, Department of Emergency Medicine,
Hospital of the University of Pennsylvania, University of Pennsylvania School of Medicine
William H Shoff, MD, DTM&H is a member of the following medical societies: American College of Physicians, American Society
of Tropical Medicine and Hygiene, International Society of Travel Medicine, Society for Academic Emergency Medicine, and
Wilderness Medical Society
Russell W Steele, MD Head, Division of Pediatric Infectious Diseases, Ochsner Children's Health Center; Clinical Professor,
Department of Pediatrics, Tulane University School of Medicine
Russell W Steele, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of
Immunologists, American Pediatric Society, American Society for Microbiology, Infectious Diseases Society of America,
Louisiana State Medical Society, Pediatric Infectious Diseases Society, Society for Pediatric Research, and Southern Medical
Association
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy;
Editor-in-Chief, Medscape Drug Reference
Disclosure: Medscape Salary Employment
Jeter (Jay) Pritchard Taylor III, MD Compliance Officer, Attending Physician, Emergency Medicine Residency, Department of
Emergency Medicine, Palmetto Health Richland, University of South Carolina School of Medicine; Medical Director, Department
of Emergency Medicine, Palmetto Health Baptist
Jeter (Jay) Pritchard Taylor III, MD is a member of the following medical societies: American Academy of Emergency Medicine,
American College of Emergency Physicians, American Medical Association, and Society for Academic Emergency Medicine
Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-
Chief, Medscape Drug Reference
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Signs and symptoms

Icterus or frank jaundice

See Clinical Presentation for more detail.

Leptospira immunoglobulin M (IgM) ELISA or IgM/immunoglobulin G (IgG) enzyme-linked immunoabsorbent assay

Complete blood cell (CBC) count

See Workup for more detail.

Antibiotics for leptospirosis requiring hospitalization include the following:

See Treatment and Medication for more detail.

Transmission and incubation

Leptospires are believed to enter the host through the following:

Abrasions in healthy skin

Animal and rodent bites

Sodden and waterlogged skin

Mucous membranes or conjunctiva

Lungs (after inhalation of aerosolized body fluid)[17]

The placenta during pregnancy

Sex- and age-related differences in incidence

Seasonal variation in incidence

Patients should be advised to do the following:

Muscle pain (typically localized to the calf and lumbar areas)

Nausea and vomiting

Nonpruritic skin rash

Other problems to be considered may include the following:

Microscopic Agglutination Testing

Diet and Activity

Penicillin G aqueous (Pfizerpen-G)

Doxycycline (Vibramycin, Doryx, Adoxa, Morgidox, Mondoxyne NL)

Erythromycin ethylsuccinate (E.E.S., EryPed, Erythrocin, PCE, Ery-Tab)

Methylprednisolone (A-Methapred, Medrol, Depo-Medrol, Solu-Medrol)

Questions & Answers

What are the signs and symptoms of leptospirosis?

What are the treatment options for leptospirosis?

How is leptospirosis transmitted?

What are the risk factors for Leptospira exposure?

What is the initial presentation of leptospirosis?

How is leptospirosis treated?

What is the historical background on leptospirosis?

What are leptospires and how are they classified?

What is the primary reservoir of leptospiral serovars?

What are the clinical manifestations of leptospirosis in animals?

What is the pathogenesis of leptospirosis?

What are the pathologic effects of leptospirosis?

What is the effect of leptospirosis on the kidneys?

What is the effect of leptospirosis on the liver?

What is the effect of leptospirosis on the lungs?

What is the effect of leptospirosis on the heart?

What is the effect of leptospirosis on the adrenal gland?

What is the effect of leptospirosis on the skin and muscles?

What is the effect of leptospirosis on the vascular system?

What is the pathogenesis of leptospirosis if left untreated?

What causes leptospirosis?

What are the clinical manifestations of leptospirosis?

How is leptospirosis transmitted to humans?

What is the incidence of leptospirosis in the US?

Which US state has the highest annual case reports of leptospirosis?

Which animal is a major vector of leptospirosis in the US?

What is the seasonal incidence of leptospirosis in the US?

What is the seasonal variation in incidence for leptospirosis?

What are the mortality rates for leptospirosis?

What is the incidence of pulmonary involvement in leptospirosis?

What is the prognosis of leptospirosis during pregnancy?

What are the long-term morbidities of leptospirosis?

What are the risks of leptospirosis during pregnancy?