Leptospira species (Leptospirosis)
Authors: Solly Faine, M.D., PhD., F.R.C.P.A.
Some major recent reviews in the English language include (11-13, 15, 23). The history of leptospirosis and the causal bacteria has been described in detail in Chapters 1 and 2 in (15), and in (22).
Microbiology
Leptospirosis is an ubiquitous zoonosis. The causal bacteria are leptospires, spirochetes that are members of the genus Leptospira, comprising at least 8 pathogenic species, with others yet to be formally published. The current main species names are borgpetersenii, fainei, inadai, interrogans, kirschneri, noguchii, santarosai, and weilii. Within these species are about 200 serovars, forming groups whose characteristic antigens are related to immunity and used in serodiagnosis. Several of the serovars appear in two or more species. Leptospires are slow-growing bacteria (doubling time about 6 hours) that can be readily cultivated in laboratories using special liquid media and strict aseptic technique. The conventional media contain long-chain fatty acids essential for growth, and a detoxicant of fatty acids, usually serum albumin, as well as an ammonium nitrogen source.
Epidemiology
All leptospires can live freely in the environment as well as in the renal tubules, and sometimes the genital tracts, of carrier animals, themselves survivors of infection. The most important carrier animals for infections in humans are rodents, especially rats of various types, dogs, pigs and cattle, including water buffalo. Leptospires excreted in urine from carrier animals survive in moist conditions such as surface water, soil or mud. They enter the body through skin abrasions or by inhalation of aerosols, or through the conjunctiva. Humans are at risk in their work or leisure activities through direct contact with animals, or indirectly via contaminated water or urine. The highest risks occur in workers in agriculture in moist conditions throughout the world; rice-planters and harvesters; miners; travelers; soldiers; canoeists; swimmers; animal attendants; milkers, and meat workers are those most at risk. In Western temperate countries most people with leptospirosis are infected through milking cows (serovar hardjo) and slaughtering or maintaining pigs (serovars pomona, tarassovi), or by exposure to domestic or agricultural conditions where there is heavy rodent infestation, sometimes after civil or military emergencies that destroy effective rat control. In Asia serovar lai is currently predominant.
Clinical Manifestations
The clinical manifestations are not pathognomonic and may initially mimic many other conditions, notably including meningitis, hepatitis, acute pulmonary distress syndrome, or interstitial nephritis. Laboratory diagnosis is essential (see below).
The main clinical feature in humans are grouped into two ill-defined and overlapping forms, depending on the serovar (10-16, 23). Both forms start suddenly with severe headache, fever of 39°C or more, excruciating muscle tenderness, especially in the back and calves, red eyes (vascular dilatation, not inflammation) and sometimes photophobia or meningism. The so-called mild or influenzal type progresses in the following 3-7 days with transient nitrogen retention, rarely jaundice, occasionally a skin rash, meningitis or abdominal pains mimicking an acute abdominal surgical emergency. Recovery is almost invariable in 2-3 weeks, sometimes longer, and fatalities are so rare that there are no recorded autopsy observations. In the severe form, also known as the icteric, renal or hemorrhagic form, (sometimes called Weil's disease or syndrome), the patient's condition deteriorates rapidly, so that the initial phase of 3-7 days is followed by increasing interstitial nephritis, liver failure and jaundice, myocarditis, or severe respiratory distress syndrome denoting pulmonary hemorrhages ranging from small to massive and fatal. Antibiotic treatment in itself cannot reverse the pathological changes once established. Clinical supportive and symptomatic treatment are essential adjuncts to chemotherapy (10-13, 15, 16, 23, 24).
Laboratory Diagnosis
Laboratory diagnosis is essential because of the non-specific clinical presentation, yet paradoxically classical diagnostic methods are so slow and often imprecise as to be of limited value when they are most needed. Blood culture taken in the febrile period (first 7-10 days of illness-not of hospitalization) as well as urine culture in the ensuing week or so, are valuable and positively diagnostic, but the bacteria grow slowly and may not be evident in laboratory tests for 2-3 weeks or more. Meanwhile treatment must be commenced immediately on presumptive diagnosis. Molecular (PCR-based) methods are sometimes more sensitive than culture, and faster, but probes are as yet not universally applicable to all serovars (23), and serovar cannot always be determined. While this deficiency is more important for epidemiology than clinical management, serovar identification can help in prognosis and eventually in prevention. PCR probes have been of great value in diagnosing leptospiral uveitis (29).
For these reasons serological tests remain the bases of diagnosis. The microscopic agglutination test (MAT) is the most specific and precise. Serum taken in the first 2 weeks shows a rising titer of agglutinating antibodies (both IgM and IgG); a positive reaction is interpreted as 1:400 - 1:800 or greater in a single test, or a rising titer to these levels in paired sera over the first 2 or 3 weeks. The maximum serum titer depends on the serovar, but is achieved by about 3-4 weeks of illness. It slowly wains thereafter. The first serum sample should be tested without waiting for the second of a pair because a clear positive result is a direct guide to diagnosis, chemotherapy and management. The MAT is performed only in specialist laboratories; it is tedious and subjective, but is the classical basis for comparison. Other ELISA tests are also useful, especially for screening; some claim that IgM-ELISA tests may diagnose leptospirosis a day or so before an MAT, but this may depend on the skills and methods of the respective laboratories (15, 23). ELISA screening kits and macroscopic agglutination tests can assist where specialist expertise is not available, but these serum tests should be confirmed by MAT in a specialist laboratory.
Pathogenesis
Pathogenesis has been reviewed in detail recently (15). Leptospires enter the body through abrasions, macerated skin or cuts, conjunctiva, or by inhalation of aerosols or of water in near-drowning or swimming immersions. The bacteria spread through the bloodstream and tissues without initial inflammatory localization. They grow in any or all tissues until their numbers are large enough to cause local or general lesions. The main lesion is damage to small blood vessels, probably by a toxin. The clinical presentation reflects secondary changes in the organs affected, and the severity of the damage. Even in clinically mild type leptospirosis there is renal functional impairment due to transient renal ischemia, which may become severe if there is underlying renal insufficiency. Vascular damage is reflected in conjunctival suffusion, pulmonary hemorrhages, muscle degenerative changes, hepatitis, meningitis and other manifestations of ischemia and hemorrhage that may lead to failure of one or more organs or systems. This is the basis for the varied and protean qualitative and quantitative pathological and clinical findings.
Once antibody appears, after 7-10 days or so, leptospires disappear from the bloodstream and tissues, except for privileged sites such as the anterior chamber of the eye, and the brain. In animals leptospires grow in proximal renal tubules about 4 weeks after infection, and later, and are excreted in urine to continue the cycle of infection. The renal carrier state has been recorded rarely in humans, possibly because nobody looks for it. The pathological changes to tissue and organs can begin to repair after the leptospires disappear, but the final outcome will depend on the severity of the lesions and the timeliness and effectiveness of the clinical support for system and organ function. Where this support, assisted by timely antibiotic treatment, is available, complete recovery is the rule, albeit after some time, and with occasional sequelae.
SUSCEPTIBILITY IN VITRO AND VIVO
Susceptibility Tests
Most tests of susceptibility of leptospires to antibiotics were conducted many years ago in media containing serum. More recent tests of newer as well as older antibiotics in oleate-albumin media suggest that the composition of the test medium is not important. The earlier tests were often carried out on only one isolate, designated by serovar, without authentication and of unspecified provenance, before species were recognized. Nevertheless repeated testing in many laboratories gives confidence in the reliability of the results. Patients treated with antimicrobial agents active in vitro as reported in the literature have better outcomes than those receiving no antibiotic therapy.
It is not usual to test leptospires for susceptibility in individual cases for several reasons. Leptospires are not usually cultured from clinical cases because they grow slowly and the culture is not available until it is too late to influence management. Faster molecular methods of diagnosis do not affect the indications for, or implementation of chemotherapy. Antibiotic resistance has been reported in the laboratory in experimental conditions, but there are no well-authenticated reports of the isolation from a patient or the environment of a leptospire that is resistant to an antibiotic expected to have therapeutic value. Because of their slow growth, many fewer generations and mutational events can be expected during an infection with leptospires than during conventional bacterial infections. Plasmids and phages have not been reported in pathogenic leptospires; the mechanisms governing genetic variability are obscure (15, 34).
Leptospires are sensitive to most antibiotics (beta-lactams, cephalosporins, aminoglycosides, macrolides) but not to chloramphenicol, vancomycin, rifampicin and metronidazole (15, 21), Table 1. There is no evidence that any serovar or species is selectively more or less susceptible to any antibiotic.
Combination Therapy
Combination therapy to overcome the development of resistance is not indicated, and there are no tests of combinations of antibiotics useful in human medicine.
ANTIMICROBIAL THERAPY
General
Although there is still some dispute about its value, penicillin is the drug of choice where it is not contraindicated, and is effective given early in infection (20). To be effective, antibiotic treatment should be instituted as early as possible, even before the diagnosis is certain, and within the first 7-10 days after infection, (not 7-10 days after diagnosis, onset of symptoms, or hospitalization), since leptospires are removed from the tissues by natural immune mechanisms after that time. In most studies of hospitalized, jaundiced patients the illness on admission was near or past its tenth day after infection. High doses (6-8 million units of benzyl (crystalline) penicillin daily, in divided doses intramuscularly or intravenously, are recommended. Alternatively 4-5 million units of equal parts of procaine penicillin and crystalline penicillin are given daily intramuscularly, reducing the dose to half after the fever subsides, for a total of 5-7 days, continuing 1.5 million units of procaine penicillin daily until 2 days after albuminuria ceases (9, 15). Gendron et al., (18) reported successfully using 10-20 million units per day routinely. A well controlled study in severe leptospirosis patients using 6 million units per day (1.5 million units 6 hourly) intravenously showed that the treatment, even if commenced late, was effective in improving all measurable parameters in the patients (40). A contrary result was obtained in another careful analysis (8), and a short prophylactic course of an unspecified dose of an undefined penicillin preparation failed to protect against a laboratory infection with a leptospire of the Icterohaemorrhagiae serogroup (19). Despite these negative findings, penicillin as described remains the recommended treatment. Defervescence can be expected within 24h (2, 3, 5, 13, 15, 33).
In Japan, streptomycin given intramuscularly in a dose of 1 to 2 g twice daily for 2 to 4 days has been used successfully in acute leptospirosis, especially when given within the first 4-5 days of illness (21).
Special Situations
There are no special situations; the general recommendations apply to all forms of leptospirosis. Antibiotic therapy was considered to have been beneficial for treating children with leptospirosis (26). In uveitis, the same chemotherapeutic considerations apply as for other forms of leptospirosis (25, 30, 32, 38).
Underlying Diseases
Leptospirosis in HIV infected patients proceeds as in normal individuals. There is too little information to generalize about mutual influences of concurrent leptospirosis with AIDS, immunosuppression or chemotherapy for malignancy (7, 31).
Alternative Therapy
Alternative antibiotics for those allergic to penicillin include erythromycin, 250 mg 6-hourly for 5 days, or streptomycin, if given early (see above) (22). A controlled trial of doxycycline given in 100 mg oral doses twice daily showed that it reduced the severity and duration of illness (28). Although tetracyclines have been recommended (in doses of 500 mg tetracycline immediately, followed by 250 mg 8-hourly orally, or intramuscularly or intravenously if the patient is vomiting or unable to absorb orally, for 24 h, then 250-500 mg 6-hourly for 6 days), they cannot be recommended nowadays where alternatives are available. The use of tetracyclines is contraindicated in the presence of renal failure because it is nephrotoxic; likewise they should not be used in pregnant women or in children because of their effects on developing teeth and bone. There is no apparent advantage currently in using newer, more expensive and more toxic antibiotics. A recent experimental animal trial confirmed these observations (1).
Jarisch-Herxheimer (JH) reactions may occur following the institution of penicillin therapy. In typical examples, fever rose to 37.8-38.4°C with severe rigors and hypotension, 4-5 h after the institution of intravenous penicillin therapy (37, 39). The mechanism of the JH reaction in leptospirosis is not established. Toxins released by lysis of the leptospires by antibiotic may induce cytokines. Treatment with penicillin released limulus lysate active material in some patients, independent of and in the absence of a JH reaction. Management of the JH reaction is supportive and symptomatic; its effects are temporary and should not contraindicate antibiotic therapy (17,39).
Although there are many traditional treatments in all parts of the world, controlled trials have not been reported. In conditions where they are used the diagnosis of leptospirosis is not necessarily confirmed.
ADJUNCTIVE THERAPY
Symptomatic and organ-failure support for any or all of liver, kidney, respiratory or heart failure or any other system failure are essential.
ENDPOINTS FOR MONITORING THERAPY
The most important index of successful therapy in the acute febrile stage is deferevescence, generally reported to occur within 24-48 h. No antibiotic can itself reverse pathological changes, but signs of meningitis, renal and liver function can be expected to improve.
Prognosis
Most patients with leptospirosis will recover in 2-6 weeks if not jaundiced, but may not be fit to return to a normal life for a further 4 weeks. The death rate in jaundiced patients may be very low, if penicillin treatment is begun early and if renal and liver failure, myocarditis and pulmonary hemorrhages can be treated successfully. The death rates in recent well-treated and well documented studies were 0.0, 2.5, or 5.7% (8, 18, 40). Patients who recover from the severe forms, including renal failure and jaundice, can expect complete recovery. A certain proportion of patients may need support for psychological and mental problems, lasting 1-2 years or more after their illness. Ten per cent or more of patients complain of recurring, persistent headaches and uveitis for some years (35).
Reinfection
Patients cannot be reinfected and do not develop a second infection with the same serovar so long as they maintain even a low level of agglutinating antibodies in their serum. There is a dearth of information about reinfection once antibody has fallen below detectable levels. Second infections are usually with a different serovar. Exacerbation of leptospirosis due to the development of resistance to antibiotic in an individual patient has never been reported. Simultaneous infection with more than one serovar has been reported.
VACCINES
Vaccines made from a polyvalent suspension of locally prevalent serovars, given annually by subcutaneous or intramuscular injection to those at risk, are effective and have been used for many years mainly in China and Japan (6, 21, 27). These are not available or licensed in USA or Europe. A vaccine to protect sewer workers has been used in France. The major drawbacks are the development of serious painful local hypersensitivity responses at the injection site following repeated vaccination. Since immunity is serovar specific, vaccines must contain the appropriate serovar or serovars to be effective. Research is in progress to produce broadly effective vaccines. Vaccines are used widely to protect domesticated animals (dogs, pigs, cattle).
PREVENTION OR INFECTION CONTROL MEASURES
Chemoprophylaxis
Doxycycline hyclate given orally in a 200 mg single dose weekly protected military personnel exposed to risks of leptospirosis (36).
Preventive Measures, Occupational Hygiene
Prevention includes avoiding contact with animals or their urine, or surface waters such as streams, lakes, or mud contaminated with animal urine. Rodent control, and vaccination of domestic dogs to reduce risks of contacts are important in urban areas. In rural areas, in addition to rodent control, vaccination of domesticated (farm) animals (cattle, pigs), is recommended particularly to protect workers at risk. Leptospirosis is predominantly occupational; workers and others can be protected by wearing impervious footwear and protective clothing and avoiding urine splash from the animals they handle (e. g. dairy workers, abattoir workers, drainers), but this is often not practicable or acceptable. Swimming in streams or lakes is inadvisable (15). It is not possible to protect against leptospirosis originating from contamination by feral animals, unless contact with those animals is controlled by avoidance or other means.
Congenital infection is well documented (15). Direct human to human spread other than by congenital infection is virtually unknown. In principle, infection could take place from blood or urine from a patient in the acute or excretor stages. Standard blood and body fluid precautions against cross infection should always be observed, in clinical practice and in autopsy practice and in diagnostic or public health laboratories. Infection of an infant from its mother s breast milk has been recorded (4, 15,23).
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Tables
Table 1. Susceptibilities of Leptospires to Antibiotics In Vitro
Serovars: australis, autumnalis, ballum, bataviae, budapest, canicola, copenhageni, grippotyphosa, hebdomadis. icterohaemorrhagiae, kremastos, pomona, pyrogenes, robinsoni, saxkoebing, sejroe, tarassovi, zanoni, and various unspecified serovars, mostly tested in serum media at 28 or 30°C.
| Antibiotica | Sensitivitya | Concentrationa b |
|---|---|---|
| amikacin | S | 1.56 - 12.5 |
| amoxycillin | S | 0.5 |
| ampicillin | S | 0.025 |
| carbomycin | S | 10 - 100 |
| cefmetazole | S | 1 - 0.78 |
| cefotaxime | S | 0.05 - 0.1 |
| ceftizoxime | S | 0.05 - 0.2 |
| cephalothin | S | 6.25 |
| cephalothin | S | 3.13 |
| cephalothin | S | 0.78 - 6.25 |
| chloramphenicol | R | >4000 |
| chloramphenicol | S | 20 |
| chloramphenicol | I | 100 |
| chloramphenicol | R | 2000 |
| chlortetracycline | S | 1.0 - 20 |
| chlortetracycline | I | 50 |
| ciprofloxacin | S | 0.6 |
| dihydrostreptomycin | S | 0.3 |
| erythromycin | S | 0.001 - 0.01 |
| erythromycin | S | 0.00002 |
| erythromycin | S | 0. 63 |
| erythromycin | S | 0.025 |
| erythromycin | S | 1 - 5 |
| erythromycin | S | 0.1 - 1 |
| kanamycin | S | 0.25 - 0.5 |
| kanamycin | S | 3.13 - 12.5 |
| lincomycin | S | 2.5 |
| methicillin | S | 6.6 |
| metronidazole | S | 100 |
| minocycline | S | 0.08 - 0.625 |
| moxalactam | S | 0.2 - 0.78 |
| novobiocin | S | 20 |
| oxytetracycline | S | 1.0 |
| oxytetracycline | S | 1 - 10 |
| oxytetracycline | S | 0.25 |
| penicillin, benzyl | S | 0.005 - 0.2 |
| penicillin V | S | 0.2 |
| penicillin G | S | 10.0 |
| pipericillin | S | 0.39 - 0.78 |
| polymyxin | S | 10 |
| sulfamethoxy-pyridazine | R | >2000 |
| streptomycin | S | 3.5 - 20 |
| streptomycin | S | 0.2 - 0.4 |
| streptomycin | S | 0.39 ->100 |
| tetracycline | S | 0.04 - 4 |
| tetracycline | S | 10 |
| tobramycin | S | 1.56 - 6.25 |
| tobramycin | S | 6.25 |
| tobramycin | S | 1.56 |
| tropolon compounds | S | 0.5 - 2 |
| vancomycin | R | 50 - 200 |
| vancomycin | R | 10 |
| viomycin | R | >500 |
| Serovar: hardjo Species: interrogans, in oleate-albumin medium at 29°C | ||
| ampicillin | S | ≥1.0 |
| chloramphenicol | R | >10.0 <100 |
| colimycin | S | >1.0 <10.0 |
| doxycycline | S | >1.0 <10.0 |
| erythromycin | S | ≥1.0 |
| ethambutol | R | >100.0 |
| furadantin | R | >10.0 <100 |
| gentamicin | S | >1.0 <10.0 |
| INH | R | >100.0 |
| keflex | R | >10.0 <100 |
| keflin | R | >10.0 <100 |
| lincomycin | S | ≥1.0 |
| neomycin | R | >10.0 <100 |
| PAS | R | >100.0 |
| polymyxin | R | >10.0 <100 |
| rifampicin | R | >100.0 |
| streptomycin | S | ≥1.0 |
| terramycin | S | >1.0 <10.0 |
| tetracycline | S | ≥1.0 |
| tetracycline | S | ≥1.0 |
| vancomycin | R | >100.0 |
a Sensitivity: S = sensitive; R = resistant; I = intermediate. Interpretations, names of antibiotics, concentrations and names of leptospires are generally those used by the authors.
b Units: µg/mL.
(Summarized and modified with copyright permission from Faine et al, (15) , where the extended Table (Appendix 1, Table 4.2, pp. 188 - 192) includes details of strains and species, susceptibilities, test conditions and references to the original tests. See also (22) , Table 2, p. 65).