Current Strategies in the Management of Leptospirosis

Conference Coverage

By Mary-Louise Scully, MD

Sansum-Santa Barbara Medical Foundation Clinic, Santa Barbara, CA

Dr. Scully reports no consultant, stockholder, speaker’s bureau, research, or other financial relationship with any company having ties to this field of study.

Drs. Clinton K. Murray and Duane R. Hospenthal convened a symposium on current strategies in the management of leptospirosis at the recent Annual Meeting of the American Society of Tropical Medicine and Hygiene in Washington DC, December 11-15, 2005. Dr. Joseph Vinetz began the symposium with an overview of the epidemiology of leptospirosis. Leptospirosis is a zoonosis caused by pathogenic spirochetes of the genus Leptospira, of which there are over 200 serovars. Leptospirosis is maintained in nature by chronic renal infection of carrier animals that excrete the organism in their urine, thus contaminating the environment. Rodents and small mammals are the most important reservoirs, but livestock and companion animals, such as dogs, can also serve as sources of infection for humans. Human infection occurs through direct or indirect contact with urine or tissues of infected animals. Traditionally, leptospirosis has been a sporadic disease of various rural and tropical settings, usually in persons with specific risk associations, such as veterinarians, farmers, abattoir, and sewer workers. Some recent outbreaks have been associated with adventure tourism and certain water-associated recreational activities, such as the Eco-Challenge and Triathlon participants.1,2

However, leptospirosis is increasingly recognized as a major urban pathogen capable of significant epidemic activity in Latin America. Dramatic urban population growth in places such as Brazil has resulted in the creation of urban slums (favelas), with poor sanitation and rodent infestation. Annual epidemics occur in these areas after seasonal heavy rainfall and flooding. In Brazil alone, approximately 10,000 cases are reported each year from all major cities, with mortality of 10-15%. However, mortality can climb to over 50% in patients who develop severe pulmonary hemorrhage, now recognized as a presentation of severe disease acquired in urban areas. In a recent study from Iquitos, Peru, of 633 febrile patients, 50.7% had serologic evidence of acute leptospiral infection. Seven patients had severe pulmonary manifestations, and 5 of these patients died. Severe cases were associated with urban as opposed to rural exposure and certain Leptospira serovars may be more virulent than others. High levels of leptospiremia as detected by PCR were present in most fatal cases, implying an inoculum effect may also contribute to the development of more severe disease.3

The urgent need for the development of new serodiagnostic tests to differentiate leptospirosis other acute illnesses in the tropics was next discussed by Dr. Albert Ko. Leptospirosis may not be high in the differential diagnosis until more classic manifestations, such as fever, jaundice, and renal failure develop (known as Weil’s disease). The standard serologic test, the microscopic agglutination test (MAT), is performed mostly in reference laboratories and often requires paired sera, making it less helpful for rapid diagnosis. Similarly, the long delay of traditional culture isolation techniques limits its usefulness to the clinician. Some whole-cell leptospiral antigen preparations have been developed but can have less than 70% sensitivity in the first week of illness. Sensitivity increases after 7-10 days, so a second sample should be taken again if the diagnosis is still in question. The use of recombinant Leptospira antigen-based ELISAs has been investigated as well.4 More recent work with leptospiral immunoglobulin-like repeat (Lig) proteins shows promise as an early diagnostic test, and may be available in the near future.

The use of antimicrobial agents for leptospirosis was addressed by Dr. Clinton Murray. To assess the increasing array of antibiotics potentially useful for treatment of leptospirosis, he and colleagues developed an in vitro microdilution technique which is more efficient at evaluating a greater number of antimicrobial agents and Leptospira serovars than the traditional macrodilution tests. Many antimicrobials were found to have in vitro activity against Leptospira including traditional antileptospiral drugs, such as penicillin G, doxycycline, and ceftriaxone but also erythromycin, clarithromycin, telithromycin, cefepime, and imipenem-cilastatin.5 A hamster model of leptospirosis also showed efficacy of various agents including doxycycline, azithromycin, and telithromycin. In related data presented in an abstract, telithromycin produced a 98% survival against a lethal challenge in the hamster model of acute leptospirosis.6 Although it is unlikely these newer, more expensive agents will supplant the use of less expensive medicines, such as penicillin or doxycycline in developing countries; the information on the newer macrolides and ketolide agents is useful. Clinical trials of antimicrobial agents are mostly limited to penicillin, doxycycline, cefotaxime, and ceftriaxone. A randomized, controlled trial in Thailand demonstrated doxycycline and cefotaxime to be satisfactory alternatives to penicillin G for the treatment of severe leptospirosis.7 In addition, ceftriaxone was found to be as effective as penicillin for the treatment of acute, severe leptospirosis.8 The advantage of once daily dosing and the possibility of intramuscular administration are 2 advantages of ceftriaxone over penicillin.

Wrapping up the symposium, Dr. David Haake presented the latest work on vaccine development, an area that has been challenging. The work on a subset of outer membrane proteins exposed on the surface of a bacterial cell (the surfaceome) is the focus of recent efforts. Some of these proteins include LipL32, LipL21, LipL41, and OmpL1. Also, the leptospiral immunoglobulin-like (Lig) proteins such as Lig A and Lig B, whose induction may be influenced by osmolarity, are potential vaccine candidates.9 Although only partial protection has been achieved to date, it is hoped that these various outer membrane proteins hold promise as vaccine candidates, in that they are relatively well conserved across the pathogenic species of Leptospira.

References

  1. Sejvar J, et al. Leptospirosis in "Eco-Challenge" Athletes, Malaysian Borneo, 2000. Emerg Infect Dis. 2003;9:702-707.
  2. Morgan J, et al. Outbreak of Leptospirosis Among Triathlon Participants and Community Residents in Springfield, Illinois, 1998. Clin Infect Dis. 2002;34:1593-1599.
  3. Segura ER, et al. Clinical Spectrum of Pulmonary Involvement in Leptospirosis in a Region of Endemicity, with Quantification of Leptospiral Burden. Clin Infect Dis. 2005;40:343-351.
  4. Flannery B, et al. Evaluation of Recombinant Leptospira Antigen-Based Enzyme-Linked Immunosorbent Assays for the Serodiagnosis of Leptospirosis. J Clin Microbiol. 2001;39:3303-3310.
  5. Murray CK and Hospenthal DR. Determination of Susceptibilities of 26 Leptospira sp. serovars to 24 Antimicrobial Agents by a Broth Microdilution Technique. Antimicrob Agents Chemother. 2004;48:4002-4005.
  6. Moon JE, et al. Efficacy of Telithromycin in the Treatment of a Hamster Model of Leptospirosis. Abstracts of the 54th Annual Meeting of the American Society of tropical Medicine and Hygiene, Washington, DC December 11-15, 2005. Abstract #169.
  7. Suputtamongkol Y, et al. An Open, Randomized, Controlled Trial of Penicillin, Doxycycline, and Cefotaxime for Patients with Severe Leptospirosis. Clin Infect Dis. 2004;39:1417-1424.
  8. Panaphut T, et al. Ceftriaxone Compared with Sodium Penicillin G for the Treatment of Severe Leptospirosis. Clin Infect Dis. 2003;36:1507-1513.
  9. Matsunaga J, et al. Osmolarity, a Key Environmental Signal Controlling Expression of Leptospiral Proteins LigA and LigB and the Extracellular Release of Lig A. Infect Immun. 2005;73:70-78.