Murine typhus is a disease caused by Rickettisa typhi, an obligate intracellular bacterium
transmitted by rodent fleas. The disease has a worldwide distribution; however the true
burden is unknown, related to its non-specific presentation and lack of access to diagnosis
in many regions. A systematic review of untreated murine typhus based on observational
studies of a total of 239 patients has estimated the mortality associated with the disease at
between 0.4% and 3.6%.
Scrub typhus is caused by Orientia tsutsugamushi and transmitted by the larval stage of
chigger mites (Trombiculidae family). It has been estimated to affect at least one million
people each year. A systematic review found varying reports of the mortality associated with
untreated scrub typhus ranging from 0-70% (median 6%).
Polymerase chain reaction (PCR) based diagnosis of rickettsial infections is only available
in one centre (Mahosot Hospital) in Vientiane. A number of hospitals use a variety of
point-of-care antibody tests to diagnose rickettsial infections however many of these have
not been validated and they are of uncertain sensitivity and specificity. In 2006 results of
a two year prospective study of 427 patients presenting to Mahosot Hospital with a febrile
illness and negative blood cultures showed that 115 (27%) patients had an acute rickettsial
infection, confirmed by serological testing. Among these patients, 41 were diagnosed with
murine typhus and 63 with scrub typhus. Antibacterial agents with activity against
rickettsial pathogens include doxycycline, azithromycin, chloramphenicol and rifampicin.
Azithromycin is often reserved for pregnant women or children below the age of 8 years due to
lasting concerns after the tetracycline-associated staining of growing bones and teeth in the
past. Evidence is accumulating that doxycycline is superior to azithromycin for the treatment
of rickettsial disease. Clinical treatment failures have occurred following azithromycin
treatment of murine typhus. The relationship between rickettsial bacteria load and both
disease severity and response to treatment has not been characterised. Rickettsial
concentrations in blood are generally low, of the order of 210 DNA copies/mL blood for R.
typhi and 284 DNA copies/mL blood for O. tsutsugamushi. At present, there is no standard
antibiotic susceptibility testing (AST) method for R. typhi and O. tsutsugamushi. The gold
standard method for AST for Rickettsia pathogens is the plaque assay which determines minimal
inhibitory concentration (MICs) from the smallest antimicrobial concentration inhibiting
rickettsial plaque forming unit formation. This method is laborious and time consuming,
taking approximately 14-16 days based on species to yield a result. Molecular detection
methods are useful for diagnosing patients infected with rickettsial pathogens and has been
applied for antibiotic susceptibility testing. Antibiotic susceptibility testing based on DNA
synthesis inhibition detecting by quantitative PCR (qPCR) for O. tsutsugamushi clinical
isolates has been reported. However, the relationship between antibiotic susceptibility
profiles and treatment response has not been studied. There is a need to develop a reliable
ex vivo method to characterize the treatment response and compare susceptibility of R. typhi
and O. tsutsugamushi to different agents.
Phase:
Phase 2/Phase 3
Details
Lead Sponsor:
Lao-Oxford-Mahosot Hospital Wellcome Trust Research Unit