Abstract
Scrub typhus, a neglected infectious disease caused by the obligate intracellular bacterium Orientia tsutsugamushi, is a major cause of fever across the Asia Pacific region with more than a billion people at risk. Treatment with antibiotics such as doxycycline or chloramphenicol is effective for the majority of patients. In the 1990s, reports from northern Thailand raised a troubling observation; some scrub typhus patients responded poorly to doxycycline, which investigators attributed to doxycycline resistance. Despite the controversial nature of these reports, independent verification was neglected, with subsequent studies speculating on the role of doxycycline resistance in contributing to failure of treatment or prophylaxis. In this review, we have outlined the evidence for drug-resistant Orientia tsutsugamushi, assessed the evidence for doxycycline resistance, and highlight more recent findings unsupportive of doxycycline resistance. We conclude that doxycycline resistance is a misconception, with treatment outcome likely to be determined by other bacterial, host, and pharmacological factors.
Highlights
In response to these reports, a small clinical trial was carried out involving patients with scrub typhus in Thailand—12 from Chiang Rai, Chiang Rai Province, and 7 from Mae Sot, Tak Province—and reported in 1996 [8]
The results appeared to show that 1 O. tsutsugamushi isolate, labeled AFC-3, was resistant to doxycycline with a minimum inhibitory concentration (MIC) of >4 μg/mL whereas another isolate, labeled AFC-27, was at least partially resistant to doxycycline [8]
An O. tsutsugamushi isolate, AFSC-4, cultured from a patient with delayed response to antibiotic treatment from western Thailand in 1990, was found to be less susceptible to doxycycline than the reference Karp strain whereas azithromycin appeared effective for both strains [9]
Summary
A neglected infectious disease caused by the obligate intracellular bacterium Orientia tsutsugamushi, is a major cause of fever across the Asia Pacific region with more than a billion people at risk Treatment with antibiotics such as doxycycline or chloramphenicol is effective for the majority of patients. An O. tsutsugamushi isolate, AFSC-4, cultured from a patient with delayed response to antibiotic treatment from western Thailand in 1990, was found to be less susceptible to doxycycline than the reference Karp strain whereas azithromycin appeared effective for both strains [9]. There have been additional O. tsutsugamushi isolates, cultured from patients from northern Thailand as part of a larger clinical trial in the 1990s with delayed responses to therapy and studied by the US military, but the detailed methodology and results remain unpublished, with only a short summary available in a recent review [16]. The natural resistance of O. tsutsugamushi to β-lactams have previously been attributed to the absence of peptidoglycan, but recent reports suggest that a peptidoglycan remnant is present [22]
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