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Randomized Controlled Trial
. 2019 Feb 15;68(5):738-747.
doi: 10.1093/cid/ciy563.

A Prospective, Open-label, Randomized Trial of Doxycycline Versus Azithromycin for the Treatment of Uncomplicated Murine Typhus

Paul N Newton  1   2 , Valy Keolouangkhot  3 , Sue J Lee  2   4 , Khamla Choumlivong  5 , Siho Sisouphone  3 , Khamloune Choumlivong  5 , Manivanh Vongsouvath  1 , Mayfong Mayxay  1   2   6 , Vilada Chansamouth  1 , Viengmon Davong  1 , Koukeo Phommasone  1 , Joy Sirisouk  1 , Stuart D Blacksell  1   2   4 , Pruksa Nawtaisong  1 , Catrin E Moore  1   2 , Josée Castonguay-Vanier  1 , Sabine Dittrich  1   2 , Sayaphet Rattanavong  1 , Ko Chang  3 , Chirapha Darasavath  3 , Oudayvone Rattanavong  3 , Daniel H Paris  2   4   7   8 , Rattanaphone Phetsouvanh  1   2   4
Affiliations
Randomized Controlled Trial

A Prospective, Open-label, Randomized Trial of Doxycycline Versus Azithromycin for the Treatment of Uncomplicated Murine Typhus

Paul N Newton et al. Clin Infect Dis. .

Abstract

Background: Murine typhus, or infection with Rickettsia typhi, is a global but neglected disease without randomized clinical trials to guide antibiotic therapy.

Methods: A prospective, open, randomized trial was conducted in nonpregnant, consenting inpatient adults with rapid diagnostic test evidence of uncomplicated murine typhus at 2 hospitals in Vientiane, Laos. Patients were randomized to 7 days (D7) or 3 days (D3) of oral doxycycline or 3 days of oral azithromycin (A3). Primary outcome measures were fever clearance time and frequencies of treatment failure and relapse.

Results: Between 2004 and 2009, the study enrolled 216 patients (72 per arm); 158 (73.2%) had serology/polymerase chain reaction (PCR)-confirmed murine typhus, and 52 (24.1%) were R. typhi PCR positive. The risk of treatment failure was greater for regimen A3 (22.5%; 16 of 71 patients) than for D3 (4.2%; 3 of 71) or D7 (1.4%; 1 of 71) (P < .001). Among R. typhi PCR-positive patients, the area under the time-temperature curve and the fever clearance time were significantly higher for A3 than for D3 (1.8- and 1.9-fold higher, respectively; P = .005) and D7 (1.5- and 1.6-fold higher; P = .02). No patients returned with PCR-confirmed R. typhi relapse.

Conclusion: In Lao adults, azithromycin is inferior to doxycycline as oral therapy for uncomplicated murine typhus. For doxycycline, 3- and 7-day regimens have similar efficacy. Azithromycin use in murine typhus should be reconsidered. Investigation of genomic and phenotypic markers of R. typhi azithromycin resistance is needed.

Clinical trial registration: ISRCTN47812566.

Keywords: Rickettsia typhi; Laos; azithromycin; doxycycline; murine typhus.

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Figures

Figure 1.
Figure 1.
Flowchart of the clinical trial. Patients were excluded (n = 264) because they were unlikely to be able to stay on the ward for 7 days and/or complete follow-up (95 patients; 36.0%), had severe disease (50; 18.9%), had taken antirickettsial antibiotics (31; 11.7%), were not admitted to the study wards (27; 10.2%), declined consent (23; 8.7%), were pregnant or breastfeeding (11; 4.2%), were children (10; 3.8%), or had an alternative confirmed diagnosis before being approached for consent (8; 3.0%); 6 patients (2.3%) were excluded for unrecorded reasons, and 3 (1.1%) withdrew from the study. The confirmed totals included those without culture or polymerase chain reaction evidence of dual pathogens.
Figure 2.
Figure 2.
Monthly recruitment of patients by admission month. Abbreviations: Aug, August; Dec, December; Feb, February; Jan, January; Nov, November; Oct, October; Sep, September.
Figure 3.
Figure 3.
Kaplan-Meier plot of fever clearance for all patients who presented with or developed fever (n = 203).
Figure 4.
Figure 4.
Kaplan-Meier plot of fever clearance for patients with serology- or polymerase chain reaction (PCR)–confirmed murine typhus (n = 146).
Figure 5.
Figure 5.
Kaplan-Meier plot of fever clearance for patients with polymerase chain reaction (PCR)–confirmed murine typhus only (n = 49).
See this image and copyright information in PMC

References

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