Plasma and Intracellular Concentrations of Doxycycline and Azithromycin in Patients with Severe Scrub Typhus
Year: 2026
Type: article
Abstract: BACKGROUND/OBJECTIVES: , is treated with doxycycline or azithromycin. In severe disease, combination therapy with azithromycin and doxycycline had better clinical outcomes than either drug alone. However, it is not clear what causes the improved efficacy. To understand the same, we examined the plasma concentrations, intracellular concentrations, and efficacy of doxycycline, azithromycin, and both drugs in combination in 51 patients with severe scrub typhus. METHODS: A randomly selected subset of adult (>18 years) participants from the INTREST trial (Clinical Trials Registry-India, number CTRI/2018/08/015159), who had been randomized in a 1:1:1 ratio to receive doxycycline, azithromycin, or both drugs, respectively, were included in this study for comparative drug concentration analysis. Blood samples were collected on days 0, 1, 3, and 7 to monitor bacterial load using quantitative polymerase chain reaction (PCR). Five milliliters of sterile blood were collected 3-10 h after the final dose on day 7 for comparative drug concentration measured using high-resolution multiple reaction monitoring. Data were analyzed in GraphPad Prism v.10.0.3. RESULTS: Fifty-one patients (males, 59%; median age, 52 years) were enrolled. Fifteen, seventeen, and nineteen patients received azithromycin, doxycycline, and both, respectively. Doxycycline achieved a median plasma concentration of 1112 (42.51-5697) ng/mL and was undetectable intracellularly. The intracellular concentration of azithromycin (1127 [16.78-19,250] ng/mL) surpassed its plasma concentration (227.1 [48.78-1022] ng/mL). On day 3, PCR negativity rates were 56.24%, 93.3%, and 94.7% in the doxycycline, azithromycin, and combination groups, respectively. CONCLUSIONS: The high plasma concentrations of doxycycline and intracellular accumulation of azithromycin may contribute to improved clinical outcomes when used in combination.
Source: Antibiotics
Authors: Debasree Kundu, Merylin Sebastian, Shadab Ahmad, Sohail Khan, Divya Dayanand, Blessed Winston Aruldhas, Binu Susan Mathew, Karthik Gunasekaran, Nalini Newbigging, Kundavaram P. P. Abhilash, Anand Zachariah, Ramya Iyadurai, Samuel George Hansdak, Sowmya Sathyendra, Thambu David Sudarsanam, Abi Manesh, John Victor Peter, Jeanne Salje, Ooriapadickal C. Abraham, Nicholas P. J. Day, Joel Tarning, George M. Varghese
Language: English
Subfield: Pharmacology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,499
Funder: Wellcome Trust
OpenAlex ID: W7160154637