Antibiotic Response to Pediatric Scrub Typhus in South India: Is Clinical Failure to Azithromycin to be Worried?

Abstract

Background Scrub typhus is typically associated with a rapid defervescence and clinical improvement within 48 h of initiation of appropriate antibiotics. But increasing reports of resistance to anti-rickettsial medications in scrub typhus are being reported in the literature. Methods This is a retrospective observational study of children up to the age of 14 years admitted between July 2017 and March 2020, to a private medical college hospital in southern part of India. The aim of this study was to compare the clinical response to antibiotic therapy with doxycycline and azithromycin in pediatric scrub typhus infection. Results One hundred thirty-eight children with scrub typhus infection were included for analysis. The median fever control time (h) was 12 (IQR = 6–29) and 24 (IQR = 10–52) with doxycycline and azithromycin respectively (p < 0.001*). Rapid fever control within 48 h was observed in 92% with doxycycline and in 74% with azithromycin (p < 0.001*). The clinical failure rate (defined by the necessity to change the antibiotics due to: (i) worsening of symptoms and signs of scrub typhus despite 48 h of antibiotics or (ii) persistence of fever and other symptoms of scrub typhus beyond 72 h), was significantly less with doxycycline (1%) compared with azithromycin (9.6%). Conclusion There has been a significant delayed clinical response to azithromycin in the treatment of scrub typhus in India, when compared to doxycycline. Hence it is preferable to use doxycycline as the first line of antibiotic for undifferentiated fever in scrub typhus endemic areas. Lay summary This retrospective study aims to compare the clinical response to doxycycline or azithromycin in the treatment of scrub typhus infection in children. The median fever control time, clinical failure rate and the proportion of children with rapid defervescence of fever within 48 h were significantly superior with doxycycline as compared to azithromycin. The findings of this study and those of similar studies in India represent a spectrum of delayed clinical response of Orientia tsutsugamushi to azithromycin as compared to doxycycline in this region.

Doxycycline vs azithromycin in patients with scrub typhus: a systematic review of literature and meta-analysis

“…There were five RCTs [ 18 , 21 , 25 – 27 ]. Four studies included only paediatric patients (less than 14-18 years) [ 21 , 22 , 24 , 25 ]. The remaining six incorporated either adults or individuals of any age.…”

“…Six studies excluded the use of antibiotics (active for scrub typhus) before presentation (Supplementary Table 4 ). Only one study explicitly mentioned that co-infections were ruled out [ 24 ]. Four studies exclusively focussed on patients with mild scrub typhus [ 21 , 25 – 27 ].…”

“…Three studies focused entirely on severe scrub typhus patients [ 18 , 19 , 23 ]. The other three studies had severe scrub typhus ranging from 16% to 51% [ 20 , 22 , 24 ].…”

Open-labeled Randomized Controlled Trial on Efficacy of Azithromycin Versus Doxycycline in Pediatric Scrub Typhus

“…Patients who did not achieve defervescence after 72 hours of the interventional drug were labeled as treatment failure cases and were switched over to the alternate drug, but the outcome of these cases was not mentioned. While observational studies have provided conflicting findings, 22,23 a comprehensive meta-analysis of RCTs demonstrated that AZ and DX exhibited similar efficacy in achieving disease cure, although this included mainly adult data. 21 Our study protocol had left the management of children who were labeled as treatment failure to the discretion of the treating physician.…”

Clinical profile and predictors of therapeutic outcome with azithromycin in pediatric scrub typhus: A study from Eastern India

“…Some previous studies have given mixed results comparing azithromycin to doxycycline in treating scrub typhus. [17][18][19] Meta-analysis from eligible studies, however, showed that azithromycin was as efficacious as doxycycline in achieving clinical cure and defervescence at 48 h, with the azithromycin group having significantly fewer adverse events and treatment failure. 11,[20][21][22][23][24] Studies have also highlighted an emerging resistance to doxycycline in south and east Asian regions, but both resistant strains were found to be highly sensitive to azithromycin.…”