Intravenous Doxycycline, Azithromycin, or Both for Severe Scrub Typhus

Varghese, George; Dayanand, Divya; Gunasekaran, Karthik; Kundu, Debasree; Wyawahare, Mukta; Sharma, Navneet; Chaudhry, Dhruva; Mahajan, S.; Saravu, Kavitha; Aruldhas, Blessed W; Mathew, Binu; Nair, Roshini G; Newbigging, Nalini; Mathew, Aswathy; Abhilash, Kundavaram Pp; Biswal, Manisha; Prasad, Ann H; Zachariah, Anand; Iyadurai, Ramya; Hansdak, Samuel George; Sathyendra, Sowmya; Sudarsanam, Thambu David; Prakash, John Antony Jude; Manesh, Abi; Tärning, Joel; Blacksell, Stuart D.; Peerawaranun, Pimnara; Waithira, Naomi; Mukaka, Mavuto; Cheah, Phaik Yeong; Peter, John Victor; Abraham, Ooriapadickal Cherian; Day, Nicholas P. J.

doi:10.1056/nejmoa2208449

Cited by 40 publications

(31 citation statements)

References 30 publications

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“…However, caution must be taken when extrapolating these results to other ST-endemic areas. The 28-day mortality rate (ie, death at day 28) in the study by Varghese et al [ 33 ] was 12% (96/794), higher than that in our study cohort (1.8%, 1/55) and that of another study in Japan (0.5%, 1/188) [ 34 ]. The difference in mortality rates among these ST-endemic areas reflects strain virulence, including differences between L. delicense –mediated strains in India and L. scutellae –mediated strains (serotype Irie/Kawasaki and Hirano/Kuroki) in Japan.…”

Section: Discussioncontrasting

confidence: 77%

“…Combination therapy with intravenous doxycycline and azithromycin in cases of severe ST is associated with a lower incidence of composite primary outcomes (ie, cardiovascular, respiratory, central nervous system, renal, and hepatic system complications) than a single administration of doxycycline or azithromycin. Meanwhile, similar rates of 28-day mortality are achieved following treatment with doxycycline or azithromycin alone or in combination [ 33 ]. However, caution must be taken when extrapolating these results to other ST-endemic areas.…”

Section: Discussionmentioning

confidence: 99%

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Masqueraders Around Disaster: Clinical Features of Scrub Typhus in Fukushima, Japan

Narita,

Monma,

Chiba

et al. 2024

Open Forum Infectious Diseases

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Background Scrub typhus (ST) is endemic in Fukushima, with the largest number of cases reported in Japan from 2006 to 2011. Although ST is highly treatable, its atypical clinical presentation impedes diagnosis, causing delays in treatment. Methods We review the clinical features of ST in adults from 2008 to 2017 at Ohta Nishinouchi General Hospital in Fukushima, Japan. Results Fifty-five cases (serotype Karp 24, Irie/Kawasaki 21, Hirano/Kuroki 10) of ST were confirmed via serology based on elevated IgM and IgG and polymerase chain reaction positivity of eschar samples. The mean age was 69 years old, and 64% were female. The case fatality rate was 1.8% (1/55). Approximately 70% of cases (38/55) were not diagnosed as ST upon the initial clinic visit. Inappropriate use of antibiotics was identified in 22% of the cases (12/55). In terms of atypical clinical features, the fever, rash, and eschar triad were absent in 31% of cases (17/55). Approximately 11% of cases presented without eschar (6/55, Karp: 1, Irie/Kawasaki: 1, Hirano/Kuroki: 4). Moreover, severe complications were observed in association with Hirano/Kuroki, with shock and disseminated intravascular coagulation in 7% of cases (4/55), Thus, while 53% of cases presented with the typical triad (29/55), unusual complications and atypical features occurred in 40% (22/55). The fatality rate was 1.8% (1/55). Conclusions The diagnosis of ST becomes clinically challenging in the absence of typical features. In Fukushima, an endemic area of ST, an atypical presentation involving multi-system disease is common.

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Section: Discussioncontrasting

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Masqueraders Around Disaster: Clinical Features of Scrub Typhus in Fukushima, Japan

Narita,

Monma,

Chiba

et al. 2024

Open Forum Infectious Diseases

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“…Ten studies with 2856 patients were included in this analysis, with sample sizes ranging from 57 to 780 [ 18 – 27 ] (Table 1 ). Seven of the ten studies were published during or after 2021.…”

Section: Resultsmentioning

confidence: 99%

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

Gupta,

Boodman,

Jouego

et al. 2023

BMC Infect Dis

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Introduction Scrub typhus is a bacterial mite-borne disease associated with poor clinical outcomes if not treated adequately. The study aimed to compare the time to defervescence, clinical failure, mortality and treatment-related adverse effects of two common drugs (doxycycline and azithromycin) used for its treatment. Methodology This was a systematic review and meta-analysis. All studies up to 20.03.2023 were screened for eligibility in Pubmed and Embase using a search string containing terms related to scrub typhus, doxycycline and azithromycin. After two phases of screening, all comparative studies where doxycycline and azithromycin were used to treat scrub typhus were included. The studies were critically appraised using standardised tools, and a meta-analysis was performed for time to defervescence (primary outcome), clinical failure, mortality and treatment-related adverse effects. Results Of 744 articles from two databases, ten were included in the meta-analysis. All but two studies had a high risk of bias. The meta-analysis for time to defervescence had a high heterogeneity and did not show any significant difference between doxycycline and azithromycin arms [Mean difference of -3.37 hours (95%CI: -10.31 to 3.57), p=0.34]. When the analysis was restricted to studies that included only severe scrub typhus, doxycycline was found to have a shorter time to defervescence [mean difference of -10.15 (95%CI: -19.83 to -0.46) hours, p=0.04]. Additionally, there was no difference between the two arms concerning clinical failure, mortality and treatment-related adverse effects. Conclusion The current data from studies with a high risk of bias did not find statistically significant differences in clinical outcomes between doxycycline and azithromycin for scrub typhus

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“…A recent publication from Varghese et al . 22 suggested that the combination of IV doxycycline and azithromycin was more effective than doxycycline or azithromycin alone for severe rickettsial diseases. This should be taken into a consideration to update Lao national prescribing guidelines for severe infections.…”

Section: Infectious Disease and Amr Epidemiology In Laosmentioning

confidence: 99%

Implementing the WHO AWaRe antibiotic book guidance in lower-resource settings: the case of the Lao PDR

Chansamouth,

Inlorkham,

Keohavong

et al. 2023

JAC-Antimicrobial Resistance

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In 2022, WHO released the WHO AWaRe (Access, Watch, Reserve) antibiotic book to promote the rational use of antibiotics. Here, we review the AWaRe antibiotic book from the perspective of implementation in low-resource settings, using the Lao PDR (Laos) as a case study. Not all recommendations in the AWaRe antibiotic book match the epidemiology of infectious diseases and antimicrobial susceptibility patterns in Laos and other low- and middle-income countries (LMICs), e.g. melioidosis, rickettsial disease and leptospirosis are common causes of sepsis and febrile illness in Laos but do not feature in the AWaRe book. Conversely, some infectious diseases like Clostridioides difficile-associated diarrhoea are in the AWaRe antibiotic book but rarely considered in Laos with no diagnostic tests available. Only 29/39 antibiotics in the AWaRe book are available in Laos, with no Reserve group antimicrobials available. The AWaRe book stimulates countries such as Laos to consider alternative diagnoses and include additional antimicrobials in the national essential medicines list (NEML). However, it should be updated to include regional important pathogens that are not included. Comprehensive antibiotic use guidelines alone might not assure appropriate use or control overuse of antibiotics. Access to antibiotics is challenging in low-resource settings in terms of unavailability in the country (low demand or small market size), patchy access, especially for those living in remote areas, and unaffordability. All these systemic factors can contribute to inappropriate use of antibiotics. Improved access to antibiotics, strengthening diagnostic capacity and promoting antibiotic stewardship should be combined.

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Intravenous Doxycycline, Azithromycin, or Both for Severe Scrub Typhus

Cited by 40 publications

References 30 publications

Masqueraders Around Disaster: Clinical Features of Scrub Typhus in Fukushima, Japan

Masqueraders Around Disaster: Clinical Features of Scrub Typhus in Fukushima, Japan

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

Implementing the WHO AWaRe antibiotic book guidance in lower-resource settings: the case of the Lao PDR

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