Treatment Response in Enteric Fever in an Era of Increasing Antimicrobial Resistance: An Individual Patient Data Analysis of 2092 Participants Enrolled into 4 Randomized, Controlled Trials in Nepal.
Enteric fever, caused by Salmonella Typhi and Salmonella Paratyphi A, is the leading cause of bacterial febrile disease in South Asia.
Individual data from 2092 patients with enteric fever randomized into 4 trials in Kathmandu, Nepal, were pooled. All trials compared gatifloxacin with 1 of the following comparator drugs: cefixime, chloramphenicol, ofloxacin, or ceftriaxone. Treatment outcomes were evaluated according to antimicrobial if S. Typhi/Paratyphi were isolated from blood. We additionally investigated the impact of changing bacterial antimicrobial susceptibility on outcome.
Overall, 855 (41%) patients had either S. Typhi (n = 581, 28%) or S. Paratyphi A (n = 274, 13%) cultured from blood. There were 139 (6.6%) treatment failures with 1 death. Except for the last trial with ceftriaxone, the fluoroquinolone gatifloxacin was associated with equivalent or better fever clearance times and lower treatment failure rates in comparison to all other antimicrobials. However, we additionally found that the minimum inhibitory concentrations (MICs) against fluoroquinolones have risen significantly since 2005 and were associated with increasing fever clearance times. Notably, all organisms were susceptible to ceftriaxone throughout the study period (2005-2014), and the MICs against azithromycin declined, confirming the utility of these alternative drugs for enteric fever treatment.
The World Health Organization and local government health ministries in South Asia still recommend fluoroquinolones for enteric fever. This policy should change based on the evidence provided here. Rapid diagnostics are urgently required given the large numbers of suspected enteric fever patients with a negative culture.
Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.|Centre for Tropical Medicine and Global Health, University of Oxford, United Kingdom.
Corinne N
CN
Thompson
Oxford University Clinical Research Unit, Patan Academy of Health Sciences, Lalitpur, and.
Abhilasha
A
Karkey
Oxford University Clinical Research Unit, Patan Academy of Health Sciences, Lalitpur, and.
Sabina
S
Dongol
Oxford University Clinical Research Unit, Patan Academy of Health Sciences, Lalitpur, and.
Amit
A
Arjyal
Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.|Centre for Tropical Medicine and Global Health, University of Oxford, United Kingdom.
Marcel
M
Wolbers
Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.
Thomas
T
Darton
Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.|Centre for Tropical Medicine and Global Health, University of Oxford, United Kingdom.
Jeremy J
JJ
Farrar
Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.|Centre for Tropical Medicine and Global Health, University of Oxford, United Kingdom.
Guy E
GE
Thwaites
Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.|Centre for Tropical Medicine and Global Health, University of Oxford, United Kingdom.|Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand ; and.
Christiane
C
Dolecek
Centre for Tropical Medicine and Global Health, University of Oxford, United Kingdom.|Oxford University Clinical Research Unit, Patan Academy of Health Sciences, Lalitpur, and.|Global Antibiotic Resistance Partnership, Nepal.
Buddha
B
Basnyat
Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.|Centre for Tropical Medicine and Global Health, University of Oxford, United Kingdom.|Department of Medicine, University of Cambridge, United Kingdom.
Stephen
S
Baker
D000293:Adolescent; D000328:Adult; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D017963:Azithromycin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D002443:Ceftriaxone / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D002648:Child; D024901:Drug Resistance, Multiple, Bacterial; D005260:Female; D024841:Fluoroquinolones / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D000077734:Gatifloxacin; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D009390:Nepal / Q000453:epidemiology; D015242:Ofloxacin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D010284:Paratyphoid Fever / Q000188:drug therapy* / Q000382:microbiology; D012482:Salmonella paratyphi A / Q000187:drug effects* / Q000302:isolation & purification; D012485:Salmonella typhi / Q000187:drug effects* / Q000302:isolation & purification; D017211:Treatment Failure; D016896:Treatment Outcome; D014435:Typhoid Fever / Q000097:blood / Q000188:drug therapy* / Q000453:epidemiology / Q000382:microbiology; D055815:Young Adult
D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D002443:Ceftriaxone; D017963:Azithromycin; D015242:Ofloxacin; D000077734:Gatifloxacin
Nepal; antimicrobial resistance; enteric fever; fluoroquinolone; typhoid