Clinically and microbiologically derived azithromycin susceptibility breakpoints for Salmonella enterica serovars Typhi and Paratyphi A.
Azithromycin is an effective treatment for uncomplicated infections with Salmonella enterica serovar Typhi and serovar Paratyphi A (enteric fever), but there are no clinically validated MIC and disk zone size interpretative guidelines. We studied individual patient data from three randomized controlled trials (RCTs) of antimicrobial treatment in enteric fever in Vietnam, with azithromycin used in one treatment arm, to determine the relationship between azithromycin treatment response and the azithromycin MIC of the infecting isolate. We additionally compared the azithromycin MIC and the disk susceptibility zone sizes of 1,640 S. Typhi and S. Paratyphi A clinical isolates collected from seven Asian countries. In the RCTs, 214 patients who were treated with azithromycin at a dose of 10 to 20 mg/ml for 5 to 7 days were analyzed. Treatment was successful in 195 of 214 (91%) patients, with no significant difference in response (cure rate, fever clearance time) with MICs ranging from 4 to 16 μg/ml. The proportion of Asian enteric fever isolates with an MIC of ≤ 16 μg/ml was 1,452/1,460 (99.5%; 95% confidence interval [CI], 98.9 to 99.7) for S. Typhi and 207/240 (86.3%; 95% CI, 81.2 to 90.3) (P < 0.001) for S. Paratyphi A. A zone size of ≥ 13 mm to a 5-μg azithromycin disk identified S. Typhi isolates with an MIC of ≤ 16 μg/ml with a sensitivity of 99.7%. An azithromycin MIC of ≤ 16 μg/ml or disk inhibition zone size of ≥ 13 mm enabled the detection of susceptible S. Typhi isolates that respond to azithromycin treatment. Further work is needed to define the response to treatment in S. Typhi isolates with an azithromycin MIC of >16 μg/ml and to determine MIC and disk breakpoints for S. Paratyphi A.
Wellcome Trust Major Overseas Programme, The Hospital for Tropical Diseases, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam Centre for Tropical Medicine and Global Health, Old Road Campus, University of Oxford, Oxford, United Kingdom Liverpool School of Tropical Medicine, Liverpool, United Kingdom London School of Hygiene and Tropical Medicine, London, United Kingdom School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki, Japan chris.parry@lshtm.ac.uk.
Christopher M
CM
Parry
Wellcome Trust Major Overseas Programme, The Hospital for Tropical Diseases, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.
Nga Tran Vu
NT
Thieu
Wellcome Trust Major Overseas Programme, The Hospital for Tropical Diseases, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam Centre for Tropical Medicine and Global Health, Old Road Campus, University of Oxford, Oxford, United Kingdom.
Christiane
C
Dolecek
Oxford University Clinical Research Unit, Patan Academy of Health Sciences, Kathmandu, Nepal.
Abhilasha
A
Karkey
Department of Microbiology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India.
Ruchi
R
Gupta
Centre for Tropical Medicine and Global Health, Old Road Campus, University of Oxford, Oxford, United Kingdom Cambodia-Oxford Research Unit, Angkor Hospital for Children, Siem Reap, Cambodia Shoklo Malaria Research Unit, Mae Sot, Thailand.
Paul
P
Turner
Centre for Tropical Medicine and Global Health, Old Road Campus, University of Oxford, Oxford, United Kingdom Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit, Mahosot Hospital, Vientiane, Laos.
David
D
Dance
Mahidol-Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
Rapeephan R
RR
Maude
The Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
Vinh
V
Ha
The Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
Chinh Nguyen
CN
Tran
Dong Thap Provincial Hospital, Cao Lanh, Dong Thap Province, Vietnam.
Phuong Le
PL
Thi
Dong Thap Provincial Hospital, Cao Lanh, Dong Thap Province, Vietnam.
Bay Pham Van
BP
Be
An Giang Provincial Hospital, Long Xuyen, Vietnam.
La Tran Thi
LT
Phi
An Giang Provincial Hospital, Long Xuyen, Vietnam.
Rang Nguyen
RN
Ngoc
Chittagong Medical College Hospital, Chittagong, Bangladesh.
Aniruddha
A
Ghose
Oxford University Clinical Research Unit, Patan Academy of Health Sciences, Kathmandu, Nepal.
Sabina
S
Dongol
Wellcome Trust Major Overseas Programme, The Hospital for Tropical Diseases, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam Centre for Tropical Medicine and Global Health, Old Road Campus, University of Oxford, Oxford, United Kingdom.
James I
JI
Campbell
Wellcome Trust Major Overseas Programme, The Hospital for Tropical Diseases, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.
Duy Pham
DP
Thanh
Wellcome Trust Major Overseas Programme, The Hospital for Tropical Diseases, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.
Tuyen Ha
TH
Thanh
Wellcome Trust Major Overseas Programme, The Hospital for Tropical Diseases, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam Cambodia-Oxford Research Unit, Angkor Hospital for Children, Siem Reap, Cambodia.
Catrin E
CE
Moore
Cambodia-Oxford Research Unit, Angkor Hospital for Children, Siem Reap, Cambodia.
Soeng
S
Sona
Department of Microbiology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India.
Rajni
R
Gaind
Department of Microbiology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India.
Monorama
M
Deb
Dong Thap Provincial Hospital, Cao Lanh, Dong Thap Province, Vietnam.
Ho Van
HV
Anh
The Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
Sach Nguyen
SN
Van
Wellcome Trust Major Overseas Programme, The Hospital for Tropical Diseases, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam Centre for Tropical Medicine and Global Health, Old Road Campus, University of Oxford, Oxford, United Kingdom.
Hien Tran
HT
Tinh
Centre for Tropical Medicine and Global Health, Old Road Campus, University of Oxford, Oxford, United Kingdom Mahidol-Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
Nicholas P J
NP
Day
Centre for Tropical Medicine and Global Health, Old Road Campus, University of Oxford, Oxford, United Kingdom Mahidol-Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
Arjen
A
Dondorp
Wellcome Trust Major Overseas Programme, The Hospital for Tropical Diseases, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam Centre for Tropical Medicine and Global Health, Old Road Campus, University of Oxford, Oxford, United Kingdom.
Guy
G
Thwaites
Mahidol-Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand Centre for Specialized Care and Research, Chittagong, Bangladesh.
Mohamed Abul
MA
Faiz
Centre for Tropical Medicine and Global Health, Old Road Campus, University of Oxford, Oxford, United Kingdom Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit, Mahosot Hospital, Vientiane, Laos.
Rattanaphone
R
Phetsouvanh
Centre for Tropical Medicine and Global Health, Old Road Campus, University of Oxford, Oxford, United Kingdom Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit, Mahosot Hospital, Vientiane, Laos London School of Hygiene and Tropical Medicine, London, United Kingdom.
Paul
P
Newton
Oxford University Clinical Research Unit, Patan Academy of Health Sciences, Kathmandu, Nepal.
Buddha
B
Basnyat
Wellcome Trust Major Overseas Programme, The Hospital for Tropical Diseases, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam Centre for Tropical Medicine and Global Health, Old Road Campus, University of Oxford, Oxford, United Kingdom.
Jeremy J
JJ
Farrar
Wellcome Trust Major Overseas Programme, The Hospital for Tropical Diseases, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam Centre for Tropical Medicine and Global Health, Old Road Campus, University of Oxford, Oxford, United Kingdom London School of Hygiene and Tropical Medicine, London, United Kingdom.
Stephen
S
Baker
D000293:Adolescent; D017963:Azithromycin / Q000494:pharmacology* / Q000627:therapeutic use*; D002648:Child; D005260:Female; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D019779:Salmonella enterica / Q000187:drug effects* / Q000472:pathogenicity*; D065288:Serogroup; D014435:Typhoid Fever / Q000188:drug therapy*; D055815:Young Adult
D017963:Azithromycin