Reconsidering azithromycin disc diffusion interpretive criteria for Salmonellae in view of azithromycin MIC creep among typhoidal and nontyphoidal salmonella

Abstract

PURPOSE: Enteric fever continues to be an important public health challenge for the developing world. With the emergence of fluoroquinolone resistance in Salmonellae spp. azithromycin is increasingly being used for oral treatment of enteric fever. We investigated the antibiotic susceptibility pattern of azithromycin in Salmonellae spp. isolates from a tertiary care hospital to detect emerging resistance.

METHODS: The study assessed the reliability of disc diffusion as a screening test to detect azithromycin resistance by comparing it with the minimum inhibitory concentrations (MICs) of the drug in 100 Salmonellae spp. strains. The strains of Salmonellae spp. showing resistance to azithromycin were further investigated for resistance markers – mphA, mphB, and mef B genes.

RESULTS: This study was conducted on 100 Salmonella enterica strains recovered from blood culture samples between 2013 and 2017. Among these isolates, 18 showed resistance to azithromycin by disc diffusion methodology with zones of inhibition <13 mm. MIC of 6 of these isolates were ≥32 mg/L. The mean MIC of azithromycin increased from 5 mg/L in 2013 to 24 mg/L in 2017. Azithromycin consumption as defined daily doses per 1000 patient days also showed an increase over the past 4 years.

CONCLUSION: Azithromycin disc diffusion diameter interpretations as recommended by Clinical and Laboratory Standards Institute can mislabel a few sensitive strains as resistant. Azithromycin resistance is emerging in typhoidal and nontyphoidal Salmonella. MphA gene is associated with high MICs in nontyphoidal Salmonella spp.

Key words

Azithromycin disc diffusion - azithromycin resistant Salmonella spp. - enteric fever - mphA gene - Salmonella spp.

Publication History

Received: 24 July 2018

Accepted: 08 December 2018

Article published online:
06 April 2020

• References

• 1 John J, Van Aart CJ, Grassly NC. The burden of typhoid and paratyphoid in India: Systematic review and meta-analysis. PLoS Negl Trop Dis 2016;10:e0004616.
• 2 Sur D, Ali M, von Seidlein L, Manna B, Deen JL, Acosta CJ, et al. Comparisons of predictors for typhoid and paratyphoid fever in Kolkata, India. BMC Public Health 2007;7:289.
• 3 Singhal L, Gupta PK, Kale P, Gautam V, Ray P. Trends in antimicrobial susceptibility of Salmonella typhi from North India (2001-2012). Indian J Med Microbiol 2014;32:149-52.
• 4 Menezes GA, Harish BN, Khan MA, Goessens WH, Hays JP. Antimicrobial resistance trends in blood culture positive Salmonella typhi isolates from Pondicherry, India, 2005-2009. Clin Microbiol Infect 2012;18:239-45.
• 5 Crump JA, Sjölund-Karlsson M, Gordon MA, Parry CM. Epidemiology, clinical presentation, laboratory diagnosis, antimicrobial resistance, and antimicrobial management of invasive Salmonella infections. Clin Microbiol Rev 2015;28:901-37.
• 6 Frenck RW Jr., Nakhla I, Sultan Y, Bassily SB, Girgis YF, David J, et al. Azithromycin versus ceftriaxone for the treatment of uncomplicated typhoid fever in children. Clin Infect Dis 2000;31:1134-8.
• 7 Frenck RW Jr., Mansour A, Nakhla I, Sultan Y, Putnam S, Wierzba T, et al. Short-course azithromycin for the treatment of uncomplicated typhoid fever in children and adolescents. Clin Infect Dis 2004;38:951-7.
• 8 Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing: Twenty Fourth Informational Supplement. M100–S24. Wayne, PA: Clinical and Laboratory Standards Institute; 2015.
• 9 EUCAST. Breakpoint Tables for Interpretation of MICs and Zone Diameters. Version 8.0; 2018. Available from: http://www.eucast.org. [Last accesses on 2018 Jul 01].
• 10 Wang J, Li Y, Xu X, Liang B, Wu F, Yang X, et al. Antimicrobial resistance of Salmonella enterica serovar typhimurium in Shanghai, China. Front Microbiol 2017;8:510.
• 11 Phuc Nguyen MC, Woerther PL, Bouvet M, Andremont A, Leclercq R, Canu A, et al. Escherichia coli as reservoir for macrolide resistance genes. Emerg Infect Dis 2009;15:1648-50.
• 12 Gibson JR, McKee RA. PCR products generated from unpurified Salmonella DNA are degraded by thermostable nuclease activity. Lett Appl Microbiol 1993;16:59-61.
• 13 Parry CM, Basnyat B, Crump JA. The management of antimicrobial-resistant enteric fever. Expert Rev Anti Infect Ther 2013;11:1259-61.
• 14 Misra R, Prasad KN. Antimicrobial susceptibility to azithromycin among Salmonella enterica typhi and paratyphi A isolates from India. J Med Microbiol 2016;65:1536-9.
• 15 Sharma P, Dahiya S, Manral N, Kumari B, Kumar S, Pandey S, et al. Changing trends of culture-positive typhoid fever and antimicrobial susceptibility in a tertiary care North Indian hospital over the last decade. Indian J Med Microbiol 2018;36:70-6.
• 16 Nair S, Ashton P, Doumith M, Connell S, Painset A, Mwaigwisya S, et al. WGS for surveillance of antimicrobial resistance: A pilot study to detect the prevalence and mechanism of resistance to azithromycin in a UK population of non-typhoidal Salmonella. J Antimicrob Chemother 2016;71:3400-8.
• 17 Sjölund-Karlsson M, Joyce K, Blickenstaff K, Ball T, Haro J, Medalla FM, et al. Antimicrobial susceptibility to azithromycin among Salmonella enterica isolates from the United States. Antimicrob Agents Chemother 2011;55:3985-9.
• 18 Glynn MK, Bopp C, Dewitt W, Dabney P, Mokhtar M, Angulo FJ, et al. Emergence of multidrug-resistant Salmonella enterica serotype typhimurium DT104 infections in the United States. N Engl J Med 1998;338:1333-8.
• 19 Roberts MC. Update on macrolide-lincosamide-streptogramin, ketolide, and oxazolidinone resistance genes. FEMS Microbiol Lett 2008;282:147-59.
• 20 Manesh A, Balaji V, Kumar DR, Rupali P. A case of clinical and microbiological failure of azithromycin therapy in Salmonella enterica serotype typhi despite low azithromycin MIC. Int J Infect Dis 2017;54:62-3.