Abstract
Ampicillin, the first semi-synthetic penicillin active against Enterobacteriaceae, was released onto the market in 1961. The first outbreaks of disease caused by ampicillin-resistant strains of Salmonella enterica serotype Typhimurium were identified in the UK in 1962 and 1964. We aimed to date the emergence of this resistance in historical isolates of S enterica serotype Typhimurium. In this retrospective, whole-genome sequencing study, we analysed 288 S enterica serotype Typhimurium isolates collected between 1911 and 1969 from 31 countries on four continents and from various sources including human beings, animals, feed, and food. All isolates were tested for antimicrobial drug susceptibility with the disc diffusion method, and isolates shown to be resistant to ampicillin underwent resistance-transfer experiments. To provide insights into population structure and mechanisms of ampicillin resistance, we did whole-genome sequencing on a subset of 225 isolates, selected to maximise source, spatiotemporal, and genetic diversity. 11 (4%) of 288 isolates were resistant to ampicillin because of acquisition of various β lactamase genes, including blaTEM-1, carried by various plasmids, including the virulence plasmid of S enterica serotype Typhimurium. These 11 isolates were from three phylogenomic groups. One isolate producing TEM-1 β lactamase was isolated in France in 1959 and two isolates producing TEM-1 β lactamase were isolated in Tunisia in 1960, before ampicillin went on sale. The vectors for ampicillin resistance were different from those reported in the strains responsible for the outbreaks in the UK in the 1960s. The association between antibiotic use and selection of resistance determinants is not as direct as often presumed. Our results suggest that the non-clinical use of narrow-spectrum penicillins (eg, benzylpenicillin) might have favoured the diffusion of plasmids carrying the blaTEM-1 gene in S enterica serotype Typhimurium in the late 1950s. Institut Pasteur, Santé publique France, the French Government's Investissement d'Avenir programme, the Fondation Le Roch-Les Mousquetaires.
Highlights
In May 2015, the 68th World Health Assembly endorsed a global action plan to tackle antimicrobial resistance,[1] a global public health issue for the 21th century
It occurred in the second half of 1962, in the United Kingdom, at a time at which dozens of S. enterica serotype Typhimurium DT2 isolates resistant to ampicillin, streptomycin, sulfonamides and tetracyclines were found in humans and pigs.[10]
With a view to improving our understanding of the emergence of resistance to ampicillin, one of the most widely used antibiotics to date, we studied a large collection of historical isolates of S. enterica serotype Typhimurium, a zoonotic agent that has remained one of the two predominant serotypes causing human disease in Europe since World War 2 (WW2).15,16 These 288 isolates were collected between 1911 and 1969, and 107 were obtained before ampicillin went on sale
Summary
In May 2015, the 68th World Health Assembly endorsed a global action plan to tackle antimicrobial resistance,[1] a global public health issue for the 21th century. 8,9 The third strain, a S. enterica serotype Typhimurium phage-type 1a (later reclassified as definitive phage-type [DT] 2), isolated in 1962 in Brighton, United Kingdom, produced a beta-lactamase with a substrate profile different from that of TEM (Table 1). The E. coli isolate from Greece obtained in 1963 (the strain and its beta-lactamase were named TEM after the patient’s name, Temoneria)[7] and the S. enterica serotype Paratyphi B isolate obtained in the United Kingdom in 1963 were subsequently found to contain the blaTEM-1A gene carried by a ~ 40 kb IncX2 plasmid and a ~ 100 kb IncF plasmid, respectively (Table 1). This S. enterica serotype Typhimurium strain was isolated during the first reported outbreak caused by an ampicillin-resistant S. enterica serotype Typhimurium strain. AY046276) and found to be a ~ 50 kb IncN plasmid carrying the blaOXA-2 gene
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