Multistrain models predict sequential multidrug treatment strategies to result in less antimicrobial resistance than combination treatment

Ahmad, Amais; Zachariasen, Camilla; Christiansen, Lasse Engbo; Græsbøll, Kaare; Toft, Nils; Matthews, Louise; Olsen, John Elmerdahl; Nielsen, Søren Saxmose

doi:10.1186/s12866-016-0724-5

Cited by 5 publications

(3 citation statements)

References 27 publications

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“…Several studies modeling the development of tetracycline resistance in pigs following treatment under different scenarios have recently been published (22,(40)(41)(42). Such models have been fed with data on the growth responses of E. coli to different concentrations of tetracycline.…”

Section: Discussionmentioning

confidence: 99%

Effect of Tetracycline Dose and Treatment Mode on Selection of Resistant Coliform Bacteria in Nursery Pigs

Græsbøll

Damborg

Mellerup³

et al. 2017

Appl Environ Microbiol

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This study describes the results of a randomized clinical trial investigating the effect of oxytetracycline treatment dose and mode of administration on the selection of antibiotic-resistant coliform bacteria in fecal samples from nursery pigs. Nursery pigs (pigs of 4 to 7 weeks of age) in five pig herds were treated with oxytetracycline for Lawsonia intracellularis-induced diarrhea. Each group was randomly allocated to one of five treatment groups: oral flock treatment with a (i) high (20 mg/kg of body weight), (ii) medium (10 mg/kg), or (iii) low (5 mg/kg) dose, (iv) oral pen-wise (small-group) treatment (10 mg/kg), and (v) individual intramuscular injection treatment (10 mg/kg). All groups were treated once a day for 5 days. In all groups, treatment caused a rise in the numbers and proportions of tetracyclineresistant coliform bacteria right after treatment, followed by a significant drop by the time that the pigs left the nursery unit. The counts and proportions of tetracyclineresistant coliforms did not vary significantly between treatment groups, except immediately after treatment, when the highest treatment dose resulted in the highest number of resistant coliforms. A control group treated with tiamulin did not show significant changes in the numbers or proportions of tetracycline-resistant coliforms. Selection for tetracycline-resistant coliforms was significantly correlated to selection for ampicillin-and sulfonamide-resistant strains but not to selection for cefotaximeresistant strains. In conclusion, the difference in the dose of oxytetracycline and the way in which the drug was applied did not cause significantly different levels of selection of tetracycline-resistant coliform bacteria under the conditions tested.IMPORTANCE Antimicrobial resistance is a global threat to human health. Treatment of livestock with antimicrobials has a direct impact on this problem, and there is a need to improve the ways that we use antimicrobials in livestock production. We hypothesized that antibiotic resistance development following treatment of diarrhea in nursery pigs could be reduced either by lowering the dose of oxytetracycline or by replacing the commonly used practice of flock treatment with individual or smallgroup treatments, since this would reduce the number of pigs treated. However, the study showed no significant difference between treatment groups with respect to the number or proportion of tetracycline-resistant coliforms selected. The most important conclusion is that under practical field conditions, there will be no added value, in terms of lowering resistance development, by exchanging flock treatment for individual or small-group treatment of nursery pigs. The reason for the lack of an

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Section: Discussionmentioning

confidence: 99%

Effect of Tetracycline Dose and Treatment Mode on Selection of Resistant Coliform Bacteria in Nursery Pigs

Græsbøll

Damborg

Mellerup³

et al. 2017

Appl Environ Microbiol

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“…Mathematical modelling is being used to identify strategies to forestall the emergence and re-emergence of antimicrobial resistance 71,72 . Models are particularly valuable for comparing alternative strategies, such as administration of different antibiotics within the same hospital ward, temporal cycling of antibiotics and combination therapy [73][74][75][76] . High-performance computing now permits the rapid exploration of multidimensional parameter space.…”

Section: Vaccine Hesitancymentioning

confidence: 99%

Modelling microbial infection to address global health challenges

et al. 2019

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“…Although there is a suggestion of an advantage of combination therapy over other approaches that use multiple drugs (namely 'mixing' and 'cycling' 15,16 ), this is not universal 17,18 . Discovering what governs the ability of combinations to prevent resistance evolution is therefore a critical area of research.…”

Section: Introductionmentioning

confidence: 99%

Mutators drive evolution of multi-resistance to antibiotics

Gifford¹,

Berríos-Caro

Joerres³

et al. 2019

Preprint

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Combination therapy aims to prevent growth of organisms not resistant to all component drugs, making it an obvious strategy for countering the global rise of multi-drug resistance. However, success relies on preventing resistance from arising to all component drugs before full inhibition is reached during treatment. Here, we investigated whether bacterial populations can overcome combination therapy by evolving 'multi-resistance', i.e. independent resistance mutations to multiple drugs, during single-drug and combination antibiotic treatment. Using both experimental evolution and in silico stochastic simulations, we studied resistance evolution in a common laboratory strain of bacteria (Escherichia coli K-12 BW25113). Populations were exposed to either single-drug or combination treatments involving rifampicin and nalidixic acid, with concentrations increasing through time. For wild-type populations, multi-resistance was not detected in any of the experimental populations, and simulations predict its evolution should be rare.However, populations comprising mixtures of wild-type and 'mutator' strains were readily capable of evolving multi-resistance. Increasing the initial frequency of mutators resulted in a higher proportion of populations evolving multi-resistance. Experiments and simulations produced the same qualitative-and in many cases, quantitative-insights about the association between resistance, mutators and antibiotic treatment. In particular, both approaches demonstrated that multi-resistance can arise through sequential acquisition of independent resistance mutations, without a need to invoke multi-drug resistance mechanisms. Crucially, we found multi-resistance evolved even when not directly favoured by natural selection, i.e. under single-drug treatments. Simulations revealed this resulted from elevated mutation supply caused by genetic hitch-hiking of the mutator allele on single-drug resistant backgrounds. Our results suggest that combination therapy does not necessarily prevent sequential acquisition of multiple drug resistances via spontaneous mutation when mutators are present. Indeed both combination and single-drug treatments actively promoted multi-resistance, meaning that combination therapy will not be a panacea for the antibiotic resistance crisis. inference, stochastic simulations, individual-based model, Markov chains W , K. B., 2016 Pairwise interactions and the battle against combinatorics in multidrug therapies.

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Multistrain models predict sequential multidrug treatment strategies to result in less antimicrobial resistance than combination treatment

Cited by 5 publications

References 27 publications

Effect of Tetracycline Dose and Treatment Mode on Selection of Resistant Coliform Bacteria in Nursery Pigs

Effect of Tetracycline Dose and Treatment Mode on Selection of Resistant Coliform Bacteria in Nursery Pigs

Modelling microbial infection to address global health challenges

Mutators drive evolution of multi-resistance to antibiotics

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