Antibiotic combination therapy can select for broad-spectrum multidrug resistance in Pseudomonas aeruginosa

Vestergaard, Martin; Paulander, Wilhelm; Marvig, Rasmus L.; Clasen, Julie; Jochumsen, Nicholas; Molin, Søren; Jelsbak, Lars; Ingmer, Hanne; Folkesson, Anders

doi:10.1016/j.ijantimicag.2015.09.014

Cited by 85 publications

(67 citation statements)

References 30 publications

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“…There are, however, several other genes involved in resistance to beta-lactam antibiotics (36, 37) that did not show mutations in this study. The dacB mutations observed at low frequencies during the development of resistance to ceftazidime influence the expression of AmpC beta-lactamases (38). The ampD mutations observed after the growth of cells made resistant to ceftazidime in antibiotic-free medium fulfill a role in peptidoglycan synthesis (39).…”

Section: Discussionmentioning

confidence: 99%

Dynamics of Mutations during Development of Resistance by Pseudomonas aeruginosa against Five Antibiotics

Feng

Jonker

Moustakas

et al. 2016

Antimicrob Agents Chemother

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cPseudomonas aeruginosa is an opportunistic pathogen that causes considerable morbidity and mortality, specifically during intensive care. Antibiotic-resistant variants of this organism are more difficult to treat and cause substantial extra costs compared to susceptible strains. In the laboratory, P. aeruginosa rapidly developed resistance to five medically relevant antibiotics upon exposure to stepwise increasing concentrations. At several time points during the acquisition of resistance, samples were taken for whole-genome sequencing. The increase in the MIC of ciprofloxacin was linked to specific mutations in gyrA, parC, and gyrB, appearing sequentially. In the case of tobramycin, mutations in fusA, HP02880, rplB, and capD were induced. The MICs of the beta-lactam compounds meropenem and ceftazidime and the combination of piperacillin and tazobactam correlated linearly with beta-lactamase activity but not always with individual mutations. The genes that were mutated during the development of beta-lactam resistance differed for each antibiotic. A quantitative relationship between the frequency of mutations and the increase in resistance could not be established for any of the antibiotics. When the adapted strains are grown in the absence of the antibiotic, some mutations remained and others were reversed, but this reversal did not necessarily lower the MIC. The increased MIC came at the cost of moderately reduced cellular functions or a somewhat lower growth rate. In all cases except ciprofloxacin, the increase in resistance seems to be the result of complex interactions among several cellular systems rather than individual mutations.T he medical consequences of antibiotic resistance, such as fewer options for and increased costs of treating infectious diseases, are well recognized. The pathway to resistance consists of sequential mutations or acquisition of resistance genes driven by the selective pressure caused by antibiotic exposure (1). Once resistance has been acquired, the cell rarely reverses to become sensitive again, compensating for the metabolic costs instead (2, 3). The increased level of resistance caused by an antibiotic treatment typically prescribed by primary care physicians is very noticeable when subsequent further treatment is necessary (4). Hence, in order to limit the development of resistance when antibiotics have to be used, treatment protocols need to be devised to prevent this side effect. Rational design of such protocols requires knowledge of the molecular mechanisms that cause resistance. One of the central questions is whether similar mechanisms are operational for all drugs or whether resistance to each drug is induced in a distinct manner. Other basic questions center on evolutionary pathways to clinically significant resistance and the persistence of molecular changes after treatment.Molecular changes that cause the development and persistence of drug resistance can be identified by combining experimental evolution and whole-genome sequencing (WGS), provided that the proper c...

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Section: Discussionmentioning

confidence: 99%

Dynamics of Mutations during Development of Resistance by Pseudomonas aeruginosa against Five Antibiotics

Feng

Jonker

Moustakas

et al. 2016

Antimicrob Agents Chemother

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“…For example, it has been reported that combination antibiotics may select for broad-spectrum multi-drug resistance, at least in P. aeruginosa where dysregulated efflux pumps appear to drive high levels of resistance following ciprofloxacin (fluoroquinolone) and ceftazidime (β-lactam) treatment [79]. Hence, further evaluation of drug combinations will be necessary to inform any decision-making.…”

Section: Discussionmentioning

confidence: 99%

A population genomics approach to exploiting the accessory 'resistome' of Escherichia coli

Goldstone

Smith

2017

Microbial Genomics

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The emergence of antibiotic resistance is a defining challenge, and Escherichia coli is recognized as one of the leading species resistant to the antimicrobials used in human or veterinary medicine. Here, we analyse the distribution of 2172 antimicrobial-resistance (AMR) genes in 4022 E. coli to provide a population-level view of resistance in this species. By separating the resistance determinants into ‘core’ (those found in all strains) and ‘accessory’ (those variably present) determinants, we have found that, surprisingly, almost half of all E. coli do not encode any accessory resistance determinants. However, those strains that do encode accessory resistance are significantly more likely to be resistant to multiple antibiotic classes than would be expected by chance. Furthermore, by studying the available date of isolation for the E. coli genomes, we have visualized an expanding, highly interconnected network that describes how resistances to antimicrobials have co-associated within genomes over time. These data can be exploited to reveal antimicrobial combinations that are less likely to be found together, and so if used in combination may present an increased chance of suppressing the growth of bacteria and reduce the rate at which resistance factors are spread. Our study provides a complex picture of AMR in the E. coli population. Although the incidence of resistance to all studied antibiotic classes has increased dramatically over time, there exist combinations of antibiotics that could, in theory, attack the entirety of E. coli, effectively removing the possibility that discrete AMR genes will increase in frequency in the population.

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“…Tulathromycin and tildipirosin are in the same class of antimicrobials and have similar mechanisms of action. Bacterial pre-exposure to antimicrobials has been implicated as an important risk factor for AMR evolution during subsequent antimicrobial treatments [24,27,28]. Recently, the effect of sequential antimicrobial treatments on the development of antimicrobial resistance has been demonstrated for Pseudomonas aeruginosa and Klebsiella pneumonia in-vitro.…”

Section: Resultsmentioning

confidence: 99%

Switching between bacteriostatic and bactericidal antimicrobials for retreatment of bovine respiratory disease (BRD) relapses is associated with an increased frequency of resistant pathogen isolation from veterinary diagnostic laboratory submissions

Coetzee

Magstadt

Follett

et al. 2019

Preprint

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Although 90% of BRD relapses are reported to receive retreatment with a different class of antimicrobial, studies examining the impact of antimicrobial selection (i.e. bactericidal or bacteriostatic) on retreatment outcomes and the emergence of antimicrobial resistance (AMR) are deficient in the published literature. A survey was conducted to determine the association between antimicrobial class selection for retreatment of BRD relapses on antimicrobial susceptibility of Mannheimia haemolytica, Pasteurella multocida, and Histophilus somni. Pathogens were isolated from samples submitted to the Iowa State University Veterinary Diagnostic Laboratory from January 2013 to December 2015. A total of 781 isolates with corresponding animal case histories, including treatment protocols, were included in the analysis. Original susceptibility testing of these isolates for ceftiofur, danofloxacin, enrofloxacin, florfenicol, oxytetracycline, spectinomycin, tilmicosin, and tulathromycin was performed using Clinical and Laboratory Standards Institute guidelines. Data were analyzed using a Bayesian approach to evaluate whether retreatment with antimicrobials of different mechanistic classes (bactericidal or bacteriostatic) increased the probability of resistant BRD pathogen isolation in calves. The posterior distribution we calculated suggests that an increased number of treatments is associated with a greater probability of isolates resistant to at least one antimicrobial. In addition, the frequency of resistant M. haemolytica isolates was greater with retreatment using antimicrobials of different mechanistic classes than retreatment with the same class. Specifically, treatment protocols using a bacteriostatic drug first followed by retreatment with a bactericidal drug was associated with a higher frequency of resistant BRD pathogen isolation. This effect was more profound with specific treatment combinations; tulathromycin (bacteriostatic) followed by ceftiofur (bactericidal) was associated with the highest probability of resistant isolates among all antimicrobial combinations. These findings suggest that the selection of antimicrobial mechanistic class for retreatment of BRD should be considered as part of an antimicrobial stewardship program.

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Antibiotic combination therapy can select for broad-spectrum multidrug resistance in Pseudomonas aeruginosa

Cited by 85 publications

References 30 publications

Dynamics of Mutations during Development of Resistance by Pseudomonas aeruginosa against Five Antibiotics

Dynamics of Mutations during Development of Resistance by Pseudomonas aeruginosa against Five Antibiotics

A population genomics approach to exploiting the accessory 'resistome' of Escherichia coli

Switching between bacteriostatic and bactericidal antimicrobials for retreatment of bovine respiratory disease (BRD) relapses is associated with an increased frequency of resistant pathogen isolation from veterinary diagnostic laboratory submissions

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