Incremental Increase in Fitness Cost with Increased β‐Lactam Resistance in Pneumococci Evaluated by Competition in an Infant Rat Nasal Colonization Model

Trzciński, Krzysztof; Thompson, Claudette M.; Gilbey, Andrea M.; Dowson, Christopher G.; Lipsitch, Marc

doi:10.1086/501367

Cited by 61 publications

(58 citation statements)

References 35 publications

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“…Third, we constrained our parameter sets to a set of scenarios with very low fitness costs, to ensure that it was possible for high-level resistance to spread. Although there are no quantitative estimates of fitness costs for fluoroquinolone resistance, it seems possible that the costs are higher than the values considered here (36,37), meaning that the actual probability for using newer fluoroquinolones without exten- Typical and atypical results are presented as mean (SD). *Typical results of highest Resistance occur with immediate switch, whereas atypical results occur with delayed switch.…”

Section: Discussionmentioning

confidence: 97%

“…The wide clonal spread of highly resistant strains (33) suggests that these strains are not much compromised in their fitness and are capable of spreading. The existence of fit, highly resistant strains may imply compensatory chromosomal changes (34,35), because animal studies showed pneumococcal strains as being greatly compromised in vivo upon acquisition of high-level resistant alleles (36,37). These characteristics suggest that, in the case of amoxicillin, the policy that maximizes treatment success (widespread use of higher doses) may unfortunately foster the emergence of higher-level resistance at the population level.…”

Section: Discussionmentioning

confidence: 99%

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Upgrading antibiotic use within a class: Tradeoff between resistance and treatment success

Wang¹,

Lipsitch

2006

Proc. Natl. Acad. Sci. U.S.A.

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Increasing resistance to antibiotics creates the need for prudent antibiotic use. When resistance to various antibiotics within a class is driven by stepwise accumulation of mutations, a dilemma may exist in regard to replacing an antibiotic that is losing effectiveness due to resistance with a new drug within the same class. Such replacement may enhance treatment success in the short term but promote the spread of highly resistant strains. We used mathematical models to quantify the tradeoff between minimizing treatment failures (by switching early) and minimizing the proliferation of the highly resistant strain (by delaying the switch). Numerical simulations were applied to investigate the cumulative prevalence of the highly resistant strain (Resistance) and the cumulative number of treatment failures (Failure) that resulted from following different antibiotic use policies. Whereas never switching to the new drug always minimizes Resistance and maximizes Failure, immediate switching usually maximizes Resistance and minimizes Failure. Thus, in most circumstances, there is a strict tradeoff in which early use of the new drug enhances treatment effectiveness while hastening the rise of high-level resistance. This tradeoff is most acute when acquired resistance is rare and the highly resistant strain is readily transmissible. However, exceptions occur when use of the new drug frequently leads to acquired resistance and when the highly resistant strain has substantial ''fitness cost''; these circumstances tend to favor an immediate switch. We discuss the implications of these considerations in regard to antibiotic choices for Streptococcus pneumoniae.antibiotic resistance ͉ fluoroquinolones ͉ mathematical models ͉ optimization

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Upgrading antibiotic use within a class: Tradeoff between resistance and treatment success

Wang¹,

Lipsitch

2006

Proc. Natl. Acad. Sci. U.S.A.

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“…tudies of within-host competition between bacteria typically measure selection by the mean change in the logarithm of the ratio of a favored to a disfavored allele (1)(2)(3)(4), sometimes called a "competitive index." In animal experiments, there is often substantial variation in the competition outcome among animal subjects (1)(2)(3)(4), which necessitates the use of a large number of animals to ensure reproducible results (5).…”

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confidence: 99%

“…In animal experiments, there is often substantial variation in the competition outcome among animal subjects (1)(2)(3)(4), which necessitates the use of a large number of animals to ensure reproducible results (5). Understanding the source of this variation is important for a number of purposes, including sample size calculations in experimental design and results interpretation.…”

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confidence: 99%

Within-Host Selection Is Limited by an Effective Population of Streptococcus pneumoniae during Nasopharyngeal Colonization

Thompson

Trzciński

et al. 2013

Infect Immun

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bStreptococcus pneumoniae (pneumococcus) is a significant pathogen that frequently colonizes the human nasopharynx. Environmental factors, including antimicrobial use and host immunity, exert selection on members of the nasopharyngeal population, and the dynamics of selection are influenced by the effective population size of the selected population, about which little is known. We measured here the variance effective population size (N e ) of pneumococcus in a mouse colonization model by monitoring the frequency change of two cocolonizing, competitively neutral pneumococcal strains over time. The point estimate of N e during nasal carriage in 16 BALB/c mice was 133 (95% confidence interval [CI] ‫؍‬ 11 to 203). In contrast, the lower-bound census population exhibited a mean of 5768 (95% CI ‫؍‬ 2,515 to 9,021). Therefore, pneumococcal N e during nasal carriage is substantially smaller than the census population. The N e during day 1 to day 4 of colonization was comparable to the N e during day 4 to day 8. Similarly, a low N e was also evident for the colonization of pneumococcus in BALB/c mice exposed to cholera toxin 4 weeks prior to challenge and in another mouse strain (DO11.10 RAG ؊/؊ ). We developed a mathematical model of pneumococcal colonization composed of two subpopulations with differential contribution to future generations. By stochastic simulation, this model can reproduce the pattern of observed pneumococcal N e and predicts that the selection coefficients may be difficult to measure in vivo. We hypothesized that such a small N e may reduce the effectiveness of within host selection for pneumococcus.

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“…Specifically, a fitness loss accompanied antibiotic resistance due to mutation of the target gene in animal models of Staphylococcus aureus (129), Salmonella enterica serovar Typhimurium (20,111), and Streptococcus pneumoniae (189) infection. An exception to these studies is the reported colonization advantage displayed by some fluoroquinolone-resistant Campylobacter jejuni strains due to mutation of gyrB (108).…”

Section: Discussionmentioning

confidence: 99%

The Role of the Transcription Factors MtrR and MtrA in the Fitness of the Pathogen Neisseria gonorrhoeae

Warner¹

2007

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Incremental Increase in Fitness Cost with Increased β‐Lactam Resistance in Pneumococci Evaluated by Competition in an Infant Rat Nasal Colonization Model

Abstract: The cost of penicillin-resistance acquisition for the Streptococcus pneumoniae strain competing with its susceptible ancestor to colonize the URT increases with the number of resistant pbp alleles acquired.

Cited by 61 publications

References 35 publications

Upgrading antibiotic use within a class: Tradeoff between resistance and treatment success

Upgrading antibiotic use within a class: Tradeoff between resistance and treatment success

Within-Host Selection Is Limited by an Effective Population of Streptococcus pneumoniae during Nasopharyngeal Colonization

The Role of the Transcription Factors MtrR and MtrA in the Fitness of the Pathogen Neisseria gonorrhoeae

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