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

Abstract

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

Large mobile genetic elements carrying resistance genes that do not confer a fitness burden in healthcare-associated meticillin-resistant Staphylococcus aureus

“…However, the unexpected lack of a significant fitness cost associated with carriage in CC30 SCCmecII isolates implies that there may be no barrier to their spread amongst CC22 SCCmecIV isolates. This lack of fitness cost associated with plasmid carriage has been previously noted in other bacteria (Andersson & Hughes, 2010;Bouma & Lenski, 1988;Helling et al, 1981;Lenski et al, 1994;Maisnier-Patin & Andersson, 2004;McDermott et al, 1993;Modi & Adams, 1991), but worryingly rarely influences clinical decisions nor the size of fitness costs in mathematical models of clinical MRSA populations (Bergstrom et al, 2004;D'Agata et al, 2007;Levin & Rozen, 2006;Wang & Lipsitch, 2006;Webb et al, 2005). It is likely that some level of co-evolution has occurred, with compensatory mutations allowing some isolates to cope better with the fitness cost than others.…”

Susceptibility of Streptococcus pneumoniae to Fluoroquinolones in Canada

“…In vitro and in vivo studies and clinical trials have determined that maintenance of an unbound AUC/ MIC ratio of 30 to 40 maximizes the bactericidal efficacy of fluoroquinolones against S. pneumoniae and minimizes the selection of resistant isolates during therapy (2). Ciprofloxacin at doses used for therapy never achieves this target, levofloxacin at a dose of 500 mg once a day will just achieve it, and moxifloxacin and gatifloxacin used at recommended daily doses will achieve AUC/MIC ratios well above it (19,27,28). The inherent activity of levofloxacin, gatifloxacin, and moxifloxacin against pneumococci may thus minimize the emergence of resistance during therapy and, thus, the broader selection of resistance in a population (14).…”

“…There is concern that this change may enhance treatment success in the short term but promote the spread of highly resistant strains in the long term (28).…”

Future antibiotics scenarios: is the tide starting to turn?

“…Considering the widespread resistance problem and the propensity to intensify the effect of class-specific resistance mechanisms, most specialists would prefer a novel chemical class with no pre-existing potential cross-resistance [21]. Discovery …”