“One-Size-Fits-All”? Optimizing Treatment Duration for Bacterial Infections

Abstract

Historically, antibiotic treatment guidelines have aimed to maximize treatment efficacy and minimize toxicity, but have not considered the evolution of antibiotic resistance. Optimizing the duration and dosing of treatment to minimize the duration of symptomatic infection and selection pressure for resistance simultaneously has the potential to extend the useful therapeutic life of these valuable life-saving drugs without compromising the interests of individual patients.Here, using mathematical models, we explore the theoretical basis for shorter durations of treatment courses, including a range of ecological dynamics of bacteria that cause infections or colonize hosts as commensals. We find that immunity is an important mediating factor in determining the need for long duration of treatment. When immunity to infection is expected, shorter durations that reduce the selection for resistance without interfering with successful clinical outcome are likely to be supported. Adjusting drug treatment strategies to account for the impact of the differences in the ecological niche occupied by commensal flora relative to invasive bacteria could be effective in delaying the spread of bacterial resistance.

Pharmacokinetic-Pharmacodynamic Model To Evaluate Intramuscular Tetracycline Treatment Protocols To Prevent Antimicrobial Resistance in Pigs

“…In contrast to most previous simulation studies, antimicrobial pressure was not assumed to be constant during the treatment but varied according to simulated plasma concentration-time profiles aac.asm.org 1639 Antimicrobial Agents and Chemotherapy based on a two-compartment PK model (22)(23)(24). Key parameters were estimated by fitting this model to the in vivo profile of tetracycline plasma concentration in a pig following i.m.…”

“…This is undesirable because the longer the period before return to equilibrium, the greater the risk of transmission of resistant strains to other pigs and humans, although this has not been explicitly modeled in the present study. In reality, treatment durations depend on the efficacy of the treatment, but it may also be possible to reduce the duration with a higher daily dose level to achieve the desired efficacy and lower resistance levels (24). The effect of the number of strains on resistance levels has not been investigated previously.…”

“…on the growth of antimicrobial-resistant bacteria (22)(23)(24). These studies focused on the impact of dosing factors on the total resistance level but did not account for differences in the numbers of competing strains or the composition of strains with different susceptibilities on the effect of a given treatment strategy.…”

The path of least resistance: aggressive or moderate treatment?

“…A consequence of this is that genetic barriers to resistance are generally evaluated in vitro. By necessity such in vitro studies do not incorporate the immune system, which is likely to be a key element in the success of moderate chemotherapy [8]. Moreover, it is often unclear how evolutionary processes [54] and drug dosing [55] can be translated from in vitro to in vivo systems.…”

Testing the optimality properties of a dual antibiotic treatment in a two-locus, two-allele model

“…This stems from the idea that overdosing with antibiotics is, at worse, therapeutically neutral and no harm results from taking drugs for prolonged periods. However, mounting clinical [10], experimental [11] and theoretical [12] evidence suggests that short-course therapy can be as effective without imposing selective pressures that favour resistant mutants. These issues have been debated openly in the literature with ensuing disagreement between different communities [13 -15].…”