Sequential antibiotic therapy in the laboratory and in the patient.

Laboratory experiments suggest that rapid cycling of antibiotics during the course of treatment could successfully counter resistance evolution. Drugs involving collateral sensitivity could be particularly suitable for such therapies. However, the environmental conditions in vivo differ from those in vitro . One key difference is that drugs can be switched abruptly in the laboratory, while in the patient, pharmacokinetic processes lead to changing antibiotic concentrations including periods of dose overlaps from consecutive administrations. During such overlap phases, drug-drug interactions may affect the evolutionary dynamics. To address the gap between the laboratory and potential clinical applications, we set up two models for comparison-a 'laboratory model' and a pharmacokinetic-pharmacodynamic 'patient model'. The analysis shows that in the laboratory, the most rapid cycling suppresses the bacterial population always at least as well as other regimens. For patient treatment, however, a little slower cycling can sometimes be preferable if the pharmacodynamic curve is steep or if drugs interact antagonistically. When resistance is absent prior to treatment, collateral sensitivity brings no substantial benefit unless the cell division rate is low and drug cycling slow. By contrast, drug-drug interactions strongly influence the treatment efficiency of rapid regimens, demonstrating their importance for the optimal choice of drug pairs.