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Randomized Controlled Trial
. 2019 Jun 21;17(1):115.
doi: 10.1186/s12916-019-1348-z.

Optimising trial designs to identify appropriate antibiotic treatment durations

Koen B Pouwels  1   2   3 , Mo Yin  4   5 , Christopher C Butler  6   7 , Ben S Cooper  4   8 , Sarah Wordsworth  9   6   10 , A Sarah Walker  6   10   11 , Julie V Robotham  12   6
Affiliations
Randomized Controlled Trial

Optimising trial designs to identify appropriate antibiotic treatment durations

Koen B Pouwels et al. BMC Med. .

Abstract

Background: For many infectious conditions, the optimal antibiotic course length remains unclear. The estimation of course length must consider the important trade-off between maximising short- and long-term efficacy and minimising antibiotic resistance and toxicity.

Main body: Evidence on optimal treatment durations should come from randomised controlled trials. However, most antibiotic randomised controlled trials compare two arbitrarily chosen durations. We argue that alternative trial designs, which allow allocation of patients to multiple different treatment durations, are needed to better identify optimal antibiotic durations. There are important considerations when deciding which design is most useful in identifying optimal treatment durations, including the ability to model the duration-response relationship (or duration-response 'curve'), the risk of allocation concealment bias, statistical efficiency, the possibility to rapidly drop arms that are clearly inferior, and the possibility of modelling the trade-off between multiple competing outcomes.

Conclusion: Multi-arm designs modelling duration-response curves with the possibility to drop inferior arms during the trial could provide more information about the optimal duration of antibiotic therapies than traditional head-to-head comparisons of limited numbers of durations, while minimising the probability of assigning trial participants to an ineffective treatment regimen.

Keywords: Antibiotics; Antimicrobial resistance; Bayesian; Design; Duration of therapy; Frequentist; Randomised trial.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Duration–response curves corresponding to an intention-to-treat analysis. Diamonds show hypothesised event rates for the two randomised groups as designed. The solid and dot-dashed lines show different hypothesised duration–response curves that are compatible with those hypothesised event rates. This figure illustrates that conventional randomised controlled trials that compare two different durations do not provide information about other durations, especially if one duration is clearly superior to the other
See this image and copyright information in PMC

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