Improved Treatment of Multidrug-Resistant Bacterial Infections: Utility of Clinical Studies

Abstract

In a time of increasing antibacterial resistance and limited availability of new antibiotics, clinical studies are much needed to assess treatment options against multidrug-resistant organisms (MDROs). In this review, we describe the clinical challenge caused by MDROs and present recent evidence on how clinical studies may generate quality data to improve antibiotic treatment of MDRO infections. To this aim, we critically assess the current status, gaps and challenges associated with observational and interventional studies performed to assess MDRO treatment options. We address why observational studies are useful, which treatment options for MDRO have been explored by observational studies and how to improve quality and usefulness of observational studies. Furthermore, the utility of clinical pharmacokinetic/pharmacodynamic studies for improving MDRO treatment is described. Finally, we discuss interventional study designs, end points and margins, as well as ethical, logistic and statistical challenges, and current regulatory changes proposed to foster the development of new antibiotics.

A Multinational, Preregistered Cohort Study of β-Lactam/β-Lactamase Inhibitor Combinations for Treatment of Bloodstream Infections Due to Extended-Spectrum-β-Lactamase-Producing Enterobacteriaceae

“…Interestingly, however, a recent retrospective study from one center showed lower survival among patients treated with BLBLIs (13). This is an observational study, and thus, the typical limitations of this design apply, including lack of randomization, the potential effects of unmeasured variables, and residual confounding (14). Although this study has, to the best of our knowledge, the biggest sample size published to date, its statistical power is still limited and cannot exclude a potential relevant difference between carbapenems and BLBLIs.…”

“…Nevertheless, this study has some methodological strengths, which should be taken into consideration. The hypothesis, design, and statistical analysis plan were preregistered so as to avoid casual post hoc findings, as recommended for observational studies (14,28,29). Very strict criteria for the assignment of treatments were applied.…”

“…Very strict criteria for the assignment of treatments were applied. Treatment changes are frequent in real life, making it difficult to assign patients appropriately to a specific antibiotic in observational studies; in fact, most observational studies lack appropriate criteria for assignment (14). We used clinical response and mortality as the main outcome measures.…”

“…Previous studies mainly evaluated mortality, which has the advantage of being a "hard" outcome but may underestimate differences between drugs; we therefore also used clinical response, a "softer" but probably more sensitive outcome measure. Finally, we used advanced methods to control for confounding and center effects (14). Other strengths of our study are the inclusion of cases from diverse geographical locations, with infections caused by non-E. coli species, and with non-urinary tract sources.…”

“…In fact, most studies published to date in this field have important drawbacks that seriously challenge their validity; some recommendations for improving the quality of observational studies in this field have been published (14).…”