Author Response: The effect of combining antibiotics on resistance: A systematic review and meta-analysis
Berit SiedentopViacheslav N. KachalovChristopher WitzanyMatthias EggerRoger D. KouyosSebastian Bonhoeffer
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When and under which conditions antibiotic combination therapy decelerates rather than accelerates resistance evolution is not well understood. We examined the effect of combining antibiotics on within-patient resistance development across various bacterial pathogens and antibiotics.We searched CENTRAL, EMBASE and PubMed for (quasi)-randomised controlled trials (RCTs) published from database inception to November 24th, 2022. Trials comparing antibiotic treatments with different numbers of antibiotics were included. A patient was considered to have acquired resistance if, at the follow-up culture, a resistant bacterium was detected that had not been present in the baseline culture. We combined results using a random effects model and performed meta-regression and stratified analyses. The trials' risk of bias was assessed with the Cochrane tool.42 trials were eligible and 29, including 5054 patients, were qualified for statistical analysis. In most trials, resistance development was not the primary outcome and studies lacked power. The combined odds ratio (OR) for the acquisition of resistance comparing the group with the higher number of antibiotics with the comparison group was 1.23 (95% CI 0.68-2.25), with substantial between-study heterogeneity (I2 =77%). We identified tentative evidence for potential beneficial or detrimental effects of antibiotic combination therapy for specific pathogens or medical conditions.The evidence for combining a higher number of antibiotics compared to fewer from RCTs is scarce and overall, is compatible with both benefit or harm. Trials powered to detect differences in resistance development or well-designed observational studies are required to clarify the impact of combination therapy on resistance.Cite
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Comparative effectiveness research
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For many years it has been claimed that observational studies find stronger treatment effects than randomized, controlled trials. We compared the results of observational studies with those of randomized, controlled trials.
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In Brief Objectives: To compare the results of randomized controlled trials versus observational studies in meta-analyses of digestive surgical topics. Summary Background Data: While randomized controlled trials have been recognized as providing the highest standard of evidence, claims have been made that observational studies may overestimate treatment benefits. This debate has recently been renewed, particularly with regard to pharmacotherapies. Methods: The PubMed (1966 to April 2004), EMBASE (1986 to April 2004) and Cochrane databases (Issue 2, 2004) were searched to identify meta-analyses of randomized controlled trials in digestive surgery. Fifty-two outcomes of 18 topics were identified from 276 original articles (96 randomized trials, 180 observational studies) and included in meta-analyses. All available binary data and study characteristics were extracted and combined separately for randomized and observational studies. In each selected digestive surgical topic, summary odds ratios or relative risks from randomized controlled trials were compared with observational studies using an equivalent calculation method. Results: Significant between-study heterogeneity was seen more often among observational studies (5 of 12 topics) than among randomized trials (1 of 9 topics). In 4 of the 16 primary outcomes compared (10 of 52 total outcomes), summary estimates of treatment effects showed significant discrepancies between the two designs. Conclusions: One fourth of observational studies gave different results than randomized trials, and between-study heterogeneity was more common in observational studies in the field of digestive surgery. Comparison of the results of randomized controlled trials versus observational studies in meta-analyses of digestive surgical topics was performed. One fourth of observational studies gave different results than randomized trials, and between-study heterogeneity was more common in observational studies in the field of digestive surgery.
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Because large randomized clinical trials (RCTs) in dialysis have been relatively scarce, evidence-based dialysis care has depended heavily on the results of observational studies. However, when results from RCTs appear to contradict the findings of observational studies, nephrologists are left to wonder which type of study they should believe. In this editorial, we explore the key differences between observational studies and RCTs in the context of such seemingly conflicting studies in dialysis. Confounding is the major limitation of observational studies, whereas low statistical power and problems with external validity are more likely to limit the findings of RCTs. Differences in the specification of the population, exposure, and outcomes can also contribute to different results among RCTs and observational studies. Rigorous methods are required regardless of what type of study is conducted, and readers should not automatically assume that one type of study design is superior to the other. Ultimately, dialysis care requires both well-designed, well-conducted observational studies and RCTs to move the field forward.
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The role of observational studies in the evaluation of treatments is a long-standing and contentious topic.1 In this issue of the Journal, Concato et al.2 and Benson and Hartz3 report that observational studies give results similar to those of randomized, controlled trials. If these claims lead to more observational studies of therapeutic interventions and fewer randomized, controlled trials, we see considerable dangers to clinical research and even to the well-being of patients.Any systematic review of evidence on a therapeutic topic needs to take into account the quality of the evidence. Any study, whether randomized or observational, may have flaws . . .
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Background: In randomized controlled trials, due to the randomization process the covariates are equally distributed between the groups. For these reason at the end of the study the researcher can assume that the outcomes happens only because of interventions. This strict control of bias leads the randomized controlled trials to become the gold standard in clinical research. However in some cases, like in surgical studies, it is very difficult to run a randomized controlled trial. Observational studies have some strengths and can play an important role in studies of surgical specialties. Discussion: Observational studies are very commonly used nowadays, once that they are easy to conduct, needs less time and budget than randomized controlled trials. It is also a great design to test new hypothesis that could be developed in future studies. Observational design could be an excellent option to surgical research when randomized controlled trials have an ethical or feasibility issue. Besides the ethical and feasibility issues the research could have a rare outcome that is difficult to assess and measure. To all this issues observational study offers a solution.
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In regulatory evaluations, high-quality randomized controlled trials (RCTs) are considered the gold standard for assessing the efficacy of medical interventions. However, during the COVID-19 pandemic, the urgent need for treatment options led to regulatory approvals being made based on evidence from non-randomized, observational studies. In this study we contrast results from observational studies and RCTs of six drugs to treat COVID-19 infection. Across a range of studies evaluating hydroxychloroquine, remdesivir, ivermectin, aspirin, molnupiravir and tenofovir for COVID-19, there was statistically significant evidence of benefit from non-randomized observational studies, which was then not seen in RCTs. We propose that all observational studies need to be labelled as 'non-randomized' in the title. This should indicate that they are not as reliable for evaluating the efficacy of a drug and should not be used independently for regulatory approval decisions.
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Hydroxychloroquine
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