Letter: bismuth, levofloxacin, amoxicillin, PPI quadruple therapy is not an effective first or second line regimen in the presence of levofloxacin resistance

We believe the authors were misled in their analysis of the results of their recent trial of a levofloxacin, bismuth, amoxicillin and PPI quadruple therapy.1 They report a per protocol eradication rate of 91%. Despite this good overall outcome, the regimen would be expected to fail to overcome levofloxacin resistance. Overcoming levofloxacin resistance is defined as similar results with both levofloxacin-resistant and -susceptible strains. Here, those subjects with levofloxacin resistance must have experienced an unacceptably low cure rate.2, 3 Failure to examine the treatment outcome in relation to anti-microbial susceptibility makes this mistake inevitable.4, 5 For example, one expects treatment success with susceptible strains with a 14-day triple therapy consisting of PPI, amoxicillin, fluoroquinolone to be greater than 95% (i.e. about 97%).2, 6, 7 The outcome among those with fluoroquinolone-resistant infections depends entirely on treatment success with the PPI, bismuth, amoxicillin triple combination2, 3 (i.e. the population outcome depends greatly on the proportion with fluoroquinolone resistance). If success with resistant strains was 70%,2 the levofloxacin resistance rate in the Gisbert et al., study would be about 20% [i.e. (97% times (1−X) + (70% times X) = 91%].2, 4, 5 If it were closer to their predicted resistance rate of 15% in Spain, treatment success would have been approximately 60% (i.e. approximately 40% of those with resistance would fail therapy). No matter, the conclusion that the regimen was effective is incorrect. The regimen was highly effective for those with susceptible strains, but would be unacceptable for those with levofloxacin resistance. The proportion with susceptibility/resistance to levofloxacin defined the population results consisting of subpopulations receiving effective (e.g. 95–97% success) and ineffective therapy (e.g. 60–70% success) (Figure 1). This is another example of how failure to collect antibiotic susceptibility in a clinical trial leads to misleading conclusions regarding the effectiveness of a treatment trial. Thus, while their data are correct, their conclusions are wrong. Author contributions: Each of the authors have been involved equally and have read and approved the final manuscript. Each meets the criteria for authorship established by the International Committee of Medical Journal Editors and verify the validity of the results reported. Declaration of personal interests: David Y. Graham has served as a speaker, a consultant and an advisory board member for Otsuka Japan, RedHill Biopharm and BioGala, and has received research funding from RedHill Biopharm. Dr Graham has received royalties from Baylor College of Medicine patents covering materials related to 13C-urea breath test. Dr Lu has nothing to declare. Declaration of funding interests: Dr Graham was supported in part by the Office of Research and Development Medical Research Service Department of Veterans Affairs, Public Health Service grants DK067366 and DK56338, which funds the Texas Medical Center Digestive Diseases Center. The contents are solely the responsibility of the authors and do not necessarily represent the official views of the VA or NIH. Dr Lu is supported in part by grants from the National Natural Science Foundation of China (81170355 and 81370592).