Identification of antibiotic pairs with disjoint resistance: innovative progress made but questions remain
Authors: Huan Zhang, Yun Cai
Journal: The Lancet Microbe (2021)

We have read the study by Andrew Beckley and Erik Wright1Beckley AM Wright ES Identification of antibiotic pairs that evade concurrent resistance via a retrospective analysis of antimicrobial susceptibility test results.Lancet Microbe. 2021; 2: e545-e554Summary Full Text Full Text PDF PubMed Google Scholar with great interest, which identified the antibiotic pairs with disjoint resistance in subpopulations of the six most frequently isolated bacterial species (Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, Enterococcus faecalis, Pseudomonas aeruginosa, and Proteus mirabilis). The results of this study are innovative and indicate progress in this field, but we have one serious concern about the classification criteria of the subpopulations and consequent high resistance rate of potential antibiotics in the subgroup. In the study, the subpopulation of a bacterial species was classified by conditioning so that all isolates in the subgroup were resistant to a given antibiotic. However, considering the ubiquity of concurrent resistance in clinical practice,1Beckley AM Wright ES Identification of antibiotic pairs that evade concurrent resistance via a retrospective analysis of antimicrobial susceptibility test results.Lancet Microbe. 2021; 2: e545-e554Summary Full Text Full Text PDF PubMed Google Scholar, 2Cherny SS Nevo D Baraz A et al.Revealing antibiotic cross-resistance patterns in hospitalized patients through Bayesian network modelling.J Antimicrob Chemother. 2021; 76: 239-248Crossref PubMed Google Scholar other antibiotics (especially those belonging to the same class as the given drug) would accordingly increase the prevalence of resistance in the subpopulation. Consequently, the high resistance of the studied antibiotic pairs might reduce the accuracy of the conditional mutual information score (MIS) and lead to a biased conclusion of disjoint resistance. Take gentamicin, the representative of strong disjoint resistance in the study, as an example. There were ten cases of antibiotic pairs with a statistically significant negative MIS (<–0·05, ie, disjoint resistance) with gentamicin as one of the antibiotics in the subpopulation of E coli, which was classified by conditioning on 100% resistance to tobramycin. Tobramycin and gentamicin are both aminoglycosides. It is noteworthy that in all cases of the antibiotic pairs, the resistance of E coli to gentamicin was notably high, varying from 81·06% to 90·17% based on appendix 2 (ten cases with 20 data in both 2015–16 and 2017–18). The subpopulation classification criteria and accordingly high resistance of antibiotic pairs, especially in the same class with the conditional drug, might lead to a tendentious score of MIS and should be treated cautiously. To focus on the changes in antimicrobial sensitivity caused by the resistance evolution of another antibiotic, another suggestion we had was to judge disjoint resistance based on the multiplied change of the minimum inhibitory concentration, instead of the minimum inhibitory concentration breakpoint used in Beckley and Wright's study.1Beckley AM Wright ES Identification of antibiotic pairs that evade concurrent resistance via a retrospective analysis of antimicrobial susceptibility test results.Lancet Microbe. 2021; 2: e545-e554Summary Full Text Full Text PDF PubMed Google Scholar Although it would be better to reduce minimum inhibitory concentration to less than the susceptibility breakpoint by alternating antibiotics, there was an almost complete absence of antibiotic pairs showing disjoint resistance based on present results. Practically, it is also important to reduce the minimum inhibitory concentration to a specific level for clinical success, even if the minimum inhibitory concentration is still several times the sensitive breakpoint. Studies have found that meropenem is still effective against carbapenem-resistant Enterobacteriaceae with a minimum inhibitory concentration of up to 32 μg/mL (eight times the susceptibility breakpoint) by increasing doses and prolonging the infusion time.3Cojutti P Sartor A Righi E et al.Population pharmacokinetics of high-dose continuous-infusion meropenem and considerations for use in the treatment of infections due to KPC-producing Klebsiella pneumoniae.Antimicrob Agents Chemother. 2017; 61: e00794-e00817Crossref PubMed Scopus (28) Google Scholar, 4Pascale R Giannella M Bartoletti M et al.Use of meropenem in treating carbapenem-resistant Enterobacteriaceae infections.Expert Rev Anti Infect Ther. 2019; 17: 819-827Crossref PubMed Scopus (10) Google Scholar Therefore, it is hoped that future studies will evaluate the disjoint resistance based on both the breakpoint and the magnitude of the minimum inhibitory concentration change. Additionally, there is an error in the article (page e549). The extremely low rate of carbapenem resistance was for K aerogenes and K oxytoca rather than K pneumoniae. Infections caused by carbapenem-resistant K pneumoniae have become a serious threat to public health. In conclusion, when evaluating the disjoint resistance within subpopulations classified by conditional resistance, the high resistance of antibiotic pairs, especially in the same class with the conditional antibiotic, should be taken into consideration. We declare no competing interests. Identification of antibiotic pairs that evade concurrent resistance via a retrospective analysis of antimicrobial susceptibility test resultsThe high frequency of concurrent resistance shows that bacteria have means of counteracting multiple antibiotics at a time. The almost complete absence of disjoint resistance at the species level implies that treatment strategies based on alternating between antibiotics might require subspecies level pathogen identification and be limited to a few antibiotic pairings. Full-Text PDF Open AccessIdentification of antibiotic pairs with disjoint resistance: innovative progress made but questions remainI read with great interest the article by Andrew Beckley and Erik Wright,1 in which a score based on mutual information was used to look for antibiotic pairs that have concurrent resistance. Full-Text PDF Open AccessIdentification of antibiotic pairs with disjoint resistance: innovative progress made but questions remain – Authors' replyWe thank Huan Zhang and Yun Cai for their comments on our Article.1 Although conditioning on resistance to an antibiotic could result in a subpopulation that is more resistant to other antibiotics, this does not inherently bias the mutual information score (MIS) of the subpopulation. Zhang and Cai note that several of the antibiotic pairs with statistically significant disjoint resistance originated from the subpopulation of Escherichia coli resistant to tobramycin, which displayed concurrent resistance with one of the antibiotics in the identified pairs. Full-Text PDF Open Access