Placing in-vitro heteroresistance in the context of clinical results

We disagree with the conclusions presented by Jacob E Choby and coworkers1Choby JE Ozturk T Satola SW JT Weiss DS Widespread cefiderocol heteroresistance in carbapenem-resistant Gram-negative pathogens.Lancet Infect Dis. 2021; 21: 597-598Summary Full Text PDF PubMed Scopus (5) Google Scholar their Correspondence, which they postulated a causal link between in-vitro observation of to bacteria imbalance all-cause mortality observed CREDIBLE-CR (NCT02714595) clinical trial. In authors attempt quantify compare frequency heteroresistant subpopulations isolates collected from surveillance study Georgia, USA, outcomes international study.1Choby The propose that numerical similarities relative pathogens rates reported suggest might have contributed deaths. Although is interesting, standard methodology used, population analysis profiling, not clinically validated as predictive or microbiological vivo, such used diagnostic laboratories inform patient care, even for drug–bug combinations well characterised. Therefore, experimental design described coworkers sufficient test hypothesis an phenomenon patients. Moreover, colleagues ignore fact 25 38 patients best-available therapy (BAT) comparator group received colistin-based regimen.2Bassetti M Echols R Matsunaga Y et al.Efficacy safety best available treatment serious infections caused (CREDIBLE-CR): randomised, open-label, multicentre, pathogen-focused, descriptive, phase 3 trial.Lancet 226-240Summary (71) Within pathogens, has been most fully documented occur within polymyxin class, including colistin, manifest at high rate among Acinetobacter spp.3Karakonstantis S Saridakis I Colistin spp: systematic review meta-analysis prevalence discussion mechanisms potential therapeutic implications.Int J Antimicrob Agents. 2020; 56106065Crossref (13) As such, if had failure mortality, we would also expected it colistin-treated BAT group, paradoxically was unusually low. explaining observations be possible, imbalances factors baseline infected baumannii—for instance, shock location intensive care unit—might provide plausible explanation difference.2Bassetti Addressing wider question development resistance during therapy, here too point but those group. Shifts minimum inhibitory concentration (MIC) were both CREDIBLE-CR.2Bassetti Scholar, 4Takemura Yamano Ariyasu Den Nagata Characterization shifts concentrations comparators APEKS-NP studies.Open Forum 7: S649-S650Crossref found MIC similar antibiotics markedly higher spp than other pathogen groups. Furthermore, almost all showed increased remained susceptible (MIC <4 μg/mL), whereas agents, shift developed amounts resistance.4Takemura 5Kawaguchi N Katsube Wajima Population pharmacokinetic pharmacokinetic/pharmacodynamic analyses cefiderocol, parenteral siderophore cephalosporin, pneumonia, bloodstream infection/sepsis, complicated urinary tract infection.Antimicrob Agents Chemother. 65: e01437-e01520Crossref Most importantly, (NCT03032380),6Wunderink RG al.Cefiderocol versus high-dose, extended-infusion meropenem nosocomial pneumonia (APEKS-NP): double-blind, 3, non-inferiority 213-225Summary (53) controlled trial primary endpoint, no high-dose groups patients, involving spp, Pseudomonas Enterobacterales. Publications reporting early experience non-trial settings further evidence good responses complex, critically ill A baumannii treated prolonged periods time osteomyelitis endocarditis, whom cause persistence.7Falcone Tiseo G Nicastro rescue ICU patients.Clin (published online Sept 17.)doi:10.1093/cid/ciaa1410PubMed 8Dagher Ruffin F Marshall al.Case report: successful extensively drug-resistant cefiderocol.Open 7ofaa150Crossref AKo, AKa, CL, YY, TDN are employees Shionogi. RE consultant Shionogi consultancy fee. MB participated advisory boards speaker honoraria Angelini, Astellas, Bayer, Basilea, bioMérieux, Cidara, Cipla, Gilead, Menarini, MSD, Pfizer, Roche, Shionogi, grants pathogensWe read interest on Matteo Bassetti colleagues.1 Cefiderocol efficacy particularly despite 95% bacterial exhibiting 4 μg/mL less. hypothesise these discrepant data due undetected heteroresistance. Full-Text