Colistin plasma concentrations are not associated with better clinical outcomes in patients with pneumonia caused by extremely drug-resistant Pseudomonas aeruginosa

ABSTRACT The objective of this study was to examine the relationship between colistin plasma concentrations and clinical outcomes in patients with hospital-acquired pneumonia (HAP) caused by extensively drug-resistant Pseudomonas aeruginosa (XDR-PA). A prospective observational cohort study was conducted at a tertiary care hospital. Patients diagnosed with HAP caused by XDR-PA between January 2010 and September 2018 were included. Steady-state plasma concentrations (C ss,avg) of colistin were measured by high performance liquid chromatography (HPLC). Based on the pharmacokinetic/pharmacodynamic data of colistin in animal models, previous clinical data, and the minimum inhibitory concentration (MIC) of the most prevalent strain in our center, an area under the ROC curve (AUC)/MIC24h between 30 and 60 mg·h/L was considered optimal. The primary outcome was 30-day mortality, and the secondary outcomes were clinical cure and colistin-associated nephrotoxicity. Seventy-five patients were included. The median C ss,avg was 1.1 (0.56–1.75) mg/L and only 23 (30.7%) patients achieved an AUC/MIC24h of 30–60 mg·h/L and the 30-day mortality was 30.7%. In multivariate analysis, sequential organ failure assessment score [adjusted hazard ratio (95% confidence interval, CI) 1.19 (1.07–1.32)] and high AUC/MIC24h (hazard ratio 1.55, 95% CI 1.17–2.04, P = 0.002) were associated with increased risk of death and clinical failure. Based on the maximally selected standardized log-rank statistic, the C ss,avg cutoff point that best predicted mortality was 1.5 mg/L. Nephrotoxicity at the end of treatment was 38.7%. High colistin exposure was not associated with improved clinical outcomes in the setting of HAP caused by XDR-PA. These data suggest that caution is required with intravenous colistin for the treatment of HAP caused by XDR-PA. IMPORTANCE In some cases, colistin is the only treatment option for infections caused by the very drug-resistant Pseudomonas aeruginosa. However, in the past decade, there have been questions concerning its pharmacokinetics and concentration at the site of infection. In this scenario, its use in a difficult-to-treat infection like pneumonia is currently debatable. This is a clinical pharmacokinetic study of colistin in patients with multidrug-resistant P. aeruginosa pneumonia. Our findings demonstrate that colistin exposure is associated with worse clinical outcomes rather than better clinical outcomes, implying that other therapeutic options should be explored in this clinical setting.

2. A short description of figure 1 should be added.
Reviewer #2 (Comments for the Author): In their manuscript, "An 8-Year Experience of Therapeutic Drug Monitoring of Colistin in Patients with Pneumonia Caused by Extremely Drug-Resistant Pseudomonas aeruginosa" Sorli and colleagues are investigating the relationship between colistin plasma concentration and the clinical outcome in patients with HAP caused by XDR Pseudomonas aeruginosa.The manuscript of one of a series of many published by the same group investigating the outcomes of using colistin in combating XDR-PA.In their findings and conclusions, the authors found that higher colistin plasma concentration was associated with a worse clinical outcome.And they suggested that nebulized colistin holds promise as a valuable treatment option for nosocomial pneumonia.
Comments: Line 103-109: Appropriate reference(s) need to be included for these statements" New on information on the pharmacokinetics of colistin ......has been recently published" and "Based on PK/PD from mouse data" For the study design and treatment regimen, I am confused by how CMS was administered.It's not clear to me whether the patient cohort of choice were those received intravenous CMS (alone or in combination therapy).Then in lines 133-134, the authors mention nebulization.Was CMS nebulized alone or in combination with other antibiotics?And was CMS administered separately or concurrently as IV and inhaled treatment (Table 1)?-In the sampling and the bioanalysis, there's no description on how the CMS was nebulized.Line 270: "A high mortality rate (30.7%) was observed in our series" Can the authors be more specific?Are they referring to previous work done by their group?What are these specific references?Line343: Is that the correct reference (Markou et al)? Figure S1 need to be in better quality.

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• Manuscript: A .DOC version of the revised manuscript • Figures: Editable, high-resolution, individual figure files are required at revision, TIFF or EPS files are preferred Thank you for submitting your paper to Microbiology Spectrum.An 8-Year Experience of Therapeu c Drug Monitoring of Colis n in Pa ents with Pneumonia Caused by Extremely Drug-Resistant Pseudomonas aeruginosa Authors: Luisa Sorli, Sonia Luque, Jian Li, Adela Benítez-Cano, Xenia Fernández, NuriaPrim, Victoria Vega, Joan Gómez-Junyent, Inmaculada López-Montesinos, Silvia Gómez-Zorrilla, M. Milagro Montero, San ago Grau, Juan Pablo Horcajada Dear Professor Fikri Avci: Thanks for the opportunity to review our manuscript.We have carefully reviewed it and here are the answers to the reviewers' comments point-by-point: The study by Sorli et al. is very important and interes ng.The study is well-designed, and the conclusion is sound.I have very minor comments.1.The tle Should be modified.According to the reviewer's recommenda on, the tle has been updated.We believe that the new tle places greater emphasis on the work's results.If it does not sa sfy the reviewer, we are open to any sugges ons.2.A short descrip on of figure 1 should be added.Thank you for your comment.As suggested by the reviewer, a concise descrip on of the Figure1has been provided.