Luisa Sorlí1, Sonia Luque2, Jian Li3, Núria Campillo4, Marc Danés5, Milagro Montero6, Concha Segura7, Santiago Grau2, Juan Pablo Horcajada6. 1. Infectious Diseases Department, Parc de Salut Mar, Passeig Marítim 25-29, E-08003 Barcelona, Spain; Infectious Pathology and Antimicrobials Research Group (IPAR), Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona, Spain; CEXS-Universitat Pompeu Fabra (UPF), Barcelona, Spain; Spanish Network for Research in Infectious Diseases (REIPI RD 16/0016/0015), Instituto de Salud Carlos III, Madrid, Spain. Electronic address: lsorli@hospitaldelmar.cat. 2. Infectious Pathology and Antimicrobials Research Group (IPAR), Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona, Spain; Spanish Network for Research in Infectious Diseases (REIPI RD 16/0016/0015), Instituto de Salud Carlos III, Madrid, Spain; Pharmacy Department, Parc de Salut Mar. Passeig Marítim 25-29, E-08003 Barcelona, Spain; Universitat Autònoma de Barcelona (UAB), Barcelona, Spain. 3. Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, Victoria 3800, Australia. 4. Infectious Pathology and Antimicrobials Research Group (IPAR), Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona, Spain; Pharmacy Department, Parc de Salut Mar. Passeig Marítim 25-29, E-08003 Barcelona, Spain. 5. CEXS-Universitat Pompeu Fabra (UPF), Barcelona, Spain. 6. Infectious Diseases Department, Parc de Salut Mar, Passeig Marítim 25-29, E-08003 Barcelona, Spain; Infectious Pathology and Antimicrobials Research Group (IPAR), Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona, Spain; CEXS-Universitat Pompeu Fabra (UPF), Barcelona, Spain; Spanish Network for Research in Infectious Diseases (REIPI RD 16/0016/0015), Instituto de Salud Carlos III, Madrid, Spain; Universitat Autònoma de Barcelona (UAB), Barcelona, Spain. 7. Laboratori de Referència de Catalunya, Carrer de la Selva, 10, E-08820 Prat de Llobregat (El), Barcelona.
Abstract
OBJECTIVES: Optimal dosage regimens of colistin for the treatment of urinary tract infections (UTI) are unknown. Colistimethate sodium (CMS), the inactive prodrug of colistin, is mainly excreted in urine and converts to colistin after filtration by glomeruli, suggesting that concentrations of colistin in urine could be much higher than in plasma. Therefore, there is a need to optimize dosage regimens of intravenous CMS for UTI. The aim of this study was to examine the relationship between AUC/MIC of formed colistin and clinical outcomes in patients with UTI caused by extremely drug resistant (XDR) Pseudomonas aeruginosa. METHODS: This prospective, observational cohort study involved patients with UTI caused by XDR P. aeruginosa. Clinical cure, bacteriological clearance and acute kidney injury (AKI) were analyzed. Steady-state colistin plasma concentrations (Css) were measured using HPLC. Based on the PK/PD of colistin in neutropenic mouse thigh infection models with P. aeruginosa, the optimal AUC/MIC should be ≥60 mg·h/L. According to the pharmacokinetics (PK) in critically-ill patients, the Css target of formed colistin in plasma was 2.5 mg/L. RESULTS: Thirty-three patients were included (24 lower UTI and 9 pyelonephritis). The MIC50 and MIC90 values for colistin were 0.5 and 2 mg/L respectively. Nineteen patients (57.6%) received colistin monotherapy (84.2% lower UTI and 15.8% pyelonephritis). Of these, clinical cure was achieved in 89.5% of cases. Among patients with clinical cure and monotherapy, only 5 (29.4%) attained an optimal plasma AUC/MIC and only 1 (5.9%) the therapeutic level of formed colistin (2.5 mg/L). However, 10 (58.8%) patients showed colistin plasma concentrations above the MIC of the isolated P. aeruginosa. Microbiological eradication was achieved in 76.9% of patients. AKI at the end of treatment was present in 29.4% of patients. CONCLUSIONS: The currently recommended dosage regimens of CMS showed high efficacy for the treatment of lower complicated UTI caused by XDR P. aeruginosa in non-critically ill patients and in the case of low MIC values, but also a considerable nephrotoxicity rate. Our data suggest that the use of lower CMS doses for lower UTI should be investigated in future studies to minimize the unnecessary nephrotoxicity.
OBJECTIVES: Optimal dosage regimens of colistin for the treatment of urinary tract infections (UTI) are unknown. Colistimethate sodium (CMS), the inactive prodrug of colistin, is mainly excreted in urine and converts to colistin after filtration by glomeruli, suggesting that concentrations of colistin in urine could be much higher than in plasma. Therefore, there is a need to optimize dosage regimens of intravenous CMS for UTI. The aim of this study was to examine the relationship between AUC/MIC of formed colistin and clinical outcomes in patients with UTI caused by extremely drug resistant (XDR) Pseudomonas aeruginosa. METHODS: This prospective, observational cohort study involved patients with UTI caused by XDRP. aeruginosa. Clinical cure, bacteriological clearance and acute kidney injury (AKI) were analyzed. Steady-state colistin plasma concentrations (Css) were measured using HPLC. Based on the PK/PD of colistin in neutropenic mouse thigh infection models with P. aeruginosa, the optimal AUC/MIC should be ≥60 mg·h/L. According to the pharmacokinetics (PK) in critically-illpatients, the Css target of formed colistin in plasma was 2.5 mg/L. RESULTS: Thirty-three patients were included (24 lower UTI and 9 pyelonephritis). The MIC50 and MIC90 values for colistin were 0.5 and 2 mg/L respectively. Nineteen patients (57.6%) received colistin monotherapy (84.2% lower UTI and 15.8% pyelonephritis). Of these, clinical cure was achieved in 89.5% of cases. Among patients with clinical cure and monotherapy, only 5 (29.4%) attained an optimal plasma AUC/MIC and only 1 (5.9%) the therapeutic level of formed colistin (2.5 mg/L). However, 10 (58.8%) patients showed colistin plasma concentrations above the MIC of the isolated P. aeruginosa. Microbiological eradication was achieved in 76.9% of patients. AKI at the end of treatment was present in 29.4% of patients. CONCLUSIONS: The currently recommended dosage regimens of CMS showed high efficacy for the treatment of lower complicated UTI caused by XDRP. aeruginosa in non-critically illpatients and in the case of low MIC values, but also a considerable nephrotoxicity rate. Our data suggest that the use of lower CMS doses for lower UTI should be investigated in future studies to minimize the unnecessary nephrotoxicity.
Authors: Roger L Nation; Samira M Garonzik; Visanu Thamlikitkul; Evangelos J Giamarellos-Bourboulis; Alan Forrest; David L Paterson; Jian Li; Fernanda P Silveira Journal: Clin Infect Dis Date: 2016-12-23 Impact factor: 9.079
Authors: S M Garonzik; J Li; V Thamlikitkul; D L Paterson; S Shoham; J Jacob; F P Silveira; A Forrest; R L Nation Journal: Antimicrob Agents Chemother Date: 2011-05-09 Impact factor: 5.191
Authors: Nicolas Grégoire; Vincent Aranzana-Climent; Sophie Magréault; Sandrine Marchand; William Couet Journal: Clin Pharmacokinet Date: 2017-12 Impact factor: 6.447
Authors: Helio S Sader; Robert K Flamm; Glenn E Dale; Paul R Rhomberg; Mariana Castanheira Journal: J Antimicrob Chemother Date: 2018-09-01 Impact factor: 5.790
Authors: D Plachouras; M Karvanen; L E Friberg; E Papadomichelakis; A Antoniadou; I Tsangaris; I Karaiskos; G Poulakou; F Kontopidou; A Armaganidis; O Cars; H Giamarellou Journal: Antimicrob Agents Chemother Date: 2009-05-11 Impact factor: 5.191
Authors: David van Duin; Judith J Lok; Michelle Earley; Eric Cober; Sandra S Richter; Federico Perez; Robert A Salata; Robert C Kalayjian; Richard R Watkins; Yohei Doi; Keith S Kaye; Vance G Fowler; David L Paterson; Robert A Bonomo; Scott Evans Journal: Clin Infect Dis Date: 2018-01-06 Impact factor: 9.079
Authors: Jose Luis Lamas Ferreiro; Judith Álvarez Otero; Lucía González González; Luis Novoa Lamazares; Alexandra Arca Blanco; Jose Ramón Bermúdez Sanjurjo; Irene Rodríguez Conde; María Fernández Soneira; Javier de la Fuente Aguado Journal: PLoS One Date: 2017-05-26 Impact factor: 3.240
Authors: Hannah Panlilio; Anh K Lam; Neda Heydarian; Tristan Haight; Cassandra L Wouters; Erika L Moen; Charles V Rice Journal: ACS Infect Dis Date: 2021-05-04 Impact factor: 5.084
Authors: Ling Guo; Dan Zhang; Shulin Fu; Jiacheng Zhang; Xiaofang Zhang; Jing He; Chun Peng; Yunfei Zhang; Yinsheng Qiu; Chun Ye; Yu Liu; Zhongyuan Wu; Chien-An Andy Hu Journal: Front Vet Sci Date: 2021-07-02