title: Validation of a colistin plasma concentration breakpoint as a predictor of nephrotoxicity in patients treated with colistin methanesulfonate.
abstract: Nephrotoxicity limits the effective use of colistin for the treatment of multidrug-resistant Gram-negative bacteria (MDR-GNB) infections. We previously defined a steady-state colistin plasma concentration (Css) of 2.42 mg/L that predicted nephrotoxicity at end of treatment (EOT). The objective of this study was to validate this breakpoint in a prospective cohort. This was a multicentre, prospective, observational study conducted at three hospitals with a cohort of patients treated for MDR-GNB infection with colistin methanesulfonate from September 2011 until January 2015. Nephrotoxicity was evaluated at Day 7 and at EOT using the RIFLE criteria. Cssvalues were measured and analysed using HPLC. Taking the previously defined breakpoint for colistin concentration as a criterion, patients were divided into two groups (Css, ≤2.42 mg/L vs. >2.42 mg/L). Sixty-four patients were included. Seven patients (10.9%) had a Css> 2.42 mg/L and were compared with the remaining patients. Bivariate analysis showed that patients with a Css> 2.42 mg/L were older and had a significantly higher incidence of nephrotoxicity at Day 7 and EOT. Although not statistically significant, nephrotoxicity occurred earlier in these patients (6.2 days vs. 9.2 days in patients with lower Css; P = 0.091). Multivariate analysis of nephrotoxicity showed that Css> 2.42 mg/L was the only predictive factor. Nephrotoxicity was more frequent and occurred earlier in patients with colistin plasma concentrations higher than the previously defined breakpoint (2.42 mg/L). Colistin therapeutic drug monitoring should be routinely considered to avoid reaching this toxicity threshold and potential clinical consequences.
authors.affiliation: Infectious Diseases Service, Hospital del Mar, Infectious Pathology and Antimicrobials Research Group (IPAR), Institut Hospital del Mar d'Investigacions Mèdicues (IMIM), CEXS-Universitat Pompeu Fabra, Barcelona, Spain. Electronic address: jhorcajada@parcdesalutmar.cat.
authors.forename: Juan P
authors.initials: JP
authors.lastname: Horcajada
authors.affiliation: Infectious Diseases Service, Hospital del Mar, Infectious Pathology and Antimicrobials Research Group (IPAR), Institut Hospital del Mar d'Investigacions Mèdicues (IMIM), CEXS-Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Luisa
authors.initials: L
authors.lastname: Sorlí
authors.affiliation: Pharmacy Service, Hospital del Mar, Barcelona, Spain.
authors.forename: Sonia
authors.initials: S
authors.lastname: Luque
authors.affiliation: Infectious Diseases Unit, Department of Internal Medicine, Hospital de la Santa Creu i Sant Pau, Barcelona, Sant Pau, Barcelona, Spain; Institut d'Investigació Biomèdica Sant Pau, Barcelona, Spain; Spanish Network for Research in Infectious Diseases (REIPI RD12/0015), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Natividad
authors.initials: N
authors.lastname: Benito
authors.affiliation: Laboratori de Referència de Catalunya, Prat de Llobregat, Barcelona, Spain.
authors.forename: Concepción
authors.initials: C
authors.lastname: Segura
authors.affiliation: Pharmacy Service, Hospital del Mar, Barcelona, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Campillo
authors.affiliation: Infectious Diseases Service, Hospital del Mar, Infectious Pathology and Antimicrobials Research Group (IPAR), Institut Hospital del Mar d'Investigacions Mèdicues (IMIM), CEXS-Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Milagro
authors.initials: M
authors.lastname: Montero
authors.affiliation: Infectious Diseases Service, Hospital del Mar, Infectious Pathology and Antimicrobials Research Group (IPAR), Institut Hospital del Mar d'Investigacions Mèdicues (IMIM), CEXS-Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Erika
authors.initials: E
authors.lastname: Esteve
authors.affiliation: Service of Microbiology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Mirelis
authors.affiliation: Infectious Diseases Unit, Department of Internal Medicine, Hospital de la Santa Creu i Sant Pau, Barcelona, Sant Pau, Barcelona, Spain; Institut d'Investigació Biomèdica Sant Pau, Barcelona, Spain; Spanish Network for Research in Infectious Diseases (REIPI RD12/0015), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Virginia
authors.initials: V
authors.lastname: Pomar
authors.affiliation: Hospital del Granollers, Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Cuquet
authors.affiliation: Hospital del Granollers, Barcelona, Spain.
authors.forename: Carmina
authors.initials: C
authors.lastname: Martí
authors.affiliation: Hospital del Granollers, Barcelona, Spain.
authors.forename: Pau
authors.initials: P
authors.lastname: Garro
authors.affiliation: Pharmacy Service, Hospital del Mar, Barcelona, Spain.
authors.forename: Santiago
authors.initials: S
authors.lastname: Grau
mesh_terms: D058186:Acute Kidney Injury; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000032:analysis*; D002851:Chromatography, High Pressure Liquid; D003091:Colistin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000032:analysis; D016903:Drug Monitoring; D005260:Female; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy; D006761:Hospitals; D006801:Humans; D008297:Male; D008875:Middle Aged; D010949:Plasma / Q000737:chemistry*; D011446:Prospective Studies; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; C004691:colistinmethanesulfonic acid; D003091:Colistin
keywords: Colistin; Nephrotoxicity; Plasma concentration; Risk factors; Therapeutic drug monitoring