Mechanisms of antimicrobial-induced nephrotoxicity in children

Abstract

Drug-induced nephrotoxicity is responsible for 20% to 60% of cases of acute kidney injury in hospitalized patients and is associated with increased morbidity and mortality in both children and adults. Antimicrobials are one of the most common classes of medications prescribed globally and also among the most common causes of nephrotoxicity. A broad range of antimicrobial agents have been associated with nephrotoxicity, but the features of kidney injury vary based on the agent, its mechanism of injury and the site of toxicity within the kidney. Distinguishing nephrotoxicity caused by an antimicrobial agent from other potential inciting factors is important to facilitate both early recognition of drug toxicity and prompt cessation of an offending drug, as well as to avoid unnecessary discontinuation of an innocuous therapy. This review will detail the different types of antimicrobial-induced nephrotoxicity: acute tubular necrosis, acute interstitial nephritis and obstructive nephropathy. It will also describe the mechanism of injury caused by specific antimicrobial agents and classes (vancomycin, aminoglycosides, polymyxins, antivirals, amphotericin B), highlight the toxicodynamics of these drugs and provide guidance on administration or monitoring practices that can mitigate toxicity, when known. Particular attention will be paid to paediatric patients, when applicable, in whom nephrotoxin exposure is an often-underappreciated cause of kidney injury.

Presence of Chromosomal crpP-like Genes Is Not Always Associated with Ciprofloxacin Resistance in Pseudomonas aeruginosa Clinical Isolates Recovered in ICU Patients from Portugal and Spain

“…A total of 55 MDR/XDR- P. aeruginosa isolates from 11 Portuguese and 8 Spanish hospitals were analyzed by WGS as a part of the STEP and SUPERIOR studies, respectively [ 16 ]. In this subset, 46 isolates (83.6%) showed a non-wild type ciprofloxacin susceptible phenotype (MIC CIP = 1 –> 2 mg/L) ( Table 2 , Table S2 ).…”

“…Note that prevalence of crpP genes was higher in the P. aeruginosa isolates recovered in Spain than in those recovered in Portuguese hospitals, and this finding could be related to a successful association between the PAGI- crpP1.1 and the CC175 high-risk clone. It should be noted that the CC175 is the most frequent P. aeruginosa clone in Spanish hospitals and that its extensive resistome has been found to be determined mainly by mutational events [ 16 , 28 , 29 ]. On the other hand, the presence of crpP genes was scarcely observed in the CC235 (1/15), the most frequent clone in the Portuguese collection.…”

“…Minimum inhibitory concentration (MIC) values were determined by standard broth microdilution and interpreted according to the EUCAST 2020 criteria ( , accessed on 10 February 2021) (S, susceptible ≤ 0.001 mg/L; I, susceptible, increased exposure >0.001–0.5 mg/L; R, resistant > 0.5 mg/L) [ 14 , 15 ]. A subset of 55 P. aeruginosa isolates with susceptible and resistant ceftolozane-tazobactam profiles were subsequently analyzed by whole genome sequencing (WGS) ( Table S1 ) [ 16 ].…”

“…Acquired quinolone resistance genes were screened using Abricate (v0.8.11) (ARG-ANNOT and ResFinder databases; threshold, 95% identity; 90% coverage). In addition, mutations from 34 chromosomal genes involved in fluoroquinolones resistance were also analyzed using SNIPPY software (v4.4.3) ( (accessed on 10 February 2021)) ( Table S2 ) [ 16 ]. Briefly, all P. aeruginosa assembled sequences were mapped against the P. aeruginosa PAO1 reference genome (GenBank accession No.…”

“…Our aim was to investigate the dissemination of crpP - like genes in MDR or extensively resistant (XDR) P. aeruginosa clinical isolates recovered in patients admitted in Spanish and Portuguese ICUs between 2016 and 2018. These isolates were obtained during surveillance studies to monitor the activity of ceftolozane-tazobactam, a novel β-lactam-β -lactamase combination with enhanced antimicrobial activity against P. aeruginosa , including MDR/XDR isolates [ 14 , 15 , 16 ].…”