Colistin Nephrotoxicity and Role of Alpha Lipoic Acid

According to World Health Organization (WHO), multidrug resistant (MDR) pathogens (e.g. Extended-spectrum beta-lactamases (ESBL), Carbapenem Resistant Enterobacteriaceae (CRE)) are one of the major public threats that yearly cause several million deaths globally. In 2019, Egypt recorded 56,600 deaths linked to antimicrobial resistance (AMR), ranking 58th out of 204 countries for age-standardized mortality rates related to AMR. Regarding the North Africa and Middle East region, Egypt has the second highest mortality rate among 21 countries. The deaths from AMR in Egypt surpass those from diabetes, kidney diseases, transport injuries, chronic respiratory diseases, respiratory infections, tuberculosis, and neurological disorders. In 2021, WHO published the list of antibiotic-resistant pathogens especially the critical group of MDR bacteria includes Pseudomonas aeruginosa, Acinetobacter baumannii, and Enterobacteriaceae, which cause severe infections in hospitalized patients. The resistance rate of carbapenem-resistant gram-negative bacteria (CR-GNB) is increasing over time. According to data from the chain antimicrobial resistance surveillance system, the resistance rate of carbapenem-resistant Klebsiella pneumoniae increased from 4.9% to 10.9% from 2013 to 2020. The resistance rates of carbapenem-resistant Acinetobacter baumannii and Enterobacteriaceae were 53.7% and 18.3%, respectively, in 2020.

Colistin is a polymyxin antibiotic first developed in 1947, fell out of favor due to its nephrotoxicity. With the rise of extensively drug-resistant Gram-negative bacteria, colistin has re-emerged as a last-resort treatment. However, its nephrotoxicity is considered as the main obstacle for using this valuable antibiotic. Colistin-induced nephrotoxicity has been reported in about 20-60% of treated patients. The mechanism of renal toxicity is through increased permeability of the renal tubular epithelium, increasing renal oxidative stress leading to cellular lysis and acute tubular necrosis. Nephrotoxicity incidence is influenced by many risk factors including dosage, and patient-related characteristics such as age, preexisting renal disease, diabetes, hypoalbuminemia, and other concomitant nephrotoxic compounds exposure.

AKI is usually diagnozed based on SCr and urine output. However, these markers are not specific and sensitive to GFR due to extra-renal factors, such as nutrition status, age, and muscle mass and fluid resuscitation. Serum creatinine is nonspecific to structural injury and has a nonlinear relationship with GFR, indicating that vast changes in GFR only signify a slight change in SCr. the changes in creatinine level lag behind the decreases in the GFR and can take up to 24-36 h to show a significant increase after obvious renal insult. Recognizing pharmacological interventions used to prevent or attenuate colistin-induced nephrotoxicity has gained special interest among healthcare professionals in recent years. Different clinical and preclinical studies were conducted to investigate the nephro-protective effect of some antioxidants e.g. melatonin, N-acetyl cysteine (NAC) and alpha lipoic acid (ALA) to prevent colistin nephrotoxicity. For example, ALA administration could reverse the effects of colistin-induced nephrotoxicity, owing to its antioxidant and anti-apoptotic effect as showed in a preclinical study on 2021.

Till now, there is no any published human study to evaluate the role of alpha lipoic acid in ameliorating colistin-induced nephrotoxicity. In addition the paucity of studies that early predict colistin-induced nephrotoxicity especially in Egypt which has a growing need for colistin therapy as it has the higher rates of antimicrobial resistance associated mortality in the North Africa and Middle East region.

• Time to Development of Acute Kidney Injury [Срок оценки: From randomization until the first occurrence of acute kidney injury, hospital discharge, death from any cause, or colistin discontinuation, whichever occurs first, assessed up to 30 days.]