Evaluation of the Efficacy and Safety of N-Acetylcysteine Versus Alpha-Lipoic Acid on the Occurrence and Severity of Colistin-Induced Nephrotoxicity in Critically Ill Patients

Nosocomial infections caused by multi-drug-resistant Gram-negative bacteria (MDR G-ve) bacteria, particularly Acinetobacter baumannii, Pseudomonas aeruginosa and Klebsiella pneumonia represent a crucial rapidly increasing health problem worldwide nowadays.

The available effective antibiotics, including broad-spectrum penicillin, fluoroquinolones, aminoglycosides, and β-lactams (carbapenems, monobactam, and cephalosporins) often fail to combat these organisms and the pharmaceutical pipeline is still facing the problem of lack of new moieties. The new and potent β-lactam/ β-lactamase combinations antibiotics "Tigecycline and other newer highly expensive β-lactam/ β-lactamase combinations as ceftazidime/avibactam, meropenem/vaborbactam "have their concerns related to their high cost and unavailability in all countries. Moreover, they are ineffective against Metallo-β-lactamase-producing CRE. Accordingly, this led to the reconsideration of old drugs such as polymyxin B and polymyxin E (also known as colistin) that were previously considered to be too toxic for clinical use in the treatment of MDR G-ve bacteria Colistin has re-emerged for treatment of severe infections caused by multidrug-resistant Gram-negative bacteria especially Pseudomonas aeruginosa, Acinetobacter baummannii, Klebsiella pneumonia and Enterobacterales .Colistin monotherapy or colistin based synergistic combinations with a carbapenem, high-dose ampicillin/sulbactam or high dose tigecycline represent the last resort option to overcome CR-GNB in critically ill patients. Colistin (colistimethate sodium) is the inactive prodrug that is hydrolyzed to colistin that act as a cationic detergent and disrupt the bacterial cytoplasmic membrane resulting in leak of intracellular substances and cell death.

Colistin associated acute kidney injury (CA-AKI) is frequently observed in the intensive care unit (ICU) patients treated with colistin especially in patients with advanced age, other comorbidities, baseline renal dysfunction and hemodynamically unstable patients Colistin is primarily eliminated renally and may induce acute kidney injury at a rate of up to 53% Many studies have discussed the prevalence of colistin induced nephrotoxicity. One recent study in 2023 stated that the incidence of nephrotoxicity was 44.9% (95% CI; 37% to 53%) and its severity according to Kidney Disease Improving Global Outcomes (KDIGO) guidelines in 2012 was stage1 (47%), stage2 (21%) and stage3 (31%). Accordingly, it is important to monitor renal functions prior to and during colistin treatment to detect the early signs of renal injury and minimize long term renal dysfunction. A serum creatinine (SCr) is commonly used for estimation of renal function.

Cockcroft-Gault equation is the most common formula for determining creatinine clearance which estimates glomerular filtration rate (GFR). Although creatinine clearance may over-estimate GFR by (10-20%) but still remains the standard for drug dosing adjustments.

Accordingly, it is important to monitor renal functions prior to and during colistin treatment to detect the early signs of renal injury.