DISCUSSION
Colistin is a cationic polypeptide-based antimicrobial agent that was first used in the 1950s but was restricted in the 1970s due to its adverse effects (12). The recent dramatic increase in resistant gram-negative bacterial infections has led to the resurgence of COL, especially in ICUs. COL-associated nephrotoxicity remains a major problem in clinical use and the incidence is reported to vary widely, between 11% and 76% (3,7,8,13,14). In our study, the acute renal failure rate was determined as 62.4%. Although most of our patients were evaluated as ‘failure’ or ‘injury’, only 5 of the patients required hemodialysis. Several factors have been associated with COL nephrotoxicity in the literature, such as higher APACHE II score, hypoalbuminemia, basal serum creatinine concentration, concomitant nephrotoxic drug use, and sex (3,6-8). In the present study, we determined that age, APACHE II score, initial serum creatinine concentration, and rate of concomitant nephrotoxic agent use were higher among patients who developed nephrotoxicity and that the female sex carried a greater risk than the male sex. Similar to our results, there are studies in the literature that identify advanced age as a risk factor for COL nephrotoxicity (15,16).
Most of the patients treated with COL in this study were older patients. Although the rate of COL nephrotoxicity was found to be higher in patients with underlying chronic diseases in the studies, when our patient population was evaluated from this point of view, no significant difference was found between the two groups (17). Aydoğan et al. reported higher rates of cardiac disease and COPD in the geriatric group but it was found that advanced age is not a risk factor for nephrotoxicity. (5). In our study, no significant difference was found between geriatric and young patients who developed nephrotoxicity in terms of underlying chronic diseases, concomitant nephrotoxic agent use, initial serum urea and creatinine values. These results have enabled us to evaluate the risk factors associated with nephrotoxicity in geriatric patients more objectively. When the literature is reviewed, there is no study investigating the risk factors associated with colistin nephrotoxicity in the geriatric group, which constitutes the majority of the patient population followed up in the intensive care unit.
We also observed that concomitant use of nephrotoxic agents was more common in the nephrotoxic group in this study. The high incidence of cardiac disease in geriatric patients increases the use of agents such as ACE inhibitors and furosemide in this group. In addition to impaired renal function, hyperkalemia is an important adverse effect of ACE inhibitors (18). Loop diuretics such as furosemide are also frequently used in ICU patients. These agents cause volume depletion with excess diuresis, causing hypotension and acute renal failure. Close monitoring of electrolyte levels and symptoms of hypotension and dehydration is necessary for ICU patients, especially those using concomitant nephrotoxic agents.
Several studies have evaluated the time from COL initiation to the appearance of COL-associated nephrotoxicity. One of these studies showed that nephrotoxicity frequently occurred in the first 72 hours after starting COL (7). In another study investigating COL nephrotoxicity in older and younger adult patients, it was observed that older patients had a significantly longer length of ICU stay before COL initiation (5). When geriatric and young patients were compared in terms of time from onset of COL to nephrotoxicity, there was no statistically significant difference.
Mortality rates are higher among ICU patients due to their advanced age, disease severity, and common healthcare-associated infections. Although some studies demonstrated higher mortality in patients with COL nephrotoxicity, others showed no difference (3,19,20). Özkarakaş et al. reported similar mortality rates between patients with and without nephrotoxicity (19). In another study comparing mortality rates in older and young adult patients receiving COL, there was no difference between the two groups (5). In contrast to these findings, mortality rates were statistically higher in the nephrotoxicity group and in the geriatric nephrotoxicity subgroup in our study.
The average human lifespan is increasing worldwide. According to World Health Organization (WHO) data, the older population is expected to increase from 12% to 22% of the total population between 2015 and 2050 (21). Age-related decline in innate immunity brings about changes in neutrophil migration, macrophage phagocytosis, and cytokine production that increase the risk of infection by extracellular pathogens (22). Also, poorer nutrition and hygiene, organ dysfunction, reduced mucociliary activity, and comorbid conditions are other factors that increase the susceptibility to infections in older patients (1,23,24). The majority of patients treated in hospitals are in the geriatric population, especially in ICUs.
In the present study, geriatric patients had higher APACHE II scores, rates of vasopressor agent use, the prevalence of COPD and cardiac disease, and COL nephrotoxicity and mortality rates; and age ≥65 years was found to be an independent risk factor for COL nephrotoxicity. Aging affects the pharmacokinetics and pharmacodynamics of antibiotics (25). Most antibiotics are highly water-soluble and bind to proteins. Antibiotics reach higher concentrations in tissues with high blood flow than in tissues with low blood flow, such as adipose tissue. A decrease in serum proteins such as albumin, lean body mass, and body water and an increase in body fat result in a reduced volume of distribution of antibiotics in older adults. Polypharmacy is common, which also increases the risk of drug–drug interactions in this patient group (26,27). Inadequate administration of antibiotics and failure to perform dose adjustment and follow-up may lead to life-threatening adverse effects. All of these factors increase susceptibility to infection and treatment failure in older patients, especially in ICUs. Therefore, dose adjustment and follow-up should be performed with consideration to the pharmacokinetic and pharmacodynamics of antibiotics.
COL is mainly excreted renally, and urinary excretion includes renal tubular secretion. It passes through large renal tubular reabsorption (up to 80%) and most of the filtered COL remains in the body and is therefore mainly cleared by non-renal mechanisms. COL nephrotoxicity is primarily associated with d-aminobutyric acid and fatty acid components, and the mechanism of nephrotoxicity is similar to its antibacterial effect. COL increases the permeability of the tubular epithelial cell membrane, which leads to an influx of cations, anions, and water, leading to cell swelling and consequently to cell lysis (28-30). The dosing regimen of COL should be determined considering the renal function of patients as assessed by creatinine clearance. Especially, care should be exercised in patients with initial serum creatinine levels close to the upper limit, and another treatment option other than COL should be considered in geriatric patients.
In summary, in our study, advanced age was found to be an independent risk factor for COL nephrotoxicity. The high mortality rate in elderly patients treated with COL may be related to the high overall mortality rate of geriatric patients followed in ICUs. Close monitoring of the serum creatinine concentrations and sign of hypovolemia and hypotension of all patients receiving COL treatment is required. If signs and symptoms of renal failure are detected, it is recommended to continue with the required dose adjustment. Vasopressor agent use was found higher in the geriatric group in our study, the reduction of blood circulation to tissues affects the distribution volume of antibiotics. In this respect, it is important that arterial blood pressure monitoring is performed regularly and that the necessary support is given at a sufficient level. Caution should be exercised especially in geriatric patients who have initial serum creatinine levels close to the upper limit or who use concomitant nephrotoxic drugs, and if possible, another treatment option other than COL should be considered in these patients.
Conflicts of interest: The authors declare that they have no conflict of interest.
Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.