1. Descriptive analysis of the cohort
The study included 163 patients with CMS prescriptions over 5 years. The mean age was 66 years, and 71.2% were male.
At the time of CMS initiation, almost half of the patients were admitted to the Intensive Care Unit ICU (42.3%). The median basal glomerular filtration rate estimated according to CKD-EPI was 92.2 ml/min/1.73m2. The most frequent infection where CMS was prescribed was lower respiratory tract infection (41.7%) followed by urinary tract infection (22.7%) and others. 17.2% of all infections were associated with bacteremia.
Other characteristics of the patients are shown in Table1.
Regarding CMS prescriptions, 95.7% were prescribed as target therapy. Most of them given in combination therapy (64.4%) with one or two antimicrobials against gram-negative pathogens, 51.5% and 12.9% respectively. The antibiotics mainly used in combination therapy were carbapenems (34.0%) and tigecycline (24.0%). Thirty-five patients (24.5%) received a loading dose. The CMS prescriptions adjusted following variation of serum creatinine were 28.2%. Hence, CMS prescriptions were appropriate for 25 patients (15.3%). The median duration of CMS treatment was 10 days (IQR: 6-14) and the median cumulative dose per patient was 63MU (IQR: 36-108).
Acinetobacter baumanii spp. was the most commonly identified pathogen (72.4%) followed by Pseudomonas aeruginosa (19.6%), Klebsiella spp. (4.3%) and Enterobacter spp. (1.8%), (Table 1). Only 4.3% of patients were treated empirically with CMS.
75 patients (46%) developed nephrotoxicity attributable to colistin treatment, although only 14 patients (8.6%) discontinued treatment for this reason. The median onset time of nephrotoxicity after initiation of CMS treatment was 7 days (IQR: 4-11).
Therefore, the reasons for discontinuation of CMS treatment were cure (57.7%) followed by patient’s death (17.8%), and treatment adjustment by isolated microorganism (10.4%), among others (Table1).
2. Risk factor associated with nephrotoxicity
In the bivariate analysis of factors associated with the incidence of nephrotoxicity, the following were found: age (70.4 years vs 62.2 years, p=0.003), Charlson Index (2 vs 1.5, p=0.012), Basal Glomerular Filtration Rate (82.7 ml/min/1.73m vs 105.7 ml/min/1.73m, p<0.001) and hemoglobin levels (9.5 vs 10.3, p< 0.001). Patients were also stratified according to baseline clearance, and those with baseline clearance below 75 ml/min/1.73m had a higher incidence rate of nephrotoxicity (68%, p=0.041) (Table 2). Furthermore, in this group of patients, the source of infection was other than respiratory (70.7%vs 47.7%, p=0.003). The duration of treatment with CMS was longer (12 days vs 9 days, p=0.009) and consequently the cumulative dose was higher (78 MU vs 60 MU, p=0.013). Due to nephrotoxicity, a higher percentage of dose adjustment was performed in these patients (37.3% vs 20.5%, p=0.017). In addition, in patients with nephrotoxicity, the rate of appropriate prescription was lower (9.3% vs 20.5%, p=0.050) Table1.
Regarding clinical outcomes, the higher mortality rate corresponded to patients with nephrotoxicity (44.0% vs 27.3%, p=0.027), lowest cure rate (48.0% vs 65.9%p=0.022), and shorter hospital stay (45 days vs 52 days; p=0.049). Table 3.
In the multivariate analysis, the risk factors that independently were associated with nephrotoxicity were Charlson Index (OR 1.29, 95%CI 1.02-1.62; p=0.032); admission to the ICU (OR 4.25, 95%CI 1.63-11.07, p=0.003) and cumulative dose per patient (OR 1.03, 95% CI 1.01-1.05, p=0.003). However, high creatinine clarence (OR 0.95, 95%CI 0.93-0.97), respiratory infection (OR 0.16, 95%CI 0.06-0.39) and appropriate CMS prescription (OR 0.29, 95%CI 0.08-1.03, p=0.056) were found to be protective factors against the onset of nephrotoxicity. Table 4.
3. Risk factor associated with in-hospital mortality
To assess the impact of nephrotoxicity on mortality, a univariate analysis was carried out. Risk factors associated with mortality were identified, including: age (OR 1.02, 95%CI 1.0-1.05, p=0.048) and nephrotoxicity (OR 2.09, 95%CI 1.09-4.03, p=0.027); on the other hand, serum hemoglobin proved to be a protective factor (OR 0.83, 95%CI 0.69-0.99, p=0.038).
Furthermore, mortality rate was compared according to the onset of nephrotoxicity at 7 days or later and statistically significant difference was found (OR 2.95, 95%CI 1.14-7.63; p=0.024). Patients who developed nephrotoxicity within the first 7 days after initiation of treatment have a higher mortality rate (57.5% vs 31.4%) (Table 6).
However, in the multivariate analysis risk factors associated with mortality were male sex (OR 2.43, 95%CI 1.06-5.56, p=0.035); age (OR 1.03, 95%CI 1.01-1.05, p=0.043) and higher maintenance doses (OR 1.21, 95%CI 1.03-1.43, p=0.023). Nephrotoxicity due to CMS treatment was not related to mortality (OR 1.42, 95%CI 0.68-2.99, p=0.351).
Otherwise, serum hemoglobin levels and length of hospital stay were protective factors against mortality (OR 0.76, 95%CI 0.63-0.92, p=0.005 and OR 0.99, 95%CI 0.98-1.00, p=0.046 respectively) Table 5.