Incidence of nephrotoxicity associated with intravenous administration of colistimethate sodium for the treatment of multidrug-resistant Gram-negative bacterial infections

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Descriptive analysis of the cohort

The study included 163 patients who received CMS prescriptions over 5 years. The average age was 66 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 common infection for which 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 patient characteristics are shown in Table 1.

Table 1 Baseline characteristics of patients in the study cohort and bivariate analysis of risk factors for CMS-associated nephrotoxicity.

Regarding CMS prescriptions, 95.7% were prescribed as a targeted therapy. Most of them administered in combination (64.4%) with one or two antimicrobials against Gram-negative pathogens, respectively 51.5% and 12.9%. The antibiotics mainly used in combination were carbapenems (31.0%), tigecycline (19.8%), aminoglycosides (13.5%), fosfomycin (6.3%), fluoroquinolones (7.1%). ) and other beta-lactams (22.2%). Thirty-five patients (24.5%) received a loading dose. CMS prescriptions adjusted for variation in serum creatinine were 28.2%. Thus, 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 63 MU (IQR: 36-108).

A.baumannii was the most frequently identified pathogen (72.4%), followed by P. aeruginosa (19.6%), Klebsiella spp. (4.3%) and Enterobacter spp. (1.8%), (Table 1).

75 patients (46%) developed nephrotoxicity attributable to colistin treatment, although only 14 patients (8.6%) discontinued treatment for this reason. Other reasons for discontinuation of CMS therapy were cure (57.7%) followed by patient death (17.8%), and adjustment of therapy with an isolated microorganism (10.4%) , among others (Table 1).

Risk factor associated with nephrotoxicity

In the bivariate analysis of the factors associated with the incidence of nephrotoxicity, we find: age (70.4 years vs. 62.2 years, p= 0.003), Charlson index (2 against 1.5, p= 0.012), basal glomerular filtration rate (82.7 ml/min/1.73 m vs 105.7 ml/min/1.73 m, ppp= 0.041) (Table 2). Moreover, in this group of patients, the source of infection was other than respiratory (70.7% vs 47.7%, p= 0.003). CMS treatment duration was longer (12 days vs 9 days, p= 0.009) and therefore the cumulative dose was higher (78 MU vs 60 MU, p= 0.013). Due to nephrotoxicity, a higher percentage of dose adjustments were made in these patients (37.3% versus 20.5%, p= 0.017). Additionally, in patients with nephrotoxicity, the appropriate prescribing rate was lower (9.3% vs 20.5%, p= 0.050) Table 1.

Table 2 Incidence of nephrotoxicity stratified by baseline creatinine clearance.

Regarding clinical outcomes, the highest mortality rate was in patients with nephrotoxicity (44.0% versus 27.3%, ppp= 0.003) (Table 3).

Table 3 Clinical results of patients treated with CMS.

In multivariate analysis, basal glomerular filtration rate (eGFR) was a risk factor independently associated with nephrotoxicity; patients with an eGFR > 90 ml/min/1.73 m had a lower risk of nephrotoxicity (HR = 0.267, 95% CI 0.161–0.443; p> 0.001). Higher hemoglobin levels were also a protective factor (HR=0.898, %CI 0.793–1.015). Finally, patients with respiratory infection have a lower risk of nephrotoxicity (39% less) (HR = 0.610, 95% CI 0.362–1.025) (Table 4).

Table 4 Risk factors for nephrotoxicity, Cox multivariate regression analysis.

Similarly, according to the Kaplan-Meier survival analysis (time without nephrotoxicity), the probabilities of not having nephrotoxicity on day 7 from the start of treatment were 71.5% and on day 14 52.5% (Fig. 1).

Figure 1

Kaplan-Meier survival curve of patients with an incidence of nephrotoxicity.

Risk factor associated with hospital mortality

To assess the impact of nephrotoxicity on mortality, a univariate analysis was performed. Risk factors associated with mortality were identified, including: age (HR 1.043, 95% CI 1.021-1.065, pppp

Table 5 Risk factors for all-cause in-hospital mortality, univariate Cox regression analysis.

However, in the multivariate analysis, the risk factors associated with mortality were age (HR 1.031, 95% CI 1.009-1.054, p= 0.006) and nephrotoxicity (HR 7.266, 95% CI 2.456–7.409, p

Table 6 Risk factors for all-cause in-hospital mortality, Cox multivariate regression analysis.

According to the Kaplan-Meier survival curve, the probability of survival to day 7 was 84.8% for patients with nephrotoxicity and 91.8% for patients without nephrotoxicity. On day 14, it was 57.6% for patients with nephrotoxicity and 82.6% for patients without nephrotoxicity. Therefore, the comparative survival analysis between patients with nephrotoxicity and without nephrotoxicity showed that patients without nephrotoxicity had a higher cumulative survival rate (log-rank test p

Figure 2
Figure 2

Kaplan-Meier survival curve for patients with and without nephrotoxicity (log-rank test).

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