This retrospective study involved critically ill patients who underwent intravenous colistin treatment for CR-GNB and evaluated the occurrence of AKI. During the colistin treatment period, the occurrence of KDIGO stage 1, stage 2, stage 3 AKI was 49.7%, 39%, and 21%, respectively. Meanwhile, 9.2% of the patients had newly initiated dialysis. Comparatively, patients who were administered with Colimycin® had a lower rate of occurrence of KDIGO stage 2 and stage 3 AKI than those administered with Locolin®. In the multivariate analysis, we found that independent factors associated with KDIGO stage 3 AKI included the presence of septic shock and inappropriate colistin dosage. In contrast, Colimycin® use was an independent factor associated with a lower rate of occurrence of KDIGO stage 3 AKI. We also found that the occurrence of KDIGO stage 3 AKI during colistin treatment was associated with longer mechanical ventilator using days, but not related to increased all-cause mortality.
Nephrotoxicity and neurotoxicity are well-documented adverse reactions associated with the treatment with intravenous colistin. Nephrotoxicity in colistin is dose-dependent and usually reversible [16, 18, 22, 23]. The nephrotoxicity of colistin is mainly related to its d-aminobutyric acid and fatty acid component. Similar to its bactericidal effects, colistin increases the membrane permeability of tubular epithelial cells, which in turn leads to cell swelling and lysis . Colistin is a multicomponent lipopeptide that contains colistin A and colistin B, which differ in the fatty acid chain attached to the cyclic decapeptide moiety of the drug . The proportion of colistin A and colistin B can have a large difference in commercial preparations of colistin . Although there are comparable bactericidal effects between colistin A and colistin B, colistin A has been shown to have a higher nephrotoxic effect than colistin B in an animal model study . The different compositions of colistin A and colistin B in various formulations of colistin might lead to different risks of colistin-induced nephrotoxicity. In the present study, we demonstrated a significant difference in the rate of occurrence of AKI between two different formulations of colistin. To our knowledge, this is the first study to evaluate the nephrotoxicity between different formulations of colistin. Although the exact mechanisms remain uncertain, we speculate that the composition of colistin A and B in various colistin products could play a pivotal role. Clinicians should therefore be aware of the possible difference in the risks of nephrotoxicity in various formulations of colistin. Further studies are also warranted to verify our findings.
The rate of occurrence of AKI reported in previous studies ranged from 27–51% and varied with the different study methodology and definition of nephrotoxicity used [7, 15, 16, 22, 26, 27]. In the present study, the overall rate of occurrence of KDIGO stage 2 and stage 3 AKI were 39% and 21%, which were consistent with previous reports. It is worth noting that all the enrolled patients were ICU-admitted cases and 90% of them had respiratory failure, which may further increase the rate of occurrence of nephrotoxicity during colistin treatment. We found that patients with KDIGO stage 3 AKI were more likely to have CR-GNB isolated from respiratory specimens and have a septic shock at the onset of colistin treatment. It may imply that patients with a respiratory infection and unstable hemodynamic status are more vulnerable to the nephrotoxicity of colistin. In addition, we found that more than 10% of our patients had inappropriate colistin dosage, which was rarely analyzed in previous studies, and it was an independent factor associated with AKI in the multivariate analysis. In contrast, both the accumulated dose and treatment duration of colistin were not significantly associated with AKI. Our findings suggest that the nephrotoxicity of colistin is more likely correlated with the disease severity and inappropriate colistin dose adjustment according to renal function. Clinicians should therefore monitor renal function rigorously at the onset and during colistin treatment and adjust colistin dose carefully to keep the risk of nephrotoxicity as low as possible. Some strategies, including N-acetylcysteine (NAC) treatment and plasma volume expansion, have been proposed to prevent or ameliorate colistin-related AKI and deserve further verification [28, 29].
We further evaluated the impact of the occurrence of colistin-related AKI on treatment outcomes, which have rarely been evaluated until now. We found that patients with colistin-induced AKI may have prolonged mechanical ventilator dependence; there were no differences in mortality and hospital stays between patients with and without colistin-related AKI. Our findings were consistent with a previous study, which prospectively enrolled patients infected by extensively drug-resistant Acinetobacter baumannii and treated by colistin . However, ventilator dependence and hospital stays were noted in that study. A study involving patients infected by drug-resistant Pseudomonas aeruginosa reported the presence of AKI as an independent factor associated with increased mortality . Another study reported that patients who experienced AKI had higher mortality if kidney function failed to return to the baseline level . Although the findings remain controversial, we believe that close monitoring of renal function during colistin treatment and discontinuation of colistin early in patients with AKI is the best way to reduce the effect of AKI on treatment outcomes in these critically ill patients.
There are some limitations to this study. First, as a retrospective study, the demographic characteristics and disease severities were not equal between patients who were treated with Colimycin® and Locolin®. Although we had used multivariate analysis to adjust the effects from clinical factors, our findings still should be interpreted with caution. Second, all the enrolled patients had CR-GNB isolated from clinical specimens and some of them may have colonization, rather than true infection. However, its effect on our analysis was limited because the present study aimed to investigate colistin-induced nephrotoxicity, rather than treatment effectiveness. Third, exposure to concomitant nephrotoxins, including vancomycin, aminoglycosides, and contrast, were not rare in our patients. Therefore, the risk of colistin-induced nephrotoxicity could be overestimated. Finally, we enrolled critically ill patients with ICU admission and high APACHE II scores. Most of them had respiratory failure and nearly one-third of them received inotropic agents. Therefore, the findings in our study may not be applicable in patients with low disease severities.