|Year : 2023 | Volume
| Issue : 4 | Page : 229-236
Colistin versus polymyxin B: A pragmatic assessment of renal and neurological adverse effects and effectiveness in multidrug-resistant Gram-negative bacterial infections
Veneta Simon1, Aathira Viswam1, Pallavi Sarah Alexander1, Emmanuel James1, S Sudhindran2
1 Department of Pharmacy Practice, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, Health Science Campus, Kochi, Kerala, India
2 Department of GI Surgery, Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham, Health Science Campus, Kochi, Kerala, India
|Date of Submission||12-Aug-2020|
|Date of Decision||15-Jul-2023|
|Date of Acceptance||08-Aug-2023|
|Date of Web Publication||11-Sep-2023|
Department of Pharmacy Practice, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, Health Science Campus, Kochi Campus, Kochi, Kerala
Source of Support: None, Conflict of Interest: None
OBJECTIVES: Our study aimed to evaluate the real-world data on renal and neurological adverse effects and effectiveness of colistimethate sodium (CMS) and polymyxin B (PMB).
MATERIALS AND METHODS: An observational prospective study was performed on inpatients receiving CMS and PMB for multidrug-resistant Gram-negative bacterial infections. CMS dose was titrated to renal function, and serum creatinine was assessed daily. The incidence of nephrotoxicity, the primary outcome, was evaluated based on an increase in serum creatinine from baseline as well as by the Risk, Injury, Failure, Loss of kidney function, and End-stage renal disease criteria. Neurological adverse effects were assessed based on clinical signs and symptoms, and the causality and severity were assessed by the Naranjo scale and modified Hartwig–Siegel scale, respectively. The effectiveness of polymyxin therapy was ascertained by a composite of microbiological eradication of causative bacteria and achievement of clinical cure. Thirty-day all-cause mortality was also determined.
RESULTS: Between CMS and PMB, the incidence of nephrotoxicity (59.3% vs. 55.6%, P = 0.653) or neurotoxicity (8.3% vs. 5.6%, P = 0.525) did not significantly differ. However, reversal of nephrotoxicity was significantly more with patients receiving CMS than PMB (48.4% vs. 23.3%, P = 0.021). Favorable clinical outcomes (67.6% vs. 37%, P < 0.001) and microbiological eradication of causative bacteria (73.1% vs. 46.3%, P = 0.001) were significantly more with CMS than PMB. Patients treated with CMS had lower all-cause mortality than those with PMB treatment (19.4% vs. 42.6%, P = 0.002).
CONCLUSION: There is no significant difference in the incidence of renal and neurotoxic adverse effects between CMS and PMB when CMS is administered following renal dose modification. CMS shows better effectiveness and lower mortality compared to PMB.
Keywords: Adverse effects, colistin, mortality, polymyxin B
|How to cite this article:|
Simon V, Viswam A, Alexander PS, James E, Sudhindran S. Colistin versus polymyxin B: A pragmatic assessment of renal and neurological adverse effects and effectiveness in multidrug-resistant Gram-negative bacterial infections. Indian J Pharmacol 2023;55:229-36
|How to cite this URL:|
Simon V, Viswam A, Alexander PS, James E, Sudhindran S. Colistin versus polymyxin B: A pragmatic assessment of renal and neurological adverse effects and effectiveness in multidrug-resistant Gram-negative bacterial infections. Indian J Pharmacol [serial online] 2023 [cited 2023 Sep 30];55:229-36. Available from: https://www.ijp-online.com/text.asp?2023/55/4/229/385501
| » Introduction|| |
Polymyxins were first introduced in the 1940s, as a polypeptide antibiotic. Despite there being five distinctly different compounds under the polymyxin group, in terms of clinical relevance, only polymyxin B (PMB) and polymyxin E (colistin) are used. A few decades later, they were abandoned due to increased occurrence of nephrotoxicity in patients treated. At present, one of the biggest challenges experienced worldwide has been a dearth of effective drugs to treat infections due to multidrug-resistant (MDR) Gram-negative bacteria. The poor treatment options due to the emergence of bacterial resistance to available antibiotics have led to the revival of polymyxins as a last resort against MDR Gram-negative bacteria such as carbapenem-resistant Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii. However, nephrotoxicity still prevails to be a major concern. Colistimethate sodium (CMS) and PMB have closely related chemical structures and similar antimicrobial activity., The less toxic prodrug of colistin, CMS, is used clinically instead of colistin sulfate. On intravenous administration, ~30% of CMS gets converted to its active form colistin in vivo, whereas PMB, when administered as its sulfate salt, can directly exert its antibacterial effect. In patients with normal renal function, 70% of the unconverted CMS undergoes renal excretion of which a considerable amount is recovered as colistin in the urine probably due to the chemical transformation of CMS to colistin within the tubular cells.,
PMB is predominantly cleared nonrenally as 90%–95% of administered PMB undergoes reabsorption through renal tubular cells. Colistin is also subjected to such extensive tubular reabsorption as a result of which its renal clearance is low. The propensity of polymyxins to produce nephrotoxicity is likely due to this high exposure to the renal tubular cells. There are conflicting reports regarding the nephrotoxicity of CMS and PMB; some studies,,, show PMB to be less nephrotoxic while others,, demonstrate comparable nephrotoxic profiles between CMS and PMB. In a prospective study from New Delhi reporting higher nephrotoxicity for CMS compared to PMB, 63% of study population received daily doses of CMS exceeding 9 million units (MU) which contributed to significant risk of renal failure. It has been shown that polymyxins can be used in patients with renal dysfunction with proper caution and that its usage in such a population did not affect the overall mortality rates. Although the reported incidence of polymyxin-induced neurotoxicity was less as compared to nephrotoxicity, there is a paucity of data regarding polymyxin-induced neurotoxicity. Furthermore, data are sparse on comparative effectiveness of the two drugs for treatment of MDR infections. Our study was, therefore, undertaken to evaluate the real-world data on nephrotoxic and neurotoxic adverse effects as well as the effectiveness of CMS versus PMB in patients with MDR Gram-negative bacterial infections.
| » Materials and Methods|| |
The study population, for this prospective observational study, consisted of inpatients receiving either CMS or PMB in the various departments of a tertiary care referral hospital (Amrita Institute of Medical Sciences and Research Centre, Kochi) for treatment of infections due to MDR Gram-negative bacteria. Before initiating the study, the Institutional Ethical Committee granted its approval (IEC-AIMS-2018-PHARM-208). Inpatients, receiving CMS and PMB from November 2018 to October 2019, were identified from the pharmacy consumption report on a day-to-day basis through digital Amrita Hospital information system. We excluded patients <18 years of age, those on dialysis, and those switched over from CMS to PMB or vice versa or patients without bacterial susceptibility data. Patients whose polymyxin therapy was discontinued within 72 h of commencement of therapy for reasons other than nephrotoxicity and neurotoxicity were additionally excluded. Only patients with complete relevant laboratory parameters such as serum creatinine at baseline and during follow-up period were included. Identification and antimicrobial susceptibility tests were done using VITEK 2 system (BioMerieux, Marcy l'Etoile, France). “Bacterial resistance to three or more different antibiotic groups (cephalosporins, carbapenems, monobactams, fluoroquinolones, and aminoglycosides) was defined as MDR” as per hospital antibiotic policy, and only patients with microbiological results of cultures reporting sole sensitivity to colistin/PMB and resistance to all other tested antibiotics were selected. Of a total of 634 patients screened, 400 patients receiving CMS and 54 patients treated with PMB were eligible for the study. All the eligible 54 PMB patients were included while 108 CMS patients were selected by random sampling of 400 eligible CMS patients through a computer-generated random sequence [Figure 1]. The study procedure was explained to the recruited patients, and informed signed consent was obtained from each one of them. The choice of CMS or PMB for a particular patient was at the discretion of the treating physicians. A loading dose was given for both the groups of patients followed by a maintenance dose at 12 h after the loading dose as per the hospital protocol [Table 1]. The maintenance dose of colistin was titrated to renal function of the patients whereas a weight-based dosing was followed for PMB.
|Figure 1: Patient selection process for our study conducted at a tertiary care hospital in Kochi, India. CMS = Colistimethate sodium, PMB = Polymyxin B|
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|Table 1: Polymyxin dosing protocol followed for hospital inpatients at the study site|
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Data collected included demographics, comorbid conditions, concomitant nephrotoxic agents, sites and types of infection, microbial culture and sensitivity reports, loading and maintenance doses, and serum creatinine before, during, and after polymyxin therapy daily during the hospital stay of the patient. Creatinine clearance was determined by Cockcroft–Gault equation. Ideal body weight (IBW) was utilized in the calculation of creatinine clearance of all the patients of CMS except for obese patients for whom adjusted body weight was used. A patient weighing >30% of the IBW was considered to be obese. All patients were prospectively monitored by the study team but were not involved in the therapy management decisions. Baseline Acute Physiology and Chronic Health Evaluation II (APACHE-II) score was calculated for intensive care unit (ICU) patients. Charlson comorbidity index (CCI) score and 10-year survival estimate based on CCI were calculated for all the patients.
The primary outcome measure was the incidence of nephrotoxicity. An increase of 0.5 mg/dL of serum creatinine from baseline for two consecutive measurements at least 24 h apart after 2 or more days of polymyxin therapy was used to determine nephrotoxicity. In addition, nephrotoxicity was graded according to the Risk, Injury, Failure, Loss of kidney function, and End-stage renal disease (RIFLE) criteria. Neurotoxicity was assessed based on clinical criteria of occurrence of symptoms such as ataxia, confusion, dizziness, facial and peripheral paresthesia, generalized muscle weakness, visual disturbances, and breathing difficulty, not related to any underlying neurologic diagnosis. Evaluation of drug effectiveness included a composite of (a) favorable clinical outcome defined as complete or partial resolution of signs and symptoms of infection as per physician's clinical judgment and a decrease in the elevated levels of C-reactive protein, white blood cell, and body temperature returning to its normal level and (b) microbiological cure defined as the eradication of isolated causative bacteria in repeat cultures after cessation of therapy. Other outcome measures were 30-day all-cause mortality and reversal of nephrotoxicity for which the patients were monitored for up to 30 days after completion of polymyxin therapy. Causality and severity of adverse drug reactions (ADRs) were assessed by the Naranjo et al. scale and Hartwig–Siegel scale, respectively.
The sample size was calculated using the sample size software nMaster version 2.0 (CMC, Vellore, Tamil Nadu, India) with the assistance of a statistician based on the comparative incidence of nephrotoxicity with CMS (39.3%) and PMB (11.8%) reported in an earlier publication for a confidence level of 95% and power of 80% and an allocation ratio of 2:1. The minimum sample size was calculated to be 54 for CMS and 27 for PMB, but twice the number of patients were recruited for the study. Statistical analysis was carried out using IBM SPSS version 20.0 software (Armonk, NY, USA: IBM Corp.). An independent sample t-test was used to test the significance of patient characteristics between the two groups. Categorical variables and the association of maintenance doses of the drugs with nephrotoxicity between the two groups were determined using Chi-square test. Binary logistic regression analysis was done to identify predictors of nephrotoxicity and favorable outcome. P < 0.05 was considered statistically significant.
| » Results|| |
The two groups of patients with their baseline demographic and clinical characteristics are shown in [Table 2]. All the patients of CMS and PMB received a loading dose and subsequently maintenance doses as per hospital protocol [Table 1]. The mean daily maintenance dose was found to be 8.15 ± 1.58 MU (range: 4–9) for CMS and 19.35 ± 1.70 lakh units (range: 15–20) for PMB. The median daily maintenance dose was 9 MU (interquartile range [IQR]: 8–9) for CMS equivalent to 300 mg of colistin base activity and that for PMB was 20 lakh units (IQR: 20–20) equivalent to 200 mg of PMB. The mean duration of treatment with CMS was 9.03 ± 4.32 days (range: 3–15) and that for PMB was 9.00 ± 4.67 days (range: 3–16, P = 0.970). The median duration of treatment was 8 days (IQR: 6–12) for both the CMS and PMB groups of patients.
|Table 2: Demographic and clinical characteristics of patients receiving colistin and polymyxin B|
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The two groups of patients did not differ significantly with respect to RIFLE criteria-based acute kidney injury (AKI) [Table 3]. Based on the Naranjo causality assessment scale, nephrotoxicity was found to be “probable” for all the patients. The median time to onset of nephrotoxicity was 5 days (IQR: 4.75–8.25) with CMS and 4 days (IQR: 3–5) with PMB (P = 0.336).
Binary logistic regression analysis showed no significant association of the previously reported risk factors such as advanced age, increased body mass index (BMI), low baseline creatinine clearance, high serum creatinine levels, presence of diabetes mellitus (DM), concomitant nephrotoxic agents, and a 10-year survival estimate <50% with nephrotoxicity in both the groups [Table 4]. However, APACHE-II score >20 was a significant contributor to the development of nephrotoxicity in PMB-treated patients whereas no such association was observed in CMS-treated patients. There was no significant association of incidence of nephrotoxicity with the size of the daily maintenance dose of CMS which was adjusted based on creatinine clearance.
|Table 4: Predictors of nephrotoxicity in patients of colistimethate sodium and polymyxin B groups|
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The neurotoxicity signs or its symptoms were noted in 9 (9/108, 8.3%) patients treated with CMS, of which 5 (5/108, 4.6%) had paresthesia and 2 each (2/108, 1.9%) had seizures and ataxia. Of 3 (3/54, 5.6%) patients who experienced neurotoxicity with PMB, 2 (2/54, 3.7%) had paresthesia, and 1 (1/54, 1.9%) had slurring of speech. The incidence of neurotoxicity among individuals receiving either CMS or PMB did not differ significantly (P = 0.525). Based on the Naranjo et al. causality assessment scale, neurotoxicity was “possible” in 6/108 CMS patients and 1/54 of PMB patients and “probable” in 3/108 CMS patients and 2/54 of PMB patients. Neurotoxicity was mild (Level 1) in severity for all the patients in both the groups according to the modified Hartwig–Siegel scale.
Patients with MDR bacterial infections who achieved favorable clinical outcomes were significantly higher in the CMS group as compared to patients in the PMB group (67.6% vs. 37%, P < 0.001). In addition, the rates of microbiological eradication in the CMS group versus the PMB group were considerably greater (73.1% vs. 46.3%; P = 0.001). Favorable outcomes and microbiological cure between CMS and PMB patients with respect to the type of infection and causative MDR organisms were compared; however, no significant difference was observed except for urinary tract infection (UTI), as shown in [Table 5]. For UTI, a greater favorable outcome (20.4% vs. 3.7%, P = 0.010) and microbiological cure (22.2% vs. 5.6%, P = 0.014) have been observed for CMS-treated patients, which may be attributable to the significant difference in baseline patient characteristics where CMS was the preferred antibiotic of choice for UTI [Table 2].
|Table 5: Effectiveness based on favorable outcome and microbiological cure in patients treated with colistimethate sodium and polymyxin B|
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Risk factors such as advanced age, higher APACHE-II scores, increased BMI, low baseline creatinine clearance, high serum creatinine levels, presence of DM, and use of concomitant nephrotoxic agents did not significantly correlate with favorable clinical outcome in both the groups as per binary logistic regression analysis. However, favorable outcomes were significantly higher for CMS patients who had a 10-year survival estimate >50% (odds ratio [OR]: 8.60, 95% confidence interval [CI]: 2.25–32.92, P = 0.002). However, no such association was observed in patients of the PMB group (OR: 4.46, 95% CI: 0.39–50.58, P = 0.227).
Recovery of renal function to the baseline level occurred in 48.4% (31/64) patients of the CMS group and 23.3% (7/30) patients of the PMB group (P = 0.021). The median time for resolution of nephrotoxicity in CMS patients was found to be 23 days (IQR: 27.5-13) and that for PMB patients was 14 days (IQR: 21-9). The mean duration for resolution of nephrotoxicity was found to be 19.84 ± 9.06 days for CMS and 14.71 ± 8.75 days for PMB (P = 0.182). Thirty-day all-cause mortality was significantly higher in patients receiving PMB (23/54, 42.6%) than CMS (21/108, 19.4%; P = 0.002).
| » Discussion|| |
In our pragmatic study, comparing the inpatient use of CMS versus PMB, we found that nephrotoxicity and neurotoxicity were similar between the two groups. This is in contrast with other reports,,, where a higher nephrotoxicity incidence was observed in CMS than in PMB patients. The lower incidence of nephrotoxicity in our study may perhaps be due to the appropriate daily adjustment of CMS dosage depending on the creatinine clearance. Indeed, our findings do corroborate other studies,,, where the incidence of nephrotoxicity was comparable between the two drugs [Figure 2].
|Figure 2: Reported studies demonstrating comparable incidence of nephrotoxicity between colistin and polymyxin B. Oliveira et al. defined acute kidney injury (AKI) as a 2-fold increase in serum creatinine or an increase by 1 mg/dL if initial creatinine was abnormal (higher than 1.4 mg/dL). Tuon et al. used AKI network (AKIN) criteria and Quintanilha et al. used Stage 1 of AKIN criteria to define nephrotoxicity. CMS = Colistimethate sodium, PMB = Polymyxin B. AKI = Acute kidney injury|
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In addition, in our study, there was no substantial difference observed between the CMS and PMB groups in the extent of AKI when graded according to the RIFLE criteria [Table 3]. A study by Aggarwal and Dewan has shown that there was an association of daily maintenance dose >9 MU/day with a higher incidence of AKI, but none of our patients received a colistin dose >9 MU/day. There was no association of the incidence of nephrotoxicity with variation in the maintenance dosage of both the drugs in our study. This may be because of dosage titration to creatinine clearance or the body weight of patients. Logistic regression analysis revealed that an APACHE-II score >20 significantly contributed to the development of nephrotoxicity in PMB patients (OR: 14.40, 95% CI: 1.80–115.31, P = 0.012). Such an association was not observed with CMS even though the baseline APACHE-II score was significantly higher in CMS-treated patients.
Aggarwal and Dewan observed that reversal of AKI monitored up to 7 days of polymyxin therapy was numerically more for PMB (83.3%) than that for CMS (75%), though not significant. In contrast to this finding, we observed a significant increase in the number of patients with reversal of nephrotoxicity after CMS therapy than with PMB therapy (48.4% vs. 23.3%, P = 0.021) and the number of days required for resolution of nephrotoxicity was (19.84 ± 9.06 for CMS and 14.71 ± 8.75 for PMB) more than 7 days. This may be because we extended our follow-up for 30 days. A recent report by Quintanilha et al. also showed a comparable incidence of nephrotoxicity between CMS and PMB, but the resolution of nephrotoxicity occurred earlier with CMS than that with PMB (11.50 ± 5.82 vs. 17.27 ± 20.16 days). It is necessary to conduct more research to examine the effects of various management approaches for the prevention of polymyxin-induced AKI as well as its treatment.
In contrast to previous studies,, showing no significant difference in 30-day mortality between CMS and PMB, our study showed lower mortality with CMS than PMB (19.4% vs. 42.6%, P = 0.002). This may be due to a higher reversal rate of nephrotoxicity, higher rate of microbiological eradication, and favorable outcomes observed in patients treated with CMS. Furthermore, a comparison of baseline characteristics of patients showed that significantly more patients used CMS compared to PMB for the treatment of MDR UTI, thereby showing significantly more favorable outcomes and microbiological cure for CMS with respect to UTI [Table 5]. Pharmacokinetic data suggest that a considerable amount of colistin is formed from the unconverted CMS excreted renally due to its chemical instability in the aqueous environment leading to the formation of colistin within the tubular cells. This gives CMS an edge over PMB in the treatment of lower UTI.
Data defining polymyxin-induced neurotoxicity in patients are limited, and the reported incidence of neurotoxicity is less as compared to nephrotoxicity. Paresthesia was the most frequent neurotoxic event that occurred in approximately 27% of patients receiving intravenous CMS after its initial introduction. However, over the years, the incidence of neurotoxicity was reduced to a few case reports,, where CMS- and PMB-induced neurotoxicity was manifested as drowsiness, encephalopathy, or oral and lower extremity paresthesia among other neurological signs and symptoms. The interaction of polymyxins with lipid-rich content of neurons could possibly attribute to the occurrence of neurotoxicity. The incidence of neurotoxicity was found to be 8.3% with CMS and 5.6% with PMB in our study (P = 0.525).
Studies reporting a direct comparison of the effectiveness of CMS and PMB for MDR Gram-negative infection treatment are sparse. In our study, effectiveness was determined based on favorable clinical outcomes (67.6% vs. 37%, P < 0.001) and microbiological eradication of bacterial isolates (73.1% vs. 46.3%, P = 0.001), and these were significantly more with CMS than PMB. In a study conducted in Sao Paulo, Brazil, Oliveira et al. classified clinical outcomes to determine the efficacy of CMS and PMB into “successful” “failure” and “indeterminate” and concluded that PMB was as effective as CMS. In contrast to our study, a recent report from Thailand compared the effectiveness and safety of PMB with CMS using the data of CMS from another study in Thailand and showed that PMB was more effective and safe based on parameters such as good clinical response rate, 28-day overall mortality, microbiological eradication, and incidence of AKI based on the RIFLE criteria. However, no statistical significance was stated when the comparison between PMB and CMS was made. Future research could be conducted to focus on randomized controlled trials comparing CMS and PMB to examine their safety as well as efficacy for specific indications, particularly by defining the endpoints for each indication and to evaluate the effectiveness of CMS and PMB in different patient populations.
Our study has several limitations. First, in our hospital, there was a propensity for physicians to prescribe CMS much more often than PMB, understandably due to familiarity with CMS. In our analysis, we picked CMS patients by random sampling while all the eligible patients who received PMB were included. Whether PMB was initially chosen for inherently high-risk patients is debatable. Nonetheless, random sampling was computer generated and thereby unlikely to have caused any bias. Second, serum CMS and PMB levels were not measured which would have provided further pharmacokinetics-pharmacodynamics (PK-PD) information about the association of drug concentration with ADRs and effectiveness. Recent studies of PK-PD data on colistin and PMB shows that creatinine clearance plays a major role in appropriate CMS and PMB dosing, thus affecting their plasma steady-state levels and in turn dictating the degree of bacterial eradication. For CMS, among PK/PD parameters that were evaluated, the mean of area under curve 0–24/minimum inhibitory concentration (MIC) ratios was relatively greater in patients who achieved a clinical cure. For PMB, it has been noted that with MIC ≥2 mg/L, a higher daily dose might achieve bacterial eradication but with an augmented risk of nephrotoxicity. Further research can be aimed at developing appropriate therapeutic drug monitoring to achieve the required steady-state plasma levels for both CMS and PMB to improve effectiveness without increasing the risk of nephrotoxicity. Third, the cost-effectiveness associated with CMS and PMB therapy was not performed. A study conducted in Sao Paulo, Brazil, showed that CMS was associated with lower cost than treatment with PMB. Further studies aimed at analyzing factors of cost-effectiveness such as direct antibiotic cost, ICU cost, and length of hospital stay can complement the comparative data between the two drugs. Nonetheless, ours is a real-world pragmatic study of a large number of patients. We feel that the results of this study, therefore, would help clinicians in making a choice between CMS and PMB and improve patient outcomes with minimal risk of nephrotoxicity and neurotoxicity.
| » Conclusion|| |
Our observational study comparing CMS and PMB, for the treatment of MDR pathogens, showed similar occurrences of nephrotoxicity and neurotoxicity between the two groups. Patients receiving CMS demonstrated higher rates of reversal of nephrotoxicity, greater microbiological eradication of pathogens, better attainment of favorable clinical outcomes, and lower inhospital mortality.
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Conflicts of interest
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]