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The efficacy and nephrotoxicity associated with colistin use in an intensive care unit in Vietnam: Use of colistin in a population of lower body weight

Open AccessPublished:March 30, 2015DOI:https://doi.org/10.1016/j.ijid.2015.03.020

      Highlights

      • Efficacy and nephrotoxicity of Colistin was evaluated among Vietnamese patients.
      • The study was conducted in a population of lower body weight (median 53 ± 8.6 kg).
      • A personalized dosing protocol of colistin was used.
      • The incidence of nephrotoxicity was 21% per RIFLE criteria.

      Summary

      Background

      There has been a growing need for colistin as a key drug for the treatment of MDR-GNB infection. Information on colistin use in Asian population is limited.

      Methods

      A retrospective observational study was conducted to assess the efficacy and nephrotoxicity in critically ill adult patients who received intravenous colistin for MDR-GNB infection in the intensive care unit (ICU) at Bach Mai Hospital in Hanoi, Vietnam. Colistin was administered according to the dosing guideline that was based on pharmacokinetic, pharmacodynamic and toxicodynamic principles, adjusted by body weight and creatinine clearance.

      Results

      Twenty-eight eligible patients were included. The mean patient age was 60 ± 20.4 years. The mean body weight was 53 ± 8.6 kg. The mean daily dose of colistin was 4.1 ± 1.6 MIU, and the mean cumulative dose of colistin was 48.2 ± 22.8 MIU. Colistin therapies were classified as clinically effective in 19 (67.9%) cases. Six (21.4%) patients developed nephrotoxicity during the study period according to RIFLE criteria.

      Conclusion

      A personalized dosing protocol of colistin was effective, with low nephrotoxicity, among critically ill Vietnamese patients with low body weight. Further studies are warranted for assessing the efficacy and toxicity in a larger cohort.

      Keywords

      1. Introduction

      Multi-drug resistant gram-negative bacteria, such as MDR-Acinetobacter baumannii, carbapenemase-producing Enterobacteriaceae, MDR-Pseudomonas aeruginosa have spread rapidly worldwide, including Asia.
      • Jean S.S.
      • Hsueh P.R.
      High burden of antimicrobial resistance in Asia.
      Colistin, which is produced in vivo after hydrolyzation of its prodrug colistimethate sodium, has been increasingly employed for over a decade as a key drug for the treatment of these MDR-GNB.
      • Yahav D.
      • Farbman L.
      • Leibovici L.
      • Paul M.
      Colistin: new lessons on an old antibiotic.
      Colistin is known for its nephrotoxicity which initially resulted in abundance of its clinical use in 1970s.
      • Yahav D.
      • Farbman L.
      • Leibovici L.
      • Paul M.
      Colistin: new lessons on an old antibiotic.
      Majority of recent studies on the clinical use of colistin were conducted in Europe or North America, and there has been debate on the appropriate dosing and its relation to the efficacy and nephrotoxicity of colistin.
      • Yahav D.
      • Farbman L.
      • Leibovici L.
      • Paul M.
      Colistin: new lessons on an old antibiotic.
      Information on colistin use pertaining to the Asian population is limited. Recently, the interim guideline to administer colistin in critically ill patients based on pharmacokinetic, pharmacodynamic, and toxicodynamic principles has been proposed.
      • Garonzik S.M.
      • Li J.
      • Thamlikitkul V.
      • Paterson D.L.
      • Shoham S.
      • Jacob J.
      • et al.
      Population pharmacokinetics of colistin methanesulfonate and formed colistin in critically ill patients from a multicenter study provide dosing suggestions for various categories of patients.
      The efficacy and toxicity of such “personalized” administration of colistin has not been well evaluated worldwide, even less so in Asian countries where people tend to have lower body weight than in Europe or North America. In this study, we evaluated the efficacy and nephrotoxicity of personalized administration of colistin in critically-ill patients admitted to ICU in Vietnam.

      2. Methods

      2.1 Study Design and Patient Population

      This was a retrospective observational study to assess the efficacy and nephrotoxicity in critically ill patients who received intravenous colistin at Bach Mai Hospital (BMH) between August 15, 2013 and January 15 2014. BMH has 2000 beds and serves as a tertiary care hospital in Hanoi, Vietnam. The study was approved by Bach Mai Hospital institutional review board. Adult patients aged greater than 18 years were included in the study if they were admitted to the intensive care unit (ICU) and received intravenous colistin for hospital acquired infection due to MDR-GNB with positive microbiological culture. Hospital acquired infection (HAI) was determined according to CDC/NHSN definitions
      • Horan T.C.
      • Andrus M.
      • Dudeck M.A.
      CDC/NHSN surveillance definition of health care-associated infection and criteria for specific types of infections in the acute care setting.
      and according to multiple physicians’ evaluation. Patients were excluded if they were pregnant or breast-feeding or were receiving renal replacement therapy (intermittent hemodialysis or continuous renal replacement therapy) before the initiation of colistin. Patients were excluded if they received colistin for less than five days, to ensure adequate exposure to the drug.

      2.2 Microbiology

      BMH has a single centralized microbiology laboratory. Standard identification and susceptibility testing of clinical isolates were performed in accordance with the Clinical and Laboratory Standards Institute (CLSI) criteria.

      The Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing; Twentieth Informational Supplement. Approved Standard M100-S23. Wayne, PA: CLSI; 2013.

      The minimum inhibitory concentrations (MICs) of collistin were determined by E-test (Sysmex-bioMerieux, Tokyo, Japan) according to the manufacturer's instructions.

      2.3 Colistin administration

      The colistin product used in this study was Coly-Mycin® produced by Sanofi-Aventis. Dosing of intravenous colistin was prospectively reviewed by clinical pharmacists. The institutional guideline for colistin dosing was as follows
      • Garonzik S.M.
      • Li J.
      • Thamlikitkul V.
      • Paterson D.L.
      • Shoham S.
      • Jacob J.
      • et al.
      Population pharmacokinetics of colistin methanesulfonate and formed colistin in critically ill patients from a multicenter study provide dosing suggestions for various categories of patients.
      :
      Loading dose (Colistin Base Activity [CBA], mg) = C-Target × 2 × Total actual body weight (kg).
      Maintenance dose (CBA, mg) = C-target × (1.5 × CrCl [Creatinine clearance, mL/min] + 30).
      Maintenance dose was initiated 24 hours after loading dose infusion. C-target was calculated as follows. C-target was equal to the identified colistin MIC for the causative organism of HAI. The doses calculated based on CBA (mg) were divided by 33.3 to convert them to MIU (million international units). The total daily dosage was divided into two doses for twice-daily administration.
      Each bottle of colistin was dissolved in 50 mL of normal saline solution (0.9% NaCl) and was infused immediately over 30 minutes to 2 hours following its dissolution. Clinical pharmacists rechecked and recalculated the maintaining colistin dose according to the patient's measured renal function during colistin therapy. Body weights and CrCl were measured within 2 days of colistin administration. Nebulized colistin was not used throughout the study period.

      2.4 Data Collection

      The following parameters were retrieved from the medical records of patients in the study: age, sex, weight, underlying diseases, baseline serum creatinine concentration, Charlson's score,
      • Charlson M.E.
      • Pompei P.
      • Ales K.L.
      • MacKenzie C.R.
      A new method of classifying prognostic comorbidity in longitudinal studies: development and validation.
      Acute Physiology and Chronic Health Evaluation (APACHE) II score,
      • Knaus W.A.
      • Draper E.A.
      • Wagner D.P.
      • Zimmerman J.E.
      APACHE II: a severity of disease classification system.
      Clinical Pulmonary Infection Score (CPIS),
      • Pugin J.
      • Auckenthaler R.
      • Mili N.
      • Janssens J.P.
      • Lew P.D.
      • Suter P.M.
      Diagnosis of ventilator-associated pneumonia by bacteriologic analysis of bronchoscopic and nonbronchoscopic “blind” bronchoalveolar lavage fluid.
      and Sequential Organ Failure Assessment (SOFA) score on ICU admission.
      • Vincent J.L.
      • Moreno R.
      • Takala J.
      • Willatts S.
      • De Mendonca A.
      • Bruining H.
      • et al.
      The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine.
      The information on the use of other nephrotoxic drugs (NSAIDs, furosemide, contrast agent, angiotensin-converting enzyme inhibitors) was also collected.

      2.5 Clinical assessment

      Clinical assessments were conducted at 3 time points: the first was prior to using colistin; the second was after day 5 of colistin treatment; the last point was after discontinuing colistin. Multiple physicians involved in the patients’ care evaluated the clinical effectiveness of colistin therapy at each time point, based on the resolution, persistence or worsening of symptoms and signs of infection.

      2.6 Microbiological assessment

      Microbiological culture samples were collected at two time points, the first was prior to administering colistin and the second was after day 5 of colistin treatment. Samples were transferred to the microbiology department, and sample culture result and MICs were determined. Microbiological efficacy was evaluated based on the comparison of two consecutive culture results; i.e., if the second culture was negative, then it was evaluated as microbiologically effective.

      2.7 Nephrotoxicity assessment

      Daily serum creatinine level was recorded from the first day of colistin therapy until discharge or death. Nephrotoxicity was defined based on the increase in the serum creatinine concentration of ≥50 percent as per RIFLE (risk, injury, failure, loss, and end-stage kidney disease) criteria.
      • Bellomo R.
      • Ronco C.
      • Kellum J.A.
      • Mehta R.L.
      • Palevsky P.
      Acute Dialysis Quality Initiative w. Acute renal failure - definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group.

      2.8 Statistical Analysis

      All analyses were performed using SPSS 20. Bivariate analyses were performed using the Fisher's exact test or the Chi-square test for categorical variables and the t-test or the Mann-Whitney U test for continuous variables. All P-values were two-sided, a p value of less than 0.05 was considered to indicate a statistically significant difference. Throughout the text, the percentages displayed are the “valid percent”, which indicates the percent excluding the missing data from the denominator.

      3. Results

      During the study period, 28 eligible patients were identified. The mean age was 60 (±20.4; range: 19-88) years, and 18 (64%) were male (Table 1). The mean body weight of the study cohort was 53 (±8.6; range: 35.5-75) kg. Eight (28.6%) patients had preexisting renal failure prior to the administration of colistin, which was defined by a serum creatinine (Scr) value > 1.2 mg/dl. The majority (n = 26, 92.9%) of patients had ventilator-associated pneumonia (VAP), and 2 (7.1%) patients had blood-stream infections.
      Table 1Patient characteristics based on the clinical response to intravenous colistin therapy (n = 28)
      CharacteristicsWhole cohort

      (n = 28)
      Clinically effective

      (n = 19, 68%)
      Clinically ineffective (n = 9, 32%)P value

      (Effective group vs ineffective-treatment group)
      Demographics
      Age (years), mean ± SD60.0 ± 20.451.8 ± 19.674 ± 12.80.01
      Male, n (%)18 (64.3%)14 (73.7%)4 (44.4%)0.21
      Body weight (kg), median (IQR), [mean ± SD]53.5 (45.5-58.5) [53 ± 8.6]57 (51-59) [54.5 ± 6.8]49.5 (41.5-54.3) [49.8 ± 11.4]0.05
      Charlson comorbidity index,

      median (IQR)
      3 (2-5)3 (1-4)5 (3-6)0.03
      SOFA score, median (IQR)8 (4.3-9)6 (4-8)8 (8-10)0.02
      APACHE II score, median (IQR)14 (10-17)12 (8-17)14 (13-17)0.41
      CPIS, median (IQR)6 (6-8)6 (5-7)8 (6-8)0.01
      Length of ICU stay prior to colistin therapy (days), median (IQR)6 (3-11)6 (3-9)6 (1-16)0.96
      Severity of illness
      Severe sepsis, n (%)19 (67.9%)11 (57.9%)8 (88.9%)0.20
      Septic shock, n (%)6 (21.4%)5 (26.3%)1 (11.1%)0.63
      Site of Infection
      VAP, n (%)26 (92.9%)17 (89.5%)9 (100%)>0.99
      BSI, n (%)2 (7.1%)2 (10.5%)0>0.99
      Microbiology
      Acinetobacter baumannii, n (%)24 (85.7%)17 (89.5%)7 (77.8%)0.57
      Pseudomonas aeruginosa, n (%)3 (10.7%)2 (10.5%)1 (11.1%)>0.99
      Klebsiella pneumonia, n (%)3 (10.7%)2 (10.5%)1 (11.1%)>0.99
      Colistin MIC of Acinetobacter baumannii, mg/L, median (IQR)0.13 (0.13-0.30)0.13 (0.09-0.16)0.38 (0.13-0.50)0.02
      Colistin therapy
      Average daily dose (MIU), median (IQR), [mean ± SD]4.0 (2.7-5.6) [4.1 ± 1.6]4.4 (3.1-6.2) [4.4 ± 1.7]3.2 (2.6-4.1) [3.5 ± 1.0]0.12
      Average daily dose per kg (MIU), median (IQR), [mean ± SD]0.08 (0.05-0.11) [0.08 ± 0.03]0.09 (0.06-0.11) [0.08 ± 0.03]0.08 (0.05-0.11) [0.07 ± 0.03]0.50
      Total cumulative dose (MIU), median (IQR), [mean ± SD]39 (33-57) [48.2 ± 22.8]50 (33-72) [54.1 ± 24.2]37.5 (26.5-43.5) [35.7 ± 13.1]0.12
      Total cumulative dose per kg (MIU), median (IQR), [mean ± SD]0.84 (0.64-1.17) [0.91 ± 0.38]0.86 (0.67-1.33) [0.98 ± 0.38]0.80 (0.4-1.13) [0.76 ± 0.35]0.27
      Duration of colistin therapy (days), median (IQR)11 (8-16)13 (9-17)10 (8-16)0.26
      Combination therapy with carbapenem, n (%)25 (89.3%)17 (89.5%)8 (88.9%)>0.99
      Use of concomitant nephrotoxic agents
      Any nephrotoxic agent11 (39.3%)8 (42.1%)3 (33.3%)>0.99
      ACEI1 (3.6%)1 (5.3%)0>0.99
      Furosemide10 (35.7%)7 (36.8%)3 (33.3%)>0.99
      Renal function
      Pre-existing renal failure (Scr > 1.2 mg/dl), n (%)8 (28.6%)5 (26.3%)3 (33.3%)>0.99
      Scr, prior to colistin therapy, mg/dl, median (IQR), [mean ± SD]0.8 (0.8-1.43) [1.2 ± 0.9]0.9 (0.8-1.2) [1.1 ± 0.6]0.8 (0.65-2.45) [1.5 ± 1.4]0.63
      Scr, worst during therapy, mg/dl, median (IQR), [mean ± SD]1.05 (0.8-2.25) [1.7 ± 1.4]1.2 (0.8-2.3) [1.5 ± 0.9]0.9 (0.75-3.85) [2.1 ± 2.2]0.73
      Scr, upon discharge from ICU, mg/dl, median (IQR), [mean ± SD]0.9 (0.7-1.5) [1.4 ± 1.3]0.9 (0.7-1.4) [1.2 ± 0.7]0.8 (0.6-3.7) [1.9 ± 2.1]0.79
      CrCl, prior to colistin therapy, ml/min, median (IQR), [mean ± SD]62.3 (34.8-76.1) [62.6 ± 37.8]67.6 (51.7-83.5) [80 ± 40.5]50 (21.1-66.2) [44.9 ± 24.8]0.06
      CrCl, worst during therapy, ml/min, median (IQR), [mean ± SD]52 (25.5-70) [53.7 ± 30]61 (34-79) [60.4 ± 31.5]48 (16-57.5) [39.4 ± 21.9]0.09
      CrCl, upon discharge from ICU, ml/min, median (IQR), [mean ± SD]60 (35.8-87.3) [63.5 ± 34.1]64 (47-99) [71 ± 33.6]55 (16.5-74) [47.7 ± 31.2]0.08
      Renal failure upon discharge (Scr > 1.2 mg/dl), n (%)9 (32.1%)6 (31.6%)3 (33.3%)>0.99
      Outcome
      Total ICU length of stay (days), median (IQR)22 (17-30)22 (19-30)21 (14-30)0.40
      Microbiologically effective, n (%)15 (62.5%)13 (81.2%)2 (25%)0.02
      Nephrotoxicity during colistin therapy per RIFLE criteria
      RIFLE criteria.10
      , n (%)
      6 (21.4%)5 (26.3%)1 (11.1%)0.63
      Increase of Scr > 150% as compared to baseline upon discharge, n (%)3 (10.7%)2 (10.5%)1 (11.1%)>0.99
      In-hospital mortality, n (%)5 (17.9%)05 (55.6%)<0.01
      14-day mortality, n (%)8 (28.6%)2 (10.5%)6 (66.7%)<0.01
      Abbreviations. ACEI, Angiotensin-converting enzyme inhibitors; APACHE, Acute Physiology and Chronic Health Evaluation; BSI, blood stream infection; CBA, colistin base activity; CrCl, Creatinine clearance; CPIS, Clinical Pulmonary Infection Score; ICU, intensive care unit; IQR, interquartile range; MIU, Million International Units; Scr, serum creatinine; SD, standard deviation; SOFA, Sequential Organ Failure Assessment; VAP, ventilator associated pneumonia.
      a RIFLE criteria.
      • Bellomo R.
      • Ronco C.
      • Kellum J.A.
      • Mehta R.L.
      • Palevsky P.
      Acute Dialysis Quality Initiative w. Acute renal failure - definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group.
      Acinetobacter baumannii were most frequently isolated (n = 24 [85.7%]; 23 from sputum, 1 from blood), followed by Pseudomonas aeruginosa (n = 3 [10.7%]; 3 from sputum), and Klebsiella pneumonia (n = 3 [10.7%]; 2 from sputum and 1 from blood). The colistin MIC50 and MIC90 of A. baumannii were 0.125 mg/L, and 0.5 mg/L, respectively, and MIC ranged from 0.064-0.75 mg/L.
      The mean daily dose of colistin used in the whole cohort was 4.1 ± 1.6 MIU (136.5 ± 53.3 mg CBA; median: 4.0 MIU [133.2 mg CBA], IQR [interquartile range]: 2.7-5.6 MIU [89.9-186.5 mg CBA]). The mean daily dose of colistin per kg was 0.08 ± 0.03 MIU/kg (2.66 ± 1.0 mg CBA/kg; median: 0.08 MIU/kg [2.66 mg CBA/kg], IQR: 0.05-0.11 MIU/kg [IQR: 1.67-3.66 mg CBA/kg]). The mean duration of colistin therapy was 12.5 ± 5.2 days (range: 5-23 days), and the mean cumulative colistin dose was 48.2 ± 22.8 MIU [1605.1 ± 759.2 mg CBA)] (median: 39 MIU [1298.7 mg CBA], IQR: 33-57 MIU [1098.9-1898.1 mg CBA]). The mean cumulative colistin dose per kg was 0.91 ± 0.38 MIU/kg [30.3 ± 12.65 mg CBA/kg] (median: 0.84 MIU [27.97 mg CBA/kg], IQR: 0.64-1.17 MIU/kg [21.31-38.96 mg CBA/kg]). In all cases, colistin was used as combination therapy and most frequently combined with carbapenem in 25 (89.3%) cases.
      Nephrotoxicity during colistin therapy was identified in 6 (21.4%) patients according to the RIFLE criteria. All six patients identified as AKI per RIFLE criteria were categorized as “risk” under RIFLE criteria. Among 8 patients with pre-existing renal failure, 3 (37.5%) developed AKI per RIFLE criteria. Among 20 patients without pre-existing renal failure, 3 (15%) developed AKI according to RIFLE criteria.
      Concomitant nephrotoxicity agents were used in 11 (39.3%) patients: 1 patient received angiotensin converting enzyme inhibitor, and 10 patients received furosemide. Other nephrotoxic agents, such as non-steroidal anti-inflammatory drug, vancomycin, aminoglycoside, or contrast agent was not used concurrently with colistin in any patient.

      3.1 Comparison between the clinically effective-treatment group and the ineffective-treatment group

      Colistin therapies were evaluated as clinically effective in 19 cases (68%) and clinically ineffective in 9 (32%) cases. The patients’ characteristics based on the clinical response to intravenous colistin therapy, were summarized in Table 1. The patients of the clinically effective-treatment group were younger than patients without response (mean age 51.8 ± 19.6 vs 74 ± 12.8, p = 0.01). The patients of the ineffective-treatment group comprised the population that showed a greater incidence of comorbidities with higher median Charlson comorbidity index (3 [IQR: 1-4] vs 5 [IQR: 3-6], p = 0.03) and had more organ dysfunction indicated by higher median SOFA score (6 [IQR: 4-8] vs 8 [IQR: 8-10], p = 0.02). The median CPIS score was significantly lower in the clinically effective-treatment group than in the ineffective-treatment group (6 [IQR: 5-7] vs 8 [IQR: 6-8], p = 0.01). The patients in clinically effective-treatment group had marginally higher median body weight than the ineffective-treatment group (57 [IQR: 51-59] vs. 49.5 [41.5-54.3], p = 0.05). The median MIC of A. baumannii is lower in clinically effective-treatment group than in ineffective-treatment group (0.13 [0.09-0.16] vs. 0.38 [0.13-0.50], p = 0.02). The other variables, including patients’ demographics (e.g. sex, APACHE II score, length of ICU stay prior to colistin use), severity of illness (e.g. severe sepsis, septic shock), site of infection, and colistin therapy (daily doses, duration, cumulative dose), and concomitant nephrotoxic agent use were similar between two groups. The prevalence of pre-existing renal failure defined as Scr >1.2 mg/dl prior to colistin therapy were similar between two groups. The frequencies of the development of nephrotoxicity, which were defined by RIFLE criteria, were similar between the two groups. No deaths were observed in the clinically effective-treatment group during the study period; however, 5 (55.6%) patients without response died (p < 0.01). The 14-day mortality was higher in the clinically ineffective-treatment group than the effective treatment group (6 [66.7%] vs. 2 [10.5%], P < 0.01).

      3.2 Comparison between nephrotoxicity and non-nephrotoxicity group

      Characteristics of patients who developed nephrotoxicity and who did not develop nephrotoxicity during colistin therapy based on RIFLE criteria were also compared (Table 2). Patients with nephrotoxicity had higher median body weight than patients without nephrotoxicity (57.8 [IQR: 53.8-65.3] vs. 51.3 [IQR: 43.8-58.1], p = 0.05). However, the colistin doses were similar between 2 groups because of decreased CrCl in the nephrotoxicity group. Duration of colistin therapy did not differ between the two groups. Other characteristics such as age, sex, severity of illness, site of infections were similar between the two groups. The prevalence of pre-existing renal failure was similar between the two groups. Outcome parameters such as microbiological and clinical effectiveness, in-hospital and 14-day mortality did not differ between the two groups.
      Table 2Patient characteristics based on nephrotoxicity to intravenous colistin therapy (n = 28)
      CharacteristicsNephrotoxicity group
      Nephrotoxicity was defined according to RIFLE criteria.10


      (n = 6, 21%)
      Non-nephrotoxicity group

      (n = 22, 79%)
      P value

      (Nephrotoxicity group vs non-nephrotoxicity group)
      Demographics
      Age (years), mean ± SD50.2 ± 26.461.4 ± 18.40.29
      Male, n (%)5 (83.3%)13 (59.1%)0.38
      Body weight (kg), median (IQR), [mean ± SD]57.8 (53.8-65.3) [59.9 ± 8.1]51.3 (43.8-58.1) [51.1 ± 8.0]0.05
      Charlson comorbidity index, median (IQR)3 (0-5)3 (2-5)0.59
      SOFA score, median (IQR)11 (6-13)8 (4-8)0.09
      APACHE II score, median (IQR)13 (15-20)14 (12-16)0.84
      CPIS, median (IQR)6 (3-7)6 (6-8)0.16
      Length of ICU stay prior to colistin therapy (days), median (IQR)4 (1-7)6 (4-12)0.14
      Severity of illness
      Severe sepsis, n (%)2 (33.3%)17 (77.3%)0.06
      Septic shock, n (%)3 (50%)3 (13.6%)0.09
      Site of Infection
      VAP, n (%)5 (83.3%)21 (95.5%)0.39
      BSI, n (%)1 (16.7%)1 (4.5%)0.39
      Microbiology
      Acinetobacter baumannii, n (%)4 (66.7%)20 (90.9%)0.19
      Pseudomonas aeruginosa, n (%)1 (16.7%)2 (9.1%)0.53
      Klebsiella pneumonia, n (%)2 (33.3%)1 (4.5%)0.11
      Colistin MIC of Acinetobacter baumannii, mg/L, median (IQR)0.13 (0.03-0.17)0.13 (0.13-0.37)0.31
      Colistin therapy
      Average daily dose (MIU), median (IQR), [mean ± SD]3.3 (2.2-5.8) [3.8 ± 1.8]4 (3-5.5) [4.2 ± 1.5]0.43
      Average daily dose per kg (MIU), median (IQR), [mean ± SD]0.07 (0.04-0.1) [0.07 ± 0.03]0.09 (0.06-0.11) [0.08 ± 0.03]0.22
      Total cumulative dose (MIU), median (IQR), [mean ± SD]42 (32-89.3) [57.2 ± 33.3]39 (33-57) [45.7 ± 19.3]0.70
      Total cumulative dose per kg (MIU), median (IQR), [mean ± SD]0.76 (0.56-1.5) [0.96 ± 0.54]0.85 (0.7-1.16) [0.9 ± 0.34]0.96
      Duration of colistin therapy (days), median (IQR)16 (12-18)11 (8-15)0.11
      Combination therapy (with carbapenem), n (%)5 (83.3%)20 (90.9%)0.53
      Use of concomitant nephrotoxicity agents
      Any nephrotoxicity agent2 (33.3%)9 (40.9%)>0.99
      ACEI01 (4.5%)>0.99
      Furosemide2 (33.3%)8 (36.4%)>0.99
      Renal function
      Pre-existing renal failure (Scr > 1.2 mg/dl), n (%)3 (50%)5 (22.7%)0.31
      Scr, prior to colistin therapy, median (IQR)1.2 (0.8-2.0) [1.5 ± 1.0]0.8 (0.7-1.3) [1.2 ± 0.9]0.26
      Scr, worst during therapy, median (IQR)2.7 (1.3-3.7) [2.7 ± 1.7]1.0 (0.8-1.4) [1.4 ± 1.2]0.03
      Scr, upon discharge from ICU, median (IQR)1.9 (1.2-3.7) [2.4 ± 1.8]0.8 (0.7-1.1) [1.1 ± 1.0]0.02
      CrCl, prior to colistin therapy, median (IQR)62.2 (25.4-119.7) [77.4 ± 66.6]62.3 (37.9-76) [58.6 ± 26.4]0.80
      CrCl, worst during therapy, median (IQR)28.5 (13.3-89) [46.7 ± 43.2]54 (44.3-68) [55.6 ± 26.4]0.40
      CrCl, upon discharge from ICU, median (IQR)42 (17.8-81) [52.2 ± 46.1]61.5 (44.8-90.3) [66.6 ± 30.7]0.31
      Renal failure upon discharge (Scr > 1.2 mg/dl), n (%)5 (83.3%)4 (18.2%)0.01
      Outcomes
      Total ICU length of stay (days), median (IQR)23 (19-33)21 (16-29)0.40
      Microbiologically effective, n (%)5 (83.3%)10 (55.6%)0.35
      Clinically effective, n (%)5 (83.3%)14 (63.6%)0.63
      In-hospital mortality, n (%)1 (16.7%)4 (18.2%)>0.99
      14-day mortality, n (%)2 (33.3%)6 (27.3%)>0.99
      Abbreviations. ACEI, Angiotensin-converting enzyme inhibitors; APACHE, Acute Physiology and Chronic Health Evaluation; BSI, blood stream infection; CrCl, Creatinine clearance; CPIS, Clinical Pulmonary Infection Score; ICU, intensive care unit; IQR, interquartile range; MIU, Million International Units; Scr, serum creatinine; SD, standard deviation; SOFA, Sequential Organ Failure Assessment; VAP, ventilator associated pneumonia.
      a Nephrotoxicity was defined according to RIFLE criteria.
      • Bellomo R.
      • Ronco C.
      • Kellum J.A.
      • Mehta R.L.
      • Palevsky P.
      Acute Dialysis Quality Initiative w. Acute renal failure - definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group.

      4. Discussion

      To our knowledge, this is the first study to describe the details of clinical experiences of colistin use in Vietnam. The vast majority of reports regarding colistin use in clinical settings have been published from Europe and North America, and the data on the clinical use of colistin in Asia is scarce.
      The previously reported incidences of nephrotoxicity during colistin therapy vary from 6% to 55%,
      • Yahav D.
      • Farbman L.
      • Leibovici L.
      • Paul M.
      Colistin: new lessons on an old antibiotic.
      and depend on various factors such as dosing, population differences (e.g. comorbidity, severity, clinical setting), and definition of nephrotoxicity. In this study, we used RIFLE criteria to identify nephrotoxicity, which was validated to correlate with prognosis.
      • Ali T.
      • Khan I.
      • Simpson W.
      • Prescott G.
      • Townend J.
      • Smith W.
      • et al.
      Incidence and outcomes in acute kidney injury: a comprehensive population-based study.
      We used only Scr changes for applying the RIFLE criteria without reference to GFR, because previous reports suggested that the changes in Scr concentrations do not correlate with the percent decreases in GFR in the RIFLE classification.
      • Pickering J.W.
      • Endre Z.H.
      GFR shot by RIFLE: errors in staging acute kidney injury.
      The incidence of nephrotoxicity in this study (21.4%) was lower than the incidence reported in previous studies (range: 31-54.6%) that have evaluated nephrotoxicity during colistin therapy using RIFLE criteria.
      • Pulluru H.K.K.
      • Pogue J.M.
      • Marchaim D.
      • Hayakawa K.
      Risk factors for and incidence of nephrotoxicity associated with intravenous colistin in the modern era: a systematic review.
      Patients received relatively lower dose of colistin in our study than the previous studies,
      • Dalfino L.
      • Puntillo F.
      • Mosca A.
      • Monno R.
      • Spada M.L.
      • Coppolecchia S.
      • et al.
      High-dose, extended-interval colistin administration in critically ill patients: is this the right dosing strategy? A preliminary study.
      • Deryke C.A.
      • Crawford A.J.
      • Uddin N.
      • Wallace M.R.
      Colistin dosing and nephrotoxicity in a large community teaching hospital.
      • Doshi N.M.
      • Mount K.L.
      • Murphy C.V.
      Nephrotoxicity associated with intravenous colistin in critically ill patients.
      • Pogue J.M.
      • Lee J.
      • Marchaim D.
      • Yee V.
      • Zhao J.J.
      • Chopra T.
      • et al.
      Incidence of and risk factors for colistin-associated nephrotoxicity in a large academic health system.
      even if their actual body weights are considered. The mortality and prevalence of non-responding patients were not higher in our study,
      • Dalfino L.
      • Puntillo F.
      • Mosca A.
      • Monno R.
      • Spada M.L.
      • Coppolecchia S.
      • et al.
      High-dose, extended-interval colistin administration in critically ill patients: is this the right dosing strategy? A preliminary study.
      • Pogue J.M.
      • Lee J.
      • Marchaim D.
      • Yee V.
      • Zhao J.J.
      • Chopra T.
      • et al.
      Incidence of and risk factors for colistin-associated nephrotoxicity in a large academic health system.
      • Paul M.
      • Bishara J.
      • Levcovich A.
      • Chowers M.
      • Goldberg E.
      • Singer P.
      • et al.
      Effectiveness and safety of colistin: prospective comparative cohort study.
      even though Charlson comorbidity index scores, SOFA scores, and patients’ ages in our study were apparently not lower than previous studies.
      • Dalfino L.
      • Puntillo F.
      • Mosca A.
      • Monno R.
      • Spada M.L.
      • Coppolecchia S.
      • et al.
      High-dose, extended-interval colistin administration in critically ill patients: is this the right dosing strategy? A preliminary study.
      • Pogue J.M.
      • Lee J.
      • Marchaim D.
      • Yee V.
      • Zhao J.J.
      • Chopra T.
      • et al.
      Incidence of and risk factors for colistin-associated nephrotoxicity in a large academic health system.
      • Paul M.
      • Bishara J.
      • Levcovich A.
      • Chowers M.
      • Goldberg E.
      • Singer P.
      • et al.
      Effectiveness and safety of colistin: prospective comparative cohort study.
      We used actual body weight in place of ideal body weight since there were no obese patients in our study cohort, in whom the dissociation between actual and ideal body weight could be significant.
      We excluded patients if they received colistin for less than five days to ensure adequate exposure to the drug. In our study, no patient developed nephrotoxicity within 5 days after starting colistin therapy. However, previous studies reported the development of nephrotoxicity of various incidences (15.5%-100%) within 7 days of colistin administration,
      • Deryke C.A.
      • Crawford A.J.
      • Uddin N.
      • Wallace M.R.
      Colistin dosing and nephrotoxicity in a large community teaching hospital.
      • Paul M.
      • Bishara J.
      • Levcovich A.
      • Chowers M.
      • Goldberg E.
      • Singer P.
      • et al.
      Effectiveness and safety of colistin: prospective comparative cohort study.
      and used inclusion criteria of receiving colistin longer than 48 to 72 hours.
      • Dalfino L.
      • Puntillo F.
      • Mosca A.
      • Monno R.
      • Spada M.L.
      • Coppolecchia S.
      • et al.
      High-dose, extended-interval colistin administration in critically ill patients: is this the right dosing strategy? A preliminary study.
      • Deryke C.A.
      • Crawford A.J.
      • Uddin N.
      • Wallace M.R.
      Colistin dosing and nephrotoxicity in a large community teaching hospital.
      • Doshi N.M.
      • Mount K.L.
      • Murphy C.V.
      Nephrotoxicity associated with intravenous colistin in critically ill patients.
      • Pogue J.M.
      • Lee J.
      • Marchaim D.
      • Yee V.
      • Zhao J.J.
      • Chopra T.
      • et al.
      Incidence of and risk factors for colistin-associated nephrotoxicity in a large academic health system.
      • Paul M.
      • Bishara J.
      • Levcovich A.
      • Chowers M.
      • Goldberg E.
      • Singer P.
      • et al.
      Effectiveness and safety of colistin: prospective comparative cohort study.
      There was no patient who died within 5 days after starting colistin therapy.
      In this study, we used a dosing strategy including the loading dose and maintenance dose, which was suggested by a recent study by Garonzik et al.
      • Garonzik S.M.
      • Li J.
      • Thamlikitkul V.
      • Paterson D.L.
      • Shoham S.
      • Jacob J.
      • et al.
      Population pharmacokinetics of colistin methanesulfonate and formed colistin in critically ill patients from a multicenter study provide dosing suggestions for various categories of patients.
      The report of Garonzik et al included patients from Thailand; however, it also included patients from the U.S., and thus the range was much wider than our study (median body weight 59.1 kg [range: 30.0–106.4] vs. 53.5 kg [35.5-75]). We evaluated the efficacy and safety of a colistin dosing strategy, including the loading dose and the maintenance dose,
      • Garonzik S.M.
      • Li J.
      • Thamlikitkul V.
      • Paterson D.L.
      • Shoham S.
      • Jacob J.
      • et al.
      Population pharmacokinetics of colistin methanesulfonate and formed colistin in critically ill patients from a multicenter study provide dosing suggestions for various categories of patients.
      which was adjusted by both body weight and CrCl, in Asian population with lower body mass. Further studies are warranted to assess the efficacy and toxicity in a larger cohort. Due to the worldwide spread of multi-drug resistant pathogens, a personalized approach is crucial for the appropriate use and evaluation of efficacy and safety of colistin therapy in clinical settings.

      Acknowledgments

      This work was supported by the J-GRID (Japan Initiative for Global Research Network on Infectious Diseases), MEXT Japan.
      Conflict of interest statement: No conflicts of interest to declare.
      The study was approved by Bach Mai Hospital institutional review board. (Approval No. 38).

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