|Year : 2013 | Volume
| Issue : 6 | Page : 608-611
Parenteral polymyxins: Assessing efficacy and safety in critically ill patients with renal dysfunction
Kavita Sekhri1, Ruchika Nandha1, Amit Mandal2, Deepak Bhasin2, Harpal Singh2
1 Department of Pharmacology, Dr. Harvansh Singh Judge Institute of Dental Sciences, Panjab University, Chandigarh, India
2 Department of Pulmonary medicine and Critical care, Medical Intensive Care Unit, Fortis Hospital, Mohali, Punjab, India
|Date of Submission||20-Sep-2012|
|Date of Decision||04-Feb-2013|
|Date of Acceptance||18-Sep-2013|
|Date of Web Publication||14-Nov-2013|
Department of Pharmacology, Dr. Harvansh Singh Judge Institute of Dental Sciences, Panjab University, Chandigarh
Source of Support: None, Conflict of Interest: None
Objectives: Studies have established the effectiveness and safety of polymyxins in treating multidrug resistant (MDR) pathogens. However, the challenge is whether these nephrotoxic drugs can be administered in compromised renal states. The present study was undertaken to establish their role in such patients. The effectiveness and nephrotoxicity of polymyxins in critically ill-patients harboring MDR Gram-negative bacteria with already compromised renal functions was compared with those with normal renal functions.
Materials and Methods: This retrospective cohort study (March 2008-March 2010) was conducted in the intensive care unit of a tertiary care hospital. A total of 48 eligible critically ill-patients receiving polymyxins were enrolled. A comparison was carried out (length of stay in hospital, mortality, renal function) between patients with acute kidney injury (AKI, n = 18; defined by the RIFLE classification) and patients with normal renal function (non-AKI, n = 30).
Results: Patients with baseline AKI had a significantly higher adjusted mortality rate at admission when compared with the non-AKI group. At the end of therapy with polymyxins, 26.66% non-AKI patients developed renal dysfunction while 38.88% of patients in the AKI group had worsening of renal function (P = 0.006). However, there was no significant difference in the length of hospital stay (23.9 ± 13.24 vs. 30.5 ± 22.50; P = 0.406) and overall mortality (44.4% vs. 36.7%; P = 0.76) between two groups.
Conclusion: Polymyxins can be administered in AKI patients with favorable results provided used judiciously with strict monitoring of renal functions, dose modification according to creatinine clearance and aggressive fluid management.
Keywords: Multidrug resistant Gram-negative septicemia, nephrotoxicity, polymyxin B, polymyxin E, renal dysfunction
|How to cite this article:|
Sekhri K, Nandha R, Mandal A, Bhasin D, Singh H. Parenteral polymyxins: Assessing efficacy and safety in critically ill patients with renal dysfunction. Indian J Pharmacol 2013;45:608-11
|How to cite this URL:|
Sekhri K, Nandha R, Mandal A, Bhasin D, Singh H. Parenteral polymyxins: Assessing efficacy and safety in critically ill patients with renal dysfunction. Indian J Pharmacol [serial online] 2013 [cited 2021 Aug 2];45:608-11. Available from: https://www.ijp-online.com/text.asp?2013/45/6/608/121373
| » Introduction|| |
The emergence and rapid spread of multidrug resistant (MDR) pathogens especially in intensive care units (ICUs) that cause nosocomial infections are of great concern world-wide. The incidence of these infections has steadily increased during the last decade.  This has led to worse outcomes, including longer hospital stays, increased mortality and greater costs of hospitalization.  Moreover, increasing number of MDR Gram-negative pathogens and limited development of newer antimicrobials have made the selection of antibiotics in critically ill-patients more difficult.  Hence it has necessitated the reintroduction of intravenous polymyxins (polymyxin B and polymyxin E), an antibiotic class discovered more than 60 years ago for the treatment of such infections in spite of its proven nephrotoxic effects in the past. ,
Polymyxins are a group of cationic polypeptide antibiotics consisting of five different compounds (polymyxin A-E). Only polymyxins B and E (colistin) have been used in clinical practice due to high toxicity of the remaining agents.  Polymyxin B has the same structure as colistin, but contains D-phenylalanine instead of D-leucine.  Polymyxins are rapid acting bactericidal agents with a detergent like mechanism of action.  The antibacterial spectrum of polymyxins includes only Gram-negative organisms. They are effective treatment for the infections caused by MDR Pseudomonas aeruginosa, Acinetobacter baumanni, Klebsiella pneumonia, Enterobacter strains. , These pathogens can cause a variety of ICU acquired infections such as pneumonia/ventilator associated pneumonia, septicemia, meningitis, urinary tract infections, skin and soft-tissue infections etc., but the fear of adverse effects like nephrotoxicity and neurotoxicity limited their use.  Recent studies demonstrate the acceptable effectiveness and less toxicity of polymyxins than the past studies. ,,,, It is seen that the incidence of nephrotoxicity in recently published data with polymyxins ranged from 15% to 55%. 
However, there is a concern regarding their use in patients with already compromised renal functions as proven nephrotoxicity of polymyxins predict the increase in mortality with their use in renal patients.  Little is known about the use of polymyxins in such patients due to non-availability of such studies. Hence, this study was undertaken to compare the effectiveness and nephrotoxicity of polymyxins in critically ill-patients with already known renal dysfunction to those with normal renal function.
| » Materials and Methods|| |
Design And Setting
A retrospective cohort study was undertaken (March 2008-2010) in critically ill-patients with ICU-acquired infections caused by MDR Gram-negative bacteria. It was conducted at the 23 bedded medical ICU of tertiary care hospital in Northern India. It was approved by ethics committee of the hospital which waived the need for informed consent due to its retrospective nature.
Medical records were reviewed to identify patients who received polymyxin B or E during these periods. Patients who received polymyxin B or E for carbepanem resistant Gram-negative sepsis, either suspected or confirmed cases for at least three consecutive days, with serum creatinine measurements available one before the start of antibiotic, one during therapy and one after completion of therapy were included in the study irrespective of the age, gender or underlying disease. Patients with baseline creatinine level greater than 4 mg/dl or patients undergoing dialysis at the beginning of the antibiotic therapy, those with obstructive renal failure, with loss or end stage kidney disease or those receiving concomitant nephrotoxic drugs were excluded from the study.
Collection and Extraction of Data
For each patient, clinical data was extracted from hospital records in the form of demographics, date of admission and discharge (i.e., length of stay), underlying disease, medical history, previous surgery, infection on ICU admission, dosing frequency and duration of therapy. Data on serum creatinine (baseline, highest level during treatment and after therapy) and outcome (recovery or death) were also collected. Patient's severity of illness on admission was calculated by acute physiology and chronic health evaluation II (APACHE II) scoring system. 
All patients in the study received intravenous polymyxin B or E for MDR Gram-negative sepsis resistant to carbapenams. Polymyxin B dose was given according to the literature provided by drug company, i.e., 5 lakhs units intravenously 8 hourly (15,000-25,000 IU/kg/day). ] Polymyxin E was given at a dose of 2 million units every 8 hourly for at least 3 days (72 h).  Dosage adjustment was done according to creatinine clearance in patients with deranged renal function. Creatinine clearance was calculated using the Cockcroft and Gault formula.
Baseline serum creatinine was defined as the creatinine level on the day when initial polymyxin dose was administered. A RIFLE criterion for acute kidney injury (AKI) at admission was used for grouping of patients. The acronym RIFLE stands for the increasing severity classes, Risk (R), Injury (I) and Failure (F) and two outcome classes, Loss (L) and End stage kidney disease (E). The three severity grades are defined on the basis of the changes in serum creatinine or urine output. The two outcome criteria, loss and end stage kidney disease, are defined by the duration of loss of kidney function. Increase in serum creatinine to more than or equal to 150-200% (1.5-2 fold) from baseline is categorized under Risk class, increase in serum creatinine to more than 200-300% (>2-3 fold) from baseline as Injury class and increase in serum creatinine to more than 300% (>3 fold) from baseline as Failure class. ]
Out of the total of 112 patients who were administered polymyxins, 48 patients met the study criteria. Patients were divided into two groups based on RIFLE criteria for AKI at admission. The group with normal renal function at the start of therapy served as the control group (non-AKI group) and other group with deranged renal function as AKI group. In AKI group, we included patients with "Risk," "Injury" or "Failure" grades only. Patients with loss or end stage kidney function were excluded. AKI was found in 18 patients at the start of therapy, which were hence grouped into AKI group and 30 patients who reported with normal renal functions served as control, i.e., non-AKI group. Comparison of patients was done between non-AKI (n = 30) and AKI (n = 18) groups. Primary end points included resolution of sepsis, survival and nephrotoxic effects with polymyxins. Safety was assessed on the basis of laboratory tests for renal function (creatinine clearance) during polymyxins administration.
Statistical analysis was performed using unpaired Student t-test, Mann-Whitney test, Pearson Chi-square and Fisher's exact test. P < 0.05 was considered to be statistically significant.
| » Results|| |
All eligible patients (n = 48) who received polymyxin B or E intravenously for treatment of ICU acquired infections caused by a carbapenem resistant Gram-negative bacterium between March 2008 and March 2010 were studied. Most of the (60.4%) patients were males while 39.6% of patients were females. Mean age of patients was 58.42 ± 17.78 years.
The most frequent pathogen isolated was found to be A. baumanni in 34 patients (70.8%). One patient each was infected with Escherichia More Details coli and P. aeruginosa. Polymicrobial infection was found in 4 (12%) patients. Major bacterial isolation sites were blood (31.25%), lungs (27.08%), abdomen (22.91%), skin or soft-tissues (8.33%) and urinary tract (2.08%).
Daily mean dose of polymyxin B was found to be 11.46 ± 3.08 lakhs units with the total mean dose of 90.73 ± 59.90 lakhs units while for polymyxin E mean daily dose was 5.3 ± 5.64 million units with total daily dose of 49.53 ± 28.12 million units. It was found that the AKI was present at the time of start of treatment in 18 (37.5%) patients (AKI group), whereas normal renal functions were seen in 30 (62.5%) patients (non-AKI group). Out of the 18 patients in AKI group, 9 patients were in Risk class, 7 were in Injury class and 2 were in Failure class.
Both AKI and non-AKI groups were similar as no statistically significant difference was seen regarding sex ratio, age and duration of therapy. Adjusted mortality rate (AMR) at admission according to APACHE II was 23.76 ± 11.58 in AKI group when compared with 13.08 ± 7.93 in non-AKI, which was significantly higher [Table 1].
|Table 1: Comparison of parameters between patients of AKI and non-AKI groups of critically ill-patients|
Click here to view
There was no significant difference in the length of hospital stay (23.89 ± 13.24 in AKI group vs. 30.5 ± 22.50 days in non-AKI group; P = 0.406). At the end of therapy with polymyxins, in non-AKI group 26.6% (8 out of 30) patients developed renal dysfunction with no alteration in renal function in 73.4% (22 out of 30) patients whereas in AKI group, worsening of renal functions was observed in 38.8% (7 out of 18) patients, improvement in 33.3% (6 out of 18) patients and there was no change in 27.8% (5 out of 18) patients. Statistically significant difference was found among AKI and non-AKI groups regarding worsening of renal functions. Out of 18 patients in AKI group, 8 died, whereas out of 30 patients in non-AKI, 11 died. No statistically significant difference was found in the overall mortality (44.4% in AKI group vs. 36.7% in non-AKI group; P = 0.762) between patients of two groups [Table 2].
|Table 2: A comparison of outcomes between patients of AKI and non-AKI groups|
Click here to view
| » Discussion|| |
This study evaluated the safety and effectiveness of polymyxin B or E in 48 critically ill-patients who acquired nosocomial infections in ICU caused by MDR Gram-negative bacilli that were susceptible only to polymyxins. Until date, clinical experience with polymyxins in renal dysfunction is very limited and that too if it is administered in patients with already compromised renal function. To the best of our knowledge, this study represents one of its kinds to evaluate the use of polymyxins in already compromised renal function. A total of 48 patients who received polymyxins, 18 had already compromised renal function (AKI group), whereas 30 had normal renal function (non-AKI group).
Good clinical response (cure/improvement) was observed in 55.5% of patients in AKI group and 63.3% of patients in non-AKI group. Renal function worsening occurred in both groups [Figure 1], but it was more in patients of AKI group, i.e., 38.8% as compared with 26.6% in non-AKI group. This increased nephrotoxicity in pre-existing renal disease was also observed in other studies. , This can be explained by the fact that potentially nephrotoxic agents are associated with a higher toxicity in patients with abnormal renal function even after adjustment of dose.  However, renal dysfunction could not be attributed only to polymyxins as other factors such as development of septic shock, multiple organ failure, hypovolemia and low cardiac output syndromes may also contribute to it. 
|Figure 1: Renal function in critically ill-patients receiving polymyxins|
Click here to view
The calculated AMR (according to APACHE II score) was significantly higher, i.e., 23.76% in patients of AKI group as compared to 13.08% in patients of non-AKI group at the start of therapy. However, the final outcome of patients in both groups was similar, i.e., polymyxins caused worsening of renal function more so in AKI group as compared to non-AKI group, but this did not lead to increase in hospitalization days in ICU [Figure 2] or any intervention like hemodialysis. No significant difference was found in mortality rate among two groups. Similar results wherein, mortality rate of 40% was reported in both renal failure and non-renal failure groups with the use of polymyxin E was shown by Turkoglu et al. in Turkey. 
|Figure 2: Days of hospitalization in critically ill patients on polymyxins|
Click here to view
The similar outcomes in both the groups can be explained by the fact that in our setup polymyxins had been used judiciously in the appropriate dose and duration according to ideal body weight. No concomitant nephrotoxic drug was administered. Further daily adjustment of the dose was done based on continuous monitoring of renal functions like creatinine clearance. Furthermore, intravenous fluid resuscitation was adequately carried out according to the inferior vena cava measurements. All these measures led to favorable results at the end of therapy even in AKI patients. The important limitation of our study is its retrospective nature and small sample size. There is a need to conduct randomized controlled trials that will further establish their role in patients with renal dysfunction at the start of therapy.
In our study, patients with AKI at admission were found to be more morbid and the use of polymyxins led to worsening of renal functions. However, despite the baseline morbidity and exacerbation of renal dysfunction, there was no increase in length of stay in a hospital or in the overall mortality rate among two groups. So in our experience, polymyxins can be used in patients with AKI with MDR Gram-negative septicemia provided adequate measures (judicious use of medication, monitoring of renal function, dose adjustment and aggressive fluid management) are taken.
| » References|| |
|1.||Gaynes R, Edwards JR, National Nosocomial Infections Surveillance System. Overview of nosocomial infections caused by gram-negative bacilli. Clin Infect Dis 2005;41:848-54. |
|2.||Pop-Vicas AE, D'Agata EM. The rising influx of multidrug-resistant gram-negative bacilli into a tertiary care hospital. Clin Infect Dis 2005;40:1792-8. |
|3.||Pastewski AA, Caruso P, Parris AR, Dizon R, Kopec R, Sharma S, et al. Parenteral polymyxin B use in patients with multidrug-resistant gram-negative bacteremia and urinary tract infections: A retrospective case series. Ann Pharmacother 2008;42:1177-87. |
|4.||Falagas ME, Rafailidis PI, Ioannidou E, Alexiou VG, Matthaiou DK, Karageorgopoulos DE, et al. Colistin therapy for microbiologically documented multidrug-resistant Gram-negative bacterial infections: A retrospective cohort study of 258 patients. Int J Antimicrob Agents 2010;35:194-9. |
|5.||Kvitko CH, Rigatto MH, Moro AL, Zavascki AP. Polymyxin B versus other antimicrobials for the treatment of pseudomonas aeruginosa bacteraemia. J Antimicrob Chemother 2011;66:175-9. |
|6.||Falagas ME, Kasiakou SK. Toxicity of polymyxins: A systematic review of the evidence from old and recent studies. Crit Care 2006;10:R27. |
|7.||Falagas ME, Kasiakou SK. Colistin: The revival of polymyxins for the management of multidrug-resistant gram-negative bacterial infections. Clin Infect Dis 2005;40:1333-41. |
|8.||Hermsen ED, Sullivan CJ, Rotschafer JC. Polymyxins: Pharmacology, pharmacokinetics, pharmacodynamics, and clinical applications. Infect Dis Clin North Am 2003;17:545-62. |
|9.||Mendes CA, Burdmann EA. Polymyxins - A review focusing on their nephrotoxicity. Rev Assoc Med Bras 2010;56:752-8. |
|10.||Ouderkirk JP, Nord JA, Turett GS, Kislak JW. Polymyxin B nephrotoxicity and efficacy against nosocomial infections caused by multiresistant gram-negative bacteria. Antimicrob Agents Chemother 2003;47:2659-62. |
|11.||Michalopoulos A, Falagas ME. Colistin and polymyxin B in critical care. Crit Care Clin 2008;24:377-91. |
|12.||Sobieszczyk ME, Furuya EY, Hay CM, Pancholi P, Della-Latta P, Hammer SM, et al. Combination therapy with polymyxin B for the treatment of multidrug-resistant Gram-negative respiratory tract infections. J Antimicrob Chemother 2004;54:566-9. |
|13.||Michalopoulos AS, Tsiodras S, Rellos K, Mentzelopoulos S, Falagas ME. Colistin treatment in patients with ICU-acquired infections caused by multiresistant Gram-negative bacteria: The renaissance of an old antibiotic. Clin Microbiol Infect 2005;11:115-21. |
|14.||Pogue JM, Lee J, Marchaim D, Yee V, Zhao JJ, Chopra T, et al. Incidence of and risk factors for colistin-associated nephrotoxicity in a large academic health system. Clin Infect Dis 2012;1:1-6. |
|15.||Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: A severity of disease classification system. Crit Care Med 1985;13:818-29 |
|16.||Product information. Inj. Polymyxin B sulphateBP 50,000 units,Samarth Poly B. Mumbai: Samarth Life Sciences private limited; 2010. |
|17.||Product information. Inj. Colistimethate SodiumBP 10,00,000 International Units, Glenmerk Coly-Monas Mumbai: Glenmerk Pharmaceuticals Limited; 2010.9. |
|18.||Kellum JA. Acute kidney injury. Crit Care Med 2008;36:S141-5. |
|19.||Mendes CA, Cordeiro JA, Burdmann EA. Prevalence and risk factors for acute kidney injury associated with parenteral polymyxin B use. Ann Pharmacother 2009;43:1948-55. |
|20.||Doshi NM, Mount KL, Murphy CV. Nephrotoxicity associated with intravenous colistin in critically ill patients. Pharmacotherapy 2011;31:1257-64. |
|21.||Clermont G, Acker CG, Angus DC, Sirio CA, Pinsky MR, Johnson JP. Renal failure in the ICU: Comparison of the impact of acute renal failure and end-stage renal disease on ICU outcomes. Kidney Int 2002;62:986-96. |
|22.||Uchino S, Doig GS, Bellomo R, Morimatsu H, Morgera S, Schetz M, et al. Diuretics and mortality in acute renal failure. Crit Care Med 2004;32:1669-77. |
|23.||Turkoglu M, Dizbay M, Ciftçi A, Aksakal FN, Aygencel G. Colistin therapy in critically ill patients with chronic renal failure and its effect on development of renal dysfunction. Int J Antimicrob Agents 2012;39:142-5. |
[Figure 1], [Figure 2]
[Table 1], [Table 2]