1. Polymyxin B and the Risk of Nephrotoxicity/Neurotoxicity
Yumi Lee, Pharm.D.
Pharmacy Practice Resident (PGY-1)
Kingsbrook Jewish Medical Center
Clinical Instructor of Pharmacy Practice
Arnold & Marie Schwartz College of Pharmacy
and Health Sciences of Long Island University
Brooklyn, New York

2. Overview of Polymyxins
Polypeptide Antibiotics
Polymyxin A, B, C, D, E
Polymyxin B: Bacillus polymixa, 1947
Polymyxin E (Colistin): Bacillus colistinus, 1950
Polymyxins are a group of polypeptide antibiotics. They consist of 5 chemically different compounds (A-E) which were first discovered in the late 1940s. Polymyxin B and E (known as colistin) are the only agents available clinically because of their more favorable safety profile when compared with the other polymyxin compounds. The sole difference between colistin and polymyxin B is by a single amino acid change: D-phenylalanine in Polymyxin B in replaced with D-leucine in colistin.
Landman et al. Clinical Microbiology Reviews 2008;21(3):449-65

3. Spectrum of Activity: Bactericidal
Gram-negative bacilli: broad spectrum
Escherichia coli, Klebsiella spp., Enterobacter spp., Pseudomonas aeruginosa, and Acinetobacter spp.
Resistant Pathogens
Proteus spp., Providencia spp., Serratia spp., Neisseria spp., Chromobacterium spp., Burkholderia spp.
Gram-positive organisms
Anaerobes
The polymyxins exhibit bactericidal activity against most gram(-) aerobic bacilli, including Acinetobacter, Pseudomonas, Klebsiella, and Enterobacter species, which are all important nosocomial pathogens.
However, several pathogens possess intrinsic resistance to the polymyxins including Proteus, Providencia, Serratia, Neisseria, Chromobacterium, and Burkholderia.
Landman et al. Clinical Microbiology Reviews 2008;21(3):449-65

4. Landman et al. Clinical Microbiology Reviews 2008;21(3):449-65
Mechanism of Action
Mechanism of action: Bactericidal
Binds to bacterial outer membrane  disruption of membrane integrity
Displaces Mg2+ and Ca2+ bridges that stabilize lipopolysaccharide molecules of outer membrane  ↑ cell permeability  leakage of cell contents  death
Uses:
Infections caused by multi-drug resistant gram (-) bacteria
Pneumonia, bacteremia, UTI, surgical site infections, CNS, orthopedic infections, and endocarditis
Also used to enhance susceptibility of hydrophobic antimicrobials (e.g., erythromycin)
Polymyxins are cationic agents that bind to the anionic bacterial outer member leading to a detergent effect that disrupts membrane integrity.
In particular, polymyxins displace magnesium and calcium bridges that stabilize the bacterial outer member which leads to an increase in the permeability of the cell envelope, leakage of cell contents, and eventually death.
Also used to enhance susceptibility of hydrophobic antimicrobials (e.g., erythromycin)  by disrupting the membrane
Landman et al. Clinical Microbiology Reviews 2008;21(3):449-65

5. Availability and Dosing
Polymyxin B sulfate
10,000 U = 1 mg polymyxin B base
Available in 500,000 U (50 mg) vials
Dose: 15, ,000 U/kg/day divided Q12H
Colistimethate sodium
30,000 U = 1 mg colistin base
Available in 150 mg vials
Dose: mg/kg/day in divided doses
Polymyxins are renally cleared and needs to be renally adjusted.
Colistin in commercially available as colistimethate sodium due to its less toxic profile.
Lexi-Comp Online. Hudson, OH: Lexi-Comp, Inc.; 2009; February 12, 2009.

6. Adverse Effects of Polymyxins
Hypersensitivity
Electrolyte disturbance
Nephrotoxicity
Neurotoxicity
Neuromuscular blockade
Respiratory arrest
Lexi-Comp Online. Hudson, OH: Lexi-Comp, Inc.; 2009; February 12, 2009.

7. Boxed Warnings Nephrotoxicity Neurotoxicity
May cause nephrotoxicity; avoid concurrent or sequential use of other nephrotoxic drugs.
Neurotoxicity
May cause neurotoxicity, which can also result in respiratory paralysis from neuromuscular blockade especially when the drug is given soon after anesthesia or muscle relaxants. Avoid concurrent or sequential use of other neurotoxic drugs.
With increased used, nephro and neurotoxicity due to the polymyxins became more apparent and as newer and safer antimicrobial agents were developed, the use of polymyxins gradually fell out of favor. However, with an increased incidence of gram(-) bacteria resistant to most classes of antibiotics, including the carbapenems, the polymyxins have resurfaced as a viable treatment options for infections because of these MDR-gram(-) organisms.
Lexi-Comp Online. Hudson, OH: Lexi-Comp, Inc.; 2009; February 12, 2009.

8. Clinical Manifestation of Nephrotoxicity
↑SrCr
Proteinuria
Azotemia
Hematuria
Cylindruria
Oliguria
Acute tubular necrosis
Frequency not defined
Azotemia includes decrease in GFR and increase serum creatinine and BUN
Cylinduria- presence of renal casts in the urine
Falagas ME et al. Critical Care 2006;10(1):1-13

9. Clinical Manifestation of Neurotoxicity
Paresthesia
Ataxia
Vertigo
Headache
Weakness
Visual disturbances
Confusion
Seizures
Neuromuscular blockade  respiratory muscle paralysis  respiratory failure
Frequency not defined
Falagas ME et al. Critical Care 2006;10(1):1-13

10. Proposed Mechanisms of Toxicities
Nephrotoxicity
Increases renal tubular epithelial cell membrane permeability  increased transepithelial conductance of bladder
Neurotoxicity
Presynaptic action of polymyxins block release of acetylcholine to synaptic gap  neuromuscular blockade
Like its MOA… it increase tubular epithelial cell membrane permeability -- acute tubular necrosis
Dose-dependent and reversible
Falagas ME et al. Critical Care 2006;10(1):1-13

11. Incidence of Nephro/Neurotoxicity
Literature search on PubMed ( )
Search terms: colistin, polymyxin E, polymyxin B, adverse effects, toxicity, nephrotoxicity, and neurotoxicity
Early reports revealed high incidence of nephrotoxicity and neurotoxicity
Less occurrence of neurotoxicity than nephrotoxicity
Recent studies do not corroborate with older literature
No reports of neuromuscular blockade over past 15 years or more

12. Initial Toxicity Reports
Study
Drug & Dose
Nephrotoxicity
Neurotoxicity
Fekety et al. Ann Intern Med 1962;57:
Colistimethate sulfate IM
17/48 (35.4%) ↑BUN
13/48 (27%) parathesias; 3/48 (6.2%) ataxia
Tallgren et al. Acta Med Scand 1965;177:
9/25 (36%) ↑SCr
(pre-existing renal impairment)
Olesen et al. Curr Ther Res Clin Exp 1967;9:283-7.
Colistimethate sulfate IV
6/23 (26%) renal impairment; 7/23 (30%) albuminuria
1/23 (4.3%) paresthesia
Koch-Weser et al. Ann Intern Med 1970;72:
64/317 (20.1%) (courses)
23/317 (7.2%)
Polymyxins fell out of favor due to these reports in the 1970s
When doing literature search…. Found….

13. Recent Toxicities Reports
Study
Drug & Dose
Nephrotoxicity
Neurotoxicity
Ouderkirk et al. Antimicrob Agents Chemother 2003;47:
Polymyxin B IV
7/50 (14%) doubling of SCr >2 mg/dl
Sobieszczyk et al. J Antimicrob Chemother 2004;54;566-9.
Polymyxin B IV (21), INH (6), both (2)
3/29 (10%) doubling of SCr
2/29 (7%) new onset seizures and neuromuscular weakness
Kasiakou et al. Antimicrob Agents Chemother 2005;49:
Colistimethate sulfate IV
4/50 (8%) doubling of SCr >1.3 mg/dl
Most neurotox were case reports…
Besides these 2 case reports, there are a hand full of other reports of neurotox possible due to poly
Jimenez-Mejias et al. Eur J Clin Microbiol Infect Dis 2003;21: Colistimethate sulfate IV 5/21 (24%) doubling of SCr
>2 mg/dl

14. Prevention & Management of Toxicities
Renal dose adjustments
Avoid co-administration of potential nephrotoxic and neurotoxic agents
Prompt discontinuation
Quick diuresis by IV mannitol
Maintain fluid and electrolyte balance
Dialysis and respiratory support if necessary
Quick diuresis by IV mannitol to enhance renal clearance of drug

15. Polymyxins Dosage Adjustments
Polymyxin B
CrCl >50 mL/min: 15,000 – 25,000 units/kg/day divided Q12H
CrCl mL/min: % of daily dose divided Q12H
CrCl mL/min: 50% of daily dose divided Q12H
CrCl <5 mL/min: 15% daily dose divided Q12H
Colistimethate
Scr <1.3 mg/dL: mg/kg/day in 2-4 divided doses
Scr mg/dL: mg/kg/day Q12H
Scr mg/dL: 2.5 mg/kg/day Q12H or Q24H
Scr mg/dL: 1.5 mg/kg/day Q36H
Lexi-Comp Online. Hudson, OH: Lexi-Comp, Inc.; 2009; February 12, 2009.

16. Conclusions
Polymyxins recently re-introduced into clinical practice for treatment of MDR-gram-negative infections
Nephrotoxicity and neurotoxicity represent major adverse effects of polymyxins
Data from recent literature suggest lower and less frequent incidence of toxicities
Caution and frequent monitoring is necessary when administering polymyxins