This document discusses the use of the old antibiotic colistin for treating infections caused by multidrug-resistant Gram-negative bacteria. It notes that colistin was largely replaced in the 1970s due to toxicity concerns but has been reintroduced for resistant infections. The document summarizes that the current dosing of colistin may be suboptimal, especially in critically ill patients; colistin is likely less nephrotoxic than originally thought; and colistin can be as effective as other antibiotics for treating ventilator-associated pneumonia.

1. Colistin: Old Antibiotic For
Emerging MDR Pathogens
Dr Mohamad Abdelsalam
ICU Specialist
KFHJ

2. Colistin (polymyxin E) is an old
antibiotic introduced in 1959 with
significant activity against Gram-
negative bacteria.

3. Colistin was largely replaced by
aminoglycosides in 1970s
because of nephrotoxicity and
neurotoxicity.

4. Colistin has been re-introduced into
clinical practice for treating
carbapenem-resistant Gram-negative
bacteria, especially Acinetobacter
baumannii, Pseudomonas aeruginosa
and Klebsiella pneumoniae.

5. Colistin is administered intravenously
in the form of colistimethate sodium
(CMS), which is hydrolyzed to the
active drug.

6. CMS Colistin
(Pro-drug)

7. Is Colistin Bactericidal Or
Bacteriostatic?

8. Bactericidal

9. Does Colistin Have
Concentration-Dependent Or
Time-Dependent Killing
Activity?

10. Concentration-Dependent

11. Is Colistin Renally
Excreted?

12. CMS Colistin
Renal Clearance
Non-renal Clearance
(Hydrolysis)
60%

13. Renal Excretion Of
Colistin Is Only Minimal.

14. Why Is Colistin
Concentration In Urine Very
High After IV Administration
Of CMS?

15. CMS Colistin
Urine

16. CMS is converted into colistin
within the urinary tract

17. Is Colistin Active Against All
Gram-Negative Bacteria?

18. Spectrum Of Colistin
Pseudomonas aeruginosa
Klebsiella pneumoniae
Acinetobacter baumannii
E. Coli
Enterobacter cloacae

19. Colistin is inactive against
Proteus, Providencia, and
Serratia.

20. Is PK/PD Profile Of Colistin
Different In Critically-Ill
Patients?

21. How Might Sepsis/Septic
Shock Affect PK/PD Profile
Of Colistin?

22. Roberts and Lipman. Critical Care Medicine 2009

23. Plasma Colistin
Concentrations Are Probably
Low In Critically-Ill Patients?
Increased volume of distribution
Increased cardiac output
Increased renal blood flow
CRRT
Increased clearance

24. Are The Current Dose
Regimens Optimal?

25. When CMS is administered at a
dose of 3 MU every 8 h, plasma
concentration of colistin is
probably suboptimal.

26. Plasma concentration of colistin following IV
administration of 2 MU of CMS

27. MIC breakpoint of colistin is 2 mcg/ml

28. Without loading dose, plasma colistin
concentration may take 2-3 days before
reaching steady state.
A loading dose might be beneficial to
reduce the time taken to reach steady state
plasma concentration.

29. Using the current dose regimen, it
is likely that ICU patients are
exposed to very low plasma
colistin concentrations during the
first 2-3 days of therapy.

30. 12 MU
9 MU
No Loading Dose

31. How Might Suboptimal
Dosing Of Colistin Adversely
Affect The Outcome Of Your
ICU Patients?

32. Without loading dose, there may
be significant delay in achieving
steady state concentration which
can lead to increased mortality
and emergence of resistance.

33. Suboptimal Dosing
Resistance

34. A loading dose of 9 MU to be
followed 24 h later by a maintenance
dose of 4.5 MU every 12 h may be
appropriate for life-threatening
infections due to Acinetobacter
baumannii, Pseudomonas aeruginosa,
or Klebsiella pneumoniae.

35. Dose Adjustment In
Renal Failure
Maintenance daily dose = Creatinine clearance
10
Million IU every 12-24 h

36. How To Adjust The Dose
Of Colistin During CRRT?

37. Colistin pharmacokinetics in intensive care
unit patients on continuous venovenous
haemodiafiltration: an observational study.
Markou N, Fousteri M, Markantonis SL, Zidianakis B, Hroni D, Boutzouka E, Baltopoulos G
Colistin is substantially removed from
the circulation in critically ill patients
undergoing CVVHDF.
J Antimicrob Chemother 2012; 67: 2459–62

38. Colistin is up to 80% adsorbed on the
surface of highly adsorbent CRRT
membranes.
With new CRRT membranes, the daily
dose should be substantially
increased.

39. Dose Adjustment During
CRRT
Current dose is 9 MU loading, then 4.5
MU/12h.
Suggested dose is 9 MU loading,
then 4.5 MU/8h.

40. Does High-Dose
Colistin Increase
Nephrotoxicity?

41. Nephrotoxicity associated with the
use of intravenous colistin
Cecilia Santamaría, Analia Mykietiuk, Elena Temporiti, Martin E. Stryjewski, Fabian Herrera, Pablo
Bonvehi
54 patients with MDR A. baumannii were included.
6/54 patients (11%) had renal impairment.
Renal impairment associated with the use of
colistin is less frequent than initially
reported.
Scand J Infect Dis 2009; 41: 767-9

42. Colistin: new lessons on an old
antibiotic
D. Yahav, L. Farbman, L. Leibovici, M. Paul
Risk factors for nephrotoxicity include older
age, pre-existing renal impairment and
concomitant use of vancomycin.
Clin Microbiol Infect 2012; 18: 18-29

43. Can IV Colistin
Effectively Treat
VAP?

44. Does IV Colistin
Adequately Penetrate
The Lung?

45. Steady-State Pharmacokinetics and BAL
Concentration of Colistin in Critically Ill
Patients After IV Colistin Methanesulfonate
Administration
Imberti R, Cusato M, Villani P, Carnevale L, Iotti GA, Langer M, Regazzi M.
In critically-ill patients with VAP, colistin was
undetectable in BAL following IV adminstrition of
CMS 2 MU/8h.
Chest 2010; 138: 1333-39

46. Colistin Was Measured In
BAL Shortly After IV
Administration Of CMS
Maybe, CMS was not converted to colistin
when BAL was collected, and it is likely that
colistin may have been detected in BAL if the
sample were collected several hours later.

47. What Is the Efficacy and Safety of Colistin for
the Treatment of Ventilator-Associated
Pneumonia? A Systematic Review and Meta-
Regression
Florescu DF, Qiu F, McCartan MA, Mindru C, Fey PD, Kalil AC
6 controlled studies were analyzed.
Mean dose of IV colistin ~ 6-8 MU.
There was no significant difference in clinical
response, mortality or nephrotoxicity between
colistin and control groups.
Clin Infect Dis 2012; 54: 670- 80

48. Colistin may be as safe and as
effective as standard antibiotics for
the treatment of ventilator-
associated pneumonia.

49. Take-Home
Message

50. ● The current colistin dosing may be sub-
optimal.
● Colistin is probably less nephrotoxic than
historically reported.
● Colistin may be as effective as standard
antibiotics for treating VAP.

51. Thank You