Colistin: Old Antibiotic For

Emerging MDR Pathogens

Dr Mohamad Abdelsalam

ICU Specialist

KFHJ

Colistin (polymyxin E) is an old

antibiotic introduced in 1959 with

significant activity against Gram-

negative bacteria.

Colistin was largely replaced by

aminoglycosides in 1970s

because of nephrotoxicity and

neurotoxicity.

Colistin has been re-introduced into

clinical practice for treating

carbapenem-resistant Gram-negative

bacteria, especially Acinetobacter

baumannii, Pseudomonas aeruginosa

and Klebsiella pneumoniae.

Colistin is administered intravenously

in the form of colistimethate sodium

(CMS), which is hydrolyzed to the

active drug.

CMS Colistin

(Pro-drug)

Is Colistin Bactericidal Or Bacteriostatic?

Bactericidal

Does Colistin Have

Concentration-Dependent Or

Time-Dependent Killing

Activity?

Concentration-Dependent

Is Colistin Renally

Excreted?

CMS Colistin

Renal Clearance

Non-renal Clearance

(Hydrolysis)60%

Renal Excretion Of

Colistin Is Only Minimal.

Why Is Colistin

Concentration In Urine Very

High After IV Administration

Of CMS?

CMS Colistin

Urine

CMS is converted into colistin

within the urinary tract

Is Colistin Active Against All

Gram-Negative Bacteria?

Spectrum Of Colistin

Pseudomonas aeruginosa

Klebsiella pneumoniae

Acinetobacter baumannii

E. Coli

Enterobacter cloacae

Colistin is inactive against

Proteus, Providencia, and

Serratia.

Is PK/PD Profile Of Colistin

Different In Critically-Ill

Patients?

How Might Sepsis/Septic

Shock Affect PK/PD Profile

Of Colistin?

Roberts and Lipman. Critical Care Medicine 2009

Plasma Colistin

Concentrations Are Probably

Low In Critically-Ill Patients?

Increased volume of distribution

Increased cardiac output

Increased renal blood flow

CRRT

Increased clearance

Are The Current Dose

Regimens Optimal?

When CMS is administered at a

dose of 3 MU every 8 h, plasma

concentration of colistin is

probably suboptimal.

Plasma concentration of colistin following IV

administration of 2 MU of CMS

MIC breakpoint of colistin is 2 mcg/ml

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.

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.

12 MU

9 MU

No Loading Dose

How Might Suboptimal

Dosing Of Colistin Adversely

Affect The Outcome Of Your

ICU Patients?

Without loading dose, there may

be significant delay in achieving

steady state concentration which

can lead to increased mortality

and emergence of resistance.

Suboptimal Dosing

Resistance

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.

Dose Adjustment In

Renal Failure

Maintenance daily dose = Creatinine clearance

10

Million IU every 12-24 h

How To Adjust The Dose

Of Colistin During CRRT?

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

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.

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.

Does High-Dose

Colistin Increase

Nephrotoxicity?

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

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

Can IV Colistin

Effectively Treat

VAP?

Does IV Colistin

Adequately Penetrate

The Lung?

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

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.

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

Colistin may be as safe and as

effective as standard antibiotics for

the treatment of ventilator-

associated pneumonia.

Take-Home

Message

● 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.

Thank You