Colistin: how to use it?

Matteo Bassetti, MD, PhD

Infectious Diseases Division

Santa Maria Misericordia University Hospital

Udine, Italy

Disclosures

Research grants

- Astellas, Pfizer, MSD, Gilead

Advisor/consultant

- Astellas, Pfizer, MSD, Gilead, Angelini, Vifor,

Shionogi, Novartis

Speaker/chairman

- Astellas, Pfizer, MSD, Gilead, Angelini, Vifor,

Shionogi, Novartis, Bayer

Colistin

Antibiotic produced by Bacillus polymyxa

Used in 1960’s but largely abandoned in 1970’s when

more effective, less toxic agents became available

Resurrected in late 1990’s and 2000s when multiresistant

pseudomonas and acinetobacter became problematic

Two forms

- colistin sulfate (topical, oral and inhalation)

- colistimethate (parenteral and inhalation)

Colistin

Colistin

The target of antimicrobial activity of

colistin is the bacterial cell membrane

Colistin has also potent anti-endotoxin

activity

- The endotoxin of G-N bacteria is the lipid A

portion of LPS molecules, and colistin

binds and neutralizes LPS

5

Metabolism of colistimethate

Li J et al. Lancet Infect Dis 2006; 6: 589–601

Spectrum of activity

Spectrum of activity

- Most gram-negative aerobic bacilli:

Acinetobacter species, P. aeruginosa, Klebsiella species, Enterobacter species, Escherichia coli, Salmonella species, Shigella species, Citrobacter species, Yersinia pseudotuberculosis, and Haemophilus influenzae

- No activity against:

Pseudomonas mallei, Burkholderia cepacia, Proteus species, Providencia species, Morganella morganii, Serratia species, Edwardsiella species, and Brucella

Resistance to colistin

Surprisingly uncommon in Pseudomonas in CF despite

extensive use and rapid resistance development to

other antibiotics in this setting

Resistance in MRAB increasingly described in some

centers where colistin has been widely used

“Hetero-resistance” may be common in MRAB

Colistin resistance in KPC-producing K pneumoniae

has been observed

Resistance associated with mutations of outer

membrane proteins or lipopolysaccharide

Colistin use in critically ill patients:

resistance?

•Colistin-resistant strains represent 12% of the carbapenemase

producing Enterobacteriaceae (SENTRY Program).

•Cross-resistance against colistin and polymyxin B is almost

complete.

•Previous use of colistin was observed to be a risk factor to the

development of resistance (prolonged treatment).

•Heteroresistance is an emerging threat associated with exposure to

suboptimal dosage (clinical significance?)

Bergen et al. J Antimicrob Chemother 2008;61:636-42

Souli et al. Antimicrob Agents Chemother 2009;53:2133-5

Elemam et al. Clin Infect Dis 2009;49:271-4

When to use?

A. baumannii

P. aeruginosa

K. pneumoniae (KPC)

Empiric use:

- VAP and septic patients in units with high incidence of carbapenemases

- Pts already colonized by MDR and PDR becoming septics

How to use

Dosage?

Number of doses?

Distribution of the drug in the body?

Mono or combo?

IV

Aerosolized?

Toxicity

…..

Recommended doses of i.v. colistin

(CMS) in critically ill patients

Normal renal function

- 3 million IU (240 mg CMS) every 8 h

- Manufacturers of European colistin products recommend 50,000 to 75,000

IU/kg/day of CMS in 2-3 divided doses

- Manufacturers of the U.S. colistin product, Coly-Mycin, recommend a dose

of 2.5 to 5 mg/kg colistin base activity daily divided in 2 to 4 doses

Renal Failure

- For serum creatinine level 1.3-1.5 mg/dl, 1.6-2.5 mg/dl, or ≥ 2.6 mg/dl, the

recommended dosage of intravenous colistin is 2 million IU (160 mg CMS)

every 8 h, 12 h, or 24 h, respectively

Renal replacement therapy

- 2 million IU (160 mg CMS) after each hemodialysis

- 2 million IU (160 mg CMS) daily during peritoneal dialysis

Michalopoulos et al Annals of Intensive Care 2011, 1:30

Pharmacokinetics of colistin

(CMS)

Metabolism: CMS is a prodrug that is hydrolyzed after i.v. administration to

produce derivatives, including the active drug colistin

It is not absorbed from the gastrointestinal tract

Distribution of CMS to lung parenchyma, pleural cavity, pericardial fluids, and

CSF is poor

Time to peak: 10 min following i.v. administration

Half-life elimination: 2-3 h (CMS i.v. administration, with normal renal function).

In patients with anuria = 2-3 days.

CMS is tightly bound to membrane lipids of cells in many body tissues,

including liver, lungs, kidneys, brain, heart, and muscles

CMS is excreted primarily in the urine (as unchanged drug). No biliary excretion

has been reported in humans

Data on the pharmacokinetics of i.v. CMS in critically ill

patients are limited

Michalopoulos et al Annals of Intensive Care 2011, 1:30

Which PK/PD parameter

predicts efficacy of colistin?

0

Cmax:MIC

Concentration

Time (hours)

MIC

Cmax = Maximum plasma concentration

Which PK/PD parameter

predicts efficacy of colistin?

Colistin serum concentrations after iv administration

in critically ill pts with serious MDR infections

2.8 MIU CMS every 8 or 12 hrs for at least 2 days

At steady state:

- mean (SD) colistin maximum concentrations were 2.93 (1.24) mg/L,

- minimum concentrations were 1.03 (0.44) mg/L

- Apparent VD was 139,9 L and t 1/2 was 7.4 hours

CMS dosage regimens were associated with suboptimal Cmax/MIC ratios for many strains of gram-negative bacilli currently reported as sensitive (MIC < or = 2 microg/mL).

Markou N. et al. Clin Ther 2008, 30 : 143-51

Time for steady state

3 Million unit every 8 hrs of CMS

Blood levels of CMS and Colistin

Colistin Cmax after first dose: 0.60 mg/L

Colistin Cmax at steady state: 2.3 mg/L

Time for steady state: 4 days

Usual MIC for Ps.aeruginosa and A.baumannii:

- 2 mg/L

Need for a loading dose ?

Plachouras D et al. Antimicrob Agenst Chemother 2009; 53: 3430-36

Colistin: dosage according to

PK/PD data

Plachouras D et al. Antimicrob Agenst Chemother 2009; 53: 3430-36

MIC’s for MDR

Colistin: dosage??

Probably:

- 9 or 12 milion loading dose, then 4,5

milion q12h

Potential benefit

of colistin concentration monitoring (TDM)

33 critical-care patients, in which Css,avg ranged from below

the limit of quantification to 6.4 mg/mL, with a median of 1.1

mg/mL

Although a plasma concentration determined at any time

would probably provide an appropriate estimate of Css,avg for

the purposes of drug monitoring, it would be more advisable

to sample immediately before CMS dosing, because CMS

concentrations would then be minimal and the risk of colistin

concentration overestimation resulting from post-sampling

CMS hydrolysis would therefore be considerably reduced.

Couet W et al. Clin Microbiol Infect 2012; 18: 30–39

Colistin in critically ill

patients

Imberti R et al. Chest 2010;138:1333-9

Colistin in critically ill

patients

Markou N et al. Chest 2011;139;232-233

Why this discrepancy?

- Concentration of the free form is much

- Less than the bound form in all tissues, lung included

- Dilutional effects of salin infusion

- Low dose of colistin

Monotherapy with colistin and long dosage

intervals (ie 24h) may be problematic for

treatment of infections caused by colistin

heteroresistant A.baumannii

Colistin

Monotherapy

Combination therapy

Combination: Looking for a partner agent…….

Colistin plus antipseudomonal agent (azlocillin,

piperacillin, aztreonam, ciprofloxacin)

Colistin plus Ceftazidime vs. P.aeruginosa

Colistin plus Imipenem vs. Acinetobacter

Colistin plus Trimethoprim-Sulfamethoxazole

vs. S. maltophilia (in vitro)

Colistin plus Rifampin vs. P.aeruginosa &

Acinetobacter spp.

Colistin + rifampicin: in vivo

better outcome!

Control

Colistin

Rifampicin

Both agents

Pantopoulou A et al. Int J Antimicrob Agents. 2007;29(1):51-5

Why Colistin plus Rifampin ?

Two-steps, sequential mechanism of action

Colistin disrupt the outer bacterial

cytoplasmic membrane

Rifampin inhibit DNA-dependent RNA-

polymerase at the ribosomal -subunit

Some preliminary experience on A.

baumannii

Multi-drug resistance was defined as resistance of the isolate to anti-pseudomonal penicillins, cephalosporins, carbapenems, quinolones and aminoglycosides.

All the patients were treated with colistin sulphomethate sodium (Bellon; Rhone-Poulenc Rorer, France) administered intravenously at the dosage of 6 million units (100 000 U/kg) divided into three doses associated with intravenous rifampicin (10 mg/kg every 12 h).

Clinical characteristics and outcome

The mean duration of treatment with intravenous

colistin and rifampicin was 17.7 (+10.4) days (range 7–36).

Clinical and microbiological responses were observed in 22 of 29 cases (76%)

Overall infection-related mortality was 21% (6/29).

Three of the 29 evaluated patients (10%) developed nephrotoxicity when treated with colistin, all of whom had previous renal failure. No cases of renal failure were observed among patients with normal baseline renal function.

Mero and colistin alone and combo for

MDR A. baumannii in a PK/PD model

Objective of this study was to evaluate CST and continuous infusion

(CI) meropenem (MEM) alone and in combination against MDR A.

baumannii

All isolates were susceptible to CST (MICs ranged 0.5-1 mcg/mL) but

resistant to MEM (MICs ranged 32-128 mcg/mL).

In the PK-PD model, CI MEM (3g and 6g) alone was unable to reach

bactericidal activity for any isolate. While CST alone reached

bactericidal activity within 4 hrs for all isolates, CST was unable to

maintain this activity for the entire 24 hrs.

The combination of CST plus CI MEM 3g demonstrated synergy but still

allowed regrowth to occur by 24 hrs.

However the combination of CST plus CI MEM 6g demonstrated

both synergy and bactericidal activity over the entire 24 hrs for all

isolates.

SRISUPHA-OLARN W et al. 50th ICAAC, 2010

Multivariate analysis of factors associated with death

among patients with bloodstream infection due to KPC

producing Klebsiella Pneumoniae.

Shock - - 0.008 7.17 (1.65-31.03)

Inadequate initial treatment - - 0.003 4.17 (1.61-10.76)

APACHE III score (mean ± SD) - - <0.001 1.04 (1.02-1.07)

Tigecycline & Colistin & Meropenem - - 0.01 0.11 (0.02-0.69)

Colistin IV plus aerosolized

versus IV alone in MDR VAP

Kofteridis DP et al. Clin Infect Dis 2010; 51:1238–44

NO BENEFIT!!!

Toxicity of colistin

Main reported toxicities

- nephrotoxicity –

- neurotoxicity – paresthesia, dizziness, ataxia,

confusion,

- neuromuscular blockade

Dose dependent and usually reversible

Potentiated by other nephrotoxic drugs (eg

aminoglycosides)

Reported recent incidence less than in older studies

Safety and effectiveness of colistin compared

with tobramycin for MDR A. baumannii infections

There were no significant differences between the

colistin and tobramycin groups in

- ICU mortality (p = 0.54)

- Nephrotoxicity (p = 0.67)

- Change in creatinine from baseline to highest

subsequent value (p = 0.11)

- Time to microbiological clearance (p = 0.75)

Gounden R et al. BMC Infect Dis 2009; 9;9:26.

Colistin use in critically ill patients:

renal toxicity? n=71;

nephrotoxicity

31 (53.5%)

Feature Median (IQR) or N (%)

Cumulative CMS dosage at AKI onset (mg/kg) 41.6 (18.9–72.3)

AKI Risk onset after CMS treatment (days) 7.5 (5–15.3)

CMS dosage (mg/kg/days) 5.5 (2.5-9.6)

Kwon et al. Int J Antimicrob Agents. 2010;35:473-7

Elias et al. J Antimicrob Chemother. 2010;65:2231-7

confounding variable concomitant use of other nephrotoxic drugs

Colistin nephrotoxicity:

systematic review

Florescu D et al. Clin Infect Dis 2012;54:670e80

Results of clinical studies assessing intravenous

colistimethate sodium (CMS): renal failure

Yahav D et al. Clin Microbiol Infect 2012; 18: 18–29

Conclusions

Few data

Loading dose

Higher dose

Combination (rifampin, tigecycline, HD

meropenem)

No clear advantages of IV + aerosol

Long treatment can select resistance

Acceptable nephrotoxicity