Colistin: how to use it? Matteo Bassetti, MD, PhD Infectious Diseases Division Santa Maria Misericordia University Hospital Udine, Italy
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