A Snapshot

of Colistin Use

in South-East Europe and

Particularly in Greece

Helen Giamarellou 02.05.2013

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When Greek Physicians Prescribe Colistin?

It is mainly prescribed in the ICU for VAP, bacteremia and FUO when:

There is confirmed in vitro resistance almost to all other available antibiotics including carbapenems, i.e. XDR strains of K. pneumoniae,

A. baumannii, P. aeruginosa

Empirically in critically ill patients if:

1. Extensively drug-resistant (XDR), or even pandrug-resistant (PDR)

gram-negative bacteria predominate as pathogens

2. Routinely performed surveillance cultures are already positive for XDR gram-negatives Not

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Colistin as Monotherapy

or in Combination?

-Europe- Greece

Santa Maria Delle Carceri church-Prato

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Greece: The Largest Cohort Study

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Analysis of Colistin Therapy for MDRa Gram-negative Infections: A Greek Retrospective Cohort Study

(Oct 2000 – Oct 2007)

No of patients 258

ICU patients 222 (86%)

APACHE II (x) 17 (2-39)

Pneumonia 155 (60%)

Bacteremia 33 (13%)

Demographic Data

Polymyxin only susceptible 135 (52.3%)

Duration of hospital or ICU stay until colistin administration (x)

18.3 versus 11.4 days

Duration of colistin administration (x) 17.9 (10-22 days)

Falagas ME, et al. IJAA 2010;35:194 a Susceptible to colistin and at least one other antibiotic

Greece

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A Greek Study: Retrospective Analysis of Colistin Therapy

for MDR Gram-negative infections

Acinetobacter baumannii 170 (65.9%)

Pseudomonas aeruginosa 68 (26.4%)

Klebsiella pneumoniae 18 (7.0%)

Polymyxin only susceptible (XDR) 135 (52.3%)

Pathogens

Falagas ME, et al. IJAA 2010;35:194

Cure of infection 79.1%

Cure of infection in XDR pathogens 78%

Hospital survival 65.1%

Nephrotoxicity 10.4%

Results of therapy

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Colistin: Monotherapy versus Combination Therapy

83% 83%

65%

75%

61%

17% 17%

35%

25%

39%

0

10

20

30

40

50

60

70

80

90

100

COLI MONO (36) COLI+MERO (162) COLI+PIP/TAZO (17) COLI+AMP/SULB

(12)

COLI+OTHER (31)

Pe

rce

nta

ge

CURE DETERIORATION

Falagas et al, Int J Antimicrob Agents 2010

* *

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The findings of the largest cohort study to date on IV colistin

show that colistin at least in ICU patients with A. baumannii or

P. aeruginosa infections is a valuable antibiotic with acceptable

nephrotoxicity and considerable effectiveness similar to that of

3rd gen Cephs and Carbapenems, that depends on the daily

dosage and infection site.

Falagas ME, et al. IJAA 2010; 35: 194

Conclusion:

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• In life-threatening XDR Acinetobacter infections (VAP,

HAP, BSI, cIAI) in 210 ICU patients, 30-day mortality was

not reduced by the addition of rifampicin to colistin (43%)

• Combination treatment with Rifampicin did only increase

the rate of Acinetobacter eradication (p=0.034)

I t a l y

Durante-Mangoni E et al.Clin Infect Dis. 2013 Not

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The combination of colistin with rifampicin in 43 pts improved clinical, radiological and microbiological

outcomes of VAP patients infected with A. baumannii

(p=NS).

Time to microbiological clearance shorter in

combination (3.1 ± 0.5 d, p=0.029)

Mortality: 63.6% vs. 38.1% (p=0.171)

Aydemiz H, et al. Epidemiol Infect 2012

Tu r ke y

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Mortality Rates According to Treatment Regimens

0

5

10

15

20

25

30

2 Active Drugs One Active Drug No Active Drug

Mo

rtal

ity

Rat

e %

GL Daikos, et al. Antimicrob Agents Chemother 2009;53:1868

*

*

* Meropenem MIC ≤4μg/ml plus genta or colistin

G r e e c e

Prospective Observational Study of K. pneumoniae Bloodstream Infections

67 patients VIM positive

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In vitro Synergy of Colistin and Meropenem

Colistin Synergism

Νο. of Isolates %

Susceptible 12/24 50%

Resistant 2/18 11%

Souli M, et al. Antimicrob Agents Chemother 2009; 53: 2133-35

G r e e c e

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Review of Clinical Studies with Carbapenemase Producing Klebsiella pneumoniae

34 studies were compiled after a systemic search of MEPLINE was performed

298 patients

161 infected with KPC(+) strains

140 with MBL(+) strains

244 blood stream infections

32 pneumonia

242 (81.1%) patients received appropriate therapy: at least one drug to which the infecting organism was susceptible in vitro

56 (18.9%) patients received inappropriate therapy: no drug to which the infecting organism was susceptible in vitro

Daikos GL, et al. Clin Microbiol Rev 2012; 25: 682

E u r o p e 2 0 1 1 *

* mostly

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Outcome of 294 infections* caused by carbapenemase-producing Klebsiella pneumoniae according to treatment regimen.

A B C D E F G

0

20

40

60

N=36

N=62

N=21

N=36

N=72

N=56

N=14

Treatment regimen

Failu

re (

%)

• Regimen A: combination therapy with 2 active drugs one of which was a carbapenem with MIC ≤4μg/ml; 8.3%**

• Regimen B: combination therapy with 2 active drugs not including a carbapenem; 29%

• Regimen C: monotherapy with an aminoglycoside; 24%

• Regimen D: monotherapy with a carbapenem (MIC ≤4μg/ml); 25%

• Regimen E: monotherapy with tigecycline; 35.7%

• Regimen F: monotherapy with colistin; 47.2%

• Regimen G: inappropriate therapy. 54%

*70% bacteremias, 20% VAP+HAP

A vs B p=0.02

A vs E p=0.03

A vs F p<0.0001

A vs G p<0.0001

B vs G p=0.014

C vs G p=0.04

D vs G p=0.03

** Failure rate

Daikos GL, et al. Clin Microbiol Rev 2012; 25: 682

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Carbapenemase-producing Klebsiella pneumoniae: To Treat or Not to Treat with a Carbapenem?

Carbapenem monotherapy (imipenem, meropenem, doripenem) for strains with MIC >4μg/ml should be prohibited, whereas for strains with lower MICs (≤4μg/ml) better to be avoided.

Meropenem may be a reasonable treatment option against carbapenemase producing K. pneumoniae, provided that:

i. Based on PK/PDs MIC MIC of the infecting organism is ≤4mg/L (even 8μg/ml)

ii. Carbapenem is given in combination with another active compound, i.e. colistin, tigecycline, aminoglycoside

iii. Carbapenem is given in high dose and prolonged infusions (3-4 hours)

Daikos GL, Markogiannis A. CMI 2011;17:1135

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Proposed Algorithm for the Treatment of Carbapemenase producing Enterobacteriaceae Infections

Daikos GL. Expert Review Anti-infective Therapy (December 2013)

MIC of Carbapenems

>4 mg/L ≤4 mg/L

AMG susceptible AMG resistance

CARB + AMG COL susceptible

COL resistance

CARB + COL CARB + Other AA

AMG susceptible

AMG resistance

AMG + Other AA

COL susceptible

COL resistance

COL + Other AA

Combination of Other AAs

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• 125 patients with bloodstream infections caused by KPC-producing Klebsiella pneumoniae isolates diagnosed between 1 January 2010 and 30 June 2011

Mortality at 30-d

Monotherapy 54.3% P=0.02

Combination 34.1%

Tumbarello M, et al. CID 2012; 55: 943

I ta l y

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Tumbarello et al. CID 2012; 55: 943

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Variable P Value OR (95% CI)

Presentation with septic shock .008 7.17 (1.65-31.03)

Inadequate initial antimicrobial treatment .003 4.17 (1.61-10.76)

High APACHE III score <.001 1.04 (1.02-1.07)

Postantibiogram therapy with tigecycline + colistin + meropenem

.01 0.11 (.02-.69)

Multivariate Analysis of Risk Factors for Mortality in Patients with Bloodstream Infection Caused by Klebsiella pneumoniae

Carbapenemase-Producing K. pneumoniae

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What Dosing Regimens

of Colistin are Typically

Used?

-Europe- Greece

Pretorium Palace-Prato

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Just to remember…

• Common Dosage Schedule in Europe: 1-3 mil units/ 8 hourly IV

Colistin (Polymyxin E) in vials containing 1 million units correspond to 80mg of CMS

1mg CMS = 12,500 units CMS

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Retrospective Analysis of Colistin Therapy of 258 MDR and XDR Gram-negative Infections:

1. Multivariate analysis: Higher daily colistin dose was

associated with increased probability of survival

(p=0.009)

Falagas ME, et al. IJAA 2010;35:194

• 38.6%

3mil iu/daily:

• 27.8%

6mil iu/daily:

• 21.7%

9mil iu/daily:

2. Mortality rate in univariate analysis:

G r e e c e 2 0 0 0 - 2 0 0 7

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The Delay in Early Attaining Efficacious Colistin Concentrations with the

Standard Treatment Regimen of Colistin

Another Greek Explanation for the Inferior Efficacy of Colistin as Monotherapy

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Greece 2009

• Slower formation of Colistin by CMS than previously described

• Longer Colistin half-life: 14.4h

• Sub-therapeutic concentrations (0.6μg/ml), after 3MU every

8 hours, during the first day, that may lead to:

• Treatment failures

• Emergence of resistance

Plachouras D et al. AAC 2009;53:3430

Population Pharmacokinetic Analysis of Colistin after

Intravenous Administration in Critically Ill Patients with

Infections Caused by Gram-Negative Bacteria

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The administration of a loading dose of 6 MU CMS resulted in colistin plasma concentrations above 1mg/L within 4 hours in the majority of the patients.

Mohamed et al. AAC 2012; 65: 4241 Friberg LE et al ICAAC 2010

Application of a loading dose of 6 MU CMS in critically ill patients

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Suggested Colistin Dosing for Various Patients Category Applied in Greece since the last 6-12 months

Targeting peak blood level of 2μg/ml in all patient category

9 MU Loading Dose

M a i n t e n a n c e d o s e

Normal renal function 4.5 MU every 12h Titrated in renal insufficiency (Clcr devided by 10) + 2 given in 2-3 doses S.O.S. The 1st dose should be given 24h post loading dose

In Hemodialysis 2 MU in two daily doses S.O.S. On the day of hemodialysis 30% of the daily dose should be given post hemodialysis

In continuous hemofiltration 9 MU in two or three daily doses

Garonzik SM, et al. AAC 2011;55:3284 Placouras D, et al. AAC 2009;53:3430

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1. Adaptive resistance to the “last hope” antibiotics polymyxin B and colistin in Pseudomonas aeruginosa is mediated by a novel two-component regulatory system ParR-ParS.

2. Does the fact of “Adaptive Resistance” indicate as appropriate single-daily dose administration of Colistin as in the aminoglycoside case?

Skiada et al. IJAA 2011; 37: 187 Not to

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• 28 critically ill pts with severe sepsis or septic shock suffering from

bloodstream infections (64.3%) and VAP (35.7%) caused by A. baumannii

(46.4%), K. pneumoniae (46.4%), and P. aeruginosa (7.2%)

• The CMS dosing schedule was based on a loading dose of 9 MU and a 9-

MU twice-daily fractioned maintenance dose for median duration of 12

(10-17) d, titrated on renal function

• Clinical cure was observed in 23 cases (82.1%)

• Acute kidney injury developed in 17.8% (revisible)

• Conclusion: the study showed that in severe infections, the high dose

extended interval CMS regimen has high efficacy, without significant renal

toxicity. Dalfino L, et al. CID 2012; 54: 1720

A Preliminary Study: Italy 2012

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Risk Factors of Nephrotoxicity

Co-administration of other nephrotoxic agents

(aminoglycosides, diuretics)

Mode of administration (8 vs 24 hourly)?

Daily dose?

Length of therapy?

Nephrotoxicity after colistin discontinuation is self-limited

Nephrotoxicity range: 33% - 55%

Safety of polymyxins

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Emergence

of Colistin Resistance

-Europe- Greece

Villa san Leonardo al Palco-Prato

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G r e e c e , 2 0 0 4 - 2 0 0 5

*

* KPC-2 producers Not to

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41 patients with Klebsiella, Acinetobacter and

Pseudomonas infections

In the multivariable model, use of colistin >14 days

was identified as the only independent risk factor

(p=.002) for resistance development to colistin

Crit Care Med 2008; 36: 807

G r e e c e

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Colonization and Infection by Colistin Resistant Gram Negative Bacteria in a Cohort of Critically Ill Patients in Greece

Among 150 ICU patients:

52% were colonized with Colistin-R Gram-negatives:

20% with K. pneumoniae and 34% by Colistin-R Proteus spp. and Serratia spp.

25% developed infections

All cause mortality: 75%

The main risk factor was duration of colistin pretherapy (>20d)

Kontopidou F, et al. CMI 2011; 17: E9

G r e e c e 2 0 0 6

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JAC 2011; 66: 946

In Addition to Heteroresistance in MDR Acinetobacter baumannii strains described from Australia and USA…

G r e e c e 2 0 0 9

12 heteroresistant strains with MICs: 8-64 μg/ml Not to

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Antibiotic MIC (μg/ml) Susceptibility

MIC50 MIC90 Min. Max. %S %I %R

Cefepime 4 >16 ≤0.5 >16 74 16 10

Ceftazidime 4 >16 ≤0.5 >16 73 9.2 18

Colistin 1 4 ≤0.12 >4 89 9.6 1.2

Gentamicin 1 >8 ≤0.25 >8 76 2.6 21

Imipenem 2 16 ≤0.03 >32 73 3 24

Levofloxacin 2 >4 ≤0.25 >4 58 7.6 34

Meropenem 0.5 8 ≤0.03 >32 81 9.6 9

Piperacillin/ tazobactam

8 >64 ≤0.5 >64 81 0 19

Haeser S. IJAA 2011; 37: 580

2 0 0 7 - 2 0 0 9 E u r o p e a n d U S A

Breakpoint: 4 μg/ml

However…

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1. Mostly in ICU patients

2. Monotherapy for Acinetobacter baumannii and Pseudomonas aeruginosa

3. Combinations for carbapenemase producing Klebsiella pneumoniae

4. Loading dose!

5. Self-limited rather low nephrotoxicity

6. Resistance development in Klebsiella in connection with duration of therapy and increase in the amount of colistin use in the hospital setting Not

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