A Snapshot of Colistin Use in South-East Europe and Particularly in Greece

Transcription

1 A Snapshot of Colistin Use in South-East Europe and Particularly in Greece Helen Giamarellou

2 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

3 Santa Maria Delle Carceri church- Prato -Europe- Greece Colistin as Monotherapy or in Combination?

4 Greece: The Largest Cohort Study

5 Analysis of Colistin Therapy for MDR a Gram-negative Infections: A Greek Retrospective Cohort Study (Oct 2000 Oct 2007) Demographic Data No of patients 258 ICU patients 222 (86%) APACHE II (x) 17 (2-39) Pneumonia 155 (60%) Bacteremia 33 (13%) Polymyxin only susceptible 135 (52.3%) Duration of hospital or ICU stay until colistin administration (x) Duration of colistin administration (x) 18.3 versus 11.4 days 17.9 (10-22 days) a Susceptible to colistin and at least one other antibiotic Greece Falagas ME, et al. IJAA 2010;35:194

6 A Greek Study: Retrospective Analysis of Colistin Therapy for MDR Gram-negative infections Pathogens Acinetobacter baumannii 170 (65.9%) Pseudomonas aeruginosa 68 (26.4%) Klebsiella pneumoniae 18 (7.0%) Polymyxin only susceptible (XDR) 135 (52.3%) Results of therapy Cure of infection 79.1% Cure of infection in XDR pathogens 78% Hospital survival 65.1% Nephrotoxicity 10.4% Falagas ME, et al. IJAA 2010;35:194

7 Percentage Colistin: Monotherapy versus * Combination Therapy 83% 83% * 17% 17% 65% 35% 75% 61% 39% 25% COLI MONO (36) COLI+MERO (162) COLI+PIP/TAZO (17) COLI+AMP/SULB COLI+OTHER (31) (12) CURE DETERIORATION Falagas et al, Int J Antimicrob Agents 2010

8 Conclusion: 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 3 rd gen Cephs and Carbapenems, that depends on the daily dosage and infection site. Falagas ME, et al. IJAA 2010; 35: 194

9 I t a l y 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) Durante-Mangoni E et al.clin Infect Dis. 2013

10 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) Tu r ke y Aydemiz H, et al. Epidemiol Infect 2012

11 Mortality Rates According to Treatment Regimens Mortality Rate % Prospective Observational Study of K. pneumoniae Bloodstream Infections * * 2 Active Drugs One Active Drug No Active Drug * Meropenem MIC 4μg/ml plus genta or colistin G r e e c e 67 patients VIM positive GL Daikos, et al. Antimicrob Agents Chemother 2009;53:1868

12 Colistin In vitro Synergy of Colistin and Meropenem Synergism Νο. of Isolates % Susceptible 12/24 50% Resistant 2/18 11% G r e e c e Souli M, et al. Antimicrob Agents Chemother 2009; 53:

13 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 * mostly E u r o p e * Daikos GL, et al. Clin Microbiol Rev 2012; 25: 682

14 Failure (%) Outcome of 294 infections* caused by carbapenemase-producing Klebsiella pneumoniae according to treatment regimen. N=36 N=62 N=21 N=36 N=14 N=72 N=56 A B C D E F G Treatment regimen *70% bacteremias, 20% VAP+HAP A vs B p=0.02 A vs E p=0.03 A vs F p< A vs G p< B vs G p=0.014 C vs G p=0.04 D vs G p=0.03 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% ** Failure rate Daikos GL, et al. Clin Microbiol Rev 2012; 25: 682

15 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. iii. Carbapenem is given in combination with another active compound, i.e. colistin, tigecycline, aminoglycoside Carbapenem is given in high dose and prolonged infusions (3-4 hours) Daikos GL, Markogiannis A. CMI 2011;17:1135

16 Proposed Algorithm for the Treatment of Carbapemenase producing Enterobacteriaceae Infections AMG susceptible CARB + AMG 4 mg/l COL susceptible MIC of Carbapenems AMG resistance COL resistance CARB + COL CARB + Other AA >4 mg/l AMG susceptible AMG + Other AA COL susceptible COL + Other AA AMG resistance COL resistance Combination of Other AAs Daikos GL. Expert Review Anti-infective Therapy (December 2013)

17 125 patients with bloodstream infections caused by KPCproducing Klebsiella pneumoniae isolates diagnosed between 1 January 2010 and 30 June 2011 Mortality at 30-d Monotherapy 54.3% Combination 34.1% P=0.02 I ta l y Tumbarello M, et al. CID 2012; 55: 943

18 Tumbarello et al. CID 2012; 55: 943

19 Multivariate Analysis of Risk Factors for Mortality in Patients with Bloodstream Infection Caused by Klebsiella pneumoniae Carbapenemase-Producing K. pneumoniae Variable P Value OR (95% CI) Presentation with septic shock ( ) Inadequate initial antimicrobial treatment ( ) High APACHE III score < ( ) Postantibiogram therapy with tigecycline + colistin + meropenem ( )

20 Pretorium Palace-Prato What Dosing Regimens of Colistin are Typically Used? -Europe- Greece

21 Just to remember Colistin (Polymyxin E) in vials containing 1 million units correspond to 80mg of CMS 1mg CMS = 12,500 units CMS Common Dosage Schedule in Europe: 1-3 mil units/ 8 hourly IV

22 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) 2. Mortality rate in univariate analysis: G r e e c e mil iu/daily: 6mil iu/daily: 9mil iu/daily: 38.6% 27.8% 21.7% Falagas ME, et al. IJAA 2010;35:194

23 Another Greek Explanation for the Inferior Efficacy of Colistin as Monotherapy The Delay in Early Attaining Efficacious Colistin Concentrations with the Standard Treatment Regimen of Colistin

24 Population Pharmacokinetic Analysis of Colistin after Intravenous Administration in Critically Ill Patients with Infections Caused by Gram-Negative Bacteria 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

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

26 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 Normal renal function In Hemodialysis In continuous hemofiltration 9 MU Loading Dose M a i n t e n a n c e d o s e 4.5 MU every 12h Titrated in renal insufficiency (Cl cr devided by 10) + 2 given in 2-3 doses S.O.S. The 1 st dose should be given 24h post loading dose 2 MU in two daily doses S.O.S. On the day of hemodialysis 30% of the daily dose should be given post hemodialysis 9 MU in two or three daily doses Garonzik SM, et al. AAC 2011;55:3284 Placouras D, et al. AAC 2009;53:3430

27 1. Adaptive resistance to the last hope antibiotics polymyxin B and colistin in Pseudomonas aeruginosa is mediated by a novel twocomponent 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

28 A Preliminary Study: Italy 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

29 Safety of polymyxins Nephrotoxicity range: 33% - 55% 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

30 Villa san Leonardo al Palco-Prato Emergence -Europe- Greece of Colistin Resistance

31 * KPC-2 producers * G r e e c e,

32 G r e e c e 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

33 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) G r e e c e 2006 Kontopidou F, et al. CMI 2011; 17: E9

34 In Addition to Heteroresistance in MDR Acinetobacter baumannii strains described from Australia and USA G r e e c e heteroresistant strains with MICs: 8-64 μg/ml JAC 2011; 66: 946

35 Antibiotic MIC (μg/ml) Susceptibility MIC 50 MIC 90 Min. Max. %S %I %R Cefepime 4 > > Ceftazidime 4 > > Colistin > Gentamicin 1 > > Imipenem > Levofloxacin 2 > > Meropenem > Piperacillin/ tazobactam However E u r o p e a n d U S A 8 > > Breakpoint: 4 μg/ml Haeser S. IJAA 2011; 37: 580

36 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