1. Tratamiento de las enterobacterias productoras de carbapenemasas George L. Daikos, MD University of Athens School of Medicine Gabriel Levy Hara, MD Buenos Aires, Argentina Chair ISC Antimicrobial Stewardship Working Group

2. Carbapenemase Producing Enterobacteriaceae (CPE). A major Public Health Threat Increased mortality (30%-70%) Limited treatment options High potential for spread 2

3. Global Distribution of Carbapenemases KPCMBL

4. Canton, et al. Clin Microbiol Infect 2012;18:413 Distribution of Carbapenemases in Europe R Canton Clin Microbiol Infect 2012; 18: 413–431

5. Current Trends in Epidemiology of CPEs Hospital setting Predominant bacterial host – K. pneumoniae Predominant enzymes – KPC – VIM – NDM – OXA-48 Community setting Predominant bacterial host – E. coli Predominant enzymes – NDM – OXA-48

6. Factors Associated with CPE Colonization/infection Stay in ICU Poor functional status of the host Prior use of antibiotics Prolonged length of stay Sharing a room with a known carrier Increased prevalence of carriers on the ward

7. CPE Colonization Median carriage time 3 months 10% of CPE colonized patients progress to infection. In the presence of severe immunosuppression this subset may be as high as 30% During carriage, shedding and transmission to other patients may take place Transmission of mobile genetic elements containing the carbapenamase gene to other strains colonizing the GIT may occur, resulting in new CPE clones and species Saidel-Odes et al Infect Control Hosp Epidemiol 2012; 33: 14–19 Borer A et al Am J Infect Control 2011 Schechner V et al Clinical Microbiology Infection 2012

8. Antibióticos con actividad in Vitro frente a las CPE Aztreonam (MBL in the absence of ESBL) Carbapenems Gentamicin (aac 6’) Colistin Tigecycline Fosfomycin

9. Distribution of Colistin MICs for 317 K. pneumoniae Blood Isolates

10. Distribution of Tigecycline MICs for 317 K. pneumoniae Blood Isolates

11. COLISTINA ATB polipeptídico utilizado originalmente en los ´60s, y reintroducido por necesidad (más que por placer…) Se administra como colistinmetansulfato (CMS), prodroga inactiva y menos tóxica, que se convierte en colistina. Potente bactericida, actividad concentración dependiente. Susceptibilidad in vitro de las polimixinas frente a aislamientos clínicos de enterobacterias productoras de carbapenemasas: 80 a 100%. Pocos estudios de PK/PD, en especial en ptes críticos.

12. COLISTINA Administración simultánea de otros ATB en 70-100% de los pacientes Eficacia también muy variable:  Desde solo un 15-75% para Enterobacteriaceae productoras de carbapenemasas (EPC): < sobrevida con monoterapia!  …hasta un 60-80% para P.aeruginosa y Acinetobacter spp. Qureshi ZA. Antimicrob Agents Chemother 2012; 56:2108-13. Daikos GL. Antimicrob Agents Chemother 2009; 53:1868-73.

13. Por qué eficacia inferior de la colistina? Regímenes subóptimos. Un análisis de sobrevida mostró que la dosis diaria total menor aumenta la mortalidad (Falagas et al. Int. J. Antimicrob. Agents 2010; 35:194 – 199. Necesidad de dosis de carga Plachouras et al. Antimicrob. Agents Chemother. 2009; 53:3430 – 3436 Optimizar dosis subsiguientes Dos o tres veces al día?

14. Estudios recientes PK/PD colistina 100 mg colistin sulfato base= 240 mg colistinmetansulfonato (CMS) = 3 MUI colistina 150 mg CBA = 400 mg CMS = 5 MUI colistin

16. Modelo predictivo de concentraciones séricas con diferentes dosificaciones de colistin methanesulfonate (CMS) Plachouras et al Antimicrob Agents Chemother 2009

17. Estudios recientes PK/PD colistina 100 mg colistin sulfato= 240 mg CMS = 3 MUI colistin 150 mg CBA = 400 mg CMS = 5 MUI colistin

18. Steady-state plasma concentration-time profiles of the prodrug CMS (A) or formed colistin (B) in 105 critically ill patients (89 not on renal replacement, 12 on intermittent HD, and 4 on CRRT). Garonzik S M et al. Antimicrob. Agents Chemother. 2011;55:3284-3294

19. Relationship between the “ideal” maintenance dose of CMS (expressed as mg per day of colistin base activity [CBA] per each 1.0 mg/liter of colistin Css,avg target) and creatinine clearance in 101 critically ill patients (89 not on renal replacement and 12 on HD). Garonzik S M et al. Antimicrob. Agents Chemother. 2011;55:3284-3294

20. Dosis actuales máximas de 300 mg/día de colistin base suelen ser subóptimas, generando concentraciones plasmáticas debajo de los puntos de corte (2 mg/l) durante las primeras administraciones. La variabilidad entre pacientes fue muy alta (± 20 veces) en pacientes típicos.

21. PolymixinsResults Conclusion WORLDWIDE COLISTIN AND POLYMIXIN USAGE, THE "LAST" GRAM-NEGATIVE ANTIBIOTICS RESULTS FROM AN ONLINE GLOBAL SURVEY Heiman F. L. Wertheim 1, Nguyen Van Kinh 2, Gabriel Levy Hara 3, Ramanan Laxminarayam 4, Otto Cars 5 1 Oxford University Clinical Research Unit, Vietnam, 2 National Hospital for Tropical Diseases, Vietnam 3 International Society Chemotherapy, 4 Global Antibiotic Resistance Partnership, USA, 5 ReAct, Action Contact: heiman.wertheim@gmail.com Figure 1. Worldmap with location of respondents. The map includes information on availibility of colistin and whether the respondent uses a colistin loading dose. Background Colistin belongs together with polymixin B to the polymyxin antibiotic group. Colistin was isolated from the bacterium Bacillus polymyxa var. colistinus in 1949 and was used in patients for the first time in 1959. Colistin is a bactericidal antibiotic with a broad Gram-negative spectrum. Due to the drug’s side effects and the availability of newer antibiotics, colistin has been used rarely until recently. Since the emergence of multi drug resistant Gram-negative infections, colistin is being used more commonly. However, it is unclear what the optimal dosage is for colistin and what drug combinations are optimal. Therefore, it is relevant to know how colistin is being used worldwide regarding indications and dosage. Methods A structured online questionnaire was developed at Free Online Survey website consisting of 24 questions covering the background of the respondent and his/her facility, indications and dosage of colistin use for adult patients. Various networks of groups working on infectious diseases were invited to complete the questionnaire. The survey was open from June to November 2011. Data were analysed using SPSS 15.0 software using descriptive statistics as appropriate. Results The survey was completed by 284 respondents from 56 countries from all continents. 12/56 (21.4%) countries had no access to colistin and 58/284 (20.4%) of the respondents stated that in the preceding year they could not treat patients with polymixin due to unavailibility of the drug. The majority of the respondents used used colisthimethate sodium (48.6%), followed by colistin sulfate (14.1%), both forms of colistin (1.4%), polymyxin B (1.4%). 84.2% of the respondents used intravenous formulation, 44.4% aerosolized or nebulized colistin, and 12.7% used oral colistin for selective gut decontamination. Common indications for intravenous colistin use were ventilator associated pneumonia, sepsis and catheter related infections with multi-drug resistant Gram-negative bacteria. Only 21.2% of respondents used a colistin loading dose, and mainly in Europe and North America. None of the Asian respondents used a colistin loading dose. Most of those that used a loading dose reported that it did not lead to an increase in side effects. Conclusion Colistin is variably used in different settings. As poor dosing may lead to colistin resistant infections, clear guidance need to be provided how dosing should be done and which antibiotic combinations are appropriate. Colistin/polymyxin should be considered a last resort drug and its use needs to be strictly controlled. It is recommended not to use colistin in agriculture. Results Polymyxin antibiotic group contains the following antibiotics: Colistin (Polymixin E) Polymixin B Colistin was isolated from Bacillus polymyxa var. colistinus in 1949 and used in patient care since 1959. Polymixins are bactericidal antibiotic by disrupting outer cell membrane of Gram-negative bacteria, leading to leakage of bacterial cell contents, and eventually death. Due to increasing multi drug resistant infections, colistin is being used more often. As there are several formulations available with different concentrations, dosing of patients is confusing. A loading dose of colistin is recommended based on recent Pk/Pd studies. However, it is unknown whether this recommendation is actually implemented around the world. To adress the issues we conducted an online global survey. Based on the results of this survey we believe it is wise to develop and disseminate a clear guideline for colistin use with the current knowledge we have. Many questions regarding dosing remain and studies are under way to have these answered. However, there is a lot of room of improvement already which can be done now. The different colistin drug formulations that are available lead to confusion and inappropriate use. A guideline will aid doctors and pharmacists around the world on proper usage and hopefully reduce the anxiety of drug toxicity. As new classes of antibiotics for Gram-negative bacteria are not within sight we need to preserve these last resort antibiotics at all costs. A ban on its use in agriculture is recommended. 284 respondendts from 56 countries (all continents represented) 12/56 (21.4%) countries had no access to colistin 58/284 (20.4%) of the respondents stated that in the preceding year they could not treat patients with polymixin due to unavailibility of the drug. VAP was the most common indication for polymixin use and Acinetobacter baumannii the most common targeted pathogen. Loading dose was done by 21.2% of the respondents and they reported that this generally did not lead to an increase in side effects (Figure 1). Colistin was most commonly combined with a carbapenem The survey revealed that underdosing likely occurs at several sites across the world, risking resistance development to this last resort Gram-negative drug. A clinical trial that studies the optimal dosing regimen of polymixins and best drug combination is needed.

22. Encuesta mundial sobre uso de colistina 284 respuestas de 56 países (todos los continentes) 12/56 (21.4%) países sin acceso a la colistina. 58/284 (20.4%) tuvieron problemas de disponibilidad durante el año previo. Indicación más frecuente: NAV Principal patógeno blanco: Acinetobacter baumannii

23. Encuesta mundial sobre uso de colistina 21.2% utiliza dosis de carga, en general no asociadas a aumento de toxicidad! Combinación más frecuente con carbapenemes. Se utilizan dosis sub-óptimas en muchos lugares del mundo, con el riesgo asociado de resistencia en este último refugio…

24. Tigeciclina Muchos estudios muestran demora en eliminación bacteriana, recurrencia y necesidad de administración prolongada. Niveles plasmáticos inadecuados con las dosis actualmente recomendadas (50 mg c/12 hs). Pico sérico varía entre 0.6 to 0.9 mg/l, y los niveles en orina y fluido epitelial son aún menores. La distribución de CIM varía entre 1 and 2 mg/L para la mayoría de las K.pneumoniae productoras de KPC, lo que explicaría su pobre eficacia como monoterapia en infecciones serias. Resistencia creciente en muchas regiones del mundo Kelesidis T. J Antimicrob Chemother 2008; 62: 895- 904. Anthony KB. Clin Infect Dis 2008; 46:567- 570

25. Tigeciclina Alerta reciente de la FDA aconseja utilizar alternativas en casos de infecciones severas. Análisis de datos agrupados provenientes de estudios comparativos para diferentes indicaciones, que mostraron un aumento de la mortalidad global en pacientes que recibieron tigeciclina FDA Drug Safety Communication: Increased Risk of Death with Tygacil (Tigecycline) Compared to Other Antibiotics Used to Treat Similar Infections. http://www.fda.gov/Drugs/DrugSafety/ucm224370.htm http://www.fda.gov/Drugs/DrugSafety/ucm224370.htm

26. Tigeciclina Sin embargo, un estudio prospectivo reciente con más de 1000 pacientes (en general infecciones abdominales complicadas o de piel y partes blandas) no mostró un aumento en la mortalidad Las respuestas clínicas fueron satisfactorias y la droga fue bien tolerada Bodmann KF et al. Therapy of 1,025 severely ill patients with complicated infections in a German Multicenter Study: Safety profile and efficacy of tigecycline in different treatment modalities. Chemotherapy 2012; 58:282-294.

27. Aminoglucósidos en EPC La resistencia a aminoglucósidos está aumentando entre las EPC. En cepas susceptibles, datos in vivo mostraron una rápida actividad bactericida de gentamicina. Cuando el patógeno es sensible a aminoglucósidos, constituyen una importante opción terapéutica en asociación siempre con otros ATB efectivos in vitro.

28. Fosfomicina Derivado natural del ácido fosfónico que inhibe la biosíntesis de la pared celular en un estadio más temprano que los β-lactámicos. Actividad in vitro frente a Enterobacteriaceae productoras de BLEE (incluyendo K. pneumoniae resistentes a carbapenems). Mayoría de estudios y experiencias en ITUs. Potencial emergencia de resistencia intra-tratamiento. Se recomienda utilizar fosfomicina en combinación con otros antibióticos para el tratamiento de EPC, con el fin de procurar evitar la aparición de resistencia.

29. Fosfomicina 68 aislamientos de K pneumoniae KPC positivas, 23 de ellas resistentes a TYG y a COL La sensibilidad a fosfomicina fue del 93%. Eran sensibles el 87% de las cepas resistentes a TYG o COL, y el 83% de las resistentes a ambas. Endimiani A et al. Antimicrob Agents Chemother 2010;54:526-529.

30. New CLSI and EUCAST Breakpoints for Enterobactericeae CLSIEUCAST S (≤)R (≥)S (≤)R (≥) Imipenem1428 Meropenem1428 Doripenem1414 Ertapenem0.52 1

31. Distribution of Meropenem MICs for 372 Consecutive Kp Bloodstream Isolates

34. PK/PD de tres regímenes diferentes de meropenem

35. PK/PD del meropenem según CIM Las probabilidades de alcanzar 50% del T>CIM para un aislamiento con CIM de 4 mg/L es 69% con el régimen tradicional (1 g c/8 hs en infusión de 30’) Aumenta al 100% en regímenes de dosis altas en infusión prolongada (2 g c/8 hs durante 3 hs) Aún para CIM de 8 mg/L, este último régimen tiene cerca de un 85% de probabilidad de alcanzar actividad bactericida.

36. PK/PD de tres regímenes diferentes de meropenem

37. Tzouvelekis LS, Markogiannakis AM, Psichogiou PT et al. Carbapenemases in Klebsiella pneumoniae and other Enterobacteriaceae: an evolving crisis of global dimensions. Clin Microbiol Rev 2012; 25: 682-707

38. A systematic search of MEDLINE and compiled 34 studies containing the necessary information to estimate the efficacy of different antimicrobials in relation to their MICs for the infecting organisms. A total of 301 patients were identified, 161 infected with KPC- and 140 with MBL-producing K. pneumoniae.

39. Outcomes of 298 infections* caused by carbapenemase- producing Klebsiella pneumoniae. 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 Tzouvelekis, et al. CMR 2012; 25: 682

40. Carbapenem Monotherapy in 50 Patients with Serious CPE Infections (Results compiled from 15 studies) MIC (μg/ml) No. of patients No. of successes No. of failures% failure ≤ 11712529.4 2129325 475228.6 864233.3 > 882675 Tzouvelekis et al CMR 2012; 25: 682-707

41. i Tumbarello M et al. Clin Infect Dis. 2012;55:943-950 Kaplan Meier Curves of Survival Probability in 125 Patients with KPC BSIs According to Treatment P=0.002

42. Multivariate Analysis of Factors Associated with all- cause 30-day Mortality of Patients with KPC BSIs VariablePOR(95% CI) Septic shock0.0087.17 (1.65-31.03 APACHE<0.0011.04 (1.02-1.07) Inadequate empirical Rx 0.0034.17 (1.61-10.76) Definitive Rx Col+tigecl+merop 0.010.11 (0.02-0.69) Tumbarello M et al. CID 2012; 55: 943

43. En infecciones por K. pneumoniae con CIM ≤4 mg/L, la inclusión de meropenem en combinaciones mostró sobrevida del 86.6%. Aún en casos de CIMs mayores, estas combinaciones alcanzaron una sobrevida del 75%.

45. Experts belonging to Argentinean Society of Infectious Diseases (SADI), International Society of Chemotherapy (ISC) Antimicrobial Resistance Working Group, Pan American Association of Infectious Diseases (API), Pan American Health Organization/World Health Organization (PAHO/WHO), Infection Control African Network (ICAN), Mediterranean Society of Chemotherapy (MSC) Federation of European Societies for Chemotherapy and for Infections (FESCI).

48. Muchas gracias por su atención!!!