1. How to treat MDR pathogens Tobias Welte Department of Respiratory Medicine and Intensive Care Medizinische Hochschule Hannover, Germany

2. Welte – MDR Pathogens, Mar del Plata 11.10.2014

3. 20082012Grading D. Antibiotic therapy 1.a. Administration of effective iv ABs within the 1. hour of recognition of septic shock1B 1.b. Administration of effective iv ABs within the 1. hour of recognition of severe sepsis1D1C↑ 2.a. Initial empiric anti-infective therapy of one or more drugs that have activity against all likely pathogens and that penetrate in adequate concentrations into tissues presumed to be the source of sepsis 1B 2.b. Antimicrobial regimen should be reassessed daily for potential deescalation1C1B↑ 3. Use of biomarkers to assist the clinician in the discontinuation of empiric antibiotics in patients who initially appeared septic, but have no subsequent evidence of infection nn2C↑ 4.a. Combination empirical therapy for neutropenic patients with severe sepsis2D2B↑ for pts with difficult to treat, MDR bacterial pathogens f.e. Acinetobacter/Pseudomonasnn2B↑ For pts with severe infections associated with respiratory failure and septic shock, combination therapy with an extended spectrum beta-lactam and either an aminoglycoside or a fluoroquinolone is for P. aeruginosa bacteremia 2D2B↑ A combination of beta-lactam and macrolide for patients with septic shock from bacteremic Streptococcus pneumoniae infections nn2B↑ 4.B Empiric combination therapy not be for more than 3–5 days. De-escalation to the most appropriate single therapy as soon as the susceptibility profile is known 2D2B↑ 5. Duration of therapy typically 7–10 days; longer courses may be appropriate in pts with a slow clinical response, undrainable foci of infection, bacteremia with S. aureus; some fungal and viral infections or immunologic deficiencies, including neutropenia 1D2C↓ 6. Antiviral therapy initiated as early as possible in patients with severe sepsis or septic shock of viral origin nn2C↑ 7. Antimicrobial agents should not be used in patients with severe inflammatory states determined to be of noninfectious cause 1DUG↑

4. Welte – MDR Pathogens, Mar del Plata 11.10.2014 Standard Treatment gram negatives E. coli/Enterobakteriacae –Ampicillin/Inhibitor Combinations –2. and 3. Generation Cephalosporines –Ertapenem Pseudomoas aeruginosa/Acinetobacter –Piperacillin/Tazobaktam –4. Generation Cephalosporines –Carbapenemes St. maltophilia –Fluorquinolones –Cotrimoxazol

5. Welte – MDR Pathogens, Mar del Plata 11.10.2014 Pseudomoas aeruginosa Combination Therapy If combination therapy is required then combine with –+ Aminoglycosid Gentamycin/Tobramycin 6 mg/kg BW per day as a single dosage (Through Level < 2 mg/L) Amikacin 20-25 (-30) mg/kg KG BW per day as a single dosage –+ Fluorquinolones Ciprofloxacin (800-1200 mg tgl.) Levofloxacin (1000 mg tgl.)

6. Welte – MDR Pathogens, Mar del Plata 11.10.2014 Standard Treatment gram negatives E. coli/Enterobakteriacae –Ampicillin/Inhibitor Combinations –2. and 3. Generation Cephalosporines –Ertapenem Pseudomoas aeruginosa/Acinetobacter –Piperacillin/Tazobaktam –4. Generation Cephalosporines –Carbapenemes St. maltophilia –Fluorquinolones –Cotrimoxazol

7. Welte – MDR Pathogens, Mar del Plata 11.10.2014 Pseudomonas aeruginosa Combination Therapy If combination therapy is required then combine with –+ Aminoglycosid Gentamycin/Tobramycin 6 mg/kg BW per day as a single dosage (Through Level < 2 mg/L) Amikacin 20-25 (-30) mg/kg KG BW per day as a single dosage –+ Fluorquinolones Ciprofloxacin (800-1200 mg tgl.) Levofloxacin (1000 mg tgl.)

8. Welte – MDR Pathogens, Mar del Plata 11.10.2014 C52H98N16O13 Introduced into the German market in 1959 Banned from the German market due to nephrotoxicity in 1981 Approved again in 2012

9. Welte – MDR Pathogens, Mar del Plata 11.10.2014 MDR Treatment Multidrug resistant pathogenes –Carbapenemase producing Enterobacteriacae –Acinetobacter spp. –Pseudomona aeruginosa

10. Welte – MDR Pathogens, Mar del Plata 11.10.2014 Proportion of Carbapenems Resistant (R) Klebsiella pneumoniae Isolates in Participating Countries in 2012 http://www.ecdc.europa.eu/en/healthtopics/antimicrobial_resistance/http://www.ecdc.europa.eu/en/healthtopics/antimicrobial_resistance/, 19.11.13

11. Welte – MDR Pathogens, Mar del Plata 11.10.2014 Acinetobacter baumannii AntibioticMIC Amikacin4S Ciprofloxacin 44R Amoxi/clav>32R Tobramicin>16R Ampicillin>32R Tigeciclin1S Cefepime>64R Ceftazidime>64R Gentamicin>16R Imipenem>16R Levofloxacin>8R Meropenem  16R Colistin<0.5S Piperacillina/tazobacta>128R Trimetoprim/sulfa>320R

12. Welte – MDR Pathogens, Mar del Plata 11.10.2014 Lancet Infect Dis 2013; 9 Jul online 18

13. Welte – MDR Pathogens, Mar del Plata 11.10.2014 Edelmann MV. Lancet Infect Dis 2013; 9 Jul online 18

14. Welte – MDR Pathogens, Mar del Plata 11.10.2014 Attributable Mortality for Carbapenem-Resistant K. Pneumoniae (KPC) 32-patient cohort with KPC bacteremia 32 non-bacteremic KPC control patients matched for time period, comorbidities, underlying disease, age, and sex Borer A, et al. Infect Control Hosp Epidemiol. 2009;30:972-6. Study patientsControl patients Required intensive care12 (37.5%)3 (9.4%) Required ventilator support 17 (53.1%)8 (25%) Required central venous catheter 19 (59.4%)9 (28.1%) Crude Mortality Rate*23 (71.9%)7 (21.9%)  Attributable Mortality for Study Patients: 50% (95% CI, 15.3 – 98.6)  Mortality Risk Ratio for Study Patients: 3.3 (95% CI, 2.9 – 28.5) *P < 0.001

15. Welte – MDR Pathogens, Mar del Plata 11.10.2014 MDR Pathogenes – Combination Therapy Retrospective analysis of 41 blood culture positive patients with Carbapenem resistent Pseudomonas Mortality in the monotherapy group 57.8% Mortality in a combination therapy group (Carbapenem and one other antibiotic) 13.3% Mortality in a combination therapy group (Carbapenem and Tigecyclin or Colistin) 12.5% Qureshi ZA et al. AAC 2012;56:2108-13 20

16. Welte – MDR Pathogens, Mar del Plata 11.10.2014

17. Revival of „old“ drugs Colistin Combination Therapy (?) with –Colistin 9 Mill. E Loading Dose 4.5 Mill E twice daily as maintenance therapy + inhaled colistin ???

18. Welte – MDR Pathogens, Mar del Plata 11.10.2014

19. Predictors of mortality in patients with bloodstream infections caused by KPC- producing Klebsiella pneumoniae and impact of appropriate antimicrobial treatment 53 patients Overall mortality was 52.8% and infection mortality was 34% In the appropriate mortality due to infection occurred in 20% –20/20 in combination:favourable infection outcome –7/15 given appropriate monotherapy died (p 0.001). In univariate analysis, risk factors for mortality were: –age (p <0.001) –APACHE II score at admission and infection onset (p <0.001) –severe sepsis (p <0.001) Variable for survival: –appropriate antimicrobial treatment (p 0.003) –Combinations of active antimicrobials (p 0.001) –catheter-related bacteraemia (p 0.04) –prior surgery (p 0.014) Zarkotou O et al. Clin Microbiol Infect. 2011;17:1798-803

20. Welte – MDR Pathogens, Mar del Plata 11.10.2014 Multicenter retrospective cohort study, in 3 large Italian teaching hospitalsbetween 1 January 2010 and 30 June 2011 125 patients with bloodstream infections (BSIs) caused by KPC-producing Kp isolates (KPC-Kp) diagnosed 30-day mortality rate was 41.6% –monotherapy (54.3% –combined drug therapy 34.1%; P =.02). 30-day mortality was independently associated with –Postantibiogram therapy with a combination of tigecycline, colistin, and meropenem was associated with lower mortality (OR: 0.11; P =.01) Tumbarello M. Clinical Infectious Diseases 2012;55(7):943–50 21

21. Welte – MDR Pathogens, Mar del Plata 11.10.2014 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) Tumbarello M, Viale PL, Viscoli C, Bassetti M et al. Clin Infect Dis, 2012; Oct;55(7):943-50

22. Welte – MDR Pathogens, Mar del Plata 11.10.2014 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

23. Welte – MDR Pathogens, Mar del Plata 11.10.2014 Colistin + rifampicin: in vivo better outcome! Control Colistin Rifampicin Both agents Pantopoulou A et al. Int J Antimicrob Agents. 2007;29(1):51-5

24. Welte – MDR Pathogens, Mar del Plata 11.10.2014 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).

25. Welte – MDR Pathogens, Mar del Plata 11.10.2014 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.

26. Welte – MDR Pathogens, Mar del Plata 11.10.2014

29. Revival of „old“ drugs Tigecyclin Phase II-Study in patients with hospital acquired pneumonia –Tigecyclin 75 mg twice daily –Tigecyclin 100mg twice daily –Imipenem/Cilastatin 1g three times a day Primary Endpoint: Advers Events –No significant difference between the groups Secondary Endpoint: Clinical Cure –Both tigecyclin groups were non inferior to Imipenem/Cilastatin –High dose tigecyclin was in trend more effective than low dose tigecyclin and imipenem/cilastatin Ramirez J et al. 2013 Apr;57(4):1756-62. 10

30. Welte – MDR Pathogens, Mar del Plata 11.10.2014 Clinical response in phase 2 (study 2000) vs. phase 3 (study 311) HAP trials Ramirez J et al. 2013 Apr;57(4):1756-62.

31. Welte – MDR Pathogens, Mar del Plata 11.10.2014 Mean tigecycline (TGC) serum concentrations in subjects with hospital- acquired pneumonia after intravenous infusions. 2000 HAP- TGC Serum concentration Ramirez J et al. 2013 Apr;57(4):1756-62.

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33. Inhaled Antibiotics in the ICU Retrospective matched case-control study in Greece Patients with VAP due gram-negative MDR pathogens –43 pts. received AS plus IV colistin –43 control patients who had received IV colistin alone Microbiology –Acinetobacter baumannii (66 cases [77%]) –Klebsiella pneumoniae (12 cases [14%]) –Pseudomonas aeruginosa (8 cases [9.3%]) No significant differences between the 2 groups were observed regarding –eradication of pathogens (P = 679) –clinical cure (P=.10) –mortality (P=.289). Kofteridis D. et al. Clinical Infectious Diseases 2010; 51(11):1238–1244

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35. Inhaled antibiotics for VAP Liu Q et al.Anesthesiology 2012; 117:1335-47

36. Welte – MDR Pathogens, Mar del Plata 11.10.2014