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New Antibiotics. Is there something on the horizon? Tobias Welte Department of Respiratory Medicine and Intensive Care.

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Presentation on theme: "New Antibiotics. Is there something on the horizon? Tobias Welte Department of Respiratory Medicine and Intensive Care."— Presentation transcript:

1 New Antibiotics. Is there something on the horizon? Tobias Welte Department of Respiratory Medicine and Intensive Care

2 Welte – New Antibiotics – Mar del Plata 2014 Sepsis Mortality Delay of antibiotic treatment Retrospective analysis (1/ /2010) of a large dataset collected prospectively for the Surviving Sepsis Campaign A total of 28,150 patients with severe sepsis and septic shock A total of 17,990 patients received antibiotics after sepsis identification In-hospital mortality was 29.7% Statistically significant increase in the probability of death associated with the number of hours of delay for first antibiotic administration. Adjusted hospital mortality increased steadily after 1 hour of time to antibiotic administration. Results were similar in patients with severe sepsis and septic shock, regardless of the number of organ failure Ferrer R. CCM 2014; 42:

3 Welte – New Antibiotics – Mar del Plata 2014 Severe infections: risk factors for increased mortality Delay of antibiotic therapy –But early therapy influences accuracy of the diagnosis Inadequate antibiotic therapy –But broad-spectrum antibiotic therapy increases antibiotic consumption Increase of MDR pathogens MDR, multi-drug resistant

4 Welte – New Antibiotics – Mar del Plata 2014 New Antibiotics The Pipeline Gram positive Infection –New Oxazolidinones Tedizolid –Pleuromutilines Gram negative Infection –ESBL/KPC Activity New beta-lactam inhibitors Pseudomonas activity –Ceftobiprole –Ceftolozan/Tazobactam –β-Hairpin Peptidomimetika (PEM)

5 Welte – New Antibiotics – Mar del Plata 2014 A pressing need for antibiotic agents effective against both MSSA and MRSA *Excludes patients with IE Nafcillin (n=18) Vancomycin (n=70) Persistent >3 days Persistent >7 days RelapseBacteriologic Failure % of patients Chang F et al. Medicine 2003;82:333–339 Efficacy of nafcillin vs vancomycin in MSSA bacteraemia* Vancomycin was an independent factor associated with failure (OR: 6.5, P=0.048) Vancomycin was an independent factor associated with failure (OR: 6.5, P=0.048)

6 Welte – New Antibiotics – Mar del Plata 2014 MRSA infections Treatment different for different sites of infection Pneumonia –Linezold Sepsis –Pneumogenic Sepsis Linezolid + Vancomycin –Sepsis of unknown origin Vancomycin or daptomycin Joint/Valve infection –Daptomycin CNS Infection –Ceftarolin

7 Welte – New Antibiotics – Mar del Plata 2014 Linezolid vs. Vancomycin in MRSA nosocomial pneumonia Adults with MRSA-HAP N = 1225 Linezolid 600 mg i.v. / p.o every 12 h * Vancomycin 15 mg/kg i.v. every 12 h * EOT- Visit  5 d after last dosage R 1:1 EOS- Visit 7-30 d after last dosage * Initial Coverage of gram-negatives with Cefepim or other non MRSA susceptible antibiotics Exclusion if no MRSA could be detected Duration of therapy7-14 d (til 21d in confirmed bacteremia)

8 Welte – New Antibiotics – Mar del Plata 2014 Clinical Cure (PP at EOS) n = 165n = 174 P-Value = 0,042 95% CI = 0,5%; 21,6% Kunkel M et al. IDSA 2010; Presentation LB-49.

9 Welte – New Antibiotics – Mar del Plata 2014 Ceftaroline fosamil: Administered as a Prodrug N S O S N N + O O NH N SN N O P HO O S CH 3 O N S S N N + O O N H N SN NH 2 N O S CH 3 O O Prodrug: Ceftaroline fosamil Active metabolite: Ceftaroline Plasma phospatase Rapid biotransformation in plasma Bactericidal activity mod. nach Zhanel et al, Drugs 2009, 69 (7):

10 Welte – New Antibiotics – Mar del Plata 2014 File TM et al. JAC 2011; 66 Suppl 3: iii19–iii32 Fokus I Outcome

11 Welte – New Antibiotics – Mar del Plata 2014 Daptomycin und MRSA Subgroup analysis of the MRSA patients (Fowler Trial) 20/45 (44.4%) daptomycin patients and 14/43 (32.6%) vancomycin/gentamicin patients were successfully treated (difference 11.9) –45% versus 27% in complicated bacteraemia –60% versus 45% in uncomplicated bacteraemia –50% versus 50% in right-sided MRSA endocarditis. Persisting or relapsing bacteraemia occurred in 27% of daptomycin and 21% of vancomycin/gentamicin patients –MICs of 2 mg/L occurred in five daptomycin and four vancomycin/gentamicin patients. Rehm SJ. JAC 2008; 62:

12 Welte – New Antibiotics – Mar del Plata 2014 Phase II schwere Haut- und –Tedizolid 200 mg einmal täglich oral –Linezolid 600 mg zweimal täglich oral über je 10 Tage primärer Outcome Parameter: –Ansprechen auf die Therapie nach Stunden Ergebnisse –Intent-to-treat Analyse für die Rate des frühen klinischen Ansprechens 79.5% in der Tedizolid Gruppe (332 Patienten) und 79.4% in der Linezolid Gruppe (335 Patienten) –klinischen Erfolgsrate nach Ende der Therapie (Tag 11) 69.3% in der Tedizolid Gruppe und 71.9% in der Linezolid Gruppe. –Die Ergebnisse für die 178 Patienten mit primären MRSA Nachweis entsprachen dem Gesamtergebnis. Prokocimer P et alJAMA Feb 13;309(6): ESTABLISH – 1 Tedizolid versus Linezolid bei cSSTI 46

13 Welte – New Antibiotics – Mar del Plata

14 Welte – New Antibiotics – Mar del Plata 2014 New Antibiotics The Pipeline Gram positive Infection –New Oxazolidinones Tedizolid –Pleuromutilines Gram negative Infection –ESBL/KPC Activity New beta-lactam inhibitors Pseudomonas activity –Ceftobiprole –Ceftolozan/Tazobactam –β-Hairpin Peptidomimetika (PEM)

15 Welte – New Antibiotics – Mar del Plata 2014 Proportion of 3rd gen. cephalosporins Resistant (R) Klebsiella pneumoniae Isolates in Participating Countries in

16 Welte – New Antibiotics – Mar del Plata 2014 ESBL Treatment Carbapenems, Carbapenems, Carbapenems …..

17 Welte – New Antibiotics – Mar del Plata 2014 Proportion of Carbapenems Resistant (R) Klebsiella pneumoniae Isolates in Participating Countries in

18 Welte – New Antibiotics – Mar del Plata 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: 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

19 Welte – New Antibiotics – Mar del Plata 2014

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22 Study description Multicenter, randomised, active-controlled, double-blind noninferiority study (ceftobiprole versus combined ceftazidime plus linezolid) Pre-specified non-inferiority margin of – 15% for the primary endpoint of clinical cure 157 clinical sites in Europe, North America, South America, and Asia-Pacific region Patients enrolled between April 2005 and May 2007 Awad et al., Clin Infect Dis. 2014

23 Welte – New Antibiotics – Mar del Plata 2014 Clinical Cure at TOC (ITT Analysis Set) 6.9% (−6.3; 20.1) 0.8% (−7.3; 8.8) Between-group difference (95% CI) ceftobiprole minus ceftazidime/linezolid Awad et al., Clin Infect Dis Welte T. ERS 2014, Poster 4643

24 Welte – New Antibiotics – Mar del Plata 2014 Clinical cure rates in subgroups (ITT) Awad et al., Clin Infect Dis Welte T. ERS 2014, Poster 4643

25 Welte – New Antibiotics – Mar del Plata 2014 Patients with bacteraemia (ITT) Clinical cure (TOC visit) 30-day all- cause mortality Awad et al., Clin Infect Dis Welte T. ERS 2014, Poster 4643

26 Welte – New Antibiotics – Mar del Plata 2014 Ceftozolane/Tazobactam intraabdominal Infection Prospective Phase II Study with 2:1 Randomisation in patients with complicated intraabdominal infection –TOL-TAZ (1.5g tid+/- i.v. Metronidazol (500 mg tid) –Meropenem (1 g tid) for 4 to 7 days 82 Pts received TOL-TAZ (90.2% + Metronidazol) 39 Pts received Meropenem Clinical cure in 83.6% in the TOL-TAZ group and 96.0% in the Meropenem group (Difference 12.4%) Clinical Cure in the ME population in 88.7% vs. 95.8% of the pts (Difference,7.1%) TOL-TAZ effectiv against Escherichia coli (89.5%), Klebsiella pneumoniae (100%) and P. aeruginosa (100%). No differences in number of adverse events (50.0% TOL-TAZ and 48.8% Meropenem, respectively) Lucasti C et al. AAC 2014 Sep;58(9):

27 Welte – New Antibiotics – Mar del Plata 2014 Hot Topics in Pneumogenic Sepsis and ARDS (Pneumogenic) Sepsis –General considerations –Treatment –New Antibiotics –Immunomodulators ARDS –Ventilation strategies –Immunomodulators

28 Welte – New Antibiotics – Mar del Plata 2014 I suggest: Use it in SELECTED cases!

29 Welte – New Antibiotics – Mar del Plata 2014 Humoral immune response: anti-bacterial modes of action 100-fold higher phagocytosis-promoting activity compared to IgG 10 IgM exhibits: 1000-fold higher affinity towards C1q (first protein in the classical complement pathway) than IgG 11 neutralization of antibiotic-induced endotoxin release Increase of bacterial phagocytosis 2. Induction of bacterial lysis due to specific activation of complement on bacterial surfaces 3. Neutralisation of toxins IgM immunoglobulins for infection - Why? Molnar Z, Nierhaus A, Esen F. Annual Update in ICEM 2013;

30 Welte – New Antibiotics – Mar del Plata 2014 A randomized, double-blind, placebo-controlled, multicenter, parallel- group, adaptive group-sequential phase II study, to determine the efficacy and safety of BT086 as an adjunctive treatment in severe community acquired pneumonia (sCAP) The CIGMA trial 30 Study Medication  BT086 - IgM Concentrate (42mg/kg bw/day)  Placebo 1% Albumin Study phases  Pre-treatment: Pts are randomised max.12 h after start of mech ventilation  Treatment: 5 consecutive days  Follow-up: Pts stay in study until d28 or discharge from hospital.

31 Welte – New Antibiotics – Mar del Plata 2014 ʺ When an idea does not sound absurd at the beginning, then there is no hope for it ʺ Albert Einstein, Physicist


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