new antibiotics. is there something on the horizon? tobias welte department of respiratory medicine...

New Antibiotics. Is there something on the horizon?Tobias Welte

Department of Respiratory Medicine and Intensive Care

Welte – New Antibiotics – Mar del Plata 2014Welte – New Antibiotics – Mar del Plata 2014

Sepsis Mortality Delay of antibiotic treatment

• Retrospective analysis (1/2005 - 2/2010) 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: 1749-55

Welte – New Antibiotics – Mar del Plata 2014Welte – 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

Welte – New Antibiotics – Mar del Plata 2014Welte – New Antibiotics – Mar del Plata 2014

New AntibioticsThe 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)

Welte – New Antibiotics – Mar del Plata 2014Welte – 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)

1

15

0

8

0

5

0

13

0

10

20

30

40

50

Persistent>3 days

Persistent>7 days

Relapse BacteriologicFailure

% o

f pat

ien t

sChang 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)

Welte – New Antibiotics – Mar del Plata 2014Welte – New Antibiotics – Mar del Plata 2014

MRSA infectionsTreatment 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

Welte – New Antibiotics – Mar del Plata 2014Welte – 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

R1:1

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)

Welte – New Antibiotics – Mar del Plata 2014Welte – New Antibiotics – Mar del Plata 2014

Clinical Cure (PP at EOS)

57.6

46.6

0

20

40

60

80

Linezolid Vancomycin

Cli

nca

l S

uce

ss R

ate

(%)

n = 165 n = 174

P-Value = 0,042

95% CI = 0,5%; 21,6%

Kunkel M et al. IDSA 2010; Presentation LB-49.

Welte – New Antibiotics – Mar del Plata 2014Welte – New Antibiotics – Mar del Plata 2014

Ceftaroline fosamil: Administered as a Prodrug

NS

OS

N

N+

O O

NHN

S N

NH

N

O

P

HO

O

HO

S

C H3

O

NS S

N

N+

O O

N HN

S N

NH2

N

O

S

C H3

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): 809-31

Welte – New Antibiotics – Mar del Plata 2014Welte – New Antibiotics – Mar del Plata 2014

File TM et al. JAC 2011; 66 Suppl 3: iii19–iii32

Fokus IOutcome

Welte – New Antibiotics – Mar del Plata 2014Welte – 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: 1413-21

Welte – New Antibiotics – Mar del Plata 2014Welte – 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 48-72 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. 2013 Feb 13;309(6):559-69.

ESTABLISH – 1Tedizolid versus Linezolid bei cSSTI

46

Welte – New Antibiotics – Mar del Plata 2014Welte – New Antibiotics – Mar del Plata 2014 47

Welte – New Antibiotics – Mar del Plata 2014Welte – New Antibiotics – Mar del Plata 2014

New AntibioticsThe 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)

Welte – New Antibiotics – Mar del Plata 2014Welte – New Antibiotics – Mar del Plata 2014

Proportion of 3rd gen. cephalosporins Resistant (R) Klebsiella pneumoniae Isolates in Participating Countries in 2012

http://www.ecdc.europa.eu/en/healthtopics/antimicrobial_resistance/, 19.11.13

Welte – New Antibiotics – Mar del Plata 2014Welte – New Antibiotics – Mar del Plata 2014

ESBL Treatment

• Carbapenems, Carbapenems, Carbapenems …..

Welte – New Antibiotics – Mar del Plata 2014Welte – New Antibiotics – Mar del Plata 2014

Proportion of Carbapenems Resistant (R) Klebsiella pneumoniae Isolates in Participating Countries in 2012

http://www.ecdc.europa.eu/en/healthtopics/antimicrobial_resistance/, 19.11.13

Welte – New Antibiotics – Mar del Plata 2014Welte – 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;30:972-6.Borer A, et al. Infect Control Hosp Epidemiol. 2009;30:972-6.

Study patients Control patients

Required intensive care 12 (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)

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*P < 0.001

Welte – New Antibiotics – Mar del Plata 2014Welte – New Antibiotics – Mar del Plata 2014

Welte – New Antibiotics – Mar del Plata 2014Welte – New Antibiotics – Mar del Plata 2014

Welte – New Antibiotics – Mar del Plata 2014Welte – New Antibiotics – Mar del Plata 2014

Welte – New Antibiotics – Mar del Plata 2014Welte – New Antibiotics – Mar del Plata 2014

Study descriptionStudy 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

Welte – New Antibiotics – Mar del Plata 2014Welte – New Antibiotics – Mar del Plata 2014

Clinical Cure at TOC (ITT Analysis Set)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. 2014

Welte T. ERS 2014, Poster 4643

Welte – New Antibiotics – Mar del Plata 2014Welte – New Antibiotics – Mar del Plata 2014

Clinical cure rates in subgroups (ITT)Clinical cure rates in subgroups (ITT)Awad et al., Clin Infect Dis. 2014

Welte T. ERS 2014, Poster 4643

Welte – New Antibiotics – Mar del Plata 2014Welte – New Antibiotics – Mar del Plata 2014

Patients with bacteraemia (ITT)Patients with bacteraemia (ITT)

Clinical cure (TOC visit)

30-day all-cause mortality

Awad et al., Clin Infect Dis. 2014

Welte T. ERS 2014, Poster 4643

Welte – New Antibiotics – Mar del Plata 2014Welte – New Antibiotics – Mar del Plata 2014

Ceftozolane/Tazobactamintraabdominal 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):5350-7

39

Welte – New Antibiotics – Mar del Plata 2014Welte – 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

Welte – New Antibiotics – Mar del Plata 2014Welte – New Antibiotics – Mar del Plata 2014

I suggest:Use it in SELECTED cases!

Welte – New Antibiotics – Mar del Plata 2014Welte – New Antibiotics – Mar del Plata 2014

Humoral immune response: anti-bacterial modes of action

100-fold higher phagocytosis-promoting activity compared to IgG10

IgM exhibits:

1000-fold higher affinity towards C1q (first protein in the classical complement

pathway) than IgG11

neutralization of antibiotic-induced endotoxin release12

1. 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; 145-52

Welte – New Antibiotics – Mar del Plata 2014Welte – 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.

Welte – New Antibiotics – Mar del Plata 2014Welte – New Antibiotics – Mar del Plata 2014

ʺWhen an idea does not sound absurd at the beginning, then

there is no hope for itʺ

Albert Einstein, Physicist