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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