New Antibiotics. Is there something on
the horizon?
Tobias Welte
Department of Respiratory Medicine and Intensive Care
Sepsis Mortality
Delay of antibiotic treatment
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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 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 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)
Welte – New Antibiotics – Mar del Plata 2014
A pressing need for antibiotic agents effective against both MSSA
and MRSA
Chang F et al. Medicine 2003;82:333–339
Efficacy of nafcillin vs vancomycin in MSSA bacteraemia*
50
Nafcillin (n=18)
Vancomycin (n=70)
40
Vancomycin was an independent factor
associated with failure
(OR: 6.5, P=0.048)
30
15
13
20
8
10
0
*Excludes patients with IE
5
1
Persistent
>3 days
0
0
Persistent
>7 days
Relapse
Welte – New Antibiotics – Mar del Plata 2014
0
Bacteriologic
Failure
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
Welte – New Antibiotics – Mar del Plata 2014
Linezolid vs. Vancomycin in MRSA
nosocomial pneumonia
Linezolid
600 mg i.v. / p.o
every 12 h *
Adults with
MRSA-HAP
N = 1225
Exclusion if
no MRSA
could be
detected
R
1:1
EOTVisit
5 d after last
dosage
EOSVisit
7-30 d after
last dosage
Vancomycin
15 mg/kg i.v.
every 12 h *
Duration of therapy7-14 d
(til 21d in confirmed bacteremia)
* Initial Coverage of gram-negatives with Cefepim or other non MRSA susceptible antibiotics
Welte – New Antibiotics – Mar del Plata 2014
Clinical Cure (PP at EOS)
P-Value = 0,042
95% CI = 0,5%; 21,6%
Clincal Sucess Rate (%)
80
60
57.6
46.6
40
20
n = 165
n = 174
Linezolid
Vancomycin
0
Kunkel M et al. IDSA 2010; Presentation LB-49.
Welte – New Antibiotics – Mar del Plata 2014
Ceftaroline fosamil: Administered as a Prodrug
C H3
mod. nach Zhanel et al, Drugs 2009, 69 (7): 809-31
N+
O
N
O
N
NH
NH
P
HO
HO
S
N
O
S
N
N
S
S
O
O
O
Plasma
phospatase
Prodrug: Ceftaroline fosamil
CH3
N+
N
Rapid
biotransformation
in plasma
O
N
H2N
NH
S
N
O
O
Active metabolite: Ceftaroline
Welte – New Antibiotics – Mar del Plata 2014
S
N
N
S
S
Bactericidal activity
O
O
Fokus I
Outcome
File TM et al. JAC 2011; 66 Suppl 3: iii19–iii32
Welte – New Antibiotics – Mar del Plata 2014
Daptomycin und MRSA
Rehm SJ. JAC 2008; 62: 1413-21
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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.
Welte – New Antibiotics – Mar del Plata 2014
ESTABLISH – 1
Tedizolid versus Linezolid bei cSSTI
• 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.
Welte – New Antibiotics – Mar del Plata 2014
46
Welte – New Antibiotics – Mar del Plata 2014
47
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)
Welte – 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 2014
ESBL Treatment
• Carbapenems, Carbapenems,
Carbapenems …..
Welte – 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 2014
Attributable Mortality for Carbapenem-Resistant
K. Pneumoniae (KPC)
Borer A, et al. Infect Control Hosp Epidemiol. 2009;30:972-6.
• 32-patient cohort with KPC bacteremia
• 32 non-bacteremic KPC control patients matched for time period,
comorbidities, underlying disease, age, and sex
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)
*P < 0.001
Welte – New Antibiotics – Mar del Plata 2014
Welte – New Antibiotics – Mar del Plata 2014
Welte – New Antibiotics – Mar del Plata 2014
Welte – New Antibiotics – Mar del Plata 2014
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
Welte – New Antibiotics – Mar del Plata 2014
Clinical Cure at TOC (ITT Analysis Set)
Awad et al., Clin Infect Dis. 2014
Welte T. ERS 2014, Poster 4643
Between-group
difference (95% CI)
ceftobiprole minus
ceftazidime/linezolid
0.8%
(−7.3; 8.8)
Welte – New Antibiotics – Mar del Plata 2014
6.9%
(−6.3; 20.1)
Clinical cure rates in subgroups (ITT)
Awad et al., Clin Infect Dis. 2014
Welte T. ERS 2014, Poster 4643
% with clinical cure at TOC
100%
Ce obiprole
74%
80%
60%
Ce azidime/Linezolid
52%
45%
37%
40%
46%
44%
50%
56%
60%
57%
54%
36%
30% 31%
20%
0%
Number
108 111
All ICU
pa ents
46 54
23 22
57 50
APACHE II ≥15 Mech. Vent.
COPD
Welte – New Antibiotics – Mar del Plata 2014
30
36
S. aureus
14 14
MRSA
10 13
P. aeruginosa
Patients with bacteraemia (ITT)
Awad et al., Clin Infect Dis. 2014
Welte T. ERS 2014, Poster 4643
Ce obiprole
60%
Clinical cure
(TOC visit)
50%
% with outcome
Ce azidime/Linezolid
30-day allcause mortality
37%
40%
30%
29%
30%
25%
24%
21%
20%
41%
17%
10%
0%
Number
27
24
All pa ents
Welte – New Antibiotics – Mar del Plata 2014
17
12
All ICU
pa ents
24
27
All pa ents
12
17
All ICU
pa ents
Ceftozolane/Tazobactam
intraabdominal Infection
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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
Welte – New Antibiotics – Mar del Plata 2014
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Hot Topics in Pneumogenic Sepsis
and ARDS
• (Pneumogenic) Sepsis
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General considerations
Treatment
New Antibiotics
Immunomodulators
• ARDS
– Ventilation strategies
– Immunomodulators
Welte – New Antibiotics – Mar del Plata 2014
I suggest:
Use it in SELECTED cases!
Welte – New Antibiotics – Mar del Plata 2014
IgM immunoglobulins for infection - Why?
Molnar Z, Nierhaus A, Esen F. Annual Update in ICEM 2013; 145-52
Humoral immune response:
anti-bacterial modes of action
IgM exhibits:
1. Increase of bacterial phagocytosis
100-fold higher phagocytosis-promoting
activity compared to IgG10
2. Induction of bacterial lysis due to
specific activation of complement on
bacterial surfaces
1000-fold higher affinity towards C1q (first
protein in the classical complement
pathway) than IgG11
3. Neutralisation of toxins
neutralization of antibiotic-induced
endotoxin release12
Welte – New Antibiotics – Mar del Plata 2014
A randomized, double-blind, placebo-controlled, multicenter, parallelgroup, 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
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Study Medication
 BT086 - IgM Concentrate (42mg/kg bw/day)
 Placebo 1% Albumin
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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 2014
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ʺWhen an idea does
not sound absurd at
the beginning, then
there is no hope for itʺ
Welte – New Antibiotics – Mar del Plata 2014
Albert Einstein, Physicist