Dr. Tobias Welte: Lessons learned from the CAPNETZ study

Community Acquired Pneumonia in
the Emergency Room
How Would You Decide?
Tobias Welte
Department of Respiratory Medicine

34-year-old female, GP visit after two days of
symptoms
• 2 days ago cough without sputum production
started
• Fever of 38.9°C
• From yesterday increasing dyspnoea
• Yesterday evening temperature 39.1°C, chills
• Until now symptomatic therapy with antipyretics
(paracetamol)

symptoms
• History
– Asthma bronchiale from childhood on
• Regular therapy with fluticasone/salmeterol 50/250 1 puff bid
– No further abnormalities known yet
• Profession
– Grammar school teacher
• Family anamnesis
– Married, two children (6 and 8 years old)
– Mother and 6-year-old daughter with asthma as well
– 6-year-old daughter with otitis media a week ago

Steroid Use in Asthma - A Risk Factor for CAP?
McKeever T. Chest 2013; 144: 1788-94
• Primary care data from The Health Improvement Network in the UK
• People with asthma with pneumonia or lower respiratory tract
infection
• Age- and sex-matched control subjects.
• The highest strength of ICS ( ≥1,000 μg) had a 2.04 increased risk of
pneumonia or LTRI compared with no prescription for ICS within the
previous 90 days

symptoms
Clinical signs and symptoms
• Pt. well orientated
• Dyspnoea at rest (RR 24/minute), not cyanotic
• Cough without sputum production
• Auscultation:
– Rales at left lower lobe dorsal
• HR 116/min, RR 85/52 mmHg, 38.9°C

Diagnosis and management of the at risk CAP patient
Who is a “patient at risk”?
• A patient at risk with regard to
– Etiology
– Severity of the disease
• Clinical assessment
• Biomarker
– Age
– Co-morbidity
– Setting
• ‘Health care associated pneumonia’

Etiology
Outpatients (%) Hospitalised Patients,
not-ICU (%)
ICU-Patients (%)
S. pneumoniae 38 27 28
M. pneumoniae 8 5 2
H. influenzae 13 6 7
C. pneumoniae 21 11 4
S. aureus 1,5 3 9
Enterobacteriaceae 0 4 9
P. aeruginosa 1 3 4
Legionella spp. 0 5 12
C. burnetii 1 4 7
RS-Virus 17 12 3
«unknown» 50 41 45
Welte T, et al. Clinical and economic burden of pneumonia among adults in Europe. Thorax. 2012

Patients with CAP and episodes of CAP
with a pathogen identified
A. Torres et al. Eur J Clin Microbiol Infect Dis. 2014 Feb 15. [Epub ahead of print]

Streptococcus pneumoniae
• Retrospective cohort study in
San Antonio, Texas
• 237 out of 787 Patients with
bacteremia
– 104 patients with combination
therapy (betalactam/macrolide)
– 133 patients with monotherapy
• 30 day mortality 20.3%
• 70% reduction of mortality if
combination therapy was
used
Restrepo MI. ERJ 2009 Jan;33(1):153-9.

Staphylococcus aureus
• Observational study in 627 patients
hospitalized with CAP from 12 university-affiliated
emergency departments during
the winter–spring of 2006 and 2007
• MRSA in 14 (2.4%) patients and in 5% of
patients admitted to the ICU
• Two (14%) MRSA pneumonia patients died
• All 9 MRSA isolates tested were pulsed-field
type USA300
• Features significantly associated with
isolation of MRSA patient history of MRSA
– nursing home admission in the previous
year
– close contact in the previous month with
someone with a skin infection
– multiple infiltrates or cavities on chest
radiograph
– and comatose state, intubation, receipt of
vasopressors, or death in the emergency
department
Moran GJ. Clinical Infectious Diseases 2012;54(8):1126–33

Mycoplasma pneumoniae
• 4,532 pts of the German CAPNETZ
Study
• 307 pts (= 6.8%) had definite M.
pneumoniae infection
– 148 with positive PCR
– 159 positive IgM titer
• 621 had other definite bacterial
pathogens
• 3604 with no known bacterial origin
• MPP pts. In comparision to the
other groups significantly
– were younger
– had less co-morbidities
– had less severe disease
– had less inflammatory response
– had better outcomes
• shorter length of hospitalization
• less mechanical ventilation
• minimal mortality.
no bacterial pathoge
2146
2494
Legionella spp.
N = 3604 367 139 307 110
PLOT
Other pyogenic bacte
M.pneumoniae
S.pneumoniae
ALT
120
100
80
60
40
20
0
13243909
1490
1167815
23480268924599244 233378289157 134025344017
Von Baum H, Welte T. BMC Infectious Disease 2009

Who is a “patient at
risk”?
Legionella
• Prospective observational
study (CAPNETZ)
• 2,503 adults
• Diagnosis of Legionella
(3.8% of all CAP cases)
confirmed by
– Culture (0.1%)
– PCR (1.7%)
– Urine antigen (2.2%)
• Mortality
– Legionella 12.8%
– Other pathogen 9.7%
– Unknown pathogens 11.3%
Variables Outpatients
N = 29
Hospitalized
N = 65
P-value
Age  65 y
  SD
31 %
55.4  15.7 y
60 %
66.9  14.5 y
0.001
Male 48% 71% ns
Smoker 35% 32% ns
Diabetes 7% 35% < 0.001
Fever 45% 59% ns
Confusion 0 11% <0.001
CRB 65
0
1-2
3-4
16 (55%)
12 (41%)
0
15 (23%)
48 (74%)
1 (1.5%9
0.003
Hyponatremia 0 15 (23%) <0.001
MV 0 4 (6%) <0.001
Died (30d) 0 10 (15.4% <0.001
Died (6 mth) 0 12 (18.5%) <0.001
Appropriate
therapy
76% 68%
Von Baum H, Welte T. CID 2008 May 1;46(9):1356-64

CAP through Gram-negative Enterobacteriaceae
(GNEB): The CAPNETZ group
Von Baum H, Welte T. ERJ 2010 Mar;35(3):598-605.
n % total population % population with
resp. samples
Pat. without resp.
samples
3914
Pat. with resp.
samples
1216
GNEB in resp.
Samples, definite
40 0.8 3.3
GNEB-bacteremia 27 0.5 2.2
GNEB, indeterminate 172 3.4 14.1

Independent risk factors
for CAP through GNEB*
Von Baum H, Welte T. ERJ 2010 Mar;35(3):598-605.
Variable p OR 95% CI
Age > 65 Yrs .000 2.60 1.51-4.51
Gender .387
Nursing home residency .000 3.90 2.00-7.47
Cardiovascular disease .000 4.16 2.49-6.93
Malignancy .405 2.43 1.79-3.30
Smoker .220
COPD .123
PEG .088
Cerebrovascular disease .000 4.79 2.76-8.26
Diabetes .003 2.35 1.34-4.09
* Gram-negative Enterobacteriaceae

Severity assessment
• C onfusion
• R espiratory rate > 30/min
• B lood pressure (RRsyst < 90 mmHg or
RRdiast < 60mmHg)
• > 65 (in CURB U=Urea> 7 mmol/L)
• 0 points treatment outside the hospital
• 1 point consider hospitalization
• > 2 points admit to hospital

Age
Ewig S et al. Thorax 2009; 64: 1092-9

Lancet 2013; 381: 1987–2015
Funding: Bill & Melinda Gates Foundation.

N Engl J Med 2013;
369:448-57.

Age
• Comparision of patients with CAP aged
18 to <65 yrs with those aged 65 yrs in
the CAPNETZ database were analysed
for potential differences in baseline
• 7,803 patients were studied
– 52.3% aged <65 yrs
• 18 to <30 yrs 6.4%
• <40 yrs 17.1%
• <50 yrs 29.4%)
• Co-morbidity 46.6% in the younger
versus 88.2% in the older patient group)
• 74.0% of the younger patients presented
with CURB-65 score of 0
• Streptococcus pneumoniae and
Mycoplasma pneumoniae were the most
frequent pathogens in the younger
patients
• Short-term mortality was very low (1.7%
versus 8.2%) and even lower in patients
without comorbidity (0.3% versus 2.4%).
• Long-term mortality was 3.2% versus
15.9%, also lower in patients without co-morbidity
(0.8% versus 6.1%)
Klapdor B et al. Eur Respir J 2012; 39: 1156–1161

Severity assessment
Clin Infect Dis 2007; 44: S27-72
• Major criteria
– Mechanical ventilation
– Septic shock (catecholamines)
• Minor criteria
– Respiratory rate >30/min.
– pO2/FiO2 < 250
– Multilobular infiltrates in chest x ray
– Altered mental status
– BUN > 20 mg/dL
– Thrombocytopenia (< 100,000/mm3)
– Hypothermia (< 36.0°C)
– Hypotension (Fluid resuscitation necesary)

Subgroup analyses - Mortality
Adjusted proportional hazard models for the effect of addition of moxifloxacin on overall survival
0.5 1 2 3 4
Hazard Ratio
0.2
B
Intention to treat
Per protocol set
SOFA score at baseline <= 9 points
SOFA score at baseline >= 10 points
Study treatment >= 4 days
Nosocomial infection
Community acquired infection
Microbiologically documented
Clinically suspected
Surgical patients
Medical patients
Gram-negative infection
Gram-positive infection
Bacteremic infection
Non-bacteremic infection
Gram-negative bacteremia
Gram-positive bacteremia
Pneumonia
Intraabdominal
Urogenital
Severe Sepsis
Septic Shock
adjusted
HR (95% CI) p-value
1.09 (0.70; 1.69)
0.84 (0.54; 1.32)
1.54 (0.89; 2.66)
0.78 (0.53; 1.15)
1.11 (0.73; 1.71)
0.82 (0.51; 1.32)
1.19 (0.75; 1.88)
1.07 (0.69; 1.64)
0.88 (0.51; 1.52)
1.10 (0.74; 1.63)
0.79 (0.33; 1.89)
0.88 (0.38; 2.06)
1.07 (0.64; 1.77)
1.15 (0.70; 1.88)
1.48 (0.56; 3.92)
0.710
0.456
0.125
0.209
0.618
0.425
0.464
0.767
0.639
0.652
0.597
0.774
0.799
0.591
0.434
1.00 (0.73; 1.36)
0.94 (0.65; 1.35)
1.05 (0.63; 1.74)
0.90 (0.60; 1.34)
1.12 (0.76; 1.66)
0.986
0.720
0.864
0.604
0.572
92 out of 277 patients died
2.01 (0.98; 4.12)
0.81 (0.57; 1.16)
0.055
0.245
No.
273
199
141
132
206
137
136
97
176
146
127
149
140
90
183
40
49
105
99
39
Monotherapy Combination Therapy
Death
Cases
85
59
37
48
57
43
42
32
53
47
38
47
43
30
55
12
14
32
37
14
No.
276
214
153
123
209
135
141
98
178
162
114
120
155
93
183
33
58
119
110
25
Death
Cases
96
70
43
53
61
46
50
28
68
50
46
46
53
37
59
19
15
38
40
8
74
199
18
67
84
192
= 33.2%
20
76
Brunkhorst FM. JAMA 2012; 307: 2390-99

symptoms
Biochemistry
• WBC 12,800/μL, Hct 34.6%, Platelets 142,000/μL
• Sodium 135 mmol/L, Glucose 12.6 mmol/L, BUN 33 mmol/L
• CRP 320mg/L, PCT 1.5 μg/L
• paO2 65mmHg, paCO2 32mmHg, pH 7.4, HCO3 17.4, SaO2 92%

CAP
paCO2 as risk factor
• Retrospective observational study in
453 hospitalized CAP patients in two
US hospitals
– 188 (41%) Pts. with normal PaCO2
– 194 (42%) Pts. with PaCO2 <35 mm Hg
– 70 (15%) Pts. with PaCO2 >45 mm Hg
• Hypocapnic pts. with increased 30d
mortality (OR=2.84) and increase of
ICU admitance (OR=2.88) compared
with normocapnic patients
• Hypercapnic pts. with increased 30d
mortality (OR=3.38) and ICU
admittance (OR=5.35)
• These differences remain after
exclusion of COPD pts
Laserna E et al CHEST 2012; 142(5):1193–1199

Biomarker
Blood glucose level
• 6,891 patients with community
acquired pneumonia included in the
German CAPNETZ study between
2003 and 2009.
• In patients without known diabetes,
an elevated glucose level at
admission was a predictor of 28- and
90-day mortality in CAP
– glucose on admission 6–<11 mmol/L
• HR for death at 90 days 1.55 (P<0.001)
– admission glucose levels ≥14 mmol/L
• HR for death 6.04 (P<0.001)
– Pts with previously diagnosed
diabetes had an increased overall
mortality as compared to patients
without diabetes (HR 2.47; P<0.001)
• This outcome was not significantly
affected by admission glucose levels
(P=0.18).
Lepper P et al. BMJ 2012 May 28;344:e3397

Biomarker
Procalcitonin
Risk Ratio (95% CI) p value
Univariate Analysis
PCT (> 0.228 ng/mL) 9.94 (5.22-18.92) <0.0001
CRB-65 (>1) 6.56 (3.95-10.92) <0.0001
Multivariate analysis
PCT (> 0.228 ng/mL) 7.75 (3.78-15.87) <0.0001
CRB-65 (>1) 4.32 (2.58-7.25) <0.0001
Krüger S et al. ERJ 2008; 31: 349-55

Co-morbidity
• Observational, retrospective study
of consecutive patients
hospitalized with CAP at the
Veterans Hospital of Louisville,
KY, USA
• 500 patients admitted to ICU
• Clinical failure was defined as
development of respiratory failure
or shock
• AMI* was diagnosed based on
abnormal troponin levels and ECG
• AMI was present in 15% of
patients with severe CAP (13/86)
• AMI was present in 20% of
patients that developed clinical
failure (13/65)
• Significant associations of AMI
with PSI score and with clinical
failure (p=0.036)
Propensity-adjusted association
P = 0.05
Julio Ramirez, ERS 2008 Poster 1854
Variable
AMI
(n = 29)
No AMI
(n = 471) P
Time to clinical stability, mean
days ± SD 4.59 ± 2.73 3.1 ± 2.25 0.008
Length of hospital stay, mean days
± SD 9.9 ± 7.90 6.3 ± 7.68 0.01
Clinical failure
15 (61.7) 52 (11.0)
<0.00
1
Mortality in hospital
8 (27.6) 32 (6.8)
<0.00
1
Mortality within 30 days after
hospital admission 9 (31.0) 45 (9.6) 0.001
NOTE: Data are no. (%) of patients, unless otherwise indicated
40
Pneumonia Severity Index Score
20
15
10
0
Risk of acute
myocardial infarction (%)
95% CI
Risk
of AMI
95% CI
60 80 100 120 160 140 180
25
Ramirez J. Clin Infect Dis 2008; 47: 182-87 5
* AMI = acute myocardial infarction

Biomarker
• 728 patients (59.0 ±18.2 yr) with CAP followed up for
180 days
– 28 day Mortality 2.5%
– 180 day Mortality 5.1%
• MR-proADM, MR-proANP, co-peptin, CT-proET-1, PCT,
CRP, WBC, and CRB-65 score were determined on
admission
• All biomarkers (except WBC) were significantly higher
in non-survivors compared with survivors
• MR-proADM had the best performance for 28 days (HR
3.67) and 180 days (HR 2.84) survival
• C index of MR-proADM for 28-day survival (0.85) was
superior to MR-proANP (0.81), co-peptin (0.78), CT-proET-
1 (0.79), and CRB-65 (0.72)
• C index of MR-proADM or 180-day survival (0.78) was
higher than that for MR-proANP (0.74), copeptin (0.73),
CT-proET-1 (0.76), PCT, CRP, and WBC
Krüger S et al.. AJRCCM 2010; 182: 1426-34

Co-morbidity
Corrales-Medina VF. Circulation. 2012;125:773-781
• 1,343 in-patients and 944 out-patients with CAP
• Cardiac complications (new or worsening heart failure, new or worsening arrhythmias, or
myocardial infarction) in 358 in-patients (26.7%) and 20 ou-tpatients (2.1%)
• Most events (89.1% in in-patients, 75% in out-patients) were diagnosed within the first week, more
than half of them were recognized in the first 24 hours
• Incident cardiac complications were associated with increased risk of death at 30 days

Frequency of co-morbid conditions in adults
with community-acquired pneumonia
Torres A, et al. Thorax 2013;68:1057–1065

Prevalence of pathogens identified in
patients with CAP with HIV or COPD
A. Torres et al. Eur J Clin Microbiol Infect Dis. 2014 Feb 15. [Epub ahead of print]

Setting: Nursing Home
60
50
40
30
20
10
0
SP Entero MRSA Leg Atyp H infl Pseudomonas
Polverino E. Thorax 2010; 65: 354-59

• CAPNETZ Data Base (Pat. > 65 years)
• Patients with ‘classical’ CAP vs patients with HCAP
• No difference in etiology
– S. pneumoniae dominant
• Multiresistent Pathogens rare (<5%)
– Staphylococcus aureus was the only one more prevalent in HCAP
• Short- and long-term mortality higher in HCAP
• No association between mortality and MDR
Thorax 2012 Feb;67(2):132-8.

Setting
Ewig S, Welte T, Chastre J, Torres A. Lancet Infect Dis 2010; 10: 279–87

Conclusion
– Etiology
• S. pneumoniae, Legionella, Enterobacteriacae, S. aureus (?)
– Severity of the disease
• CRB 65/CURB 65 ≥ 2
• Patients < 65 years of age with significant clinical symptoms
– Co-morbidity
• Heart, lung, kidney, liver, malignancy, neurological diasease
– Setting
• Disabled functional status

What does it mean in terms of treatment?
Extraordinary
circumstances require
extraordinary measures
Helmut Kohl, German Chanecellor, 1982

Mono- vs Combination Therapy
• Observational study of the German
competence network CAPNETZ
• 1,854 patients
– Betalactam monotherapy
– Betalactam/Macrolide
Combination Therapy (BLM)
• BLM-therapy was associated with
– lower 14-day mortality in total
(OR 0.49; CI: 0.28-0.85).
– 14-day mortality risk was
reduced in pts with CRB65 =2
(OR 0.35; CI: 0.12-0.99) and
CRB65 ≥2 (OR 0.38; CI: 0.17-
0.86), but not in CRB65 ≤1
– lower risk of treatment failure at
14 days (OR 0.65; CI 0.47-0.89)
and 30 days (OR 0.69; CI 0.51-
0.94)
• CRB65, neoplastic disease and
nursing home residency were
independent predictors of death.
4692 patients with CAP
prospectively evaluated July 2002 – December 2006
with complete data for CRB65 and follow-up
Hospitalised patients
N= 3216
Initial intravenous (iv) ß-lactam regimen
N= 2255
Initial ß-lactam iv ≥72h (mono- or + macrolide)
N= 1854
BL
N= 908
BLM
N= 946
Out-patients
N= 1476
Other antibiotic regimen
N= 961
ß-lactam iv + other antibiotic
or ß-lactam iv < 72h, N= 401
Tessmer A, Welte T. JAC 2009; 63: 1025-33

Ewig S. et al.
Thorax 2011; online

Streptococcus pneumoniae
• Retrospective cohort study in
San Antonio, Texas
• 237 out of 787 patients with
bacteremia
– 104 Patients with combination
therapy (betalactam/macrolide)
– 133 patients with monotherapy
• 70% reduction of mortality if
combination therapy was
used

CAP – combination vs Mono-betalactam
therapy

Antibiotics and inflammatory response
• BALB/cJ mice infected with
influenza virus and superinfected
with S. pneumoniae were treated
with either the cell-wall–active
antibiotic ampicillin or the protein
synthesis inhibitor clindamycin
or azithromycin.
• Ampicillin therapy performed
significantly worse (survival rate,
56%) than
– clindamycin therapy alone (82%)
– or in combination with ampicillin
(80%)
• Improved survival appeared to be
mediated by decreased
inflammation manifested
Karlstrom A. JID 2009; 2009; 199:311–9

MOTIV Study
Torres et al. ECCMID 2006, Poster 1061; Read et al. ERS 2006, Poster 2083;
Pre-therapy
Test of cure
Days 5–7
post-therapy
Days 3–5
Stratification Randomisation
PSI IV&V (≥50%)
MXF 400 mg IV/PO daily (4–14 days)
LFX 500 mg IV/PO twice daily + CTX 2 g daily (4–14 days)
MXF 400 mg IV/PO daily (4–14 days)
LFX 500 mg IV/PO twice daily + CTX 2 g daily (4–14 days)
Clinical
evaluation
Late follow up
Days 21–28
post-therapy
Patients with
CAP and
PSI score >II
PSI III (<50%)
Cmax and ECG x 3
15 min post-dose Day 1 and 3

Clinical cure at TOC (PP population) –
PSI risk classes IV–V
95% CI : -8.8% to 6.0%
84,6 86,8
(143/169) (145/167)
100
80
60
40
20
0
Patients (%)
Moxifloxacin Ceftriaxone + levofloxacin

Betalactam vs moxifloxacin monotherapy
early survival
Observational study
in Germany (CAPNETZ)
moxifloxacin mono 365 pts
(blue line)
betalactam mono 1703 pts
(green line)
Primary endpoint:
• time to death
Adjusted for:
• severity
• age
• co-morbidities
Ewig S et al. J Infect 2011; 62: 218-25

Combination therapy
Macrolides or fluorquinolones
• Prospective, observational cohort,
multicenter study
• 27 ICUs of 9 European countries
• 218 consecutive patients requiring
invasive mechanical ventilation for
an admission diagnosis of CAP
– Severe sepsis and septic shock
were present in 165 (75.7%) patients
• Monotherapy was given in
43(19.7%) and combination therapy
in 175 (80.3%) patients.
• Macrolide use was associated with
lower ICU mortality (HR 0.48, P =
0.04) when compared with the use
of fluoroquinolones
– for severe sepsis and septic shock
(n = 92) HR 0.44, P = 0.03.
Martin-Loeches I et al. Intensive Care Med (2010) 36:612–620

Who is a “patient at
risk”?
Legionella
• Prospective observational
study (CAPNETZ)
• 2,503 adults
• Diagnosis of Legionella
(3.8% of all CAP cases)
confirmed by
– Culture (0.1%)
– PCR (1.7%)
– Urine antigen (2.2%)
• Mortality
– Legionella 12.8%
– Other pathogen 9.7%
– Unknown pathogens 11.3%
Variables Outpatients
N = 29
Hospitalized
N = 65
P-value
Age  65 y
  SD
31 %
55.4  15.7 y
60 %
66.9  14.5 y
0.001
Male 48% 71% ns
Smoker 35% 32% ns
Diabetes 7% 35% < 0.001
Fever 45% 59% ns
Confusion 0 11% <0.001
CRB 65
0
1-2
3-4
16 (55%)
12 (41%)
0
15 (23%)
48 (74%)
1 (1.5%9
0.003
Hyponatremia 0 15 (23%) <0.001
MV 0 4 (6%) <0.001
Died (30d) 0 10 (15.4% <0.001
Died (6 mth) 0 12 (18.5%) <0.001
Von Baum H, Welte T. CID 2008 May 1;46(9):1356-64 76% 68%
Approbriate
Therapy

Enterobacteriacae
* 55% of all EB isolates were indeterminate Von Baum H, Welte T. ERJ 2010 Mar;35(3):598-605.
Resp. sample
available, no
EB/PA
(n = 1840)
Definite EB
(n = 22)
Indeterminate EB
(n = 27) *
Age (mean, yrs) 58 ± 18 64 ± 17 68 ± 11
Nursing home
resident (%)
2 23 7
Chronic resp.
disease
37 68 52
Enteral tube
feeding
0.6 23 11
Mortality 4 18 4
28

Pseudomonas aeruginosa
Combination therapy
• If combination therapy is required then
combine with
– + Aminoglycoside
• Gentamycin/tobramycin 6 mg/kg body weight/day as a
single dosage (trough level < 2 mg/L)
• Amikacin 20-25 (-30) mg/kg body weight/day as a single
dosage
– + Fluoroquinolones
• Ciprofloxacin (800-1200 mg daily)
• Levofloxacin (1000 mg daily)

Proportion of 3rd generation cephalosporin-resistant (R) Klebsiella
pneumoniae Isolates in participating countries in 2012
http://www.ecdc.europa.eu/en/healthtopics/antimicrobial_resistance/, 19.11.13

ESBL Treatment
• Carbapenems, Carbapenems,
Carbapenems …..

Proportion of carbapenem-resistant (R) Klebsiella
pneumoniae isolates in participating countries in 2012

Clinical Infectious Diseases 2012;55(7):943–50
• Multicenter retrospective cohort study, in 3 large Italian teaching hospitals
between 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
• septic shock at BSI onset (OR: 7.17; P = .008)
• inadequate initial antimicrobial therapy (OR: 4.17; P = .003)
• high APACHE III scores (OR: 1.04; 95% P < .001).

34-year-old female, Intermediate Care Unit
• Pneumoccal urine antigen positive
• Blood culture positive for S. pneumoniae
• Therapy:
– 400 mg moxifloxacin o.d. intravenously
• Oxygen supplementation
• Low dose low molecular heparin

Day 3
• CRP and PCT decrease quickly
• Respiratory Rate at rest 16/minute
• Temperature: 37.8°C
• SaO2 (2 l oxygen supplementation) 96%
• Biochemistry
– BUN 19 mmol/L
– Glucose 9.8 mmol/L

C-reactive protein (CRP): Correlation with
appropriateness of therapy
Bruns et al. Eur Respir J 2008;32:726–32
• Patients with inappropriate antibiotic treatment have a slower
decline in CRP levels in first week of follow-up

Day 3
• Patient transferred to a normal ward
• Moxifloxacin i.v. switched to 400mg Moxifloxacin
oral
• Early mobilisation out of bed

The ProCAP study – Antibiotic duration
Christ-Crain M et al, AJRCCM 2006; 174(1):84-93
p < 0.001
Standard
group
PCT
group
20
19
17
13
12
10
8
6
4
2
Antibiotic duration (days)
15
Standard group PCT group
100
90
80
70
60
50
40
30
20
10
0
AB started > 4d > 6d > 8d > 10d > 14d > 21d
Antibiotic Prescriptoin (%)

34-year-old female, normal ward
When to discharge from the hospital?
• Heart rate ≤ 100/min,
• Respiratory rate ≤ 24/min,
• Systolic blood pressure ≥ 90 mmHg
• Temperature ≤ 37.8 °C,
• Eating and drinking not altered
• Normal mental status
• No hypoxemia (PO2 ≥ 60 mm Hg, SaO2 ≥ 90%)

Hot Topics in Pneumogenic Sepsis
and ARDS
• (Pneumogenic) Sepsis
– General considerations
– Treatment
– New Antibiotics
– Immunomodulators
• ARDS
– Ventilation strategies
– Immunomodulators

2008 2012 Grading
D. Antibiotic therapy
1.a. Administration of effective iv ABs within the 1. hour of recognition of septic shock 1B 1B
1.b. Administration of effective iv ABs within the 1. hour of recognition of severe sepsis 1D 1C ↑
2.a. Initial empiric anti-infective therapy of one or more drugs that have activity against
1B 1B
all likely pathogens and that penetrate in adequate concentrations into tissues
presumed to be the source of sepsis
2.b. Antimicrobial regimen should be reassessed daily for potential deescalation 1C 1B ↑
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
nn 2C ↑
4.a. Combination empirical therapy for
neutropenic patients with severe sepsis 2D 2B ↑
for pts with difficult to treat, MDR bacterial pathogens f.e. Acinetobacter/Pseudomonas nn 2B ↑
For pts with severe infections associated with respiratory failure and septic shock,
2D 2B ↑
combination therapy with an extended spectrum beta-lactam and either an
aminoglycoside or a fluoroquinolone is for P. aeruginosa bacteremia
A combination of beta-lactam and macrolide for
patients with septic shock from bacteremic Streptococcus pneumoniae infections
nn 2B ↑
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
2D 2B ↑
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
1D 2C ↓
6. Antiviral therapy initiated as early as possible in patients with severe sepsis or septic
shock of viral origin
nn 2C ↑
7. Antimicrobial agents should not be used in patients with severe inflammatory states
determined to be of noninfectious cause
1D UG ↑

Sepsis Trials - Site and Source of Infection
MeroMono
N = 273
MeroMoxi
N = 278
All patients
N = 551
Site of infection
Pneumonia 105 (38.46) 119 (42.81) 224 (40.65)
Other respiratory tract 18 (6.59) 18 (6.47) 36 (6.53)
Intraabdominal 99 (36.26) 111 (39.93) 210 (38.11)
Bones or soft tissue 20 (7.33) 16 (5.76) 36 (6.53)
Surgical wound infection 15 (5.49) 5 (1.80) 20 (3.63)
Urogenital 39 (14.29) 25 (8.99) 64 (11.62)
Primary bacteremia 5 (1.83) 11 (3.96) 16 (2.90)
Other 13 (4.76) 11 (3.96) 24 (4.36)
Source of infection
Community-acquired 136 (49.82) 141 (50.72) 277 (50.27)
Nosocomial 137 (50.18) 136 (48.92) 273 (49.55)
Missing 0 1 (0.36) 1 (0.18)
Infection at study enrollment
Microbiologically confirmed 97 (35.53) 99 (35.61) 196 (35.57)
Clinical evidence 176 (64.47) 179 (64.39) 355 (64.43)
Brunkhorst F. JAMA 2012; 307: 2390-9

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

Sepsis Mortality
Ferrer R. CCM 2014; 42: 1749-55

Delay of Antibiotic Therapy
• Retrospective review of adult
admissions for CAP for 2 periods
– group 1 (255 pts), when the core quality
measure was a TFAD of less than 8 hours
– group 2 (293 pts), when the TFAD was
lowered to less than 4 hours.
• Accuracy of diagnosis of CAP were
assessed by ED physicians
• At admission, group 2 patients were
39.0% less likely to meet predefined
diagnostic criteria for CAP than were
group 1 patients (odds ratio, 0.61;
95% confidence interval, 0.42-0.86)
(P=.004).
• At discharge, there was agreement
CAP
between the ED physician’s diagnosis
and the predefined criteria for CAP in
62.0% of group 1 and 53.9% of group
2 patients (P=.06)
Welker JA. Arch Intern Med. 2008;168(4):351-356

Lancet Infect Dis 2012; 12: 774–80
• Pre-/post study in a surgical ICU in the US
– Aggressive therapy (01.09.2008-31.08.2009)
• If an infection was suspected antibiotic treatment was initiated
immediately
– Conservative therapy (01-09.2009-31.08.2010)
• Initiation of an antibiotic therapy only, when an inection has been
confirmed by diagnostic results
4

• Prä-/post Studie auf einer chirurgischen Intensivstation in den
USA
• konservative Therapie vs. aggressive Therapie
– verringerten Krankenhaussterblichkeit (13/100 [13%] gegenüber 27/101
[27%]; p=0·015)
– höheren Rate an primär adäquater Antibiotikatherapie (158/214 [74%] im
Vergleich zu 144/231 [62%]; p=0·0095)
– kürzere Therapiedauer (12·5 Tage [SD 10·7] gegenüber 17·7 [28·1 Tage:
p=0·0080)
Hranjec T et al. Lancet Infect Dis 2012; 12: 774–80
4
Suspected infectious disease

• Pre-/post study in a surgical
ICU in the US
• conservative vs. aggressive
antibiotic therapy results in
– Lower hospital mortality (13/100
[13%] versus 27/101 [27%];
p=0·015)
– Increased rate of intial adaequate
antibiotic therapy (158/214 [74%]
versus 144/231 [62%]; p=0·0095)
– Shorter treatment duration (12·5
Tage [SD 10·7] versus 17·7 [28·1
days: p=0·0080)
Hranjec T et al. Lancet Infect Dis 2012; 12: 774–80
4
Suspected infectious disease

FM Brunkhorst, M Oppert, G Marx and
coauthors
Effect of Empirical Treatment With
Moxifloxacin and Meropenem vs
Meropenem on Sepsis-Related Organ
Dysfunction in Patients With Severe
Sepsis: A Randomized Controlled Trial
Published online May 21, 2012

SOFA Score (Points) – mean and 95% CI
Organ Dysfunction (SOFA Score)
Intention-to-treat population Per-protocol population
1 3 5 7 9 11 13
Study Day
14
12
10
8
6
4
2
0
Monotherapy
Combination therapy
t-test p=0.36 *
Monotherapy
Combination therapy
t-test p=0.37 *
1 3 5 7 9 11 13
14
12
10
8
6
4
2
0
SOFA Score (Points) – mean and 95% CI
Study Day
Patients evaluable:
Monotherapy
249 212 167 137 124 103 89
Combination therapy
255 209 179 153 125 95 81
Patients evaluable
Monotherapy
181 156 122 96 88 71 63
Combination therapy
198 165 141 119 96 71 57

100
90
80
70
60
50
40
30
20
10
0
Overall Survival
Intention-to-treat population Per-protocol population
Monotherapy
Combination therapy
0 14 28 42 56 70 84
Days
Overall Survival (%)
log rank p=0.42
Patients at risk:
Monotherapy
273 222 211 193 188 184 179
Combination therapy
276 224 210 193 186 180 177
Overall Survival (%)
100
90
80
70
60
50
40
30
20
10
0
Monotherapy
Combination therapy
log rank p=0.59
0 14 28 42 56 70 84
Days
Patients at risk:
Monotherapy
199 164 156 143 138 137 132
Combination therapy
214 176 166 155 150 146 144

ß-Lactam Monotherapy vs. ß-Lactam-
Aminoglycosid Combination Therapy in Sepsis: A
Metaanalysis
Total Mortality
Treatment Failure
Bakterial Superinfection
Adverse Events
Nephrotoxicity
N Studies N Patients ß-Mono vs. ß-AG Combi
43
63
27
39
45
Paul M.BMJ 2004; 328: 668
5527
6616
3085
4945
5213
0,90 (0,77 - 1,06)
0,87 (0,78 - 0,97)
0,79 (0,59 - 1,06)
0,91 (0,80 - 1,04)
0,36 (0,28 - 0,47)

Mono- vs. Combination Therapy for VAP
• Randomised controlled
trial in 740 pts
– Mechanical ventilated
– VAP suspected after 4
days in the ICU
– Pts. with known
Pseudomonas or MRSA
excluded
• Meropenem 1g tid +
Ciprofloxacin 400 mg bid
• vs. Meropenem alone
• Outcome Parameters:
– No difference in 28-day
mortality (RR 1.05, p=0.74)
Heyland D. CCM 2008; 36: 737-44

Mono- versus Combination Therapy
Kumar A. Crit Care Med 2010; 38:1651–1664
• Metaanalysis of RCTs or observational studies comparing mono- and combination therapy
in patients with sepsis
• no overall mortality/clinical response benefit with combination therapy (odds ratio, 0.856)
• substantial benefit in the most severely ill subset (monotherapy risk of death >25%; odds
ratio of death, 0.51)
• Meta-regression indicated that efficacy of combination therapy was dependent only on the
risk of death in the monotherapy group.
30

Antibiotics
Pharmacokinetics in severly ill patients
• Charakteristic of severly ill patients
– High Cardiac Index
– Increased distribution volume
– Altered plasma protein binding

Antibiotics
Pharmacokinetics in severly ill patients
• Consequences
– Dosage of antibiotics at the highest approved
level (and above)
– Take pentrtaion properties into the tissue were
the infection is suspected, into account
– Combination therapy for MDR pathogenes

2000 HAP- TGC Serum concentration
Mean tigecycline (TGC) serum concentrations in subjects with hospital-acquired
pneumonia after intravenous infusions.
Ramirez J et al. 2013 Apr;57(4):1756-62.

Clinical response in phase 2 (study 2000) vs.
phase 3 (study 311) HAP trials

Sepsis Therapy
Primary Site of Infection
• Pneumonia
– Community Acquired
• S. pneumoniae
• L. pneumophila
– Ventilator Associated Pneumonia
• MRSA
• ESBL
• P. aeruginosa
• Intraabdominal Infection
– Peritonitis
• Anaerobes
• Vancomycin resistant Enterococci
• Urinary Tract Infection
• ESBL
• Soft and Skin Tissue Infection
• MRSA
• Sepsis of Unknown Origin
• MRSA

Rodriguez. CCM: 35(6)June 2007: 1493-1498

A pressing need for antibiotic agents effective against both MSSA
and MRSA
50
40
30
20
10
*Excludes patients with IE
Nafcillin (n=18)
Vancomycin (n=70)
1
15
0
8
0
5
0
13
0
Persistent
>3 days
Persistent
>7 days
Relapse Bacteriologic
Failure
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)

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

Linezolid vs. Vancomycin in MRSA
nosocomial pneumonia
Adults with
MRSA-HAP
N = 1225
Linezolid
600 mg i.v. / p.o
every 12 h *
Exclusion if
no MRSA
could be
detected
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
Duration of therapy7-14 d
(til 21d in confirmed bacteremia)
* Initial Coverage of gram-negatives with Cefepim or other non MRSA susceptible antibiotics

Clinical Cure (PP at EOS)
57,6
P-Value = 0,042
95% CI = 0,5%; 21,6%
46,6
80
60
40
20
0
Linezolid Vancomycin
Clincal Sucess Rate (%)
n = 165 n = 174
Kunkel M et al. IDSA 2010; Presentation LB-49.

Ceftaroline fosamil: Administered as a Prodrug
N
S
O
S
N
N+
O O
NH
N
S N
NH
N
O
P
HO
O
HO
S
CH
3
O
N
N
S S
N+
O O
N H
N
S N
H N
2
N
O
S
CH
3
O
O
Prodrug: Ceftaroline fosamil
Active metabolite: Ceftaroline
Plasma
phospatase
mod. nach Zhanel et al, Drugs 2009, 69 (7): 809-31
Rapid
biotransformation
in plasma
Bactericidal activity

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

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

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.)

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

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

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

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
10

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 ???

Predictors of mortality in patients with bloodstream infections caused by KPC-producing
K. pneumoniae and impact of appropriate antimicrobial treatment
• 53 patients
• Overall mortality was 52.8% and infection mortality was 34%
• In the appropriate therapy group mortality due to infection
occurred in 20%
– 0/20 given combination therapy
– 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

Tumbarello M. Clinical Infectious Diseases 2012;55(7):943–50
• 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)
21

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

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

Durante-Mangoni E. et al. Clinical Infectious Diseases 2013; 57(3):349–58

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

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

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)

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.
46

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

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
Welte T. ERS 2014, Poster 4643

Clinical cure rates in subgroups (ITT)
52%
37%
30%
74%
50%
57% 60%
45% 44%
31%
46%
56%
36%
54%
100%
80%
60%
40%
20%
0%
% with clinical cure at TOC
Ce obiprole Ce azidime/Linezolid
Number 111 57 50 46 54 23 22 30 36 14 10
108
All ICU
pa ents
APACHE II ≥15
14 13
Mech. Vent. COPD S. aureus MRSA P. aeruginosa

Patients with bacteraemia (ITT)
29%
25%
21%
17%
30%
24%
37%
41%
60%
50%
40%
30%
20%
10%
0%
% with outcome
Ce obiprole Ce azidime/Linezolid
Number 27 12 17 24 27 12 17
24
All pa ents All ICU
pa ents
All ICU
pa ents
All pa ents
Clinical cure
(TOC visit)
30-day all-cause
mortality

I suggest:
Use it in SELECTED cases!

IgM immunoglobulins for infection - Why?
Humoral immune response:
anti-bacterial modes of action
IgM exhibits:
100-fold higher phagocytosis-promoting
activity compared to IgG10
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
Molnar Z, Nierhaus A, Esen F. Annual Update in ICEM 2013; 145-52

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
122
• 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.

ARMA trial, NEJM 342:1301, 2000

ARMA trial - major outcome parameters
ARMA trial, NEJM 342:1301, 2000

Potential advantages of the „awake ECMO“ concept
vs. conventional therapy
• Pat. awake, cooperative, able to eat and drink
• No risk of ventilator-associated pneumonia,
i.e. potentially lower risk of septicemia
• Detrimental effects of long-term mechanical
ventilation and analgosedation avoided
• Active exercise programs allows avoiding
muscular atrophy

Awake ECMO in ARDS
• Six patients with severe ARDS, four
immunocompromised
• 4 out of 6 survived
Hoeper MM et al. ICM 2013 (in press)

ARDS
Prone Position
• Multicenter, prospective, RCT
• 466 patients with severe ARDS
– prone-positioning sessions
of at least 16 hours (237 pts)
– supine position (229 pts)
• 28-day mortality 16.0% in the
prone group, 32.8% in the
supine group (P<0.001).
• 90-day mortality 23.6% in the
prone group, 41.0% in the
supine group (P<0.001)
• Incidence of AEs not
significantly different between
the groups
Guerin C et al. NEJM 2013; 368:2159-68

ARDS
Etiology
ARDS Network. NEJM 2014; 370 (23):2191-200

Subgroup analyses - Mortality
Adjusted proportional hazard models for the effect of addition of moxifloxacin on overall survival
0.5 1 2 3 4
Hazard Ratio
0.2
B
Intention to treat
Per protocol set
SOFA score at baseline <= 9 points
SOFA score at baseline >= 10 points
Study treatment >= 4 days
Nosocomial infection
Community acquired infection
Microbiologically documented
Clinically suspected
Surgical patients
Medical patients
Gram-negative infection
Gram-positive infection
Bacteremic infection
Non-bacteremic infection
Gram-negative bacteremia
Gram-positive bacteremia
Pneumonia
Intraabdominal
Urogenital
Severe Sepsis
Septic Shock
adjusted
HR (95% CI) p-value
1.09 (0.70; 1.69)
0.84 (0.54; 1.32)
1.54 (0.89; 2.66)
0.78 (0.53; 1.15)
1.11 (0.73; 1.71)
0.82 (0.51; 1.32)
1.19 (0.75; 1.88)
1.07 (0.69; 1.64)
0.88 (0.51; 1.52)
1.10 (0.74; 1.63)
0.79 (0.33; 1.89)
0.88 (0.38; 2.06)
1.07 (0.64; 1.77)
1.15 (0.70; 1.88)
1.48 (0.56; 3.92)
0.710
0.456
0.125
0.209
0.618
0.425
0.464
0.767
0.639
0.652
0.597
0.774
0.799
0.591
0.434
1.00 (0.73; 1.36)
0.94 (0.65; 1.35)
1.05 (0.63; 1.74)
0.90 (0.60; 1.34)
1.12 (0.76; 1.66)
0.986
0.720
0.864
0.604
0.572
70 out of 225 patients died
2.01 (0.98; 4.12)
0.81 (0.57; 1.16)
0.055
0.245
No.
273
199
141
132
206
137
136
97
176
146
127
149
140
90
183
40
49
105
99
39
Monotherapy Combination Therapy
Death
Cases
85
59
37
48
57
43
42
32
53
47
38
47
43
30
55
12
14
32
37
14
No.
276
214
153
123
209
135
141
98
178
162
114
120
155
93
183
33
58
119
110
25
Death
Cases
96
70
43
53
61
46
50
28
68
50
46
46
53
37
59
19
15
38
40
8
74
199
18
67
84
192
20
76
= 31.1%
Brunkhorst FM. JAMA 2012; 307: 2390-99

Statins to treat infammation in ARDS
ARDS Network. NEJM 2014; 370 (23):2191-200

ʺWhen an idea does
not sound absurd at
the beginning, then
there is no hope for itʺ
Albert Einstein, Physicist

What does “patient at risk” means in terms of
treatment?
Conclusion
• Risk stratification essential for pneumonia
patients
– Cave: Severity underestimated in young patients
• Risk factors necessitate broader antibiotic therapy
– cover a broad spectrum of pathogens including S.
pneumoniae, atypicals and Enterobacteriacae
– demonstrate bactericidal activity with a fast clinical
efficacy
– penetrate very well into the bronchopulmonary
compartment
– Demonstrate a good safety profile mainly in the elderly
and in co-morbid patients

Dr. Tobias Welte: Lessons learned from the CAPNETZ study

Dr. Tobias Welte: Lessons learned from the CAPNETZ study

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Dr. Tobias Welte: Lessons learned from the CAPNETZ study