Dr. Tobias Welte: Lessons learned from the CAPNETZ study

Community Acquired Pneumonia in the Emergency RoomHow 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)


• 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

• 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

Steroid Use in Asthma - A Risk Factor for CAP?

McKeever T. Chest 2013; 144: 1788-94


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 patientWho 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’

Who is a “patient at risk”?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]

http://1.bp.blogspot.com/-Rq7R9-8Lkb0/TufQQ2ektWI/AAAAAAAACGs/WZyYncG_cYA/s1600/Bevo%CC%88lkerungspyramide+Deutschland+2012.png







Who is a “patient at risk”?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%• 90 day mortality 24.5%• 70% reduction of mortality if

combination therapy was used

Restrepo MI. ERJ 2009 Jan;33(1):153-9.

• 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

Who is a “patient at risk”?Staphylococcus aureus

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.

1103071393673604N =

PLOT

Other pyogenic bacte

M.pneum

oniae

Legionella spp.

S.pneumoniae

no bacterial pathoge

AL

T

120

100

80

60

40

20

0

12393490149011811675

22448994022389446533813897272530471531424024942146

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 OutpatientsN = 29

HospitalizedN = 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 6501-23-4

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

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

Von Baum H, Welte T. ERJ 2010 Mar;35(3):598-605.

Independent risk factors for CAP through GNEB*

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

Von Baum H, Welte T. ERJ 2010 Mar;35(3):598-605.

* Gram-negative Enterobacteriaceae

Who is a “patient at risk”?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

Who is a “patient at risk”?Age

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

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

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

Who is a “patient at risk”?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

Who is a “patient at risk”?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

0.5 1 2 3 4

Hazard Ratio

0.2

B

Nosocomial infectionCommunity acquired infectionMicrobiologically documentedClinically suspected

Surgical patientsMedical patients

Gram-negative infectionGram-positive infectionBacteremic infection

Non-bacteremic infectionGram-negative bacteremiaGram-positive bacteremia

Pneumonia

IntraabdominalUrogenital

Intention to treatPer protocol set

SOFA score at baseline <= 9 pointsSOFA score at baseline >= 10 pointsStudy treatment >= 4 days

Severe SepsisSeptic Shock

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

0.1250.209

0.618

0.4250.464

0.7670.639

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

0.6040.572

adjustedHR (95% CI) p-value

2.01 (0.98; 4.12)

0.81 (0.57; 1.16)

0.055

0.245

13713697

176

146

127

149

140

90

18340

49

1059939

273199

141

132

206

No.

434232534738

4743

30

5512

14

323714

8559

37

48

57

Death Cases

135141

98

178

162

114

120

155

93

18333

58

11911025

276214

153

123

209

No.

465028685046

4653

37

59

15

38408

9670

43

53

61

Death Cases

Monotherapy Combination Therapy

74199

1867

84192

2076

19

Adjusted proportional hazard models for the effect of addition of moxifloxacin on overall survival

92 out of 277 patients died= 33.2%

Brunkhorst FM. JAMA 2012; 307: 2390-99

34-year-old patient with CAP


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%

CAPpaCO2 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

BiomarkerBlood 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 ProcalcitoninRisk 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

Who is a “patient at risk”?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)

Julio Ramirez, ERS 2008 Poster 1854

VariableAMI

(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 failure15 (61.7) 52 (11.0)

<0.001

Mortality in hospital8 (27.6) 32 (6.8)

<0.001

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

0

10

15

20R

isk

of a

cute

m

yoca

rdia

l inf

arct

ion

(%) 95% CI

60 80 100 120 160 140 180

Risk of AMI

Propensity-adjusted associationP = 0.05

95% CI

25

5Ramirez J. Clin Infect Dis 2008; 47: 182-87

* AMI = acute myocardial infarction

Who is a “patient at risk”?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

Who is a “patient at risk”?Co-morbidity

• 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

Corrales-Medina VF. Circulation. 2012;125:773-781

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]

http://www.destatis.de/






Who is a “patient at risk”?Setting: Nursing Home

0

10

20

30

40

50

60

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.

Who is a “patient at risk”?Setting

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

Who is a “patient at risk”?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

Who is a “patient at risk”?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 CAPprospectively evaluated July 2002 – December 2006

with complete data for CRB65 and follow-up

Hospitalised patientsN= 3216

Initial intravenous (iv) ß-lactam regimenN= 2255

Initial ß-lactam iv ≥72h (mono- or + macrolide)N= 1854

BLN= 908

BLMN= 946

Out-patientsN= 1476

Other antibiotic regimenN= 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

Who is a “patient at risk”?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%• 90 day mortality 24.5%• 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

Pre-therapyTest of cure

Days 5–7post-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)

Clinicalevaluation

Late follow upDays 21–28

post-therapy

Patients with CAP and

PSI score >II

PSI III (<50%)

Cmax and ECG x 315 min post-dose Day 1 and 3

Torres et al. ECCMID 2006, Poster 1061; Read et al. ERS 2006, Poster 2083;

95% CI : -8.8% to 6.0%

Clinical cure at TOC (PP population) – PSI risk classes IV–V

(143/169) (145/167)

84,6 86,8

0

20

40

60

80

100

Pat

ien

ts (

%)

Moxifloxacin Ceftriaxone + levofloxacin

Betalactam vs moxifloxacin monotherapyearly survival

Observational studyin 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 therapyMacrolides 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 OutpatientsN = 29

HospitalizedN = 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 6501-23-4

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

Approbriate Therapy

76% 68%Von Baum H, Welte T. CID 2008 May 1;46(9):1356-64

Who is a “patient at risk”?Enterobacteriacae

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

* 55% of all EB isolates were indeterminate Von Baum H, Welte T. ERJ 2010 Mar;35(3):598-605.

28

Pseudomonas aeruginosaCombination therapy

If combination therapy is required then combine with

+ AminoglycosideGentamycin/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

+ FluoroquinolonesCiprofloxacin (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

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

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 2011125 patients with bloodstream infections (BSIs) caused by KPC-producing Kp isolates (KPC-Kp) diagnosed30-day mortality rate was 41.6%

monotherapy 54.3%)combined drug therapy 34.1%; P = .02.

30-day mortality was independently associated withseptic 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

34-year-old female, Intermediate Care UnitDay 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

Patients with inappropriate antibiotic treatment have a slower decline in CRP levels in first week of follow-up

Bruns et al. Eur Respir J 2008;32:726–32

34-year-old female, Intermediate Care UnitDay 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

p < 0.001

Standard group

PCT group

2

4

6

8

10

12

13

20

An

tib

ioti

c d

ura

tio

n (

da

ys

)

15

17

19

Standard group PCT group

0

10

20

30

40

50

60

70

80

90

100

AB started > 4d > 6d > 8d > 10d > 14d > 21d

An

tib

ioti

c P

resc

rip

toin

(%

)

Christ-Crain M et al, AJRCCM 2006; 174(1):84-93

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 all likely pathogens and that penetrate in adequate concentrations into tissues presumed to be the source of sepsis

1B 1B

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, combination therapy with an extended spectrum beta-lactam and either an aminoglycoside or a fluoroquinolone is for P. aeruginosa bacteremia

2D 2B ↑

A combination of beta-lactam and macrolide forpatients 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 ↑

MeroMonoN = 273

MeroMoxiN = 278

All patientsN = 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)

Sepsis Trials - Site and Source of Infection

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 Delay of antibiotic treatment

Ferrer R. CCM 2014; 42: 1749-55

• 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 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)

CAPDelay of Antibiotic Therapy

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 diseaseDelay of antibiotic treatment

• 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 diseaseDelay of antibiotic treatment

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

SO

FA S

core

(P

oin

ts)

– m

ean

an

d 9

5% C

I

1 3 5 7 9 11 13

Study Day

0

2

4

6

8

10

12

14Monotherapy

Combination therapy

t-test p=0.36 *

1 3 5 7 9 11 13

0

2

4

6

8

10

12

14

SO

FA S

core

(P

oin

ts)

– m

ean

an

d 9

5% C

I

Study Day

Monotherapy

Combination therapy

t-test p=0.37 *

249 212 167 137 124 103 89

255 209 179 153 125 95 81

Patients evaluable:

Monotherapy

Combination therapy

181 156 122 96 88 71 63

198 165 141 119 96 71 57

Patients evaluable

Monotherapy

Combination therapy

Organ Dysfunction (SOFA Score)

Intention-to-treat population Per-protocol population

0

10

20

30

40

50

60

70

80

90

100

0 14 28 42 56 70 84

Days

Ov

era

ll S

urv

iva

l (%

)

log rank p=0.42

Monotherapy

Combination therapy

Patients at risk:

273 222 211 193 188 184 179

276 224 210 193 186 180 177

Monotherapy

Combination therapyO

ve

rall

Su

rviv

al

(%)

0

10

20

30

40

50

60

70

80

90

100

0 14 28 42 56 70 84

Days

log rank p=0.59

Monotherapy

Combination therapy

Patients at risk:

199 164 156 143 138 137 132

214 176 166 155 150 146 144

Monotherapy

Combination therapy

Overall Survival

Intention-to-treat population Per-protocol population

ß-Lactam Monotherapy vs. ß-Lactam-Aminoglycosid Combination Therapy in Sepsis: A Metaanalysis

Total MortalityTreatment FailureBakterial SuperinfectionAdverse EventsNephrotoxicity

43632739

45

5527661630854945

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)

Paul M.BMJ 2004; 328: 668

N Studies N Patients ß-Mono vs. ß-AG Combi

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• 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.

Kumar A. Crit Care Med 2010; 38:1651–1664

30

AntibioticsPharmacokinetics in severly ill patients

• Charakteristic of severly ill patients

– High Cardiac Index

– Increased distribution volume

– Altered plasma protein binding

AntibioticsPharmacokinetics 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

Mean tigecycline (TGC) serum concentrations in subjects with hospital-acquired pneumonia after intravenous infusions.

2000 HAP- TGC Serum concentration Ramirez J et al. 2013 Apr;57(4):1756-62.

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

Ramirez J et al. 2013 Apr;57(4):1756-62.




Sepsis TherapyPrimary 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

*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)

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

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)

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.

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

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

Fokus IOutcome

Standard Treatmentgram negatives

E. coli/EnterobakteriacaeAmpicillin/Inhibitor Combinations2. and 3. Generation CephalosporinesErtapenem

Pseudomoas aeruginosa/AcinetobacterPiperacillin/Tazobaktam4. Generation CephalosporinesCarbapenemes

St. maltophiliaFluorquinolonesCotrimoxazol

Pseudomoas aeruginosaCombination Therapy

If combination therapy is required then combine with

+ AminoglycosidGentamycin/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

+ FluorquinolonesCiprofloxacin (800-1200 mg tgl.)Levofloxacin (1000 mg tgl.)

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



ESBL Treatment

• Carbapenems, Carbapenems, Carbapenems …..

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



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.

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

Ramirez J et al. 2013 Apr;57(4):1756-62.

10

Revival of „old“ drugsColistin

• 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 therapy7/15 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

• 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)

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

21

Multivariate analysis of factors associated with death among patients with bloodstream infection due to KPC producing

Klebsiella Pneumoniae.

Shock - - 0.0087.17 (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 VAPLiu Q et al.Anesthesiology 2012; 117:1335-47




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)

• 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

47

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)Awad et al., Clin Infect Dis. 2014


Patients with bacteraemia (ITT)

Clinical cure (TOC visit)

30-day all-cause mortality






I suggest:Use it in SELECTED cases!

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

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, NEJM 342:1301, 2000

ARMA trial - major outcome parameters

Potential advantages of the „awake ECMO“ concept vs. conventional therapy

Pat. awake, cooperative, able to eat and drinkNo risk of ventilator-associated pneumonia, i.e. potentially lower risk of septicemiaDetrimental effects of long-term mechanical ventilation and analgosedation avoidedActive exercise programs allows avoiding muscular atrophy

Awake ECMO in ARDS

Awake ECMO in ARDS

• Six patients with severe ARDS, four immunocompromised

• 4 out of 6 survived

Hoeper MM et al. ICM 2013 (in press)

ARDSProne 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




ARDSEtiology

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


0.5 1 2 3 4

Hazard Ratio

0.2

B





Pneumonia





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

0.1250.209

0.618

0.4250.464

0.7670.639

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

0.6040.572


2.01 (0.98; 4.12)

0.81 (0.57; 1.16)

0.055

0.245

13713697

176

146

127

149

140

90

18340

49

1059939

273199

141

132

206

No.

434232534738

4743

30

5512

14

323714

8559

37

48

57

Death Cases

135141

98

178

162

114

120

155

93

18333

58

11911025

276214

153

123

209

No.

465028685046

4653

37

59

15

38408

9670

43

53

61

Death Cases


74199

1867

84192

2076

19




Statins to treat infammation in ARDS

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


0.5 1 2 3 4

Hazard Ratio

0.2

B





Pneumonia





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

0.1250.209

0.618

0.4250.464

0.7670.639

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

0.6040.572


2.01 (0.98; 4.12)

0.81 (0.57; 1.16)

0.055

0.245

13713697

176

146

127

149

140

90

18340

49

1059939

273199

141

132

206

No.

434232534738

4743

30

5512

14

323714

8559

37

48

57

Death Cases

135141

98

178

162

114

120

155

93

18333

58

11911025

276214

153

123

209

No.

465028685046

4653

37

59

15

38408

9670

43

53

61

Death Cases


74199

1867

84192

2076

19




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

Health & Medicine

mrsa pneumonia patients

risk cap patientwho

risk factor

patients withbacteremia

hospitalised patients

patient atrisk

age comparision of patients

increased risk ofpneumonia