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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)
34-year-old female, GP visit after two days of 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
• 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
34-year-old female, GP visit after two days of 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 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]
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
34-year-old female, GP visit after two days of 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%
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]
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
Restrepo MI. ERJ 2009 Jan;33(1):153-9.
CAP – combination vs Mono-betalactam therapy
Restrepo MI. ERJ 2009 Jan;33(1):153-9.
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
ESBL Treatment
• Carbapenems, Carbapenems, Carbapenems …..
Proportion of carbapenem-resistant (R) Klebsiella pneumoniae isolates in participating countries in 2012
http://www.ecdc.europa.eu/en/healthtopics/antimicrobial_resistance/, 19.11.13
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.
Hot Topics in Pneumogenic Sepsis and ARDS
• (Pneumogenic) Sepsis– General considerations– Treatment– New Antibiotics– Immunomodulators
• ARDS– Ventilation strategies– Immunomodulators
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
http://www.ecdc.europa.eu/en/healthtopics/antimicrobial_resistance/, 19.11.13
ESBL Treatment
• Carbapenems, Carbapenems, Carbapenems …..
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
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
Hot Topics in Pneumogenic Sepsis and ARDS
• (Pneumogenic) Sepsis– General considerations– Treatment– New Antibiotics– Immunomodulators
• ARDS– Ventilation strategies– Immunomodulators
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
Awad et al., Clin Infect Dis. 2014
Welte T. ERS 2014, Poster 4643
Clinical cure rates in subgroups (ITT)Awad et al., Clin Infect Dis. 2014
Welte T. ERS 2014, Poster 4643
Patients with bacteraemia (ITT)
Clinical cure (TOC visit)
30-day all-cause mortality
Awad et al., Clin Infect Dis. 2014
Welte T. ERS 2014, Poster 4643
Hot Topics in Pneumogenic Sepsis and ARDS
• (Pneumogenic) Sepsis– General considerations– Treatment– New Antibiotics– Immunomodulators
• ARDS– Ventilation strategies– Immunomodulators
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.
Hot Topics in Pneumogenic Sepsis and ARDS
• (Pneumogenic) Sepsis– General considerations– Treatment– New Antibiotics– Immunomodulators
• ARDS– Ventilation strategies– Immunomodulators
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
Hot Topics in Pneumogenic Sepsis and ARDS
• (Pneumogenic) Sepsis– General considerations– Treatment– New Antibiotics– Immunomodulators
• ARDS– Ventilation strategies– Immunomodulators
ARDSEtiology
ARDS Network. NEJM 2014; 370 (23):2191-200
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
70 out of 225 patients died= 31.1%
Brunkhorst FM. JAMA 2012; 307: 2390-99
Statins to treat infammation in ARDS
ARDS Network. NEJM 2014; 370 (23):2191-200
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
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