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Dr. Tobias Welte: Lessons learned from the CAPNETZ study

The document discusses the clinical assessment and management of community-acquired pneumonia (CAP) in a 34-year-old female patient, highlighting her symptoms, risk factors, and possible pathogens involved. It also reviews various studies linking asthma and its treatment to an increased risk of pneumonia, the importance of assessing comorbidities, and factors influencing the severity of the disease. Additionally, it underscores the significant role of biomarkers like procalcitonin and blood glucose levels in predicting mortality in CAP patients.

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Community Acquired Pneumonia in the Emergency Room How Would You Decide? Tobias Welte Department of Respiratory Medicine
34-year-old female, GP visit after two days of symptoms • 2 days ago cough without sputum production started • Fever of 38.9°C • From yesterday increasing dyspnoea • Yesterday evening temperature 39.1°C, chills • Until now symptomatic therapy with antipyretics (paracetamol)
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
Steroid Use in Asthma - A Risk Factor for CAP? McKeever T. Chest 2013; 144: 1788-94 • Primary care data from The Health Improvement Network in the UK • People with asthma with pneumonia or lower respiratory tract infection • Age- and sex-matched control subjects. • The highest strength of ICS ( ≥1,000 μg) had a 2.04 increased risk of pneumonia or LTRI compared with no prescription for ICS within the previous 90 days
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 patient Who is a “patient at risk”? • A patient at risk with regard to – Etiology – Severity of the disease • Clinical assessment • Biomarker – Age – Co-morbidity – Setting • ‘Health care associated pneumonia’
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.
Who is a “patient at risk”? Staphylococcus aureus • Observational study in 627 patients hospitalized with CAP from 12 university-affiliated emergency departments during the winter–spring of 2006 and 2007 • MRSA in 14 (2.4%) patients and in 5% of patients admitted to the ICU • Two (14%) MRSA pneumonia patients died • All 9 MRSA isolates tested were pulsed-field type USA300 • Features significantly associated with isolation of MRSA patient history of MRSA – nursing home admission in the previous year – close contact in the previous month with someone with a skin infection – multiple infiltrates or cavities on chest radiograph – and comatose state, intubation, receipt of vasopressors, or death in the emergency department Moran GJ. Clinical Infectious Diseases 2012;54(8):1126–33
Mycoplasma pneumoniae • 4,532 pts of the German CAPNETZ Study • 307 pts (= 6.8%) had definite M. pneumoniae infection – 148 with positive PCR – 159 positive IgM titer • 621 had other definite bacterial pathogens • 3604 with no known bacterial origin • MPP pts. In comparision to the other groups significantly – were younger – had less co-morbidities – had less severe disease – had less inflammatory response – had better outcomes • shorter length of hospitalization • less mechanical ventilation • minimal mortality. no bacterial pathoge 2146 2494 Legionella spp. N = 3604 367 139 307 110 PLOT Other pyogenic bacte M.pneumoniae S.pneumoniae ALT 120 100 80 60 40 20 0 13243909 1490 1167815 23480268924599244 233378289157 134025344017 Von Baum H, Welte T. BMC Infectious Disease 2009
Who is a “patient at risk”? Legionella • Prospective observational study (CAPNETZ) • 2,503 adults • Diagnosis of Legionella (3.8% of all CAP cases) confirmed by – Culture (0.1%) – PCR (1.7%) – Urine antigen (2.2%) • Mortality – Legionella 12.8% – Other pathogen 9.7% – Unknown pathogens 11.3% Variables Outpatients N = 29 Hospitalized N = 65 P-value Age  65 y   SD 31 % 55.4  15.7 y 60 % 66.9  14.5 y 0.001 Male 48% 71% ns Smoker 35% 32% ns Diabetes 7% 35% < 0.001 Fever 45% 59% ns Confusion 0 11% <0.001 CRB 65 0 1-2 3-4 16 (55%) 12 (41%) 0 15 (23%) 48 (74%) 1 (1.5%9 0.003 Hyponatremia 0 15 (23%) <0.001 MV 0 4 (6%) <0.001 Died (30d) 0 10 (15.4% <0.001 Died (6 mth) 0 12 (18.5%) <0.001 Appropriate therapy 76% 68% Von Baum H, Welte T. CID 2008 May 1;46(9):1356-64
CAP through Gram-negative Enterobacteriaceae (GNEB): The CAPNETZ group Von Baum H, Welte T. ERJ 2010 Mar;35(3):598-605. n % total population % population with resp. samples Pat. without resp. samples 3914 Pat. with resp. samples 1216 GNEB in resp. Samples, definite 40 0.8 3.3 GNEB-bacteremia 27 0.5 2.2 GNEB, indeterminate 172 3.4 14.1
Independent risk factors for CAP through GNEB* Von Baum H, Welte T. ERJ 2010 Mar;35(3):598-605. Variable p OR 95% CI Age > 65 Yrs .000 2.60 1.51-4.51 Gender .387 Nursing home residency .000 3.90 2.00-7.47 Cardiovascular disease .000 4.16 2.49-6.93 Malignancy .405 2.43 1.79-3.30 Smoker .220 COPD .123 PEG .088 Cerebrovascular disease .000 4.79 2.76-8.26 Diabetes .003 2.35 1.34-4.09 * Gram-negative Enterobacteriaceae
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: 1987–2015 Funding: 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 Adjusted proportional hazard models for the effect of addition of moxifloxacin on overall survival 0.5 1 2 3 4 Hazard Ratio 0.2 B Intention to treat Per protocol set SOFA score at baseline <= 9 points SOFA score at baseline >= 10 points Study treatment >= 4 days Nosocomial infection Community acquired infection Microbiologically documented Clinically suspected Surgical patients Medical patients Gram-negative infection Gram-positive infection Bacteremic infection Non-bacteremic infection Gram-negative bacteremia Gram-positive bacteremia Pneumonia Intraabdominal Urogenital Severe Sepsis Septic Shock adjusted HR (95% CI) p-value 1.09 (0.70; 1.69) 0.84 (0.54; 1.32) 1.54 (0.89; 2.66) 0.78 (0.53; 1.15) 1.11 (0.73; 1.71) 0.82 (0.51; 1.32) 1.19 (0.75; 1.88) 1.07 (0.69; 1.64) 0.88 (0.51; 1.52) 1.10 (0.74; 1.63) 0.79 (0.33; 1.89) 0.88 (0.38; 2.06) 1.07 (0.64; 1.77) 1.15 (0.70; 1.88) 1.48 (0.56; 3.92) 0.710 0.456 0.125 0.209 0.618 0.425 0.464 0.767 0.639 0.652 0.597 0.774 0.799 0.591 0.434 1.00 (0.73; 1.36) 0.94 (0.65; 1.35) 1.05 (0.63; 1.74) 0.90 (0.60; 1.34) 1.12 (0.76; 1.66) 0.986 0.720 0.864 0.604 0.572 92 out of 277 patients died 2.01 (0.98; 4.12) 0.81 (0.57; 1.16) 0.055 0.245 No. 273 199 141 132 206 137 136 97 176 146 127 149 140 90 183 40 49 105 99 39 Monotherapy Combination Therapy Death Cases 85 59 37 48 57 43 42 32 53 47 38 47 43 30 55 12 14 32 37 14 No. 276 214 153 123 209 135 141 98 178 162 114 120 155 93 183 33 58 119 110 25 Death Cases 96 70 43 53 61 46 50 28 68 50 46 46 53 37 59 19 15 38 40 8 74 199 18 67 84 192 = 33.2% 20 76 Brunkhorst FM. JAMA 2012; 307: 2390-99
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%
CAP paCO2 as risk factor • Retrospective observational study in 453 hospitalized CAP patients in two US hospitals – 188 (41%) Pts. with normal PaCO2 – 194 (42%) Pts. with PaCO2 <35 mm Hg – 70 (15%) Pts. with PaCO2 >45 mm Hg • Hypocapnic pts. with increased 30d mortality (OR=2.84) and increase of ICU admitance (OR=2.88) compared with normocapnic patients • Hypercapnic pts. with increased 30d mortality (OR=3.38) and ICU admittance (OR=5.35) • These differences remain after exclusion of COPD pts Laserna E et al CHEST 2012; 142(5):1193–1199
Biomarker Blood glucose level • 6,891 patients with community acquired pneumonia included in the German CAPNETZ study between 2003 and 2009. • In patients without known diabetes, an elevated glucose level at admission was a predictor of 28- and 90-day mortality in CAP – glucose on admission 6–<11 mmol/L • HR for death at 90 days 1.55 (P<0.001) – admission glucose levels ≥14 mmol/L • HR for death 6.04 (P<0.001) – Pts with previously diagnosed diabetes had an increased overall mortality as compared to patients without diabetes (HR 2.47; P<0.001) • This outcome was not significantly affected by admission glucose levels (P=0.18). Lepper P et al. BMJ 2012 May 28;344:e3397
Biomarker Procalcitonin Risk Ratio (95% CI) p value Univariate Analysis PCT (> 0.228 ng/mL) 9.94 (5.22-18.92) <0.0001 CRB-65 (>1) 6.56 (3.95-10.92) <0.0001 Multivariate analysis PCT (> 0.228 ng/mL) 7.75 (3.78-15.87) <0.0001 CRB-65 (>1) 4.32 (2.58-7.25) <0.0001 Krüger S et al. ERJ 2008; 31: 349-55
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) Propensity-adjusted association P = 0.05 Julio Ramirez, ERS 2008 Poster 1854 Variable AMI (n = 29) No AMI (n = 471) P Time to clinical stability, mean days ± SD 4.59 ± 2.73 3.1 ± 2.25 0.008 Length of hospital stay, mean days ± SD 9.9 ± 7.90 6.3 ± 7.68 0.01 Clinical failure 15 (61.7) 52 (11.0) <0.00 1 Mortality in hospital 8 (27.6) 32 (6.8) <0.00 1 Mortality within 30 days after hospital admission 9 (31.0) 45 (9.6) 0.001 NOTE: Data are no. (%) of patients, unless otherwise indicated 40 Pneumonia Severity Index Score 20 15 10 0 Risk of acute myocardial infarction (%) 95% CI Risk of AMI 95% CI 60 80 100 120 160 140 180 25 Ramirez J. Clin Infect Dis 2008; 47: 182-87 5 * AMI = acute myocardial infarction
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 Corrales-Medina VF. Circulation. 2012;125:773-781 • 1,343 in-patients and 944 out-patients with CAP • Cardiac complications (new or worsening heart failure, new or worsening arrhythmias, or myocardial infarction) in 358 in-patients (26.7%) and 20 ou-tpatients (2.1%) • Most events (89.1% in in-patients, 75% in out-patients) were diagnosed within the first week, more than half of them were recognized in the first 24 hours • Incident cardiac complications were associated with increased risk of death at 30 days
Frequency of co-morbid conditions in adults with community-acquired pneumonia Torres A, et al. Thorax 2013;68:1057–1065
Prevalence of pathogens identified in patients with CAP with HIV or COPD A. Torres et al. Eur J Clin Microbiol Infect Dis. 2014 Feb 15. [Epub ahead of print]
Who is a “patient at risk”? Setting: Nursing Home 60 50 40 30 20 10 0 SP Entero MRSA Leg Atyp H infl Pseudomonas Polverino E. Thorax 2010; 65: 354-59
• CAPNETZ Data Base (Pat. > 65 years) • Patients with ‘classical’ CAP vs patients with HCAP • No difference in etiology – S. pneumoniae dominant • Multiresistent Pathogens rare (<5%) – Staphylococcus aureus was the only one more prevalent in HCAP • Short- and long-term mortality higher in HCAP • No association between mortality and MDR Thorax 2012 Feb;67(2):132-8.
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 CAP prospectively evaluated July 2002 – December 2006 with complete data for CRB65 and follow-up Hospitalised patients N= 3216 Initial intravenous (iv) ß-lactam regimen N= 2255 Initial ß-lactam iv ≥72h (mono- or + macrolide) N= 1854 BL N= 908 BLM N= 946 Out-patients N= 1476 Other antibiotic regimen N= 961 ß-lactam iv + other antibiotic or ß-lactam iv < 72h, N= 401 Tessmer A, Welte T. JAC 2009; 63: 1025-33
Ewig S. et al. Thorax 2011; online
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 Torres et al. ECCMID 2006, Poster 1061; Read et al. ERS 2006, Poster 2083; Pre-therapy Test of cure Days 5–7 post-therapy Days 3–5 Stratification Randomisation PSI IV&V (≥50%) MXF 400 mg IV/PO daily (4–14 days) LFX 500 mg IV/PO twice daily + CTX 2 g daily (4–14 days) MXF 400 mg IV/PO daily (4–14 days) LFX 500 mg IV/PO twice daily + CTX 2 g daily (4–14 days) Clinical evaluation Late follow up Days 21–28 post-therapy Patients with CAP and PSI score >II PSI III (<50%) Cmax and ECG x 3 15 min post-dose Day 1 and 3
Clinical cure at TOC (PP population) – PSI risk classes IV–V 95% CI : -8.8% to 6.0% 84,6 86,8 (143/169) (145/167) 100 80 60 40 20 0 Patients (%) Moxifloxacin Ceftriaxone + levofloxacin
Betalactam vs moxifloxacin monotherapy early survival Observational study in Germany (CAPNETZ) moxifloxacin mono 365 pts (blue line) betalactam mono 1703 pts (green line) Primary endpoint: • time to death Adjusted for: • severity • age • co-morbidities Ewig S et al. J Infect 2011; 62: 218-25
Combination therapy Macrolides or fluorquinolones • Prospective, observational cohort, multicenter study • 27 ICUs of 9 European countries • 218 consecutive patients requiring invasive mechanical ventilation for an admission diagnosis of CAP – Severe sepsis and septic shock were present in 165 (75.7%) patients • Monotherapy was given in 43(19.7%) and combination therapy in 175 (80.3%) patients. • Macrolide use was associated with lower ICU mortality (HR 0.48, P = 0.04) when compared with the use of fluoroquinolones – for severe sepsis and septic shock (n = 92) HR 0.44, P = 0.03. Martin-Loeches I et al. Intensive Care Med (2010) 36:612–620
Who is a “patient at risk”? Legionella • Prospective observational study (CAPNETZ) • 2,503 adults • Diagnosis of Legionella (3.8% of all CAP cases) confirmed by – Culture (0.1%) – PCR (1.7%) – Urine antigen (2.2%) • Mortality – Legionella 12.8% – Other pathogen 9.7% – Unknown pathogens 11.3% Variables Outpatients N = 29 Hospitalized N = 65 P-value Age  65 y   SD 31 % 55.4  15.7 y 60 % 66.9  14.5 y 0.001 Male 48% 71% ns Smoker 35% 32% ns Diabetes 7% 35% < 0.001 Fever 45% 59% ns Confusion 0 11% <0.001 CRB 65 0 1-2 3-4 16 (55%) 12 (41%) 0 15 (23%) 48 (74%) 1 (1.5%9 0.003 Hyponatremia 0 15 (23%) <0.001 MV 0 4 (6%) <0.001 Died (30d) 0 10 (15.4% <0.001 Died (6 mth) 0 12 (18.5%) <0.001 Von Baum H, Welte T. CID 2008 May 1;46(9):1356-64 76% 68% Approbriate Therapy
Who is a “patient at risk”? Enterobacteriacae * 55% of all EB isolates were indeterminate Von Baum H, Welte T. ERJ 2010 Mar;35(3):598-605. Resp. sample available, no EB/PA (n = 1840) Definite EB (n = 22) Indeterminate EB (n = 27) * Age (mean, yrs) 58 ± 18 64 ± 17 68 ± 11 Nursing home resident (%) 2 23 7 Chronic resp. disease 37 68 52 Enteral tube feeding 0.6 23 11 Mortality 4 18 4 28
Pseudomonas aeruginosa Combination therapy • If combination therapy is required then combine with – + Aminoglycoside • Gentamycin/tobramycin 6 mg/kg body weight/day as a single dosage (trough level < 2 mg/L) • Amikacin 20-25 (-30) mg/kg body weight/day as a single dosage – + Fluoroquinolones • Ciprofloxacin (800-1200 mg daily) • Levofloxacin (1000 mg daily)
Proportion of 3rd generation cephalosporin-resistant (R) Klebsiella pneumoniae Isolates in participating countries in 2012 http://www.ecdc.europa.eu/en/healthtopics/antimicrobial_resistance/, 19.11.13
ESBL Treatment • Carbapenems, Carbapenems, Carbapenems …..
Proportion of carbapenem-resistant (R) Klebsiella pneumoniae isolates in participating countries in 2012 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 2011 • 125 patients with bloodstream infections (BSIs) caused by KPC-producing Kp isolates (KPC-Kp) diagnosed • 30-day mortality rate was 41.6% – monotherapy 54.3%) – combined drug therapy 34.1%; P = .02. • 30-day mortality was independently associated with • septic shock at BSI onset (OR: 7.17; P = .008) • inadequate initial antimicrobial therapy (OR: 4.17; P = .003) • high APACHE III scores (OR: 1.04; 95% P < .001).
34-year-old female, Intermediate Care Unit • Pneumoccal urine antigen positive • Blood culture positive for S. pneumoniae • Therapy: – 400 mg moxifloxacin o.d. intravenously • Oxygen supplementation • Low dose low molecular heparin
34-year-old female, Intermediate Care Unit Day 3 • CRP and PCT decrease quickly • Respiratory Rate at rest 16/minute • Temperature: 37.8°C • SaO2 (2 l oxygen supplementation) 96% • Biochemistry – BUN 19 mmol/L – Glucose 9.8 mmol/L
C-reactive protein (CRP): Correlation with appropriateness of therapy Bruns et al. Eur Respir J 2008;32:726–32 • Patients with inappropriate antibiotic treatment have a slower decline in CRP levels in first week of follow-up
34-year-old female, Intermediate Care Unit Day 3 • Patient transferred to a normal ward • Moxifloxacin i.v. switched to 400mg Moxifloxacin oral • Early mobilisation out of bed
The ProCAP study – Antibiotic duration Christ-Crain M et al, AJRCCM 2006; 174(1):84-93 p < 0.001 Standard group PCT group 20 19 17 13 12 10 8 6 4 2 Antibiotic duration (days) 15 Standard group PCT group 100 90 80 70 60 50 40 30 20 10 0 AB started > 4d > 6d > 8d > 10d > 14d > 21d Antibiotic Prescriptoin (%)
34-year-old female, normal ward When to discharge from the hospital? • Heart rate ≤ 100/min, • Respiratory rate ≤ 24/min, • Systolic blood pressure ≥ 90 mmHg • Temperature ≤ 37.8 °C, • Eating and drinking not altered • Normal mental status • No hypoxemia (PO2 ≥ 60 mm Hg, SaO2 ≥ 90%)
Hot Topics in Pneumogenic Sepsis and ARDS • (Pneumogenic) Sepsis – General considerations – Treatment – New Antibiotics – Immunomodulators • ARDS – Ventilation strategies – Immunomodulators
2008 2012 Grading D. Antibiotic therapy 1.a. Administration of effective iv ABs within the 1. hour of recognition of septic shock 1B 1B 1.b. Administration of effective iv ABs within the 1. hour of recognition of severe sepsis 1D 1C ↑ 2.a. Initial empiric anti-infective therapy of one or more drugs that have activity against 1B 1B all likely pathogens and that penetrate in adequate concentrations into tissues presumed to be the source of sepsis 2.b. Antimicrobial regimen should be reassessed daily for potential deescalation 1C 1B ↑ 3. Use of biomarkers to assist the clinician in the discontinuation of empiric antibiotics in patients who initially appeared septic, but have no subsequent evidence of infection nn 2C ↑ 4.a. Combination empirical therapy for neutropenic patients with severe sepsis 2D 2B ↑ for pts with difficult to treat, MDR bacterial pathogens f.e. Acinetobacter/Pseudomonas nn 2B ↑ For pts with severe infections associated with respiratory failure and septic shock, 2D 2B ↑ combination therapy with an extended spectrum beta-lactam and either an aminoglycoside or a fluoroquinolone is for P. aeruginosa bacteremia A combination of beta-lactam and macrolide for patients with septic shock from bacteremic Streptococcus pneumoniae infections nn 2B ↑ 4.B Empiric combination therapy not be for more than 3–5 days. De-escalation to the most appropriate single therapy as soon as the susceptibility profile is known 2D 2B ↑ 5. Duration of therapy typically 7–10 days; longer courses may be appropriate in pts with a slow clinical response, undrainable foci of infection, bacteremia with S. aureus; some fungal and viral infections or immunologic deficiencies, including neutropenia 1D 2C ↓ 6. Antiviral therapy initiated as early as possible in patients with severe sepsis or septic shock of viral origin nn 2C ↑ 7. Antimicrobial agents should not be used in patients with severe inflammatory states determined to be of noninfectious cause 1D UG ↑
Sepsis Trials - Site and Source of Infection MeroMono N = 273 MeroMoxi N = 278 All patients N = 551 Site of infection Pneumonia 105 (38.46) 119 (42.81) 224 (40.65) Other respiratory tract 18 (6.59) 18 (6.47) 36 (6.53) Intraabdominal 99 (36.26) 111 (39.93) 210 (38.11) Bones or soft tissue 20 (7.33) 16 (5.76) 36 (6.53) Surgical wound infection 15 (5.49) 5 (1.80) 20 (3.63) Urogenital 39 (14.29) 25 (8.99) 64 (11.62) Primary bacteremia 5 (1.83) 11 (3.96) 16 (2.90) Other 13 (4.76) 11 (3.96) 24 (4.36) Source of infection Community-acquired 136 (49.82) 141 (50.72) 277 (50.27) Nosocomial 137 (50.18) 136 (48.92) 273 (49.55) Missing 0 1 (0.36) 1 (0.18) Infection at study enrollment Microbiologically confirmed 97 (35.53) 99 (35.61) 196 (35.57) Clinical evidence 176 (64.47) 179 (64.39) 355 (64.43) Brunkhorst F. JAMA 2012; 307: 2390-9
Sepsis Mortality Delay of antibiotic treatment • Retrospective analysis (1/2005 - 2/2010) of a large dataset collected prospectively for the Surviving Sepsis Campaign • A total of 28,150 patients with severe sepsis and septic shock • A total of 17,990 patients received antibiotics after sepsis identification • In-hospital mortality was 29.7% • Statistically significant increase in the probability of death associated with the number of hours of delay for first antibiotic administration. • Adjusted hospital mortality increased steadily after 1 hour of time to antibiotic administration. • Results were similar in patients with severe sepsis and septic shock, regardless of the number of organ failure Ferrer R. CCM 2014; 42: 1749-55
Sepsis Mortality Delay of antibiotic treatment Ferrer R. CCM 2014; 42: 1749-55
Delay of Antibiotic Therapy • Retrospective review of adult admissions for CAP for 2 periods – group 1 (255 pts), when the core quality measure was a TFAD of less than 8 hours – group 2 (293 pts), when the TFAD was lowered to less than 4 hours. • Accuracy of diagnosis of CAP were assessed by ED physicians • At admission, group 2 patients were 39.0% less likely to meet predefined diagnostic criteria for CAP than were group 1 patients (odds ratio, 0.61; 95% confidence interval, 0.42-0.86) (P=.004). • At discharge, there was agreement CAP between the ED physician’s diagnosis and the predefined criteria for CAP in 62.0% of group 1 and 53.9% of group 2 patients (P=.06) Welker JA. Arch Intern Med. 2008;168(4):351-356
Lancet Infect Dis 2012; 12: 774–80 • Pre-/post study in a surgical ICU in the US – Aggressive therapy (01.09.2008-31.08.2009) • If an infection was suspected antibiotic treatment was initiated immediately – Conservative therapy (01-09.2009-31.08.2010) • Initiation of an antibiotic therapy only, when an inection has been confirmed by diagnostic results 4
• Prä-/post Studie auf einer chirurgischen Intensivstation in den USA • konservative Therapie vs. aggressive Therapie – verringerten Krankenhaussterblichkeit (13/100 [13%] gegenüber 27/101 [27%]; p=0·015) – höheren Rate an primär adäquater Antibiotikatherapie (158/214 [74%] im Vergleich zu 144/231 [62%]; p=0·0095) – kürzere Therapiedauer (12·5 Tage [SD 10·7] gegenüber 17·7 [28·1 Tage: p=0·0080) Hranjec T et al. Lancet Infect Dis 2012; 12: 774–80 4 Suspected infectious disease Delay 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 disease Delay 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
SOFA Score (Points) – mean and 95% CI Organ Dysfunction (SOFA Score) Intention-to-treat population Per-protocol population 1 3 5 7 9 11 13 Study Day 14 12 10 8 6 4 2 0 Monotherapy Combination therapy t-test p=0.36 * Monotherapy Combination therapy t-test p=0.37 * 1 3 5 7 9 11 13 14 12 10 8 6 4 2 0 SOFA Score (Points) – mean and 95% CI Study Day Patients evaluable: Monotherapy 249 212 167 137 124 103 89 Combination therapy 255 209 179 153 125 95 81 Patients evaluable Monotherapy 181 156 122 96 88 71 63 Combination therapy 198 165 141 119 96 71 57
100 90 80 70 60 50 40 30 20 10 0 Overall Survival Intention-to-treat population Per-protocol population Monotherapy Combination therapy 0 14 28 42 56 70 84 Days Overall Survival (%) log rank p=0.42 Patients at risk: Monotherapy 273 222 211 193 188 184 179 Combination therapy 276 224 210 193 186 180 177 Overall Survival (%) 100 90 80 70 60 50 40 30 20 10 0 Monotherapy Combination therapy log rank p=0.59 0 14 28 42 56 70 84 Days Patients at risk: Monotherapy 199 164 156 143 138 137 132 Combination therapy 214 176 166 155 150 146 144
ß-Lactam Monotherapy vs. ß-Lactam- Aminoglycosid Combination Therapy in Sepsis: A Metaanalysis Total Mortality Treatment Failure Bakterial Superinfection Adverse Events Nephrotoxicity N Studies N Patients ß-Mono vs. ß-AG Combi 43 63 27 39 45 Paul M.BMJ 2004; 328: 668 5527 6616 3085 4945 5213 0,90 (0,77 - 1,06) 0,87 (0,78 - 0,97) 0,79 (0,59 - 1,06) 0,91 (0,80 - 1,04) 0,36 (0,28 - 0,47)
Mono- vs. Combination Therapy for VAP • Randomised controlled trial in 740 pts – Mechanical ventilated – VAP suspected after 4 days in the ICU – Pts. with known Pseudomonas or MRSA excluded • Meropenem 1g tid + Ciprofloxacin 400 mg bid • vs. Meropenem alone • Outcome Parameters: – No difference in 28-day mortality (RR 1.05, p=0.74) Heyland D. CCM 2008; 36: 737-44
Mono- versus Combination Therapy Kumar A. Crit Care Med 2010; 38:1651–1664 • Metaanalysis of RCTs or observational studies comparing mono- and combination therapy in patients with sepsis • no overall mortality/clinical response benefit with combination therapy (odds ratio, 0.856) • substantial benefit in the most severely ill subset (monotherapy risk of death >25%; odds ratio of death, 0.51) • Meta-regression indicated that efficacy of combination therapy was dependent only on the risk of death in the monotherapy group. 30
Antibiotics Pharmacokinetics in severly ill patients • Charakteristic of severly ill patients – High Cardiac Index – Increased distribution volume – Altered plasma protein binding
Antibiotics Pharmacokinetics in severly ill patients • Consequences – Dosage of antibiotics at the highest approved level (and above) – Take pentrtaion properties into the tissue were the infection is suspected, into account – Combination therapy for MDR pathogenes
2000 HAP- TGC Serum concentration Mean tigecycline (TGC) serum concentrations in subjects with hospital-acquired pneumonia after intravenous infusions. Ramirez J et al. 2013 Apr;57(4):1756-62.
Clinical response in phase 2 (study 2000) vs. phase 3 (study 311) HAP trials 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 Therapy Primary Site of Infection • Pneumonia – Community Acquired • S. pneumoniae • L. pneumophila – Ventilator Associated Pneumonia • MRSA • ESBL • P. aeruginosa • Intraabdominal Infection – Peritonitis • Anaerobes • Vancomycin resistant Enterococci • Urinary Tract Infection • ESBL • Soft and Skin Tissue Infection • MRSA • Sepsis of Unknown Origin • MRSA
Rodriguez. CCM: 35(6)June 2007: 1493-1498
A pressing need for antibiotic agents effective against both MSSA and MRSA 50 40 30 20 10 *Excludes patients with IE Nafcillin (n=18) Vancomycin (n=70) 1 15 0 8 0 5 0 13 0 Persistent >3 days Persistent >7 days Relapse Bacteriologic Failure Chang F et al. Medicine 2003;82:333–339 Efficacy of nafcillin vs vancomycin in MSSA bacteraemia* Vancomycin was an independent factor associated with failure (OR: 6.5, P=0.048)
MRSA infections Treatment different for different sites of infection • Pneumonia – Linezold • Sepsis – Pneumogenic Sepsis • Linezolid + Vancomycin – Sepsis of unknown origin • Vancomycin or daptomycin • Joint/Valve infection – Daptomycin • CNS Infection – Ceftarolin
Linezolid vs. Vancomycin in MRSA nosocomial pneumonia Adults with MRSA-HAP N = 1225 Linezolid 600 mg i.v. / p.o every 12 h * Exclusion if no MRSA could be detected Vancomycin 15 mg/kg i.v. every 12 h * EOT-Visit 5 d after last dosage R 1:1 EOS-Visit 7-30 d after last dosage Duration of therapy7-14 d (til 21d in confirmed bacteremia) * Initial Coverage of gram-negatives with Cefepim or other non MRSA susceptible antibiotics
Clinical Cure (PP at EOS) 57,6 P-Value = 0,042 95% CI = 0,5%; 21,6% 46,6 80 60 40 20 0 Linezolid Vancomycin Clincal Sucess Rate (%) n = 165 n = 174 Kunkel M et al. IDSA 2010; Presentation LB-49.
Ceftaroline fosamil: Administered as a Prodrug N S O S N N+ O O NH N S N NH N O P HO O HO S CH 3 O N N S S N+ O O N H N S N H N 2 N O S CH 3 O O Prodrug: Ceftaroline fosamil Active metabolite: Ceftaroline Plasma phospatase mod. nach Zhanel et al, Drugs 2009, 69 (7): 809-31 Rapid biotransformation in plasma Bactericidal activity
Fokus I Outcome File TM et al. JAC 2011; 66 Suppl 3: iii19–iii32
Standard Treatment gram negatives • E. coli/Enterobakteriacae – Ampicillin/Inhibitor Combinations – 2. and 3. Generation Cephalosporines – Ertapenem • Pseudomoas aeruginosa/Acinetobacter – Piperacillin/Tazobaktam – 4. Generation Cephalosporines – Carbapenemes • St. maltophilia – Fluorquinolones – Cotrimoxazol
Pseudomoas aeruginosa Combination Therapy • If combination therapy is required then combine with – + Aminoglycosid • Gentamycin/Tobramycin 6 mg/kg BW per day as a single dosage (Through Level < 2 mg/L) • Amikacin 20-25 (-30) mg/kg KG BW per day as a single dosage – + Fluorquinolones • Ciprofloxacin (800-1200 mg tgl.) • Levofloxacin (1000 mg tgl.)
Proportion of 3rd gen. cephalosporins Resistant (R) Klebsiella pneumoniae Isolates in Participating Countries in 2012 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) Borer A, et al. Infect Control Hosp Epidemiol. 2009;30:972-6. • 32-patient cohort with KPC bacteremia • 32 non-bacteremic KPC control patients matched for time period, comorbidities, underlying disease, age, and sex Study patients Control patients Required intensive care 12 (37.5%) 3 (9.4%) Required ventilator support 17 (53.1%) 8 (25%) Required central venous catheter 19 (59.4%) 9 (28.1%) Crude Mortality Rate* 23 (71.9%) 7 (21.9%)  Attributable Mortality for Study Patients: 50% (95% CI, 15.3 – 98.6)  Mortality Risk Ratio for Study Patients: 3.3 (95% CI, 2.9 – 28.5) *P < 0.001
Revival of „old“ drugs Tigecyclin • Phase II-Study in patients with hospital acquired pneumonia – Tigecyclin 75 mg twice daily – Tigecyclin 100mg twice daily – Imipenem/Cilastatin 1g three times a day • Primary Endpoint: Advers Events – No significant difference between the groups • Secondary Endpoint: Clinical Cure – Both tigecyclin groups were non inferior to Imipenem/Cilastatin – High dose tigecyclin was in trend more effective than low dose tigecyclin and imipenem/cilastatin Ramirez J et al. 2013 Apr;57(4):1756-62. 10
Revival of „old“ drugs Colistin • Combination Therapy (?) with – Colistin • 9 Mill. E Loading Dose • 4.5 Mill E twice daily as maintenance therapy • + inhaled colistin ???
Predictors of mortality in patients with bloodstream infections caused by KPC-producing K. pneumoniae and impact of appropriate antimicrobial treatment • 53 patients • Overall mortality was 52.8% and infection mortality was 34% • In the appropriate therapy group mortality due to infection occurred in 20% – 0/20 given combination therapy – 7/15 given appropriate monotherapy died (p 0.001). • In univariate analysis, risk factors for mortality were: – age (p <0.001) – APACHE II score at admission and infection onset (p <0.001) – severe sepsis (p <0.001) • Variable for survival: – appropriate antimicrobial treatment (p 0.003) – Combinations of active antimicrobials (p 0.001) – catheter-related bacteraemia (p 0.04) – prior surgery (p 0.014) Zarkotou O et al. Clin Microbiol Infect. 2011;17:1798-803
Tumbarello M. Clinical Infectious Diseases 2012;55(7):943–50 • Multicenter retrospective cohort study, in 3 large Italian teaching hospitalsbetween 1 January 2010 and 30 June 2011 • 125 patients with bloodstream infections (BSIs) caused by KPC-producing Kp isolates (KPC-Kp) diagnosed • 30-day mortality rate was 41.6% – monotherapy (54.3% – combined drug therapy 34.1%; P = .02). • 30-day mortality was independently associated with – Postantibiogram therapy with a combination of tigecycline, colistin, and meropenem was associated with lower mortality (OR: 0.11; P = .01) 21
Multivariate analysis of factors associated with death among patients with bloodstream infection due to KPC producing Klebsiella Pneumoniae. Shock - - 0.008 7.17 (1.65-31.03) Inadequate initial treatment - - 0.003 4.17 (1.61-10.76) APACHE III score (mean ± SD) - - <0.001 1.04 (1.02-1.07) Tigecycline & Colistin & Meropenem - - 0.01 0.11 (0.02-0.69) Tumbarello M, Viale PL, Viscoli C, Bassetti M et al. Clin Infect Dis, 2012; Oct;55(7):943-50
Why Colistin plus Rifampin ? • Two-steps, sequential mechanism of action • Colistin disrupt the outer bacterial cytoplasmic membrane • Rifampin inhibit DNA-dependent RNA-polymerase at the ribosomal -subunit • Some preliminary experience on A. baumannii
Durante-Mangoni E. et al. Clinical Infectious Diseases 2013; 57(3):349–58
Inhaled Antibiotics in the ICU • Retrospective matched case-control study in Greece • Patients with VAP due gram-negative MDR pathogens – 43 pts. received AS plus IV colistin – 43 control patients who had received IV colistin alone • Microbiology – Acinetobacter baumannii (66 cases [77%]) – Klebsiella pneumoniae (12 cases [14%]) – Pseudomonas aeruginosa (8 cases [9.3%]) • No significant differences between the 2 groups were observed regarding – eradication of pathogens (P = 679) – clinical cure (P=.10) – mortality (P=.289). Kofteridis D. et al. Clinical Infectious Diseases 2010; 51(11):1238–1244
Inhaled antibiotics for VAP Liu Q et al.Anesthesiology 2012; 117:1335-47
Hot Topics in Pneumogenic Sepsis and ARDS • (Pneumogenic) Sepsis – General considerations – Treatment – New Antibiotics – Immunomodulators • ARDS – Ventilation strategies – Immunomodulators
New Antibiotics The Pipeline • Gram positive Infection – New Oxazolidinones • Tedizolid – Pleuromutilines • Gram negative Infection – ESBL/KPC Activity • New beta-lactam inhibitors • Pseudomonas activity – Ceftobiprole – Ceftolozan/Tazobactam – β-Hairpin Peptidomimetika (PEM)
ESTABLISH – 1 Tedizolid versus Linezolid bei cSSTI • Phase II schwere Haut- und – Tedizolid 200 mg einmal täglich oral – Linezolid 600 mg zweimal täglich oral über je 10 Tage • primärer Outcome Parameter: – Ansprechen auf die Therapie nach 48-72 Stunden • Ergebnisse – Intent-to-treat Analyse für die Rate des frühen klinischen Ansprechens 79.5% in der Tedizolid Gruppe (332 Patienten) und 79.4% in der Linezolid Gruppe (335 Patienten) – klinischen Erfolgsrate nach Ende der Therapie (Tag 11) 69.3% in der Tedizolid Gruppe und 71.9% in der Linezolid Gruppe. – Die Ergebnisse für die 178 Patienten mit primären MRSA Nachweis entsprachen dem Gesamtergebnis. Prokocimer P et alJAMA. 2013 Feb 13;309(6):559-69. 46
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) 52% 37% 30% 74% 50% Awad et al., Clin Infect Dis. 2014 Welte T. ERS 2014, Poster 4643 57% 60% 45% 44% 31% 46% 56% 36% 54% 100% 80% 60% 40% 20% 0% % with clinical cure at TOC Ce obiprole Ce azidime/Linezolid Number 111 57 50 46 54 23 22 30 36 14 10 108 All ICU pa ents APACHE II ≥15 14 13 Mech. Vent. COPD S. aureus MRSA P. aeruginosa
Patients with bacteraemia (ITT) 29% 25% 21% Awad et al., Clin Infect Dis. 2014 Welte T. ERS 2014, Poster 4643 17% 30% 24% 37% 41% 60% 50% 40% 30% 20% 10% 0% % with outcome Ce obiprole Ce azidime/Linezolid Number 27 12 17 24 27 12 17 24 All pa ents All ICU pa ents All ICU pa ents All pa ents Clinical cure (TOC visit) 30-day all-cause mortality
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!
IgM immunoglobulins for infection - Why? Humoral immune response: anti-bacterial modes of action IgM exhibits: 100-fold higher phagocytosis-promoting activity compared to IgG10 1000-fold higher affinity towards C1q (first protein in the classical complement pathway) than IgG11 neutralization of antibiotic-induced endotoxin release12 1. Increase of bacterial phagocytosis 2. Induction of bacterial lysis due to specific activation of complement on bacterial surfaces 3. Neutralisation of toxins Molnar Z, Nierhaus A, Esen F. Annual Update in ICEM 2013; 145-52
A randomized, double-blind, placebo-controlled, multicenter, parallel-group, adaptive group-sequential phase II study, to determine the efficacy and safety of BT086 as an adjunctive treatment in severe community acquired pneumonia (sCAP) The CIGMA trial 122 • Study Medication  BT086 - IgM Concentrate (42mg/kg bw/day)  Placebo 1% Albumin • Study phases  Pre-treatment: Pts are randomised max.12 h after start of mech ventilation  Treatment: 5 consecutive days  Follow-up: Pts stay in study until d28 or discharge from hospital.
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 - major outcome parameters ARMA trial, NEJM 342:1301, 2000
Potential advantages of the „awake ECMO“ concept vs. conventional therapy • Pat. awake, cooperative, able to eat and drink • No risk of ventilator-associated pneumonia, i.e. potentially lower risk of septicemia • Detrimental effects of long-term mechanical ventilation and analgosedation avoided • Active exercise programs allows avoiding muscular atrophy
Awake ECMO in ARDS
Awake ECMO in ARDS • Six patients with severe ARDS, four immunocompromised • 4 out of 6 survived Hoeper MM et al. ICM 2013 (in press)
ARDS Prone Position • Multicenter, prospective, RCT • 466 patients with severe ARDS – prone-positioning sessions of at least 16 hours (237 pts) – supine position (229 pts) • 28-day mortality 16.0% in the prone group, 32.8% in the supine group (P<0.001). • 90-day mortality 23.6% in the prone group, 41.0% in the supine group (P<0.001) • Incidence of AEs not significantly different between the groups Guerin C et al. NEJM 2013; 368:2159-68
Hot Topics in Pneumogenic Sepsis and ARDS • (Pneumogenic) Sepsis – General considerations – Treatment – New Antibiotics – Immunomodulators • ARDS – Ventilation strategies – Immunomodulators
ARDS Etiology ARDS Network. NEJM 2014; 370 (23):2191-200
Subgroup analyses - Mortality Adjusted proportional hazard models for the effect of addition of moxifloxacin on overall survival 0.5 1 2 3 4 Hazard Ratio 0.2 B Intention to treat Per protocol set SOFA score at baseline <= 9 points SOFA score at baseline >= 10 points Study treatment >= 4 days Nosocomial infection Community acquired infection Microbiologically documented Clinically suspected Surgical patients Medical patients Gram-negative infection Gram-positive infection Bacteremic infection Non-bacteremic infection Gram-negative bacteremia Gram-positive bacteremia Pneumonia Intraabdominal Urogenital Severe Sepsis Septic Shock adjusted HR (95% CI) p-value 1.09 (0.70; 1.69) 0.84 (0.54; 1.32) 1.54 (0.89; 2.66) 0.78 (0.53; 1.15) 1.11 (0.73; 1.71) 0.82 (0.51; 1.32) 1.19 (0.75; 1.88) 1.07 (0.69; 1.64) 0.88 (0.51; 1.52) 1.10 (0.74; 1.63) 0.79 (0.33; 1.89) 0.88 (0.38; 2.06) 1.07 (0.64; 1.77) 1.15 (0.70; 1.88) 1.48 (0.56; 3.92) 0.710 0.456 0.125 0.209 0.618 0.425 0.464 0.767 0.639 0.652 0.597 0.774 0.799 0.591 0.434 1.00 (0.73; 1.36) 0.94 (0.65; 1.35) 1.05 (0.63; 1.74) 0.90 (0.60; 1.34) 1.12 (0.76; 1.66) 0.986 0.720 0.864 0.604 0.572 70 out of 225 patients died 2.01 (0.98; 4.12) 0.81 (0.57; 1.16) 0.055 0.245 No. 273 199 141 132 206 137 136 97 176 146 127 149 140 90 183 40 49 105 99 39 Monotherapy Combination Therapy Death Cases 85 59 37 48 57 43 42 32 53 47 38 47 43 30 55 12 14 32 37 14 No. 276 214 153 123 209 135 141 98 178 162 114 120 155 93 183 33 58 119 110 25 Death Cases 96 70 43 53 61 46 50 28 68 50 46 46 53 37 59 19 15 38 40 8 74 199 18 67 84 192 20 76 = 31.1% Brunkhorst FM. JAMA 2012; 307: 2390-99
Statins to treat infammation in ARDS ARDS Network. NEJM 2014; 370 (23):2191-200
Subgroup analyses - Mortality Adjusted proportional hazard models for the effect of addition of moxifloxacin on overall survival 0.5 1 2 3 4 Hazard Ratio 0.2 B Intention to treat Per protocol set SOFA score at baseline <= 9 points SOFA score at baseline >= 10 points Study treatment >= 4 days Nosocomial infection Community acquired infection Microbiologically documented Clinically suspected Surgical patients Medical patients Gram-negative infection Gram-positive infection Bacteremic infection Non-bacteremic infection Gram-negative bacteremia Gram-positive bacteremia Pneumonia Intraabdominal Urogenital Severe Sepsis Septic Shock adjusted HR (95% CI) p-value 1.09 (0.70; 1.69) 0.84 (0.54; 1.32) 1.54 (0.89; 2.66) 0.78 (0.53; 1.15) 1.11 (0.73; 1.71) 0.82 (0.51; 1.32) 1.19 (0.75; 1.88) 1.07 (0.69; 1.64) 0.88 (0.51; 1.52) 1.10 (0.74; 1.63) 0.79 (0.33; 1.89) 0.88 (0.38; 2.06) 1.07 (0.64; 1.77) 1.15 (0.70; 1.88) 1.48 (0.56; 3.92) 0.710 0.456 0.125 0.209 0.618 0.425 0.464 0.767 0.639 0.652 0.597 0.774 0.799 0.591 0.434 1.00 (0.73; 1.36) 0.94 (0.65; 1.35) 1.05 (0.63; 1.74) 0.90 (0.60; 1.34) 1.12 (0.76; 1.66) 0.986 0.720 0.864 0.604 0.572 92 out of 277 patients died 2.01 (0.98; 4.12) 0.81 (0.57; 1.16) 0.055 0.245 No. 273 199 141 132 206 137 136 97 176 146 127 149 140 90 183 40 49 105 99 39 Monotherapy Combination Therapy Death Cases 85 59 37 48 57 43 42 32 53 47 38 47 43 30 55 12 14 32 37 14 No. 276 214 153 123 209 135 141 98 178 162 114 120 155 93 183 33 58 119 110 25 Death Cases 96 70 43 53 61 46 50 28 68 50 46 46 53 37 59 19 15 38 40 8 74 199 18 67 84 192 = 33.2% 20 76 Brunkhorst FM. JAMA 2012; 307: 2390-99
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

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Dr. Tobias Welte: Lessons learned from the CAPNETZ study

  • 1.
    Community Acquired Pneumoniain the Emergency Room How Would You Decide? Tobias Welte Department of Respiratory Medicine
  • 2.
    34-year-old female, GPvisit 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)
  • 3.
    34-year-old female, GPvisit 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
  • 4.
    Steroid Use inAsthma - A Risk Factor for CAP? McKeever T. Chest 2013; 144: 1788-94 • Primary care data from The Health Improvement Network in the UK • People with asthma with pneumonia or lower respiratory tract infection • Age- and sex-matched control subjects. • The highest strength of ICS ( ≥1,000 μg) had a 2.04 increased risk of pneumonia or LTRI compared with no prescription for ICS within the previous 90 days
  • 5.
    34-year-old female, GPvisit 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
  • 6.
    Diagnosis and managementof the at risk CAP patient Who is a “patient at risk”? • A patient at risk with regard to – Etiology – Severity of the disease • Clinical assessment • Biomarker – Age – Co-morbidity – Setting • ‘Health care associated pneumonia’
  • 7.
    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
  • 8.
    Patients with CAPand episodes of CAP with a pathogen identified A. Torres et al. Eur J Clin Microbiol Infect Dis. 2014 Feb 15. [Epub ahead of print]
  • 9.
    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.
  • 10.
    Who is a“patient at risk”? Staphylococcus aureus • Observational study in 627 patients hospitalized with CAP from 12 university-affiliated emergency departments during the winter–spring of 2006 and 2007 • MRSA in 14 (2.4%) patients and in 5% of patients admitted to the ICU • Two (14%) MRSA pneumonia patients died • All 9 MRSA isolates tested were pulsed-field type USA300 • Features significantly associated with isolation of MRSA patient history of MRSA – nursing home admission in the previous year – close contact in the previous month with someone with a skin infection – multiple infiltrates or cavities on chest radiograph – and comatose state, intubation, receipt of vasopressors, or death in the emergency department Moran GJ. Clinical Infectious Diseases 2012;54(8):1126–33
  • 11.
    Mycoplasma pneumoniae •4,532 pts of the German CAPNETZ Study • 307 pts (= 6.8%) had definite M. pneumoniae infection – 148 with positive PCR – 159 positive IgM titer • 621 had other definite bacterial pathogens • 3604 with no known bacterial origin • MPP pts. In comparision to the other groups significantly – were younger – had less co-morbidities – had less severe disease – had less inflammatory response – had better outcomes • shorter length of hospitalization • less mechanical ventilation • minimal mortality. no bacterial pathoge 2146 2494 Legionella spp. N = 3604 367 139 307 110 PLOT Other pyogenic bacte M.pneumoniae S.pneumoniae ALT 120 100 80 60 40 20 0 13243909 1490 1167815 23480268924599244 233378289157 134025344017 Von Baum H, Welte T. BMC Infectious Disease 2009
  • 12.
    Who is a“patient at risk”? Legionella • Prospective observational study (CAPNETZ) • 2,503 adults • Diagnosis of Legionella (3.8% of all CAP cases) confirmed by – Culture (0.1%) – PCR (1.7%) – Urine antigen (2.2%) • Mortality – Legionella 12.8% – Other pathogen 9.7% – Unknown pathogens 11.3% Variables Outpatients N = 29 Hospitalized N = 65 P-value Age  65 y   SD 31 % 55.4  15.7 y 60 % 66.9  14.5 y 0.001 Male 48% 71% ns Smoker 35% 32% ns Diabetes 7% 35% < 0.001 Fever 45% 59% ns Confusion 0 11% <0.001 CRB 65 0 1-2 3-4 16 (55%) 12 (41%) 0 15 (23%) 48 (74%) 1 (1.5%9 0.003 Hyponatremia 0 15 (23%) <0.001 MV 0 4 (6%) <0.001 Died (30d) 0 10 (15.4% <0.001 Died (6 mth) 0 12 (18.5%) <0.001 Appropriate therapy 76% 68% Von Baum H, Welte T. CID 2008 May 1;46(9):1356-64
  • 13.
    CAP through Gram-negativeEnterobacteriaceae (GNEB): The CAPNETZ group Von Baum H, Welte T. ERJ 2010 Mar;35(3):598-605. n % total population % population with resp. samples Pat. without resp. samples 3914 Pat. with resp. samples 1216 GNEB in resp. Samples, definite 40 0.8 3.3 GNEB-bacteremia 27 0.5 2.2 GNEB, indeterminate 172 3.4 14.1
  • 14.
    Independent risk factors for CAP through GNEB* Von Baum H, Welte T. ERJ 2010 Mar;35(3):598-605. Variable p OR 95% CI Age > 65 Yrs .000 2.60 1.51-4.51 Gender .387 Nursing home residency .000 3.90 2.00-7.47 Cardiovascular disease .000 4.16 2.49-6.93 Malignancy .405 2.43 1.79-3.30 Smoker .220 COPD .123 PEG .088 Cerebrovascular disease .000 4.79 2.76-8.26 Diabetes .003 2.35 1.34-4.09 * Gram-negative Enterobacteriaceae
  • 15.
    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
  • 16.
    Who is a“patient at risk”? Age Ewig S et al. Thorax 2009; 64: 1092-9
  • 17.
    Lancet 2013; 381:1987–2015 Funding: Bill & Melinda Gates Foundation.
  • 18.
    N Engl JMed 2013; 369:448-57.
  • 19.
    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
  • 20.
    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)
  • 21.
    Subgroup analyses -Mortality Adjusted proportional hazard models for the effect of addition of moxifloxacin on overall survival 0.5 1 2 3 4 Hazard Ratio 0.2 B Intention to treat Per protocol set SOFA score at baseline <= 9 points SOFA score at baseline >= 10 points Study treatment >= 4 days Nosocomial infection Community acquired infection Microbiologically documented Clinically suspected Surgical patients Medical patients Gram-negative infection Gram-positive infection Bacteremic infection Non-bacteremic infection Gram-negative bacteremia Gram-positive bacteremia Pneumonia Intraabdominal Urogenital Severe Sepsis Septic Shock adjusted HR (95% CI) p-value 1.09 (0.70; 1.69) 0.84 (0.54; 1.32) 1.54 (0.89; 2.66) 0.78 (0.53; 1.15) 1.11 (0.73; 1.71) 0.82 (0.51; 1.32) 1.19 (0.75; 1.88) 1.07 (0.69; 1.64) 0.88 (0.51; 1.52) 1.10 (0.74; 1.63) 0.79 (0.33; 1.89) 0.88 (0.38; 2.06) 1.07 (0.64; 1.77) 1.15 (0.70; 1.88) 1.48 (0.56; 3.92) 0.710 0.456 0.125 0.209 0.618 0.425 0.464 0.767 0.639 0.652 0.597 0.774 0.799 0.591 0.434 1.00 (0.73; 1.36) 0.94 (0.65; 1.35) 1.05 (0.63; 1.74) 0.90 (0.60; 1.34) 1.12 (0.76; 1.66) 0.986 0.720 0.864 0.604 0.572 92 out of 277 patients died 2.01 (0.98; 4.12) 0.81 (0.57; 1.16) 0.055 0.245 No. 273 199 141 132 206 137 136 97 176 146 127 149 140 90 183 40 49 105 99 39 Monotherapy Combination Therapy Death Cases 85 59 37 48 57 43 42 32 53 47 38 47 43 30 55 12 14 32 37 14 No. 276 214 153 123 209 135 141 98 178 162 114 120 155 93 183 33 58 119 110 25 Death Cases 96 70 43 53 61 46 50 28 68 50 46 46 53 37 59 19 15 38 40 8 74 199 18 67 84 192 = 33.2% 20 76 Brunkhorst FM. JAMA 2012; 307: 2390-99
  • 22.
  • 23.
    34-year-old female, GPvisit 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%
  • 24.
    CAP paCO2 asrisk 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
  • 25.
    Biomarker Blood glucoselevel • 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
  • 26.
    Biomarker Procalcitonin RiskRatio (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
  • 27.
    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) Propensity-adjusted association P = 0.05 Julio Ramirez, ERS 2008 Poster 1854 Variable AMI (n = 29) No AMI (n = 471) P Time to clinical stability, mean days ± SD 4.59 ± 2.73 3.1 ± 2.25 0.008 Length of hospital stay, mean days ± SD 9.9 ± 7.90 6.3 ± 7.68 0.01 Clinical failure 15 (61.7) 52 (11.0) <0.00 1 Mortality in hospital 8 (27.6) 32 (6.8) <0.00 1 Mortality within 30 days after hospital admission 9 (31.0) 45 (9.6) 0.001 NOTE: Data are no. (%) of patients, unless otherwise indicated 40 Pneumonia Severity Index Score 20 15 10 0 Risk of acute myocardial infarction (%) 95% CI Risk of AMI 95% CI 60 80 100 120 160 140 180 25 Ramirez J. Clin Infect Dis 2008; 47: 182-87 5 * AMI = acute myocardial infarction
  • 28.
    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
  • 29.
    Who is a“patient at risk”? Co-morbidity Corrales-Medina VF. Circulation. 2012;125:773-781 • 1,343 in-patients and 944 out-patients with CAP • Cardiac complications (new or worsening heart failure, new or worsening arrhythmias, or myocardial infarction) in 358 in-patients (26.7%) and 20 ou-tpatients (2.1%) • Most events (89.1% in in-patients, 75% in out-patients) were diagnosed within the first week, more than half of them were recognized in the first 24 hours • Incident cardiac complications were associated with increased risk of death at 30 days
  • 30.
    Frequency of co-morbidconditions in adults with community-acquired pneumonia Torres A, et al. Thorax 2013;68:1057–1065
  • 31.
    Prevalence of pathogensidentified 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]
  • 32.
    Who is a“patient at risk”? Setting: Nursing Home 60 50 40 30 20 10 0 SP Entero MRSA Leg Atyp H infl Pseudomonas Polverino E. Thorax 2010; 65: 354-59
  • 33.
    • CAPNETZ DataBase (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.
  • 34.
    Who is a“patient at risk”? Setting Ewig S, Welte T, Chastre J, Torres A. Lancet Infect Dis 2010; 10: 279–87
  • 35.
    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
  • 36.
    Who is a“patient at risk”? What does it mean in terms of treatment? Extraordinary circumstances require extraordinary measures Helmut Kohl, German Chanecellor, 1982
  • 37.
    Mono- vs CombinationTherapy • Observational study of the German competence network CAPNETZ • 1,854 patients – Betalactam monotherapy – Betalactam/Macrolide Combination Therapy (BLM) • BLM-therapy was associated with – lower 14-day mortality in total (OR 0.49; CI: 0.28-0.85). – 14-day mortality risk was reduced in pts with CRB65 =2 (OR 0.35; CI: 0.12-0.99) and CRB65 ≥2 (OR 0.38; CI: 0.17- 0.86), but not in CRB65 ≤1 – lower risk of treatment failure at 14 days (OR 0.65; CI 0.47-0.89) and 30 days (OR 0.69; CI 0.51- 0.94) • CRB65, neoplastic disease and nursing home residency were independent predictors of death. 4692 patients with CAP prospectively evaluated July 2002 – December 2006 with complete data for CRB65 and follow-up Hospitalised patients N= 3216 Initial intravenous (iv) ß-lactam regimen N= 2255 Initial ß-lactam iv ≥72h (mono- or + macrolide) N= 1854 BL N= 908 BLM N= 946 Out-patients N= 1476 Other antibiotic regimen N= 961 ß-lactam iv + other antibiotic or ß-lactam iv < 72h, N= 401 Tessmer A, Welte T. JAC 2009; 63: 1025-33
  • 38.
    Ewig S. etal. Thorax 2011; online
  • 39.
    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.
  • 41.
    CAP – combinationvs Mono-betalactam therapy Restrepo MI. ERJ 2009 Jan;33(1):153-9.
  • 42.
    Antibiotics and inflammatoryresponse • 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
  • 43.
    MOTIV Study Torreset al. ECCMID 2006, Poster 1061; Read et al. ERS 2006, Poster 2083; Pre-therapy Test of cure Days 5–7 post-therapy Days 3–5 Stratification Randomisation PSI IV&V (≥50%) MXF 400 mg IV/PO daily (4–14 days) LFX 500 mg IV/PO twice daily + CTX 2 g daily (4–14 days) MXF 400 mg IV/PO daily (4–14 days) LFX 500 mg IV/PO twice daily + CTX 2 g daily (4–14 days) Clinical evaluation Late follow up Days 21–28 post-therapy Patients with CAP and PSI score >II PSI III (<50%) Cmax and ECG x 3 15 min post-dose Day 1 and 3
  • 44.
    Clinical cure atTOC (PP population) – PSI risk classes IV–V 95% CI : -8.8% to 6.0% 84,6 86,8 (143/169) (145/167) 100 80 60 40 20 0 Patients (%) Moxifloxacin Ceftriaxone + levofloxacin
  • 45.
    Betalactam vs moxifloxacinmonotherapy early survival Observational study in Germany (CAPNETZ) moxifloxacin mono 365 pts (blue line) betalactam mono 1703 pts (green line) Primary endpoint: • time to death Adjusted for: • severity • age • co-morbidities Ewig S et al. J Infect 2011; 62: 218-25
  • 46.
    Combination therapy Macrolidesor 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
  • 47.
    Who is a“patient at risk”? Legionella • Prospective observational study (CAPNETZ) • 2,503 adults • Diagnosis of Legionella (3.8% of all CAP cases) confirmed by – Culture (0.1%) – PCR (1.7%) – Urine antigen (2.2%) • Mortality – Legionella 12.8% – Other pathogen 9.7% – Unknown pathogens 11.3% Variables Outpatients N = 29 Hospitalized N = 65 P-value Age  65 y   SD 31 % 55.4  15.7 y 60 % 66.9  14.5 y 0.001 Male 48% 71% ns Smoker 35% 32% ns Diabetes 7% 35% < 0.001 Fever 45% 59% ns Confusion 0 11% <0.001 CRB 65 0 1-2 3-4 16 (55%) 12 (41%) 0 15 (23%) 48 (74%) 1 (1.5%9 0.003 Hyponatremia 0 15 (23%) <0.001 MV 0 4 (6%) <0.001 Died (30d) 0 10 (15.4% <0.001 Died (6 mth) 0 12 (18.5%) <0.001 Von Baum H, Welte T. CID 2008 May 1;46(9):1356-64 76% 68% Approbriate Therapy
  • 48.
    Who is a“patient at risk”? Enterobacteriacae * 55% of all EB isolates were indeterminate Von Baum H, Welte T. ERJ 2010 Mar;35(3):598-605. Resp. sample available, no EB/PA (n = 1840) Definite EB (n = 22) Indeterminate EB (n = 27) * Age (mean, yrs) 58 ± 18 64 ± 17 68 ± 11 Nursing home resident (%) 2 23 7 Chronic resp. disease 37 68 52 Enteral tube feeding 0.6 23 11 Mortality 4 18 4 28
  • 49.
    Pseudomonas aeruginosa Combinationtherapy • If combination therapy is required then combine with – + Aminoglycoside • Gentamycin/tobramycin 6 mg/kg body weight/day as a single dosage (trough level < 2 mg/L) • Amikacin 20-25 (-30) mg/kg body weight/day as a single dosage – + Fluoroquinolones • Ciprofloxacin (800-1200 mg daily) • Levofloxacin (1000 mg daily)
  • 50.
    Proportion of 3rdgeneration cephalosporin-resistant (R) Klebsiella pneumoniae Isolates in participating countries in 2012 http://www.ecdc.europa.eu/en/healthtopics/antimicrobial_resistance/, 19.11.13
  • 51.
    ESBL Treatment •Carbapenems, Carbapenems, Carbapenems …..
  • 52.
    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
  • 53.
    Clinical Infectious Diseases2012;55(7):943–50 • Multicenter retrospective cohort study, in 3 large Italian teaching hospitals between 1 January 2010 and 30 June 2011 • 125 patients with bloodstream infections (BSIs) caused by KPC-producing Kp isolates (KPC-Kp) diagnosed • 30-day mortality rate was 41.6% – monotherapy 54.3%) – combined drug therapy 34.1%; P = .02. • 30-day mortality was independently associated with • septic shock at BSI onset (OR: 7.17; P = .008) • inadequate initial antimicrobial therapy (OR: 4.17; P = .003) • high APACHE III scores (OR: 1.04; 95% P < .001).
  • 54.
    34-year-old female, IntermediateCare 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
  • 55.
    34-year-old female, IntermediateCare Unit Day 3 • CRP and PCT decrease quickly • Respiratory Rate at rest 16/minute • Temperature: 37.8°C • SaO2 (2 l oxygen supplementation) 96% • Biochemistry – BUN 19 mmol/L – Glucose 9.8 mmol/L
  • 56.
    C-reactive protein (CRP):Correlation with appropriateness of therapy Bruns et al. Eur Respir J 2008;32:726–32 • Patients with inappropriate antibiotic treatment have a slower decline in CRP levels in first week of follow-up
  • 57.
    34-year-old female, IntermediateCare Unit Day 3 • Patient transferred to a normal ward • Moxifloxacin i.v. switched to 400mg Moxifloxacin oral • Early mobilisation out of bed
  • 58.
    The ProCAP study– Antibiotic duration Christ-Crain M et al, AJRCCM 2006; 174(1):84-93 p < 0.001 Standard group PCT group 20 19 17 13 12 10 8 6 4 2 Antibiotic duration (days) 15 Standard group PCT group 100 90 80 70 60 50 40 30 20 10 0 AB started > 4d > 6d > 8d > 10d > 14d > 21d Antibiotic Prescriptoin (%)
  • 59.
    34-year-old female, normalward 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%)
  • 60.
    Hot Topics inPneumogenic Sepsis and ARDS • (Pneumogenic) Sepsis – General considerations – Treatment – New Antibiotics – Immunomodulators • ARDS – Ventilation strategies – Immunomodulators
  • 62.
    2008 2012 Grading D. Antibiotic therapy 1.a. Administration of effective iv ABs within the 1. hour of recognition of septic shock 1B 1B 1.b. Administration of effective iv ABs within the 1. hour of recognition of severe sepsis 1D 1C ↑ 2.a. Initial empiric anti-infective therapy of one or more drugs that have activity against 1B 1B all likely pathogens and that penetrate in adequate concentrations into tissues presumed to be the source of sepsis 2.b. Antimicrobial regimen should be reassessed daily for potential deescalation 1C 1B ↑ 3. Use of biomarkers to assist the clinician in the discontinuation of empiric antibiotics in patients who initially appeared septic, but have no subsequent evidence of infection nn 2C ↑ 4.a. Combination empirical therapy for neutropenic patients with severe sepsis 2D 2B ↑ for pts with difficult to treat, MDR bacterial pathogens f.e. Acinetobacter/Pseudomonas nn 2B ↑ For pts with severe infections associated with respiratory failure and septic shock, 2D 2B ↑ combination therapy with an extended spectrum beta-lactam and either an aminoglycoside or a fluoroquinolone is for P. aeruginosa bacteremia A combination of beta-lactam and macrolide for patients with septic shock from bacteremic Streptococcus pneumoniae infections nn 2B ↑ 4.B Empiric combination therapy not be for more than 3–5 days. De-escalation to the most appropriate single therapy as soon as the susceptibility profile is known 2D 2B ↑ 5. Duration of therapy typically 7–10 days; longer courses may be appropriate in pts with a slow clinical response, undrainable foci of infection, bacteremia with S. aureus; some fungal and viral infections or immunologic deficiencies, including neutropenia 1D 2C ↓ 6. Antiviral therapy initiated as early as possible in patients with severe sepsis or septic shock of viral origin nn 2C ↑ 7. Antimicrobial agents should not be used in patients with severe inflammatory states determined to be of noninfectious cause 1D UG ↑
  • 63.
    Sepsis Trials -Site and Source of Infection MeroMono N = 273 MeroMoxi N = 278 All patients N = 551 Site of infection Pneumonia 105 (38.46) 119 (42.81) 224 (40.65) Other respiratory tract 18 (6.59) 18 (6.47) 36 (6.53) Intraabdominal 99 (36.26) 111 (39.93) 210 (38.11) Bones or soft tissue 20 (7.33) 16 (5.76) 36 (6.53) Surgical wound infection 15 (5.49) 5 (1.80) 20 (3.63) Urogenital 39 (14.29) 25 (8.99) 64 (11.62) Primary bacteremia 5 (1.83) 11 (3.96) 16 (2.90) Other 13 (4.76) 11 (3.96) 24 (4.36) Source of infection Community-acquired 136 (49.82) 141 (50.72) 277 (50.27) Nosocomial 137 (50.18) 136 (48.92) 273 (49.55) Missing 0 1 (0.36) 1 (0.18) Infection at study enrollment Microbiologically confirmed 97 (35.53) 99 (35.61) 196 (35.57) Clinical evidence 176 (64.47) 179 (64.39) 355 (64.43) Brunkhorst F. JAMA 2012; 307: 2390-9
  • 65.
    Sepsis Mortality Delayof 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
  • 66.
    Sepsis Mortality Delayof antibiotic treatment Ferrer R. CCM 2014; 42: 1749-55
  • 67.
    Delay of AntibioticTherapy • Retrospective review of adult admissions for CAP for 2 periods – group 1 (255 pts), when the core quality measure was a TFAD of less than 8 hours – group 2 (293 pts), when the TFAD was lowered to less than 4 hours. • Accuracy of diagnosis of CAP were assessed by ED physicians • At admission, group 2 patients were 39.0% less likely to meet predefined diagnostic criteria for CAP than were group 1 patients (odds ratio, 0.61; 95% confidence interval, 0.42-0.86) (P=.004). • At discharge, there was agreement CAP between the ED physician’s diagnosis and the predefined criteria for CAP in 62.0% of group 1 and 53.9% of group 2 patients (P=.06) Welker JA. Arch Intern Med. 2008;168(4):351-356
  • 68.
    Lancet Infect Dis2012; 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
  • 69.
    • Prä-/post Studieauf einer chirurgischen Intensivstation in den USA • konservative Therapie vs. aggressive Therapie – verringerten Krankenhaussterblichkeit (13/100 [13%] gegenüber 27/101 [27%]; p=0·015) – höheren Rate an primär adäquater Antibiotikatherapie (158/214 [74%] im Vergleich zu 144/231 [62%]; p=0·0095) – kürzere Therapiedauer (12·5 Tage [SD 10·7] gegenüber 17·7 [28·1 Tage: p=0·0080) Hranjec T et al. Lancet Infect Dis 2012; 12: 774–80 4 Suspected infectious disease Delay of antibiotic treatment
  • 70.
    • Pre-/post studyin a surgical ICU in the US • conservative vs. aggressive antibiotic therapy results in – Lower hospital mortality (13/100 [13%] versus 27/101 [27%]; p=0·015) – Increased rate of intial adaequate antibiotic therapy (158/214 [74%] versus 144/231 [62%]; p=0·0095) – Shorter treatment duration (12·5 Tage [SD 10·7] versus 17·7 [28·1 days: p=0·0080) Hranjec T et al. Lancet Infect Dis 2012; 12: 774–80 4 Suspected infectious disease Delay of antibiotic treatment
  • 71.
    FM Brunkhorst, MOppert, 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
  • 72.
    SOFA Score (Points)– mean and 95% CI Organ Dysfunction (SOFA Score) Intention-to-treat population Per-protocol population 1 3 5 7 9 11 13 Study Day 14 12 10 8 6 4 2 0 Monotherapy Combination therapy t-test p=0.36 * Monotherapy Combination therapy t-test p=0.37 * 1 3 5 7 9 11 13 14 12 10 8 6 4 2 0 SOFA Score (Points) – mean and 95% CI Study Day Patients evaluable: Monotherapy 249 212 167 137 124 103 89 Combination therapy 255 209 179 153 125 95 81 Patients evaluable Monotherapy 181 156 122 96 88 71 63 Combination therapy 198 165 141 119 96 71 57
  • 73.
    100 90 80 70 60 50 40 30 20 10 0 Overall Survival Intention-to-treat population Per-protocol population Monotherapy Combination therapy 0 14 28 42 56 70 84 Days Overall Survival (%) log rank p=0.42 Patients at risk: Monotherapy 273 222 211 193 188 184 179 Combination therapy 276 224 210 193 186 180 177 Overall Survival (%) 100 90 80 70 60 50 40 30 20 10 0 Monotherapy Combination therapy log rank p=0.59 0 14 28 42 56 70 84 Days Patients at risk: Monotherapy 199 164 156 143 138 137 132 Combination therapy 214 176 166 155 150 146 144
  • 74.
    ß-Lactam Monotherapy vs.ß-Lactam- Aminoglycosid Combination Therapy in Sepsis: A Metaanalysis Total Mortality Treatment Failure Bakterial Superinfection Adverse Events Nephrotoxicity N Studies N Patients ß-Mono vs. ß-AG Combi 43 63 27 39 45 Paul M.BMJ 2004; 328: 668 5527 6616 3085 4945 5213 0,90 (0,77 - 1,06) 0,87 (0,78 - 0,97) 0,79 (0,59 - 1,06) 0,91 (0,80 - 1,04) 0,36 (0,28 - 0,47)
  • 75.
    Mono- vs. CombinationTherapy 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
  • 76.
    Mono- versus CombinationTherapy Kumar A. Crit Care Med 2010; 38:1651–1664 • Metaanalysis of RCTs or observational studies comparing mono- and combination therapy in patients with sepsis • no overall mortality/clinical response benefit with combination therapy (odds ratio, 0.856) • substantial benefit in the most severely ill subset (monotherapy risk of death >25%; odds ratio of death, 0.51) • Meta-regression indicated that efficacy of combination therapy was dependent only on the risk of death in the monotherapy group. 30
  • 77.
    Antibiotics Pharmacokinetics inseverly ill patients • Charakteristic of severly ill patients – High Cardiac Index – Increased distribution volume – Altered plasma protein binding
  • 78.
    Antibiotics Pharmacokinetics inseverly 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
  • 79.
    2000 HAP- TGCSerum concentration Mean tigecycline (TGC) serum concentrations in subjects with hospital-acquired pneumonia after intravenous infusions. Ramirez J et al. 2013 Apr;57(4):1756-62.
  • 80.
    Clinical response inphase 2 (study 2000) vs. phase 3 (study 311) HAP trials Ramirez J et al. 2013 Apr;57(4):1756-62.
  • 81.
    Hot Topics inPneumogenic Sepsis and ARDS • (Pneumogenic) Sepsis – General considerations – Treatment – New Antibiotics – Immunomodulators • ARDS – Ventilation strategies – Immunomodulators
  • 82.
    Sepsis Therapy PrimarySite 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
  • 83.
  • 84.
    A pressing needfor antibiotic agents effective against both MSSA and MRSA 50 40 30 20 10 *Excludes patients with IE Nafcillin (n=18) Vancomycin (n=70) 1 15 0 8 0 5 0 13 0 Persistent >3 days Persistent >7 days Relapse Bacteriologic Failure Chang F et al. Medicine 2003;82:333–339 Efficacy of nafcillin vs vancomycin in MSSA bacteraemia* Vancomycin was an independent factor associated with failure (OR: 6.5, P=0.048)
  • 85.
    MRSA infections Treatmentdifferent 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
  • 86.
    Linezolid vs. Vancomycinin MRSA nosocomial pneumonia Adults with MRSA-HAP N = 1225 Linezolid 600 mg i.v. / p.o every 12 h * Exclusion if no MRSA could be detected Vancomycin 15 mg/kg i.v. every 12 h * EOT-Visit 5 d after last dosage R 1:1 EOS-Visit 7-30 d after last dosage Duration of therapy7-14 d (til 21d in confirmed bacteremia) * Initial Coverage of gram-negatives with Cefepim or other non MRSA susceptible antibiotics
  • 87.
    Clinical Cure (PPat EOS) 57,6 P-Value = 0,042 95% CI = 0,5%; 21,6% 46,6 80 60 40 20 0 Linezolid Vancomycin Clincal Sucess Rate (%) n = 165 n = 174 Kunkel M et al. IDSA 2010; Presentation LB-49.
  • 88.
    Ceftaroline fosamil: Administeredas a Prodrug N S O S N N+ O O NH N S N NH N O P HO O HO S CH 3 O N N S S N+ O O N H N S N H N 2 N O S CH 3 O O Prodrug: Ceftaroline fosamil Active metabolite: Ceftaroline Plasma phospatase mod. nach Zhanel et al, Drugs 2009, 69 (7): 809-31 Rapid biotransformation in plasma Bactericidal activity
  • 89.
    Fokus I Outcome File TM et al. JAC 2011; 66 Suppl 3: iii19–iii32
  • 90.
    Standard Treatment gramnegatives • E. coli/Enterobakteriacae – Ampicillin/Inhibitor Combinations – 2. and 3. Generation Cephalosporines – Ertapenem • Pseudomoas aeruginosa/Acinetobacter – Piperacillin/Tazobaktam – 4. Generation Cephalosporines – Carbapenemes • St. maltophilia – Fluorquinolones – Cotrimoxazol
  • 91.
    Pseudomoas aeruginosa CombinationTherapy • If combination therapy is required then combine with – + Aminoglycosid • Gentamycin/Tobramycin 6 mg/kg BW per day as a single dosage (Through Level < 2 mg/L) • Amikacin 20-25 (-30) mg/kg KG BW per day as a single dosage – + Fluorquinolones • Ciprofloxacin (800-1200 mg tgl.) • Levofloxacin (1000 mg tgl.)
  • 92.
    Proportion of 3rdgen. cephalosporins Resistant (R) Klebsiella pneumoniae Isolates in Participating Countries in 2012 http://www.ecdc.europa.eu/en/healthtopics/antimicrobial_resistance/, 19.11.13
  • 93.
    ESBL Treatment •Carbapenems, Carbapenems, Carbapenems …..
  • 94.
    Proportion of CarbapenemsResistant (R) Klebsiella pneumoniae Isolates in Participating Countries in 2012 http://www.ecdc.europa.eu/en/healthtopics/antimicrobial_resistance/, 19.11.13
  • 95.
    Attributable Mortality forCarbapenem-Resistant K. Pneumoniae (KPC) Borer A, et al. Infect Control Hosp Epidemiol. 2009;30:972-6. • 32-patient cohort with KPC bacteremia • 32 non-bacteremic KPC control patients matched for time period, comorbidities, underlying disease, age, and sex Study patients Control patients Required intensive care 12 (37.5%) 3 (9.4%) Required ventilator support 17 (53.1%) 8 (25%) Required central venous catheter 19 (59.4%) 9 (28.1%) Crude Mortality Rate* 23 (71.9%) 7 (21.9%)  Attributable Mortality for Study Patients: 50% (95% CI, 15.3 – 98.6)  Mortality Risk Ratio for Study Patients: 3.3 (95% CI, 2.9 – 28.5) *P < 0.001
  • 96.
    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
  • 97.
    Revival of „old“drugs Colistin • Combination Therapy (?) with – Colistin • 9 Mill. E Loading Dose • 4.5 Mill E twice daily as maintenance therapy • + inhaled colistin ???
  • 98.
    Predictors of mortalityin patients with bloodstream infections caused by KPC-producing K. pneumoniae and impact of appropriate antimicrobial treatment • 53 patients • Overall mortality was 52.8% and infection mortality was 34% • In the appropriate therapy group mortality due to infection occurred in 20% – 0/20 given combination therapy – 7/15 given appropriate monotherapy died (p 0.001). • In univariate analysis, risk factors for mortality were: – age (p <0.001) – APACHE II score at admission and infection onset (p <0.001) – severe sepsis (p <0.001) • Variable for survival: – appropriate antimicrobial treatment (p 0.003) – Combinations of active antimicrobials (p 0.001) – catheter-related bacteraemia (p 0.04) – prior surgery (p 0.014) Zarkotou O et al. Clin Microbiol Infect. 2011;17:1798-803
  • 99.
    Tumbarello M. ClinicalInfectious Diseases 2012;55(7):943–50 • Multicenter retrospective cohort study, in 3 large Italian teaching hospitalsbetween 1 January 2010 and 30 June 2011 • 125 patients with bloodstream infections (BSIs) caused by KPC-producing Kp isolates (KPC-Kp) diagnosed • 30-day mortality rate was 41.6% – monotherapy (54.3% – combined drug therapy 34.1%; P = .02). • 30-day mortality was independently associated with – Postantibiogram therapy with a combination of tigecycline, colistin, and meropenem was associated with lower mortality (OR: 0.11; P = .01) 21
  • 100.
    Multivariate analysis offactors associated with death among patients with bloodstream infection due to KPC producing Klebsiella Pneumoniae. Shock - - 0.008 7.17 (1.65-31.03) Inadequate initial treatment - - 0.003 4.17 (1.61-10.76) APACHE III score (mean ± SD) - - <0.001 1.04 (1.02-1.07) Tigecycline & Colistin & Meropenem - - 0.01 0.11 (0.02-0.69) Tumbarello M, Viale PL, Viscoli C, Bassetti M et al. Clin Infect Dis, 2012; Oct;55(7):943-50
  • 101.
    Why Colistin plusRifampin ? • 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
  • 102.
    Durante-Mangoni E. etal. Clinical Infectious Diseases 2013; 57(3):349–58
  • 105.
    Inhaled Antibiotics inthe 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
  • 107.
    Inhaled antibiotics forVAP Liu Q et al.Anesthesiology 2012; 117:1335-47
  • 108.
    Hot Topics inPneumogenic Sepsis and ARDS • (Pneumogenic) Sepsis – General considerations – Treatment – New Antibiotics – Immunomodulators • ARDS – Ventilation strategies – Immunomodulators
  • 109.
    New Antibiotics ThePipeline • 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)
  • 110.
    ESTABLISH – 1 Tedizolid versus Linezolid bei cSSTI • Phase II schwere Haut- und – Tedizolid 200 mg einmal täglich oral – Linezolid 600 mg zweimal täglich oral über je 10 Tage • primärer Outcome Parameter: – Ansprechen auf die Therapie nach 48-72 Stunden • Ergebnisse – Intent-to-treat Analyse für die Rate des frühen klinischen Ansprechens 79.5% in der Tedizolid Gruppe (332 Patienten) und 79.4% in der Linezolid Gruppe (335 Patienten) – klinischen Erfolgsrate nach Ende der Therapie (Tag 11) 69.3% in der Tedizolid Gruppe und 71.9% in der Linezolid Gruppe. – Die Ergebnisse für die 178 Patienten mit primären MRSA Nachweis entsprachen dem Gesamtergebnis. Prokocimer P et alJAMA. 2013 Feb 13;309(6):559-69. 46
  • 111.
  • 115.
    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
  • 116.
    Clinical Cure atTOC (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
  • 117.
    Clinical cure ratesin subgroups (ITT) 52% 37% 30% 74% 50% Awad et al., Clin Infect Dis. 2014 Welte T. ERS 2014, Poster 4643 57% 60% 45% 44% 31% 46% 56% 36% 54% 100% 80% 60% 40% 20% 0% % with clinical cure at TOC Ce obiprole Ce azidime/Linezolid Number 111 57 50 46 54 23 22 30 36 14 10 108 All ICU pa ents APACHE II ≥15 14 13 Mech. Vent. COPD S. aureus MRSA P. aeruginosa
  • 118.
    Patients with bacteraemia(ITT) 29% 25% 21% Awad et al., Clin Infect Dis. 2014 Welte T. ERS 2014, Poster 4643 17% 30% 24% 37% 41% 60% 50% 40% 30% 20% 10% 0% % with outcome Ce obiprole Ce azidime/Linezolid Number 27 12 17 24 27 12 17 24 All pa ents All ICU pa ents All ICU pa ents All pa ents Clinical cure (TOC visit) 30-day all-cause mortality
  • 119.
    Hot Topics inPneumogenic Sepsis and ARDS • (Pneumogenic) Sepsis – General considerations – Treatment – New Antibiotics – Immunomodulators • ARDS – Ventilation strategies – Immunomodulators
  • 120.
    I suggest: Useit in SELECTED cases!
  • 121.
    IgM immunoglobulins forinfection - Why? Humoral immune response: anti-bacterial modes of action IgM exhibits: 100-fold higher phagocytosis-promoting activity compared to IgG10 1000-fold higher affinity towards C1q (first protein in the classical complement pathway) than IgG11 neutralization of antibiotic-induced endotoxin release12 1. Increase of bacterial phagocytosis 2. Induction of bacterial lysis due to specific activation of complement on bacterial surfaces 3. Neutralisation of toxins Molnar Z, Nierhaus A, Esen F. Annual Update in ICEM 2013; 145-52
  • 122.
    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.
  • 123.
    Hot Topics inPneumogenic Sepsis and ARDS • (Pneumogenic) Sepsis – General considerations – Treatment – New Antibiotics – Immunomodulators • ARDS – Ventilation strategies – Immunomodulators
  • 124.
    ARMA trial, NEJM342:1301, 2000
  • 125.
    ARMA trial -major outcome parameters ARMA trial, NEJM 342:1301, 2000
  • 128.
    Potential advantages ofthe „awake ECMO“ concept vs. conventional therapy • Pat. awake, cooperative, able to eat and drink • No risk of ventilator-associated pneumonia, i.e. potentially lower risk of septicemia • Detrimental effects of long-term mechanical ventilation and analgosedation avoided • Active exercise programs allows avoiding muscular atrophy
  • 129.
  • 130.
    Awake ECMO inARDS • Six patients with severe ARDS, four immunocompromised • 4 out of 6 survived Hoeper MM et al. ICM 2013 (in press)
  • 131.
    ARDS Prone Position • Multicenter, prospective, RCT • 466 patients with severe ARDS – prone-positioning sessions of at least 16 hours (237 pts) – supine position (229 pts) • 28-day mortality 16.0% in the prone group, 32.8% in the supine group (P<0.001). • 90-day mortality 23.6% in the prone group, 41.0% in the supine group (P<0.001) • Incidence of AEs not significantly different between the groups Guerin C et al. NEJM 2013; 368:2159-68
  • 132.
    Hot Topics inPneumogenic Sepsis and ARDS • (Pneumogenic) Sepsis – General considerations – Treatment – New Antibiotics – Immunomodulators • ARDS – Ventilation strategies – Immunomodulators
  • 133.
    ARDS Etiology ARDSNetwork. NEJM 2014; 370 (23):2191-200
  • 134.
    Subgroup analyses -Mortality Adjusted proportional hazard models for the effect of addition of moxifloxacin on overall survival 0.5 1 2 3 4 Hazard Ratio 0.2 B Intention to treat Per protocol set SOFA score at baseline <= 9 points SOFA score at baseline >= 10 points Study treatment >= 4 days Nosocomial infection Community acquired infection Microbiologically documented Clinically suspected Surgical patients Medical patients Gram-negative infection Gram-positive infection Bacteremic infection Non-bacteremic infection Gram-negative bacteremia Gram-positive bacteremia Pneumonia Intraabdominal Urogenital Severe Sepsis Septic Shock adjusted HR (95% CI) p-value 1.09 (0.70; 1.69) 0.84 (0.54; 1.32) 1.54 (0.89; 2.66) 0.78 (0.53; 1.15) 1.11 (0.73; 1.71) 0.82 (0.51; 1.32) 1.19 (0.75; 1.88) 1.07 (0.69; 1.64) 0.88 (0.51; 1.52) 1.10 (0.74; 1.63) 0.79 (0.33; 1.89) 0.88 (0.38; 2.06) 1.07 (0.64; 1.77) 1.15 (0.70; 1.88) 1.48 (0.56; 3.92) 0.710 0.456 0.125 0.209 0.618 0.425 0.464 0.767 0.639 0.652 0.597 0.774 0.799 0.591 0.434 1.00 (0.73; 1.36) 0.94 (0.65; 1.35) 1.05 (0.63; 1.74) 0.90 (0.60; 1.34) 1.12 (0.76; 1.66) 0.986 0.720 0.864 0.604 0.572 70 out of 225 patients died 2.01 (0.98; 4.12) 0.81 (0.57; 1.16) 0.055 0.245 No. 273 199 141 132 206 137 136 97 176 146 127 149 140 90 183 40 49 105 99 39 Monotherapy Combination Therapy Death Cases 85 59 37 48 57 43 42 32 53 47 38 47 43 30 55 12 14 32 37 14 No. 276 214 153 123 209 135 141 98 178 162 114 120 155 93 183 33 58 119 110 25 Death Cases 96 70 43 53 61 46 50 28 68 50 46 46 53 37 59 19 15 38 40 8 74 199 18 67 84 192 20 76 = 31.1% Brunkhorst FM. JAMA 2012; 307: 2390-99
  • 135.
    Statins to treatinfammation in ARDS ARDS Network. NEJM 2014; 370 (23):2191-200
  • 136.
    Subgroup analyses -Mortality Adjusted proportional hazard models for the effect of addition of moxifloxacin on overall survival 0.5 1 2 3 4 Hazard Ratio 0.2 B Intention to treat Per protocol set SOFA score at baseline <= 9 points SOFA score at baseline >= 10 points Study treatment >= 4 days Nosocomial infection Community acquired infection Microbiologically documented Clinically suspected Surgical patients Medical patients Gram-negative infection Gram-positive infection Bacteremic infection Non-bacteremic infection Gram-negative bacteremia Gram-positive bacteremia Pneumonia Intraabdominal Urogenital Severe Sepsis Septic Shock adjusted HR (95% CI) p-value 1.09 (0.70; 1.69) 0.84 (0.54; 1.32) 1.54 (0.89; 2.66) 0.78 (0.53; 1.15) 1.11 (0.73; 1.71) 0.82 (0.51; 1.32) 1.19 (0.75; 1.88) 1.07 (0.69; 1.64) 0.88 (0.51; 1.52) 1.10 (0.74; 1.63) 0.79 (0.33; 1.89) 0.88 (0.38; 2.06) 1.07 (0.64; 1.77) 1.15 (0.70; 1.88) 1.48 (0.56; 3.92) 0.710 0.456 0.125 0.209 0.618 0.425 0.464 0.767 0.639 0.652 0.597 0.774 0.799 0.591 0.434 1.00 (0.73; 1.36) 0.94 (0.65; 1.35) 1.05 (0.63; 1.74) 0.90 (0.60; 1.34) 1.12 (0.76; 1.66) 0.986 0.720 0.864 0.604 0.572 92 out of 277 patients died 2.01 (0.98; 4.12) 0.81 (0.57; 1.16) 0.055 0.245 No. 273 199 141 132 206 137 136 97 176 146 127 149 140 90 183 40 49 105 99 39 Monotherapy Combination Therapy Death Cases 85 59 37 48 57 43 42 32 53 47 38 47 43 30 55 12 14 32 37 14 No. 276 214 153 123 209 135 141 98 178 162 114 120 155 93 183 33 58 119 110 25 Death Cases 96 70 43 53 61 46 50 28 68 50 46 46 53 37 59 19 15 38 40 8 74 199 18 67 84 192 = 33.2% 20 76 Brunkhorst FM. JAMA 2012; 307: 2390-99
  • 137.
    ʺWhen an ideadoes not sound absurd at the beginning, then there is no hope for itʺ Albert Einstein, Physicist
  • 138.
    What does “patientat 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