Transcript Folie 1

Ventilator associated Pneumonia
Tobias Welte
Department of Respiratory Medicine and Intensive Care
Subgroup analyses - Mortality
Adjusted proportional hazard models for the effect of addition of moxifloxacin on overall survival
Brunkhorst FM. JAMA 2012; 307: 2390-99
Monotherapy
B
No.
273
199
141
132
206
137
136
97
176
146
127
149
140
90
183
40
49
105
99
39
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
74
199
0.2
0.5
1
Hazard Ratio
Welte – VAP – Mar del Plata 11.10.2014
2
3
4
Combination Therapy
Death
Cases
adjusted
HR (95% CI)
p-value
276
214
153
123
209
135
141
98
178
162
114
120
155
93
183
33
58
119
110
25
96
70
43
53
61
46
50
28
68
50
46
46
53
37
59
19
15
38
40
8
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)
1.09 (0.70; 1.69)
0.84 (0.54; 1.32)
1.54 (0.89; 2.66)
0.78 (0.53; 1.15)
0.986
0.720
0.864
0.604
0.572
0.710
0.456
0.125
0.209
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)
0.618
0.425
0.464
0.767
0.639
84
192
20
76
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)
2.01 (0.98; 4.12)
0.81 (0.57; 1.16)
0.652
0.597
0.774
0.799
0.591
0.434
0.055
0.245
Death
Cases
No.
85
59
37
48
57
43
42
32
53
47
38
47
43
30
55
12
14
32
37
14
18
67
70 out of 225 patients died
= 31.1%
• Diagnostics
Dalhoff K et al. Pneumologie 2012; 66:707-65
Dt. Ärzteblatt Int. 2013; 110 (38): 634-40
1. Clinical diagnosis and differential diagnosis
2. Imaging procedures in the diagnostic work up
3. The role of scoring in the diagnostics and for risk assessment
4. The role of biomarkers in the diagnostics
5. The role of blood cultures in the diagnostics
6. The role of an antigen test in the diagnostics
7. What microbiological tests should be carried out??
8. Invasive or non invasive diadnostic techniques?
9. Standards in diagnostics
10. Mykological diagnostics
Welte – VAP – Mar del Plata 11.10.2014
CDC and prevention national healthcare
safety network clinical definition for VAP
Klompas. Curr Opin Infect Dis 2012;25:176-82
Patients must fulfil radiographic, systemic and pulmonary criteria:
Two or more serial radiographic,
systemic and pulmonary criteria
New or progressive and peristent
infiltrate
Consolidation
Cavitation
One of the
following
Two of the
following
Fever
(>38ºC or >100.4ºF)
New onset of purulent sputum or
change in character of sputum or
increased respiratory secretions or
increased suctioning requirements
Leukopenia (<400 WBC/µl)
or leukocytosis (>12000
WBC/µl)
New onset or worsening cough,
or dypsnea, or tachypnea
For adults ≥70 years old,
altered mental status with no
other recognised cause
Rales or bronchial breath sounds
Worsening gas exchange
(eg oxygen desaturation, increased
oxygen requirements,
or increased ventilation demand)
Welte – VAP – Mar del Plata 11.10.2014
Do we have an objective, independent and
reliable surveillance system?
Clinical signs for VAP are subjective and non-specific
Initiatives intended to decrease the occurrence of
nosocomial infection can artefactually lower VAP rates
Bonten. Clin Infect Dis 2011;52:115-21;
Klompas. Curr Opin Infect Dis 2012;25:176-82
Welte – VAP – Mar del Plata 11.10.2014
A comparison of VAP rates as identified
according to intensivists vs infection
control practitioners
• Prospective comparison of 5 months of VAP
surveillance by surgical intensivists vs infection
preventionists in a surgical ICU using CDC
definitions
• Intensivists found much higher rates of VAP than
infection preventionists (28.5% vs 8.3%; p<0.001)
• When compared with BAL, intensivist-VAP had 61%
sensitivity and preventionist-VAP had 29%
sensitivity
Thomas et al. Am Surg 2011;77:998-1002
Welte – VAP – Mar del Plata 11.10.2014
Prevention and therapy of HAP using
a bundle approach
•
Zack JE, et al. Effect of an educational program aimed at reducing the occurrence of ventilatorassociated pneumonia. Crit Care Med 2002;30:2407-12.
•
Babcock HM, et al. An educational intervention to reduce ventilator-associated pneumonia in an
integrated health system: a comparison of effects. Chest 2004;125:2224-31.
•
Resar R, et al. Using a bundle approach to improve ventilator care processes and reduce ventilatorassociated pneumonia. Jt Comm J Qual Patient Saf 2005;31:243-8.
•
Institute for Healthcare Improvement. Implement the ventilator bundle. Available at:
http://www.ihi.org.
•
Apisarnthanarak A, et al. Effectiveness of an educational program to reduce ventilator-associated
pneumonia in a tertiary care center in Thailand: a 4-year study. Clin Infect Dis 2007:45:704-11.
•
Bird D, et al. Adherence to ventilator-associated pneumonia bundle and incidence of ventilatorassociated pneumonia in the surgical intensive care unit. Arch Surg 2010;145:465-70.
•
DePalo VA, et al. The Rhode Island ICU collaborative: a model for reducing central line-associated
bloodstream infection and ventilator-associated pneumonia statewide. Qual Saf Health Care
2010;19:555-61.
•
Berenholtz SM, et al. Collaborative cohort study of an intervention to reduce ventilator-associated
pneumonia in the intensive care unit. Infect Control Hosp Epidemiol 2011;32:305-14.
•
Anon. Five years without VAP? Two years without BSI? Hosp Peer Rev 2011;36:42-6.
Welte – VAP – Mar del Plata 11.10.2014
Mean VAP rates reported to the national healthcare
safety network, data summary for 2009
Dudeck et al. Am J Infect Control
2011;39:349-67
VAP rate
Percentile
Type of location
No.
Ventilato Pooled
No. VAPs
locations
r days
mean
10%
50%
25% (median 75%
)
90%
Critical care units
Burn
21
109
14,703
7.4
0.0
0.0
2.7
10.9
14.2
Medical, major teaching
74 (74)
263
140,784
1.9
0.0
0.0
1.1
2.9
5.6
Medical, all other
97 (92)
178
131,185
1.4
0.0
0.0
0.2
2.2
4.6
Medical cardiac
125 (116)
149
100,768
1.5
0.0
0.0
0.0
2.4
4.8
Medical / surgical, major
teaching
116 (115)
398
194,776
2.0
0.0
0.0
1.2
3.1
5.6
Medical / surgical, all other,
≤15 beds
359 (305)
284
209,206
1.4
0.0
0.0
0.0
1.6
5.1
Medical / surgical, all other,
>15 beds
154 (152)
348
295,884
1.2
0.0
0.0
0.7
1.9
3.5
Welte – VAP – Mar del Plata 11.10.2014
What is the clinical relevance of studies having
demonstrated a VAP rate of zero?
• None of them were rigorously evaluated and
demonstrated a benefit using relevant
endpoints
such as:
–
–
–
–
Antibiotic use
Duration of mechanical ventilation
Length of stay in the ICU and the hospital
Overall mortality
Bonten. Clin Infect Dis 2011;52:115-21;
Klompas. Curr Opin Infect Dis 2012;25:176-82
Welte – VAP – Mar del Plata 11.10.2014
Blood Culture Diagnostics
The Reality
• Structured telephone interviews about blood culture
diagnostics in Great Britain (Gb), France (F), Italien
(I) and Germany (G)
– 59 Intensivists
– 79 Clinical mikrobiologists
• Time from taking the blood cultures to inkubation of
them in Gb 2, F 3, I 4, G 20 hours
– If the microbiological lab was inhouse 2h
• Satisfaction with the quality of the blood cultures
– Intensivists 62%
– Mikrobiologists 47%
Welte – VAP – Mar del Plata 11.10.2014
Schmitz RP et al. Crit Care 2013; 17 (5): R248
1
9
PCR diagnostics in blood cultures
• SeptiFast®, Roche, Basel, Switzerland
– Multiplex real-time PCR that simultaneously detects a pre-defined panel of the most
important sepsis pathogens by species- or genus-specific fluorescent probes
• SepsiTestTM, Molzym, Bremen, Germany
– Eubacterial and pan-fungal real-time PCR that is able to detect nearly all known bacterial
and fungal pathogens by a 16S and 18S rRNA gene-based universal PCR, followed by
sequencing of the amplification product for species identification
• VYOO®, SIRS Lab, Jena, Germany
– Multiplex PCR that detects a predefined panel of the most important sepsis pathogens
by microarray-based detection of target-specific amplicons
• Plex-IDTM, Abbott, Wiesbaden, Germany
– Eubacterial and pan-fungal PCR that is able to detect nearly all known bacterial and
fungal pathogens by genome-specific targets followed by mass spectrometry for
species identification
PCR, polymerase chain reaction; rRNA, ribosomal ribonucleic acid
Welte – VAP – Mar del Plata 11.10.2014
Pletz MW et al. Intensive Care Med 2011;37:1069-76
11
PCR diagnostics in blood cultures
Septifast®
Bloos F et al. Intensive Care Med 2010;36:241-7
PCR
BC
61 microorganisms from
47 samples
•
142 patients with severe sepsis and 63
surgical control individuals
•
Presence of microbial DNA was assessed
by multiplex PCR (SeptiFast®) on enrolment
and each time a BC was obtained
•
Control individuals had ~4% positive PCRs
and BCs
•
In severe sepsis, 34.7% of PCRs were
positive vs 16.5% of BCs (p<0.001)
•
70.3% of BCs had a corresponding PCR
result, while only 21.4% of PCR results were
confirmed by BC
•
Patients with positive PCRs had higher
SOFA scores (12 vs 9; p=0.023) and a trend
towards higher mortality (PCR negative
25.3%; PCR positive 39.1%; p=0.115)
Welte – VAP – Mar del Plata 11.10.2014
32
41 microorganisms from
39 samples
6
18
(7 not on PCR
panel)
8
15
9
289
(75 not on PCR panel)
Specimen
321 microorganisms from 135 samples
PCR diagnostics in blood cultures
Vyoo ®
Bloos F et al. PLoS One 2012;7:e46003
•
Observational study in a 50-bed ICU
•
311 concomitant blood cultures and blood
for multiplex PCR (VYOO®) were obtained
from patients with suspected sepsis (n =
245)
–
14.5% of blood cultures and 30.1% of PCRs
were were positive
–
Median time to positivity was 24.2 hours for
the PCR and 68 hours for BC
–
In 34% of patients with positive PCRs,
antimicrobial therapy was considered
inadequate
•
5 patients with VRE
•
3 patients with multi-resistant Staphylococci
•
4 patients with fungi
Welte – VAP – Mar del Plata 11.10.2014
PCR
MiBi
85
18
227
97 not on
target list
7
7
10
29
7 not on
target list
BC
PCR diagnostics in Sputum / BAL
Jamal W et al. J Clin Microbiol 2014;52:2487-92
Impact of the rapid multiplex PCR-based UPA in detecting aetiological
pathogens
and resistance markers in patients with NP
•
49 patients with NP
– 27 (55.1%) and 4 (8.2%) harboured multiple bacteria by UPA and conventional
culture, respectively
– A single pathogen was detected in 8 (16.3%) and 4 (8.2%) patients, respectively
– 13 different genes were detected from 38 patients, including the ermB gene
(40.8%),the blaOXA-51-like gene (28.6%), the sul1 (28.6%) and int1 (20.4%) integrase
genes, and the mecA and blaCTX-M genes (12.3% each)
– The time from sample testing to results was 4 hours by UPA vs 48–96 hours by
culture
– Initial empirical treatment was changed within 5–6 hours in 33 (67.3%) patients
based on the availability of UPA results
Welte – VAP – Mar del Plata 11.10.2014
14
PCR diagnostics in Sputum / BAL
Jamal W et al. J Clin Microbiol 2014;52:2487-92
Microorganism (no. of isolates)
A. baumannii (13)
Patientsa infected according to indicated detection type, n
Group 1 (n=8)
Group 2 (n=26)
Group 3 (n=15)
PCR
Culture
PCR
Culture
PCR
Culture
p valueb
1
0
4
2
8
1
0.007
H. influenzae (2)
0
0
1
0
1
0
0.24
K. pneumoniae (10)
0
0
4
1
6
0
0.0013
K. oxytoca (2)
0
0
2
0
0
0
0.24
Legionella pneumophila (2)
0
0
2
0
0
0
0.24
Moraxella catarrhalis (1)
0
0
0
0
1
0
0.5
Proteus spp. (1)
0
0
0
0
1
0
0.5
P. aeruginosa (12)
1
0
4
1
5
1
0.015
S. marcescens (3)
0
0
1
0
2
0
0.12
S. aureus (2)
0
0
1
0
1
0
0.24
MRSA (3)
0
0
1
0
2
0
0.12
S. maltophilia (12)
2
0
3
0
6
1
0.0027
S. pneumoniae (12)
6
2
2
0
2
0
0.015
Welte – VAP – Mar del Plata 11.10.2014
14
Etiology of Infections in the ICU
Vincent et al. JAMA 2009; 302:2323–9
EPIC II
8 May 2007, 667 Western European ICUs
Welte – VAP – Mar del Plata 11.10.2014
Welte – VAP – Mar del Plata 11.10.2014
Welte – VAP – Mar del Plata 11.10.2014
Aspergillus: not only in neutropenic and immunosuppressed pts
Meerssman, CID, 2007
Welte – VAP – Mar del Plata 11.10.2014
Radiology
•
•
•
HERBRECHT ET AL: SEMINARS IN RESPIRATORY AND
CRITICAL CARE MEDICINE/VOLUME 25, NUMBER 2 2004
Chest X-Ray: in early stages often normal
CT-Thorax (HR-CT) Nodules, even in early stages (AII)
Halo-Sign (dd: Bleeding, Embolus,..), Air crescent sign
Welte – VAP – Mar del Plata 11.10.2014
Reverse Halo-Zeichen: Etiology
Marchiori, Chest, 2012
Organising Pneumonia
Aspergillosis
• Retrospective CT-Study
• 15 Pts. with invasive fungal infection
Welte – VAP – Mar del Plata 11.10.2014
Zygomycosis
Serology
1. Galaktomannan-Assay (Pastorex® Aspergillus) 1, 2
Specifity 90-100%, Sensitivity 26-76%
2. Galaktomannan ELISA (Platelia® Aspergillus) 3, 4
Specifity 80-100%, Sensitivity 70-90% (PPV 87,5%)
 Galactomannan in neutropenic pts 2x/week (AII), cave: Tazobactam or Amoxyclav.
Negative predictive Value 95– 98%
3. Galaktomannan BAL
Specifity 94–100%, Sensitivity 76–85% 5, 6, 7
4. G-Test: Beta-D-Glucan (Fungitec®G) Sensitivity+Specifity ?
1. Haynes K, Rogers TR (1994) Eur J Clin Microbiol Infect Dis 13:670–674
2. Machetti M, Feasi M, Mordini N, Van-Lint MT, Bacigalupo A, Latge JP, Sarfati J, Viscoli C (1998). Bone Marrow Transplant
21:917–921
3. Maertens J, Verhaegen J, Lagrou K, Van-Eldere J, Boogaerts M (2001). Blood 97:1604–1610
4. Sulahian A, Boutboul F, Ribaud P, Leblanc T, Lacroix C, Derouin F (2001). 91:311–338
5. Musher B, Fredricks D, Leisenring W et al. J Clin Microbiol 2004;42: 5517–5522.
6. Becker MJ, Lugtenburg EJ, Cornelissen JJBr J Haematol 2003; 121: 448–457
7. Meersseman W, Lagrou K, Maertens J, Am J Respir Crit Care Med 2008; 177: 27–34
Welte – VAP – Mar del Plata 11.10.2014
Aspergillosis: Galactomannan in BAL
D`Haese, JCM, 2012
•Design
•Retrospective, Leuven
•Patients (n=241)
•3 proven
•56 probable
•63 possible
•129 none
•Results (OD)
•<0,5 rule out
•>=0,8 (Sens. 86%, Spez. 91%)
•> 3,0 rule in
Welte – VAP – Mar del Plata 11.10.2014
• Therapy
–
–
–
–
–
–
–
–
–
–
–
–
Dalhoff K et al. Pneumologie 2012; 66:707-65
Dt. Ärzteblatt Int. 2013; 110 (38): 634-40
When should the antibiotic therapy starts?
Calculated therapy in patients without risk for MDR pathogens
Calculated Therapie in patients with risk for MDR pathogens
Combination therapy
Early stop of therapy
Evaluation of treatment success
Deescalation therapy
Duration of treatment
Treatment failure
Ventilator Tracheobronchitis
Inhaled antibiotic therapy
Targeted therapy for special therapies
Welte – VAP – Mar del Plata 11.10.2014
Welte – VAP – Mar del Plata 11.10.2014
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
Welte – VAP – Mar del Plata 11.10.2014
Sepsis Mortality
Delay of antibiotic treatment
Ferrer R. CCM 2014; 42: 1749-55
Welte – VAP – Mar del Plata 11.10.2014
CAP
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
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)
Welte – VAP – Mar del Plata 11.10.2014
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 infection has been
confirmed by diagnostic results
Welte – VAP – Mar del Plata 11.10.2014
4
Standard Treatment
gram positive infections
• S. pneumoniae
– Beta-Laktam-Macrolid combination therapy
• A and B-Streptococci
– Penicillin-/Clindamycin combination therapy
• Staph. Aureus
– Sensibel: Oxacillin or 1. Gen. Cephalosporin
– MRSA: Vancomycin/Linezolid/Daptomycin/Rifampicin
• Enterococci
– E. faecalis: Ampicillin or Ampicillin/Inhibitor Combination
– E. faecium: Vancomycin/Linezolid
Welte – VAP – Mar del Plata 11.10.2014
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
Welte – VAP – Mar del Plata 11.10.2014
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
Welte – VAP – Mar del Plata 11.10.2014
Organ Dysfunction (SOFA Score)
14
Monotherapy
12
Combination therapy
10
8
6
4
2
t-test p=0.36 *
0
1
3
5
7
9
11
13
Per-protocol population
SOFA Score (Points) – mean and 95% CI
SOFA Score (Points) – mean and 95% CI
Intention-to-treat population
14
Monotherapy
12
Combination therapy
10
8
6
4
2
t-test p=0.37 *
0
1
3
Study Day
5
Patients evaluable
Monotherapy
Monotherapy
249 212 167 137 124 103
89
Combination therapy
Welte – VAP – Mar del Plata 11.10.2014
9
11
13
88
71
63
96
71
57
Study Day
Patients evaluable:
255 209 179 153 125
7
181 156 122
96
Combination therapy
95
81
198 165 141 119
Overall Survival
Intention-to-treat population
Per-protocol population
100
100
90
Monotherapy
80
70
Combination therapy
60
50
40
30
Overall Survival (%)
Overall Survival (%)
90
Monotherapy
80
70
Combination therapy
60
50
40
30
20
20
log rank p=0.42
10
log rank p=0.59
10
0
0
0
14
28
42
56
70
84
0
14
28
Days
Patients at risk:
Monotherapy
Monotherapy
222
211
193
188
184
179
Combination therapy
276
224
210
193
Welte – VAP – Mar del Plata 11.10.2014
56
70
84
138
137
132
150
146
144
Days
Patients at risk:
273
42
199
164
156
143
Combination therapy
186
180
177
214
176
166
155
ß-Lactam Monotherapy vs. ß-LactamAminoglycosid Combination Therapy in Sepsis: A
Metaanalysis
Paul M.BMJ 2004; 328: 668
N Studies
Total Mortality
Treatment Failure
Bakterial Superinfection
Adverse Events
Nephrotoxicity
Welte – VAP – Mar del Plata 11.10.2014
N Patients
ß-Mono vs. ß-AG Combi
43
63
27
39
5527
6616
3085
4945
0,90
0,87
0,79
0,91
(0,77 - 1,06)
(0,78 - 0,97)
(0,59 - 1,06)
(0,80 - 1,04)
45
5213
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)
Welte – VAP – Mar del Plata 11.10.2014
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.
Welte – VAP – Mar del Plata 11.10.2014
30
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.)
Welte – VAP – Mar del Plata 11.10.2014
Antibiotics
Pharmacokinetics in severly ill patients
• Charakteristic of severly ill patients
– High Cardiac Index
– Increased distribution volume
– Altered plasma protein binding
Welte – VAP – Mar del Plata 11.10.2014
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
Welte – VAP – Mar del Plata 11.10.2014
2000 HAP- TGC Serum concentration
Mean tigecycline (TGC) serum concentrations in subjects with hospitalacquired pneumonia after intravenous infusions.
Welte – VAP – Mar del Plata 11.10.2014
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.
Welte – VAP – Mar del Plata 11.10.2014
Proportion of 3rd gen. cephalosporins Resistant (R) Klebsiella
pneumoniae Isolates in Participating Countries in 2012
http://www.ecdc.europa.eu/en/healthtopics/antimicrobial_resistance/, 19.11.13
Welte – VAP – Mar del Plata 11.10.2014
ESBL Treatment
• Carbapenems, Carbapenems,
Carbapenems …..
Welte – VAP – Mar del Plata 11.10.2014
Proportion of Carbapenems Resistant (R) Klebsiella
pneumoniae Isolates in Participating Countries in 2012
http://www.ecdc.europa.eu/en/healthtopics/antimicrobial_resistance/, 19.11.13
Welte – VAP – Mar del Plata 11.10.2014
Revival of „old“ drugs
Tigecyclin
Ramirez J et al. 2013 Apr;57(4):1756-62.
• 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
Welte – VAP – Mar del Plata 11.10.2014
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 ???
Welte – VAP – Mar del Plata 11.10.2014
Welte – VAP – Mar del Plata 11.10.2014