Alternative Antibiotikastrategien zur
Verhinderung von Resistenzen
Tobias Welte
Klinik für Pneumologie und Infektionsmedizin
Welte – Wien – Alternative Strategien 17.02.2017
Alternative Strategien zur
Vermeidung von Resistenz
• Kontinuierliche Antibiotikagabe
• Therapeutisches Drug Monitoring
• Verkürzte Therapiedauer (Biomarker
gesteuert)
• Inhalative Antibiotika
• Antibiotic Stewardship
Welte – Wien – Alternative Strategien 17.02.2017
Continuous versus Intermittent
b-Lactam Infusion in Severe Sepsis
Abdul-Aziz M et al. Intensive Care Med. 2016 Jan 11. [Epub ahead of print]
• Two-centre RCT in critically ill
pts with severe sepsis who not
on renal replacement therapy
• Betalactam CI (70 pts) versus IB
(70 pts) dosing.
• CI participants had – A higher clinical cure rates (56
versus 34 %, p = 0.011)
– a higher median ventilator-free days
(22 versus 14 days, p<0.043)
– higherPK/PD target attainment rates
on day 1 (97 versus 70 %, p<0.001)
and day 3 (97 versus 68 %, p<0.001)
• There was no difference in 14-
day or 30-day survival
Welte – Wien – Alternative Strategien 17.02.2017
Welte – Wien – Alternative Strategien 17.02.2017
Continuous versus Intermittent
b-Lactam Infusion in Severe Sepsis
Abdul-Aziz M et al. Intensive Care Med. 2016 Jan 11. [Epub ahead of print]
Welte – Wien – Alternative Strategien 17.02.2017
Continuous versus Intermittent
b-Lactam Infusion in Severe Sepsis
• Efficacy of continuous versus
intermittent infusion in patients
with severe sepsis
• Randomized controlled trial in
• 25 intensive care units (ICUs).
• Pts. were randomized to receive
continuous or 30-minute
intermittent infusion – piperacillin–tazobactam
– ticarcillin–clavulanate
– or meropenem
Dulhunty JM et al. Am J Respir Crit Care Med 2015; Vol 192, Iss 11, pp 1298–1305,
Welte – Wien – Alternative Strategien 17.02.2017
Continuous versus Intermittent
b-Lactam Infusion in Severe Sepsis
• 432 eligible pts (median age of
64 y and APACHE II score of 20
• no difference in ICU-free days:
18 days vs. 20 days, (P = 0.38)
• No difference in 90-day survival:
74.3% (156 of 210) vs. 72.5%; P =
0.61)
• Clinical cure 52.4% (111 of 212)
vs. 49.5% (109 of 220); P = 0.56).
• No difference in organ failure–
free days (6 d; P = 0.27) and
duration of bacteremia (0 d; P =
0.24).
Dulhunty JM et al. Am J Respir Crit Care Med 2015; Vol 192, Iss 11, pp 1298–1305,
Welte – Wien – Alternative Strategien 17.02.2017
Alternative Strategien zur
Vermeidung von Resistenz
• Kontinuierliche Antibiotikagabe
• Therapeutisches Drug Monitoring
• Verkürzte Therapiedauer (Biomarker
gesteuert)
• Inhalative Antibiotika
• Antibiotic Stewardship
Welte – Wien – Alternative Strategien 17.02.2017
Antibiotika Pharmakokinetik bei schwer kranken Patienten
• Charakteristika schwer kranker Patienten
– Höheres Herzminutenvolumen
– Größeres Verteilungsvolumen
– Plasmaeinweißbindung
Welte – Wien – Alternative Strategien 17.02.2017
Sub-therapeutic antibiotic levels in ICU
patients caused by increase in Vd and Cl
Cl, drug clearance; MIC, minimum inhibitory concentration;
T, time; Vd, volume of distribution Gonçalves-Pereira J, Póvoa P. Crit Care 2011;15:R206
Vd
CI
Vd
CI CI
Vd
Cmax
AUC
MIC T>MIC
T
Cmax AUC
MIC T>MIC
T
AUC
MIC T>MIC
T
Welte – Wien – Alternative Strategien 17.02.2017
Relationship between augmented renal clearance
and low trough drug concentrations
Design
• Cohort study
• Trough levels in 52 ICU patients
Results
• Trough drug concentration was
<1 x MIC
– In 42% of all patients
– In 82% of patients with
ClCR ≥130mL/min/1.73m2
(p<0.001)
Udy AA et al. Chest 2012;142:30-9
ClCR (mL/min/1.73m2)
R2 =
0.528
0 50 100 150 200 250 300 350
0.1
1
10
100
Tro
ug
h c
on
ce
ntr
atio
n / M
IC r
atio
(lo
g10 s
ca
le)
R2 =
0.528
Welte – Wien – Alternative Strategien 17.02.2017
Therapeutic Drug Monitoring Nephrotoxicity
Schuts EC et al. Lancet Infect Dis 2016, Online,March 2, 2016
Welte – Wien – Alternative Strategien 17.02.2017
Alternative Strategien zur
Vermeidung von Resistenz
• Kontinuierliche Antibiotikagabe
• Therapeutisches Drug Monitoring
• Verkürzte Therapiedauer (Biomarker
gesteuert)
• Inhalative Antibiotika
• Antibiotic Stewardship
Welte – Wien – Alternative Strategien 17.02.2017
• For patients with VAP, we recommend
a 7-day course of antimicrobial therapy
rather than a longer duration (strong
recommendation, moderate-quality
evidence).
Kalil AC et al. Clin Infect Dis. 2016 Sep 1;63(5):e61-e111.
Welte – Wien – Alternative Strategien 17.02.2017
• Prospective, multicentre, randomised, controlled, open-label
intervention trial in 15 hospitals in the Netherlands
• Critically ill patients aged at least 18 years, admitted to the ICU,
In the
– Procalcitonin-guided group • non-binding advice to discontinue antibiotics was provided if procalcitonin concentrationhad
decreased by 80% or more of its peak value or to 0・5 μg/L or lower
– Standard-of-care group, patients weretreated according to local antibiotic
protocols.
Welte – Wien – Alternative Strategien 17.02.2017
Procalcitonin guided antibiotic therapy
• Between Sept 18, 2009, and July 1, 2013, 1575 were randomly
assigned to
– procalcitonin-guided group (761)
• In 538 patients (71%) in the procalcitonin-guided group antibiotics were
discontinued in the ICU
– standard-of-care (785).
• Median consumption of antibiotics was 7.5 in the PCT-guided group
versus 9.3 daily defined doses in the SOC group
– between-group absolute difference 2.69, p<0.0001)
• Median duration of treatment was 5 days in the PCT guided group
and 7 days in the SOC group
– between-group absolute difference 1.22, p<0・0001).
• 28 day mortality was 149 (20%) in the PCT-guided group and 196
(25%) in the SOC group (
– between-group absolute difference 5.4%, p=0.0122) according to ITT analysis
Welte – Wien – Alternative Strategien 17.02.2017
De Jong E et al. Lancet Infect Dis 2016, Online, Feb 29 2016
Welte – Wien – Alternative Strategien 17.02.2017
Alternative Strategien zur
Vermeidung von Resistenz
• Kontinuierliche Antibiotikagabe
• Therapeutisches Drug Monitoring
• Verkürzte Therapiedauer (Biomarker
gesteuert)
• Inhalative Antibiotika
• Antibiotic Stewardship
Welte – Wien – Alternative Strategien 17.02.2017
• Intratracheal antibiotic administration was a current practice in 87 ICUs
(45.3%), with 40 (46%) having experience with the technique (>3 y).
• Sixty-six (78.6%) of 84 health-care workers reported avoiding
intratracheal antibiotic administration due to an absence of evidence-
based guidelines (78.6%).
• Jet nebulizers were the most commonly used devices for delivery, in 24
less experienced ICUs (27.6%) and in 18 (20.7%) experienced ICUs.
Candela Solé-Lleonart et al. Respir Care. 2016 Mar 8. pii: respcare.04519. [Epub ahead of print
Welte – Wien – Alternative Strategien 17.02.2017
Intracheal Administration of
Antimicrobial Agents
• The most common prescribed nebulized agents were – colistin methanesulfonate and sulfate (36/87, 41.3% and 24/87, 27.5%), tobramycin
(32/87, 36.7%) and amikacin (23/87, 26.4%).
– Colistin methanesulfonate, amikacin and tobramycin daily doses for VAP were
significantly higher than for VAT (p < 0.05).
– Combination of parenteral and nebulized antibiotics occurred in 50 (86%) of 58
prescriptions for VAP and 36 (64.2%) of 56 of prescriptions for VAT.
– The use of nebulized antimicrobial agents in MV patients is common. There is marked
heterogeneity in clinical practice, with significantly different in use between patients
with VAP and VAT.
Candela Solé-Lleonart et al. Clin Microbiol Infect. 2015 Dec 23. pii: S1198-743X(15)01042-3. doi: 10.1016/j.cmi.2015.12.016. [Epub ahead of print]
Welte – Wien – Alternative Strategien 17.02.2017
Nebulization of Anti-infective Agents in Invasively Mechanically
Ventilated Adult Patients: a systematic review and meta-analysis.
• Eleven studies were included in the meta-analysis
regarding bacterial infections (six randomized
controlled trials)
– VAT
• Palmer 2008 and 2014
– VAP due to MDR pathogens
• Niederman 2012, Ghannam 2009, Kofteridis 2010, Doshi 2013,
Tumbarello 2013
– VAP due to sensible pathogens
• Lu 2011
– VAP independently of the pathogen’s susceptibility pattern
• Hallal 2007, Rattanaumpawan 2010; Arnold 2012
Candela Solé-Lleonart et al. Anaethesiology 2016 (in revision)
Welte – Wien – Alternative Strategien 17.02.2017
• Nebulized antibiotics administration for the
treatment of VAT was associated with significant
decrease
– in the emergence of resistant strains (RR=0.18; 95% CI, 0.05-
0.64).
• Antibiotic nebulization against VAP caused by
resistant pathogens was associated with
– higher clinical resolution (OR=1.96; 95% CI, 1.30-2.96)
– decrease in the length of mechanical ventilation (3.72 days
less; 95% CI from -5.86 to -1.59 days) when a combination of
nebulized and iv colistin or aminoglycosides was used
Nebulization of Anti-infective Agents in Invasively Mechanically
Ventilated Adult Patients: a systematic review and meta-analysis.
Candela Solé-Lleonart et al. Anaesthesiology 2016 (in revision)
Welte – Wien – Alternative Strategien 17.02.2017
Emergence of resistant strains in patients
treated with nebulized antibiotics for VAT
Candela Solé-Lleonart et al. Chest 2016 (in revision)
Welte – Wien – Alternative Strategien 17.02.2017
Clinical resolution of patients treated with
nebulized antibiotics for VAP caused by
resistant pathogens Candela Solé-Lleonart et al. Anaesthesiology 2016 (in revision)
Welte – Wien – Alternative Strategien 17.02.2017
Mortality of patients treated with nebulized
antibiotics for VAP caused by resistant
pathogens Candela Solé-Lleonart et al. Anaesthesiology2016 (in revision)
Welte – Wien – Alternative Strategien 17.02.2017
Nephrotoxicity in patients treated with
nebulized antibiotics for VAP
Candela Solé-Lleonart et al. Chest 2016 (in revision)
Welte – Wien – Alternative Strategien 17.02.2017
Amikacin-fosfomycin
• Cardeas Pharma (Seattle, WA, USA)1 recently completed a Phase 2 clinical trial of an
inhaled antibiotic to treat Gram-negative pneumonia in mechanically ventilated patients
receiving IV antibiotics
– Amikacin and fosfomycin were delivered as an adjunctive to IV standard of care using an
experimental nebulizer (PARI Pharma GmbH, Munich, Germany) (n=72) vs placebo
(n=72)
• Primary endpoint was CPIS improvement from baseline
• Secondary endpoint was clinical cure at Day 14 or no mortality
• The trial failed its primary endpoint:1
– CPIS improvement from baseline did not differ between treatment and comparator
groups
(p = 0.70)
• Secondary endpoints were also not significantly different between groups
– No mortality and clinical cure did not differ between groups (p = 0.68)
• Mortality was comparable in both groups
– Amikacin-fosfomycin 24% (n=17); placebo 17% (n=12) p = 0.32
Kollef et al. Chest 2016:doi: 10.1016/j.chest.2016.11.026. [Epub ahead of print];
Welte – Wien – Alternative Strategien 17.02.2017
Amikacin Inhale is currently in Phase 3
clinical development (‘INHALE’ trials)
• Two prospective, randomized,
double-blind, placebo-controlled,
multi-centre superiority studies
(INHALE 1 and INHALE 2)1,2
– Evaluating safety and efficacy of
Amikacin Inhale as empiric therapy
in combination with standard of
care in intubated and mechanically
ventilated patients with
Gram-negative pneumonia
• Both trials will conclude when the total
reaches 724 patients (planned for Q1 2017)
– Single consolidated analysis
– Last patient last visit Q2 2017
INHALE 1:
Countries enrolling include US, AU, CZ,
TW, KR, TH, CA, PH, CO, MX, TR
INHALE 2:
Countries enrolling include FR, HU, ES,
BE, JP, PL, PT, IL, CN, GR, NL, RU, UA
1. Clinicaltrials.gov entry, 25 May 2016, https://clinicaltrials.gov/ct2/show/NCT01799993 (accessed 22 June
2016); 2. Clinicaltrials.gov entry, 25 May 2016, https://clinicaltrials.gov/ct2/show/NCT00805168 (accessed 22
June 2016); 3. Bayer. Integrated Clinical Study Protocol No. 13084 version 4.0.
Welte – Wien – Alternative Strategien 17.02.2017
Alternative Strategien zur
Vermeidung von Resistenz
• Kontinuierliche Antibiotikagabe
• Therapeutisches Drug Monitoring
• Verkürzte Therapiedauer (Biomarker
gesteuert)
• Inhalative Antibiotika
• Antibiotic Stewardship
Welte – Wien – Alternative Strategien 17.02.2017
• Significant benefits for one or more of the four outcomes
for – Empirical therapy according to guidelines
– De-escalation of therapy
– Switch from intravenous to oral treatment
– Therapeutic drug monitoring
– Use of a list of restricted antibiotics
– Bedside consultation the overall evidence
• Relative risk reduction for mortality for – Guideline-adherent empirical therapy by 35% (relative risk 0·65,
p<0⋅0001)
– De-escalation by 66% (0·44, p<0⋅0001)
Lancet Infect Dis 2016, Online,March 2, 2016
Welte – Wien – Alternative Strategien 17.02.2017
Antibiotic
therapy
according to
the
guidelines Mortality
Schuts EC et al. Lancet Infect Dis 2016, Online,March 2, 2016
Welte – Wien – Alternative Strategien 17.02.2017
Stapylococcus aureus Bacteremia Bedside Consultation
Mortality
Schuts EC et al. Lancet Infect Dis 2016, Online,March 2, 2016
Welte – Wien – Alternative Strategien 17.02.2017