alternative antibiotikastrategien zur verhinderung von

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


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




Abdul-Aziz M et al. Intensive Care Med. 2016 Jan 11. [Epub ahead of print]




• 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,




• 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,







gesteuert)




Antibiotika Pharmakokinetik bei schwer kranken Patienten

• Charakteristika schwer kranker Patienten

– Höheres Herzminutenvolumen

– Größeres Verteilungsvolumen

– Plasmaeinweißbindung


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


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


Therapeutic Drug Monitoring Nephrotoxicity

Schuts EC et al. Lancet Infect Dis 2016, Online,March 2, 2016







gesteuert)




• 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.


• 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.


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


De Jong E et al. Lancet Infect Dis 2016, Online, Feb 29 2016







gesteuert)




• 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


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]


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)


• 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)


Emergence of resistant strains in patients

treated with nebulized antibiotics for VAT

Candela Solé-Lleonart et al. Chest 2016 (in revision)


Clinical resolution of patients treated with

nebulized antibiotics for VAP caused by

resistant pathogens Candela Solé-Lleonart et al. Anaesthesiology 2016 (in revision)


Mortality of patients treated with nebulized

antibiotics for VAP caused by resistant

pathogens Candela Solé-Lleonart et al. Anaesthesiology2016 (in revision)


Nephrotoxicity in patients treated with

nebulized antibiotics for VAP

Candela Solé-Lleonart et al. Chest 2016 (in revision)


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];


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.







gesteuert)




• 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


Antibiotic

therapy

according to

the

guidelines Mortality



Stapylococcus aureus Bacteremia Bedside Consultation

Mortality


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