Rational use of antibiotics in clinical practiceSelection of resistance: how to resist it?

Patrick Lacor

UZ Brussel

Advanced Education Program of theBelgian Society of Internal Medicine

February 6th, 2015

What’s the problem with antibiotics?

l resistanceg changing pattern of susceptibilityg MDRO= multidrug resistant organisms

l side effectsg allergyg CDI= Clostridium difficile infectiong interactions

l costsg hospital reimbursement systemg new drugs

Why are antibiotics often prescribed?

l judged to be effective, safe and inexpensive

l prescribing AB more comfortable than practicing restraint

→ the “just-in-case” approachl concerns about relapse

→ AB duration based more on tradition than evidence

‘The most common errors in antibiotic therapy’

l use of broad-spectrum AB when narrow-spectrum would suffice

l combination therapy when single AB would suffice

l initial prescription of wrong agent if resistance data neglected

l failure to change AB when antibiogram becomes available

l failure to adjust the dosage in case of ↓ hepatic/renal functionl IV therapy when oral therapy would be equally effective

l excessive duration of therapy

The Daschner Guide to In-Hospital Antibiotic Therapy – European Standards – 2nd Edition, 2012-2013by U.Frank & E.Tacconelli

In short…

l too often

l too long

l too broadresistance

Antibiotic Selection of resistant strains

Awareness and actions

Amoxicillin for acute lower-respiratory-tract infection in primary care when pneumonia is not suspected: a 12-country, randomised, placebo-

controlled trial

Paul Little, FRCGP, Beth Stuart, PhD, Michael Moore, FRCGP, Samuel Coenen, DMSc, Christopher C Butler, FRCGP, Maciek Godycki-Cwirko, PhD, Artur Mierzecki, PhD, Slawomir Chlabicz, PhD, Antoni Torres, PhD, Jordi Almirall, MD, Mel Davies, MSc, Tom Schaberg, PhD, Sigvard Mölstad, PhD, Francesco Blasi, MD, An De Sutter, PhD, Janko Kersnik,

PhD, Helena Hupkova, PhD, Pia Touboul, MD, Kerenza Hood, PhD, Mark Mullee, MSc, Gilly O'Reilly, PhD, Curt Brugman, MSc, Herman Goossens, PhD, Theo Verheij, PhD and on behalf of the GRACE consortium

The Lancet Infectious DiseasesVolume 13, Issue 2, Pages 123-129 (February 2013)

DOI: 10.1016/S1473-3099(12)70300-6

Copyright © 2013 Elsevier Ltd Terms and Conditions

Figure 1

Source: The Lancet Infectious Diseases 2013; 13:123-129 (DOI:10.1016/S1473-3099(12)70300-6)

primary outcome= duration of symptoms rated by pts as “moderately bad” or worse after initial presentationsecondary endpoint= symptom severity and new or worsening symptoms

previous diagnoses of asthma, COPD andother comorbid disorders were not exclusion criteriaand thus acute infective exacerbations were included

Figure 2

Source: The Lancet Infectious Diseases 2013; 13:123-129 (DOI:10.1016/S1473-3099(12)70300-6)

Terms and Conditions

Rationeel antibioticumgebruik in België

l BAPCOC= coördinatiecommissie antibioticabeleid in België (1998)l registreren / rapporteren / informeren

l richtlijnen opstellen

l voorstellen formuleren

l sensibiliseringscampagnes

l project “antibiotherapiebeleidsgroep” l maatregelen ter beperking van resistentie

l advies verstrekken aan artsen

l functioneel geïntegreerd in het comité voor ziekenhuishygiëne en het medicofarmaceutisch comité

http://www.health.fgov/antibiotics

www.gebruikantibioticacorrect.bewww.usagecorrectantibiotiques.be

It’s in our hands

Titel van de presentatie| pag. 16

Selection of antibiotics: different players

l the infectiong site

g severity

l the host g immune system

g allergy

l the infectingorganismg most likely?

g susceptibility

l the antibioticg spectrum

g PK/PD properties

Empirical vs documented AB therapy

First signs of infection

Empirical therapy

Day 1

Gram stain of -sputum-swab-Urine-Puncture-BAL--…

à Leukocytesà Gram + coccior GNBà Polymicrobialà yeast

Day 2-3

Positive cultures:- Gram positive cocci(Staph or Strepto)- Gram negative bacilli(Enterobacteriaceae, Pseudomonas,..)

Adaptation of empirical therapy

Day 3-4

Identification of the pathogenAntimicrobial susceptibility

Documentedtherapy

When to start empirical AB therapy ?

Empirical antibiotics…

l Are they really necessary?

l When are they an emergency?

l Microbiology sampling, sampling…!

13/02/2015

Microbiological documentation

l Blood cultures (≥ 2)g to increase the sensitivityg to distinguish between

contamination & true infection

l Urine

l Respiratory samples

l Wound swabs

l Puncture of any abscess/collection

l Removal of catheters, if possible

systemic inflammatory response syndrome (SIRS)

l fever (>38°C) or hypothermia (90/’)

l tachypnea (>20/’)

l leukocytosis (>12000/µL) or >10% bands (shift to the left) or leukopenia (

Not only infections…

13/02/2015

l Stimuli

g infections

g trauma

g malignant neoplasms

g burns

g tissue infarction

g immunologically mediated and crystal-induced inflammatory states

g strenuous exercice

g childbirth

g even some evidence: major depression, schizophrenia, psychological stresses

acute-phase response

Changes in concentration of secretory proteins (eg fromhepatocytes).

IL-6= chief stimulator.

13/02/2015

acute phase proteins

l proteins that increase in concentration in response to “early alarm mediators” (IL-1, IL-6, TNF-α)

l released as a result of infection or “tissue injury”

l they use pattern recognition receptors to generate defensive effector functions

activation of the MP-system

l cell surface receptors recognizeg PAMPs=pathogen-associated molecular patterns

l gram-negative LPSl yeast cell wall mannansl mycobacterial glycolipids

g DAMPs= danger-associated molecular patternsl heat shock proteinl fibrinogenl HMGB-1 protein

l recognition activates the phagocyte

l goal= pathogen clearance and tissue repair

pattern recognition receptorPRR

acute phase proteins

CRP

l a pentameric β-globulinl produced by the liver in response to IL-6

l levels can rise rapidly (1000 fold

procalcitonin

l produced byg C-cells of the thyroid glandg in inflammatory conditions: also by the liver and PBMC

l levels peak at 8 - 24hl elevations more pronounced in bacterial and fungal infectionl downregulated in viral infectionsl levels fall with response to AB therapy ® monitoringl but also elevated in non-infectious conditions!

Role of biomarkers?

l CRP

l procalcitoning in 1 meta-analysis, sensitivity and specificity were 71% in

differentiating non-septic SIRS from sepsisg 70% sensitive= true positive rate= 70%= only 2/3 of “PCT positive” are septic

g 70% specific= true negative rate= 70%= only 2/3 of “PCT negative” are not septic

13/02/2015

Tang BM et al. Lancet Infect Dis 2007; 7: 210-7.Uzzan et al. Critical Care Medicine 2006, 34: 1996-2003.

Conclusion

l CRP, PCT (and IL-6) and are strongly associated withlikelihood of infection and septicaemia

l but: wideranging biomarker concentrations

l no cutoff point with high sensitivity /specificity in diagnosinginfection or septicaemia

l can serve as useful adjuncts when sepsis remains in doubtbut should not serve as the only criterion

l PCT levels most useful in sequential use to determine ifantibacterial therapy can be stopped

clinical suspicion of infection/sepsis

medical historyclinical examination

microbiologyimaging / biomarkerssurgical exploration

diagnosis confirmedno yes

supportive therapyobserve

follow-upclinical exam/biomarkersmicrobiology/imaging?

supportive treatmentsurgery if indicatedinitiate antibiotics

resolution/recoveryyes no

adequate source control?

appropriate antibiotherapy?

Sakr Y and Reinhart K. Biomarkers of host response: diagnostic purposes. In: Sepsis Handbook, Ed.Biomerieux, 2007

Still…

Angus DC et al. Severe sepsis ad septic shock .NEJM 2013; 369: 841-851

Recommendation grades1. Strong recommendation: Benefits clearly outweigh the risks and burdens (or vice versa) for most, if not all, patients2. Weak recommendation: Benefits and risks closely balanced and/or uncertain

Evidence gradesA. High-quality evidence: Consistent evidence from randomized trials, or overwhelming evidence of some other formB. Moderate-quality evidence: Evidence from randomized trials with important limitations, or very strong evidence of some other formC. Low-quality evidence: Evidence from observational studies, unsystematic clinical observations, or from randomized trials with serious flaws

Rules of fist …

l react promptly to the early signs of sepsis with appropriate“best-guess” parenteral therapy

for every hour of delay in giving parenteral antibiotics, survival ↓ by 8%

l as most episodes of bacteraemia are intermittent, more than oneset of blood cultures should be taken before starting antibiotics

IV antibiotics should be started

Which antibiotics?

l first choice for sepsis syndrome depends on g the presumed source of the infection

g the presumedly causative organism

g the immune status of the patient

l then, guided by cultures/susceptibility testing

13/02/2015

empiric treatment = “best-guess” treatment

And: the 5 D’s !

l the right DRUG

l the right DOSE

l the best DELIVERY route

l can you DE-ESCALATE?

l the appropriate DURATION

13/02/2015

Beware of possible interactions !

Antimicrobial stewardship

l primary goalg to optimize clinical outcomeg while minimizing unintended consequences of antimicrobials,

includingl toxicity

l selection of pathogenic organismsl emergence of resistance

l secondary goalg to reduce health care costs without adversely impacting

quality of care

Antimicrobial Stewardship Guidelines • Clinical Infectious Diseases 2007: 44

Antimicrobial stewardship

l who?g a multidisciplinary team (an infectious disease physician, a

clinical microbiologist, clinical pharmacist, hospitalepidemiologist, infection control professional, information system specialist…)

l what?g education

l streamlining or de-escalation of therapyl dose optimizationl parenteral to oral conversion

g guidelines and clinical pathways

l how?g prospective audit with intervention and feedbackg fomulary restriction and preauthorization requirementsg computer-based surveillance

The microbiologist can help if the clinician sends relevant specimens

together with useful clinicalinformation!

In clinical practice

l the antibiotic check listÖ is antibiotherapy indicated?Ö have appropriate specimens been obtained?Ö what organisms are most likely?Ö which antibiotic probably is the best?Ö monotherapy or combination therapy?Ö host factors?Ö route of administration?Ö appropriate dose?Ö has antibiotherapy to be modified?Ö optimal duration of treatment?