Dr Boudewijn Catry Drs Katrien Latour

ANTIBIOTICABELEID MDRO bij acute zieke patiënten : welke afwegingen maken bij keuze van (toedieningsweg) antibiotica, bovendien rekening houdend met farmacokinetiek van geriatrische patiënten Symposium, 29 september 2015

Rue Juliette Wytsmanstraat 14 | 1050 Brussels | Belgium T +32 2 642 51 11 | F +32 2 642 50 01 | email: [email protected] | www.wiv-isp.be

Dr Boudewijn Catry Drs Katrien Latour

Definitie Zorginfectie •

Ook gekend als “nosocomiale infectie” of “ziekenhuisinfectie”, hetzij ‘zorggerelateerde infectie’ •“infectie

die een patiënt tijdens de zorg in het ziekenhuis of een andere gezondheidszorgvoorziening oploopt die niet aanwezig of in incubatie was op het moment van opname of op het ogenblik van zorg omvat ook infecties die opgelopen zijn in een gezondheids-zorgvoorziening maar die zich pas na het ontslag manifesteren”

Jaarlijks aantal slachtoffers

+-2000 in 2008 (www.wiv-isp.be)

<750 in 2012 (bivv.be)

Dodelijke zorginfecties: 2650 in 2007 (KCE 92A)

Preventie -

Monitoring Hygiëne – omgeving & -

-

Minder invasieve handelingen Basisvereisten vs Naleving indicaties

Antibioticumgebruik – minder = niet (!), geen onnodige combinatie, minder lang, hogere niet toxische dosis, beste toedieningsweg, interval Enkel bij combinatie (!) van betere hygiëne en verminderd antibioticumgebruik is een significante daling van resistente zorginfecties merkbaar -

Lafaurie M et al. J. Antimicrob. Chemother. 2012;67:10101015

Koninklijk Besluit 2015 = o.a. MDRO MultiDrug Resistente Organismen

MULTIDRUG RESISTENTE (MDR) ORGANISMEN

Micro-organisme

Resistentie

MRSA

Staphylococcus aureus

Methicilline

ESBL+

Enterobacteriaceae (E.coli / Klebsiella / …)

3de generatie cefalosporines

CPE

Enterobacteriaceae

Carbapenems

VRE

Enterococcus faecalis/faecium

Vancomycine

MDR

Pseudomonas/Acinetobacter

Verschillende antibioticaklassen

CDIF

Clostridium difficile

Intrinsiek (Anaëroob)

Courtesy: Latour & Jans

Point prevalence survey: PPS (photo)

Surveillance contineously (film)

&

http://www.ecdc.europa.eu/en/publications/Publications/healthcareassociated-infections-antimicrobial-use-PPS.pdf

Point Prevalence Survey: Hai - ABU N pts (a)

Prevalence% (95%CI) (b)

N HAI (c)

Relative % HAI (d)

Pneumonia & other LRTI

392

2.0% (1.8-2.2)

394

25.7%

Surgical site infections (e)

290

1.5% (1.3-1.6)

290

18.9%

Urinary tract infections

263

1.3% (1.2-1.5)

264

17.2%

Bloodstream infections (BSI)(f)

216

1.1% (0.9-1.2)

217

14.2%

Gastro-intestinal system infections

118

0.6% (0.5-0.7)

119

7.8%

Skin and soft tissue infections

59

0.3% (0.2-0.4)

59

3.9%

Bone and joint infections

38

0.2% (0.1-0.3)

39

2.5%

Eye, Ear, Nose or Mouth infection

47

0.2% (0.2-0.3)

47

3.1%

Systemic infections(f)

40

0.2% (0.1-0.3)

40

2.6%

Zarb et al., 2012 Eurosurveillance

EVOLUTIE MRSA IN ACUTE ZH EN WZC

17 NHs1 (n=2.857) 4.9 % MRSA

1 3

24 NHs2 (n=2.908) 4.7 % MRSA (0% - 14%)

Hoefnagels-Schuermans et al. (ICHE, 2002); 2 Suetens et al. (JAGS, 2006) Denis et al. (JAC, 2009); 4 Jans et al. (PlosOne, 2013)

60 NHs3 (n=2.953) 19 % MRSA (2% - 43%)

60 NHs4 (n=2.789) 12.2 % MRSA (0% - 36%)

Monthly FQ consumption, expressed as DDD/1000 PD. Filled circles, pre-intervention period values; open circles, intervention period values; diamonds, post-intervention period values.

Lafaurie M et al. J. Antimicrob. Chemother. 2012;67:10101015 © The Author 2012. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: [email protected]

Monthly consumption of ABHR solution.


Change in monthly MRSA rates, from 2002 to 2010.


EVOLUTIE ESBL+ ENTEROBACTERIACEAE IN ACUTE ZH EN WZC ZIEKENHUIZEN (NATIONALE SURVEILLANCE)

WOONZORGCENTRA (STUDIE 2011) E. coli

90%

5%

K. pneumoniae

Prevalentie van dragerschap van ESBL+ enterobacteriën in WZC: 6.2% (0-20%)

2%

E. cloacae C. freundii

Bron: Jans B. (WIV-ISP)

3%

E. aerogenes

ESBL+ bacteriën, verdeling volgens species

0,5%

www.nsih.be Neely et al., 2014 WIV-ISP

Carbapenemase producing enterobacteriae = CPE Klebsiella pneumoniae Escherichia coli Enterobacter cloacae ….

Resistant : Amoxicillin (ESBL) – Cephalosporines – Aminoglycosides – Sulfa-Trimethoprim – Tetracyclines – Fluoroquinolones - Temocilline (oxa-48)… Sensitive: Colistin, Tigecycline, Fosfomycine, …

Gecumuleerd aantal CPE gevallen 1/1/2012 - 30/6/2014 (1127 CPE-positieve patiënten)

19

Fonguh, S WIV-ISP 2013

Tabel 5: Percentage van handhygiënecompliantie volgens type van contact Aantal geobserveerde opportuniteiten (n)

Type contact

Handhygiëne Compliantie alcohol+zeep (n) (%)

Vóór rechtstreeks contact met de patiënt

30349

20090

67.6

Na rechtstreeks contact met de patiënt

35983

29061

82.5

Vóór contact intravasculair stelsel (IV)

7759

5777

71.8

Vóór contact urinair stelsel (URI)

1614

1341

73.8

Vóór contact respiratoir stelsel (RESP)

1905

1265

64.2

Vóór contact beschadigde huid/slijmvliezen (BH/SV)

2887

2249

76.1

Vóór contact geneesmiddelen (GM)

4119

2720

66.0

Na blootstelling lichaamsvochten of slijmvliezen (LV/SV)

9403

8125

84.9

Na contact directe patiëntenomgeving

21580

15703

75.1

%=Gemiddeld percentage (hoger gewicht voor instellingen met hoger aantal observaties)

Fonguh Sylvanus, 2013 www.nsih.be

Fonguh Sylvanus, 2013 www.nsih.be

Mortaliteit & inadequate antibioticumtherapie The Influence of Inadequate Antimicrobial Treatment of Bloodstream Infections on Patient Outcomes in the ICU Setting*

Ibrahim et al., Chest 2000, 118 (1)

Septic shock (2731 human patients): Each hour of delay in antimicrobial administration over the ensuing 6 hrs was associated with an average decrease in survival of 7.6% (Kamur et al., 2006).

Conclusies (1) MRSA komt minder voor, VRE in opmars. Gram-negative MDRO’s & VRE zijn toegenomen. In 2014, 3 participating hospitals reported an outbreak with resistant E. faecium, totalizing 68 cases (14 infected and 54 colonized patients). Since January 2015 an increasing number of hospitals declared VRE-clusters, involving an important number of cases (Jans, B. WIV-ISP 2015).

Handhygiëne alleen is onvoldoede om zorginfecties te reduceren. Invasieve handelingen gaan onvoldoende gepaard met gepaste hygiëne Antibiotica redden levens, maar…

Box 1. Leidraad Zorgvuldig gebruik van antibiotica in ouderen 1.

Evalueer het risico van ernst van infectie en multidrug-resistente organismen (MDRO) o.b.v. levenstijl en functionele status

Rusthuisbewoners & Geriatrische patiënten Puntprevalentiestudie Healthcare-associated infections and Antimicrobial use in European Long-Term care facilities (HALT) Dr Katrien Latour, Béatrice Jans

STUDIEPOPULATIE

81.9 jaar

82.8 jaar

86.0 jaar

84.2 jaar

85.0 jaar

83.7 jaar

HALT: studiepopulatie 11 911 geïncludeerde bewoners 53.7% 85+ jaar

25.2% ♂

100 80

61.0%

60

49.3%

42.1%

40 20

2.5%

8.2%

3.5%

0.2%

0 o I nc

e nti e n nti

r ng t er i e ete k h r h t t e ka ka ep o e e b s n r i s i it De Ur ul a ite l c i s b Va Mo ie tat n rië

it ub c De

us de An

re

e nd o w

PREVALENTIE ZORGINFECTIES & ANTIMICROBIEEL GEBRUIK PPS in woonzorgcentra Zorginfecties 3.6%

PPS op geriatrische afdelingen 8.5% 7.1% in acute ziekenhuizen

Antimicrobieel gebruik 5.1%

25.3% 28.7% in acute ziekenhuizen

ZORGINFECTIES IN WZC Luchtweginfecties (LWI) Verkoudheid/faryngitis Griep Pneumonie Andere lage LWI Urineweginfecties (UWI) Bevestigde UWI Vermoedelijke UWI Huidinfecties Cellulitis/weke delen/wondinfecties Herpes simplex of zoster Schimmelinfecties Scabies Gastro-intestinale infecties Gastroenteritis Clostridium difficile infectie

37% 29% 4% 8% 58% 34% 51% 49% 14% 96% 2% 2% 0% 6% 85% 15%

3% + 21% van alle infecties

Figuur 1Non-pediatric antimicrobial use in the community in Daily Defined Doses per 1000 inhabitant days. Belgium 2007-2013

ZORGINFECTIES OP GERIATRIE

Geriatrie

Totaal ZH’en

36%

18%

20% + 8%

20% + 6%

Gastro-intestinale infecties

11%

8%

Bloedstroominfecties

9%

13%

Infecties van de huid of weke delen

5%

4%

Postoperatieve wondinfecties

4%

16%

Urineweginfecties Pneumonie & andere lage LWI’s

ANTIMICROBIEEL GEBRUIK IN WZC 98% via orale toediening Profylactische behandelingen (n=178)

39%

Urinewegen Luchtwegen Therapeutische behandelingen (n=277)

61%

Luchtwegen Urinewegen Huid of wond Gastro-intestinale infecties Andere infecties 57.4%

91.0 3.9

35.6%

42.2 35.7 12.6 2.1 2.1

AM GEBRUIK IN GERIATRIE 54% parenterale toediening, 46% orale toediening Profylaxe (n=16)

2%

Andere of onbekende indicatie (n=13)

2%

21% 2%

Therapeutische behandelingen (n=688)

96%

77%

Luchtwegen Bronchitis (acute of chronisch) Pneumonie Urinewegen

34%

39% 32% 68%

13%

26%

Asymptomatische bacteriurie Cystitis Pyelonefritis Systemische infecties 11% Huid/weke delen/been & gewrichten 10%

3% 81% 16% 13% 16% 15% GI

ANTIMICROBIEEL GEBRUIK IN WZC Therapeutische behandelingen (ATC J01)

57% furadantine 21% monuril 18% urfadyn

1%

60% amoxicilline & clavulaanzuur 34% amoxicilline

J01C Beta-lactams, penicillines J01D Overige beta-lactams

21% 0%

39%

25%

46% ciprofloxacine 38% moxifloxacine

J01A Tetracyclines

J01E Sulfonamiden & trimethoprim J01F Macroliden, lincosamiden & streptogramines J01G Aminoglycosiden J01M Chinolonen

8% 0%

3%

3%

J01R Combinaties van antibacteriële middelen J01X Overige antibacteriële middelen

AM GEBRUIK OP GERIATRIE 44% ciprofloxacine 39% levofloxacine

37% ceftriaxone 25% cefuroxime

58% amoxicilline & enzyme inhibitor 19% piperacilline & enzyme inhibitor


2.

Evalueer het risico van ernst van infectie en multidrug-resistente organismen (MDRO) o.b.v. levenstijl en functionele status Snel & Breed empirische therapie o.b.v. nationale richtlijnen & lokaal Antibiogram indien beschikbaar Cave: BEVESTIGDE DIAGNOSE?

HALT: UWI diagnostische testen Totaal

0%

20%

Geen antwoord

40%

Geen cultuur

60%

80%

Cultuur, geen MO

100%

Cultuur, MO

Therapeutisch

Profylactisch

0%

20%

40%

60%

Staalafname: 27% ♂, 39%♀

80%

100%

UWI in WZC: HALT 300 Tekens/Symptomen

Bevestigde infecties

250 -34.9%

200 -70.1%

150

-37.4% 100 50 0

I W L

I g d o n W ere O o U d / n W O / A K d i N Hu

S

GI isch em t s y

rts o Ko

UWI in WZC: McGeer Verblijfskatheter

Ja: minstens 2 criteria (a, c, d, e, f) Nee: min. 3 criteria (a, b, c, e, f)

(a)

Koorts (> 38°C) of rillingen Brandend gevoel bij het urineren: nieuw of toegenomen

(b)

Nieuwe of toegenomen frequentie van urineren Drang om te urineren: nieuw of toegenomen

(c)

Nieuwe pijn of gevoeligheid in de flank of suprapubisch

(d)

Verandering in het aspect van de urine

(e)

Achteruitgang van mentale of functionele status (kan nieuwe of toegenomen incontinentie zijn)

(f)

Gediagnosticeerd door behandelende arts (= HALT)

UWI: tekens & symptomen

Midthun S, Paur R, Bruce AW, et al. Urinary tract infections in the elderly: A survey of physicians and nurses. Geriatr Nurs 2005;26:245-251.

BIJZONDERHEDEN INFECTIES BIJ OUDEREN Diagnose Atypische klinische presentatie Moeilijkere staalname Gewijzigde sensitiviteit van diagnostische procedures en biologische markers

Behandeling Gewijzigde farmacokinetiek: Nier >> Lever - nevenwerkingen - interacties Toedieningsproblemen Ethische aspecten Verminderde weerstand (immunosenescentie) Comorbiditeiten Cognitieve en/of functionele beperkingen Nutritionele status Kathetergebruik, wonden...

Gavazzi G, Krause KH. (2002) Ageing and infection. Lancet Infect Dis. 2: 659-666


2.

3.

Evalueer het risico van ernst van infectie en multidrug-resistente organismen (MDRO) o.b.v. levenstijl en functionele status Snel & Breed empirische therapie o.b.v. nationale richtlijnen & lokaal Antibiogram indien beschikbaar Volledige medische geschiedenis opvragen & vermijd ernstige bijwerkingen: ziekte/drug & drug/drug

Interacties (monitoring INR) Warfarine combinaties risico voor: 1. Bloedingen – ernstig: aminoglycosides, metronidazole, S/TMP, azoles. Minder ernstig: ciprofloxacine, erythromycine Repressie Vit K in darm: betalactams, fluoroquinolones, clindamycine. 2. ThromboEmbolie: rifampin, nafcilline, griseofulvine

Interacties (monitoring INR) Digoxine i.c.m. 1. Erythromycine, clarithromycine, tetracyclines 2. Itraconzole (eliminatie wordt verhindert) Statines/sulfonylureas i.c.m. Macroliden, azoles (inhibitoren CYP 450) Risico op rhabdomyolyse HYPOGLYCEMIE Gatifloxacine: hypoglycemie Linezoled: versterking hypertensie

Which Drugs Should Be Deprescribed in the Elderly? Medscape. Jul 02, 2015.

A study in Canada recently showed that in a group of elderly patients (mean age, 81 years), the average number of medications taken was 15 (range, 6-28) with 8.9 drugrelated problems occurring per patient. When these problems were analyzed, 2.5 of those 8.9 problems were found to be caused by drugs that were not needed.[2] In the United States, 28% of hospitalizations in seniors are caused by medication-related problems.[1] 1. Task force on Aging Research: Medications and Errors. 2009. https://www.ascp.com/sites/default/files/file_Task_Force_2009_FINAL-3.pdf Accessed June 15, 2015. 2. Farrell B, Szeto W, Shamji S. Drug-related problems in the frail elderly. Can Fam Physician. 2011;57:168 -169. Abstract


2.

3.

4.

Evalueer het risico van ernst van infectie en multidrugresistente organismen (MDRO) o.b.v. levenstijl en functionele status Snel & Breed empirische therapie o.b.v. nationale richtlijnen & lokaal Antibiogram indien beschikbaar Volledige medische geschiedenis opvragen & vermijd ernstige bijwerkingen: ziekte/drug & drug/drug Doseer i.f.v. leeftijdsgebonden Pharmacokinetiek/pharmacodynamiek, zonder de maximale therapeutische dosis op te offeren.

James M. Wooten, PharmD South Med J. 2012;105(8):437-445.

PK/PD & leeftijd Maag pH gestegen = absorptie verminderd van (zuur-stabiele) producten: - ketoconazole, itroconazole, cefuroxime Maag pH gestegen = absorptie vermeerderd van (zuur-labiele) producten: penicillines, erythromycine, clarithromycine Effect PPI (?) Vertraagde maaglediging: ciprofloxacine (diabetici) AUC verminderd – gn ‘eradicatie’ bacteriën

PK/PD & leeftijd Vet /Spierverhouding (18-36% man, 33-44% vrouw) DistributieVolume (Vd) stijgt lipofiele producten: tetracyclines Vd daalt voor hydrofiele drugs: aminoglycosides, vancomyicne, betalactams, daptomycine Nierfunctie +++: GFR Cockcroft-Gaul formule Modification of Diet in Renal Disease equation

PK/PD & leeftijd Vet /Spierverhouding (vet percentage 18->36% man, 33->44% vrouw) DistributieVolume (Vd) stijgt voor lipofiele producten: tetracyclines Vd daalt voor hydrofiele drugs: aminoglycosides, vancomyicne, betalactams, daptomycine Nierfunctie +++: (GFR) Cockcroft-Gaul formule Modification of Diet in Renal Disease equation

PK/PD & leeftijd Leverfunctie + (hartfalen, COPD: leverperfusie daalt), eliminatie (halfwaardetijd T1/2) wordt verlengd. mechanisme: cytochrome P450 inhibitie : hypoglycemie

Richtlijnen: acute cystitis (BAPCOC) Niet-verwikkelde cystitis Nitrofurantoïne (Furadantine) • • •

Geringe resistentie

3x 100 mg per dag gedurende 3 dagen Tegenaangewezen bij nierinsufficiëntie Alternatief: nifurtoïnol (Urfadyn): 2 à 3x 100 mg per dag gedurende 3d

Trimethoprim •

300 mg per dag gedurende 3 dagen

Fosfomycine is geen eerste keuze

HALT: profylactische AB behandeling

Betalactams 2.7%

Overige AB 94.6%

Sulfo. & trimeth oprim 0.7%

Profylaxe (n=147) Chinolonen 2.0%

Nifurtoïnol

41.5%

Nitrofurantoïne

34.7%

Fosfomycine

18.4%

Ciprofloxacine

2.0%

Flucloxacilline

1.4%

Co-trimoxazol

0.7%

Amox. + enzym

0.7%

Amoxicilline

0.7%

Kidney function and the use of nitrofurantoin to treat urinary tract infections in older women INTRODUCTION

Reduction in the estimated glomerular filtration rate is common among older adults, and over 25% of those 65 years of age or older have an estimated glomerular filtration rate less than 60 mL/min per 1.73 m . The renal elimination of nitrofurantoin is reduced in patients with low estimated glomerular filtration rate, which can increase the risk of treatment failure for urinary tract infection and possibly also the risk of adverse events caused by elevated blood concentrations of the drug. 2

4

5,6

Kidney function and the use of nitrofurantoin to treat urinary tract infections in older women

CMAJ, 2015 April

Nitrofurantoin revisited: a systematic review and meta-analysis of controlled trials Objectives: Nitrofurantoin’s use has increased exponentially since recent guidelines repositioned it as firstline therapy for uncomplicated lower urinary tract infection (UTI). We conducted a systematic review and metaanalysis to assess nitrofurantoin’s efficacy and toxicity in the treatment of lower UTI. Methods: We performed a systematic review of all human controlled clinical trials published from 1946 to 2014 and assessing short-term (≤14 days) nitrofurantoin for lower UTI. Meta-analyses assessing efficacy and adverse events were conducted on randomized trials. Results: Twenty-seven controlled trials including 4807 patients fulfilled entry criteria; most were conducted between the 1970s and 1990s and were at increased risk for various biases. Nitrofurantoin appears to have good clinical and microbiological efficacy for UTI caused by common uropathogens, with clinical cure rates varying between 79% and 92%. The most methodologically robust studies surveyed indicate overall equivalence between nitrofurantoin when given for 5 or 7 days and trimethoprim/sulfamethoxazole, ciprofloxacin and amoxicillin. Meta-analyses of randomized controlled trials confirmed equivalence in clinical cure, but indicated a slight advantage to comparator drugs in microbiological efficacy (risk ratio 0.93, 95% CI 0.89–0.97). If given for only 3 days, nitrofurantoin’s clinical efficacy was diminished (61%–70%). Toxicity was infrequent (5%–16% in the 17 reporting studies), mild, reversible and predominantly gastrointestinal; meta-analyses confirmed no difference between nitrofurantoin and comparators. Hypersensitivity reactions such as pulmonary fibrosis and hepatotoxicity were not observed. Acquisition of resistance to nitrofurantoin is still relatively rare. Conclusions: When given short term for lower UTI, nitrofurantoin has good clinical and microbiological efficacy; toxicity is mild and predominantly gastrointestinal.

J Antimicrob Chemother. 2015 Sep;70(9):2456-64. doi: 10.1093/jac/dkv147.

HALT: diagnostische testen (Latour K, WIV-ISP 2015) Micro-organismen (n=62): Top 6 Escherichia coli

30

48.4%

100% ♀

Proteus mirabilis

11 (1)

17.7%

63.6% ♀

Klebsiella pneumoniae

4

6.5%

Klebsiella spp.

3

4.8%

Providencia spp.

3

4.8%

Enterococcus spp.

2

3.2%

Nitrofurantoin revisited: a systematic review and meta-analysis of controlled trials

Indeed, despite several decades of use, much of it prolonged and at lower doses in the context of UTI prophylaxis, nitrofurantoin has generally retained its broad-spectrum activity against Gram-negative and Gram-positive bacteria, including most enterococci, but with the important exception of some Klebsiella strains, Pseudomonas aeruginosa and the Proteae (e.g. Proteus, Morganella and Providencia spp.), which carry intrinsic resistance. (ref8)

J Antimicrob Chemother doi:10.1093/jac/dkv147

Latour et al., ICPIC, Geneve 2013


2.

3.

4.


Antimicrobial resistance Microbiological

MIC: Minimal Inhibitory Concentration

59 cases vs 64 ctls (Grimshaw et al., 1987)

Pharmacological

Clinical

Dosis-effect relation with resistance

100

P lasm a- of w eefselcon cen tratie

Plasma or Lung concentration (µg/mL)

µg/ml

B 10

A MPC

1

SC

0.1

0.01 0

4

8

12

16

na toediening TimeTijdafter administration

20

24 uren (hours)

Drlica et al., 2007

PK/PD

AUIC > 125 Cmax/MIC > 8 Mutant prevention

(MPC/MSW)

Routes of administration Intravenously: -

‘No’ resorption phase

-

No first-pass effect liver (metabolisation)

-

No gut resistance selection

-

Injection site adverse events

-

Nsocomial CLA-BSI

-

Doses can be lower to attain Cmax -

-

compared to oral

less diet dependent


2.

3.

4.


COMBANITIE & DUUR VAN BEHANDELING

DUUR: steeds korter 3 versus 8 dagen AMOXICILLINE voor ongecompliceerde CA-pneumonia: geen verschil in klinische efficaciteit (El Massaoui et al., Chest 2006) COMBINATIE: Chochrane: combinatie betalactam & aminoglycoside voor Sepsis: - ‘Vermijd de combinatie’

[Intervention Review] 2014 COCHRANE Beta lactam antibiotic monotherapy versus beta lactamaminoglycoside antibiotic combination therapy for sepsis

Duur behandeling lage UWI …several studies showed that trimethoprim, pivmecillinam, amoxicillin and certain cephalosporins are less effective than fluoroquinolones, co-amoxiclav or cotrimoxazole - given the same treatment duration (Ewer 1988; Gallacher 1986; Hooton 1995; Jonsson 1990). These findings may explain the better bacterial efficacy of a 3-day course of ofloxacin compared to a 7day course with cephalexin (Raz 1996). Some antibioticsmay not be appropriate for short course treatment (1 to 3 days) for pharmacokinetic reasons. Several penicillins and cephalosporins have a relatively short half-life (1 to 2 h in young people, 2 to 4 h in older people), whereas the fluoroquinolones, cotrimoxazole and fosfomycin have longer half-lives (4 to 12 h, 8 to 13 h, 4 to 50 h respectively) (Compendium 1998; McCue 1992). Indeed, Norrby 1990 has shown in his systematic review, that the optimal treatment duration for lower, uncomplicatedUTI in women (of all age) depends on the type of antibiotic: three days for cotrimoxazole and the fluoroquinolones and five days for betalactam antibiotics.

Lutters M, Vogt-Ferrier NB. Antibiotic duration for treating uncomplicated, symptomatic lower urinary tract infections in elderly women. Cochrane Database of Systematic Reviews 2002, Issue 3. Art. No.: CD001535. DOI: 10.1002/14651858.CD001535.

Duur behandeling lage UWI Main results Thirteen trials involving 1435 elderlywomenwere included. Six trials compared single dosewith short-course treatment, three compared single dose with long-course treatment and four compared short- (3-6 days) with long-course treatment (7-14 days). Methodological quality of all trials was low. Persistent bacteriuria rate at short-term (2 weeks post-treatment) was better in the longer treatment group (3 to 14 days) than in the single dose group (RR 1.84, 95% CI 1.18 to 2.86). However, the rate of persistent bacteria at long-term and the clinical cure rate showed no statistically significant difference between the two groups. Patients preferred single dose treatment (RR 0.73, 95% CI 0.66 to 0.88), however this was based on one trial comparing different antibiotics. Short versus longer treatments showed no significant difference, but the number of included studies and sample size were low. Single dose antibiotic treatment may be less effective but better accepted by patients than longer treatment durations (3 to 14 days). There was no significant difference between short (3-6days) versus longer (7-14 days) course antibiotics. The methodological quality of included studies was poor and the optimal treatment duration could not be determined. More appropriately designed RCTs testing the effect - on clinical relevant outcomes - of different treatment durations of a given antibiotic in a strictly defined population of elderly women.

Lutters M, Vogt-Ferrier NB. Antibiotic duration for treating uncomplicated, symptomatic lower urinary tract infections in elderly women. Cochrane Database of Systematic Reviews 2002, Issue 3. Art. No.: CD001535. DOI: 10.1002/14651858.CD001535.

Box 1. Leidraad Zorgvuldig gebruik van antibiotica in ouderen 1. 2. 3. 4.

5.

…. … … Doseer i.f.v. leeftijdsgebonden Pharmacokinetiek/pharmacodynamiek, zonder de maximale therapeutische dosis op te offeren. De-escaleer AB therapie op basis van klinische status en geïdentificeerd pathogeen

Staalnames Rectaal, keelwisser, BAL/tracheaal aspiraat, wonde, catheter, urine sonde….. nodigt uit tot breed spectrum antibiotica. Langere duur van behandeling, met switch IV/PO

Administratie route Switch IV/PO/IV Belast de commensale flora twee maal, En bovendien verschillend wanneer de switch Een ander product inhoudt. -

Earlier switching from intravenous to oral antibiotics owing toelectronic reminders , Patrick E. Beelera, Stefan P. Kusterb, Emmanuel Eschmanna, Rainer Weberb,Jürg Blasera,∗aResearch Center for Medical Informatics, University Hospital Zurich and University of Zurich, Zurich, SwitzerlandbDivision of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich and University of Zurich, Zurich, Switzerland – International J Antimicrob Agents, 2015 in press.

Antimicrobials Predisposing to CDI Very commonly related Clindamycin Ampicillin Amoxicillin Cephalosporins Fluoroquinolons

Less commonly related Uncommonly related Sulfa Macrolides Carbapenems Other penicillins

Aminoglycosides Rifampin Tetracycline Chloramphincol

Among symptomatic patients with CDI: • 96% received antimicrobials within the 14 days before onset •100% received an antimicrobial within the previous 3 months 20% of hospitalized patients are colonized with C. diff Sherif Ibrahim, MD, MPH 84

CDC, 2013 http://www.cdc.gov/drugresistance/threat-report-2013/

CDI: Pathogenesis Step 1Ingestion of spores transmitted from other patients

Step 2- Germination into growing (vegetative) form

Step 4 . Toxin B & A production leads to colon damage +/- pseudomembrane

Step 3 - Altered lower intestine flora (due to antimicrobial use) allows proliferation of C. difficile in colon

Sunenshine et al. Cleve Clin J Med. 2006;73:187-97. 87

Table 1 : Epidemiological surveillance of Clostridium difficile infections (CDI): characteristics of cases Year

2007

2008

2009

2010

2011

2012

2013

1,886

2,992

2,947

2,461

2,515

2,507

2,658

65%

64%

61%

61%

63%

61%

59%

No

75%

71%

72%

74%

76%

74%

73%

Yes

11%

11%

10%

9%

8%

9%

9%

Unknown

14%

17%

18%

17%

16%

17%

17%

Episodes Total episodes reported Hospital acquired infection (HAI)* (%) Recurrent episodes** (%)

Suspected origin of infection (% of infections other than those defined as HAI* i.e. “non-HAI”) Community

57%

56%

57%

59%

60%

63%

62%

Long term care facilities

12%

16%

14%

12%

10%

10%

11%

Other hospital§

22%

19%

16%

17%

18%

15%

15%

Unknown/missing

8%

10%

12%

11%

12%

12%

13%

1,811

2,831

2,787

2343

2414

2,401

2,528

58%

59%

59%

60%

59%

57%

57%

Hospital acquired case

78

80

80

79

80

79

80

Other cases

74

75

74

74

74

74

74

Death within 30 days – CDI indirect or direct cause (% )

11%

10%

5%

4%

3%

3%

4%

Patients Total patients reported with CDI Sex: female (%) Median age (years)

*Defined as onset of diarrhoea 2 days or more after admission in the declaring hospital (onset date – admission date >2) **Defined as the proportion of infections which are recurrent, and not the incidence of recurrences in patients presenting with a new episode of CDI § includes episodes acquired in a hospital other than the declaring hospital and cases arising in the declaring hospital which are thought to be hospital acquired but do not fulfil the strict definition of HAI

Table 1 : Hospital stays with an intestinal infection due to Clostridium difficile (code ICD-9_CM 008.45*), Belgium 1999-2010 1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

CDI as primary diagnostic code (no.) 415

467

423

501

723

907

959

1007

1040

1116

1148

920

866

26%

23%

23%

25%

23%

22%

23%

22%

23%

25%

24%

24%

% of the total 25%

CDI as secondary diagnostic code (no.)

Total

1270

1356

1404

1698

2155

3086

3456

3383

3646

3633

3514

2947

2715

1685

1823

1827

2199

2878

3993

4415

4390

4686

4749

4662

3867

3581

*ICD9-CM International classification of diseases, CDI: Clostridium difficile infection

Neely, Lambert et al., 2014 – WIV-ISP

Table 1 : Mean incidence* of Clostridium difficile infections (CDI)per 1000 admissions to hospital, Belgium, 2008-2010, according to data source 2007

2008

2009

2010

2011

Hospital discharge data (RCM)(a)

2.56

2.49

2.43

1.99

1.83

Mandatory hospital surveillance data (b)

1.38

1.97

1.83

1.48

1.44

186%

126%

132%

135%

127%

a/b

Figuur 1Non-pediatric antimicrobial use in the community in Daily Defined Doses per 1000 inhabitant days. Belgium 2007-2013

Neely, Lambert et al., 2014 – WIV-ISP

EID 12: 409-415.2006

EID 12: 409-415.2006

Experiment I Lancet 1979

Tetracyclines PE vs PE vs CTR: Evolution tetracycline resistance E. coli

Antibiotic Administration Routes Significantly Influence the Levels of Antibiotic Resistance in Gut Microbiota Lu Zhang et al. 2013, AAC

Ampicillin PE vs PE vs CTR: Evolution betalactamase resistance E. coli

Antibiotic Administration Routes Significantly Influence the Levels of Antibiotic Resistance in Gut Microbiota Lu Zhang et al. 2013, AAC

Comparison Oral (Feed) vs Injection

Checkley e.a., CVJ / VOL 51 / AUGUST 2010

Box 1. Leidraad Zorgvuldig gebruik van antibiotica in ouderen 1. 2. 3. 4.

5.

6.

…. … … Doseer i.f.v. leeftijdsgebonden Pharmacokinetiek/pharmacodynamiek, zonder de maximale therapeutische dosis op te offeren. De-escaleer AB therapie op basis van klinische status en geïdentificeerd pathogeen Overweeg deelname aan studies en rapporteert ongewenste bijwerkingen

Faecal Microbiota Transplantation by Colonoscopy vs. Vancomycin for the Treatment of Recurrent Clostridium Difficile Infection G. Cammarota; L. et al. Aliment Pharmacol Ther. 2015;41(9):835-843. Background Faecal microbiota transplantation (FMT) from healthy donors is considered an effective treatment against recurrent Clostridium difficile infection. Aim To study the effect of FMT via colonoscopy in patients with recurrent C. difficile infection compared to the standard vancomycin regimen. Methods In an open-label, randomised clinical trial, we assigned subjects with recurrent C. difficile infection to receive: FMT, short regimen of vancomycin (125 mg four times a day for 3 days), followed by one or more infusions of faeces via colonoscopy; or vancomycin, vancomycin 125 mg four times daily for 10 days, followed by 125–500 mg/day every 2–3 days for at least 3 weeks. The latter treatment did not include performing colonoscopy. The primary end point was the resolution of diarrhoea related to C. difficile infection 10 weeks after the end of treatments. Results The study was stopped after a 1-year interim analysis. Eighteen of the 20 patients (90%) treated by FMT exhibited resolution of C. difficile-associated diarrhoea. In FMT, five of the seven patients with pseudomembranous colitis reported a resolution of diarrhoea. Resolution of C. difficile infection occurred in 5 of the 19 (26%) patients in vancomycin (P < 0.0001). No significant adverse events were observed in either of the study groups. Conclusions Faecal microbiota transplantation using colonoscopy to infuse faeces was significantly more effective than vancomycin regimen for the treatment of recurrent C. difficile infection. The delivery of donor faeces via colonoscopy has the potential to optimise the treatment strategy in patients with pseudomembranous colitis.

Conclusies (2) Antibiotica zijn ook ‘invasief’, zeker wanneer oraal toegediend. Korte hoge antibioticaduur is evidence based voor Urineweginfecties (UWI), gemeenschapsverworven-pneumonia, bloedstroominfecties (SEP), … Faecale transplantatie biedt mogelijkheden, maar een duurzame oplossing voor MDRO ligt in een reductie van multi- en langdurige antibioticatoedieningen, gecombineerd met goede hygiëne.

Dank voor uw aandacht: Het NSIH team, ECDC, BAPCOC De labo’s, NRCs & ziekenhuizen & WZC

[email protected]

Slides available on: www.nsih.be

Dr Boudewijn Catry Drs Katrien Latour

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