De behandeling van infecties met multi-resistente Gram ... - VZA

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De behandeling van infecties met multi-resistente Gram ... - VZA

De behandeling van infecties

met multi-resistente Gram-

negatieve kiemen

Prof. Dr. Dirk Vogelaers

Dienst algemene inwendige ziekten, infectieziekten en

psychosomatiek

Universitair Ziekenhuis Gent

© 2008 Universitair Ziekenhuis Gent


Antibiotic

resistance

Resistance spiral of Fernando Bacquero

Time

2


The Challenging MDR

Nosocomial Pathogens

Gram- Positive Gram- Negative

Staphylococcus aureus

(MRSA, GISA, GRSA)

Fluoroquinolone–R

Clostridium difficile

Glycopeptide-Resistant

Enterococci (GRE)

ESBL-producing

Enterobacteriacae

MBL & MDR Pseudomonas

MDR Acinetobacter

Carbapenemase producing K.

pneumoniae (KPC)

3


Main mechanisms of resistance to antimicrobial agents used for

the treatment of Pseudomonas aeruginosa infection

4

Mesaros CMI 13 (6), 560-578.


Proportion of Carbapenems (R) resistant

Pseudomonas aeruginosa isolates in

participating countries in 2008 vs. 2010

5


6

Kanj 2011_ Mayo Clin Proc


Ambler classes of β-lactamases hydrolyze

Class C:

ESBL:CTX-M, SHV, TEM

AmpC: CMY, FOX, MOX, DHA

Class A: serine

carbapenemases

KPC,IMI,SME, NMC-A, GES

Class B: MBL (metallo)

VIM, IMP, SPM-1, NDM-1

Class D penicillinases: OXA,

variants OXA 23-24, -40, -48

Penicillins, cephalosporins,

aztreonam

Cephalosporins and

cefamycins

Penicillins, cephalosporins,

carbapenems (weakly)

All β-lactams and

carbapenems

Carbapenems(weakly)

7


Detection of ESBL production using

the combined disk test

Stürenburg J infect 2003 47; 273 - 95

8


Proportion of 3rd gen. cephalosporins (R) resistant

Klebsiella pneumoniae isolates in participating countries

2005 vs. 2010

9


Bad bugs, no drugs in Belgium?

National Surveillance of Healthcare associated Infections and Antimicrobial Resistance in Belgian

hospitals (NSIH) National report 2002-2008

10


Y. Glupczynski et al. National multicenter survey of ESBL- producing Enterobacteriaceae and

of multi-drug resistant gram negative non-fermenters in Belgium in 2010

11


12

WIV-ISP 2009 Surveillance of multi-resistant microorganisms in Belgian hospitals


WIV-ISP 2009 Surveillance of multi-resistant microorganisms in Belgian hospitals

13


Clonal spread

Spread of ESBL genes

Donor organism

Plasmid

Transposon

Chromosome

14


Transmission of ESBL-producing

Enterobacteriaceae

Local epidemics (clones/plasmids):

ICU

Hospital-wide

Long-term care facilities

Inter-hospital epidemic spread

K.pneumoniae, E.aerogenes

USA, France, Belgium, Spain…

Epidemic clones

co-resistant to fluoroquinolones, SXT and

aminoglycosides

15


Leverstein-van Hall 2011

Clinical Microbiology and

17

Infection


18

Lautenbach 2007

Am J Health-Syst Pharm


19

Kanj 2011_ Mayo Clin Proc


Kanj 2011_ Mayo Clin Proc

20


Modified Hodge Test

Confirmatory testing for KPC-producing bacteria is

recommended in geographical locations where

Enterobacteriaceae are noted to have decreased

susceptibility to carbapenems or resistance to most

non-carbapenem beta-lactams by routine testing.

⇒ modified Hodge test:

100% sensitive for the detection of a carbapenemase,

although not specific for KPC production.

Performed first by culturing a susceptible E coli isolate on

a Mueller-Hinton plate, after which a carbapenem disk

is placed in the center.

Isolates suspected of carbapenemase production then

are streaked from the disk to the outer margin of the

plate. Growth of E coli near the disk or along the isolate

streak indicates that a carbapenemase is present.

21

Arnold 2011 South Med J


NDM-1:

a local clone with worldwide aspirations

•Easy horizontal resistance gene transfer in vivo

•Found in Enterobacteriaceae (opportunity for

broad community dissemination)

•Elevated MIC’s to many antibiotic classes

•Gene location on mobile genetic elements

Andrea Marra.Future microbiology 2011;6(2):137-141 www.futuremedicine.com 22


NDM-1

a local clone with worldwide aspirations has to:

•Accumulate resistance elements

•Maintain infectivity and fitness

•Spread rapidly around the world

•Andrea Marra.Future microbiology 2011;6(2):137-141 www.futuremedicine.com

•K. Kumarasamy et all. Emergence of a new antibiotic resistance mechanism in India, Pakistan and the UK: a

23

molecular, biological and epidemiological study. 2010 Lancet Infect. Dis. 9 p 597-602


Proportion of Carbapenem-Resistant

K. pneumoniae by Country

in 2008 vs. 2010

Courtesy: H. Grundmann, EARSS report 2009

24


Table 2. Predicted Issues in Gram-Negative Bacteria Resistance in the Next

Decade

Widespread occurrence of carbapenem resistance in hospitalized patients

necessitating “routine” use of polymyxins or tigecycline

Resistance to polymyxins and tigecycline commonplace in some hospitals

Loss of improvement in intensive care unit survival rates due to impact of

resistance in gramnegative bacilli

Calls for universal screening for multidrug-resistant gram-negative bacilli at

hospital admission

Increased acquisition of carbapenem-resistant organisms outside of hospitals

Increased hospitalizations for community-onset urinary tract infections due to

pathogens resistant to all orally administered antibiotics

David L. Paterson and Benjamin A. Rogers How Soon Is Now? The Urgent Need for Randomized,

Controlled Trials Evaluating Treatment of Multidrug-Resistant Bacterial Infection. Clinical Infectious

Diseases 2010; 51(11):1245–1247

25


Kanj 2011_ Mayo Clin Proc

26


27

Engel 2010

Am J Med Sci


Colistine: revival van polymyxines

Cyclisch polypeptide: celwandsynthese inhibitie + antiendotoxine

activiteit

Polymyxine B en E op markt

Colistine sulfaat (tabletten en siroop voor SDD en poeder voor

topisch gebruik)

Colistine methanesulfonaat voor IV gebruik + inhalatie

In vitro actief tegen Enterobacteriaceae (incl carbapenemase

producers), H influenzae, Legionella, MDR P aeruginosa en

Acinetobacter spp + S maltophilia (incl pan-drug resistente

stammen)

Gaps in spectrum: Proteus spp, Serratia spp

28


Colistine

Mogelijke in vitro synergie met rifampicine tegen MDR P

aeruginosa stammen (12-42 %; afhankelijk van exposure

time)

(Giamarellos-Bourbolis et al. J Chemother 2003; 15: 235-8)

Rapporten van synergie tussen colistine

+ rifa in MDR A baumanii stammen (OXA-58 carbapenemase

pos)

(Tripodi Int J Antimicrob Agents 2007; 30: 537-40)

Minocycline in imipenem-R A baumanii klinische isolaten

(Tan JAC 2207; 60: 421-3)

Meropenem tegen P aeruginosa en A baumanii stammen

(Souli AAC 2009; 53: 2133-5)

29


Enterobacteriaceae

Resurgence of colistin

MIC

breakpoint

(mg/L)

Dis

k

con

tent

(µg)

Zone diameter

breakpoint

(mm)

S ≤ R > S ≥ R <

Notes

Letters for comments on

disk diffusion

Colistin 2 2 Note A Note A A. Use an MIC

method.

Pseudomonas spp

Colistin 4 4 Note A Note A A. Use an MIC

method.

Acinetobacter spp

Colistin 2 2 Note A Note A A. Use an MIC

method.

European Committee on Antimicrobial Susceptibility Testing. Colistin:

Rationale for the clinical breakpoints, version 1.0, 2010 www.eucast.org

30


Colistine

Gebrek aan PK/PD studies (o.a PK in

lichaamscompartimenten)

Reversiebele nefrotoxiciteit (0-36 %; 15-58 %)

( > neurotoxiciteit)

Uiteenlopende posologieën in richtlijnen

31


•Acquired resistance to colistin occurs in Enterobacteriaceae,

Acinetobacter spp. and P. aeruginosa, and is mainly due to

lipopolysaccharide modifications.

•Colistin is used in treatment of infections caused by organisms

resistant to less toxic antimicrobial agents.

•EUCAST has defined clinical breakpoints for colistin for parenteral

use.

European Committee on Antimicrobial Susceptibility Testing. Colistin: Rationale for the

clinical breakpoints, version 1.0, 2010 www.eucast.org

32


Colistine

Uiteenlopende posologieën in richtlijnen

Noodzaak tot ladingsdosis in kritische patiënten

Spiegels vaak < 2 mg/l na eerste doses klassieke posologie

Ladingsdosis van 9 M IU govolgd door onderhoudsdosis van 4.5 M IU

bid → snellere steady state conc

(Plachouras AAC 2009; 53: 3430-6)

Extrapoleerbaar naar alle moeilijk te behandelen infecties?

Mogelijkheid van intrathecale toediening

Bijv in MDR A baumanii CNS infecties (ventriculitis,…) met snelle CNS

sterilisatie op 3.5-10 mg intrathecaal/12-24 u (125-250.000 E per dag)

Hoge response rate in 32 ptn

(Cascio Int J Infect Dis 2010; 14: e572-9)

33


Colistine: klinische studies/ervaring

Overzicht in Giamarellou Int J Antimicrob Ag 2010; 36S:

S50-54)

Retrospectieve studies in 300 patîënten zonder

mucoviscidose (meestal ICU VAP met MDR P aeruginosa

of A baumannii) IV natrium colistimethaat 1-3 M IU tid IV

Klinische genezing 57-73 %; mortaliteit 20-62 % (vergelijkbaar

met andere reeksen van nosocomiale pneumonie behandeld

met piptazo, carbapenems en cipro

Beperkingen: geen controlegroep, retrospectief, uiteenlopende

dosis en behandelingsduur, concomitante toediening van

andere antibiotica (vooral carbapenems), geen monitoring van

resistentie op einde behandeling en brede range van

nefrotoxiciteit met moeilijke attribueerbaarheid in retrospectieve

design

34


Colistine: klinische studies/ervaring

2 retrospectieve monotherapie studies met

colistimethate

Geen verschil in mortaliteit tussen 31 ptn R/ met colistine IV

voor VAP met stammen enkel gevoelig aan colistine (51.6 %)

vs 30 ptn met VAP door carbapenem-S stammen, R/ met

carbapenem monotherapie

(Rios Eur Resp J 2007; 30: 307-13)

Vergelijkbare efficiëntie van monotherapie colistine in VAP met

stammen enkel gevoelig aan coli (n =60) vs met imipenem bij

carbapenem-S stammen

A baumannii (51.6 vs 61.7 %)

P aeruginosa (48.4 vs 38.3 %)

(Kallel Int Care Med 2007; 33: 1162-7)

35


Colistine: klinische ervaring

Geen significant verschil in response

rates in meta-analyse van colistimethate

monotherapie vs combinaties met

meropenem, piptazo of ampi/sulbactam

(Falagas Int J Antimicrob Agents 2010; 35: 194-9)

36


Tigecycline

Minocycline analoog (glycylglycine); sterkere ribosomiale binding dan tetra

Enkel IV formulering: ladingsdosis 100 mg → 50 mg bid

Lineaire PK; lang half-leven (37±12 u); bacteriostatisch

Geen dosisaanpassing bij nierinsufficiëntie; hepatische metabolisatie

Goede concentraties in gal, galblaas, colon; controverse over bot- en

longconcentraties

(MacGowan JAC 2008; 62 (Suppl 1): i11-6)

Gram neg spectrum: MDR A baumannii, ESBL Enterobacteriaceae, KPC en

VIM K pneumoniae en S maltophilia

Geen activiteit tegen P aerug, Morganella en Providencia

↑ resistentie bij Enterobacteriaceae, vermoedelijk gerelateerd met lage

serum spiegels; meestal marginaal tov MIC MDR Gram neg (A baumannii);

breed spectrum effluxpompen

GI toxiciteit (braken, diarrhee,…) frekwent

37


Tigecycline

Niche: monotherapie van ernstige polymicrobiële infecties, incl MDR

pathogenen (MRSA en Gram neg)

Positionering in gerichte therapie van gedocumenteerde niet-P aerug

infecties

Meestal retrospectieve, niet-vergelijkende studies, zelden in monotherapie

in de behandeling van MDR Gram negatieve infecties (niet steeds duidelijke

informatie over MIC)

Overzicht 15 publicaties over 55 ptn met KPC infectie

(Hirsch JAC 2010; 65: 1119-25)

Beperkte documentering:

Controle outbreaks carbapenemase prod A baumannii in ICU

(Jamal J Hosp Infect 2009; 72: 234-42)

succespercentages van 90.5 % voor VAP/HCAP en 80 % in BSI met A baumannii

(MIC tige 1-8 mg/l) en K pneumoniae (0.5-3 mg/l)

(Poulakou J Infect 2009; 58: 273-84)

38


Fosfomycine

Inhibitor van celwand-biosynthese (inactivatie van

pyruvyl transferase); bactericide

Actief tegen brede waaier Gram pos en Gram neg

Orale fosfomycine (Monuril) in R/ van ongecompliceerde

UWI bij vrouwen door E coli en E faecalis (enkelvoudige

dosis 3 g)

Beperkte klinische studies over gebruik bij behandeling

van MDR Gram neg

Goede in vitro activiteit tegen carbapenem-R P

aeruginosa en K pneumoniae

(Falagas Int J Antimicrob Agents 2010;35: 240-3)

39


Fosfomycine

Prospectieve evaluatie 2-4 g IV/6 u, in

combinatie, bij 11 volwassen ICU ptn met

carbapenem-R K pneumoniae infecties : lage

mortaliteit 18 %

(Michalopoulos Clin Microb Infect 2010; 16: 184-6)

Geen monotherapie gezien snelle inductie

resistentie

Noodzaak van vergelijkende studies

40


Rifampicine

DNA dependente RNA polymerase inhibitor

In vitro synergie, steeds in combinatie, tegen carbapenemase prod E

coli en K pneumoniae

(Urban AAC 2010; 54: 2732-4)

MDR P aerug (in het bijzonder bacteriëmie refractair aan standaard

behandeling): geen duidelijk voordeel

RCT prospectief 121 ptn anti-Pseud β lactam + aminoglycoside + rifampin (600

mg po or IV tid→ bid vs β lactam + AG)

(Korvick AAC 1992; 36: 620-5)

Overzicht van klinische studies combinatietherapie met rifa in Gram

neg infectie: alle case reports, kleine niet gecontroleerde reeksen

Nood aan klinische gegevens

Interacties

(Drapeau Int J Antimicrob Ag 2010; 35: 39-44)

41


Table 1. Potential Randomised, Controlled Trials in the Arena of Treatment of

Infection with Gram-Negative Bacilli That Could Be Evaluated for Fast-

Tracked Funding

Betalactam antibiotics plus aminoglycoside combination therapy versus

betalactam antibiotics alone for serious Pseudomonas aeruginosa infection

Pharmacodynamically optimized versus standard therapy for serious infections

due to gramnegative bacilli

Combinations including colistin versus colistin alone for bacterial infections

resistant to all other options

Inhaled plus intravenously administered antibiotics versus intravenous

administration alone for ventilator-associated pneumonia

Short-course versus long-course therapy for bloodstream infection due to gramnegative

bacilli

David L. Paterson and Benjamin A. Rogers How Soon Is Now? The Urgent Need for Randomized,

Controlled Trials Evaluating Treatment of Multidrug-Resistant Bacterial Infection. Clinical Infectious

Diseases 2010; 51(11):1245–1247

42


In 2002, out of 89 new drugs, no new

antibiotics were approved…..

“Infectious diseases physicians are alarmed by the prospect

that effective antibiotics may not be available to treat

seriously ill patients in the near future. There simply aren’t

enough new drugs in the pharmaceutical pipeline to keep

pace with drugresistant bacterial infections, so-called

‘superbugs.’” Joseph R. Dalovisio, IDSA President

A growing number of drug companies appear to

be withdrawing from new antibiotic research and

development……

43

Bad bugs, no drugs IDSA 2004


Bad bugs need drugs?

Spellberg et al Clin Infect Dis 2004, (modified)

Boucher et al Clin Infect Dis 2009 (modified)

44


45

45


New antibiotics to meet resistance

New targets

Low output from target based screens

Target selection important

New agents from known classes

Aminoglycosides

Tetracyclines

Monobactam

β-lactamase inhibitors (βLI) with

Carbapenems

cephalosporins

46


ESBL:

Worldwide

Longstanding problem

Polyclonal

Occurence:

Common hospitalised

patients, outpatients

Common healthy

population

Good treatment options

Summary

Carbapenemases:

Localized

Recent spread

Primarily clonal

Occurence

Rare among hospitalised

patients

Extremely rare elsewhere

Poor treatment options

47


Besluiten

Onvoldoende therapeutische opties voor

behandeling van MDR Gram negatieve infecties

Weinige opties onvoldoende gedocumenteerd (zowel

naar PK/PD toe als klinische outcome)

Beperkte pipeline voor nieuwe behandelingen tegen

MDR Gram negatieven

Fast track

Selectieve “tolerantie” voor toxischer producten met minder

gunstige veiligheidsprofielen in selectieve indicaties

(“benefit outweighs potential harm”)

Antimicrobiële stewardship en “bundel” benadering

van expertise (infectiologie, medische microbiologie,

ziekenhuishygiëne en klinische farmacie)

48

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