De behandeling van infecties met multi-resistente Gramnegatieve kiemen Prof. Dr. Dirk Vogelaers Dienst algemene inwendige ziekten, infectieziekten en psychosomatiek Universitair Ziekenhuis Gent
© 2008 Universitair Ziekenhuis Gent
Resistance spiral of Fernando Bacquero Antibiotic resistance
Time 2
The Challenging MDR Nosocomial Pathogens
Gram- Positive
Gram- Negative
Staphylococcus aureus (MRSA, GISA, GRSA)
ESBL-producing Enterobacteriacae
Fluoroquinolone–R Clostridium difficile
MBL & MDR Pseudomonas
Glycopeptide-Resistant Enterococci (GRE)
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
Penicillins, cephalosporins, aztreonam
AmpC: CMY, FOX, MOX, DHA
Cephalosporins and cefamycins
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, 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
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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
Spread of ESBL genes Clonal spread
Donor organism
Chromosome Plasmid Transposon 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
16
Leverstein-van Hall 2011 Clinical Microbiology and 17 Infection
Lautenbach 2007 18 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
22 Andrea Marra.Future microbiology 2011;6(2):137-141 www.futuremedicine.com
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
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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
Engel 2010 Am J Med27Sci
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
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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)
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Resurgence of colistin Enterobacteriaceae MIC breakpoint (mg/L)
Colistin
S≤
R>
2
2
Dis k con tent (µg)
Zone diameter breakpoint (mm) S≥
Notes Letters for comments on disk diffusion
R< A
Note
A
Note
A. Use an MIC method.
Pseudomonas spp Colistin
A
4
4
Note
2
2
Note
A
Note
A. Use an MIC method.
Acinetobacter spp Colistin
A
A
Note
A. Use an MIC method.
European Committee on Antimicrobial Susceptibility Testing. Colistin: 30 Rationale for the clinical breakpoints, version 1.0, 2010 www.eucast.org
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
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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)
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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
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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)
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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
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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 (Drapeau Int J Antimicrob Ag 2010; 35: 39-44)
Nood aan klinische gegevens Interacties 41
Table 1. Potential Randomised, Controlled Trials in the Arena of Treatment of Infection with Gram-Negative Bacilli That Could Be Evaluated for FastTracked 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……
Bad bugs, no drugs IDSA 200443
Bad bugs need drugs?
Spellberg et al Clin Infect Dis 2004, (modified) Boucher et al Clin Infect Dis 2009 (modified) 44
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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 (β βLI) with Carbapenems cephalosporins 46
Summary ESBL: Worldwide Longstanding problem Polyclonal Occurence: Common hospitalised patients, outpatients Common healthy population
Carbapenemases: Localized Recent spread Primarily clonal Occurence Rare among hospitalised patients Extremely rare elsewhere
Poor treatment options
Good treatment options
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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
