HAP ja VAP: mikrobioloogia
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- Jared Snow
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1 Definitsioon HAP ja VAP: mikrobioloogia VAP haiglas ilmnenud kopsuinfektsioon, eelduseks on >48 tundi varem eelnenud intubatsioon ja ventilatsioon. Probleem millal on tegemist infektsiooniga kopsus? Klassikalised markerid palavik, leukotsütoos, infiltraat, positiivne röga külv sageli kannavad vastuolulist informatsiooni. Miks on traditsioonilised markerid kopsuinfektsiooni korral sageli eksitavad? Need markerid esinevad ventileeritavatel patsientidel sageli ja peegeldavad tihti ka teisi patoloogiaid: Infiltraat: ödeem, atelektaas, hemorraagia Leukotsütoos ja palavik suvaline SIRS põhjus Mädane endobronhiaalne sekretsioon on intubeeritud patsientidel sage ja peegeldab tihti trahheobronhiiti Positiivne külv: infektsioon või kolonisatsioon? Kontaminatsioon, infektsioon ja põletik KONTAMINATSIOON INFEKTSIOON PÕLETIK Kontaminatsioon - patogeenid steriilses koes, põletik puudub Infektsioon - patogeenid steriilses koes koos põletikuga Põletik (ka SIRS) - patogeenid puuduvad, põletik jätkub Igapäevane dignostika Kliiniline pilt Mikrobiooogia - mikroskoopia, külvid: Röga (mitte VAP, vaid HAP) Trahhea aspiraat - TA Endobronhiaalse sekreedi kogumine pime BAL ja PSB. Bronhioskoopial saadud materjal BAL ja PSB Diagnostiline etalon Kopsubiopsial saadud materjal, milles võimalik näha histoloogiliselt näha põletikukolde formeerumist koos neutrofiilide akumulatsiooniga ja kvantitatiivne külv kopsu parenhüümist on positiivne - > 4 bakterit/g kohta. Autopsia leid ja kliiniline pilt lähevad tegelikkuses sageli lahku. VAP dignoosimisel patoloogide arvamused histoloogia kohta samuti lähevad lahku. 1
2 Operating characteristics of four sampling methods for the diagnosis of ventilator-associated pneumonia Thresh. Method (cfu/ml) p value RR a 95% CI Se Sp PPV NPV CC Blind TA Blind PTC Blind PTC vse Broncho PTC Broncho PTC vse Broncho BAL < < < < Metec, Int Car Med 2004;30:1432 Areas under receiver operating characteristics curves and best threshold of four sampling methods for the diagnosis of ventilator-associated pneumonia Method aurocc 95% CI Best threshold p value p versus BAL (cfu/ml) Blind TA Blind PTC < Blind PTC vse < or 3 Bronchoscopic PTC < or 3 Bronchoscopic PTC vse < or 3 Bronchoscopic BAL < Metec, Int Car Med 2004;30:1432 Invasiivsed meetodid uuritava materjali kogumiseks Invasiised meetodid pros et contras Bronihoskoopia: BAL - bronchoalveolar lavage PSB - protected specimen brush Siin kvantitatiivne bakterioloogiline kriteerium (spetsiifiline PMÜ number ml või grammi uuritava materjali kohta). Eelised Potentsiaalselt suurem tõenäosus etioloogilise dignoosi saamiseks. Lubab paremini optimeerida AB ravi. Hingamisteede otsese visualiseerimise võimalus - tagab kindluse sellest rippuvate otsuste ja manipulatsioonide tegemisel. Puudused Invasiivne Hind Aeg Potentsiaalne oht riskile ja traumal Torres, Chest 2000;117:198S...We recommend that EA cultures are not used for the diagnosis of VAP. Recommendation Grade A...We recommend that there is no evidence that any one invasive sampling method is better than any other. Recommendation Grade A...We recommend that the least expensive, least invasive and most rapid sampling technique requiring minimal expertise should be used for establishing the microbiological diagnosis of HAP, e.g. non-bronchoscopy-directed (blind) BAL. Recommendation Grade GPP Otsesed bronhioskoopilised meetodid ja kvantitatiivne külv Bronhioskoopia koos BAL/ bronhial brushin gug ( 4 kuni 5 PMÜ/ml ja vähem kui 1% epiteelrakke) Protected specimen brush meetod (>³ CFU/ml) Protected BAL with a balloon tipped catheter (>5% of neutrofiile või makrofaage koos rakusiseselt paiknevate mikroobidega mikroskoopial) 2
3 Difference of AUCs between the ROC curves No AT-group patients and AT-group patients (p = 0.04) BAL/PSB kvalitatiivne koherentsus (n=14) Sirvent, J.-M. et al. Chest 2003;123: Gerbeaux Am J Res Crit Car Med 1998;157:76...Although they may provide an indication to the causal pathogen, we recommend that quantitative cultures of respiratory specimens such as PSB and BAL should not be relied on for the diagnosis of HAP/VAP. Recommendation Grade A...We recommend that quantification of intracellular organisms in BAL specimens is a rapid and specific test and can be used as a guide to initial therapy. Recommendation Grade A...We recommend that there is inadequate evidence to support the use of invasive and quantitative microbiology for the diagnosis and initial therapy to improve outcome of VAP in individual patients. Recommendation Grade C...We recommend that initial appropriate antibiotic therapy should be instituted as soon as VAP is suspected and should be based on local microbiological surveillance data. Recommendation Grade C...We recommend that initial therapy should not be delayed while awaiting microbiological results. Recommendation Grade C Patogenees Nina-neelu normaalne mikrofloora valdavalt ei sisalda Gram-negatiivseid Enterobacteriacaeae esindajaid. Nina-neel - Enterobacteriaceae koloniseerib 70-75% raskelt haigeid (critically ill) patsiente. Trahhea ja bronhid Enterobacteriacaea koloniseerib 45-0% intubeeritud patsiente. Lisaks siinuste ja hambakatu kolonisatsioon, biofilm intubatsioonitorus ja trahheas Limaskesta trauma (aspiratsioonil) soodustab lima peetust ja bakteritega koloniseerumist. Kuidas see toimub 1. Ülemised hingamisteed koloniseeruvad 2. Mikroobid satuvad ülemistest alumistest hingamisteedesse, ventilaator ja intubatsioon aitavad kaasa. 3. Pneumoonia tekkes olulised faktorid: suur inokulum, virulentsus, peremeesorganimsi kaitsevõime. 4. Kui bakteriaalne infektsioon eskaleerub ja lisandub invasiooni komponent, kaasneb SIRS Intubatsio ioon Makro- organismi muutunud vastupanu Trahhea kolonisatsioon Hospitaal- pneumoonia 3
4 Kuidas ülemised hingamisteed koloniseeruvad? Transmissiooni võimalikud viisid Gastro-pulmonaalne hüpotees: Magu on Gram-negatiivsete pulkade reservuaar > ülekasvu fenomen > retrograadne liikumine ninaneelu > aspiratsioon alumistesse hingamisteedesse. Kellelt Gram-negatiivsed pulgad pärit on? Endogeensed patsiendi enda omad. ~50% juhtudel eksogeensed Empiiriline AB ravi ning VAP/HAP AB ravi alustades on võtmeküsimuseks, kas tegemist ravimresistentsete bakteritega HAP või VAP kahtlus Hiline algus või RR riskitegurid Antibiootikum resistentsus Vale ja liigne antibiootikumide kasutamine Ei jah Kitsas AB spekter Lai AB spekter, RR sobivad ATS/IDSA Guidelines. Am J Respir Crit Care Med 2005;171:388 RR bakterite riskifaktorid Etioloogia Varajane (<72 tundi) Staphylococcus aureus Streptococcus pneumoniae Streptococcus spp. H. Influenzae Hiline (>72 tundi) Pseudomonas aeruginosa MRSA Acinetobacter baumanii > 50% haigestunutel on põhjuseks normaalne hingamisteede floora > 50% on põhjuseks rohkem kui üks mikroobiliik Anaeroobid kaasnevad sageli varajase VAP-ga. MRSA seotud suurima suremusega. 4
5 Patogeen Gram-neg P. aeruginosa Acinetobacter spp. Stenotrophomonas maltophilia Enterobacteriaceae* Haemophilus spp. Gram-pos S. aureus MRSA S. pneumoniae Hospitaalse kosupõletiku etioloogia N USA % Euroopa N % Lõuna Ameerika N % HAP (%) HAP seotud patogeenid 40 P =.003 Varjane algus Hiline algus 35 PA = P aeruginosa OSSA = Oxacillin-tundlik 30 S aureus ORSA = Oxacillin-resistentne 25 P =.408 S aureus ES = Enterobacter liigid P =.043 SM = S marcescens P =.985 P = PA OSSA ORSA ES SM Patogeen Ibrahim, et al. Chest. 2000;117: Gram-negatiivsed pulgad Pseudomonas aeruginosa. Sagedaseim multiresistentne Gram-negatiivne patogeen, põhjustab HAP ja VAP, loomulikult resistentne paljude antibiootikumide suhtes. Klebsiella spp. Loomulikult resistente ampitsilliini suhtes, omandab asageli resistentsuse tsefalosporiinide ja azreonaami suhtes > ESBL ESBL-positiivsed tüved säilitavad tundlikkuse karbapeneemide suhtes Enterobacter, Citrobacter ja Serratia spp. indutseeritav AmpC tüüpi β-laktamaas. We recommend that there is no proven optimal antibiotic regimen for patients with HAP suspected or proven to be caused by P. aeruginosa. Treatment options include ceftazidime, ciprofloxacin, meropenem and piperacillin/tazobactam. Recommendation GPP Pseudomonas aeruginosa ja tema resistentsuse mehhanismid Pechere Clin Microbiol Infect 1999;5:S15 Penitsilliinid, tsefalosporiinid, tetratsükliinid, kinoloonid, klooramfenikoool, TMP-SMX, meropeneem Imipeneem, meropeneem Meropeneem, enamus AB Biofilm AmpC Β-laktamaas MexEF OprN MexAB-OprM MexGH Opr D poriin MexCD OprJ Tetratsükliinid, kinoloonid, klooramfenikool, TMP-SMX, ka karbapeneemid Tetratsükliinid, aminoglükosiidid 4. pk. tsefalosporiinid, tetratsükliinid, klooramfenikool, TMP-SMX, makroliidid A, B, C klassi β-laktamaasid Battin Nature Rev Microbiol 2007;5:76 5
6 DPB ja erütromütsiini toime elulemusele: lisaväärtus Klaritromütsiini ja ofloksatsiini toime P. aeruginosa biofilmile Kudoh Am J Respir Crit Care ;1829 Yasuda AAC 1993; 37 Klebsiella spp. resistentsus tingitud kromosomaalsetest ß-laktamaasidest Antibiootikum K. pneumoniae K. oxytoca SHV-1 K1 (baas) K1 (hüperprod.) Ampitsiliin Amox-klavulaanhape Piperatsiliin Pip-tasobaktaam Cefuroxime Cefotaxime 0,03 0,03 32 Ceftazidime 0,06 0,06 0,03 Cefepime 0,03 0,03 2 Imipeneem 0,12 0,12 0,25 Meropeneem 0,03 0,06 0,06 Miks teatud osa E. coli ja Klebsiella dest ei allu3. pk. tsefalosporiinidele... Tavaline Extended spectrum ß-lactamases Antibiootikum TEM-1, TEM-2, TEM-3 TEM-12 TEM-, SHV-2 SHV-1 TEM-26 Ampitsilliin Amoksitsilliin/klavulaanhape Tikartsilliin Tikarstilliin/klavulaanhape Piperatsilliin / Piperatsilliin/tasobaktaam / / / / Tsefalotiin / Tsefaperasoon Tsefuroksiim Tsefotaksiim Tseftazidiim Tsefepiim Tsefoksitiin Astreonaam Imipeneem Meropeneem Livermore DM Clin Microbiol Rev 1995;8:557 Indutseeritavad β-laktamaasid Mikroob Ekspressiooni viis Indutseeritavus Konstitutiivne Madal Mõõdukas Kõrge E.coli AmpC C Shigella AmpC C Enterobacter AmpC C 1 - C.freundii AmpC C 1 - M.morganii AmpC C Providencia spp. AmpC C 1 - Serratia spp. AmpC C K.pneumoniae SHV-1 A 2b - - K.oxytoca K1 A 2be - - P.vulgaris Cxase A 2e - - Nimi Klass Bush grupp Enterobakter ja teised AB MIK μg/ml E. cloacea C. freundii M. morganii S. marcescens Ind Hyp Baas Ind Hyp Baas Ind Hyp Ind Hyp Ampcillin Piperacillin , Pip/tazobac , Cephalotin >2048 >2048 >2048 >2048 Cefperazone 0, ,25 0, , Cefuroxime Cefotaxime 0, ,06 0, ,03 0, ,25 8 Ceftazidime 0, ,25 0, ,5 0,06 8 0,25 1 Cefepime 0,12 2 0,12 0,03 0,5 0,06 0,03 0,03 0,12 0,25 Cefoxitin Axtreonam 0, ,06 0, ,015 0,06 0,12 0,06 2 Imipenem 0,25 0,25 0,25 0,25 0,25 0, ,25 0,25 Meropenem 0,06 0,06 0,015 0,03 0,03 0,03 0,03 0,03 0,03 0,03 Livermore DM Clin Microbiol Rev 1995;8:557 6
7 Gram-negatiivsed pulgad Acinetobacter spp. rohkem kui 85% isolaatidest tundlikud karbapeneemide suhtes, kuid levimus% väga variaabelne, sõltudes haiglast/osakonnast üks ravi võimalusi - sulbaktaam Stenotrophomonas maltophilia ja Burkholderia cepacia: karbapeneemidele resistentsed toimib(?) - TMP/SMX, tkarstislliin-klavulaanhape, fluorokinoloonid. Dijkshoorn Nature Rev Microbiol 2007;5:939 Mõned antibiootikumid Linezolid oksazolidinon ainult Gram+ spekter. Vankomütsiinist parem MRSA VAP korral > paranemine suurem ja letaalsus väiksem. Siiski on juba leitud resistentsust. Vanko probleeme kopsukoesse jõudmisega. Meropeneem karbapeneem lai toimespekter, nii Gram + kui Gram - ; aeroobid ja anaeroobid. Teicoplanin glükopeptiid, sobib aeroobsete ja anaeroobsete Gram+ ja Gram- bakterite raviks. Aztreonam monobaktaam, spekter on ainult Gram-positiivsed aeroobid. Tazocin piperatsilliin koos beeta-laktamaasi inhibiitori tazobaktaamiga) - pseudomonase vastane penitsilliin, hea Gram-negatiivne kate, sünergia aminoglükosiididega. 7
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