Raba cefalosporinov. dr. Kristina Nadrah, dr.med., mag.farm., spec.infekt. Klinika za infekcijske bolezni Univerzitetni klinični center Ljubljana
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1 Raba cefalosporinov dr. Kristina Nadrah, dr.med., mag.farm., spec.infekt. Klinika za infekcijske bolezni Univerzitetni klinični center Ljubljana
2 spekter Cefalosporini betalaktamski baktericidni antibiotiki več generacij: 1. generacija: cefazolin, cefaleksin 2. generacija: cefuroksim 3. generacija: cefotaksim, ceftazidim generacija: cefepim 5. generacija: ceftarolin, ceftalozan
3 Porast odpornosti proti 3. generaciji cefalosporinov K. pneumoniae ECDC Surveillance Atlas
4 Rizični dejavniki za okužbo/kolonizacijo z ESBL poraba cefalosporinov 3. generacije korelira s pojavom ESBL na pojav ESBL vpliva tudi poraba drugih razredov antibiotikov: fluorokinoloni TMP/SMX pomembna tudi dolžina terapije in kumulativna izpostavjenost antibiotikom (celokupno trajanje terapije in število prejetih antibiotikov) penicilini sami ali v kombinaciji z inhibitorji betalaktamaz ne zvišujejo rizika okužbe z ESBL? razsoj odpornih sevov bolnišnična higiena! Lautenbach, E et al. CID 2001; 32:1162. Paterson, DL et al. CMR 2005, 18:657
5 Zakaj je visoka poraba širokospektralnih cefalosporinov dolgoročno nevzdržna? ko poraba razreda antibiotika presega DDD/100 BOD, se pojavi bakterijska odpornost na ta razred zmanjšanje porabe za vsaj 50% -> zmanjšanje odpornosti kolateralna škoda: facilitira okužbe z MRSA in VRE večja pojavnost klostridijskih drisk Peterson, LR. CMI 2005,11(Suppl. 5): 4 16.
6 DDD / 100 BOD Bolnišnična poraba cefalosporinov 3.generacije v Sloveniji v letu 2016 nad 1,5 DDD/100 BOD 7,00 6,00 5,00 J01DD14 ceftibuten J01DD08 cefiksim J01DD04 ceftriakson J01DD02 ceftazidim J01DD01 cefotaksim 4,00 3,00 2,00 1,00 0,00 Medicor UKC MB SB Ptuj SB Murska Sobota SB Celje SB Slovenj Gradec SB Brežice Bolnišnica Golnik SB Novo mesto Bolnišnica Topolščica UKC LJ SB Jesenice Diagnostični center Bled vir: prof.dr. Čižman DDD: Definirani dnevni odmerki (defined daily doses), BOD: bolnišnično oskrbni dnevi
7 Rešitve predpisati antibiotik le za pravilne indikacije zmanjšanje porabe širokospektralnih cefalosporinov in zamenjava za drug razred antibiotikov: penicilini ± inhibitor betalaktamaze aminoglikozidi izbira cefalosporina ožjega spektra zmanjšati porabo fluorokinolonov le del intervencij! tudi ukrepi za preprečevanje širjenja odpornih sevov (bolnišnična higiena!)
8 WHO seznam ključnih zdravil 2017 antibiotiki 1. in 2. izbire key access cefalosporini 1. generacije (npr. cefazolin) antibiotiki, ki so 1. ali 2. izbira le v omejenih indikacijah watch list večja možnost razvoja odpornosti in so ključne tarče programov nadzorovane rabe antibiotikov cefalosporini 3. generacije (npr. cefotaksim) rezervni antibiotiki antibiotiki, ki se uporabljajo v zelo omejenih indikacijah, kjer so druge možnosti izčrpane: ključne tarče programov nadzorovane rabe antibiotikov za ohranitev učinkovitosti last resort cefalosporini 4. in 5.generacije (npr. cefepim, ceftarolin)
9 WHO indikacije za rabo cefalosporinov Učinkovina Prva izbira Druga izbira 1. generacija cefaleksin / akutno poslabšanje KOPB faringitis okužbe kože in mehkih tkiv cefazolin / okužbe kosti in sklepov 3. generacija 4. in 5. generacija cefalosporinov v komplementarni skupini, potrebna posebna znanja, indikacije niso navedene! cefiksim* / akutna invazivna bakterijska driska/griža gonoreja cefotaksim* ceftriakson* akutni bakterijski meningitis pljučnica (domačega okolja in bolnišnična) zapletene intraabdominalne okužbe (blage do hude) pielonefritis ali prostatitis (huda oblika) akutni bakterijski meningitis pljučnica (domačega okolja in bolnišnična) zapletene intraabdominalne okužbe (blage do hude) gonoreja pielonefritis ali prostatitis (huda oblika) okužbe kosti in sklepov pielonefritis ali prostatitis (blaga do zmerna oblika) sepsa pri novorojencih in otrocih akutna invazivna bakterijska driska/griža okužbe kosti in sklepov pielonefritis ali prostatitis (blaga do zmerna oblika) sepsa pri novorojencih in otrocih
10 Zmanjšanje porabe širokospektralnih cefalosporinov zmanjšanje porabe cefalosporinov z omejitvijo predpisovanja je zmanjšalo incidenco ESBL v več študijah zvišanje porabe piperacilin/tazobaktama ni vplivalo na bakterijsko odpornost vsaka menjava antibiotičnih razredov ni ugodna: zvišanje porabe karbapenemov lahko povroči pojav odpornosti pri Pseudomonas aeruginosa in Acinetobacter baumanii. neugodne menjave: fluorokinoloni karbapenemi Rahal JJ, et al. JAMA. 1998;280:1233.Lee S et al. Infect. Control Hosp. Epidemiol. 2004;25:832. Andersen SE, et al. BMJ Qual. Saf. 2013;22:907. Oliveira P, et al. Infect. Drug Resist. 2011;149. Antoniadou A, et al. Scand. J. Infect. Dis. 2013;45:438. Tangden T, et al. JAC 2011;66:1161.
11 Recommendations for management of antimicrobial agent resistance (Peterson LR 2005) The goal of using less than 1.5 DDD/100 patient-days Problem Useful solution Rating >10% CR P.aeruginosa >=50 % FQ and/or carbapenem use BIII >10% FQ R P.aeruginosa >=50% FQ use and change primary drug to ciprofloksacin AI >10% CR A.baumanii >=50% carbapenem use and assess for clonal problem AII >10% beta-lactam R P.aeruginosa >=50% cef.3.gen BIII >10% ESBL + Enterobactericeae >=50% cef.3.gen AI >10% genta/tobra R Enterobacteria Replace with amikacin AI Concern over presence of VRE >=50% cephalosp. and FQ AI Concern over presence of MRSA >=50% cephalosp. and FQ BIII Concern of presence of C. difficile Use of cephalosporins, clindamycin and FQ and replace with piperacilin /tazobactam Peterson, LR. CMI 2005,11(Suppl. 5): AI
12 Izbira cefalosporina ožjega spektra 1. generacija okužbe sečil? okužbe kože in mehkih tkiv akutno poslabšanje KOPB faringitis testiranje občutljivosti? 2. generacija okužbe sečil okužbe zgornjih/spodnjih dihal Občutljivost na cefuroksim l.2015 v Sloveniji. Bakterija % S E. coli 90% (i.v.) K. pneumoniae 80% (i.v.) H. influenzae 76% (i.v.) M. catarrhalis 99% (i.v.) Štrumbelj I et al. Pregled občutljivosti bakterij za antibiotike - Slovenija 2015 SKUOPZ.
13 Cefalosporini 1.generacije multicentrična retrospektivna raziskava pri bolnikih z akutnim pielonefritisom: i.v. cefazolin vs. ceftriakson: 184 pt (92 prejelo cefazolin), primarni patogen E. coli (88% S na cefazolin v ZDA) čas do kliničnega izboljšanja, čas i.v. terapije in dolžina hospitalizacije se ni razlikovalo aplikabilnost? predhodna terapija z antibiotikom z delovanjem na po Gramu negativne patogene nadaljevanje z p.o. antibiotiki (tudi fluorokinoloni) le bolniki brez uroloških nepravilnosti, obstrukcij Hobbs, JAC, 2016
14 Cefalosporini 1.generacije retrospektivna raziskava pri bolnikih z monomikrobno bakteremijo pridobljeno v domačem okolju: i.v. cefazolin vs. cefalosporini 3. generacije 591 bolnikov (135 prejelo cefazolin), ki so imeli bakteremijo, primerjali 121 izbrani povzročitelji: E. coli, K. pneumoniae, P. mirabilis huje bolni so prejeli cefalosporin 3. generacije v skupini s cefazolinom manj bolnikov s K. pneumoniae bakteremijo manj pljučnic, okužb v trebuhu, seps, manjkrat v EIT več bolnic z okužbo sečil manj malignih bolezni, ciroz Zaključek: cefazolin je primeren za empirično zdravljenje manj bolnih bolnikov z bakteremijo domačega okolja, povzročeno z E. coli, K. pneumoniae, P. mirabilis Hsieh CC et al. IJAA 2016,48:712
15 Cefalosporini 2.generacije retrospektivna raziskava pri bolnicah z nezapletenim akutnim pielonefritisom: i.v. cefuroksim vs. cefotaksim 255 bolnic (144 prejelo cefuroksim), 30% bakteremij deleža izboljšanja se nista razlikovala (94% - 98%) ugoden profil občutljivosti: E. coli 83% S na cefuroksim Chang, U-I et al. Yonsei Med J 2015:56: 1266.
16 Cefalosporini 2.generacije retrospektivna raziskava pri bolnicah z zapletenim pielonefritisom brez obstrukcije sečil: i.v. cefuroksim vs. cefotaksim 322 bolnic (156 prejelo cefuroksim), 42% do 53% bakteremij deleža izboljšanja se nista razlikovala (97%) uspeh nekoliko slabši pri postmenopavznih bolnicah napovedniki slabšega odziva: bakteremija, ESBL, višji L in CRP Chang, U-I et al. AAC 2015, 59:2488.
17 Cefalosporini 2.generacije prospektivna multicentrična randomizirana enojno slepa raziskava pri bolnikih z akutnim bakterijskim sinusitisom: amoksicilin/klavulanska kislina vs. cefuroksim p.o. 317 bolnikov (157 prejelo cefuroksim) aspirat maksilarnega sinusa: 22% pneumokok, 17% hemofilus, 13% zlati stafilokok primerljiv klinični uspeh več neželenih učinkov ob jemanju amoksicilin/klavulanske kisline Higuera, F et al. JAC 1996, 37:555.
18 Cefalosporini 2.generacije prospektivna multicentrična randomizirana enojno slepa raziskava pri bolnikih s pljučnico domačega okolja: amoksicilin/klavulanska kislina vs. cefuroksim p.o. 162 ambulantnih bolnikov (84 prejelo cefuroksim) 60% sputum pozitiven (38% pnevmokok, 18% H. influenzae) klinični uspeh primerljiv Camacho, AE et al. JAMA 1992, 93:271.
19 Cefalosporini 2.generacije retrospektivna raziskava pri bolnikih s pnevmokokno pljučnico in bakteremijo ali empiemom vsi prejeli cefuroksim, nekateri tudi makrolid in druge kombinacije (70%) primerjava bolnikov: pneumokok I vs S na penicilin (I MIK med 0,12 in 1 mg/l) zdravljeni s cefuroksimom klinični izid primerljiv Britanske smernice (2009, dopolnjene 2015) postavljajo cefuroksim ob bok cefotaksimu za i.v. zdravljenje srednje hude do hude pljučnice domačega okolja, ki zahteva hospitalizacijo (kombinacija z makrolidom) Wiener-Well, Y et al. Chemotherapy 2009;55:97. BTS Guideline for the management of CAP 2009, annotated 2015.
20 Predlog za zmanjšanje porabe širokospektralnih cefalosporinov omejeno predpisovanje preveriti indikacijo namesto cefalosporina 3.generacije - penicilin+inhibitor betalaktamaze (če možno) izbira ožjega spektra misliti tudi na kolateralno škodo drugih širokospektralnih antibiotikov fluorokinoloni karbapenemi za širokospektralen antibiotik se odločimo le za izbrane indikacije ob posvetu in v soglasju z infektologom
21 Alternative širokospektralnim cefalosporinom okužbe sečil: nitrofurantoin, fosfomicin (spodnja sečila) cefuroksim (cefazolin?), aminoglikozidi (± ampicilin) piperacilin/tazobaktam bakterijska pljučnica: cefuroksim piperacilin/tazobaktam
22 Alternative širokospektralnim cefalosporinom sepsa neznanega izvora, domače okolje: protistafilokokni penicilin + aminoglikozid ampicilin/sulbaktam ali amoksiklav/klavulanska kislina + aminoglikozid okužbe kože in mehkih tkiv protistafilokokni penicilini ampicilin/sulbaktam ali amoksiklav/klavulanska kislina cefazolin? TMP/SMX
23 Antibiotične alternative ob omejitvi predpisovanja cefalosporinov v UKC Ljubljana Cefalosporin 3. generacija 4. generacija ceftazidim Penicilin+inhibitor betalaktamaze amoksicilin/klavulanska kislina ampicilin/sulbaktam piperacilin/tazobaktam karbapenemi piperacilin/tazobaktam karbapenemi cefalosporine 3.generacije je dovoljeno uporabiti v določenih izjemnih primerih npr. akutni bakterijski meningitis
24 Take home message ne pozabimo na antibiotike ožjega spektra, ki imajo mnogo skritih talentov huje bolan bolnik ne potrebuje vedno antibiotika najširšega spektra, ampak pravi antibiotik (izbiro narekuje pravilno postavljena indikacija)
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