Febril nötropenik hastada ampirik antibiyotik tedavisi Dr Recep ÖZTÜRK İÜ Cerrahpaşa Tıp Fakültesi Enfeksiyon Hastalıkları ve Klinik Mikrobiyoloji AD ozturkrecep@superonline.com

Febril nötropenide etken spektrumunda değişiklikler Son 20 yıl içinde önemli değişiklikler oldu Escherichia coli, Pseudomonas aeruginosa, Klebsiella spp. (%60-70 ) Staphylococcus aureus Mutad etkenlerin sıklığı azalmış Mutad etkenlerde antimikrobik maddelere karşı çoklu ilaç direnci önem kazanmış Ramphal R. Clin Infect Dis 2004(Suppl 1);39:S25-3.

Febril nötropenik hastalarda infeksiyon etkeni Gram-pozitif bakteriler Koagulaz pozitif stafilokoklar (Staphylococcus aureus) Koagulaz negatif stafilokoklar (Staphylococcus epidermidis vd) Streptococcus pneumoniae Streptococcus pyogenes Viridans streptokoklar (S.mitis, S.milleri) Enterococcus faecalis/faecium Corynebacterium spp(C.jeikeium, C.urealyticum) Rhodococcus equi Bacillus spp. Clostridium spp (C.septicum, C.tertium) Listeria monocytogenes Rothia mucilaginosa Lactobacillus rhamnosus Leuconostoc spp.

Direnç Pseudomonas aeruginosa 3 K Sef:%9-12; İmipenem %8, Cip:%13 Enterobacter spp:Seftazidim, Piperasilin tazobaktam:%10-21 GN’lerde kinolon direnci %25 den fazla olan merkezler var(profilaksi) Seftazidim+Amikasine %20’den fazla direnç (Malezya, pediatrik Onkoloji) Vento S et al. Lancet Oncol 2003;4:595

Direnç İmipenem:%3,8 Sefepim %19 Seftazidim :%42,5 Piperasilin tazobaktam %42,9 Sefoperazon sulbakam %22,5 Esparza F et al. Rev Esp Quimioter. 2006 ;19:247

Ülkemizde direnç durumu E.coli, Klebsiella, P.aeruginosa %71.7 gram negatif, %28.3 gram pozitif bakteri Gram negatif bakterilerin duyarlılık oranları Karbapenemler %95-97, amikasin %87, sefepim %84, siprofloksasin %79, seftazidim % 71, seftriakson %68 Gram pozitif bakterilerin duyarlılık oranları, oksasilin %60, siprofloksasin %53 Gençer ve ark. 2001

Ülkemizde direnç durumu E.coli’de direnç:IMP %2.5, Sefepim %20.6, piperasilin tazobaktam %10, siprofloksasin %46.8 Pseudomonas:IMP %31.8 Şenol E ve ark 2003

Ülkemizde direnç durumu Gram negatif bakterilerin duyarlılık oranları Karbapenemler %100(2004:%95-96) Sefepim , seftriakson, sefotaksim , seftazidim %90; Piperasilin/tazobaktam %80, Siprofloksasin %70(%81) Gentamisin, tobramisin %80, netilmisin %90, amikasin %100 Stafilokok suşlarında metisilin direnci %55(%61) CTF FEN Grubu 2001, 2004

Ampirik antibiyotik tedavisi Acil geniş spektrumlu antibiyotik başlanması zorunlu Mikroorganizmanın cins ve türü, antibiyotik duyarlılığı, hastanın bireysel özellikleri(risk faktörleri, böbrek/KC yetmezliği) Kan dolaşımı ve pnömoni yapan major yaygın patojenler kapsanmalı Yeni tanımlanan dirençli bakteri profillerine karşı etkili olmalı Jones RN et al. Clin Infect Dis 1999;29:495-502 Genellikle kombinasyon, monoterapiye eğilim

Nötropenik hastada antibakteriyel ajanlar Bütün nötropenik hastalara uygulanabilecek özgül bir şema ve belirli antibiyotik(ler) yok Rehberler (IDSA, Japon, Alman, Türk FEN Grubu) hasta risk faktörleri, infeksiyon tipi, antibiyotik duyarlılık paternleri, nötropeni süresi vb dikkate alarak hazırlanmıştır Hughes WTet al CID 2002;34:730-51 Link H. Ann Hematol. 2003 t;82 Suppl 2:S105-17 Masaoka T. Clin Infect Dis 2004; 39(suppl 2)S49-52

Nötropenik ateş Düşük risk Yüksek risk Oral İV GP gereksiz GP gerekli Monoterapi Sefepim Seftazidim Piperasillin /Tazobaktam* Karbapenem İkili antibiyotik Aminoglikozit + Antipsödomonal penisilin(APP) Sefepim Seftazidim veya Karbapenem GP + Sefepim Seftazidim APP Karbapenem Aminoglikozit Siprofloksasin/ levofloksasin + Amoksisilin klavulanat Seftazidimin Vir Strep ve pnömokok aktivitesi yetersiz Tamura K CID 2004;39(Suppl 1):S59-64 CAZ’e karşı direnç GP ve GN bakterilerde artıyor AMC Japon rehberinde +/-(oral mukozit ve deri lezyonları barizse AII); penisiline allerji varsa sefaleksin, klindamisin Oral tedavi olamayacağını hekim hissederse Sefepim veya karbapenem monoterapisi verebilir(AII) AG ile ikili tedavi özellikle(Sefepim/Karbapenem+AG) uzama ihtimali olan ciddi nötropenide tercih edilir(BI) Monoterapide sefepim 8 saatte bir 1-2 g olarak tercih edilir Japonyada piperasilin tazobaktam, sefpirom, sefoperazon-sulbactam, panipenem/betamipron alternatif Monoterapide gatifloksasin ve moksifloksasin araştırmaları devam etmektedir Linezolid ve kinopristin/dalfopristinin başlangıç ampirik rejimlere eklenmesi için yeterli veri yoktur

Febril nötropenide sefoperazon sulbaktam Sefoperazon/sulbaktam geniş spektrumlu bir antibiyotik kombinasyonudur İV/İM uygulama sonrasında pek çok doku ve sıvıda yüksek terapötik yoğunluk sağlanır ve devam eder Tekrarlayıcı dozlar sonrasında birikme bulgusu yok Yaşlılar, çocuklar, hafif/orta böbrek yetmezlikli hastalarda kullanımı uygun İlaç etkileşimleri az Sulbaktamın -laktamaz indüklemesi klavulanik asitten zayıf

Etki sepktrumu Gram-pozitif aeroplar Gram-negatif aeroblar Anaeroblar Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, and Streptococcus pyogenes Gram-negatif aeroblar Haemophilus influenzae, Moraxella catarrhalis, ve Enterobacteriaceae (Klebsiella pneumoniae, Enterobacter spp., Proteus spp., Escherichia coli) Anaeroblar Bacteroides fragilis, Bacteroides spp., Fusobacterium ve Peptostreptococcus spp. Sefoperazon/sulbaktam hastanede tedavi edilen infeksiyonların empirik tedavisinin çoğu için uygundur

In Vitro Duyarlılık n=736, 9 merkezde yapılan çalışma Test edilen 7 antibiyotik Sefepim, seftazidim, sefotaksim, imipenem, aztreonam, sefoperazon/sulbaktam, tikarsilin/klavulanat Denenen İzolatlar Enterobacter türleri(%73), E. Coli(%93-eSBL %78), Klebsiella türleri(%71, ESBL %62,8), Serratia türleri, Citrobacter türleri, Acinetobacter türleri(%73,8), P. Aeruginosa(%59,4), S.aureus Test edilen yedi beta laktamajan arasında 736 izolata karşı en yüksek etkinliği sağlayanlar( sırasıyla) İmipenem, sefepim ve sefoperazon/sulbaktam’dı Korten V ve ark. Diagn Microbiol Infect Dis 1999;35:65

The Turkish Antimicrobial Resistance Study Group. Pfaller M The Turkish Antimicrobial Resistance Study Group. Pfaller M. A, Korten V. et al. Diagn Microbiol Infect Dis 1999;35:65-73

The Japan Antimicrobial Resistance Study Group The Japan Antimicrobial Resistance Study Group. DIAGN MICROBIOL INFECT DIS 1999;35:307–315

HigginS PG et al. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY 2004, p

Jacoby GA. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 1990<;34:858-862

Sefoperazon/sulbaktamın kanıtlanmış klinik etkinliği Nozokomiyal sinüzit , pnömoni (pediatrik hastalar dahil) Karın içi infeksiyonlar Obstetrik/jinekolojik infeksiyonlar Üriner sistem infeksiyonları Nötropenik ateş A large number of clinical trials have demonstrated the clinical efficacy of cefoperazone/sulbactam to treat adult and pediatric infections. Comparative studies have demonstrated that the clinical efficacy of cefoperazone/sulbactam is comparable or superior to that of standard treatment options, including antibiotic combinations. As a result of this proven clinical efficacy, guidelines for the treatment of community-acquired respiratory tract infections and the treatment or prophylaxis of intra-abdominal/surgical infections have acknowledged a role for cefoperazone/sulbactam in the hospital-based management of patients with community- or hospital-acquired infections.

Nötropenik ateş Eşleştirmeli, prospektif, çift kör çalışma (ABD) Kemoterapi ilişkili nötropenik ateşi olan erişkin kanser hastaları ( >16 yaş) Tedavi: Cefoperazone/sulbactam 2 g/1 g günde 3 kez IV Ceftazidime 2 g günde 3 kez IV İnfeksiyon iyileşene kadar Değerlendirme: Klinik cevap (semptom ve bulgular) Bakteriyolojik cevap Adult (age >16 years) cancer patients with chemotherapy-associated neutropenia (absolute neutrophil count of 500/mm3 confirmed or likely) and fever (38.5°C) were enrolled in a comparative, prospective, double-blind study conducted in the USA.1 Patients were randomized to treatment with cefoperazone/sulbactam 2 g/1 g three times daily or ceftazidime 2 g three times daily, administered intravenously until the resolution of infection. Ceftazidime is a well accepted single-agent therapy for neutropenic fever.2 Clinical response was evaluated after 72 h, on Day 5 and at the end of therapy and was classified as: initial response (marked improvement in signs and symptoms within 72 h), continued response (initial response maintained beyond 72 h), no response (persistence of signs and symptoms beyond 72 h) or relapse (initial response followed by reappearance of signs or symptoms).1 Bacteriologic response was based on the elimination of culturable material or the elimination of principal pathogens after therapy. Chandrasekar PH. J Pharm Technol 1998;14:63–9. 1. Chandrasekar PH et al. Safety and efficacy of cefoperazone plus sulbactam versus cetazidime in the empiric treatment of febrile neutropenia. J Pharm Technol 1998;14:63–90. 2. Hughes WT et al. 1997 guidelines for the use of antimicrobial agents in neutropenic patients with unexplained fever. Clin Infect Dis 1997;25:551–73.

Nötropenik ateş Klinik cevap (hasta, %) C/S Ctz 72 saatte (n=38) (n=44) Başlangıçta cevap 20 (52.6) 23 (52.3) Cevap yok 18 (47.3) 21 (47.7) 5. gün (n=38) (n=44) Devamlı cevap 20 (52.6) 23 (52.3) Relaps 3 (7.9) 4 (9.1) Cevap yok 15 (39.5) 16 (36.4) Tedavi sonunda (n=59) (n=59) Devam eden cevap 19 (32.2) 26 (44.1) Fifty-nine patients (median age 42 years) were randomized to cefoperazone/sulbactam and 59 (median age 44 years) to ceftazidime. The mean durations of therapy were 8.5 days (range 1–28 days) and 9.5 days (range 1–37 days) respectively. More than two-thirds of patients in each group received norfloxican/fluconazole prophylaxis from the start of chemotherapy until resolution of neutropenia. The clinical response rate among clinically evaluable patients was similar for cefoperazone/sulbactam and ceftazidime at 72 h, on Day 2 and at the end of therapy (p>0.05 in all cases). A total of 56 isolates (of which 51 [86.4%] were Gram-positive, predominantly staphylococci and streptococci) were isolated from bacteremic patients. The pathogen eradication rate was 15/19 (78.9%) for cefoperazone/sulbactam and 13/24 (54.2%) for ceftazidime (p=0.09). The results of this study indicate that cefoperazone/sulbactam is clinically and bacteriologically as effective as ceftazidime in the treatment of fever-inducing bacterial infections in neutropenic patients. C/S, cefoperazone/sulbactam; Ctz, ceftazidine. Chandrasekar PH. J Pharm Technol 1998;14:63–90. Chandrasekar PH et al. Safety and efficacy of cefoperazone plus sulbactam versus cetazidime in the empiric treatment of febrile neutropenia. J Pharm Technol 1998;14:63–90.

Febril granulositopenik hastalar Açık, eşleştirmeli, prospektif, tek merkezli çalışma (ABD) Granulositopeni ve ateşi (>38ºC) olan erişkin (16 yaş) hastalar Tedavi: Cefoperazone/sulbactam 4 g/2 g günde 2 kez IV Imipenem/cilastatin 500 mg IV 4 kez Tedavi süresi sınırlı değil Değerlendirme: Klinik cevap Bakteriyolojik cevap An open-label, comparative, prospective, single-center study conducted in the USA enrolled adult (age 16 years) febrile granulocytopenic patients.1 Patients were randomized to receive either cefoperazone/sulbactam 4 g/2 g twice daily or imipenem/cilastatin 500 mg four times daily, administered by intravenous drip infusion over 30–60 minutes. There was no fixed treatment period. Imipenem/cilastatin is a well accepted single-agent therapy for neutropenic fever.2 Clinical response at the end of therapy was classified as improvement (disappearance of fever with clinical improvement and pathogen eradication) or failure (persistence of fever and/or pathogen requiring modification of therapy).1 Bacteriologic response at the end of therapy was assessed according to the eradication of isolates collected prior to therapy. Winston DJ et al. Clin Infect Dis 1998;26:576–83. 1. Winston DJ et al. Randomized comparison of sulbtactam/cefoperazone with imipenem as empirical monotherapy for febrile granulocytopenic patients. Clin Infect Dis 1998;26:576–83. 2. Hughes WT et al. 1997 guidelines for the use of antimicrobial agents in neutropenic patients with unexplained fever. Clin Infect Dis 1997;25:551–73.

Winston DJ et al. Clin Infect Dis 1998;26:576–83. The median age of patients in the cefoperazone/sulbactam group was 47 years (range 16–76 years) compared with 39 (16–81) years for patients who received imipenem/cilastatin. The median duration range of therapy was 12 (3–69) days and 14 (3–50) days, respectively. For all infections, the overall clinical response rates for cefoperazone/sulbactam and imipenem/cilastatin were similar (p=0.17). The response rates for microbiologically documented infections, clinically documented infections or possible infections for the two groups were also similar. Of 78 pre-therapy isolates, 52 (66.7%) were Gram-positive organisms (the most common being viridans group streptococcus, 21 isolates).The overall eradication rate was similar for the cefoperazone/sulbactam and imipenem/cilastatin groups (p=0.37). These data demonstrate that cefoperazone/sulbactam is clinically and bacteriologically as effective as imipenem/cilastatin in the treatment of fever-inducing bacterial infections in neutropenic (granulocytopenic) patients. Winston DJ et al. Clin Infect Dis 1998;26:576–83.

Febril nötropenik hastalar Akan et al Açık, prospektif, eşleştirmeli, tek merkezli çalışma(Turkiye) Erişkin febril nötroepnik hastalar Tedavi: Cefoperazone/sulbactam 2 g 2 kez günde ve amikacin günde 2 kez 500 mg IV Ceftazidime 2 g günde 3 kez ve amikacin günde 2 kez 500 mg IV Minimum tedavi süresi 7 gün Değerlendirme: Klinik cevap (teavinin başlamasından sonra 72 saat veya ateşsiz 5. gün) In an open-label, prospective, comparative, single-center study conducted in Turkey, adult febrile neutropenic patients were randomized to one of two intravenous treatments: cefoperazone/sulbactam 2 g twice daily plus amikacin 500 mg twice daily, or ceftazidime 2 g three times daily plus amikacin 500 mg twice daily.1 Each treatment was given for at least 7 days. Ceftazidime plus amikacin is a standard therapy for febile neutropenia.2 Clinical response (assessed 72 h after the start of therapy and after the fifth afebrile day) was classified as success (eradication of the pathogen, or five fever-free days without clinical findings of infection) or failure (need for alternative antibiotic therapy, death after five days’ treatment or withdrawal from treatment).1 Akan H et al. Mikrobiyol Bült 1995;29:131–5. 1. Akan H et al. A single center randomized study comparing the efficacy of sulbactam/cefoperazone and amikacin versus ceftazidim and amikacin in febrile neutropenic patients. Mikrobiyol Bült 1995;29:131–5. 2. Agaoglu L et al. Cost-effectiveness of cefepime + netilmicin or ceftazidime + amikacin or meropenem monotherapy in febrile neutropenic children with malignancy in Turkey. J Chemother 2001;13:281–7.

Akan H et al. Mikrobiyol Bült 1995;29:131–5. The mean age (range) of the patients was 37 (16–64) years in the cefoperazone/ sulbactam plus amikacin group and 32 (14–69) years in the ceftazidime plus amikacin group. The most common underlying disease was acute myeloblastic leukemia (60% and 52% of patients, respectively). There was a trend towards greater clinical success with cefoperazone/sulbactam plus amikacin at both endpoints but this did not reach statistical significance (p>0.05). Therefore, these data indicate that cefoperazone/sulbactam is as clinically effective as ceftazidime when combined with amikacin in the treatment of fever-inducing bacterial infections in neutropenic patients. Akan H et al. Mikrobiyol Bült 1995;29:131–5.

Nötropenik ateş Prospektif, eşleştirmeli, değerlendiren-kör, tek merkezli çalışma (ABD) Ateş ve nötroepnili erişkin kanser hastaları Tedavi: Cefoperazone/sulbactam 2 g/1 g günde 3 kez + vancomycin 1 g günde 2 kez Imipenem/cilastatin 500 mg/m2 günde 4 kez + vancomycin 1 g günde 2 kez Tedavi süresi sınırlı değil Değerlendirme: Yalnızca klinik cevap In a prospective, comparative, evaluator-blinded, single-center study conducted in the USA adult cancer patients admitted to hospital with fever (38.3ºC for >2 h) and neutropenia (neutrophil count <1000/mm3) were randomized to one of two regimens:1 Cefoperazone/sulbactam 2 g/1 g three times daily plus vancomycin 1 g twice daily Imipenem/cilastatin 500 mg/m2 four times daily plus vancomycin 1 g twice daily. Imipenem/cilastatin is an established monotherapy for neutropenic fever,2 and vancomycin was added to ensure coverage of methicillin-resistant pathogens. All agents were administered by intravenous drip infusion. Bone marrow transplant patients received imipenem/cilastatin at a lower dose (500 mg four times daily) because of expected lower tolerability in those patients. Clinical success was defined as the disappearance of all clinical and laboratory evidence of infection. Bodey G et al. Eur J Clin Microbiol Infect Dis 1996;15:625–34. 1. Bodey G et al. Imipenem or cefoperzone/sulbactam combined with vancomycin for therapy of presumed or proven infection in neutropenic cancer patients. Eur J Clin Microbiol Infect Dis 1996;15:625–34. 2. Hughes WT et al. 1997 guidelines for the use of antimicrobial agents in neutropenic patients with unexplained fever. Clin Infect Dis 1997;25:551–73.

Nötropenik ateş Klinik başarı (%) Ateş tipi C/S + V I + V Kaynak belli değil 75 (n=80) 72 (n=103) Dokümante edilen infeksiyon 71 (n=80) 86 (n=72) Klinik olarak dokümante 54 (n=39) 59 (n=29) Mikrobiyolojik olarak dokümante 88 (n=41) 86 (n=43) Toplam 74 (n=194) 73 (n=175) C/S + V, cefoperazone/sulbactam + vancomycin; I + V, imipenem/cilastatin + vancomycin. A total of 369 febrile/infections episodes were clinically evaluable. The median age (range) of patients was 52 (17–84) years for the cefoperazone/sulbactam plus vancomycin group and 50 (18–79) years for the imipenem plus vancomycin group. The distribution of disease conditions was similar for the two groups except that a greater proportion of patients in the cefoperazone/sulbactam group had lymphoma or myeloma (18.6% versus 10.3%). Clinical success rates were similar for the two treatment groups. There were no significant differences in success rate between treatments in relation to documentation of infection, underlying disease, pathogens or prior antibacterial prophylaxis. The results of this study indicate that cefoperazone/sulbactam plus vancomycin is clinically and bacteriologically effective as imipenem/cilastatin plus vancomycin in the treatment of neutropenic fever. Bodey G et al. Eur J Clin Microbiol Infect Dis 1996;15:625–34. Bodey G et al. Imipenem or cefoperzone/sulbactam combined with vancomycin for therapy of presumed or proven infection in neutropenic cancer patients. Eur J Clin Microbiol Infect Dis 1996;15:625–34.

Febril nötropeni Prospektif, randomize, tek merkezli çalışma (Türkiye) Hematolojik malinite ve solid tümorlü hastalar Tedavi Cefoperazone/sulbactam 2 g/1 g günde 3 kez + amikacin 1 g /gün(n:15) Imipenem/cilastatin 500 mg günde 4 kez Tedavi süresi sınırlı değil %73 kültür pozitif (izolatların %62si gram pozitif) En sık infeksiyon:bakteremi Başlangıç klinik cevap: her iki rejimle %60 Önemli yan etki yok İmipenem monoterapisi ve sulbactam-cefoperazone+ amikacin kombine tedavisi eşit etkili Ozyilkan O, Yalcintas U, Baskan S.Imipenem-cilastatin versus sulbactam-cefoperazone plus amikacin in the initial treatment of febrile neutropenic cancer patients.Korean J Intern Med. 1999 ;14(2):15-9.

Japon FEN Rehberi In Japan, a third-generation cephalosporin (cefoperazone/sulbactam) and fourth-generation cephalosporins other than cefepime, (e.g., cefpirome and cefozopran) are often used, although the efficacy of these agents as empirical therapy for febrile neutropenia has not been documented in large randomized trials Tamura K. Clinical Infectious Diseases 2004; 39:S59–64

Türk FEN Rehberi Seftazidim Sefepim İmpenem Meropenem Piperasilin tazobaktam Sefoperazon sulbaktam

Böbrek ve KC yetmezliğinde doz Kreatinin klirensi 30 ml/dak olunca ikinci doz sulbaktamsız verilir Ağır karaciğer yetmezliğinde(ileri devre siroz) doz yarıya indirilir(maks:4g/gün sefoperazon)

Yan etkiler(1) Sefoperazon/sulbaktam genel olarak iyi tolere edilir Geniş bir hasta grubuna uygulama için uygun Sefoperazon gebelik için B kategorisinde En sık yan etkiler (%1-10): Döküntüğ(makülopapüler)(%2) Artmış KC fonksiyon testleri (AST,ALT)(%5-10) Pozitif direkt Coombs testi İshal(%3) Nötropeni(%2), hematokrit azalması(%5), geçici eozinofili(%10) Clinical studies have indicated that cefoperazone/sulbactam is generally well tolerated and is as well tolerated as gold-standard comparator regimens. Clinical trials involving approximately 2500 patients have reported a variety of adverse events, none of which occurs at a frequency of more than 6.2%. Most adverse events are of mild or moderate severity and are tolerated with continued treatment. The most common adverse events are: elevated liver function tests (serum glutamic–pyruvic transaminase and serum glutamic–oxaloacetic transaminase), positive direct Coombs test, diarrhea/loose stools, hypo-prothrombinemia, and transient eosinophilia. Cefoperazone/sulbactam is appropriate for administration to a wide variety of patients. Dose adjustments may be required in patients with renal and/or hepatic dysfunction, and should be used with care in pregnant women and nursing mothers.

Yan etkiler(2) Seyrek yan etkiler(%1) Bulantı, kusma Psödomembranoz kolit Hipoprotrombinemi Vit K yapan bakterilerin yıkımı; sahip olunan metiltetrazolitol yan zincirinin protrombin aktivitesini önlemesi Kreatinin artması İlaç ateşi İnjeksiyon yerinde endürasyon, flebit