Turkish Journal of Hematology Volume: 35 - Issue: 4

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BRIEF REPORTDOI: 10.4274/tjh.2018.0127Turk J Hematol 2018;35:290-295Hematologic Adverse Effects of Prolonged Piperacillin-Tazobactam Use in AdultsErişkinlerde Piperasilin-Tazobaktamın Uzamış Kullanımıyla Gelişen İstenmeyen Hematolojik EtkilerAysun Benli 1 , Serap Şimşek-Yavuz 2 , Seniha Başaran 2 , Atahan Çağatay 2 , Halit Özsüt 2 , Haluk Eraksoy 21Muş State Hospital, Clinic of Infectious Diseases and Clinical Microbiology, Muş, Turkey2İstanbul University İstanbul Faculty of Medicine, Department of Infectious Diseases and Clinical Microbiology, İstanbul, TurkeyAbstractObjective: We aimed to find the incidence and risk factors ofhematologic adverse effects of piperacillin-tazobactam (TZP).Materials and Methods: Adult patients who used TZP for more than10 days were included in the study.Results: The incidence of leukopenia, neutropenia, and eosinophiliain 110 TZP therapy episodes was found to be 16.3%, 10%, and 10%,respectively. Lower Charlson Comorbidity Index score, lower initialleukocyte count, combination of TZP with another antibiotic, and totalduration of TZP therapy were found to be independent risk factors forleukopenia, while initial higher eosinophil count (IHEC) and usage ofTZP for >20 days were independent risk factors for neutropenia andIHEC and total duration of TZP therapy were independent risk factorsfor eosinophilia.Conclusion: Longer duration of therapy, combination with otherantibiotics, younger age with fewer comorbidities, and IHEC couldresult in hematologic adverse effects in patients treated with TZP.Patients with IHEC may be more prone to allergic reactions, soimmunological mechanisms may facilitate the development ofhematological adverse effects of TZP.Keywords: Neutropenia, Leukopenia, Eosinophilia, Piperacillintazobactam,Adverse effectsÖzAmaç: Piperasilin-tazobaktamın (TZP) hematolojik istenmeyen etkiinsidansını ve risk faktörlerini bulmayı amaçladık.Gereç ve Yöntemler: On günden uzun süre TZP kullanan erişkinhastalar çalışmaya dahil edildi.Bulgular: Yüz on tedavi epizodunda lökopeni, nötropeni ve eozinofiliinsidansları sırasıyla %16,3, %10 ve %10 olarak bulundu. Charlson’ınKomorbidite İndeksi’nin düşük olması, başlangıç lökosit sayısınındüşük olması, TZP ile başka antibiyotiğin kombine kullanılması veTZP’nin toplam tedavi süresi; başlangıç eozinofil sayısının yüksekolması (BESYO) ve 20 günden uzun süreli TZP kullanımı; BESYO veTZP’nin toplam tedavi süresi sırasıyla lökopeni, nötropeni ve eozinofiliiçin bağımsız risk faktörleri olarak bulundu.Sonuç: TZP ile tedavi edilen hastaların tedavi süresinin uzunolması, kombine antibiyotik tedavisi almaları, daha genç yaşta dahaaz komorbiditelerinin olması ve BESYO hematolojik istenmeyenetkilerin gelişmesine neden olabilir. BESYO olması hastaların alerjikreaksiyonlara daha yatkın olmasına neden olabilir, bu nedenleimmünolojik mekanizmalar TZP kullanımıyla hematolojik istenmeyenetkilerin gelişmesini kolaylaştırabilir.Anahtar Sözcükler: Nötropeni, Lökopeni, Eozinofili, Piperasilintazobaktam,İstenmeyen etkilerIntroductionPiperacillin-tazobactam (TZP) is a broad-spectrum semisyntheticantibiotic. It has increased activity against Pseudomonasaeruginosa when compared with other penicillins [1].It is commonly used in nosocomial infections and manyother conditions that require broad-spectrum antibiotics,such as febrile neutropenia. Adverse effects of TZP includehypersensitivity reactions and gastrointestinal, renal, andhematologic effects. Although the most frequently reportedhematologic adverse effect of TZP is reversible neutropenia,Coombs-positive hemolytic anemia and thrombocytopeniaare also reported [1,2]. After the observation of fever andneutropenia in some patients who received prolonged TZPtherapy, we aimed to identify the incidence and risk factors forthe development of these adverse effects.©Copyright 2018 by Turkish Society of HematologyTurkish Journal of Hematology, Published by Galenos Publishing HouseAddress for Correspondence/Yazışma Adresi: Aysun BENLİ, M.D.,Muş State Hospital, Clinic of Infectious Diseases and Clinical Microbiology, Muş, TurkeyPhone : +90 436 212 06 70E-mail : aysunsb@gmail.com ORCID-ID: orcid.org/0000-0003-0679-0990Received/Geliş tarihi: April 10, 2018Accepted/Kabul tarihi: June 01, 2018290
Turk J Hematol 2018;35:290-295Benli A, et al: Piperacillin-Tazobactam MyelosuppressionMaterials and MethodsPatient SelectionAdult patients (aged >18 years) who were given original TZP formore than 10 days at our faculty from January 2013 to December2014 were included in the study. Usual adult doses were usedand TZP was adjusted to renal function if necessary. Patientswith HIV infection and hematologic malignancy, patientswith leukopenia and neutropenia, and patients using systemicsteroid therapy or chemotherapy within the last 3 monthswere excluded from the study. If the duration between twoepisodes of TZP therapy exceeded 1 month, those episodes wereevaluated separately.Data CollectionPatient information was recorded on previously prepared forms byreviewing medical records. The Charlson Comorbidity Index (CCI)was calculated for all patients.DefinitionsLeukopenia was defined as absolute leukocyte count of <4000cells/mm 3 . Anemia was defined as hemoglobin level of <13.5g/dL in males or <12 g/dL in females, or a decline of 2 g/dLin patients with low hemoglobin levels at the beginning oftherapy. Thrombocytopenia was defined as absolute plateletcount of <150,000 cells/mm 3 , neutropenia was defined asabsolute neutrophil count of <2000 cells/mm 3 , eosinophilia wasdefined as absolute eosinophil count of ≥500 cells/mm 3 , andhypereosinophilia was defined as absolute eosinophil count of≥1500 cells/mm 3 .Statistical AnalysisStatistical analyses were performed using SPSS 21 (IBM Corp.,Armonk, NY, USA). The univariate analyses were investigatedusing chi-square tests, Fisher’s exact test, Student’s t-test, andMann-Whitney U tests as appropriate. For multivariate analysis,the possible factors identified with univariate analyses werefurther entered into logistic regression analysis to determineindependent risk factors for leukopenia, neutropenia, andeosinophilia. Hosmer-Lemeshow goodness-of-fit statistics wereused to assess model fit and p<0.05 was considered statisticallysignificant.ResultsOne hundred and ten TZP therapy episodes of 102 patientswere included in the study. The epidemiological, clinical,and laboratory data of the patients are given in Table1. Total TZP dose and duration of TZP therapy had no significanteffect on the development of anemia or thrombocytopenia.However, they were detected as significant risk factors for thedevelopment of leukopenia (16.3%), neutropenia (10%), andeosinophilia (10%).Drug fever appeared in five of the 11 neutropenic patientsand in six of the 18 patients with leukopenia who wereafebrile beforehand. All of the patients were alive until theend of TZP therapy. Therapy was continued with anotherantibiotic in 8 patients with leukopenia and in 5 patients withneutropenia. Body mass index was normal in all patients whodeveloped leukopenia and neutropenia.Characteristics of patients and statistical analysis with andwithout leukopenia, neutropenia, and eosinophilia during TZPtherapy are given in Table 2. In multivariate analysis, lowerCCI score, lower initial blood leukocyte count, combinationof TZP with another antibiotic, and total duration of TZPtherapy were found to be independent risk factors forleukopenia; initial higher blood eosinophil count (IHEC)and use of TZP for >20 days were found to be independentrisk factors for neutropenia; and IHEC and total duration ofTZP therapy were found to be independent risk factors foreosinophilia. The characteristics of leukopenia, neutropenia,and eosinophilia episodes are given separately in Tables 3, 4,and 5, respectively.Table 1. Characteristics of patients within 110 therapyepisodes.Characteristic Number (%)Female sex, n (%) 47 (42.7)Mean age (years), mean ± SD 59.5±16Charlson Comorbidity Index, mean ± SD 4.07±2.19Reason for piperacillin-tazobactam usageLower respiratory tract infections, n (%) 60 (54.5)Bone and joint infections, n (%) 26 (23.6)Skin and soft tissue infections, n (%) 18 (16.3)Other infections, n (%) 6 (5.4)Mean duration of therapy (days), mean ± SD (total) 21±14Mean dose of therapy (g), mean ± SD (total) 244±149Combination antibiotic therapy with, n (%) 63 (57.2)Ciprofloxacin 37 (58.7)Glycopeptides 17 (26.9)Others 9 (14.2)Leukopenia developed during treatment, n (%) 18 (16.3)Neutropenia developed during treatment, n (%) 11 (10)Eosinophilia developed during treatment, n (%) 11 (10)Hypereosinophilia developed during treatment n (%) 1 (0.9)Anemia developed during treatment, n (%) 21 (19)Thrombocytopenia developed during treatment, n (%) 7 (6.3)SD: Standard deviation.291
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