Abstract
Background/Aim: Infections are a major cause of morbidity and mortality in children with haematologic malignancies and solid tumors as well as those undergoing hematopoietic stem cell transplantation (HSCT). The purpose of our study was to record the epidemiological characteristics and outcomes of bacteremias, focusing on pathogens, as well as risk factors and mortality rates in patients of a pediatric hematology-oncology unit from Northern Greece.
Materials and Methods: A retrospective analysis was conducted, which included all positive blood cultures from pediatric hematology oncology patients aged from 1 to 16 years old admitted to the Pediatric and Adolescent Hematology Oncology Unit of AHEPA University Hospital of Thessaloniki between January 2014 and December 2018. Data were collected from patients’ printed and electronic medical records.
Results: 73 episodes of bacteremias were identified (41% male and 32% female with a ratio of 1.28:1; median age 6.5 years; 13.7% solid tumor, 72.6% acute lymphoblastic leukemia, 13.7% acute myeloid leukemia, and 95.8% with an indwelling permanent catheter). 49.3% of the isolates were Gram-positive bacteria and 50.7% Gram-negative, and the ratio of Gram-negative to Grampositive was 1.02. Coagulase-negative staphylococci were most frequent (39.7%), followed by E. coli (17.8%) and Klebsiella pneumoniae (17.8%). Out of all Gram-negatives, 13.5% carbapenemase producers and 8.1% ESBL-producers were found. In relation to Gram-positive, 79.3% were identified as methicillin-resistant CoNS. During the study period, 10.9% of indwelling catheters were removed, and 2.73% of episodes resulted in ICU transfer. The 3-month mortality rate was 8.2%.
Conclusion: This study demonstrated an almost equal distribution of Gram-positive and Gramnegative bacteremias in total in this population but with an increase in the isolation of Grampositive bacteria over the last years, which is consistent with other similar studies in this patient group. Knowledge of the local epidemiology and bacterial antimicrobial resistance is important to prevent and timely treat these life-threatening infections in immunocompromised pediatric oncology patients.
Graphical Abstract
[1]
Lund, B.; Åsberg, A.; Heyman, M.; Kanerva, J.; Harila-Saari, A.; Hasle, H.; Söderhäll, S.; Jónsson, Ó.G.; Lydersen, S.; Schmiegelow, K. Risk factors for treatment related mortality in childhood acute lymphoblastic leukaemia. Pediatr. Blood Cancer, 2011, 56(4), 551-559.
[http://dx.doi.org/10.1002/pbc.22719] [PMID: 21298739]
[http://dx.doi.org/10.1002/pbc.22719] [PMID: 21298739]
[2]
Abdul, R.H.B.; Yusoff, Z.B.; Bin Othman, S. Association of neutropenia onset and severity with chemotherapy regimens and schedules. Asian Pac. J. Cancer Prev., 2011, 12(6), 1425-1428.
[PMID: 22126475]
[PMID: 22126475]
[3]
Hakim, H.; Billett, A.L.; Xu, J.; Tang, L.; Richardson, T.; Winkle, C.; Werner, E.J.; Hord, J.D.; Bundy, D.G.; Gaur, A.H. Mucosal barrier injury–associated bloodstream infections in pediatric oncology patients. Pediatr. Blood Cancer, 2020, 67(8)e28234
[http://dx.doi.org/10.1002/pbc.28234] [PMID: 32386095]
[http://dx.doi.org/10.1002/pbc.28234] [PMID: 32386095]
[4]
Loeffen, E.A.H.; Knops, R.R.G.; Boerhof, J.; Feijen, L.E.A.M.; Merks, J.H.M.; Reedijk, A.M.J.; Lieverst, J.A.; Pieters, R.; Boezen, H.M.; Kremer, L.C.M. Treatment-related mortality in children with cancer: Prevalence and risk factors. Eur. J. Cancer, 2019, 121, 113-122.
[5]
O’Connor, D.; Bate, J.; Wade, R.; Clack, R.; Dhir, S.; Hough, R.; Vora, A.; Goulden, N.; Samarasinghe, S. Infection-related mortality in children with acute lymphoblastic leukemia: An analysis of infectious deaths on UKALL2003. Blood, 2014, 124(7), 1056-1061.
[http://dx.doi.org/10.1182/blood-2014-03-560847] [PMID: 24904116]
[http://dx.doi.org/10.1182/blood-2014-03-560847] [PMID: 24904116]
[6]
Chessells, J.M.; Harrison, G.; Richards, S.M.; Bailey, C.C.; Hill, F.G.H.; Gibson, B.E.; Hann, I.M. Down’s syndrome and acute lymphoblastic leukaemia: Clinical features and response to treatment. Arch. Dis. Child., 2001, 85(4), 321-325.
[http://dx.doi.org/10.1136/adc.85.4.321] [PMID: 11567943]
[http://dx.doi.org/10.1136/adc.85.4.321] [PMID: 11567943]
[7]
Dal Forno, C.B.; Correa, L.; Scatena, P.D.; Silva, C.V.; Shiramizo, S.; Pavão dos Santos, O.F.; Cendoroglo Neto, M.; Teich, V.; Teich, N.; Sardenberg, C. Bloodstream infection in intensive care unit: Preventable adverse events and cost savings. Value Health Reg. Issues, 2012, 1(2), 136-141.
[http://dx.doi.org/10.1016/j.vhri.2012.10.002] [PMID: 29702892]
[http://dx.doi.org/10.1016/j.vhri.2012.10.002] [PMID: 29702892]
[8]
McGee, D.C.; Gould, M.K. Preventing complications of central venous catheterization. N. Engl. J. Med., 2003, 348(12), 1123-1133.
[http://dx.doi.org/10.1056/NEJMra011883] [PMID: 12646670]
[http://dx.doi.org/10.1056/NEJMra011883] [PMID: 12646670]
[10]
Castagnola, E.; Caviglia, I.; Pistorio, A.; Fioredda, F.; Micalizzi, C.; Viscoli, C.; Haupt, R. Bloodstream infections and invasive mycoses in children undergoing acute leukaemia treatment: A 13-year experience at a single Italian institution. Eur. J. Cancer, 2005, 41(10), 1439-1445.
[http://dx.doi.org/10.1016/j.ejca.2005.03.007] [PMID: 15963894]
[http://dx.doi.org/10.1016/j.ejca.2005.03.007] [PMID: 15963894]
[11]
Greenberg, D.; Moser, A.; Yagupsky, P.; Peled, N.; Hofman, Y.; Kapelushnik, J.; Leibovitz, E. Microbiological spectrum and susceptibility patterns of pathogens causing bacteraemia in paediatric febrile neutropenic oncology patients: Comparison between two consecutive time periods with use of different antibiotic treatment protocols. Int. J. Antimicrob. Agents, 2005, 25(6), 469-473.
[http://dx.doi.org/10.1016/j.ijantimicag.2005.01.020] [PMID: 15890499]
[http://dx.doi.org/10.1016/j.ijantimicag.2005.01.020] [PMID: 15890499]
[12]
Wisplinghoff, H.; Seifert, H.; Wenzel, R.P.; Edmond, M.B. Current trends in the epidemiology of nosocomial bloodstream infections in patients with hematological malignancies and solid neoplasms in hospitals in the United States. Clin. Infect. Dis., 2003, 36(9), 1103-1110.
[http://dx.doi.org/10.1086/374339] [PMID: 12715303]
[http://dx.doi.org/10.1086/374339] [PMID: 12715303]
[13]
Yadegarynia, D.; Tarrand, J.; Raad, I.; Rolston, K. Current spectrum of bacterial infections in patients with cancer. Clin. Infect. Dis., 2003, 37(8), 1144-1145.
[http://dx.doi.org/10.1086/378305] [PMID: 14523785]
[http://dx.doi.org/10.1086/378305] [PMID: 14523785]
[14]
Koll, B.S.; Brown, A.E. The changing epidemiology of infections at cancer hospitals. Clin. Infect. Dis., 1993, 17(Suppl. 2), S322-S328.
[http://dx.doi.org/10.1093/clinids/17.Supplement_2.S322] [PMID: 8274595]
[http://dx.doi.org/10.1093/clinids/17.Supplement_2.S322] [PMID: 8274595]
[15]
Ortega, M.; Rovira, M.; Almela, M.; Marco, F.; de la Bellacasa, J.P.; Martínez, J.A.; Carreras, E.; Mensa, J. Bacterial and fungal bloodstream isolates from 796 hematopoietic stem cell transplant recipients between 1991 and 2000. Ann. Hematol., 2005, 84(1), 40-46.
[http://dx.doi.org/10.1007/s00277-004-0909-0] [PMID: 15480665]
[http://dx.doi.org/10.1007/s00277-004-0909-0] [PMID: 15480665]
[16]
Collin, B.A.; Leather, H.L.; Wingard, J.R.; Ramphal, R. Evolution, incidence, and susceptibility of bacterial bloodstream isolates from 519 bone marrow transplant patients. Clin. Infect. Dis., 2001, 33(7), 947-953.
[http://dx.doi.org/10.1086/322604] [PMID: 11528564]
[http://dx.doi.org/10.1086/322604] [PMID: 11528564]
[17]
Haupt, R.; Romanengo, M.; Fears, T.; Viscoli, C.; Castagnola, E. Incidence of septicaemias and invasive mycoses in children undergoing treatment for solid tumours. Eur. J. Cancer, 2001, 37(18), 2413-2419.
[http://dx.doi.org/10.1016/S0959-8049(01)00274-X] [PMID: 11720836]
[http://dx.doi.org/10.1016/S0959-8049(01)00274-X] [PMID: 11720836]
[18]
Raymond, J.; Aujard, Y. Nosocomial infections in pediatric patients: A European, multicenter prospective study. Infect. Control Hosp. Epidemiol., 2000, 21(4), 260-263.
[http://dx.doi.org/10.1086/501755] [PMID: 10782588]
[http://dx.doi.org/10.1086/501755] [PMID: 10782588]
[19]
Jarvis, W.R. Epidemiology of nosocomial infections in pediatric patients. Pediatr. Infect. Dis. J., 1987, 6(4), 344-351.
[http://dx.doi.org/10.1097/00006454-198704000-00003] [PMID: 3588109]
[http://dx.doi.org/10.1097/00006454-198704000-00003] [PMID: 3588109]
[20]
Allen, U.; Lee Ford-Jones, E. Nosocomial infections in the pediatric patient: An update. Am. J. Infect. Control, 1990, 18(3), 176-193.
[http://dx.doi.org/10.1016/0196-6553(90)90183-S] [PMID: 2194407]
[http://dx.doi.org/10.1016/0196-6553(90)90183-S] [PMID: 2194407]
[21]
Kuo, F.C.; Wang, S.M.; Shen, C.F.; Ma, Y.J.; Ho, T.S.; Chen, J.S.; Cheng, C.N.; Liu, C.C. Bloodstream infections in pediatric patients with acute leukemia: Emphasis on gram-negative bacteria infections. J. Microbiol. Immunol. Infect., 2017, 50(4), 507-513.
[http://dx.doi.org/10.1016/j.jmii.2015.08.013] [PMID: 26442676]
[http://dx.doi.org/10.1016/j.jmii.2015.08.013] [PMID: 26442676]
[22]
Simon, A.; Ammann, R.A.; Bode, U.; Fleischhack, G.; Wenchel, H.M.; Schwamborn, D.; Gravou, C.; Schlegel, P.G.; Rutkowski, S.; Dannenberg, C.; Körholz, D.; Laws, H.J.; Kramer, M.H. Healthcare-associated infections in pediatric cancer patients: Results of a prospective surveillance study from university hospitals in Germany and Switzerland. BMC Infect. Dis., 2008, 8(1), 70.
[http://dx.doi.org/10.1186/1471-2334-8-70] [PMID: 18500998]
[http://dx.doi.org/10.1186/1471-2334-8-70] [PMID: 18500998]
[23]
Rondinelli, P.I.P.; Ribeiro, K.C.B.; de Camargo, B. A proposed score for predicting severe infection complications in children with chemotherapy-induced febrile neutropenia. J. Pediatr. Hematol. Oncol., 2006, 28(10), 665-670.
[http://dx.doi.org/10.1097/01.mph.0000212996.94929.0b] [PMID: 17023827]
[http://dx.doi.org/10.1097/01.mph.0000212996.94929.0b] [PMID: 17023827]
[24]
Katsibardi, K.; Papadakis, V.; Charisiadou, A.; Pangalis, A.; Polychronopoulou, S. Blood stream infections throught the entire course of acute lymphoblastic leukemia treatment. Neoplasma, 2011, 58(4), 326-330.
[http://dx.doi.org/10.4149/neo_2011_04_326] [PMID: 21520989]
[http://dx.doi.org/10.4149/neo_2011_04_326] [PMID: 21520989]
[25]
Santolaya, M.E.; Alvarez, A.M.; Becker, A.; Cofré, J.; Enríquez, N.; O’Ryan, M.; Payá, E.; Pilorget, J.; Salgado, C.; Tordecilla, J.; Varas, M.; Villarroel, M.; Viviani, T.; Zubieta, M. Prospective, multicenter evaluation of risk factors associated with invasive bacterial infection in children with cancer, neutropenia, and fever. J. Clin. Oncol., 2001, 19(14), 3415-3421.
[http://dx.doi.org/10.1200/JCO.2001.19.14.3415] [PMID: 11454890]
[http://dx.doi.org/10.1200/JCO.2001.19.14.3415] [PMID: 11454890]
[26]
Hakim, H.; Flynn, P.M.; Srivastava, D.K.; Knapp, K.M.; Li, C.; Okuma, J.; Gaur, A.H. Risk prediction in pediatric cancer patients with fever and neutropenia. Pediatr. Infect. Dis. J., 2010, 29(1), 53-59.
[http://dx.doi.org/10.1097/INF.0b013e3181c3f6f0] [PMID: 19996816]
[http://dx.doi.org/10.1097/INF.0b013e3181c3f6f0] [PMID: 19996816]
[27]
Viscoli, C.; Castagnola, E.; Giacchino, M.; Cesáro, S.; Properzi, E.; Tucci, F.; Mura, R.M.; Alvisi, P.; Zanazzo, G.; Surico, G.; Bonetti, F.; De Sio, L.; Izzi, G.; Di Cataldo, A.; Ziino, O.; Massolo, F.; Nardi, M.; Santoro, N.; Binda, S. Bloodstream infections in children with cancer: A multicentre surveillance study of the Italian Association of Paediatric Haematology and Oncology. Eur. J. Cancer, 1999, 35(5), 770-774.
[http://dx.doi.org/10.1016/S0959-8049(99)00052-0] [PMID: 10505037]
[http://dx.doi.org/10.1016/S0959-8049(99)00052-0] [PMID: 10505037]
[28]
Garrido, M.M.; Garrido, R.Q.; Cunha, T.N.; Ehrlich, S.; Martins, I.S. Comparison of epidemiological, clinical and microbiological characteristics of bloodstream infection in children with solid tumours and haematological malignancies. Epidemiol. Infect., 2019, 147e298
[http://dx.doi.org/10.1017/S0950268819001845] [PMID: 31699182]
[http://dx.doi.org/10.1017/S0950268819001845] [PMID: 31699182]
[29]
Mikulska, M.; Viscoli, C.; Orasch, C.; Livermore, D.M.; Averbuch, D.; Cordonnier, C.; Akova, M. Aetiology and resistance in bacteraemias among adult and paediatric haematology and cancer patients. J. Infect., 2014, 68(4), 321-331.
[http://dx.doi.org/10.1016/j.jinf.2013.12.006] [PMID: 24370562]
[http://dx.doi.org/10.1016/j.jinf.2013.12.006] [PMID: 24370562]
[30]
Katsimpardi, K.; Papadakis, V.; Pangalis, A.; Parcharidou, A.; Panagiotou, J.P.; Soutis, M.; Papandreou, E.; Polychronopoulou, S.; Haidas, S. Infections in a pediatric patient cohort with acute lymphoblastic leukemia during the entire course of treatment. Support. Care Cancer, 2006, 14(3), 277-284.
[http://dx.doi.org/10.1007/s00520-005-0884-6] [PMID: 16270193]
[http://dx.doi.org/10.1007/s00520-005-0884-6] [PMID: 16270193]
[31]
Roilides, E.; Sidi, V.; Gompakis, N.; Tsivitanidou, M.; Katsaveli, A.; Koliouskas, D. Patterns and outcome of septicemia in neutropenic children with cancer in a Greek Hospital. Infection, 1998, 26(3), 189-191.
[http://dx.doi.org/10.1007/BF02771853] [PMID: 9646116]
[http://dx.doi.org/10.1007/BF02771853] [PMID: 9646116]
[32]
Funada, H.; Matsuda, T. Changes in the incidence and etiological patterns of bacteremia associated with acute leukemia over a 25-year period. Intern. Med., 1998, 37(12), 1014-1018.
[http://dx.doi.org/10.2169/internalmedicine.37.1014] [PMID: 9932631]
[http://dx.doi.org/10.2169/internalmedicine.37.1014] [PMID: 9932631]
[33]
Arora, B.; Thacker, N.; Pereira, N.; Banavali, S.D.; Narula, G.; Vora, T.; Chinnaswamy, G.; Prasad, M.; Kelkar, R.; Biswas, S. Epidemiology of blood stream infections in pediatric patients at a tertiary care cancer centre. Indian J. Cancer, 2014, 51(4), 438-441.
[http://dx.doi.org/10.4103/0019-509X.175311] [PMID: 26842152]
[http://dx.doi.org/10.4103/0019-509X.175311] [PMID: 26842152]
[34]
Kumar, P.; Medhekar, A.; Ghadyalpatil, N.S.; Noronha, V.; Biswas, S.; Kurkure, P.; Nair, R.; Kelkar, R.; Banavali, S.D. The effect of age on the bacteria isolated and the antibiotic-sensitivity pattern in infections among cancer patients. Indian J. Cancer, 2010, 47(4), 391-396.
[http://dx.doi.org/10.4103/0019-509X.73574] [PMID: 21131751]
[http://dx.doi.org/10.4103/0019-509X.73574] [PMID: 21131751]
[35]
Miliaraki, M.; Katzilakis, N.; Chranioti, I.; Stratigaki, M.; Koutsaki, M.; Psarrou, M.; Athanasopoulos, E.; Stiakaki, E. Central line-associated bloodstream infection in childhood malignancy: Single-center experience. Pediatr. Int., 2017, 59(7), 769-775.
[http://dx.doi.org/10.1111/ped.13289] [PMID: 28376269]
[http://dx.doi.org/10.1111/ped.13289] [PMID: 28376269]
[36]
Tural Kara, T.; Erat, T.; Yahşi̇, A.; Özdemi̇r, H.; İleri̇, T.; İnce, E.; Taçyildiz, N.; Ünal, E.; Çi̇ftçi̇, E.; İnce, E. Bloodstream infections in pediatric hematology/oncology patients: Six years’ experience of a single center in Turkey. Turk. J. Med. Sci., 2019, 49(4), 1157-1164.
[http://dx.doi.org/10.3906/sag-1812-101] [PMID: 31342734]
[http://dx.doi.org/10.3906/sag-1812-101] [PMID: 31342734]
[37]
Mvalo, T.; Eley, B.; Bamford, C.; Stanley, C.; Chagomerana, M.; Hendricks, M.; Van Eyssen, A.; Davidson, A. Bloodstream infections in oncology patients at Red Cross War Memorial Children’s Hospital, Cape Town, from 2012 to 2014. Int. J. Infect. Dis., 2018, 77, 40-47.
[http://dx.doi.org/10.1016/j.ijid.2018.09.012] [PMID: 30244075]
[http://dx.doi.org/10.1016/j.ijid.2018.09.012] [PMID: 30244075]
[38]
Diekema, D.J.; Pfaller, M.A.; Jones, R.N. Age-related trends in pathogen frequency and antimicrobial susceptibility of bloodstream isolates in North America. Int. J. Antimicrob. Agents, 2002, 20(6), 412-418.
[http://dx.doi.org/10.1016/S0924-8579(02)00204-2] [PMID: 12458134]
[http://dx.doi.org/10.1016/S0924-8579(02)00204-2] [PMID: 12458134]
[39]
Kouni, S.; Tsolia, M.; Roilides, E.; Dimitriou, G.; Tsiodras, S.; Skoutelis, A.; Kourkouni, E.; Gkentzi, D.; Iosifidis, E.; Spyridis, N.; Kopsidas, I.; Karakosta, P.; Tsopela, G.C.; Spyridaki, I.; Kourlaba, G.; Coffin, S.; Zaoutis, E.T.; Papaevangelou, V.; Triantafyllidou, P.; Fanaraki, E.; Kaisari, K.; Kalabalikis, P.; Karachristou, K.; Katsibardi, K.; Kattamis, A.; Kazantzi, M.; Kitra, V.; Lourida, A.; Mpouza, E.; Papadopoulou, S.; Petrikkos, L.; Polychronopoulou, S.; Siahanidou, T.; Zannikos, K.; Giannopoulos, A.; Hatzipantelis, E.; Tragiannidis, A.; Goumperi, S.; Sdougka, M.; Lithoxopoulou, M.; Soubasi, V.; Baka, M.; Dimolitsa, C.; Doganis, D.; Kapetanakis, I.; Mavrogeorgos, G.; Nika, A.; Papachristidou, S.; Papadatos, I.; Tsintoni, A.; Baroutis, G.; Stratiki, E.; Skordala-Riti, M.; Tsouvala, E.; Gaitana, C.; Grivea, I.; Kaffe, A.; Giapros, V.; Gouvias, T.; Drougia, A.; Theodoraki, M.; Karavana, G.; Koropouli, M.; Thomou, C.; Kapetanaki, A.; Tzaki, M.; Maistreli, S. Establishing nationally representative central line-associated bloodstream infection surveillance data for paediatric patients in Greece. J. Hosp. Infect., 2019, 101(1), 53-59.
[http://dx.doi.org/10.1016/j.jhin.2018.07.032] [PMID: 30059747]
[http://dx.doi.org/10.1016/j.jhin.2018.07.032] [PMID: 30059747]
[40]
Kirby, J.T.; Fritsche, T.R.; Jones, R.N. Influence of patient age on the frequency of occurrence and antimicrobial resistance patterns of isolates from hematology/oncology patients: Report from the Chemotherapy Alliance for Neutropenics and the Control of Emerging Resistance Program (North America). Diagn. Microbiol. Infect. Dis., 2006, 56(1), 75-82.
[http://dx.doi.org/10.1016/j.diagmicrobio.2006.06.004] [PMID: 16876375]
[http://dx.doi.org/10.1016/j.diagmicrobio.2006.06.004] [PMID: 16876375]
