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7-3617

FEBRILE NEUTROPENIA IN PAEDIATRIC PERIPHERAL BLOOD
STEM CELL TRANSPLANTATION, IN -VITRO
SENSITIVITY DATA
AND CLINICAL RESPONSE TO EMPIRICAL ANTIBIOTIC
THERAPY
Ansari SH, Nasim S, Ahmed A, Irfan M, Ishaque A, Farzana T, Panjwani VK, Taj M and Shamsi TS
ABSTRACT
Objective: To find the in-vitro sensitivity data and clinical response in order to determine the changes required in empiric antibiotic
therapy for management of febrile neutropenia in paediatric patients undergoing peripheral blood stem cell transplantation.
Design: A descriptive study.
Place and Duration of Study: Paediatric bone marrow transplant unit at Bismillah Taqee Institute of Health Sciences and Blood
Disease Center from September 1999 to May 2004.
Patients and Methods: All patients were treated according to institutional protocol for febrile neutropenia. Empirical antibiotics
include Ceftriaxone and Amikacin. In non-responders, changes made included Imipenem and Amikacin, Piperacillin
Tazobactum/Tiecoplanin or Vancomycin/Cloxacilin/Ceftazidime. In non-responders, amphotaracin was added until recovery.
Results: Out of 52 patients, 5 did not develop any fever; in the remaining 47 patients there were 57 episodes of febrile neutropenia.
The mean days of febrile episodes were 4.71 (range 3-8). Fever of unknown origin (FUO) occurred in 31 (54.3%) episodes.
Microbiologically documented infection (MDI) occurred in 17 (29.8%) episodes of fever. Clinically documented infection (CDI)
occurred in 9 (15.7%) episodes. Gram-negative organisms were isolated in 10 while gram-positive organisms in 7. Klebseilla, S. aureus
were the most common isolates. Empirical therapy was effective in 12 of the 33 (36%) episodes. Out of 28, 26 (92%) responded
to Imipenem/Amikacin as second line therapy while those who received any other second line combination, only 11 out of 22 (50%)
showed response. Systemic Amphotericin was used in 4 patients, 2 responded. Infection related mortality rate was 4%.
Conclusion: Gram-negative infections predominated, Imipenem/ Amikacin found to be most effective therapy while a low mortality
rate is recorded in our setting suggesting good infection control.
KEY WORDS:
Febrile neutropenia. Paediatric stem cell transplantation. Antibiotic sensitivity. frequency of severe infection that is associated with a low granulocyte count. Gram-negative infections can cause Paediatric bone marrow and peripheral blood stem cell morbidity and mortality; particularly, if they are unrecognized or transplantation procedures are increasingly performed for inappropriately treated. Any delay in instituting effective gram- malignant and non-malignant haematological disorders.
negative antibiotic coverage in FN patients can result in high Congenital disorders like beta-thalassaemia major and mortality. However, there is more time available to make Fanconi’s anemia in children are important indications in treatment modification when dealing with gram-positive developing world, where consanguineous marriages result in infections.3 There has been a trend towards more gram an increasing proportion of these disorders. Bacteria and fungi positive infections reported in this group of patients.4 In cause 95% of infections in allogeneic stem cell transplant contrast, few reports from the developing world still show setting.1,2 Life threatening complications due to bacterial predominant gram-negative infections.5,6 In pediatric stem infections have been reported in 10-20% of febrile episodes in cells transplant patients, FN may differ from adults in neutropenic patients.3 The clinical hallmark of bacteremia in presentation, antibiotic choice, response and outcome. This is the febrile neutropenic host has been the development of the data of febrile neutropenic episodes in pediatric patients fever. Empirical treatment, i.e. broad-spectrum antimicrobial received peripheral blood stem cell transplantation for various therapy without waiting for microbiological and/or clinical malignant and non-malignant disorders, institutional antibiotic documentation of an infection, is justified in patients with fever policy was revised according to in-vitro sensitivity data and and neutropenia (febrile neutropenia, FN). There is high Department of Haematology, Bismillah Taqee Institute of Health Sciences & Blood Disease Centre, Gulshan-e-Iqbal, Karachi.
It was a descriptive study conducted at Paediatric Bone Correspondence: Dr. Ansari SH. Consultant Haematologist, 30/II, 10th Commercial
Marrow Transplant Unit at Bismillah Taqee Institute of Health Street, Phase IV, D.H.A. Karachi. E-mail: shamsi@super.net.pk Sciences and Blood Disease Center from September 1999 to Received February 07, 2005 accepted July 17, 2006.
Antibiotic sensitivity in febrile neutropenia in paediatric patients undergoing stem cell transplantation May 2004. All patients were treated according to institutional was added or if there was suspicion of fungal infection, protocol for conditioning, graft versus host disease (GvHD) prophylaxis and antimicrobial therapy for FN. Fiftyone Treatment outcome was classified as a success without allogeneic and one autologous transplant were performed for modification when patient recovered from fever and various haematological conditions; including aplastic anemia, neutropenia on initial empirical therapy. Success with Fanconi’s anemia, b-thalassemia major, acute leukemia, modification involved ultimate recovery from fever and neutropenia but requiring alteration of different antibiotic, Conditioning regimen for b-thalassemia major consisted of antifungal or antiviral agent. The treatment was considered as Cyclophosphamide 50mg/kg/day for 4 days, Busulphan failure if fever persisted for longer than 7 days without any 4 mg/kg/day for 4 days (Bu/Cy). In aplastic anemia, response leading to patient’s death or the patient showed Cyclophosphamide 50mg/kg/day for 4 days and ATG 5 clinical deterioration with or without persistence of primary mcg/kg/day for 3 days in heavily pre-transfused patients. For isolated microorganism or detection of a new organism. acute lymphoblastic leukemia and acute myeloid leukemia, Febrile episodes were classified according to the kind of Busulphan 4mg/kg for 4 days and Cyclophosphamide infection as (i) fever of unknown origin (FUO); (ii) 50mg/kg/day for 4 days followed by stem cells transfusion microbiologically documented infection (MDI); (iii) clinically after one day rest. CD-20 antibodies purging was done in CD documented infection (CDI); and according to the suspected 20+ pre-B-cell leukemia. One autologous stem cells source or site of infection (unknown, bacteraemia, fungaemia, transplantation (SCT) was performed who received (BEAM) viraemia, lower respiratory tract infection, upper respiratory B.C.N.U, Etoposide, ARA-C, and Melphalan as conditioning tract infection, gastrointestinal tract infection, soft tissue regimen. Graft-verses-host diseases prophylaxis was cyclosporine 5 mg/kg/day, methotrexate 5 mg/m2 on day 1, 3, both the absence of any clinical or radiological sign of infection 6, 11 and then weekly. Anti-fungal prophylaxis was given other than fever and no isolation of causative organism. with Itraconazole 3 mg/kg/day. Granulocyte colony stimulatingfactor was started on fourth day posttransplant (3-5 The diagnosis of microbiologically documented infections was mcg/kg/day) till Absolute Neutrophil Count (ANC) reached based on both isolation of causative organism from body fluidsand accompanied by clinical symptoms adopted from the case definitions of the Centers for Disease Control (CDC) All patients aged less then 20 years admitted in BMT ward surveillance system for nosocomial infection.7 Bacteraemia or from September 1999 to May 2004 for stem cells fungaemia (MDI) was defined as fever with positive blood transplantation were included. Neutropenia was defined as an cultures for bacteria or fungi with or without septic symptoms ANC of less than 500 cells/mm.3 Patients who had more than or signs of localized infection. Fever arising from a clinically one episodes of neutropenic fever were enrolled more than evident source of infection including radiological findings once. Fever was defined as single oral temperature of 38.3oC without detection of any pathogen was classified as clinically (101 F) or a temperature of 38.0 C (100.4 F) for more than documented infection (CDI).7,8 Bacterial isolates were one hour. Each episode of fever was defined as the period identified and tested according to standard identification from the first day of fever till the day when maximum techniques and antibiotic susceptibility tests as suggested in temperature was less than 37.5 C (100 F) and patient remained afebrile for 48 hours. Patients with history of allergicreaction to any of the antibiotics used in the study, or age morethan 20 years were excluded. After a detailed history and thorough physical examination From November 1999 to May 2004, a total of 57 episodes offebrile episodes were documented in 52 pediatric transplants during the neutropenic episodes, complete blood count, who received PBSC for allogenic (MRD) (n=51) or autologous electrolytes, urinalysis, liver, renal function test and blood (n=1) transplantation. There were 38 males and 14 females cultures from peripheral line and central venous catheter whose age ranged from 2 to 20 years (mean age 10.37 years).
(CVC) were checked. Chest X-rays were performed only when Clinical characteristics of these patients are given in Table I. clinically indicated. Stool of patients, who had diarrhea, wassent for microscopy. For sore throat and cough, throat swabs The incidence of neutropenic fever was 91% (52/57). Meandays of febrile episodes were 4.71(3-8) days. E. coli, S. aureus, and sputum was collected for culture and sensitivity. Catheter- Klebsiella, and P. aeruginosa, were most commonly encountered related infections were identified by local signs of infection at organisms (Table II). FUO occurred in 31 (54.3%) episodes, the site of catheter or by CVC blood cultures with a greater MDI occurred in 17 (29.8%) episodes of fever and CDI colony count than in peripheral blood cultures when taken at occurred in 9 (15.7%) episodes. Fungal and viral episodes the same time. All patients were started with first line antibiotic were not documented microbiologically, but there was clinical regimen according to protocol, Ceftriaxone 80 mg/kg/ day in response to anti-fungal therapy and anti-viral therapy in 2 and two divided doses along with Amikacin 15 mg/kg/day in two 1 episode respectively. Twelve of the 33 (36%) episodes divided doses. Antibiotic response was observed during next responded to empirical therapy. Twentysix out of 28 (92%) 72 hours, whether patient had organism isolated from culture episodes responded to Imipenem alone or with combination, or any site of infection identified like pneumonia, whether the as a second line therapy while those who received any other fever has resolved, and whether patient’s condition has second line combination, only 11 out of 22 (50%) episodes, the deteriorated. Second line therapy was started in those who did fever effervesced. All 7 episodes of gram-positive sepsis not respond to first line that included Inj. Imipenem + Amikacin.
responded to Vancomycin or Cloxacillin. Four episodes After 5-7 days, if fever did not settle then either Vancomycin required systemic Amphotericin, 2 responded. Infectionrelated mortality rate was 4%. Response to antibiotic regimen Ansari SH, Nasim S, Ahmed A, Irfan M, Ishaque A, Farzana T, Panjwani VK, Taj M and Shamsi TS cephalosporins, and quinolones were highly resistant. A total of 120 samples were sent for culture during 57 febrileneutropenic episodes; 17 cultures yielded an organism. Three most common gram negative organisms isolated fromspecimens were E. coli, Klebsiella, and P. aeruginosa. Four drugs High-dose chemotherapy with stem cell or bone marrow consistently showing sensitivity against these organisms were transplantation (BMT) is currently used in the treatment of Imipenem, Cefepime, and Amikacin. While 3rd generation solid tumors9,10 hematological malignancies, acquired andcongenital hematological diseases.11 For both autologous and Table I: Characteristics of pediatric patients, who underwent peripheral
allogeneic transplantation, bacterial and fungal infections blood stem cells transplantation from 1999-2004. are the important source of early morbidity and Diagnosis Number of patients (%) Febrile neutropenic episode mortality.12,13 Recently, peripheral blood stem cells (PBSC) have been increasingly used as a source of stem cells and carry the advantage of faster neutrophil and platelets recovery, whereas there is increased risk of chronic graft versus hostdisease. (GVHD).14,15 Febrile neutropenia is mostly seen during the first week of transplantation.
Traditionally, broad-spectrum antibiotic combination is used as empirical therapy in febrile neutropenia, 44% febrile episodes require a modification. Modification of antibacterial therapy is a reality in clinical practice in the treatment of febrile neutropenia. Several studies have reported various response rates to empirical therapy from 50-70%.16,17 This study has included a large group of profoundly neutropenic pediatric patients for stem cells transplantation (absolute neutrophilcount of <100/cmm).
ALL; acute lymphoblastic leukemia, AML; Acute myeloid leukemia, AA; aplastic anaemia, HD; A study performed in Italy showed 156 episodes of fever Hodgkin’s disease, CML; chronic myeloid leukemia, MRD; matched related donor. occurred in 102 children during first 100 days post bonemarrow transplant (BMT). Fever of unknown origin (FUO) was Table II: Documentation of infection, and antibiotic sensitivity in
found in most cases (40%) followed by other infections pediatric patients who underwent peripheral blood stem cells (33.4%), Pneumonia (19.2%) and Septicemia (7.1%). The overall incidence of mortality was 22.6% and has mortality due A retrospective review of 75-haemopoietic stem cell transplantation showed fever in 74 patients (98%). FUO occurred in 43%, Bacteremia without focus occurred in 29%, whereas 17% neutropenic fever was CVC associated. The Gram negative Isolates
10 (58.8%)
median duration of fever was 12.5 days and time of In this study, 57 episodes of febrile neutropenia occurred in 50 children who received PBSC for malignant and non malignant hematological conditions, the incidence of neutropenic fever was 91%, the overall incidence of mortality was 4%, which is Gram positive isolates
7 (41.2%)
compatible with the data from developed countries.19 The median duration of fever in our group of patients was 4.7 days and median time of engraftment was 11 days.
In this cohort patients, FUO, MDI and CDI, were seen in 31(54.3%), 17 (29.8%) and 9 (15.7%) episodes respectively,which is in accordance with the results reported in Table III:
Pattern of response to antibiotic regimen use in pediatric Gram-negative bacilli, especially, P.
patients who underwent peripheral blood stem cells transplan- aeruginosa, Escherichia coli and Klebsiella species, remain prominent causes of infection in neutropenic patients.21 The most commonly encountered organisms were similar in our In the selection of the initial antibiotic regimen, one should consider the type, frequency of occurrence, and antibiotic susceptibility of bacterial isolates recovered from other patients at the same hospital. The use of certain antibiotics may be limited by special circumstances, such as drug allergy or organ (e.g., renal or hepatic) dysfunction. The rate of gram- negative infections is increasing in most of the centers and Antibiotic sensitivity in febrile neutropenia in paediatric patients undergoing stem cell transplantation double gram-negative coverage is recommended by most of 3. Pizzo PA. Management of fever in patients with cancer and treatment the guidelines. As gram-negative sepsis is a life-threatening induced neutropenia. N Engl J Med 1993; 328:1323-32.
condition, aminoglycoside plus Ceftriaxone was used as first 4. Perez-Simon JA, Garic-Escobar I, Martinez J, Vazquez L, Caballero D, line empirical therapy in the present cohort, but it worked in Canizo C, et al. Antibiotic prophylaxis with meropenem after allogeneic only 12 of the 33 (36%) episodes. Imipenem has excellent stem cell transplantation. Bone Marrow Transplant 2004; 33:183-7.
activity against gram-negative organisms, Viridians streptococci 5. Shamsi TS. Farzana T, Ansari SH, Ahmed A, Ishaque A. Febrile and pneumococci used as second line empirical therapy in our neutropenia in haematological disorders: a single center review of group of patients. Response to second line therapy was 26 out antibiotic policy and the outcome. J Pak Med Assoc 2003; 53: 190-3.
of 28 (92%) episodes. Similar results have been observed in 6. Malik I, Shaharyar. Comparison of meropenem with ceftazidime as other studies in febrile neutropenic patients.21,23 While those monotherapy of cancer patients with chemotherapy induced febrile who received any other combination, only 11 out of 22 (50%) neutropenia. J Pak Med Assoc 2002; 52:15-8.
episodes, the fever effervesced. All 7 episodes of gram- 7. Pizzo PA, Armstrong D, Bodey G. The design, analysis and reporting of positive sepsis responded to Vancomycin or Cloxacillin. Four clinical trials on empiric antibiotic management of neutropenic patients: episodes required systemic Amphotericin in which 2 report of consensus panel from the immunocompromised host society. J Infect Dis 1990;161:397-401.
Institutional antibiotic policy was revised in 2002 which 8. Hughes WT, Armstrong D, Bodey GP, Brown AE, Edwards JE, Feld R, showed 50% response to first line therapy which included, et al. Guidelines for the use of antimicrobial agents in neutropenic Ceftriaxone and Amikacin, 5.5% response to second line, patients with unexplained fever. Infectious Diseases Society of America.
Piperacillin-Tazobactam plus Amikacin, third line antibiotics Clin Infect Dis 1997; 25:551-73.
included Ceftazidime work in 7% cases. Imipenem and 9. Lazarus HM. Hematopoietic progenitor cell transplantation in breast Amikacin responded in 30/40 patients. Ten patients had fungal cancer: current status and future directions. Cancer Invest 1998; 16:
infection.5 According to new antibiotic policy, we continue to use Ceftriaxone plus Amikacin at first position and Imipenem 10. Rahman ZU, Hortobagyi GN, Buzdar AU, Champlin R. High-dose and Amikacin started as second line therapy. This present chemotherapy with autologous stem cell support in patients with breast study showed 36% sensitivity to first line therapy, which was cancer. Cancer Treat Rev 1998; 24: 249-63.
50% in the previous study whereas sensitivity to imipenem 11. Apperley JF. Bone marrow transplant for the haemo-globinopathies: was 92%, which is still satisfactory. Failure or low response to past, present and future. Baillières Clin Haematol 1993; 6: 299-325.
Ceftriaxone could be due to production of extended spectrum 12. Schiodt I, Bergmann OJ, Johnsen HE, Hansen NE. Early infections after b-lactamases (ESBL). b-lactamase is an enzyme that autologous transplantation for haematological malignancies. Med hydrolyzes the beta lactam ring of beta- lactam Oncol 1998; 15: 103-8.
antibiotics. The extended spectrum cephalosporin such as 13. Mossad SB, Longworth DL, Goormastic M, Serkey JM, Keys TF, third generation was widely used as a b-lactamase Bolwell BJ. Early infectious complications in autologous bone marrow inhibitor especially for enteric bacilli such as E. coli and transplantation: a review of 219 patients. Bone Marrow Transplant Klebsiella. Later on it was found that new type of beta 1996; 18: 265-71.
lactamase is produced by Klebsiella spp. and E. coli that 14. Bensinger WI, Weaver CH, Appelbaum FR, Rowley S, Demirer T, Sander hydrolyze the beta-lactam ring of cephalosporins also. These J, et al. Transplantation of allogeneic peripheral blood stem cells new b-lactamases are collectively known as mobilized by recombinant human granulocyte colony-stimulating factor.
Although ESBLs was not detected by our lab, Blood 1995; 85: 1655-68.
however, antibiogram is suggestive of ESBL producer 15. Talmadge JE, Reed E, Ino K, Kessinger A, Kuszynski C, Heinmann D, organisms. Based on the above evidence, it is suggested that et al. Rapid immunologic reconstitution following transplantation with the institutional antibiotic policy for pediatric PBSCT patients mobilized peripheral blood stem cells as compared to bone marrow.
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16. Mustafa MM, Carlson L, Tkaczewski I, Mc Cracken GH Jr, Buchanan GR. Comparative study of cefepime versus ceftazidime in the empiric treatment of paediatric cancer patients with fever and neutropenia.
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Decline of clomiphene for PCOS-related infertility Metformin and aromatase inhibitors may promise fewer spontaneous abortions and multiple gestationsformin 850 mg twice daily for 6 months orclomiphene 150 mg for cycle days 3 to 7 Robert L. Barbieri, MD F or decades clomiphene citrate has been the first-line agent for ovulationinduction in women with PCOS, butand aromatase inhibitors

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