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: email@example.com
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
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
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Guidance on the participation of the Notified Bodies. "Guidance on the participation of the Notified Bodies in the attestation of conformity under the Construction Products Directive 89/106/CE" is available for the Notified Bodies on the CPD-GNB CIRCA as document NB-CPD/01/002-rev04. Introduction It has to be clear from the beginning that the systems of attestation of conformity
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