2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

mented infection on presentation; (5) evidence of bone marrow
recovery 5 ; and (6) magnitude of fever (Sidebar 2). 5
By using these risk criteria, patients with acute lymphoblastic
leukemia (ALL) or AML in induction, relapsed ALL
or AML, Burkitt’s lymphoma in induction, and hematopoietic
stem cell transplantation would all be considered highrisk
patients. These patients not only have severe and
prolonged neutropenia but also have profound lymphopenia,
hypogammaglobulinemia, severe mucositis, and gut microbial
dysbiosis. Thus, these high-risk patients might benefit
from implementation of prophylactic strategies to prevent
infectious complications.
KEY POINTS
● Infectious diseases, particularly bacterial and fungal
infections, continue to be major causes of morbidity
and mortality in pediatric patients with cancer.
● Pediatric patients with cancer at highest risk for
developing infectious complications are those with
severe and prolonged neutropenia; substantial medical
comorbidity, and specific cancer types and status
(i.e., hematologic malignancy, relapse).
● Besides severe and prolonged neutropenia, “highrisk”
patients also have concomitant host immune
deficits: severe mucositis, lymphopenia, hypogammaglobulinemia,
and gut microbial dysbiosis.
● Continuation of empirical antibacterial antibiotics
that were initiated at the onset of febrile neutropenia
and prompt initiation of empirical antifungal therapy
in the setting of prolonged fever and neutropenia
continue to be the standard of care for pediatric
patients with cancer with prolonged neutropenia.
● Adjunctive therapies (i.e., granulocyte transfusion or
keratinocyte growth factor treatment for mucositis)
and prophylactic use of antibacterial and antifungal
antibiotics in high-risk patients have shown promise,
but more definitive studies need to be done.
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Sidebar 1. Predominant Microbial Pathogens
Infecting Pediatric Patients with Cancer and
Prolonged Neutropenia
Bacteria
Gram-negative enteric organisms
Escherichia coli, Klebsiella pneumoniae, Enterobacter
spp., Citrobacter spp., Pseudomonas
aeruginosa, Bacteroides spp.
Gram-positive
Staphylococci: coagulase-negative, coagulasepositive
Streptococci: group D, �-hemolytic, anaerobic
Clostridia
Fungi
Candida spp. (C. albicans, C. tropicalis, other
species)
Aspergillus spp. (A. fumigatus, A. flavus)
ANDREW Y. KOH
Sidebar 2. Risk Assessment for Cancer Patients
with Fever and Neutropenia
High Risk
1) Anticipated prolonged (� 7 days in duration)
and profound neutropenia (absolute neutrophil
count � 100 cells/�L after cytotoxic chemotherapy)
4,6
2) Significant medical comorbid conditions, including
hypotension, pneumonia, new-onset
abdominal pain, or neurologic changes 4,6
3) Cancer type (i.e., hematologic malignancy,
Burkitt’s lymphoma)
4) Cancer status (e.g., relapse)
5) Documented infection on presentation
Low Risk
1) Anticipated brief (� 7 days in duration) neutropenic
periods 4
2) No or few comorbidities 4
Standard Management and Presumptive Therapy
The single most important advance in infectious diseases
oncology supportive care leading to improved survival has
been the prompt initiation of empirical antibacterial antibiotics
when the neutropenic patient with cancer becomes
febrile. Before this approach was instituted in the early
1970s, the mortality rate from gram-negative infections,
especially that of P. aeruginosa, E. coli, and K. pneumoniae,
approached 80%, but with the widespread use of effective
empirical antibiotics, the overall mortality rate has declined
to approximately 10% to 40%.
Approximately 85% to 90% of pathogens that are documented
to be associated with new fevers in neutropenia
patients are gram-positive and gram-negative bacteria. Several
empirical regimens have been devised over the last
several decades. Many of the regimens studied are equivalent
in their efficacy, although study designs and definitions
of success have not been uniform. The Infectious Diseases
Society of America has published general guidelines for use
of antimicrobial agents in neutropenic patients with unexplained
fever. 6
Duration of Therapy
The management of high-risk patients with prolonged
neutropenia is addressed in a series of prospective clinical
studies that stratified according to those who defervesced
after the initiation of broad-spectrum antibiotics or who
remained persistently febrile. 7 Among patients with prolonged
neutropenia who defervesced while undergoing
therapy, 41% again became febrile within 3 days of stopping
antibiotics on day 7; new bacterial isolates from those
with documented infections were susceptible to the antibiotics
that had been withdrawn. No subsequent infections
were observed among patients who continued receiving
antibiotics.
The duration of antibiotic therapy depends on several
factors, including isolation of the presumed pathogen, clinical
identification of a presumed infectious process, duration
of both fever and neutropenia, and the patient’s schedule for
chemotherapy. Traditionally, broad-spectrum antibiotic