Original Paper

Acta Haematol 2014;132:112117

DOI: 10.1159/000356626

Received: July 25, 2013

Accepted after revision: September 23, 2013
Published online: February 12, 2014

Prophylactic First-Line Antibiotics Reduce

Infectious Fever and Shorten Hospital Stay
during Chemotherapy-Induced Agranulocytosis
in Childhood Acute Myeloid Leukemia
XiaoqinFeng YongshengRuan YuelinHe YumingZhang XuedongWu
HuayinLiu XuanLiu LanHe ChunfuLi
Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou, PR China

Abstract
Background/Aims: There exists few pediatric data on the
safety and efficacy of prophylactic antibiotics during chemotherapy-induced agranulocytosis. Methods: We prospectively studied the incidence of infection-related fever in 38
children, aged 216 years, with acute myeloid leukemia
(AML) over 121 chemotherapy treatment cycles. A prophylactic group (n= 18) was given either vancomycin/cefepime
(400 mg/m2, q12 h/50 mg/kg, q12 h) or piperacillin/tazobactam (110 mg/kg, q12 h). Control patients (n= 20) received no
preventive antibiotics. Results: The prophylactic group (59
treatment cycles) experienced fever less frequently than the
control group (0.4 vs. 0.9 events; p< 0.001), had a longer interval between agranulocytosis and fever (6.4 vs. 3.8 days;
p= 0.007), had a shorter duration of hospitalization (21.5 vs.
28.5 days; p< 0.001), and had a lower rate of lung infection
(38.8 vs. 80.0%; p< 0.001). One patient taking vancomycin
experienced a skin rash and 3 patients taking piperacillin/
tazobactam had diarrhea; these side effects subsided after
antibiotics were discontinued. Conclusions: In children with

2014 S. Karger AG, Basel

00015792/14/13210112$39.50/0
E-Mail karger@karger.com
www.karger.com/aha

AML, prophylactic antibiotics during the period of chemotherapy-induced agranulocytosis can effectively reduce the
incidence of infectious fever and can shorten the average
length of hospital stay, improving treatment success and
quality of life.
2014 S. Karger AG, Basel

Introduction

Approximately 20% of childhood leukemias are of myeloid origin, and the majority of myeloid leukemias are
acute. With the intensification and optimization of chemotherapy protocols and the improvement of hematopoietic stem cell transplantation techniques, the 5-year
disease-free survival rate of childhood acute myeloid leukemia (AML) has improved by 5060% over the past decade [13]. However, relapse and treatment-related death
is still the main cause of mortality in pediatric patients
with AML, and infection is one of the leading factors in
treatment-related death. In particular, the heterogeneous
viridans streptococci (Streptococcus viridans), which
commonly colonize the oral, gastrointestinal and vaginal
mucosa, are a leading cause of sepsis and pneumonia in
Chunfu Li
Department of Pediatrics, Nanfang Hospital
No. 1838, North Guangzhou Avenue
Guangzhou City 510515 (PR China)
E-Mail fxq126126@126.com

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Key Words
Antibiotics Child Leukemia Myeloid Prophylaxis

neutropenic children and adolescents, and such infections are particularly troublesome in patients who are undergoing therapy for AML [47]. In addition, infection
prolongs the length of hospital stay, which increases medical expenses, delays chemotherapy and decreases the
quality of life in pediatric patients.
In China, several medical centers have reported that
infection was the main cause of early death in children
with AML [8, 9]. A prospective study conducted by the
Nordic Society of Pediatric Hematology and Oncology
(NOPHO) [10] reported that 10% of pediatric patients
died mainly from infections after the 15th day of chemotherapy, and the NOPHO suggested the use of prophylactic antibiotic treatment and also emphasized the
necessity of studying the benefits of combining the use
of prophylactic antibiotics [11]. Various clinical studies
and meta-analyses have demonstrated that preventive
use of fluoroquinolone antibiotics effectively reduce
bacterial infection rate, infectious fever and overall
mortality rate [1214]. Thus, the guidelines of ECIL
(European Conference on Infections in Leukemia),
NCCN (National Comprehensive Cancer Network) and
IDSA (Infectious Diseases Society of America) 2010 all
suggest the preventive use of fluoroquinolone antibiotics during agranulocytosis in high-risk adult leukemia
patients [1517]. Although the long-term use of broadspectrum antibiotics may result in the generation of
drug-resistant bacteria and the accumulation of toxic
side effects [1820], a recent large-scale meta-analysis
reported that the preventive use of quinolones in adults
did not significantly increase the colonization and infection of bacteria resistant to fluoroquinolones [21].
Accordingly, the application of preventive antibiotics is
recognized in adult patients with hematologic malignancy after chemotherapy.
Despite this evidence, reports on the use of preventive antibiotics in pediatric patients with AML and other hematological malignancies are lacking. A prospective study conducted by the Department of Oncology at
St. Jude Childrens Research Hospital in Memphis
(Tenn., USA) in 78 pediatric patients with acute nonlymphocytic leukemia [21] showed that oral administration of cephalosporin antibiotics failed to reduce the
incidence of bacterial sepsis, but prophylactic intravenous injection of cefepime or intravenous vancomycin
injection in combination with oral ciprofloxacin or
cephalosporins not only reduced the incidence of bacterial sepsis and its related death by 90%, but also significantly reduced the length of hospital stay and medical
expenses. In addition, no increase in fungal infection

was found during the prophylactic use of antibiotics

[21].
To study this further, we adopted a strategy of prophylactic antibiotics administration in pediatric patients with
AML showing agranulocytosis after high-intensity chemotherapy with the goal of reducing the incidence of
bacterial infection during agranulocytosis. We also investigated the efficacy and short-term safety of different prophylactic protocols in pediatric patients.

Antibiotics in Childhood AML Treatment

Acta Haematol 2014;132:112117

DOI: 10.1159/000356626

Patients and Methods

Patients
Confirmed by bone marrow morphology (FAB classification)
and immunological phenotyping, 38 children and adolescents
were diagnosed with de novo AML hospitalized at the department
of Pediatrics, Nanfang Hospital, from January 2011 to October
2012. Patients were prospectively analyzed (age 216 years; 24
males and 14 females). There were 21 patients with AML-M2, 2
with AML-M3 (PML/RAR negative), 5 with AML-M4, 7 with
AML-M5, 1 patient with AML-M6 and 2 patients with AML-M7.
Infectious fever events in 121 treatment cycles of these patients
were analyzed. One reported fever was regarded as a febrile event;
therefore, several febrile events may be found in 1 child. We took
temperatures four times a day as a routine procedure. When the
children showed signs of an elevated temperature, body temperature would be taken at any given moment. A temperature >38.3 C
would be recorded as a febrile event during this fever episode. All
patients were kept in the hospital after each course until they recovered. Oropharyngeal swabs were taken of patients to test for
cavity ulcers. After the patient had gargled with physiological saline, we wiped the secretions in the part of the patients mouth with
ulcers using a throat swab to be used in a standard plate culture.
The pathogenic bacteria was reported to be positive if there were
50% pathogenic bacteria or colony counts, and negative if there
were <50% bacterial colonies.

Chemotherapy Protocols
The choice of vancomycin plus cefepime was based on the
study by Kurt et al. [21], and the choice of piperacillin/tazobactam
was because of its broad spectrum, low side effects and low occurrence of secondary infections. We adopted the NOPHO 2004
study for 38 patients without anti-CD33 monoclonal antibody
(gemtuzumab) [1]. This includes 6 courses: (1) AIET (6-thioguanine 100 mg/m2, days 14; cytarabine 200 mg/m2, days 14; etoposide 100 mg/m2, days 14; idarubicin 12 mg/m2, days 2, 4 and
6); (2) AM (cytarabine 100 mg/m2, days 15; mitoxantrone
10mg/m2, days 13); (3) HA1M (cytarabine 1 g/m2, q12 h, days
13; mitoxantrone 10 mg/m2, days 35); (4) HA2E (cytarabine
2g/m2, q12 h, days 13; etoposide 100 mg/m2, days 25); (5) HA3
(cytarabine 3 g/m2, q12 h, days 13), and (6) repeat HA2E.

Grouping of Clinical Study

The prophylactic group (n = 18) consisted of those patients
demonstrating agranulocytosis (absolute neutrophil counts, ANC
<0.5 109/l) after each round of chemotherapy without specific

113

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infection symptoms and signs. Agranulocytosis was found in all

patients after chemotherapy while antibiotics was administrated in
the prophylactic group and ceased after ANC >0.5 109/l. The
control group did not receive antibiotic treatment; patients in this
group waited for ANC >0.5 109/l without treatment. Except for
the antibiotic treatment, interventions in both groups were the
same. The duration of agranulocytosis was expected to last >7 days.
When either pneumonia or lung infection or both were observed
in a child, that child was designated as a case with lung infection.
Seven patients (7/18= 38.9%) in the prophylactic group and 16
patients (16/20= 80%) in the control group were recognized in accordance with this definition. The percentages indicate the prevalence of lung infection in the two groups.
Preventive use of antibiotics included the combination of
vancomycin (Vancocin/vancomycin hydrochloride for injection,
400 mg/m2, q12 h) and cefepime (maxipime or cefepime dihydrochloride for injection, 50 mg/kg, q12 h), or single use of piperacillin/tazobactam (Tazocin, 110 mg/kg, q812 h). Timing of prophylactic drug withdrawal complied with one of the following conditions: (a) neutrophil counts 0.5 109/l, (b) fever with temperature
38.3 C or (c) obvious typical infection symptoms. The control
group included pediatric patients with similar symptoms as the
prophylactic group but received no preventive antibiotics treatment except as noted below. Patients in both the prophylactic and
control groups received oral administration of voriconazole (47
mg/kg bid) to prevent invasive fungal infections.

p value

8.54.4

8.13.2

0.730

12 (60)
8 (40)
20 (100)

12 (67)
6 (33)
18 (100)

0.671
NA

Data are presented as mean SD, or n with percentage in parentheses. Age was tested by independent t test and gender was
tested by 2 test. GC-SF= Granulocyte colony-stimulating factor;
NA= statistical comparison was unavailable.

Results

Table1 shows the baseline characteristics of the 38

pediatric patients. The two groups had a similar age and
gender distribution. The average age was 8.3 3.8 years
(range 216); more than half of the 38 patients (n= 24)
were boys. All patients used granulocyte colony-stimulating factor during the period of agranulocytosis.

Treatment of Fever at Stage of Agranulocytosis

Once a febrile event (38.3 C) occurred in enrolled patients,
we took blood cultures immediately. For prophylactic group patients, the antibiotic administration protocol was changed to carbapenem antibiotics. Some of the patients who used prophylactic
piperacillin/tazobactam (Tazocin) were treated with a combination of vancomycin (Vancocin or vancomycin hydrochloride for
injection) or teicoplanin (teicoplanin for injection) according to
infection locations and symptoms. Infection events in the control
group were treated with carbapenem antibiotics or piperacillin/
tazobactam (Tazocin).

Statistical Analysis
Mean and standard deviation (SD) were calculated for continuous variables and number (n) as well as percentage are shown for
categorical variables. The independent t test was performed for
comparison of continuous variables between the two groups. A
generalized estimating equation was carried for repeated (or related) data. 2 test or Fishers exact test was implemented for independent (or unrelated) categorical variables. A statistical significance was declared with p< 0.05. All statistics were implemented
on PASW statistical software (version 18; IBM SPSS Inc., Chicago,
Ill., USA).

114

Prophylactic group
(n= 18)

Observation Indicators
Fever events were defined as single axillary temperature
38.3 C. The day of absolute neutrophil count <0.5 109/l was set
as day 0, and the time from day 0 to fever event was the interval
time of fever after agranulocytosis. The average length of hospital
stay was defined as the days from the start of chemotherapy to the
time at which the following discharge criteria were met: WBC
>1.0 109/l, neutrophil counts >0.5 109/l, platelet counts >20
109/l, and the effective control of infection.

Age, years
Gender
Male
Female
GC-SF used

Control group
(n= 20)

Acta Haematol 2014;132:112117

DOI: 10.1159/000356626

Comparison of Infectious Fever Events in Prophylactic

and Control Groups
Agranulocytosis occurred after each round of highintensity chemotherapy treatment cycles in all patients
with childhood AML. There were 59 treatment cycles in
the prophylactic patients, including 27 cycles of prophylactic treatment with the combination of vancomycin and
cefepime (11 febrile events) and 25 cycles of piperacillin/
tazobactam prophylactic treatment (8 febrile events) and
8 cycles without antibiotics (8 febrile events). One patient
experienced a skin rash after using the vancomycin/cefepime regimen, and was therefore switched to the piperacillin/tazobactam regimen. In addition, 3 patients receiving piperacillin/tazobactam developed diarrhea and
were switched to vancomycin/cefepime.
No significant difference was found between the two
preventive treatment protocols. As table2 shows, relative to the control group, the prophylactic group had
significantly less frequent fever (0.1 vs. 0.6 febrile events;
p< 0.001), a longer interval to fever (6.4 vs. 3.8 days;
p=0.007) and shorter duration of hospitalization (21.5
vs. 28.5 days; p< 0.001). Although there was no difference in the incidence of infections in the upper respiratory, bronchus, oral cavity, surrounding of anus, peripherally inserted central catheter line, skin or digesFeng/Ruan/He/Zhang/Wu/Liu/Liu/He/Li

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Table 1. Baseline characteristics of the 38 children

in the 38 children
Control
group
(n= 20)

Prophylactic p value
group
(n= 18)

Accumulative frequency of
0.90.1 0.40.1
fever1,2,4
Interval between agranulocytosis
3.80.4 6.40.9
and fever, days4
28.51.7 21.50.7
Hospitalization, days4
Upper respiratory infection6
1 (5)
1 (6)
1 (5)
3 (17)
Bronchitis6
16 (80)
7 (39)
Lung infection5, 7
6 (30)
5 (28)
Oral infection5
6 (3)
2 (11)
Perianal infection6
1 (5)
2 (11)
PICC-line infection6
1 (5)
0 (0)
Skin infection6
6 (30)
2 (11)
Digestive tract infection6, 8
7 (70)
1 (100)
Gram negative3,9
3 (30)
0 (0)
Gram positive3,9
C. difficile infection
0 (0)
0 (0)

<0.001*
0.007*
<0.001*
0.999
0.328
<0.001
0.880
0.238
0.999
0.999
0.238
NA
NA
NA

Continuous variables are presented as mean SD and categorical variables are expressed as n with percentage in parentheses.
*Significant difference between groups, p< 0.05. PICC= Peripherally inserted central catheter; NA= statistical comparison was
unavailable because the sample size was too small to reflect the
study population.
1A child may have fever multiple times.
2Data of children with unknown sites of infection were not reported.
3n and percentage were calculated based on the data from children with detectable pathogens.
4 p values were derived from GEE.
5
p values were derived from 2 test.
6 p values were derived from Fishers exact test.
7
Lung infection included pneumonia and other infections observed by CT scan.
8Infections of the digestive tract from the esophagus to rectum.
9
All were blood infections.

tive tracts, the preventive group had fewer children with

lung infection than the control group (38.9 vs. 80.0%;
p< 0.001).
Comparison of Infectious Complications during
Agranulocytosis
Pulmonary and oral infection were the most common
infectious events during agranulocytosis in AML patients. In the prophylactic group, 1 patient was Ochrobactrum anthropi positive, as indicated by blood culture, and
1 patient was Acinetobacter baumannii positive, as indicated by oropharyngeal swab culture. These bacteria were
Antibiotics in Childhood AML Treatment

resistant to the preventive antibiotics cefepime, and thus

these patients were treated with and cured by meropenem. In the control group, 1 patient was also infected with
A. baumannii and 1 patient was infected with Stenotrophomonas maltophilia, both of which were confirmed by
sputum culture. These bacteria were all multidrug resistant. One patient who had no prophylaxis infected with
S. maltophilia and A. baumannii died. A rash occurred in
1 patient and slight diarrhea was reported in 3 patients in
the prophylactic group during the application of vancomycin and piperacillin/tazobactam (Tazocin), respectively, which subsided after withdrawal. No other antibiotic-related side effects were observed in the prophylactic
group.

Discussion

Currently, treatment for childhood AML includes

high-intensity chemotherapy or combined hematopoietic stem cell transplantation. Chemotherapy protocols often nearly reach the level of myeloablation, which can significantly decrease the relapse rate after chemotherapy,
but can also significantly increase the risk of chemotherapy-related severe infection. Effective prevention of chemotherapy-related severe infection and reduction of
mortality caused by infection are particularly crucial to
pediatric patients with AML.
Although prophylactic use of antibiotics may be beneficial during chemotherapy-induced agranulocytosis in
childhood AML, it is also controversial. Many clinical
studies have investigated the efficacy and advantages/disadvantages of antibiotics, the proper selection of prophylactic antibiotics and relevant efficacy and malpractice
has been their main focus. The key focus of our study was
the use of first-line antibiotics in prophylaxis in developing countries. Until our analysis, few studies had documented the combination of vancomycin and cefepime or
single-use piperacillin/tazobactam to prevent bacterial
infection during chemotherapy in childhood AML.
In addition, the average number of chemotherapy cycles was not always the same per protocol. The complete
chemotherapy of the 38 patients would be 6 treatment
cycles. However, those patients with infection in the first
treatment cycle were excluded. Thus, only 5 cycles were
observed in the treatment program. Some patients
changed to hematopoietic stem cell transplantation after
23 treatment cycles and chemotherapy was interrupted.
The randomized, double-blind and multicenter prospective study conducted by Pillon et al. [10] showed that
Acta Haematol 2014;132:112117
DOI: 10.1159/000356626

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Table 2. Fever characteristics and causes of febrile agranulocytosis

116

Acta Haematol 2014;132:112117

DOI: 10.1159/000356626

served. The patients had used broad-spectrum antibiotics

for a long period of time, but no C. difficile infection could
be detected. This may have been because both vancomycin and piperacillin/tazobactam had antimicrobial effects
on C. difficile; therefore, the prophylactic group were less
likely to suffer from C. difficile-induced pseudomembranous colitis.
These reports illustrate that preventive use of antibiotics in high-risk child cancer patients can be clinically significant. However, the choice of drug is not always clear.
Fluoroquinolones, which are commonly used in adult patients, might be harmful to cartilage development in children and the drug is not recommended in children under
18 years of age. For prophylactic purposes, antibiotics
should have the characteristics of a broad spectrum, high
efficiency and low superinfection incidence. Cefepime
and piperacillin/tazobactam comply with the above characteristics. Considering our ward epidemiology and the
experience at St. Jude Childrens Research Hospital [21],
vancomycin and cefepime were chosen in our clinical
study, and in some patients we used piperacillin/tazobactam sodium as a further preventive measure. Significant
clinical efficacy was achieved by these protocols of prophylactic antibiotic administration. Not only did the incidence of infectious febrile events significantly decrease,
but also the time of occurrence of febrile agranulocytosis
was significantly delayed and the average length of hospital stay significantly shortened. Thus, the pediatric patients significantly benefited from these protocols. The use
of prophylactic first-line antibiotics in high-risk children
has not been described in relevant guidelines and largerscale, multicenter, prospective studies will be required to
further address the prophylactic antibiotics-induced generation, colonization and pathogenicity of drug-resistant
bacteria, and the longer-term adverse effects.

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