SUPPLEMENT ARTICLE

Microbiological Data for Patients

with Febrile Neutropenia
Akihisa Kanamaru and Youichi Tatsumi
Department of Hematology, Rheumatology, and Nephrology, Kinki University School of Medicine, Osaka, Japan

The pattern of bacterial infections and antimicrobial susceptibility has changed significantly during the past
20–30 years. The causative organisms for bacteremia or fungemia identified at Kinki University Hospital in
1985–1996 were compared with the isolates identified during 1997–2002. The prevalence of gram-negative
organisms decreased, whereas the prevalence of gram-positive organisms increased. Staphylococcal species

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predominated in the second period, accounting for 22% of isolates, and methicillin-resistant Staphylococcus
aureus (MRSA) increased from 5% to 14% of isolates. Pseudomonas aeruginosa ranked second, although the
prevalence decreased in the second period compared with the first. Candida species were also relatively frequent
(11%). Enterococcal species had an 8% prevalence. A comparison of all culture isolates showed that gram-
negative isolates still predominated among the general patient population, whereas almost equal prevalence
was observed in patients with hematological diseases. MRSA was the organism most frequently isolated in
the general patient population, followed by P. aeruginosa. Among staphylococcal species, MRSA accounted for
as much as 90% of isolates.

The pattern of bacterial organisms causing infection in
patients with neutropenia and cancer has changed over
the past 2 decades. When empirical therapy was first
introduced [1], bacteremia was reported in !20% of
febrile patients with neutropenia. In most centers,
gram-negative bacteria were responsible for 60%–70%
of these infections, with Escherichia coli, Pseudomonas
aeruginosa, and Klebsiella species accounting for most
of these episodes. Infections caused by Staphylococcus
aureus were also common. Studies conducted by the
International Antimicrobial Therapy Cooperative
Group of the European Organization for Research and
Treatment of Cancer have documented a shift in the
pattern of the pathogens. Currently, 60%–70% of bac-
teremia episodes due to a single organism are due to
gram-positive cocci [2, 3]. Similar trends have been
documented elsewhere: of 320 isolates from 288 epi-
sodes of bacteremia among patients with neutropenia
Reprints or correspondence: Dr. Akihisa Kanamaru, Department of Hematology,
Nephrology, and Rheumatology, Kinki University School of Medicine, 377-2 Ohno-
Higashi, Osaka-Sayama, Osaka 589-8511 Japan (kanamaru@med.kindai.ac.jp).
Clinical Infectious Diseases 2004; 39:S7–10
 2004 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2004/3901S1-0002$15.00
in Barcelona, 200 (63%) were gram-positive and 120
(38%) gram-negative [4]. Of note, in addition to S.
aureus and coagulase-negative staphylococci, infections
caused by viridans streptococci, Enterococcus species,
and other streptococci are more common than they
were 20 years ago.
Although specific evidence is lacking, some of the fac-
tors believed to be responsible for the shift toward a
greater incidence of infection with gram-positive path-
ogens include the following: oral mucositis associated
with increasingly potent chemotherapeutic agents, such
as cytosine arabinoside; profound and prolonged neu-
tropenia; increasing use of indwelling intravascular cath-
eters; fluoroquinolone and trimethoprim-sulfamethox-
azole prophylaxis; and use of antacids and histamine
blockers [5, 6]. Several meta-analyses have shown that
fluoroquinolone prophylaxis has had an impact on the
decline in the incidence of bacteremia due to gram-
negative rods in patients with neutropenia and cancer,
but use of these antibiotics has not prevented bacteremia
due to gram-positive organisms [7, 8].
We compared the trends in infections in febrile pa-
tients with neutropenia in our institution during the
periods 1985–1996 and 1997–2002. We also reviewed
antimicrobial susceptibility data of the pathogens iso-

Microbiology of Infections in Febrile Neutropenia • CID 2004:39 (Suppl 1) • S7

 Table 1. Characteristics of patients in a survey of particular, gram-positive organisms prevailed among patients
causative organisms for bacteremia or fungemia at with hematological disease who had more prolonged neutro-
Kinki University Hospital during 1985–2002.
penia and indwelling catheters (table 3).
Characteristic Value
Table 4 describes the coincidence rate between the initial
blood culture results and the surveillance cultures in both study
Age in years
periods. Mortality tended to be higher in cases with septicemia
Range 15–87
Median 48
due to MRSA, P. aeruginosa, and fungi, which is also observed
Sex, no. male / no. female 98/72 in the data from the Ministry of Health, Welfare, and Labor
Underlying disease (table 5).
Acute myeloblastic leukemia 47
Acute lymphoblastic leukemia 19 DISCUSSION
Myelodysplastic syndrome 25
The incidence of septicemia and/or bacteremia with gram-neg-
Chronic myelogenous leukemia 10
ative microorganisms decreased slightly in the later period of
Malignant lymphoma 31
Adult T cell leukemia 5
the study, whereas the prevalence of staphylococci, especially
Aplastic anemia 8 MRSA and coagulase-negative staphylococci, increased. These
Multiple myeloma 14 trends are similar to those reported by other investigators [9–
Other 11 11]. Factors underlying these trends probably include the in-

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Total 170 creased use of broad-spectrum antibiotics and indwelling
catheters.
Infections due to gram-positive organisms were more prev-
lated from febrile neutropenic patients collected from a na-
alent among patients with hematological diseases. On the other
tionwide surveillance study of 60 institutions conducted
hand, gram-negative bacteria, particularly Pseudomonas species,
through 2002.
were more frequently isolated from the general patient popu-
lation. Again, among individual pathogens isolated, staphylo-
MATERIALS AND METHODS
coccal species, including coagulase-negative staphylococci, were
Study design. We conducted an observational study from the more prevalent among patients with hematological diseases,
mid-1980s through 2002 in the hematology ward at Kinki Uni- whereas infections with MRSA were more frequently observed
versity School of Medicine (KUSM), a 1000-bed tertiary referral in the general patient population.
hospital. The potential population area includes 1.2 million Regarding the duration of neutropenia, infections with gram-
inhabitants. KUSM also offers extensive cardiovascular surgery negative organisms accounted for a greater proportion of in-
services and organ transplantation facilities. The hematology
ward is equipped with 50 beds with laminar flow. The hema-
Table 2. Organisms isolated from culture of blood from febrile
tology ward admits ∼200 patients per year, with a mean of 50 neutropenic patients.
hospital days per admittance.
Identification of organisms. All isolates were identified at No. (%) of isolates
the microbiological laboratory of KUSM by routine methods. 1985–1996 1997–2002
Species identifications were confirmed with the Vitek system Pathogen (n p 250) (n p 181)
(bioMérieux Vitek) or API (bioMérieux Vitek) products and Staphylococci 35 (14.0) 39 (21.5)
standard reference methods. Methicillin-resistant
Staphylococcus aureus 12 (4.8) 25 (13.8)
RESULTS Streptococci 24 (9.6) 6 (3.3)
Pseudomonas species 42 (16.8) 21 (11.6)
From 1985 through 2002, a total of 170 patients were treated Enterococci 11 (4.4) 14 (7.7)
at the hematology ward (table 1). Escherichia coli 7 (2.8) 10 (5.5)
We divided the data into 2 time periods: 1985–1996 and Klebsiella species 11 (4.4) 5 (2.8)
1997–2002. The patterns of the microbiological features were Candida species 18 (7.2) 21 (11.6)
compared between these periods. Gram-negative organisms Corynebacterium species 14 (5.6) 7 (3.9)
were more prevalent during 1985–1996, but gram-positive or- Serratia species 7 (2.8) 3 (1.7)
ganisms were more prevalent during 1997–2001 (table 2). Anaerobes 8 (3.2) 3 (1.7)
Gram-positive organisms prevailed in the general patient pop- Mycobacteria 0 0
ulation among all culture isolates, whereas almost equal prev- Fungi 2 (0.8) 2 (1.1)
Other 59 (23.6) 25 (13.8)
alence was observed in patients with hematological disease. In

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Table 3. Types of pathogens in the general patient population MRSA. MRSA may be resistant to a wide variety of antibiotics,
and in patients with hematological disorders at Kinki University except to vancomycin and arbekacin sulfate, an aminoglycoside.
Hospital during 1985–2002.
The rate of positive results of blood culture may be !20%
No. of patients
among febrile neutropenic patients. The remaining 80% of pa-
tients may have negative blood culture results; thus Matsuhisa
Type of General With hematological
pathogen population disorders et al. [12] emphasized the usefulness of in situ hybridization
to detect bacterial DNA phagocytized by neutrophils. They ob-
Gram-negative 3324 227
Gram-positive 1869 216
served that among many febrile neutropenic patients, most
Anaerobes 302 14 bacteria are phagocytized by neutrophils and only a few remain
Fungi 397 56 in the blood to form colonies detectable by culture. Shimada
et al. [13] compared the sensitivity of in situ hybridization with
that of culture of blood from 292 febrile patients. Results of
fections associated with the longest duration, that is, ⭓29 days. in situ hybridization were positive and of blood culture were
Infections with gram-negative organisms were also common in negative among 38.0% of patients, both methods yielded pos-
patients without intravascular catheters. In contrast, among itive results among only 4.1%, results of in situ hybridization
patients with indwelling catheters, infections with gram-posi- were negative and of blood culture were positive among 6.9%,
tive organisms were more prevalent than those caused by gram- and both methods yielded negative results among 51.0%. The
negative bacteria, but with a lesser difference compared to pa-

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total rate of positivity was 11.0% for culture of blood and 42.1%
tients with intravascular catheters. for in situ hybridization. This suggests that a microbiological
Data from a 2002 study of strains from Kyoto University cause is likely to be identified in 40% of patients with fever of
Hospital (Dr. N. Fujiwara, personal communication), on the unknown origin.
other hand, showed a rather different situation. Among a total Unfortunately, we were not able to collect antimicrobial sus-
of 519 strains cultured from blood during 2002 (table 6), the ceptibility data of our recent blood culture isolates. However,
prevalence of gram-positive bacteria was 56% for the entire at Toho University, Tokyo, they collected 594 bacterial patho-
patient population but only 37% for patients with febrile neu- gens most frequently cited as the cause of infections in febrile
tropenia. P. aeruginosa accounted for only 3% of infections in neutropenic patients from 60 institutes in Japan and tested for
the general patient population but for 23% in febrile neutro- their susceptibilities to antibiotics commonly used as empirical
penic patients. The incidence and mortality rate from fungal therapy for febrile neutropenia (Dr. K. Yamaguchi, personal
infections remained virtually unaltered, despite the use of oral communication). The most remarkable finding was that 30%
empirical antifungal drugs such as fluconazole. Coincident mi- of P. aeruginosa isolates were resistant to imipenem, 22% to
croorganisms isolated from culture of blood and from sur- cefpirome, 15% to piperacillin, and 12% to cefepime and cef-
veillance cultures occurred less frequently than predicted. How- tazidime. Production of blaIMP-1, that is, the gene that codes
ever, surveillance cultures may be useful for screening for class B b-lactamase, which hydrolyzes cartapenems, was iden-
tified in 1.9% of P. aeruginosa strains.
Table 4. Coincidence rate of isolation of microorganisms from
culture of blood and from surveillance cultures.
Table 5. Attributable mortality due to septicemia, by bacterial
No. isolations from both strain, among febrile neutropenic patients (n p 181).
sets of cultures/total no. of
isolations (%), by time period Mortality rate, % of patients
Pathogen 1985–1996 2001–2002 Kinki University Ministry of Health,
Staphylococcus species 16/33 (48) 0/10 Pathogen School of Medicine Welfare, and Labor
Methicillin-resistant Staphylococcus species 67 58
Staphylococcus aureus 16/22 (73) 6/8 (75) Methicillin-resistant
Streptococcus species 6/14 (43) 0/2 Staphylococcus aureus 84 56
Pseudomonas species 23/40 (58) 4/8 (50) Streptococcus species 40 63
Enterococcus species 10/13 (77) 4/11 (36) Pseudomonas species 76 63
Escherichia coli 3/10 (30) 1/3 (33) Enterococcus species 69 52
Klebsiella species 3/11 (27) 0/2 Escherichia coli 60 58
Serratia species 3/5 (60) 1/2 (50) Klebsiella species 67 53
Fungi 12/25 (48) 2/5 (40) Serratia species 67 44
Other 2/7 (29) 0/10 Fungi 95 44
Total 94/180 (52) 18/61 (30) Other 30 86

Microbiology of Infections in Febrile Neutropenia • CID 2004:39 (Suppl 1) • S9

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Acknowledgments
smears from septicemia-suspected blood by in situ hybridization using
The authors thank Dr. Nasko Fujiwara (Central Clinical Laboratory, biotinylated probes. Microbiol Immunol 1994; 38:511–7.
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