MAJOR ARTICLE

Epidemiology and Risk Factors for Gram-

Positive Coccal Infections in Neutropenia:
Toward a More Targeted Antibiotic Strategy
Catherine Cordonnier,1 Agnès Buzyn,3 Guy Leverger,4 Raoul Herbrecht,5 Mathilde Hunault,6 Roland Leclercq,6
and Sylvie Bastuji-Garin,2 for the Club de Réflexion sur les Infections en Onco-Hématologie
1
Hematology Department and 2Public Health Department, University Paris XII, Henri Mondor Hospital, Créteil, 3Hematology Department, Necker
Hospital, and 4Pediatrics Department, Trousseau Hospital, Assistance Publique–Hôpitaux de Paris, Paris, 5Hautepierre Hospital, Strasbourg,
6
Hematology Department, University Hospital, Angers, and 7Microbiology Department, University Hospital, Caen, France

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The objective of this study was to evaluate the risk of acquiring gram-positive coccal infections in febrile
neutropenic patients and to develop risk indexes for gram-positive and streptococcal infections. This pro-
spective, multicenter study included 513 patients. The prevalence of gram-positive coccal infections was 21%
(14% were staphylococcal infections and 7.8% were streptococcal infections). The mortality rate during the
month after study enrollment was 5%. On multivariate analysis, the occurrence of gram-positive coccal in-
fections was significantly associated with receipt of high-dose cytarabine therapy, proton pump inhibitors,
and gut decontamination with colimycin without glycopeptides and presence of chills. Staphylococcal infection
was significantly associated with use of nonabsorbable colimycin, and streptococcal infection was associated
with diarrhea, use of nonabsorbable antifungals, receipt of high-dose cytarabine, and gut decontamination
with colimycin. The relative risks for streptococcal infection were 2.9, 13.2, and 20.7 in the presence of 1, 2,
and ⭓3 parameters, respectively. Risk factors for staphylococcal and streptococcal infections differ among
neutropenic patients. A simple scoring system for predicting streptococcal infection is proposed.

The increasing mortality rate for patients with febrile
neutropenia due to gram-positive coccal infections (es-
pecially streptococcal infections) has been attributed to
receipt of quinolone prophylaxis, receipt of high-dose
cytarabine treatment, and the presence of central ve-
nous catheters [1–3]. The current challenge for phy-
sicians is to choose appropriate antibiotics to protect
against septic shock and acute respiratory distress syn-
Received 9 April 2002; accepted 30 September 2002; electronically published
3 January 2003.
Financial support: The Club de Réflexion sur les Infections en Onco-Hématologie
is part of the Institut Maurice Rapin (Paris). This study was supported by a grant
from Laboratoires Roussel (Paris).
Reprints or correspondence: Dr. Catherine Cordonnier, Hematology Dept., Henri
Mondor Hospital, 94000 Créteil, France (carlcord@club-internet.fr).
Clinical Infectious Diseases 2003; 36:149–58
 2003 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2003/3602-0003$15.00
drome due to streptococci while avoiding an increase
in the prevalence of antibiotic-resistant organisms [4].
b-Lactams do not all have adequate activity against
gram-positive organisms: cefotaxime and ceftriaxone
are effective against b-lactam–susceptible strains, but
they have limited antipseudomonal activity, and cef-
tazidime, which is commonly used to treat patients with
Pseudomonas aeruginosa infection, may not be the best
choice to treat streptococcal bacteremia [5]. The routine
use of glycopeptides remains controversial [6, 7]. Co-
agulase-negative staphylococci are the most common
cause of gram-positive bacteremia [8–11], but staphy-
lococcal bacteremia results in a low mortality rate,
whereas oral streptococci, which are responsible for up
to 39% of infections in neutropenic hosts [12], have
been associated with mortality rates of 4%–22% [1, 13].
We conducted this prospective study to determine the
prevalence of and risk factors for gram-positive coccal

Gram-Positive Infections and Neutropenia • CID 2003:36 (15 January) • 149

infection in febrile neutropenic patients and to establish a risk
index to aid physicians in their choice of first-line antibiotics
for the treatment of individual patients.
PATIENTS AND METHODS
Patients. All consecutive patients who had a first episode
of fever while they had neutropenia were prospectively en-
rolled at 36 French hematology centers during a 2-month
period (table 1). Fever was defined as a temperature of
⭓38.3C once or ⭓38C twice within 8 h. Neutropenia was
defined as a granulocyte count of !500 cells/mL or as a gran-
ulocyte count that was expected to decrease to !500 cells/mL
⭐48 h after study enrollment because of recent receipt of
chemotherapy. Patients could be included in the study only
once. Patients with solid tumors were excluded, except for
those who had neutropenia after they underwent autologous
stem cell transplantation.
Of the 532 enrolled patients, 14 did not meet the inclusion
criteria and 5 had missing data. Of the remaining 513 patients,
291 were male and 222 were female. The mean age (SD) was
40.8  21.7 years; 92 (18%) of the patients were children (age,
!15 years). The number of patients included per center was
1–48 (median, 11).
Neutropenia was most often due to chemotherapy without
stem cell transplantation. At the time of study enrollment, two-
thirds of the patients had granulocyte counts of !100 cells/mL,
81% had a central venous catheter in place, and 77% were
already hospitalized. All patients had blood samples obtained
for ⭓2 cultures for aerobic and anaerobic organisms before
they began receiving antibiotics. In accordance with interna-
tional guidelines for first-line treatment [14], 91% of the pa-
tients received b-lactams, 66% received aminoglycosides, and
31% received glycopeptides, usually vancomycin.
Data collection. Data that were collected at study enroll-
ment included the following: hematological diagnosis and
status, cause of neutropenia, conditioning regimen for trans-
plantation (when applicable), chemotherapy received during
the month before enrollment, all anti-infective drugs taken ⭐7
days before study enrollment (including drugs used for gut
decontamination, antifungal agents, and growth factors), ad-
ministration of antiulcer and antacid drugs, location during the
week before study enrollment (laminar air-flow room, single
room, ⭓2-bed room, or outpatient status), and site of the
intravenous catheter (central or peripheral). Clinical data in-
cluded information regarding the presence of infection focus and
organ failure. Day 1 was the day of study enrollment. On day
30 after enrollment, the patient’s clinical status was recorded or
the cause of death was determined by the investigator at each
center, and the findings were independently reviewed by 2 of the
principal investigators (C.C., A.B, or G.L.). Decreased suscepti-
150 • CID 2003:36 (15 January) • Cordonnier et al.
bility of streptococci to penicillin and methicillin-resistant staph-
ylococci were defined according to the recommendations of the
Comité Français de l’Antibiogramme [15].
Classification of patients and definitions. For each febrile
neutropenic episode, patients were classified as having fever of
unknown origin, clinically documented infection, or micro-
biologically documented infection, according to the definitions
of the Immunocompromised Host Society [14]. “High-dose
cytarabine” was defined as a dose of ⭓1.5 g/m2. Mucositis was
graded according to the World Health Organization score. Den-
tal status at enrollment was graded as follows: 1, no visible
teeth; 2, teeth without dental lesions or prior work; 3, presence
of crowns, bridges, or implants without lesions; and 4, cavities,
broken teeth, or exposed roots.
Statistical analysis. Prevalences of gram-positive coccal,
streptococcal, and staphylococcal infections were computed by
use of the total number of included patients as the denominator.
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Ninety-five percent CIs were also calculated.
To identify risk factors, the baseline characteristics of patients
who had gram-positive coccal infections (streptococcal and
staphylococcal infections), including those who had concom-
itant gram-negative infections, were compared with the baseline
characteristics of patients who did not have gram-positive coc-
cal infections. ORs with 95% CIs were calculated separately for
each parameter by means of unconditional logistic regression
models. Age (adulthood or childhood) was included in all of
the models. Variables with a P value of ⭐.15 on univariate analy-
sis were then entered into multivariate logistic models [16]. Mul-
tiple 2 ⫻ 2 analyses were used to assess interaction and confusion.
When an interaction was found, a composite variable was built.
The same analyses were done to identify risk factors for strep-
tococcal infection and for staphylococcal infection.
Independent risk factors determined on multivariate analysis
(P ⭐ .05) were used to create a gram-positive risk index (GPRI)
and a streptococcal infection risk index (SRI) by adding the
number of factors for each patient. The GPRI was then com-
pared between patients with and patients without gram-positive
coccal infection, and the SRI was compared between patients
with and patients without streptococcal infection. To determine
the risk of infection, the relative risk (estimated with the OR)
for gram-positive coccal infection and the relative risk for strep-
tococcal infection were calculated according to the number of
factors present at study enrollment. A formal goodness-of-fit
test was used to evaluate the calibration of both models [17],
and the area under the receiver operating characteristic (ROC)
curve was calculated to evaluate the discriminatory power of
the indexes [18]. To assess the predictive value of the GPRI
and SRI, we compared the scores of patients who had gram-
negative infection with the scores of patients who did not have
gram-negative infection; patients who had both gram-positive
and gram-negative infections were excluded. For the SRI, the
Table 1. Characteristics of 513 hospitalized patients with Table 1. (Continued.)
neutropenia and fever who were investigated for assessment
of risk factors for gram-positive coccal infection.

No. (%) No. (%)

Characteristic of patients Characteristic of patients
Hematologic disease Death 28 (5)
Acute leukemia 261 (51) Cause of death
Lymphoproliferative disease 159 (31) Directly related to initial infectious episode 7 (1)
Chronic myeloid leukemia 24 (5) Initial episode as contributing factor 2 (0.4)
Othera 69 (13) Subsequent infection that was independent from
Cause of neutropenia first infection 5 (1)
Chemotherapy 298 (58) Unrelated to initial or subsequent infection 13 (3)
Stem cell transplantation Unknown 1 (0.2)
Autologous 96 (19) a
For example, aplastic anemia.
b
Allogeneic 52 (10) Eleven patients experienced several types of clinical infection.
c
World Health Organization score of ⭓1.
Spontaneous neutropenia 67 (13) d
Cellulitis, folliculitis, or necrotic lesions.
Granulocyte count at study enrollment, cells/mL e
Four patients had both streptococcal and staphylococcal infections, and
!100 353 (69) 6 patients had both gram-positive coccal and gram-negative infections.

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100–499 150 (29)
⭓500 but !500 within 48 h after study
enrollment 10 (2) sidered to be statistically significant. Data were analyzed with
Origin of fever use of BMDP software (University of California, Berkeley).
Unknown 305 (59)
Clinically documented infectionb 40 (8)
Bronchopulmonary focus 20 RESULTS
Mucositisc 10
Causes of fever, prevalence of infection, and mortality rate.
Cutaneous infectiond 11
The causes of fever, the prevalence of infection, and the mor-
Sinusitis 2
Infection with dental focus 8
tality rate are shown in table 1. Of the 168 microbiologically
Microbiologically documented infection 168 (33) documented infections, 147 (87.5%) were documented by
Gram-positive coccal infectione 108 (21) blood culture. The prevalence of streptococcal infection was
Streptococci and enterococci 40 (8) 7.8% (95% CI, 5.5%–10.1%). Of the 24 isolates of oral (viri-
Oral streptococci 24 dans) streptococci isolates (Streptococcus mitis and others), 13
Streptococcus pneumoniae 3 (54%) were susceptible to penicillin, 7 (29%) had decreased
Enterococci 6 susceptibility to penicillin, 1 (4%) was resistant to penicillin,
Other streptococci 7 and 3 had unknown resistance profiles. Four patients had both
Staphylococci 72 (14) streptococcal and staphylococcal infections, and 1 had both
Coagulase-negative staphylococci 52
streptococcal and gram-negative infections. The prevalence of
Staphylococcus aureus 14
staphylococcal infection was 14.0% (95% CI, 11.0%–17.0%).
Nonidentified staphylococci 6
Of the 53 isolates of coagulase-negative staphylococci, suscep-
Gram-negative infectionse 55 (11)
Escherichia coli 30
tibility to methicillin was known for 47; of these, 27 (57%)
Other enterobacteria 11 were resistant to methicillin. Of 14 Staphylococcus aureus iso-
Pseudomonas species 13 lates, methicillin susceptibility status was known for 12; of these
Salmonella species 1 12 isolates, 4 were methicillin resistant. Five patients had both
Other 5 (1) staphylococcal and gram-negative infections. The overall prev-
(continued) alence of gram-positive coccal infection was 21.0% (95% CI,
17.5%–24.6%). Among these patients, 6 also had gram-negative
infections. The overall prevalence of gram-negative infections
scores of patients with and patients without staphylococcal in- was 10.7% (95% CI, 8.0%–13.4%).
fection were also compared; patients who had both strepto- The overall mortality rate during the first 30 days of the
coccal and gram-negative or streptococcal and staphylococcal study was 5%. The mortality rates were 3% for patients with
infections were excluded. fever of unknown origin (9 of 305 patients), 15% for those
Data are presented as mean  SD or as proportions, as ap- with clinically documented infection (6 of 40 patients), and
propriate. All significance tests were 2-tailed. P ⭐ .05 was con- 8% for those with microbiologically documented infection (13

Gram-Positive Infections and Neutropenia • CID 2003:36 (15 January) • 151

 Table 2. Comparisons of patients with and patients without gram-positive coccal infection.

a,b
Percentage of patients with factor Multivariate analysis
Gram-positive No gram-positive P on
Factor (no. of patients coccal infection coccal infection univariate
with missing data) (n p 108) (n p 405) analysisa OR (95 % CI) P
Age !15 years 12 19 .06 1.4 (0.7–2.9) .36
Living condition before day 1c
Home 14 25 — 1
Conventional hospital room 42 41 — 1.5 (0.8–3.0) —
Laminar air-flow room (4) 44 34 .03 1.3 (0.7–2.5) .49
Treatment received before day 1
High-dose cytarabined 33 24 .04 1.7 (1.0–2.8) .05
Growth factors 13 20 .07 0.6 (0.3–1.1) .07
Proton pump inhibitors 20 13 .08 1.7 (1.1–3.8) .05
Antacids (9) 14 8 .08 1.4 (0.7–2.9) .32
Histamine2 antagonists 18 18 .99
Nonabsorbable antifungals 83 72 .04 0.9 (0.6–1.6) .83

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e
Oral colimycin without glycopeptide 34 17 .001 3.0 (1.8–5.0) .0001
f
Trimethoprim-sulfamethoxazole 5 12 .08 0.3 (0.1–1.0) .04
Symptom at day 1
Chills (8) 34 24 .05 1.6 (1.0–2.7) .05
Mucositisg (4) 44 34 .05 1.2 (0.7–1.9) .60
Inflammatory catheter insertion site 7 3 .12 1.9 (0.7–5.3) .21
Diarrhea 21 14 .05 1.5 (0.8–2.6) .22

NOTE. Day 1, day of study enrollment.

a
All analyses were age adjusted.
b
Only factors with P ! .15 on univariate analysis were used for multivariate analysis.
c
Reference class was “home.”
d
More than 1.5 g/m2.
e
Reference class was all other categories—that is, neither colimycin nor glycopeptide, glycopeptide without colimycin, and colimycin
plus glycopeptide.
f
OR reflecting negative association.
g
World Health Organization score of ⭓1.

of 168 patients). Death was not directly related to the initial
episode in any of the patients who had fever of unknown origin,
but it was related to the initial episode in 3 (7.5%) of those
who had clinically documented infection and in 6 (4%) of those
who had microbiologically documented infections (2 patients
with streptococcal infections and 1 patient each infected P.
aeruginosa, Escherichia coli, Klebsiella pneumoniae, and Candida
species). Of the 3 patients whose deaths were attributed to
streptococcal infection alone or were associated with another
contributing factor, 1 was infected with penicillin-susceptible
Streptococcus pneumoniae, 1 was infected with an oral Strep-
tococcus species, and 1 was infected with an untyped strepto-
coccal strain. These 3 patients had all been treated with first-
line b-lactams that are active against streptococci (1 patient
each was treated with piperacillin, ticarcillin plus clavulanic
acid, and cefpirome), and 2 of these patients had also received
vancomycin. None of the patients with staphylococcal infec-
tions died as a result of the initial episode. Of the 14 deaths
that were considered to have been due to an infectious cause,
9 (2%) were related to the initial episode alone (n p 7 ) or were
associated with a contributory cause (n p 2 ). No relationship
was found between the number of positive blood culture results
and the risk of death.
Factors associated with gram-positive coccal infections.
On univariate analysis, previous hospitalization in a laminar
air-flow room, treatment with high-dose cytarabine, oral non-
absorbable antifungals, or oral colimycin without glycopeptide,
and chills, mucositis, and diarrhea at study enrollment were
significantly associated with gram-positive coccal infection (ta-
ble 2). Quinolone use (5% among gram-positive coccal infec-
tions vs. 6% among others), severe neutropenia (71% vs. 69%),
underlying disease, dental status, presence of cutaneous lesions
(7% vs. 8%), and bronchopulmonary focus (6% vs. 10%) did
not influence the occurrence of gram-positive coccal infection.
On multivariate analysis, only administration of high-dose cy-
tarabine, proton pump inhibitors, and colimycin without gly-
copeptides and the presence of chills were independent risk
factors for gram-positive coccal infection. Mucositis was no

152 • CID 2003:36 (15 January) • Cordonnier et al.

longer associated with gram-positive coccal infection because
of its strong relationship with use of proton pump inhibitors
and colimycin use alone (P p .04 and P p .001, respectively).
Trimethoprim-sulfamethoxazole (TMP-SMZ) use appeared to
be a significant protective factor.
On univariate analysis, use of high-dose cytarabine, use of
colimycin without glycopeptides, and diarrhea at study enroll-
ment were significantly associated with streptococcal infection,
and use of colimycin without glycopeptides and inflammation
of the catheter site were significantly associated with staphylo-
coccal infection (table 3). On multivariate analysis, the indepen-
dent risk factors for streptococcal infection were use of high-
dose cytarabine, use of colimycin without glycopeptides, use of
nonabsorbable antifungals, and diarrhea; for staphylococcal in-
fection, only administration of colimycin without glycopeptides
was found to be significant (table 4). There was a trend for TMP-
SMZ use to protect from staphylococcal infection.
GPRI. Each of the 4 independent risk factors for gram-
gram-positive and gram-negative infections, according to the
GPRI. The risk for gram-positive infection increased 3.0, 3.9,
7.0, and 17.5 times when the GPRI was 1, 2, 3, and 4, respec-
tively. For each additional point on the GPRI, the OR was 1.85
(95% CI, 1.43–2.38; P ! 10⫺4) for gram-positive infection and
1.14 (95% CI, 0.81–1.61; P p .46) for gram-negative infection.
The observed (20.5%) and expected (21.2%) numbers of
gram-positive infections were similar; the high P value deter-
mined with use of the goodness-of-fit test indicated good agree-
ment (calibration) (P 1 .50 ). The area under the ROC curve
was 69%  16%.
SRI. Each of the 4 independent risk factors for strepto-
coccal infection was assigned a value of 1. The prevalence of
and relative risks for streptococcal, gram-negative, and staph-
ylococcal infections according to the SRI are shown in table 6.
The risk for streptococcal infection increased 2.9, 13.2, and
20.7 times when the SRI was 1, 2, and ⭓3 respectively. For
each additional point on the SRI, the OR was 2.44 (95% CI,

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positive coccal infection was assigned a value of 1 so that the 1.69–3.52; P p 10⫺4) for streptococcal infection, 0.86 (95% CI,
GPRI ranged from 0 (no factor present) to 4 (all factors pre- 0.63–1.19; P p .37) for gram-negative infection, and 1.27 (95%
sent). Table 5 shows the prevalence of and the relative risks for CI, 0.96–1.69; P p .09) for staphylococcal infection. The ob-

Table 3. Comparisons of patients with streptococcal infection, patients with staphylococcal infection, and control
subjects, on univariate analyses.

a
Percentage of patients with factor P
Streptococcus- Staphylococcus- Streptococcus- Staphylococcus-
infected infected Control infected infected
patients patients subjects patients vs. patients vs.
Factor (n p 40) (n p 72) (n p 405) control subjects control subjects
Age !15 years 10 13 19 .12 .14
Prior stay in laminar
air-flow room 44 44 34 .20 .13
Therapy received
High-dose cytarabineb 42 28 24 .02 .44
Growth factor 14 12 20 .32 .08
Proton pump inhibitors 22 16 13 .16 .54
Antacids 17 13 8 .12 .18
Nonabsorbable antifungals 94 78 72 .06 .57
Colimycin without
glycopeptide 39 31 17 .001 .005
Trimethoprim-sulfamethoxazole 6 4 12 .47 .10
Symptom
Granulocyte count of
!100 cells/mL 83 62 69 .06 .25
Chills 33 34 24 .29 .12
Mucositisc 44 44 34 .22 .11
Inflammatory catheter
insertion site 3 9 3 .90 .04
Diarrhea 31 16 14 .01 .58

NOTE. Control subjects were persons who had neither streptococcal nor staphylococcal infection.
a
All analyses were age adjusted; only factors with P ! .15 on univariate analysis were used in multivariate analyses.
b
More than 11.5 g/m2.
c
World Health Organization score of ⭓1.

Gram-Positive Infections and Neutropenia • CID 2003:36 (15 January) • 153

 Table 4. Comparisons of patients with streptococcal infection, patients with
staphylococcal infection, and control subjects, on multivariate analysis.

Streptococcus- Staphylococcus-
infected patients infected patients
vs. control subjects vs. control subjects
Factor OR (95% CI)a P OR (95% CI)a P
Prior stay in a laminar
air-flow room 1.2 (0.6–2.5) .35 1.4 (0.8–2.4) .14
Therapy received
High-dose cytarabineb 2.2 (1.1–4.6) .04 — —
c
Growth factor — — 0.5 (0.2–1.1) .08
Antacids 1.6 (0.6–4.4) .40 1.4 (0.6–3.3) .20
Nonabsorbable antifungals 4.4 (1.0–19.1) .02 — —
Colimycin without glycopeptide 2.8 (1.3–6.0) .01 2.6 (1.4–4.7) .01
Trimethoprim-sulfamethoxazole — — 0.3 (0.1–1.1)c .06
Symptom
Granulocyte count of
!100 cells/mL 1.4 (0.5–3.6) .48 — —

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Chills — — 1.6 (0.9–2.8) .11
Mucositisd — — 1.3 (0.7–2.4) .14
Inflammatory catheter
insertion site — — 2.7 (0.9–7.6) .08
Diarrhea 2.5 (1.1–5.5) .03 — —
a
Multivariate ORs were age adjusted; only factors with P ! .15 on univariate analysis were
used in multivariate analyses.
b
More than 1.5 g/m2.
c
OR reflecting negative association.
d
World Health Organization score of ⭓1.

served (7.8%) and expected (7.2%) numbers of streptococcal
infections (P 1 .40) were similar. The area under the ROC curve
was 76%  15%.
DISCUSSION
This prospective epidemiologic study of 513 febrile neutropenic
patients allowed us to establish predictive scores to optimize
first-line treatment for febrile neutropenic patients with gram-
positive coccal and streptococcal infections. The strengths of
this study included prospective collection of data, unbiased
patient recruitment and independent review, classification of
patients according to outcome measures, and accurate mea-
surement of risk factors. Our study population was represen-
tative of patients with febrile neutropenia hospitalized in French
hematology centers, because 95% of the centers in France par-
ticipated in the study. Furthermore, 96% of the consecutive
patients were included in the analysis, which was largely because
of the convenient 2-month study period and 1-month follow-
up period.
In our study, the prevalence of gram-positive coccal infection
(21%) was similar to that reported in prospective therapeutic
trials [19–21], and the prevalence of streptococcal infection
(7.8%) was in the lower range compared with other studies.
Bacteremia due to viridans streptococci was detected in 4.7%
of our patients and in up to 31% of patients described in other
series [12]. Our overall mortality rate of 5% was consistent
with that noted in antibiotic trials that involve patients with
febrile neutropenia, and our mortality rate for patients infected
with coagulase-negative staphylococci, which approached 0%,
was similar to that reported in most other series [8, 19, 22,
23]. The mortality rate associated with a-hemolytic strepto-
coccal bacteremia is 4%–18% [1, 2, 12, 13, 24–26], and, al-
though low mortality rates have been reported [27], it is gen-
erally recognized that streptococcal bacteremia in neutropenic
patients may progress rapidly to septic shock and acute res-
piratory distress syndrome, which require appropriate man-
agement to avoid irreversible septic complications [2, 5, 28,
29]. Previous retrospective studies of patients with bacteremia
due to viridans streptococci have identified profound neutro-
penia, use of high-dose cytarabine therapy, mucositis, and use
of histamine2 antagonists, antacids, quinolones, and TMP-SMZ
as risk factors [1, 2, 3, 5, 8, 12, 13]. However, these findings
have never been prospectively validated.
Our prospective study revealed that receipt of high-dose cy-
tarabine, proton pump inhibitors, and colimycin without gly-
copeptides and presence of chills were independent risk factors
for gram-positive coccal infections. Independent risk factors

154 • CID 2003:36 (15 January) • Cordonnier et al.

 Table 5. Prevalences and relative risks of gram-positive coccal and
gram-negative infections, according to gram-positive risk index (GPRI).

Gram-positive Gram-negative
coccal infection infection
No. of Infection Infection
GPRI patients rate, % OR (95% CI) rate, % OR (95% CI)
a
0 195 10.3 1 8.3 1
b
1 206 25.2 3.0 (1.7–5.2) 9.4 1.1 (0.6–2.3)
2 98 30.6 3.9 (2.1–7.3) 14.3 1.8 (0.8–3.9)
3 11 36.4 7.0 (1.3–18.6) 0 —
4 3 66.7 17.5 (1.5–203.0) 0 —

NOTE. The GPRI represents the no. of parameters among 4 that emerged from
multivariate analysis comparing patients with and patients without gram-positive coccal
infection for which P ⭐ .05 (receipt of high-dose cytarabine [11.5 g/m2], proton pump
inhibitors, or colimycin without glycopeptide and presence of chills). A weight of 1 was
assigned to each independent parameter.
a
Two patients with both gram-positive coccal and gram-negative infections were
excluded from analysis that compared patients with and patients without gram-negative
infection.

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b
Four patients with both gram-positive coccal and gram-negative infections were
excluded from analysis that compared patients with and patients without gram-negative
infection.

for streptococcal infections were use of high-dose cytarabine,
colimycin without glycopeptides, and nonabsorbable anti-
fungals and the occurrence of diarrhea. Although a retrospec-
tive study suggested that high-dose cytarabine therapy causes
gut damage and favors the translocation of streptococci [13],
no significant association between receipt of high-dose cytar-
abine and mucositis of any grade was observed in our series.
On our multivariate analysis, oropharyngeal mucositis, which
has previously been identified as a risk factor for streptococcal
infection [2, 3, 27], was not associated with gram-positive coc-
cal or streptococcal infection. This difference may have been
due to the high incidence of mucositis (34%) in our control
population. The low percentage of patients receiving quino-
lones in our series may have precluded us from showing the
impact of these antibiotics on the occurrence of gram-positive
coccal or streptococcal infection, as has been reported elsewhere
[1, 2]. Although severe neutropenia has been significantly as-
sociated with infection due to viridans streptococci by means
of comparison with control subjects who had other gram-
positive infections [2], we observed only a trend on univariate
analysis in our series. However, the high rate of severe neutro-
penia (69%) in our control population—including gram-

Table 6. Prevalences and relative risks of streptococcal, gram-negative, and staphylococcal in-
fections, according to streptococcal infection risk index (SRI).

Streptococcal infection Gram-negative infection Staphylococcal infection

No. of Infection Infection Infection
SRI patients rate, % OR (95% CI) rate, % OR (95% CI) rate, % OR (95% CI)
a
0 86 1.2 1 8.1 1 4.7 1
1 212b 3.3 2.9 (0.3–24.1) 13.7 1.8 (0.8–4.3) 15.6 3.7 (1.3–10.9)
2 164a 13.4 13.2 (1.7–100.0) 9.1 1.1 (0.4–2.9) 14.7 3.5 (1.2–10.5)
c
3 45 20.0 21.3 (2.6–174.8) 6.6 0.8 (0.2–3.3) 11.6 2.7 (0.7–10.5)
4 6 16.7 17.0 (0.9–313.5) 0 — 33.3 10.0 (1.4–73.0)
≥3 51c 19.6 20.7 (2.6–168.4) 5.9 0.7 (0.2–2.9) 14.3 3.4 (0.9–12.2)

NOTE. The SRI represents the no. of parameters among 4 that emerged from multivariate analysis comparing patients
with and patients without streptococcal infection for which P ⭐ .05 (receipt of high-dose cytarabine [11.5 g/m2], colimycin
without glycopeptide, or nonabsorbable antifungals and presence of diarrhea). A weight of 1 was assigned to each
independent parameter.
a
One patient with both streptococcal and staphylococcal infections was excluded from analysis that compared patients
with and patients without staphylococcal infection.
b
One patient with both streptococcal and gram-negative infections was excluded from analysis that compared patients
with and patients without gram-negative infection.
c
Two patients with both streptococcal and staphylococcal infections was excluded from analysis that compared patients
with and patients without staphylococcal infection.

Gram-Positive Infections and Neutropenia • CID 2003:36 (15 January) • 155

negative bacteremia, which is usually associated with severe
neutropenia [30]—compared with the 20% rate in the control
population described by Elting et al. [2] may have precluded
our ability to show any significant relationship between severe
neutropenia and streptococcal infection. In our study, although
the presence of chills at the time of study enrollment was sig-
nificantly associated with gram-positive coccal infection (table
2), this was not the case when streptococcal infections and
staphylococcal infections were analyzed separately. The most
likely explanation for this difference is the lower power of our
series of patients with streptococcal infection (table 3) com-
pared with that in the study of Elting et al. [2].
Gram-positive coccal infections may have a gut origin. Such
drugs as histamine2 antagonists, antacids, and sucralfate select
patients with gut lesions and may favor streptococcal bacter-
emia [2] by increasing the gastric pH and so favor microbial
growth and translocation from the gut. In our experience, the
use of antiulcer drugs, especially proton pump inhibitors, was
an independent risk factor for gram-positive coccal infection
but was not significant for streptococcal infection, possibly be-
cause of the lower power of this series.
Gut decontamination with use of nonabsorbable antibiotics
(mainly colimycin without glycopeptides) was a risk factor for
both streptococcal and staphylococcal infections in our series.
Because of the low number of enterococcal infections (n p 6),
this effect is not explained by the effect of colimycin on en-
terococci overgrowth in the gut, as illustrated by animal models
[31]. Although quinolone prophylaxis is seldom used in France,
most patients receiving chemotherapy for acute leukemia and
almost all allogeneic stem cell transplant recipients are given
nonabsorbable antibiotics (usually colimycin and aminoglyco-
sides) during the neutropenic phase. Consequently, approxi-
mately one-half of the patients in our study had received non-
absorbable antibiotics. Previous studies from countries in which
gut decontamination is not performed could not identify this
risk factor for gram-positive coccal infections [1–3].
Similarly, use of nonabsorbable antifungals, namely polyenes,
was associated with an increased risk of streptococcal infection
in our study. Several studies have reported bacteremia to be
associated with antifungal prophylaxis, and a recent large study
showed a relationship between use of both absorbable and non-
absorbable antifungals and bacteremia [30, 32–35]. Taken to-
gether, these findings argue in favor of the role of oral polyenes
in gram-positive coccal growth. In contrast with a previous
report, which showed that TMP-SMZ use increased the risk of
streptococcal infection [2], we found that TMP-SMZ was as-
sociated with a decreased incidence of gram-positive coccal
infection, but this was mainly the result of a decreased risk for
staphylococcal infection.
Because b-lactams are widely used for empirical therapy for
156 • CID 2003:36 (15 January) • Cordonnier et al.
neutropenic patients, in line with international recommenda-
tions, the presence of gram-negative infection may have limited
impact on the choice of initial treatment. More accurate iden-
tification of specific risk factors for streptococci could facilitate
evaluation of the benefit of glycopeptides or other anti–gram-
positive drugs in first-line treatment compared with results of
previous trials [22, 23, 36]. As determined with our GPRI, the
risk for gram-positive coccal infection increased 3-fold for pa-
tients with 1 risk factor at the onset of febrile neutropenia, and
it increased 17.5-fold for patients with all 4 risk factors. Sim-
ilarly, the relative risk for streptococcal infection increased from
2.9 to 20.7 according to the number of risk factors present.
Because the GPRI was not relevant for gram-negative infection,
and because the SRI was moderately relevant for staphylococcal
infection, these 2 indexes should allow reasonably accurate pre-
diction of the occurrence of gram-positive coccal infections in
general and of streptococcal infections in particular. We are
prospectively validating these 2 scores among a new cohort of
Downloaded from http://cid.oxfordjournals.org/ by guest on April 7, 2016
neutropenic patients. Use of these indexes could improve the
treatment of neutropenic patients and help investigators design
antibacterial trials to specifically address the question of the
best strategy to manage gram-positive coccal infections and
streptococcal infections in this population.
INVESTIGATORS AND PARTICIPATING
CENTERS
Investigators and participating centers (all of which are in
France) are as follows: A. Auvrignon, Hôpital Trousseau, Paris;
Bendahmane, Institut Gustave Roussy, Villejuif; C. Bergeron,
Hôpital Sud, Rennes; C. Berthou, Centre Hospitalo-Universi-
taire (CHU) Augustin Morvan, Brest; M. Boasson, Centre Hos-
pitalier Regional Universitaire (CHRU), Angers; O. Bouscary,
Hôpital Cochin, Paris; P. Chastagner, Hôpital de Brabois, Van-
doeuvre Les Nancy; L. Collet, Institut Paoli Calmettes, Mar-
seille; P. Cony-Makhoul, Hôpital du Haut-Leveque, Pessac; J.
Beaune, Hôpital Henri Mondor, Créteil; Th. De Revel, Hôpital
du Val de Grâce, Paris; M. Delain, CHRU Bretonneau, Tours;
M. Macro, CHU, Caen; B. Desablens, CHRU, Amiens; M. C.
Escande, Institut Curie, Paris; N. Fegueux, CHR Lapeyronie,
Montpellier; B. Girier, Hôpital Saint-Louis, Paris; H. Guy, Hôp-
ital du Bocage, Dijon; D. Guyotat, Hôpital Nord, Saint-Etienne;
Ph. Henon, Hôpital du Has, Mulhouse; R. Herbrecht and I.
Zix-Kieffer, Hôpital de Hautepierre, Strasbourg; M. Hunault,
Hôtel Dieu, Paris; H. Laurichesse, Hôpital de Clermont-
Ferrand; O. Lortholary, Hôpital Avicennes, Bobigny; D. N’Daw,
Hôpital Paul Brousse, Villejuif; G. Michel, Hôpital de La Ti-
mone, Marseille; N. Parquet, Hôpital Saint-Louis, Paris; A. M.
Peny, Centre Francois Baclesse, Caen; Y. Perel, Hôpital Pelle-
grin, Bordeaux; C. Rose, Hôpital Huriez, Lille; L. Sutton, Pitié
Salpétriere, Paris; M. Tiab, Hôpital de l’Hôtel Dieu, Nantes; A.
Buzyn-Lévy, Hôpital Necker, Paris; P. Vic, Hôpital Huriez, Lille.
Acknowledgements
We thank Jean-Pierre Ghanassia (Agence Medicom, Paris)
and Martine Rozenbaum (Laboratoires Hoescht-Marion-Rous-
sel, Paris), for help in design and management of the study,
and Isabel Cunningham (Beth Israel Hospital, New York), for
help in finalization of the manuscript.
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158 • CID 2003:36 (15 January) • Cordonnier et al.