MAJOR ARTICLE
Streptococcus pneumoniae Bacteremia:
Duration of Previous Antibiotic Use
and Association with Penicillin Resistance
Jörg J. Ruhe and Rodrigo Hasbun
Department of Medicine, Infectious Diseases Section, Tulane University School of Medicine, New Orleans, Louisiana
Previous antibiotic exposure is one of the most important predictors for acquisition of penicillin-nonsusceptible
Streptococcus pneumoniae (PNSP) infection. To determine the impact of duration of exposure to different
antibiotic classes, a study of 303 patients with S. pneumoniae bacteremia was undertaken. Ninety-eight cases
of bacteremia (32%) were caused by a penicillin-nonsusceptible isolate. Bivariate analysis revealed that use of
b-lactams, sulfonamides, and macrolides within the last 1 and 6 months before presentation was associated
with PNSP bacteremia (P ! .05 ). Fluoroquinolone consumption was not related to bacteremia due to PNSP
(P 1 .1). Both short- and long-term b-lactam use significantly increased the risk for PNSP infection. Logistic
regression analysis revealed that use of b-lactams and macrolides in the 6 months before the first positive
blood culture result were independent risk factors (P ! .05 ). Risk for acquiring PNSP infection depends on
both the class of antibiotic to which the patient was exposed and the duration of therapy.
An alarming worldwide increase in the rates of penicillin-nonsusceptible Streptococcus pneumoniae (PNSP)
infection has been observed in the past decade [1, 2].
Previous antibiotic exposure has been found to be one
of the most important risk factors for PNSP infection
in several studies [3]. Associations between use of different antibiotics (b-lactams, macrolides, and sulfonamides) and PNSP carriage or infection have been demonstrated in case-control studies involving children and
in cross-sectional studies [4–7]. Analytical studies of
risk factors for infection with PNSP in adult populations primarily report on previous b-lactam use or have
small numbers of resistant isolates [8–10]. The association of individual antibiotic classes and duration of
treatment with PNSP infections has not been studied
Received 10 September 2002; accepted 22 January 2003; electronically
published 22 April 2003.
Reprints or correspondence: Dr. Rodrigo Hasbun, Infectious Diseases Section,
Tulane University School of Medicine, 1430 Tulane Ave., SL-87, New Orleans, LA
70112 ([email protected]).
Clinical Infectious Diseases 2003; 36:1132–8
2003 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2003/3609-0006$15.00
1132 • CID 2003:36 (1 May) • Ruhe and Hasbun
in detail in this patient population [3]. Therefore, we
performed this study to evaluate the impact of the
length of treatment with all major antibiotic classes on
the risk of acquiring PNSP bacteremia in a mostly adult
population.
PATIENTS AND METHODS
Setting. A retrospective cohort study of 303 pediatric
and adult patients with S. pneumoniae bacteremia was
conducted at 4 tertiary care hospitals in New Orleans,
Louisiana, from January 1996 through October 2001.
Tulane University Hospital and Clinic and the New
Orleans Veterans Affairs Medical Center mainly serve
the insured and veteran populations, respectively. Charity Hospital and University Hospital of the Medical
Center of Louisiana at New Orleans provide medical
care to the urban indigent population.
Study design and definition of terms. S. pneumoniae bacteremia was defined as isolation of the organism from ⭓1 set of blood cultures for patients with
clinical symptoms consistent with infection or sepsis
[11]. The “zero time” of the study was defined as the
date of the first positive blood culture result. All blood cultures
positive within 14 days after zero time were counted as 1 bacteremic episode. Any subsequent episodes in the same patient
were excluded.
“Nosocomial acquisition” was defined as bacteremia first occurring 148 h after admission. “Treatment course” was defined
as the generally recommended number of antibiotic treatment
days for a certain type of infection in a given population (7–14
days). An application of an antibiotic was considered to be
“short-term” if the treatment duration was shorter than a treatment course (i.e., !5 days for azithromycin or !7 days for other
antibiotics). Patients receiving long-term antibiotic prophylaxis
during the study period were those who received ⭓2 treatment
courses, although the daily doses might have differed from
those received by the treatment group.
Blood cultures positive for S. pneumoniae were identified by
review of the clinical microbiology records. We used a standardized extraction form to collect information on drug class
and treatment duration for any antibiotic prescribed within the
previous 1 and 6 months before zero time by review of all
inpatient, emergency department, and outpatient medical records at the 4 hospitals. Furthermore, we analyzed all computerized inpatient and outpatient pharmacy records at all hospitals. Antibiotics were classified as penicillin or penicillin
derivatives, cephalosporins, carbapenems, aztreonam, sulfonamides, macrolides, vancomycin, rifampin, aminoglycosides,
clindamycin, fluoroquinolones, and tetracyclines. Antibiotics
were also classified as b-lactams (penicillin or penicillin derivatives, cephalosporins, carbapenems, and aztreonam). Singledose applications were also considered significant and were
recorded as 1 day of treatment. We excluded patients if any
existing medical or pharmacy records for the 6 months before
zero time were unavailable. The study was approved by the
Tulane University Committee on Use of Human Subjects.
Microbiological methods.
S. pneumoniae was isolated,
identified, and tested for penicillin sensitivity according to the
guidelines of the NCCLS [12]. Isolates were screened for penicillin resistance by use of the oxacillin disk test and classified
as penicillin susceptible (MIC, !0.12 mg/mL), intermediate-level
penicillin nonsusceptible (MIC, 0.12–1 mg/mL), or high-level
penicillin nonsusceptible (MIC, ⭓2 mg/mL) by use of the Etest
methodology (AB Biodisk).
Statistical analysis. The outcome variable was PNSP bacteremia (MIC, ⭓0.12 mg/mL). Bivariate analysis was conducted
by Pearson’s x2 test or Fisher’s exact test to identify antibiotic
classes significantly associated with the outcome and to test for
associations between consumption of different antibiotic classes
(P ! .05). The Wilcoxon rank sum test was used to detect differences in patients’ median age and durations of antibiotic
treatment. Multivariate analysis was performed with forward
and backward stepwise logistic regression. All statistical analyses
were conducted with SPSS for Windows software, version 11.0
(SPSS).
RESULTS
We identified a total of 447 episodes of S. pneumoniae bacteremia at the 4 hospitals from January 1996 through October
2001. A total of 144 bacteremic episodes were excluded for the
following reasons: the patient’s medical records were incomplete (n p 121), susceptibility of the isolate to penicillin was
not determined (n p 17), and the same patient had 11 episode
of pneumococcal bacteremia during the study period (n p 6).
A total of 303 patients with S. pneumoniae bacteremia were
included; 204 patients (67%) were enrolled from the Medical
Center of Louisiana, 59 (19%) were enrolled from Tulane University Hospital and Clinic, and 40 (13%) were enrolled from
the Veterans Affairs Medical Center.
The median age of the total cohort was 40 years; 76 patients
(25%) were !6 years old, and only 6 patients (2%) were aged
6–17 years. The pneumococcal isolate was penicillin susceptible
(penicillin-susceptible S. pneumoniae [PSSP]) in 205 bacteremic
episodes (68%), and it was penicillin nonsusceptible in 98 bacteremic episodes (32%). Sixty-five isolates (21%) were intermediate-level penicillin nonsusceptible, and 33 (11%) were
high-level penicillin nonsusceptible. Of 121 excluded patients
for whom penicillin susceptibility tests were performed, 80
(66%) were infected with a penicillin-susceptible isolate, and
41 (34%) were infected with a penicillin-nonsusceptible isolate
(P 1 .2). Table 1 compares baseline characteristics between patients with PNSP and PSSP bacteremia. No significant differences were found regarding age, sex, race, HIV infection/AIDS
status, primary source of infection, and type of acquisition
(P 1 .05). Patients with PNSP bacteremia had a higher Charlson
comorbidity score than did patients with PSSP bacteremia [13].
Previous antibiotic intake as risk factor for PNSP bacteremia. Previous antibiotic use within the last 1 and 6 months
before zero time is shown in table 2. Other antimicrobials
prescribed within 6 months before zero time were as follows:
vancomycin (n p 6), aminoglycosides (n p 5 ), tetracyclines
(n p 5), rifampin (n p 3), and clindamycin (n p 3). Separate
analyses were not performed for these antibiotics because of
the small sample size. A total of 155 patients (51%) received
antibiotics during the 6 months before zero time: 118 (39%)
received antibiotics for therapeutic indications as ⭓1 treatment
course, 17 (6%) received them as long-term prophylaxis only,
and 20 (7%) received them for both treatment and prophylactic
indications.
Use of the following antibiotics was significantly associated
with PNSP bacteremia (P ! .05): penicillin or penicillin derivatives, any b-lactam, sulfonamides, and macrolides within the
1 and 6 months before zero time, and cephalosporins within
S. pneumoniae Bacteremia • CID 2003:36 (1 May) • 1133
Table 1. Associations of baseline variables with penicillin-nonsusceptible Streptococcus pneumoniae (PNSP) bacteremia.
Patients
with PNSP
bacteremia
(n p 98)
Characteristic
Patients
with PSSP
bacteremia
(n p 205)
OR (95% CI)
P
—
.103
Age, median years
38
40
Age of !6 years
31 (32)
45 (22)
1.65 (0.96–2.82)
.069
Male sex
62 (63)
129 (63)
1.01 (0.62–1.67)
.954
African American race
73 (74)
148 (72)
1.12 (0.65–1.94)
.674
Tobacco use
40 (41)
98 (48)
0.75 (0.46–1.23)
.253
Injection drug abuse
11 (11)
20 (10)
1.17 (0.54–2.55)
.693
HIV infection/AIDS
26 (27)
40 (20)
1.49 (0.85–2.62)
.166
Charlson comorbidity score of 11
47 (48)
73 (36)
1.67 (1.02–2.72)
.040
74 (76)
168 (82)
0.68 (0.38–1.22)
.191
6 (6)
5 (2)
2.61 (0.78–8.77)
.109
a
Lungs as source of infection
Nosocomially acquired infection
NOTE. Data are no. (%) of patients, unless otherwise indicated. PSSP, penicillin-susceptible S.
pneumoniae.
a
Other sources: otitis (n p 26 ), unknown (n p 26 ), meningitis (n p 4 ), skin (n p 3 ), and septic arthritis
(n p 2).
the 6 months before zero time. Fluoroquinolone exposure
within the 1 and 6 months before zero time was not associated
with PNSP bacteremia (P p .34 and P p .18, respectively).
We conducted bivariate analyses to identify associations between the uses of different antibiotic classes within the previous
6 months (table 3). Use of any antibiotic of the b-lactam,
sulfonamide, macrolide, or fluoroquinolone class was related
to use of any drug of the other 3 classes (P ! .05). Subgroup
analysis of all patients aged ⭓6 years (n p 227 ) revealed that
risk factors were identical to those for the total cohort—that
is, use of b-lactams (OR, 6.45; 95% CI, 4.42–12.19; P ! .001),
sulfonamides (OR, 2.60; 95% CI, 1.20–5.62; P p .013), and
macrolides (OR, 7.08; 95% CI, 3.20–15.65; P ! .001) during the
6 months before zero time. A Charlson comorbidity score of
11 (OR, 2.70; 95% CI, 1.48–4.91; P p .001) and HIV infection/
AIDS (OR, 1.91; 95% CI, 1.03–3.53; P p .037) were also associated with the outcome. Fluoroquinolone use was not related
to the outcome (P 1 .05).
Duration of previous antibiotic use. Table 4 shows the
median duration of total treatment days within the 6 months
before zero time with b-lactams, sulfonamides, and macrolides
in patients with penicillin-susceptible S. pneumoniae and PNSP
bacteremia. Patients with PNSP bacteremia had significantly
longer total exposure to b-lactams (15 vs. 10 days; P p .001).
In contrast, total duration of therapy with sulfonamides or
macrolides did not differ significantly between both groups
(P p .199 and P p .290, respectively).
The risk for PNSP bacteremia among patients with either 1
or ⭓2 treatment courses compared with patients without previous antibiotic use is shown in table 5. Receipt of 1 or ⭓2
courses of b-lactams or macrolides and receipt of ⭓2 courses
1134 • CID 2003:36 (1 May) • Ruhe and Hasbun
of sulfonamides were associated with PNSP bacteremia (P !
.001). The odds for ⭓2 courses of b-lactams (OR, 34.36) were
significantly higher than the odds for only 1 course (OR, 3.95;
P ! .001). Differences between the odds for ⭓2 versus only 1
treatment course were of borderline significance or were nonsignificant for the sulfonamide and macrolide groups (P p
.041 and P p .172, respectively).
Ten patients (3%) received b-lactams (median duration of
therapy, 2 days; range, 1–5 days) or macrolides (median duration of therapy, 2 days; range, 1–4 days) as short-term applications. These patients did not receive any additional antibiotics within the study period. Six patients received first- or
second-generation cephalosporins as short-term applications.
The indication in most patients was perioperative surgical prophylaxis. When compared with 148 patients (49%) who did
not receive previous antibiotics, this small subgroup had a significantly higher likelihood of developing bacteremia due to a
penicillin-nonsusceptible isolate (OR, 5.73; 95% CI, 1.53–21.43;
P p .014).
Regression analysis. We then performed logistic regression
analysis to determine antibiotic classes that were independently
related to penicillin nonsusceptibility. Factors associated with
the outcome with P ! .20 in unadjusted models were considered
as candidates for the final model. Interaction terms, including
b-lactams, sulfonamides, and macrolides, were also included in
the model. Independent predictors were b-lactam use in the 6
months before zero time (adjusted OR, 5.61; 95% CI, 3.27–9.64;
P ! .001) and macrolide use in the 6 months before zero time
(adjusted OR, 2.83; 95% CI, 1.39–5.77; P p .004). Logistic regression analysis of patients aged ⭓6 years revealed identical
independent risk factors for this subgroup—that is, use of b-
Table 2. Association of previous antibiotic use with penicillin-nonsusceptible Streptococcus pneumoniae (PNSP) bacteremia.
No. (%) of patients
With PNSP
bacteremia
(n p 98)
With PSSP
bacteremia
(n p 205)
OR (95% CI)
P
76 (78)
79 (39)
5.51 (3.17–9.57)
!.001
Previous 1 month
26 (27)
20 (10)
3.34 (1.76–6.36)
!.001
Previous 6 months
65 (66)
48 (23)
6.44 (3.80–10.94)
!.001
Antibiotic use
Any in the previous 6 months
b-Lactams
Penicillin or penicillin derivatives
Previous 1 month
22 (22)
12 (6)
4.66 (2.20–9.87)
!.001
Previous 6 months
52 (53)
32 (16)
6.11 (3.54–10.57)
!.001
Cephalosporins
Previous 1 month
8 (8)
9 (4)
1.94 (0.72–5.18)
Previous 6 months
39 (40)
22 (11)
5.50 (3.02–10.01)
.182
Previous 1 month
19 (19)
17 (8)
2.66 (1.31–5.38)
.005
Previous 6 months
22 (22)
26 (13)
1.99 (1.06–3.73)
.029
!.001
Sulfonamides
Macrolides
Previous 1 month
14 (14)
10 (5)
3.25 (1.39–7.61)
.005
Previous 6 months
28 (29)
18 (9)
4.16 (2.16–7.98)
!.001
Fluoroquinolones
Previous 1 month
5 (5)
6 (3)
1.78 (0.53–5.99)
.343
Previous 6 months
13 (13)
17 (8)
1.69 (0.79–3.64)
.175
NOTE.
PSSP, penicillin-susceptible S. pneumoniae.
lactams (adjusted OR, 5.16; 95% CI, 2.65–10.05; P ! .001) and
macrolides (adjusted OR, 4.97; 95% CI, 2.12–11.67; P ! .001)
during the 6 months before zero time.
DISCUSSION
Various factors, such as young age, previous hospitalization,
HIV infection, and previous antibiotic use, have been reported
to be associated with increased risk of PNSP colonization or
infection [3]. Previous studies on the importance of previous
antibiotic use were limited to b-lactams or to the pediatric
population, or they were of cross-sectional design. To our
knowledge, we have performed the first study involving a combined pediatric and adult cohort to have investigated the association between the duration of exposure to all major antibiotic classes and the subsequent occurrence of invasive PNSP
infections. On bivariate analyses, use of penicillin and penicillin
derivatives, cephalosporins, all b-lactams combined, macrolides, and sulfonamides in the 6 months before zero time were
all highly significantly associated with PNSP bacteremia (P ⭐
.05). Separate analyses of antibiotic consumption within the
last 1 month before zero time also showed a significant correlation between the outcome and the use of penicillin, blactams, macrolides, and sulfonamides (P ! .01). The associa-
tion of previous antibiotic exposure within the last 1- and
6-month periods with PNSP infection could be explained by
prolonged carriage of nonsusceptible pneumococci selected by
previous antibiotic use [14].
In contrast, fluoroquinolone use in the last 1 and 6 months
before zero time was not a significant predictor (P p .34 and
P p .18, respectively). These data suggest a potential benefit of
responsible fluoroquinolone use in the further prevention of
penicillin resistance in S. pneumoniae. However, recent reports
describing increasing resistance to fluoroquinolones and subsequent associated treatment failures warrant their cautious use
[15, 16].
On multivariate analyses, previous b-lactam use and previous
macrolide use within the 6 months before zero time were both
independently associated with the outcome of PNSP bacteremia. These results were confirmed by separate analysis of patients aged ⭓6 years. Unlike the findings of 2 large crosssectional studies [6, 7], in our study, b-lactam use (adjusted
OR, 5.61) was more strongly correlated with penicillin resistance than was macrolide use (adjusted OR, 2.83). Previous use
of sulfonamide, which was recently reported to be the only
antibiotic associated with PNSP carriage in children in one
Swedish study, was not an independent factor in our model
[17].
S. pneumoniae Bacteremia • CID 2003:36 (1 May) • 1135
Table 3. Associations of use of different antibiotic classes within the 6 months before
diagnosis of pneumococcal bacteremia.
No. (%) of patients
Antibiotic
b-Lactams (n p 113)
Sulfonamides (n p 48)
Macrolides (n p 46)
Fluoroquinolones (n p 30)
a
b
b-Lactams
(n p 113)
Sulfonamides
(n p 48)
—
27 (56)
30 (65)
—
a
a
27 (24)
a
30 (27)
b
17 (15)
Macrolides
(n p 46)
a
17 (57)
24 (52)
a
9 (30)
—
10 (33)
a
24 (50)
b
9 (19)
Fluoroquinolones
(n p 30)
b
b
a
b
10 (22)
—
P ! .01.
.01 ⭐ P ! .05.
We were interested in determining whether repeated exposure to an antibiotic correlated with a higher likelihood of PNSP
bacteremia. For this purpose, we divided patients into those
who received one antibiotic course and those who received ⭓2
courses over the 6-month period. Patients who received ⭓2 blactam treatment courses in the previous 6 months had a higher
risk of subsequent PNSP bacteremia compared with patients
who received only 1 course (P ! .001). Differences in the number of courses for the sulfonamide and macrolide groups (1
vs. ⭓2 courses) were of borderline significance or were nonsignificant (P p .04 and P p .17, respectively). Similarly, the
total median duration of previous treatment with b-lactams
was significantly higher (15 days) in the penicillin-nonsusceptible group compared with the penicillin-susceptible group (10
days). No significant differences were found for the sulfonamide
or macrolide group. These findings correlate with the findings
of the study by Guillernot et al. [18], who examined the risk
for carriage of PNSP in children. Longer duration of oral blactam treatment (15 days) in the preceding 30 days contributed
to the likelihood of being a PNSP carrier (OR, 3.5; P p .02).
Carsenti-Etesse et al. [19] studied the in vitro development of
pneumococcal resistance to b-lactams after serial passage in
media containing various subinhibitory concentrations of different b-lactams. The MIC breakpoint of ⭓0.125 mg/mL was
reached after a mean of 18 daily amoxicillin passages, and the
breakpoint of 2 mg/mL was reached in 5 isolates after a mean
of 7.8 exposures to cefixime. These observations are consistent
with stepwise acquisition of resistance through multiple penicillin-binding protein alterations and might provide an explanation for our clinical findings [20].
We also examined patients at the other end of the treatment
spectrum: 10 patients with very short-term applications of blactams and/or macrolides (median, 2 days for both) also had
a significantly higher risk of PNSP bacteremia compared with
patients without recent antibiotic intake (OR, 5.73; P p .014).
To our knowledge, this is the first report to describe a correlation between very brief antibiotic exposure and penicillinnonsusceptible pneumococcal infections. Larger studies are certainly needed to validate these data.
1136 • CID 2003:36 (1 May) • Ruhe and Hasbun
Our study has several advantages over previous work. To our
knowledge, this is the first large study of both adult and pediatric patients to have evaluated the impact of use of all major
antibiotics and duration of antibiotic exposure on the acquisition of PNSP bacteremia. Furthermore, our heterogeneous
study population makes our results more generalizable across
age and socioeconomic status. Finally, we had a large number
of outcomes in our study, which enabled us to perform valid
multivariable analyses without overfitting our logistic regression
model [21].
A disadvantage of our study is the retrospective design. It is
possible that patients received antibiotic prescriptions by an
outside provider without documentation in our hospitals’ medical records. However, meticulous abstraction of all existing
medical and pharmacy records at all 4 hospitals was undertaken
to minimize this problem. In addition, patients enrolled from
3 of the 4 medical centers (Charity and University Hospital of
the Medical Center of Louisiana, Veterans Affairs Medical Cen-
Table 4. Median duration of treatment with different antibiotics
in the 6 months before diagnosis of pneumococcal bacteremia.
Patients
with PNSP
bacteremia
(n p 98)
Patients
with PSSP
bacteremia
(n p 205)
No. (%) of patients
65 (66)
48 (23)
Length of treatment,
median days
15
10
No. (%) of patients
22 (22)
26 (13)
Length of treatment,
median days
95
28
No. (%) of patients
28 (29)
18 (9)
Length of treatment,
median days
10
Treatment
P
.001
b-Lactams
Sulfonamides
.199
Macrolides
.290
7
NOTE. PNSP, penicillin-nonsusceptible Streptococcus pneumoniae; PSSP,
penicillin-susceptible S. pneumoniae.
Table 5. Number of treatment courses with different antibiotics in the
6 months before diagnosis of infection and association with penicillinnonsusceptible Streptococcus pneumoniae (PNSP) bacteremia.
No. (%) of patients
With PNSP
bacteremia
(n p 98)
With PSSP
bacteremia
(n p 205)
OR (95% CI)
22 (22)
126 (61)
1.00
1 Course
29 (30)
42 (20)
3.95 (2.05–7.61)
⭓2 Courses
36 (37)
6 (3)
34.36 (12.95–91.17)
Antibiotic,
no. of courses
No antibiotic
P
b-Lactams
!.001
!.001
Sulfonamides
1 Course
⭓2 Courses
4 (4)
12 (6)
1.91 (0.56–6.46)
18 (18)
14 (7)
7.36 (3.20–16.93)
!.001
.288
20 (20)
15 (7)
7.64 (3.40–17.14)
!.001
9 (9)
2 (1)
25.77 (5.22–127.36)
!.001
Macrolides
1 Course
⭓2 Courses
ter) receive most of their medical care from these institutions.
These patients constituted 81% of the total study population.
Potential use of free drug samples in these hospitals is recorded
as a regular treatment course in the medical records and should
not have significantly affected our data. However, differences
regarding dose or duration of individual antibiotic treatment
(e.g., as a result of management errors or different treatment
indications) or noncompliance with the therapy were not accounted for in our analysis.
Second, data on resistance to non–b-lactams, especially macrolides and sulfonamides, were not available for the majority
of the isolates. Thus, we cannot completely exclude the possibility that the demonstrated association of previous intake of
these antibiotics with the outcome of penicillin resistance is at
least partially the result of confounding. Pneumococcal isolates
were not available for serotyping or molecular subtyping. Consequently, other epidemiological factors, such as horizontal
spread in the community, could not be considered. Last, we
selected patients with penicillin-susceptible pneumococcal bacteremia as control group. This might have introduced selection
bias into our study and may have led to an overestimation of
the ORs for previous antibiotic use as risk factors for PNSP
infection [22].
In summary, our study provides detailed information about
previous antibiotic exposure in patients with PNSP bacteremia.
On multivariate analysis, previous b-lactam and macrolide use
in the last 6 months before zero time were associated with
PNSP bacteremia, confirming recent findings from crosssectional and pediatric studies. Use of fluoroquinolones is not
related to the development of PNSP. Multiple treatment courses
and short-term applications of b-lactams and macrolides place
patients at increased risk for developing PNSP bacteremia. Ju-
dicious use of b-lactams and macrolides might reduce the incidence of PNSP infection.
Acknowledgments
We thank Megan O’Brien for statistical advice and Anupama
Menon for technical support.
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