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Antimicrobial Agents and Chemotherapy, June 2001, p. 1721-1729, Vol. 45, No. 6
Medical Microbiology Division, Department of
Pathology, University of Iowa College of Medicine, Iowa City, Iowa
52242
Received 20 December 2000/Returned for modification 14 February
2001/Accepted 19 March 2001
A total of 1,531 recent clinical isolates of Streptococcus
pneumoniae were collected from 33 medical centers nationwide
during the winter of 1999-2000 and characterized at a central
laboratory. Of these isolates, 34.2% were penicillin nonsusceptible
(MIC Antimicrobial resistance with
Streptococcus pneumoniae was first recognized in 1917, when
optochin (ethylhydrocupreine) was used to treat infections caused by
S. pneumoniae, and resistance developed while patients were
on therapy (13). Fifty years later, the first isolate of
penicillin-nonsusceptible S. pneumoniae of recognized
clinical significance (MIC = 0.5 µg/ml) was recovered in
Australia (9). In the United States, the first report of infection due to a non-penicillin-susceptible isolate of S. pneumoniae (MIC = 0.25 µg/ml) was in 1974. The patient had
pneumococcal meningitis and did not respond to penicillin therapy, even
when high doses of this agent were administered (15).
Antimicrobial resistant S. pneumoniae became widespread in
many parts of the world during the 1980s (13). In the
United States, however, resistance first became manifest during the
early part of the decade of the 1990s. During the 1980s two national surveillance studies revealed overall penicillin resistance rates in
the United States to be at levels of 3 to 5%, and importantly, where
resistance was observed, it was typically only of the intermediate level (11, 24). By 1991-1992, however, overall penicillin resistance rates (intermediate plus resistant [I + R]) had
jumped to 17.8% in the United States (27).
A national surveillance study conducted in 1994-1995 with 30 United
States medical centers reported S. pneumoniae overall penicillin resistance at 23.6%; multiresistance was 9.1%
(5). In 1997-1998, this surveillance project was
repeated, with 24 of the 1994-1995 medical centers participating plus
an additional 10 centers. Results of the 1997-1998 study indicated
that overall rates of penicillin resistance had increased to 29.5% and
the rate of multiresistance was 16.0% (6). The present
report describes the results of a third surveillance project, performed
in 1999-2000. This study included 33 of the 34 centers participating
in the 1997-1998 study. Twenty-two medical centers have been
participants in all three national surveillance studies, which provides
an opportunity for evaluation of resistance rates among a common group
of medical centers over a 5-year period of time in the United States.
Unique patient isolates of S. pneumoniae were
collected in each of 33 United States medical center microbiology
laboratories from November 1, 1999, through April 30, 2000. Fifty
consecutive S. pneumoniae isolates were requested from each
medical center. At the study centers, pure cultures of S. pneumoniae were propagated on 5% sheep blood agar plates, the
growth was transferred to a rayon swab, and the swab was placed in a
transport tube containing 12 ml of semisolid Ames transport medium with
charcoal (Becton Dickinson, Sparks, Md.). Swabs were mailed overnight
to the University of Iowa College of Medicine. Only isolates judged by
the submitting laboratories as being of clinical significance were
included. Demographic data sheets were completed by the contributing
medical center and submitted along with every isolate. The following
information was obtained: patient medical record number, age, sex,
service (inpatient or outpatient), specimen date, and specimen source. Upon receipt at the University of Iowa, isolates were subcultured and
isolate identification was verified using conventional criteria. Stock
cultures were made using a porous bead system (ProLab Diagnostics, Inc., Austin, Tex.) and stored at Susceptibility testing was performed following the National Committee
for Clinical Laboratory Standards (NCCLS) guidelines explicitly
(16). Broth microdilution trays were made in-house using
Mueller-Hinton broth plus 3% lysed horse blood and were stored at
The in vitro activities of 32 antimicrobial agents against 1,531 S. pneumoniae isolates are presented in Table
1. Resistance rates are listed for
antimicrobials with NCCLS-approved pneumococcal susceptibility
breakpoints. The NCCLS recently changed the breakpoints for S. pneumoniae of amoxicillin, amoxicillin-clavulanate, and cefuroxime
(17). The breakpoints for amoxicillin and
amoxicillin-clavulanate were shifted by two log2 dilutions
(from
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.6.1721-1729.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Antimicrobial Resistance among Clinical Isolates of
Streptococcus pneumoniae in the United States during
1999-2000, Including a Comparison of Resistance Rates since
1994-1995
ABSTRACT
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
0.12 µg/ml) and 21.5% were high-level resistant
(MIC 2 µg/ml). MICs to all beta-lactam antimicrobials
increased as penicillin MICs increased. Resistance rates among
non-beta-lactam agents were the following: macrolides, 25.2 to 25.7%;
clindamycin, 8.9%; tetracycline, 16.3%; chloramphenicol, 8.3%; and
trimethoprim-sulfamethoxazole (TMP-SMX), 30.3%. Resistance to
non-beta-lactam agents was higher among penicillin-resistant strains
than penicillin-susceptible strains; 22.4% of S. pneumoniae were multiresistant. Resistance to vancomycin and
quinupristin-dalfopristin was not detected. Resistance to rifampin was
0.1%. Testing of seven fluoroquinolones resulted in the following rank
order of in vitro activity: gemifloxacin > sitafloxacin > moxifloxacin > gatifloxacin > levofloxacin = ciprofloxacin > ofloxacin. For 1.4% of strains, ciprofloxacin MICs were 4 µg/ml. The MIC90s (MICs at which 90% of
isolates were inhibited) of two ketolides were 0.06 µg/ml (ABT773)
and 0.12 µg/ml (telithromycin). The MIC90 of linezolid
was 2 µg/ml. Overall, antimicrobial resistance was highest among
middle ear fluid and sinus isolates of S. pneumoniae;
lowest resistance rates were noted with isolates from cerebrospinal
fluid and blood. Resistant isolates were most often recovered from
children 0 to 5 years of age and from patients in the southeastern
United States. This study represents a continuation of two previous
national studies, one in 1994-1995 and the other in 1997-1998.
Resistance rates with S. pneumoniae have increased markedly
in the United States during the past 5 years. Increases in resistance
from 1994-1995 to 1999-2000 for selected antimicrobial agents were as
follows: penicillin, 10.6%; erythromycin, 16.1%; tetracycline, 9.0%;
TMP-SMX, 9.1%; and chloramphenicol, 4.0%, the increase in
multiresistance was 13.3%. Despite awareness and prevention efforts,
antimicrobial resistance with S. pneumoniae continues to
increase in the United States.
INTRODUCTION
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
70°C.
70°C until use. Thirty-two antimicrobial agents were tested:
penicillin, amoxicillin, amoxicillin-clavulanate, cefuroxime, ceftriaxone, cefpodoxime, cefixime, cefprozil, cefaclor, loracarbef, cefditoren, cefdinir, clarithromycin, erythromycin, azithromycin, clindamycin, tetracycline, chloramphenicol,
trimethoprim-sulfamethoxazole (TMP-SMX), rifampin, vancomycin,
quinupristin-dalfopristin, ofloxacin, ciprofloxacin, levofloxacin,
gatifloxacin, gemifloxacin, sitafloxacin, moxifloxacin, ABT773,
telithromycin, and linezolid. Drug powders were obtained from their
manufacturers or Sigma-Aldrich (St. Louis, Mo.). S. pneumoniae isolates were subcultured twice before susceptibility testing was performed. Broth microdilution trays were inoculated with
approximately 5 × 105 CFU of organism/ml (final
concentration; 100-µl final volume per well) and incubated for
24 h at 35°C in ambient air before MICs were visually determined.
RESULTS
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
0.5, 1, 2 µg/ml to 2, 4, 8 µg/ml [susceptible
{S}, intermediate {I}, resistant {R}, respectively]).
Application of the new breakpoints to the current data resulted in a
dramatic reduction in the percentage of resistant strains compared to
rates determined based on 1999 breakpoints (18), 24.2%
versus 6.3%, for both amoxicillin and amoxicillin-clavulanate (Table
1). The breakpoints for cefuroxime were changed by one twofold dilution
(from 0.5, 1, 2 µg/ml to 1, 2, 4 µg/ml [S, I, R,
respectively]). This resulted in a resistance rate of 29.1% when 2000 breakpoints were applied to the current data, versus 27.3% when old
breakpoints were applied. In addition, the NCCLS established
susceptibility breakpoints for cefpodoxime, cefprozil, cefaclor,
loracarbef, and cefdinir, cephalosporins for which S. pneumoniae breakpoints were previously lacking.
TABLE 1.
In vitro activities of 32 antimicrobial agents for 1,531 isolates of S. pneumoniae
Of this collection of S. pneumoniae isolates, 34.2% were
penicillin nonsusceptible, 12.7% were intermediate (MIC = 0.12 to 1 µg/ml), and 21.5% were penicillin resistant (MIC 2 µg/ml) (Table 1). The overall rate of ceftriaxone resistance (I + R) was 24.7%; 14.4% of isolates were resistant. Among the other
cephalosporins tested
cefuroxime, cefpodoxime, cefixime, cefprozil,
cefaclor, loracarbef, cefditoren and cefdinircefditoren was the most
active (MIC90 [MIC at which 90% of isolates were
inhibited] = 0.5 µg/ml) and loracarbef the least active
(MIC90 = 128 µg/ml). When isolates were grouped
according to penicillin susceptibility category, consistently highest
rates of resistance to all beta-lactam agents were observed among
penicillin-resistant strains. For example, 100% of
penicillin-susceptible strains were also susceptible to ceftriaxone,
26.3% of penicillin-intermediate strains were intermediate or
resistant to ceftriaxone, and 99.4% of all penicillin-resistant strains were ceftriaxone intermediate or resistant. A similar relationship was seen between penicillin and each beta-lactam tested in
this study.
Three macrolide agents were examined: erythromycin, clarithromycin, and
azithromycin. While NCCLS breakpoints differ for each macrolide, the
resistance rates (I + R) are virtually identical: 0.5 to 0.9%
intermediate and 25.2 to 25.7% resistant for all three macrolides
(Table 1). In this collection of S. pneumoniae isolates, 394 (25.7%) were characterized as erythromycin resistant (MICs 1 µg/ml); erythromycin MICs were 1 to 32 µg/ml for 262 (66.5%) of
these 394 isolates and 64 µg/ml for the remaining 132 strains.
Two principal mechanisms of erythromycin resistance are known to exist
among isolates of S. pneumoniae: a ribosomal methylase encoded by ermB, and an efflux pump encoded by
mefA (10, 20, 21, 22, 25, 28). Generally,
strains with the ermB gene have erythromycin MICs of 64
µg/ml and clindamycin MICs of 8 µg/ml and are also resistant to
streptogramin B agents, a phenotype referred to as MLSB. In
contrast, mefA-positive strains have erythromycin MICs of 1 to 32 µg/ml and clindamycin MICs of 0.25 µg/ml. Table 2 describes the patterns of erythromycin
and clindamycin susceptibility for the 394 erythromycin-resistant
S. pneumoniae isolates tested in this study. Of 262 strains
for which erythromycin MICs were 1 to 32 µg/ml, for 255 (97.3%)
clindamycin MICs were 0.25 µg/ml. The phenotype of these isolates
was consistent with mefA-mediated efflux. For 128 (97.0%)
of 132 isolates for which erythromycin MICs were 64 clindamycin MICs
were 8 µg/ml. This profile implies ermB-mediated
ribosomal methylation. Only 11 (2.8%) of the total of 394 erythromycin-resistant isolates did not fit one of these two profiles.
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Resistance rates (I + R) to other non-beta-lactam agents tested in this study were as follows: clindamycin, 9.2%; tetracycline, 16.6%; chloramphenicol, 8.3%; and TMP-SMX, 35.9%. Only one strain was resistant to rifampin (MIC > 4 µg/ml), and only one strain was intermediate to quinupristin-dalfopristin (MIC = 2 µg/ml). No vancomycin-resistant strains were detected. The highest vancomycin MIC was 0.5 µg/ml.
Testing of the antimicrobial activities of seven fluoroquinolones
against S. pneumoniae resulted in the following overall rank
order of activity: gemifloxacin > sitafloxacin > moxifloxacin > gatifloxacin > levofloxacin = ciprofloxacin > ofloxacin. NCCLS breakpoints currently exist for
four of the fluoroquinolones tested in this study: ofloxacin,
levofloxacin, gatifloxacin, and moxifloxacin (17).
Resistance (I + R) rates were noted to be 5.6, 0.7, 0.4, and
0.3%, respectively. Although there are no NCCLS-approved breakpoints for ciprofloxacin versus S. pneumoniae, Chen and colleagues
suggested a ciprofloxacin MIC of 4 µg/ml as a criterion for
fluoroquinolone resistance based on the association between isolates
with a ciprofloxacin MIC of 4 µg/ml and mutations in the
fluoroquinolone-resistance-determining region of S. pneumoniae, as well as the fact that a ciprofloxacin of MIC 4
µg/ml exceeds the usual peak achievable serum level of ciprofloxacin
(2). Based on this definition, 1.4% (n = 21) of the current collection of pneumococci were resistant to
ciprofloxacin. Also of note is that 6 of these 21 strains had
penicillin MICs of 2 µg/ml, 6 had penicillin MICs of 0.25 to 1 µg/ml, and the remaining 9 strains were penicillin susceptible. All
six with penicillin MICs of 2 µg/ml were also multiresistant, with
between two and four additional resistances.
Two ketolides were tested, ABT773 (Abbott Pharmaceutical) and telithromycin (Aventis Pharmaceutical). ABT773 was consistently four- to eightfold more active than telithromycin (Table 1). In comparison to penicillin-susceptible strains, the MIC90s of ABT773 and telithromycin increased slightly among penicillin-intermediate (0.06 and 0.12 µg/ml, respectively) and penicillin-resistant (0.25 and 0.5 µg/ml, respectively) strains. These values for penicillin-susceptible strains were 0.015 and 0.015 µg/ml, respectively. NCCLS breakpoints have not yet been established for either of these agents; therefore, rates of resistance were not determined.
The MIC50 of linezolid, an oxazolidinone, was 1 µg/ml,
and the MIC90 was 2 µg/ml. No differences were seen when
isolates were categorized based on their penicillin susceptibility
category. NCCLS breakpoints have not yet been established for this
antimicrobial; however, the Food and Drug Administration-approved
susceptibility breakpoint included in the package insert is 2
µg/ml. Based on this criterion, 100% of S. pneumoniae
strains in this study were susceptible to linezolid.
Of this collection of isolates, 22.4% (n = 343) were
found to be multiresistant (defined as intermediate or resistant to
penicillin plus intermediate or resistant to at least two
non-beta-lactam agents) (Table 3). Of the
multiresistant strains, 36.4% (n = 125) were resistant
to penicillin, erythromycin, and TMP-SMX, 28.6% (n = 98) were resistant to penicillin, erythromycin, chloramphenicol, tetracycline, and TMP-SMX, and 23.6% (n = 81) were
resistant to penicillin, erythromycin, tetracycline, and TMP-SMX. The
remaining 39 isolates (11.4%) exhibited other combinations of three or
four resistances.
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Table 4 indicates rates of antimicrobial
resistance to selected antimicrobial agents sorted according to
selected patient and specimen demographic characteristics. Of the
S. pneumoniae isolates in this collection, 65.8%
(n = 1,007) were obtained from respiratory specimens
(44.5% lower respiratory, 21.3% upper respiratory); 32.1%
(n = 491) were invasive isolates recovered from blood,
cerebrospinal fluid, or other normally sterile body fluids; 45.4% of
upper respiratory specimens, 34.9% of lower respiratory specimens, and
25.9% of invasive isolates were penicillin intermediate or high-level
resistant.
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Of the S. pneumoniae isolates collected from children 0 to 5 years of age, 42.5% (n = 190) were penicillin intermediate or high-level resistant, a level 7 to 10% higher than the penicillin resistance rate in any other age category. Rates of penicillin resistance among inpatients (32.3%, n = 278) versus outpatients (36.4%, n = 242) were similar.
Table 5 compares resistance rates of
selected antimicrobials by individual study center. Each medical center
contributed an average of 46 unique patient isolates (range, 20 to 59 isolates). The frequency with which resistant (I + R) strains were
recovered varied considerably between individual study centers:
penicillin, 13.8 to 65.9%; ceftriaxone, 5.2 to 56.1%; erythromycin,
6.1 to 53.7%; tetracycline, 7.3 to 50.0%; TMP-SMX, 14.3 to 63.4%;
and chloramphenicol, 1.9 to 27.3%. Of the 33 centers, 19 had
penicillin resistance rates (I + R) that were lower than the
national rate of 34.2%; 14 had rates of penicillin resistance higher
than the national rate. Compared by geographic region, penicillin
resistance rates (I + R) were as follows: west (five centers),
33.2%; southwest (six centers), 37.3%; midwest (eight centers),
29.3%; northeast (9 centers), 32.2%; and southeast (five centers),
42.9%.
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DISCUSSION |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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The results of this study indicate that rates of antimicrobial
resistance among clinical isolates of S. pneumoniae in the United States continue to increase. The current overall national rate
of penicillin resistance is 34.2%; 21.5% are high-level resistant (MICs 2 µg/ml). Among 329 isolates for which MICs were 2
µg/ml, the percentages of organisms for which MICs were 2 and 4 µg/ml were 71.4 and 28.6%, respectively. No isolates for which MICs were 8 µg/ml were recognized. When organisms were grouped according to penicillin susceptibility categories, rates of resistance to all
beta-lactam agents increased in parallel with penicillin resistance. Penicillin resistance in S. pneumoniae is the result of
alterations in cell wall penicillin-binding proteins (PBPs)(8,
23). All beta-lactam antimicrobials, to at least some extent,
use essentially the same PBPs as their target of action; therefore,
alterations in PBPs that cause resistance to penicillin will result in
some degree of resistance to all beta-lactam antimicrobials. Indeed, an
absolute linear relationship between penicillin MICs and MICs of eight
other 
-lactam antimicrobials has recently been described for a large
collection (n = 3,194) of recent S. pneumoniae clinical isolates from the United States
(1).
Resistance rates (I + R) among non-beta-lactam agents were the following: macrolides, 26%, clindamycin, 9.2%; tetracycline, 16.6%; chloramphenicol, 8.3%; and TMP-SMX, 35.9%. Rates of resistance to all of these non-beta-lactam antimicrobials were consistently higher among penicillin-intermediate and -resistant S. pneumoniae strains compared to penicillin-susceptible strains.
The phenotypic expression of macrolide resistance in this study indicated that the efflux and MLSB phenotypes remain the dominant mechanisms of resistance among pneumococci in the United States. Organisms in the first group account for approximately 65% of macrolide-resistant isolates; MLSB isolates account for approximately 32%. It is possible that other recently described macrolide resistance determinants are present in those rare strains that do not clearly fit into either of these two phenotypes (26).
Vancomycin and quinupristin-dalfopristin resistance was not detected, and only 0.1% of S. pneumoniae strains were resistant to rifampin. Newer agents such as the ketolides and linezolid were consistently active, even among penicillin-nonsusceptible S. pneumoniae isolates.
Multiresistance continues to grow as a problem among S. pneumoniae isolates in the United States. Overall, 22.4% of the S. pneumoniae isolates tested in this study were resistant to at least three different classes of antimicrobials; 28.6% of the multiresistant strains were resistant to five different antimicrobial classes: penicillin, erythromycin, chloramphenicol, tetracycline, and TMP-SMX.
Antimicrobial resistance rates were highest among middle ear fluid and
sinus isolates, isolates recovered from children 5 years of age, and
isolates from patients residing in the southeastern United States.
Inpatient and outpatient resistance rates were comparable.
The modal MICs of ofloxacin, ciprofloxacin, levofloxacin, gatifloxacin,
moxifloxacin, sitafloxacin, and gemifloxacin for the S. pneumoniae isolates characterized in this study were 2, 1, 1, 0.25, 0.12, 0.03, and 0.015 µg/ml, respectively. For 21 strains (1.4%), ciprofloxacin MICs were 4 µg/ml. For 11 of these isolates, the ciprofloxacin MICs were 4 µg/ml; the MICs of ofloxacin,
levofloxacin, gatifloxacin, moxifloxacin, sitafloxacin, and
gemifloxacin for these 11 isolates were 2 to 16, 1 to 8, 0.25 to 2, 0.12 to 1, 0.06 to 0.25, and 0.03 to 0.12 µg/ml, respectively. For
five strains, MICs were as follows: ciprofloxacin, 8 µg/ml;
ofloxacin, 4 to 16 µg/ml; levofloxacin, 2 to 8 µg/ml; gatifloxacin,
0.5 to 4 µg/ml; moxifloxacin, 0.25 to 2 µg/ml; sitafloxacin, 0.12 to 0.25 µg/ml; and gemifloxacin, 0.03 to 0.25 µg/ml. Two strains
with ciprofloxacin MICs of 16 µg/ml had ofloxacin MICs of 4 and 8 µg/ml, levofloxacin MICs of 2 and 4 µg/ml, gatifloxacin MICs of 1 µg/ml, moxifloxacin MICs of 0.25 µg/ml, sitafloxacin MICs of 0.25 µg/ml, and gemifloxacin MICs of 0.25 µg/ml. For one strain, MICs
were as follows: ciprofloxacin, 32 µg/ml; ofloxacin, 32 µg/ml;
levofloxacin, 16 µg/ml; gatifloxacin, 4 µg/ml; moxifloxacin, 2 µg/ml; sitafloxacin, 0.25 µg/ml; and gemifloxacin, 0.25 µg/ml.
Finally, two strains with ciprofloxacin MICs of >64 µg/ml also had
the following MICs: ofloxacin, >64 µg/ml; levofloxacin, 64 µg/ml;
gatifloxacin, 16 µg/ml; moxifloxacin, 4 and 8 µg/ml; sitafloxacin,
2 µg/ml; and gemifloxacin, 2 µg/ml.
While overall resistance rates among fluoroquinolones remain at low levels, it is important to note that 6 of the 21 ciprofloxacin-resistant strains in this study were high-level penicillin resistant and multiresistant (resistant to erythromycin, tetracycline, chloramphenicol, or TMP-SMX). Four strains had ciprofloxacin MICs of 4 to 8 µg/ml, penicillin MICs of 2 µg/ml, and resistance to two to four additional antimicrobials; two strains had ciprofloxacin MICs of 16 µg/ml, penicillin MICs of 2 to 4 µg/ml, and resistance to two to three additional antimicrobials.
Resistance rates among individual medical centers varied widely. Penicillin resistance (I + R) ranged from 13.8% to 65.9%, and rates of resistance to non-beta-lactam agents varied in a similar manner. Those medical centers with lower rates of penicillin resistance also tended to have lower rates of resistance to other antimicrobial classes, and those centers with the highest rates of penicillin resistance were among the centers with the highest rates of resistance to non-beta-lactam agents.
It is of interest to compare the observations of this study with those of Whitney and colleagues, who recently described the results of a longitudinal population based survey of antimicrobial resistance among invasive isolates of S. pneumoniae from seven large United States metropolitan areas and the State of Connecticut (29). Data were presented for the years 1995 to 1998. Accepting that the period of our study, winter of 1999-2000, was roughly one year more recent than the latest acquisition year of their survey and accepting the fact that their study was much more restricted geographically than ours, there were striking similarities between rates of resistance observed in the two surveys among systemic isolates of S. pneumoniae. For example, resistance rates in our survey and the study conducted by Whitney et al. were 25.8 and 24% with penicillin, 17.5 and 17% with cefotaxime, 18.6 and 17% with erythromycin, 29.1 and 30% with TMP-SMX, 8.1 and 7% with tetracycline, and 4.7 and 3% with chloramphenicol, respectively.
Since the present study is a continuation of a longitudinal
surveillance program including two previous national studies, it
presents a unique opportunity for comparison of resistance rates from a
common group of geographically distributed medical centers over a
5-year period. The number of medical centers in each study was between
30 and 34. Twenty-four medical centers were common to the 1994-1995
and 1997-1998 studies, 32 centers were common to the 1997-1998 and
1999-2000 studies, and 22 medical centers participated in all three
studies. The numbers of isolates collected were comparable (1,527 to
1,601), and the isolates were collected during the exact same time
periodthe winter months between November 1 and April 30. All of the
studies were similar with respect to the age distribution of the
patients from whom isolates were obtained as well as the proportion of
isolates obtained from each specimen source (Table 5).
Penicillin resistance (I + R) increased significantly during the past 5 years in the United States, from 23.6% in 1994-1995 to 34.2% in 1999-2000 (Table 5). Macrolide resistance increased from 10.3% in 1994-1995 to 26.2% in 1999-2000. Clindamycin resistance increased 3.5% between 1997-1998 and 1999-2000 to a current rate of 9.2%. (Clindamycin was not tested in 1994-1995.) Tetracycline resistance has more than doubled, increasing from 7.6% in 1994-1995 to 16.6% in 1999-2000. TMP-SMX resistance has increased 9.1% since 1994-1995, to a current rate of 35.9%. Chloramphenicol resistance doubled, from 4.3% to 8.3% during the past five winter seasons.
The increase in macrolide resistance is of particular interest. In view
of the relationship between MICs and resistance mechanisms, i.e.,
erythromycin MICs of 1 to 32 µg/ml suggest efflux (mefE) while MICs of 64 µg/ml imply MLSB as a result of
ribosomal methylation (ermB), we were able to assess the
contribution of these two resistance determinants to macrolide
resistance over time. The relative percentage of macrolide-resistant
strains with these two mechanisms did not change during the three
studies we have conducted, i.e., 68.1 to 74.7% efflux phenotype in
1994-1995, 1997-1998, and 1999-2000, with 25.3 to 31.9%
MLSB phenotype during the same three periods.
In a recent survey of invasive pneumococcal isolates conducted over essentially the same period in the metropolitan Atlanta area, the relative percentage of efflux strains was found to have increased (7). Furthermore, there was a shift during the study period toward higher macrolide MICs with efflux-positive strains (7). Again, we have not observed this. The MIC50s for efflux-positive isolates in our three surveys have all been 4 µg/ml; the MIC90s for such isolates were 16 µg/ml in 1994-1995 and 8 µg/ml in both 1997-1998 and 1999-2000. The differences between our observations and those of Gay et al. (7) might be accounted for by the limited geographic area surveyed in their study and/or the fact that they reported results only for invasive isolates of S. pneumoniae.
Fluoroquinolone resistance with S. pneumoniae in the United
States has remained stable during the past 5 years. Using a
ciprofloxacin MIC of 4 µg/ml as a marker for fluoroquinolone
resistance, resistance to ciprofloxacin in the United States has
remained unchanged (i.e., 1.2 to 1.6%) during the last 5 years.
Current overall fluoroquinolone resistance rates in Canada and the
United States are remarkably similar (2). One difference,
however, is that fluoroquinolone resistance rates in Canada appear to
be changing rapidly, while our study indicates that resistance rates in
the United States, as noted above, have remained essentially unchanged
over the past 5 years.
Another important observation in this study is that the proportion of
high-level penicillin resistant strains present in the United States
now exceeds the proportion of penicillin-intermediate strains. Overall,
63% of penicillin-nonsusceptible strains in this study were high-level
penicillin resistant, compared to 41% in 1997-1998 (6)
and 40% in 1994-1995 (5). This is a startling increase
in high-level penicillin resistance within just the past 2 years, but
it is even more alarming compared to the resistance rates reported only
8 years ago. In 1991-1992, the overall national rate of penicillin
resistance was 17.8%; only 2.6% of resistant isolates were high-level
resistant (27). Of particular importance is the
observation that the increased proportion of high-level penicillin-resistant isolates was noted in all three major specimen categories: upper respiratory tract, 68.9%; lower respiratory tract,
59.9%; and invasive isolates, 59.8%. While the clinical relevance of
penicillin-resistant S. pneumoniae in lower respiratory tract infections is debatable, there can be no doubt as to the clinical
relevance and therapeutic challenge of penicillin
resistanceparticularly high-level resistanceamong isolates causing
systemic infections such as meningitis and perhaps other closed-space
infections such as sinusitis or otitis media (12, 14, 19).
The rate of multiresistant S. pneumoniae has increased steadily: 9.1% in 1994-1995, 16.0% in 1997-1998, and 22.4% in 1999-2000. In this study, 65.5% of penicillin-resistant S. pneumoniae isolates were multiresistant. This also differs significantly from previous years. In 1997-1998, 54.0% of penicillin-nonsusceptible strains were multiresistant (P < 0.0001); in 1994-1995, 38.2% of penicillin-nonsusceptible strains were multiresistant (P < 0.0001). It is disconcerting to note that currently one-third of clinical isolates of S. pneumoniae are resistant to penicillin, of which ca. two-thirds are both high-level resistant as well as resistant to two or more non-beta-lactam antimicrobial classes.
One possible explanation for the increase in high-level penicillin resistance and multiresistance is the proliferation of a few major clones of penicillin-resistant or multiresistant strains in the United States. Two separate studies have characterized recent (1994-1995 and 1996-1997) clinical isolates of penicillin-resistant pneumococci at a molecular level to determine whether clonal relationships exist among these resistant organisms (3, 4). Both studies found that 9 to 10 major clones of penicillin-resistant S. pneumoniae exist in the United States, which together comprise 70 to 85% of the penicillin-resistant pneumococci in the United States (3, 4). The study by Corso and colleagues also determined that the most frequently occurring clone within the collection of 328 S. pneumoniae isolates that they characterized was the 23F clone from Spain, which is also a multiresistant clone (3). We speculate that the substantial increase in resistance rates during such a short period of time is suggestive of further proliferation of a few of these major clones of pneumococci, particularly high-level penicillin-resistant and multiresistant clones. Molecular characterization of the penicillin-resistant isolates from our study is under way and will hopefully provide additional insight into the epidemiology that surrounds the spread of antimicrobial-resistant S. pneumoniae. In conclusion, the problem of antimicrobial resistance with S. pneumoniae in the United States continues to grow.
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ACKNOWLEDGMENTS |
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This study was supported by a grant from Abbott Laboratories.
We are also grateful to the following individuals and medical centers for providing the isolates of S. pneumoniae characterized in this study: Dale Schwab, San Diego, Calif.; David Bruckner, Los Angeles, Calif.; Mary York, San Francisco, Calif.; David Sewell, Portland, Oreg.; Thomas Fritschie, Seattle, Wash.; Susan Rossmann, Houston, Tex.; Virginia Quenzer, Albuquerque, N.Mex.; Paul Southern, Dallas, Tex.; Michael Wilson, Denver, Colo; Karen Carroll, Salt Lake City, Utah; Michael Saubolle, Phoenix, Ariz.; Gerri Hall, Cleveland, Ohio; Susan Kehl, Milwaukee, Wis.; William Dunne, Detroit, Mich.; Franklin Cockerill, Rochester, Minn.; Gerald Denys, Indianapolis, Ind.; Carmen Clark, Iowa City, Iowa; Melodie Beard, Chicago, Ill.; Richard Thompson, Evanston, Ill.; Joseph Schwartzman, Lebanon, N.H.; Phyllis Della-Latta, New York, N.Y.; Paola DeGirolami, Boston, Mass.; Allan Truant, Philadelphia, Pa. Yvette McCarter, Hartford, Conn.; Joseph Campos, Washington, D.C.; Betty Forbes, Syracuse, N.Y.; Paul Bourbeau, Danville, Pa.; Dwight Hardy, Rochester, N.Y.; Peter Gilligan, Chapel Hill, N.C.; Robert Jerris, Decatur, Ga.; Elliot Carter, Mobile, Ala.; Susan Sharp, Miami Beach, Fla.; and James Snyder, Louisville, Ky.
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FOOTNOTES |
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* Corresponding author. Mailing address: Medical Microbiology Division, C606 GH, Department of Pathology, University of Iowa College of Medicine, Iowa City, IA 52242. Phone: (319) 356-8616. Fax: (319) 356-4916. E-mail: gary-doern{at}uiowa.edu.
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REFERENCES |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Antimicrobial Agents and Chemotherapy, June 2001, p. 1721-1729, Vol. 45, No. 6
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.6.1721-1729.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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Karlowsky, J. A., Jones, M. E., Draghi, D. C., Sahm, D. F.
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47: 3155-3160
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(2003). High-Dose Azithromycin versus High-Dose Amoxicillin-Clavulanate for Treatment of Children with Recurrent or Persistent Acute Otitis Media. Antimicrob. Agents Chemother.
47: 3179-3186
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Schentag, J. J, Meagher, A. K, Forrest, A.
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Schentag, J. J, Meagher, A. K, Forrest, A.
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Montanari, M. P., Cochetti, I., Mingoia, M., Varaldo, P. E.
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47: 2236-2241
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Bingen, E., Doit, C., Loukil, C., Brahimi, N., Bidet, P., Deforche, D., Geslin, P.
(2003). Activity of Telithromycin against Penicillin-Resistant Streptococcus pneumoniae Isolates Recovered from French Children with Invasive and Noninvasive Infections. Antimicrob. Agents Chemother.
47: 2345-2347
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Zhanel, G. G., DeCorby, M., Noreddin, A., Mendoza, C., Cumming, A., Nichol, K., Wierzbowski, A., Hoban, D. J.
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Karlowsky, J. A., Thornsberry, C., Critchley, I. A., Jones, M. E., Evangelista, A. T., Noel, G. J., Sahm, D. F.
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Zhanel, G. G., Palatnick, L., Nichol, K. A., Bellyou, T., Low, D. E., Hoban, D. J.
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47: 1867-1874
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Johnson, C. N., Benjamin, W. H. Jr., Moser, S. A., Hollingshead, S. K., Zheng, X., Crain, M. J., Nahm, M. H., Waites, K. B.
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51: 1269-1282
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Mason, E. O. Jr., Lamberth, L. B., Wald, E. R., Bradley, J. S., Barson, W. J., Kaplan, S. L.
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47: 166-169
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Montanari, M. P., Mingoia, M., Cochetti, I., Varaldo, P. E.
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Noreddin, A. M., Roberts, D., Nichol, K., Wierzbowski, A., Hoban, D. J., Zhanel, G. G.
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40: 3313-3318
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46: 1295-1301
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Sahm, D. F., Thornsberry, C., Mayfield, D. C., Jones, M. E., Karlowsky, J. A.
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