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Antimicrobial Agents and Chemotherapy, November 2000, p. 3008-3011, Vol. 44, No. 11
Laboratories International for Microbiology
Studies, Rolling Meadows, Illinois,1 and
Department of Anti-Infectives, Research and Development,
SmithKline Beecham Pharmaceuticals, Collegeville,
Pennsylvania2
Received 12 May 2000/Returned for modification 13 June
2000/Accepted 5 August 2000
From 1997 to 1999, 94 study centers in 15 European, 3 North
American, and 2 South American countries contributed 2,632 isolates of
Streptococcus pneumoniae to an international antimicrobial susceptibility testing study. Only 62.0% of isolates were susceptible to penicillin, while 22.3% were penicillin intermediate and 15.6% were penicillin resistant. Resistance to trimethoprim-sulfamethoxazole (24.4%), azithromycin (26.0%), and clarithromycin (27.1%) was also
highly prevalent. For the penicillin-resistant isolates
(n = 411), the MICs at which 90% of isolates are
inhibited (MIC90s) for gemifloxacin, levofloxacin,
ofloxacin, clarithromycin, and azithromycin were 0.03, 1, 2, >16, and
>64 µg/ml, respectively. Similarly, for isolates resistant to both
azithromycin and clarithromycin (n = 649),
gemifloxacin, levofloxacin, ofloxacin, and penicillin MIC90s were 0.03, 1, 2, and 4 µg/ml, respectively.
Overall rates of resistance to trovafloxacin (0.3%), levofloxacin
(0.3%), grepafloxacin (0.6%), and ofloxacin (0.7%) were low. For
ofloxacin-intermediate and -resistant isolates (n = 142), gemifloxacin had the lowest MIC90 (0.12 µg/ml)
compared to the MIC90s of trovafloxacin (0.5 µg/ml),
grepafloxacin (1 µg/ml), and levofloxacin (2 µg/ml). For all
S. pneumoniae isolates tested, gemifloxacin MICs were Streptococcus pneumoniae
is an important bacterial pathogen in upper and lower respiratory tract
infections such as community-acquired pneumonia, meningitis, otitis
media, and sinusitis. The rapid emergence of penicillin, macrolide, and
multidrug resistance among isolates of S. pneumoniae during
the 1990s (8) has encouraged the development, testing, and
marketing of new antimicrobial agents such as quinolones with increased
activity against respiratory pathogens. It has also resulted in new
recommendations for the treatment of community-acquired pneumonia
(3) and has necessitated antibiotic resistance surveillance
studies to ensure continued efficacious, empiric therapy for patients
(1, 2). Newer quinolones are now recommended for the
treatment of respiratory tract infections due to S. pneumoniae, particularly for isolates resistant to Gemifloxacin (SB 265805) has been reported to possess excellent in
vitro activity against S. pneumoniae, albeit against limited collections of isolates (<500 isolates) that were typically components of regional or national studies (5, 6, 10, 15, 16). The
preceding investigations demonstrated that gemifloxacin possessed more
potent activity than currently available quinolones against clinically
significant gram-positive cocci, including S. pneumoniae (5, 6, 10, 15, 16). In addition, gemifloxacin also retained
excellent activity against gram-negative bacilli and modest potency
against nonfermentative gram-negative bacilli and anaerobes (5,
10, 15, 16). Gemifloxacin MICs have also been shown to be less
affected in strains of S. pneumoniae harboring target site
mutations (GyrA, GyrB, ParC, ParE) that resulted in significantly
elevated MICs of other currently marketed quinolones, most noticeably,
ciprofloxacin (4, 6, 9). The current study extends previous
reports and presents comparative gemifloxacin susceptibility data by
using a large collection of 2,632 recent international isolates of
S. pneumoniae, including 141 ofloxacin-intermediate and
-resistant isolates.
S. pneumoniae isolates.
Between September 1997 and August 1999, 94 study sites in 20 countries each prospectively
collected up to 50 isolates of S. pneumoniae. An isolate was
accepted, one per patient, from a variety of specimen sources. Isolate
inclusion was independent of medical history, patient age, or gender.
Each isolate was identified as S. pneumoniae and was deemed
to be a significant pathogen by using local laboratory criteria. The
S. pneumoniae isolates described here are a component of a
larger prospective international surveillance study of the activity of
gemifloxacin against selected aerobic gram-positive and gram-negative
pathogens. The demographic information available was limited to patient age.
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
A Comparative In Vitro Surveillance Study of Gemifloxacin
Activities against 2,632 Recent Streptococcus pneumoniae
Isolates from across Europe, North America, and South
America
ABSTRACT
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
Appendix
References
0.5 µg/ml, suggesting that gemifloxacin has the potential to be used as a
treatment for pneumococcal infections, including those arising from
isolates resistant to 
-lactams and macrolides.
INTRODUCTION
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
Appendix
References
-lactam
antibiotics (3).
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
Appendix
References
Antimicrobial susceptibility testing. MICs were determined by the National Committee for Clinical Laboratory Standards (NCCLS)-recommended broth microdilution testing method (13). The dried microdilution panels used in this study, MicroScan (Dade Behring Inc., Sacramento, Calif.) and Sensititre (Trek Diagnostics Inc., West Sussex, United Kingdom), were purchased from two companies and used identical antibiotic dilution configurations. Gemifloxacin was supplied by SmithKline Beecham (Collegeville, Pa.), and the 10 comparative antimicrobials were supplied by their respective manufacturers or the panel manufacturer. Appropriate broth medium was also provided directly by the panel manufacturers. MICs were determined in each participating country at one or more designated testing laboratories. Each designated testing laboratory performed daily quality control testing that included S. pneumoniae ATCC 49619 (13). Test isolate results were accepted into the final analysis only if the MIC for the quality control isolate tested was within the acceptable range defined by NCCLS guidelines (13).
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RESULTS |
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Abstract
Introduction
Materials and Methods
Results
Discussion
Appendix
References
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A total of 2,632 isolates of S. pneumoniae were tested
for their susceptibilities to gemifloxacin and comparative
antimicrobials (Table 1). The European
study centers provided 76.1% (n = 2,002) of the
isolates, with the study centers in North America (16.5%; n = 435) and South America (7.4%; n = 195)
supplying the remaining organisms. The overall rates of resistance to
penicillin (15.6%), cefuroxime (20.5%), azithromycin (26.0%),
clarithromycin (27.1%), and trimethoprim-sulfamethoxazole (24.4%)
were considerable and were a contrast to the low rates of resistance to
trovafloxacin (0.3%), levofloxacin (0.3%), grepafloxacin (0.6%), and
ofloxacin (0.7%) (14). Ofloxacin-intermediate (MIC, 4 µg/ml) isolates were prevalent (4.7%; n = 123), but
most (>90%) retained their susceptibilities to the other quinolones
tested. The activity of gemifloxacin against the 2,632 isolates was
notably more potent than those of the other quinolones tested, with the
MICs for all isolates being 0.5 µg/ml and with 99.7% of isolates
being susceptible to gemifloxacin at 0.25 µg/ml. On the basis of
comparisons of the MICs at which 90% of isolates are inhibited
(MIC90s) for the quinolones, gemifloxacin was 8-fold more
potent than trovafloxacin and grepafloxacin, 32-fold more potent than
levofloxacin, and 64-fold more potent than ciprofloxacin and ofloxacin
(Table 1).
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Table 2 depicts the in vitro activities
of gemifloxacin and the 10 comparative antibiotics against
penicillin-resistant, macrolide-resistant, and ofloxacin-intermediate
and -resistant isolates of S. pneumoniae.
Macrolide-resistant isolates were defined as isolates resistant to both
azithromycin and clarithromycin (14). Rates of resistance to
grepafloxacin, levofloxacin, ofloxacin, and trovafloxacin were low
(<2%) for penicillin-resistant and macrolide-resistant isolates.
Among the 142 ofloxacin-intermediate and -resistant isolates
identified, 12.0, 9.8, and 4.9% were also nonsusceptible to
grepafloxacin, levofloxacin, and trovafloxacin, respectively. On the
basis of MIC90 comparisons, gemifloxacin was 4-, 8-, 16-, 32-, and 64-fold more potent than trovafloxacin, grepafloxacin,
levofloxacin, ciprofloxacin, and ofloxacin, respectively, against
ofloxacin-intermediate and -resistant isolates (Table 2).
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All isolates for which ofloxacin MICs were 
16 µg/ml (n = 9) were uniformly resistant to grepafloxacin, with seven of nine (77.8%) isolates resistant to trovafloxacin and six of nine (66.7%) isolates resistant to levofloxacin. For seven of the nine isolates for
which ofloxacin MICs were 16 µg/ml, ciprofloxacin MICs were also
16 µg/ml. For isolates for which ofloxacin MICs were 16 µg/ml,
gemifloxacin MICs ranged from 0.015 to 0.5 µg/ml (Table 2).
Ofloxacin-intermediate and -resistant isolates were primarily from
European (5.8%; 117 of 2,002) and North American (5.1%; 22 of 435)
study centers and were less prevalent among isolates from South America
(1.5%; 3 of 195). Age data were provided for 2,491 of the 2,632 patients. Patients 16 years of age accounted for 43.5% (n = 1,083) of the isolates, while 33.2% (n = 828)
and 23.3% (n = 580) of the patients were aged 17 to 64 and 65 years, respectively. Of the ofloxacin-intermediate and
-resistant S. pneumoniae isolates, 5.1% (55 of 1,083) were
isolated from patients 16 years of age, 5.7% (47 of 828) were
isolated from patients 17 to 64 years of age, and 6.9% (40 of 580)
were isolated from patients 65 years of age. In comparison,
penicillin-resistant S. pneumoniae isolates were isolated
from 18.7% (202 of 1,083) of patients 16 years of age, 12.3% (102 of 828) of patients 17 to 64 years of age, and 11.5% (67 of 580) of
patients 65 years of age. Macrolide-resistant S. pneumoniae isolates were isolated from 23.5% (255 of 1,083) of
patients 16 years of age, 22.8% (189 of 828) of patients 17 to 64 years of age, and 24.5% (142 of 580) of patients 65 years of age.
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DISCUSSION |
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Abstract
Introduction
Materials and Methods
Results
Discussion
Appendix
References
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The 2,632 global isolates of S. pneumoniae tested in this study demonstrated high levels of penicillin (37.9%), trimethoprim-sulfamethoxazole (35.8%), clarithromycin (28.8%), and azithromycin (28.1%) nonsusceptibility. These data concur with those from other recent studies in which it was concluded that for patients with penicillin-resistant S. pneumoniae infections, one can assume almost complete cross-resistance to oral cephalosporins such as cefuroxime and a high likelihood (approximately 40%) of additional cross-resistance to macrolides, tetracycline, and/or trimethoprim-sulfamethoxazole (8, 17). The rapid increase in the rate of isolation of penicillin-intermediate, penicillin-resistant, and multidrug-resistant S. pneumoniae isolates will continue to alter empiric treatment guidelines for both community-acquired respiratory infections such as pneumonia, acute exacerbations of chronic bronchitis, sinusitis, and otitis media, as well as the treatment of hospitalized patients (3, 17).
In the present study, gemifloxacin was the most potent antibiotic
tested against S. pneumoniae, an important respiratory tract pathogen. The potent activity of gemifloxacin against pneumococci resistant to penicillin, azithromycin, clarithromycin, and ofloxacin supports similar findings by other investigators (5, 6, 10, 15,
16). Most recently, Davies and coworkers (6) reported
that gemifloxacin demonstrated similar activity against pneumococci
irrespective of penicillin susceptibility, with MIC90s of
0.03 to 0.06 µg/ml (range, 0.03 to 0.25 µg/ml). In addition, those
investigators (6) reported that gemifloxacin retained potent
activity against 28 isolates for which ciprofloxacin MICs were 8
µg/ml and that possessed defined GyrA and ParC mutations and efflux
resistance mechanisms. The gemifloxacin MIC90 for this collection was 0.5 µg/ml (range, 0.03 to 1 µg/ml) and demonstrated that gemifloxacin was 8- to >64-fold more potent than levofloxacin, sparfloxacin, grepafloxacin, and trovafloxacin against the same isolates (6). Others have shown similarly potent activity
for gemifloxacin against strains for which ciprofloxacin (9, 11, 15) and levofloxacin (12) MICs are elevated.
Investigators have also reported that the antipneumococcal potency of
gemifloxacin is two- to fourfold greater than that of clinafloxacin
(12), fourfold greater than that of moxifloxacin
(11), and eightfold greater than that of sparfloxacin
(11).
Prior to the recent introduction of quinolones specific for respiratory
tract infections into clinical use, quinolones were generally not
recommended for the treatment of S. pneumoniae infections. Irrespective of this, low levels of resistance (<1%) to
grepafloxacin, levofloxacin, sparfloxacin, and trovafloxacin have been
reported, with higher levels (approximately 1.7%) of S. pneumoniae isolates demonstrating decreased susceptibility to
ciprofloxacin (4). For all 2,632 isolates of S. pneumoniae tested in the present study gemifloxacin MICs were
0.5 µg/ml, despite concurrent resistance to grepafloxacin,
levofloxacin, ofloxacin and trovafloxacin among some isolates, and for
3.4% (n = 89) of isolates ciprofloxacin MICs were 4
µg/ml.
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APPENDIX |
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Materials and Methods
Results
Discussion
Appendix
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The participating centers or contact investigators in Europe were Institute für Hygeine, Innsbruck, Austria; B. Sixl, Graz, Austria; Bundesst. Bakteriologie-Serologie Untersuchangsanstalt, Salzburg, Austria; Bundesst. Bakteriologie-Serologie, Klagenfurt, Austria; Institute für Pathologie, Steyr, Austria; Pathologie Institute, Neustadt, Austria; Universität-Klinik für Innere Medizin, Vienna, Austria; Laboratorium Micro UZ St. Rafael, Lueven, Belgium; Medisch Centrum Huisartsen, Leuven, Belgium; Lab. Cliniques Université U.C.L. De Mont-Godinne, Yvoir, Belgium; Eeinheid Antibiotica-Onderzoek Pasteurinstitut, Brussels, Belgium; Lab. De Micro Hopital Université Erasme, Brussels, Belgium; La Microbiologia UZ Antwerpen, Edegern, Belgium; Aarhus University Hospital, Aarhus, Denmark; Haartman Institute, Helsinki, Finland; R. Leclercq, Chucote de Nacre, France; M. Chomarat, Centre Hospitalier Lyon-SUD, Lyon, France; Faculte De Medecine, Strasbourg, France; Hospital Calmette, Lille, France; Hospital Central, Nancy, France; Pharmazeutische Mikrobiologie, Bonn, Germany; Zentrum für Hygiene, Freiburg, Germany; Institut für Medizinische Mikrobiologie, Cologne, Germany; Institut für Medizinische Mikrobiologie, Frankfurt, Germany; MEDQM, Berlin, Germany; Institut für Medizinische Mikrobiologie, Aachen, Germany; LAIKON General Hospital, Athens, Greece; Ippokrateion Hospital, Thessaloniki, Greece; Geniko Nomarhiako Mitilinis Hospital, Mitilini, Greece; Geniko Nomarhiako Kerkyras Hospital "Agia Eirini," Kerkyra, Greece; Geniko Nomarhiako Rethimnou Hospital, Rethimno, Greece; AHEPA Hospital, Thessaloniki, Greece; Geniko Kratiko Periferiako Patras Hospital "Agios Andreas," Patra, Greece; National and Capodistrian University of Athens, Athens, Greece; Universita degli studi di Genova, Genoa, Italy; Laboratorio Analisi Presidio Ospedaliero Macedon, Milan, Italy; Laboratorio Analisi Chimicocliniche Microbiologia, Sondalo, Italy; Streeklaboratorium Siunt Elisabeth Ziekenhuis, Tilburg, The Netherlands; Medische Microbiologie Diaconessenhuis, Utrecht, The Netherlands; Medische Microbiologie Ziekenhuis De Heel, Zaandam, The Netherlands; Streeklaboratorium Zeeland, Terneuzen, The Netherlands; Eijkman-Winkler Institute, Utrecht, The Netherlands; St. P.A.M.M., Veldhoven, The Netherlands; Academisch Ziekenhuis Maastricht, Maastricht, The Netherlands; Medische Microbiologie Vrije Universiteit AZVU, Amsterdam, The Netherlands; Streeklaboratorium GG & GD, Amsterdam, The Netherlands; Laborator. Medische Microbiologie D. C. SSDZ, Delft, The Netherlands; Medische Microbiologie, Groot Ziekengasthuis, Den Bosch, The Netherlands; Medische Microbiologie Westende Ziekenhuis, Den Haag, The Netherlands; Streeklaboratorium vd Volsgezondheid, Enschede, The Netherlands; Streeklaboratorium Zeeland, Goes, The Netherlands; Streeklaboratorium vd Volksgezondheid, Groningen, The Netherlands; Streeklaboratorium vd Volksgezondheid, Haarlem, The Netherlands; C.B.S.L., Hilversum, The Netherlands; Streeklaboratorium vd Volksgezondheid, Leeuwarden, The Netherlands; Regionaal Med. Microbiologisch Lab. Zuiderzieknhuis, Rotterdam, The Netherlands; Central Sera and Vaccines Laboratory, Warsaw, Poland; Hospital Gregorio Maranon, Madrid, Spain; Lund University Hospital, Lund, Sweden; Universitaire Vaudois Hospitalier, Lausanne, Switzerland; St. Thomas Hospital, London, United Kingdom; and The North Middlesex Hospital, London, United Kingdom.
The participating centers in North America were Mount Sinai Hospital, Toronto, Ontario, Canada; Health Sciences Centre, Winnipeg, Manitoba, Canada; Calgary Laboratory Services, Calgary, Alberta, Canada; Victoria General Hospital, Victoria, British Columbia, Canada; St. Joseph's Health Centre, London, Ontario, Canada; General Hospital, St. John's Newfoundland, Canada; Hospital Maisonneuve-Rosemont, Montreal, Quebec, Canada; The Moncton Hospital, Moncton, New Brunswick, Canada; QE II Health Services Centre, Halifax, Nova Scotia, Canada; Ottawa Hospital, Ottawa, Ontario, Canada; Princess Margaret Hospital, Toronto, Ontario, Canada; The Toronto Hospital, Toronto, Ontario, Canada; Hospital General de Durango; Durango, Mexico; Instituto Nacional de la Nutricion "Salvador Zubiran," Mexico City, Mexico; Departamento de Infectologia Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico; Instituto Mex. del Seguro Social, Monterrey, Mexico; Asesores Especializadores en Lab., Puebla, Mexico; Lab. de Bacteriologia 3er Piso, Instituto Nacional Ped., San Jose Insurgentes, Mexico; Hospital Infantil de Mexico, Mexico City, Mexico; Stanford University Hospital, Stanford, Calif.; The Bryn Mawr Hospital, Bryn Mawr, Pa.; and Evanston Northwestern Healthcare, Evanston, Ill.
The participating centers in South America were FUNCEI Centro de Estudios Infectologicos, Buenos Aires, Argentina; Hospital Medico Policial Churruca-Visca, Buenos Aires, Argentina; Centro de Infectologia, Buenos Aires, Argentina; Hospital Britanico de Buenos Aires, Buenos Aires, Argentina; Centro de Estudios Microbiologicos, Buenos Aires, Argentina; Instituto de Infectologia Emilio Ribas, Sao Paulo, Brazil; Silo Controle de Qualidade em Alimentos E Productos Ltda., Rio de Janeiro, Brazil; Laboratorio do Hospital Santa Helena, Sao Paulo, Brazil; Laboratorio Medico Santa Luzia, Florianopolis, Brazil; Laboratorio Fleury, Sao Paulo, Brazil; and Laboratorio da Faculdade de Ciencias Farmaceuticas, Sao Paulo, Brazil.
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ACKNOWLEDGMENT |
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This study was supported by a grant from SmithKline Beecham.
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FOOTNOTES |
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* Corresponding author. Mailing address: International Health Management Associates, Inc., West Meadows Business Park, 1675 Winnetka Circle, Rolling Meadows, IL 60008. Phone: (847) 577-9135. Fax: (847) 577-7192. E-mail: dhoban{at}ihmainc.com.
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Materials and Methods
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Discussion
Appendix
References
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Antimicrobial Agents and Chemotherapy, November 2000, p. 3008-3011, Vol. 44, No. 11
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Copyright © 2000, American Society for Microbiology. All rights reserved.
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