Regional trends in β-lactam, macrolide, fluoroquinolone and telithromycin resistance among Streptococcus pneumoniae isolates 2001–2004

Journal of Infection (2007) 55, 111e118

www.elsevierhealth.com/journals/jinf

Regional trends in b-lactam, macrolide, fluoroquinolone and telithromycin resistance among Streptococcus pneumoniae isolates 2001—2004 ´n b, Stephen G. Jenkins c David Felmingham a,*, Rafael Canto a

G.R. Micro Ltd, 7-9 William Road, London NW1 3ER, UK Hospital Universitario Ramo´n y Cajal, Servicio de Microbiologı´a, Carretera de Colmenar Km 9.1, Madrid, Spain c Clinical Microbiology Laboratories, Mount Sinai School of Medicine, New York, NY 10029-6574, USA b

Accepted 17 April 2007 Available online 12 June 2007

KEYWORDS Streptococcus pneumoniae; Antimicrobial resistance; Multiple resistance; Penicillin; Macrolides; Ketolide; Telithromycin; erm (A); erm (B); erm (TR); mef (A)

Summary Objectives: To determine global antibacterial resistance rates among communityacquired isolates of Streptococcus pneumoniae. Methods: Between 2001 and 2004, 20,142 S. pneumoniae isolates from 151 centres in 40 countries were collected and tested for susceptibility to common antibacterials in the PROTEKT surveillance study. Results: The prevalence of b-lactam and macrolide resistance did not change, but there was marked geographic variability. The most common macrolide resistance mechanism was ribosomal methylation mediated by erm(B), except in Canada, Greece and the USA where drug efflux mediated by mef(A) was predominant. The erythromycin minimum inhibitory concentration for mef(A) isolates increased significantly (P < 0.001; c2 test). The global prevalence of macrolide-resistant isolates positive for both erm(B) and mef(A) was 12.0% in 2003e2004; erm(B)þmef(A) strains were particularly common in South Korea (40.8%), South Africa (46.4%) and the USA (29.6%). Telithromycin was the most active antibacterial tested. Over the studied period, 99.7% of all isolates and >99% of erythromycin-resistant isolates, irrespective of genotype, were susceptible to telithromycin. Conclusions: These results confirm the high worldwide prevalence of resistance to commonly used antibacterial agents and multiple resistance phenotypes among clinical isolates of S. pneumoniae and suggest that high-level macrolide resistance is continuing to increase in most countries. ª 2007 The British Infection Society. Published by Elsevier Ltd. All rights reserved.

* Corresponding author. Tel.: þ44 (0)20 7388 7320; fax: þ44 (0)20 7388 7324. E-mail address: [email protected] (D. Felmingham). 0163-4453/$30 ª 2007 The British Infection Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jinf.2007.04.006

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Introduction Streptococcus pneumoniae remains the most common bacterial pathogen causative of community-acquired pneumonia,1 and is also a major aetiological agent implicated in episodes of acute bacterial exacerbations of chronic bronchitis2 and acute bacterial sinusitis.3 In recent years, a number of international and national surveillance studies4e8 have documented high levels of antibacterial resistance in S. pneumoniae, leading to concerns over the continued clinical utility of agents such as the macrolides for the empirical treatment of communityacquired respiratory tract infections (RTIs).9 For example, published studies and case reports (reviewed by Rzeszutek and colleagues10 and a recent report by Daneman et al.11) have suggested a link between pneumococcal macrolide resistance and treatment failure (resulting in hospitalization) in patients with community-acquired RTIs. Two mechanisms account for the majority of cases of pneumococcal macrolide resistance: methylation of ribosomal macrolide target sites, typically encoded by erm(B), and drug efflux, encoded by mef(A),12,13 with the erm(B)mediated mechanism predominating in most parts of the world. S. pneumoniae isolates positive for both erm(B) and mef(A) have also been confirmed in the USA and elsewhere14,15 and are predominantly multiresistant and clonal in nature.15 The prevalence of erm(B)þmef(A)-mediated resistance has risen in some countries, in particular the USA, in recent years.15,16 Pneumococcal resistance to macrolides may also be conferred by ribosomal mutations, including mutations in domains II and V of the 23S ribosomal RNA and in genes encoding riboproteins L4 and L22.17 However, reports are rare to date of such ribosomal mutations among macrolide-resistant clinical isolates of S. pneumoniae.17 The PROTEKT (Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin) study was initiated in 1999. This longitudinal, international surveillance study was designed to evaluate the activity of telithromycin, a new ketolide antibacterial, against S. pneumoniae and other common RTI pathogens and to compare its activity with that of other antibacterial agents.6 This report analyses temporal and geographical trends in the phenotypic susceptibility and genotypes of S. pneumoniae isolates collected during Years 3e5 of PROTEKT (2001e2004) with a focus on the most recent (Year 5) patterns of macrolide resistance.

Materials and methods Collection centres Isolates of S. pneumoniae were collected from a total of 151 centres from 40 countries worldwide over the latest 3 years of the PROTEKT study (Year 3, 2001e2002; Year 4, 2002e2003; Year 5, 2003e2004).

Bacterial isolates Respiratory tract isolates of S. pneumoniae, deemed pathogenic on isolation, were collected from adult and paediatric outpatients with clinically diagnosed community-acquired

D. Felmingham et al. RTIs (bacterial sinusitis, acute otitis media, community-acquired pneumonia, acute bacterial exacerbations of chronic bronchitis and acute exacerbations of chronic obstructive pulmonary disease). S. pneumoniae isolates cultured from material collected from hospitalized patients within 48 h of admission were also included. The following specimens/sources were considered acceptable: blood, sputum, bronchoalveolar lavage fluid, middle-ear fluid (via tympanocentesis), nasopharyngeal swab or aspirate, and sinus aspirate. Patients with nosocomial RTIs and those with cystic fibrosis were excluded. Duplicate strains, or strains originating from existing banked collections, were also excluded from the study. Details of the methods for isolate storage, transportation and identification have been reported previously along with the demographic data collected from each patient (e.g. age and sex).6

Antibacterial susceptibility testing Minimum inhibitory concentrations (MICs) of antibiotics commonly used in the empiric treatment of communityacquired RTIs were determined at a central laboratory (G.R. Micro Ltd, London, UK) using the Clinical and Laboratory Standards Institute broth microdilution method.18 MIC interpretive criteria (breakpoints) were used to determine susceptibility to a panel of antibacterials.19 In the case of cefuroxime, the interpretative criteria for oral cefuroxime axetil were used.

Genotyping Erythromycin-resistant (MIC  1 mg/L) pneumococcal isolates were analysed for the presence of erm(B), erm(A) subclass erm(TR) and mef(A) macrolide resistance genes using a multiplex rapid-cycle polymerase chain reaction (PCR) with microwell-format probe hybridization in Year 120 and a Taqman-based PCR assay in subsequent years.21

Regions For the purposes of some analyses, isolates were grouped according to the following geographical regions: Far East (China, Hong Kong, Japan, South Korea and Taiwan); Latin America (Argentina, Brazil, Colombia, Ecuador, Guatemala, Mexico, Peru and Venezuela); Middle East (Saudi Arabia, Israel); North America (Canada and USA); Northern Europe (Austria, Belgium, Czech Republic, Finland, Germany, Hungary, Ireland, The Netherlands, Poland, Russia, Slovak Republic, Sweden, Switzerland and UK); and Southern Europe (Bulgaria, France, Greece, Italy, Portugal, Spain and Turkey). South Africa and Australia were not grouped with other countries.

Statistical methods Homogeneity of data between years was tested globally and by country using either a c2 test (number of expected isolates 5 in all cells of the contingency table) with Yates’s correction for expected cases <10, or by Fisher’s exact test (number of expected isolates < 5 in any cell). Analysis by country was performed by aggregating data from centres that had participated in all 3 years of the study. Temporal trends

S. pneumoniae resistance trends (2001e2004) were examined only among isolates supplied from centres that participated in Years 3, 4 and 5. A significance level of 0.05 was used throughout.

Results A total of 20,142 S. pneumoniae isolates were collected over the 3 years of this analysis: 6320 in Year 3, 6739 in Year 4 and 7083 in Year 5.

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Antibacterial resistance patterns Table 1 summarizes the in vitro activity of a range of antibacterials against S. pneumoniae isolates collected between 2001 and 2004. Overall, more than one-third of the isolates exhibited reduced susceptibility to penicillin (comprising penicillin-intermediate S. pneumoniae [PISP] and penicillin-resistant S. pneumoniae [PRSP] isolates), with most of these isolates being PRSP. Approximately one-quarter of the S. pneumoniae isolates demonstrated

Table 1 In vitro activity of a range of antibacterials against Streptococcus pneumoniae isolates collected during Years 3e5 (2001e2004) of the PROTEKT study Antibacterial

Year 3 (n Z 6320)

Year 4 (n Z 6739)

Year 5 (n Z 7083)

Penicillin MIC50 (mg/L) MIC90 (mg/L) MIC range (mg/L) Susceptible (%) Intermediate (%) Resistant (%)

0.03 4 0.008 to 8 62.4 13.6 24.0

0.03 4 0.008 to 8 63.8 13.9 22.3

0.03 4 0.008 to 8 62.6 13.4 23.9

Amoxicillineclavulanate MIC50 (mg/L) MIC90 (mg/L) MIC range (mg/L) Susceptible (%) Intermediate (%) Resistant (%)

0.03 2 0.008 to 8 93.1 3.3 3.6

0.03 2 0.008 to 8 93.4 3.5 3.2

0.03 2 0.008 to 8 92.6 3.4 4.0

Cefuroxime MIC50 (mg/L) MIC90 (mg/L) MIC range (mg/L) Susceptible (%) Intermediate (%) Resistant (%)

0.06 8 0.015 to 16 71.3 1.9 26.8

0.06 8 0.015 to 16 72.7 1.9 25.4

0.06 8 0.015 to 16 68.1 3.2 28.7

Erythromycin MIC50 (mg/L) MIC90 (mg/L) MIC range (mg/L) Susceptible (%) Intermediate (%) Resistant (%)

0.06 128 0.03 to 128 63.0 0.1 36.9

0.06 128 0.03 to 128 63.5 0.1 36.4

0.06 128 0.03 to 128 62.6 0.1 37.2

Telithromycin MIC50 (mg/L) MIC90 (mg/L) MIC range (mg/L) Susceptible (%) Intermediate (%) Resistant (%)

0.015 0.12 0.002 to 8 99.8 0.1 0.1

0.015 0.12 0.002 to 8 99.7 0.1 0.2

0.015 0.25 0.002 to 16 99.8 0.1 0.1

Levofloxacin MIC50 (mg/L) MIC90 (mg/L) MIC range (mg/L) Susceptible (%) Intermediate (%) Resistant (%)

1 1 0.5 to 64 99.2 0.1 0.7

1 1 0.5 to 64 99.0 0.1 1.0

1 1 0.5 to 64 99.1 0.1 1.0

MIC, minimum inhibitory concentration.

114

D. Felmingham et al. 90 PISP PRSP

80

Prevalence (%)

70 60 50 40 30 20 10 0 Y3 Y4 Y5

Y3 Y4 Y5

Y3 Y4 Y5

Y3 Y4 Y5

Australia

Far East

n = 657

n = 5155

Latin America n = 2889

North America n = 4155

Y3 Y4 Y5

Y3 Y4 Y5

Y3 Y4 Y5

Northern Southern South Europe Europe Africa n = 7170 n = 5479 n = 1611

Figure 1 Regional prevalence of penicillin nonsusceptibility among Streptococcus pneumoniae isolates collected during Years 3e5 of the PROTEKT study. PISP, penicillin-intermediate S. Pneumoniae. PRSP, penicillin-resistant S. pneumoniae. Y, year.

resistance to cefuroxime, while >90% were susceptible to amoxicillineclavulanate. Susceptibility rates for penicillin, cefuroxime and amoxicillineclavulanate did not change substantially over the 3 years. Global macrolide resistance remained stable over the 3 years (37% in Year 5); the MIC50 of erythromycin and clarithromycin remained at 0.06 mg/L, while the MIC50 of azithromycin was 0.12 mg/L in Years 3e5. The prevalence of levofloxacin resistance remained stable at around 1%, while a mean of 0.2% of isolates showed resistance to telithromycin. There was no significant temporal trend in the prevalence of penicillin resistance in any one country. Combining data from Years 3e5, the prevalence of penicillin nonsusceptibility (PISP þ PRSP) varied markedly among different regions of the world (Fig. 1). Isolates from South Africa showed the highest rates (74%), followed by the Far East (w63%) and the Middle East (54%). Rates in Southern Europe were higher than those in Northern Europe (Year

3e5 PRSP 25.7% versus 6.1%; PISP 12.7% versus 7.3%, Years 3e5; P < 0.0001). The prevalence of penicillin nonsusceptibility (PISP þ PRSP) was particularly high in France (40.4% þ 15.9%), Greece (42.0% þ 15.9%) and Spain (29.4% þ 13.1%). As with penicillin resistance, there was no significant temporal trend in the prevalence of macrolide resistance in any country and therefore the data from Years 3e5 were combined. The geographical pattern of macrolide resistance was somewhat different to that of penicillin nonsusceptibility (Fig. 2); the highest rates (w80%) were recorded among isolates collected in the Far East, followed by South Africa (w54%) and Southern Europe (w37%), whereas resistance was lowest in Latin America (w15%), Australia (w18%) and Northern Europe (w18%). Macrolide resistance in Europe was notably high for isolates collected in Year 5 from Belgium (31.5%), Spain (33.5%), Hungary (39.4%), Italy (40.8%), Greece (51.4%) and France (55.6%).

90 80

Prevalence (%)

70 60 50 40 30 20 10 0 Y3 Y4 Y5

Y3 Y4 Y5

Australia

Far East

n = 657

n = 5155

Y3 Y4 Y5

Latin America n = 2889

Y3 Y4 Y5

North America n = 4155

Y3 Y4 Y5

Northern Europe n = 7170

Y3 Y4 Y5

Southern Europe n = 5479

Y3 Y4 Y5

South Africa n = 1611

Figure 2 Regional prevalence of erythromycin resistance among Streptococcus pneumoniae isolates collected during Years 3e5 of the PROTEKT study.

S. pneumoniae resistance trends (2001e2004) 100

Susceptibility (%)

80

99.1 99.4 98.1 98.3

PRSP ERSP

84.9

115

69.2

60 34.4

40

29.0 21.8

21.8

21.9

20 0

0

0

0.1

0.2

Am ox Pe ic ni illi ci n– llin cl av ul an at e C ef ur ox im Er e yt hr om yc in Az ith ro m yc C in la rit hr om yc in Te lit hr om yc in Le vo flo xa ci n

0

Figure 3 Antibacterial susceptibility prevalence among penicillin-resistant Streptococcus pneumoniae (PRSP; n Z 1696) and erythromycin-resistant S. pneumoniae (ERSP; n Z 2638) isolates collected during Year 5 of the PROTEKT study.

Approximately 50% of the isolates exhibited no resistance to any of the antibacterial classes tested. Among organisms exhibiting antibacterial resistance, 47% were resistant to one or two antibacterial classes, 35% showed resistance to 3 or 4 antibacterial classes and 18% showed resistance to 5 or 6 antibacterial classes. The prevalence of the various categories of multiple-resistant organisms did not change significantly over the 3 years of the study. A total of 46 isolates (0.2%) were resistant to all six classes of antibacterials tested, but all of these isolates were susceptible to telithromycin. The susceptibility to various antibacterials of PRSP and erythromycin-resistant S. pneumoniae (ERSP) isolates collected in Year 5 of the study is shown in Fig. 3. More than three-quarters of PRSP isolates were resistant to the three macrolides tested and only w70% were susceptible to amoxicillineclavulanate. Almost all PRSP isolates were coresistant to cefuroxime. Among ERSP isolates, approximately one-third were susceptible to penicillin or cefuroxime; 84.9% of the ERSP isolates were susceptible to amoxicillineclavulanate. More than 98% of the PRSP and ERSP isolates were susceptible to levofloxacin, with >99% susceptible to telithromycin.

Macrolide resistance mechanisms Globally, the most common macrolide resistance genotype among ERSP was erm(B) (w58%), followed by mef(A) (w30%). Isolates positive for both resistance genes [erm(B)þmef(A)] made up 12% of all macrolide-resistant isolates collected in Year 5. The prevalence of these genotypes did not change substantially over the 3 years. Isolates exhibiting the erm(B) or erm(B)þmef(A) genotypes exhibited high-level erythromycin resistance (MIC90  128 mg/L), whereas isolates expressing mef(A) alone were associated with lower-level erythromycin resistance (MIC90 16 mg/L) (Table 2). However, the erythromycin MIC values for a large proportion of the mef(A) isolates were >8 mg/L. Among mef(A) strains, the distribution of MICs differed significantly between Years 3 and 5 (P < 0.0001; c2 test) and the MIC90 increased from 8 mg/L in Year 3 to 16 mg/L in Years 4 and 5 (Fig. 4). In total, 6 mef(A) isolates exhibited an erythromycin MIC of 128 mg/L; five of these isolates were from Japan and one from the USA. The distribution of resistance genotypes among Year 5 isolates differed considerably between countries (Fig. 5). For example, erm(B) predominated in most European countries (e.g. Belgium [91.5%], France [90.0%], Italy [55.8%], Poland [80.8%] and Spain [88.3%]), whereas mef(A) was the most common genotype among isolates collected in Canada (57.7%), Greece (66.2%) and the USA (55.2%). Erm(B)þmef(A) isolates were particularly common in China (21.6%), South Africa (46.4%), South Korea (40.8%) and the USA (29.6%). Telithromycin exhibited good antibacterial activity against ERSP isolates irrespective of the resistance mechanism. All mef(A)-positive isolates were susceptible to telithromycin; for the 6 mef(A) isolates with erythromycin MICs  128 mg/L, the telithromycin MICs ranged from 0.03e1 mg/L. Fewer than 1% of erm(B) and erm(B)þmef(A) strains exhibited telithromycin resistance. All isolates with ribosomal mutations were susceptible to telithromycin.

Discussion The current analysis demonstrates that pneumococcal antibacterial resistance remains common across many

Table 2 Erythromycin and azithromycin MICs for erythromycin-resistant Streptococcus pneumoniae isolates collected during PROTEKT Years 3e5 by genotype Genotype

No. of isolates

MIC (mg/L) Erythromycin

erm(B) mef(A) erm(B)þmef(A) Ribosomal mutation erm(TR) erm(TR)þmef(A)

3289 1971 720 86 5 1

MIC, minimum inhibitory concentration.

Azithromycin

MIC50

MIC90

MIC range

MIC50

MIC90

MIC range

128 4 128 128

128 16 128 128

1 to 1 to 1 to 1 to 1 to 16

128 128 128 128 128

128 4 128 128

128 16 128 128

2 to 128 1 to 128 2 to 128 0.25 to 128 4 to 128 32

116

D. Felmingham et al.

Year 3 50 40 30 20

*

10 0 1

2

4

8

16

32

128

32

128

32

128

Year 4 Isolates (%)

50 40 30 20

*

10 0 1

2

4

8

16

Year 5 50 40 30

*

20 10 0 1

2

4

8

16

Erythromycin MIC (mg/L)

Figure 4 MIC distribution of mef(A)-positive strains over Years 3e5 of the PROTEKT study. The asterisk denotes the MIC90 in each year. MIC, minimum inhibitory concentration.

regions of the world. Approximately one-third of S. pneumoniae isolates worldwide were nonsusceptible to penicillin with little substantial change between 2001 and 2004. Other studies have indicated that, in some individual countries with very high penicillin resistance levels, penicillin resistance may be decreasing.22 Macrolide resistance is

erm(B)

mef(A)

also exhibited by approximately one-third of pneumococcal isolates and there is evidence that this type of resistance may still be increasing. It is of concern that there may be a considerable delay between the restriction of macrolide prescriptions and a reduction in the resistance of S. pneumoniae to these agents.23 In the majority of regions, macrolide resistance was more prevalent than penicillin resistance, which is corroborated by previous surveillance studies.24e27 Different levels of macrolide resistance are associated with the two most common macrolide resistance mechanisms.28,29 The predominant macrolide resistance mechanism globally was ribosomal methylation mediated by erm(B). This genotype is associated with high-level resistance to macrolide, lincosamide and streptogramin B antibacterials.28,29 Consistent with this, erythromycin MICs were 128 mg/L for >97% of the erm(B) isolates analysed in the present study. Isolates positive for mef(A) remained common in several parts of the world and mef(A) was found to be the most prevalent macrolide resistance mechanism in the USA and Canada, as well as in a number of other countries. There was evidence that the prevalence of mef(A)-mediated resistance may be declining in the face of an increasing prevalence of isolates exhibiting both mef(A) and erm(B) mechanisms, as will be discussed later. One notable finding from the current analysis was an increase in the level of macrolide resistance observed among isolates positive for mef(A), a genotype traditionally associated with lower-level resistance (MICs of 2e4 mg/L).29,30 The MIC range for erythromycin among mef(A) isolates was from 0.06 to 128 mg/L, with an MIC90 of 16 mg/L. A number of hypotheses may explain these findings including the possibility that a specific clone with higher resistance to erythromycin is emerging among mef(A)-positive strains. This would not explain the isolates with very high erythromycin MICs (128 mg/L), but could explain the general upwards shift in the erythromycin MIC distribution. Alternatively, additional resistance mechanisms may be present in these mef(A) isolates, which were not detected by the genotyping method used in this study, or isolates

erm(B) + mef(A)

Othera

Proportion of isolates (%)

100

80

60

40

20

0 Belgium (n = 59)

Canada China France Germany (n = 104) (n = 102) (n = 170) (n = 111)

Greece (n = 77)

Hong Kong (n = 50)

Italy Japan (n = 104) (n = 715)

Poland (n = 26)

S Africa (n = 263)

S Korea (N=98)

Spain Taiwan USA (n = 128) (n = 123) (n = 125)

Figure 5 Distribution of macrolide resistance mechanisms among erythromycin-resistant Streptococcus pneumoniae isolates collected in selected countries during Year 5 of the PROTEKT study. aIsolates exhibiting ribosomal mutations, erm(TR) and those not viable for testing.

S. pneumoniae resistance trends (2001e2004) may be exhibiting more efficient expression of the drug efflux pump encoded by mef(A). In countries where mef(A) remains the predominant mechanism of resistance there is, therefore, the risk of high-level erythromycin resistance developing among isolates with this genotype. Further surveillance will be required to confirm these trends and validate the different hypotheses. A second notable finding arising from the genotyping analysis performed in this study was the rise in the global prevalence of macrolide-resistant isolates with combined erm(B)- and mef(A)-encoded resistance. Recent US data suggest that >90% of erm(B)þmef(A) isolates from paediatric patients are related to the international Taiwan19F-14 clone 15 and are either serotype 19A or 19F.31 The distribution of these two serotypes has changed since the introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) into the US vaccine schedule in 2000. Serotype 19F predominated in 2000e2001 but, by 2004e2005, 19A and 19F were approximately equal in prevalence. Other evidence suggests that pneumococcal disease in the USA caused by 19A has increased from 2.0% of cases in children below the age of 2 during 1999 to 8.3% during 2004.32 Serotype 19F is included in PCV7 but it is the least effective component of the vaccine 33 and there is little evidence of cross protection against 19A, which is not included in the vaccine. The switch among pneumococci from serotype 19F to 19A predates the introduction of PCV-7,34 but it is likely that selective immunological pressure in favour of 19A is occurring in the USA and other countries that have introduced PCV-7. Many isolates with the erm(B)þmef(A) genotype exhibit high-level macrolide resistance coupled with co-resistance to multiple antibacterial classes which may be conferring a selective advantage in an age of high antibacterial use.15 Combined with the potential for serotype switching to escape coverage by currently available vaccines, these isolates may pose serious problems in the future for the treatment of patients with community-acquired RTIs. Fortunately, telithromycin resistance in S. pneumoniae remains uncommon, with an overall rate of 0.1%. Moreover, telithromycin was the most effective antibacterial tested against ERSP, including strains with the erm(B)þmef(A) genotype. In summary, results from Years 3e5 of the PROTEKT study indicate that resistance to commonly used b-lactams and macrolide antibacterials and multiple antibacterial resistance in S. pneumoniae remains high worldwide. However, considerable geographical variability exists and, among macrolide-resistant strains, there is evidence of an increasing prevalence of isolates with the combined erm(B)þmef(A) genotype. The ketolide telithromycin retained potent activity against S. pneumoniae isolates collected between 2001 and 2004, including strains resistant to other antibacterials.

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