Journal of Antimicrobial Chemotherapy (2001) 48, 659-665
© 2001 The British Society for Antimicrobial Chemotherapy
Increasing resistance of Streptococcus pneumoniae to fluoroquinolones: results of a Hong Kong multicentre study in 2000
a Department of Microbiology, Division of Infectious Diseases, The University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Pokfulam, Hong Kong SAR; h School of Professional and Continuing Education, The University of Hong Kong; b Department of Clinical Pathology, Pamela Youde Nethersole Eastern Hospital; c Department of Clinical Pathology, Queen Elizabeth Hospital; d Department of Clinical Pathology, Tuen Mun Hospital; e Department of Clinical Pathology, Kwong Wah Hospital; f Department of Microbiology, Queen Mary Hospital; g Department of Clinical Pathology, Princess Margaret Hospital, Hong Kong SAR, China
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Abstract |
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The MICs of 13 antimicrobial agents including seven fluoroquinolones (ciprofloxacin, levofloxacin, sparfloxacin, grepafloxacin, gatifloxacin, moxifloxacin and clinafloxacin) for Streptococcus pneumoniae isolates obtained from all regions of Hong Kong in the year 2000 were determined by the Etest. Overall, 39.4% of 180 isolates were susceptible to penicillin, 11.7% were intermediate and 48.9% were resistant. The overall prevalence of fluoroquinolone non-susceptibility (levofloxacin MIC 4 mg/L) was 13.3% but increased to 27.3% among the penicillin-resistant isolates. For the fluoroquinolone non-susceptible isolates, within-class cross-resistance was common. For the fluoroquinolone non-susceptible isolates, the median MICs of clinafloxacin, gatifloxacin, moxifloxacin, sparfloxacin and grepafloxacin were, respectively, six-, 24-, 32- 84- and 128-fold higher than those for the susceptible isolates. All fluoroquinolone non-susceptible strains were derived from adults. The prevalence of fluoroquinolone resistance was higher in isolates from older patients (17.1% among those 65 years of age versus 9.1% among those 18–64 years of age, P < 0.001) and from adults with chronic obstructive pulmonary disease (24.6% versus 9.3%, P = 0.01). All fluoroquinolone non-susceptible strains were non-susceptible to penicillin (MIC range 2–4 mg/L), cefotaxime (MIC range 1–4 mg/L) and erythromycin (MIC range 4–256 mg/L). The fluoroquinolone non-susceptible isolates were genetically related to the Spain23F-1 clone when analysed by pulse-field gel electrophoresis and multilocus sequence typing. In conclusion, a rapid increase in the prevalence of fluoroquinolone resistance among S. pneumoniae was found in Hong Kong. Typing analysis suggests that this is due to the pan-regional dissemination of a fluoroquinolone-resistant variant (designated Hong Kong23F-1) of the globally distributed Spain23F-1 clone.
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Introduction |
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The upsurge of multiply resistant strains of Streptococcus pneumoniae in recent years has spawned interest in the use of fluoroquinolones to treat respiratory tract infections. Many agents in this antimicrobial class have been evaluated both experimentally and clinically. The newer members have been termed ‘respiratory fluoroquinolones’ or ‘third generation fluoroquinolones’ because of their superior activities against Gram-positive cocci compared with the older fluoroquinolones.1 In recent surveys involving large numbers of S. pneumoniae isolates, the newer agents gatifloxacin and moxifloxacin were generally eight- to 16-fold more potent than older agents such as ciprofloxacin, ofloxacin and levofloxacin. Among the pneumococci, resistance to the respiratory fluoroquinolones remains rare in most countries but continued surveillance is required, particularly in regions where there are strains showing reduced susceptibility to the older fluoroquinolones. Hong Kong, together with Ireland, Canada and Spain, are regions that have reported increasing rates of fluoroquinolone resistance among the pneumococci.2–5 In Hong Kong, for example, the percentage of S. pneumoniae resistant to fluoroquinolones has increased from <0.5% in 1995 to 5.5% in 1998.4 The purpose of the present study was to evaluate the comparative activities of fluoroquinolones including four recent fluoroquinolones (grepafloxacin, gatifloxacin, moxifloxacin and clinafloxacin) against contemporary isolates of S. pneumoniae from Hong Kong.
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Materials and methods |
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Bacterial isolates and patient data
During a 4 month period from January to April 2000, isolates of S. pneumoniae were collected from six participant hospital laboratories located in widely separated areas of Hong Kong. These hospitals cover over half of the population in this region. Each laboratory submitted 30 consecutive, non-duplicate isolates of S. pneumoniae derived from clinical samples. Isolates obtained from the same patient during the same episode of infection were only included once. From each laboratory only one isolate per patient accompanied by relevant strain-specific patient data (date of isolation, site of bacterial isolation, age, gender, patient identifying number and co-morbidity) was referred for study. Co-morbidity was defined as any underlying illness that might increase the risk of infection. All isolates were subcultured and re-identified using colony morphology, Gram's stain, optochin susceptibility and bile solubility. Isolates were stored at –20°C until tested in batches. Only pure culture isolates were included in the final study. During the study period, the infection control service in the hospitals did not identify any clustering of pneumococcal diseases.
Antimicrobial agents
Etest strips of penicillin, amoxicillin (as co-amoxiclav 2:1), erythromycin, cefuroxime, cefotaxime, quinupristin/dalfopristin, ciprofloxacin, levofloxacin, sparfloxacin, grepafloxacin, gatifloxacin, moxifloxacin and clinafloxacin were purchased from AB Biodisk, Solna, Sweden. Moxifloxacin and levofloxacin powders with known potencies were kindly provided by Bayer China Company, Ltd, Hong Kong, China and the R. W. Johnson Pharmaceutical Research Institute, Raritan, NJ, USA, respectively.
Determination of MICs and interpretation
Etest MICs were determined according to the manufacturer's instructions. All susceptibility testing was carried out in a single laboratory at the University of Hong Kong. Test inocula were prepared from pneumococcal colonies grown on sheep blood agar that had been incubated for 20–24 h in 5% CO2. Colonies were suspended in 0.9% saline to obtain a suspension equivalent to the turbidity of a 0.5 McFarland standard. From this suspension, Etests were performed on Mueller–Hinton agar with 5% sheep blood (BBL, Becton Dickinson Microbiology Systems, Cockeysville, MD, USA). The plates were incubated at 35°C in 5% CO2 for 20–24 h. MICs falling between two marks on the Etest strip were rounded up to the next highest two-fold dilution, as recommended in the instructions. Broth microdilution tests were performed using the procedures described by the NCCLS. Cation-adjusted Mueller–Hinton broth (Difco, Detroit, MI, USA) supplemented with 5% horse blood was used as the test medium. Test inocula were prepared as above and further diluted within 15 min to provide a final inoculum density of 5 x 105 cfu/mL in the wells of the microdilution panels. For all MIC determinations, the bacterial inocula were validated by back titration in 10% of the tests to ensure the desired inoculum density. Quality control strains (S. pneumoniae ATCC 49619, Staphylococcus aureus ATCC 29213 and Escherichia coli ATCC 25922) were included with each run. Interpretation of results was according to published breakpoints of the NCCLS.6 For ciprofloxacin, the criteria were: susceptible, 
2 mg/L; resistant, 
4 mg/L.2 Fluoroquinolone non-susceptible pneumococci were defined as those for which the MIC of levofloxacin was at least 4 mg/L.
Typing of isolates
The subset of 24 isolates with reduced susceptibility to levofloxacin was examined further by serotyping, multilocus sequence typing (MLST) and pulsed-field gel electrophoresis (PFGE). Serotyping of the isolates was determined by the Quellung reaction7 using sera with various reactivities from the Statens Seruminstitut (Copenhagen, Denmark). Protocols for PFGE analysis and MLST have been described previously.8,9 SmaI was used for digestion of DNA in the PFGE analysis and the results were interpreted according to a scheme suggested by Tenover et al.10 Strain SP264 (kindly provided by K. P. Klugman), representative of the Spain23F-1 clone was used as a control in the PFGE and MLST analysis.
Statistical analysis
The 
2, Fisher's exact or the Kruskal–Wallis test was used for statistical analysis. A P value of <0.05 was considered significant.
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The number of isolates obtained from different age groups was as follows: <2 years (four); 2–5 years (six); 6–17 years (nine); 18–49 years (23); 50–64 years (21) and
65 years (117). Of the isolates, 156 (86.7%) were from sputum, eight from tracheal aspirate, three from blood, two from bronchoalveolar lavage fluid and 11 from eye, ear or nose. The patient's co-morbidity was provided for 172 (95.6%) isolates. One or more co-morbidity was present in 59.9% (103/172) of the patients. The most common was chronic obstructive pulmonary disease (COPD) (57), followed by neurological disease (20), malignancy (18), heart disease (10), diabetes mellitus (eight), bronchiectasis (four) and systemic lupus erythematosis (two).
The susceptibilities of the 180 pneumococcal isolates to 13 antimicrobial agents are summarized in Table 1
. The MICs of amoxicillin were generally identical or within a two-fold dilution of that of penicillin. High MICs of penicillin (4 mg/L), cefotaxime (4 mg/L) and erythromycin (32–256 mg/L) were found in 11.1% (20/180), 3.9% (7/180) and 25.6% (46/180) of the isolates, respectively. Rates of penicillin non-susceptibility were not significantly different between the various age groups. Penicillin MICs (geomean ± s.d.) were highest in hospital A (0.66 ± 1.1 mg/L), followed by hospitals C (0.51 ± 1.1 mg/L), E (0.5 ± 1.1 mg/L), B (0.23 ± 1.1 mg/L), F (0.21 ± 1.1 mg/L) and D (0.14 ± 0.7 mg/L) (Kruskal–Wallis test, P = 0.001). Between 12.2 and 17.8% of the strains were intermediately resistant or resistant to the seven fluoroquinolones. All fluoroquinolone non-susceptible strains were non-susceptible to penicillin (MIC range 2–4 mg/L), cefotaxime (MIC range 1–4 mg/L) and erythromycin (MIC range 4–256 mg/L).
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All fluoroquinolone non-susceptible isolates were from adults. Frequency of isolation was dissimilar in the hospitals (nine in A, three in B, four in C, one in D, six in E and one in F, P = 0.02). The prevalence of fluoroquinolone non-susceptibility was higher in isolates from older patients [17.1% (20/117) among those
65 years of age compared with 9.1% (4/44) among those 18–64 years of age, P < 0.001] and from adults with COPD [24.6% (14/57) compared with 9.3% (9/97), P = 0.01]. Fluoroquinolone non-susceptibility was not associated with the other co-morbidities. The MIC distribution of the seven fluoroquinolones for levofloxacin-susceptible and non-susceptible isolates is shown in Table 2. For fluoroquinolone-susceptible isolates, the rank order of potency (MIC50/MIC90 in mg/L) was as follows: clinafloxacin (0.094/0.125) > moxifloxacin (0.125/0.19) > gatifloxacin (0.25/0.38) > grepafloxacin (0.25/0.5) > sparfloxacin (0.38/0.5) > levofloxacin (0.75/1) > ciprofloxacin (1/2). For the levofloxacin non-susceptible isolates, within-class cross-resistance was common. For the fluoroquinolone non-susceptible isolates, the median MICs of clinafloxacin, gatifloxacin, moxifloxacin, sparfloxacin and grepafloxacin were six-, 24-, 32-, 84- and 128-fold higher than those for the susceptible isolates. For levofloxacin, MICs determined by Etest were generally two- to four-fold higher than those determined by broth microdilution. For moxifloxacin, Etest MICs were identical or within a two-fold dilution difference of those by broth microdilution. Overall interpretive agreement between the two methods was good for the two fluoroquinolones, with no major discrepancy.
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The levofloxacin non-susceptible isolates could be divided into three groups on the basis of their capsular serotypes, 23F (n = 9), 19F (n = 10) or 14 (n = 5). However, only one major cluster was identified by molecular analysis. Using MLST it was shown that a single allelic profile (4-4-2-4-4-1-1) was shared by strain SP264 and all 24 isolates. Similarly, by PFGE, 22 isolates gave patterns that were either indistinguishable from or closely related to that of SP264. The remaining two isolates were possibly related to SP264.
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Discussion |
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A marked increase in the overall prevalence of non-susceptibility to the fluoroquinolones was found compared with our previous study with strains obtained by a similar method in 1998.4 Over a period of <2 years, the prevalence of levofloxacin non-susceptibility increased from 5.5% to 13.3% among all the strains and from 9.2% to 28.4% among the penicillin-resistant strains. Such strains were found in all the participant laboratories involving 10 hospitals located in widely separated areas in Hong Kong. This indicated that levofloxacin non-susceptible S. pneumoniae is now widespread in this locality. Although the trend of decreasing susceptibility to fluoroquinolones is similar to that observed by others, studies in other countries have found only a modest increase in the rates of resistance. Chen et al. reported a rise in ciprofloxacin-resistant (MIC
4 mg/L) pneumococci from 1.5% to 2.9% in Canada between 1993 and 1998.2 In Spain, pneumococci with the same degree of fluoroquinolone non-susceptibility have increased from 0.9% in 1991–1992 to 3% in 1997–1998. In the USA, fluoroquinolone non-susceptibility (levofloxacin MIC 4 mg/L) among pneumococcal samples was 1.2% in 1999 compared with 0.2% in 1997–1998 and 0.03% in 1997.11–13
This investigation, in agreement with our earlier study,14 showed that fluoroquinolone non-susceptibility in pneumococci is associated with COPD and old age. Of the 24 resistant isolates, 20 (83.3%) were isolated from patients aged 65 years and 14 (58.3%) from patients with COPD. COPD patients are a group that are commonly colonized or infected with S. pneumoniae and when an exacerbation occurs the colony counts increase,15 therefore increasing the likelihood of first-step mutants being present. If such mutants are not killed or eradicated, as might happen when patients are treated with a fluoroquinolone with borderline activity, when an inadequate dose is used or in the case of poor absorption, then a higher level of resistance will emerge. Indeed, a history of suboptimal use of fluoroquinolone was common among our patients with fluoroquinolone-resistant pneumococci.14 Such practice might be related in part to confusion regarding the relative potency, dosage and indications of ofloxacin and levofloxacin. For both ofloxacin and levofloxacin, the 100 mg tablet is the only oral formulation available in Hong Kong, and in MIMS Hong Kong16 (an index of essential prescribing information similar to the British National Formulary in the UK), the recommended doses of both ofloxacin and levofloxacin for various infections, including respiratory tract infections, were 200–600 mg/day in one to three divided doses. Finally, a drug efflux mechanism is known to be common in local strains of S. pneumoniae,17 which might also facilitate mutational resistance by permitting short-term bacterial survival. In the study by Chodosh et al.,18 the pneumococcal isolates that persisted in two chronic bronchitis patients treated with ciprofloxacin were found to change from susceptible to resistant. Weiss et al.19 also reported a similar finding recently.
In agreement with reports by other investigators,2,3,5 this and our previous study14 showed that fluoroquinolone non-susceptibility is associated with resistance to penicillin, cephalosporins, co-trimoxazole and macrolides. Molecular analyses confirmed that this finding is due to the dissemination of a multiply resistant clone that shares an identical MLST allelic profile (4-4-2-4-4-1-1) with the globally distributed strain Spain23F-1. This fluoroquinolone-resistant variant, designated Hong Kong23F-1, was found to have serotype 14 and 19F variants. In contrast, fluoroquinolone non-susceptible strains in Spain and Canada were not clonally related.2,5
Dissemination of resistant clones of S. pneumoniae has often been associated with increasing antimicrobial usage.20 In Hong Kong, the most frequently prescribed fluoroquinolones are ofloxacin, ciprofloxacin and levofloxacin (these three fluoroquinolones together constitute >90% of the total usage of this antibiotic class locally). Ofloxacin was licensed for use in this area in 1985, followed by ciprofloxacin in 1988 and levofloxacin in 1994. Data obtained on the inpatient and outpatient use of these three agents from 1994 to 2000 in the Hospital Authority (HA) are shown in the Figure. The HA manages all the public hospitals and specialist outpatient services in this area. Serving a population of 7 million, there are approximately 1 million inpatient discharges, 8 million specialist outpatient attendances and 2 million emergency room attendances each year. Between 1994 and 2000, fluoroquinolone prescriptions increased from 66.8 to 91.8 daily defined doses (DDDs)/1000 persons/year. A breakdown of the usage in terms of clinical indication was not available but we believe that most of the increase is related to increased use for empirical therapy of respiratory tract infections.
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, Ciprofloxacin; •, ofloxacin; 
, levofloxacin; 
, all.Finally, almost all levofloxacin non-susceptible isolates in this study were intermediate or resistant to gatifloxacin and moxifloxacin, making these agents unlikely to be useful in the management of infection by these strains. For isolates with a penicillin MIC of
2 mg/L, appropriate dosing of a suitable ß-lactam remains a valid therapeutic option. Owing to a recent revision of the susceptible breakpoint for amoxicillin from 0.5 to 2 mg/L21 whilst penicillin breakpoints remain unchanged, most (97.2%) of the penicillin non-susceptible S. pneumoniae in the present study were categorized as amoxicillin susceptible. For penicillin, the respiratory breakpoint for susceptibility has been suggested to be 2–4 mg/L.22 In the present sample, 88.9% and 100% of the isolates were inhibited at 2 and 4 mg/L, respectively. In conclusion, fluoroquinolone resistance in pneumococci has reached disturbingly high rates in Hong Kong both quantitatively and qualitatively. Our data showed that this is related to the emergence and widespread dissemination of a fluoroquinolone-resistant, and multiply-resistant clone. Typing studies suggests that this clone (Hong Kong23F-1) is genetically related to the globally distributed strain Spain23F-1. These findings are of major significance for local patient care, public health and the pharmaceutical industry.
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Acknowledgements |
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We would like to thank Mr P. W. Lee for the fluoroquinolone usage data, Ms Judy Lau for the drug registration information, Ms Frances Wong for secretarial services, Mr Frankie Chow and Mr K. H. Tsang for technical assistance. This study was supported by grants from the University Research Committee, The University of Hong Kong and the Bayer China Company, Ltd, Hong Kong, China. Part of the MIC data were presented as an abstract (P1.12) at the Seventh Western Pacific Congress of Chemotherapy and Infectious Diseases, Hong Kong, 2000.
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Notes |
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* Corresponding author. Tel.: +852-2855-4897; Fax: +852-2855-1241; E-mail: plho{at}hkucc.hku.hk
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Received 16 January 2001; returned 9 April 2001; revised 30 July 2001; accepted 14 August 2001
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R. R. Reinert, S. Reinert, M. van der Linden, M. Y. Cil, A. Al-Lahham, and P. Appelbaum Antimicrobial Susceptibility of Streptococcus pneumoniae in Eight European Countries from 2001 to 2003 Antimicrob. Agents Chemother., July 1, 2005; 49(7): 2903 - 2913. [Abstract] [Full Text] [PDF]
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E. Sadowy, R. Izdebski, A. Skoczynska, M. Gniadkowski, and W. Hryniewicz High Genetic Diversity of Ciprofloxacin-Nonsusceptible Isolates of Streptococcus pneumoniae in Poland Antimicrob. Agents Chemother., May 1, 2005; 49(5): 2126 - 2129. [Abstract] [Full Text] [PDF]
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H. J. Smith-Adam, K. A. Nichol, D. J. Hoban, and G. G. Zhanel Stability of Fluoroquinolone Resistance in Streptococcus pneumoniae Clinical Isolates and Laboratory-Derived Mutants Antimicrob. Agents Chemother., February 1, 2005; 49(2): 846 - 848. [Abstract] [Full Text] [PDF]
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S. D. Brown, D. J. Farrell, and I. Morrissey Prevalence and Molecular Analysis of Macrolide and Fluoroquinolone Resistance among Isolates of Streptococcus pneumoniae Collected during the 2000-2001 PROTEKT US Study J. Clin. Microbiol., November 1, 2004; 42(11): 4980 - 4987. [Abstract] [Full Text] [PDF]
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Z. Tiemei, F. Xiangqun, and L. Youning Resistance Phenotypes and Genotypes of Erythromycin-Resistant Streptococcus pneumoniae Isolates in Beijing and Shenyang, China Antimicrob. Agents Chemother., October 1, 2004; 48(10): 4040 - 4041. [Abstract] [Full Text] [PDF]
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M. W. R. Pletz, L. McGee, J. Jorgensen, B. Beall, R. R. Facklam, C. G. Whitney, and K. P. Klugman Levofloxacin-Resistant Invasive Streptococcus pneumoniae in the United States: Evidence for Clonal Spread and the Impact of Conjugate Pneumococcal Vaccine Antimicrob. Agents Chemother., September 1, 2004; 48(9): 3491 - 3497. [Abstract] [Full Text] [PDF]
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D. Croisier, M. Etienne, L. Piroth, E. Bergoin, C. Lequeu, H. Portier, and P. Chavanet In vivo pharmacodynamic efficacy of gatifloxacin against Streptococcus pneumoniae in an experimental model of pneumonia: impact of the low levels of fluoroquinolone resistance on the enrichment of resistant mutants J. Antimicrob. Chemother., September 1, 2004; 54(3): 640 - 647. [Abstract] [Full Text] [PDF]
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 {blacktriangledown}Moxifloxacin - a new fluoroquinolone antibacterial DTB, August 1, 2004; 42(8): 61 - 62. [Abstract] [Full Text] [PDF]
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R. Wise The relentless rise of resistance? J. Antimicrob. Chemother., August 1, 2004; 54(2): 306 - 310. [Abstract] [Full Text] [PDF]
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K. J. Christiansen, J. M. Bell, J. D. Turnidge, and R. N. Jones Antimicrobial Activities of Garenoxacin (BMS 284756) against Asia-Pacific Region Clinical Isolates from the SENTRY Program, 1999 to 2001 Antimicrob. Agents Chemother., June 1, 2004; 48(6): 2049 - 2055. [Abstract] [Full Text] [PDF]
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J.-H. Song, S.-I. Jung, K. S. Ko, N. Y. Kim, J. S. Son, H.-H. Chang, H. K. Ki, W. S. Oh, J. Y. Suh, K. R. Peck, et al. High Prevalence of Antimicrobial Resistance among Clinical Streptococcus pneumoniae Isolates in Asia (an ANSORP Study) Antimicrob. Agents Chemother., June 1, 2004; 48(6): 2101 - 2107. [Abstract] [Full Text] [PDF]
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D. Croisier, M. Etienne, E. Bergoin, P.-E. Charles, C. Lequeu, L. Piroth, H. Portier, and P. Chavanet Mutant Selection Window in Levofloxacin and Moxifloxacin Treatments of Experimental Pneumococcal Pneumonia in a Rabbit Model of Human Therapy Antimicrob. Agents Chemother., May 1, 2004; 48(5): 1699 - 1707. [Abstract] [Full Text] [PDF]
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S. J. Harnett, A. P. Fraise, J. M. Andrews, G. Jevons, N. P. Brenwald, and R. Wise Comparative study of the in vitro activity of a new fluoroquinolone, ABT-492 J. Antimicrob. Chemother., May 1, 2004; 53(5): 783 - 792. [Abstract] [Full Text] [PDF]
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 T. M. File Jr, J. Garau, F. Blasi, C. Chidiac, K. Klugman, H. Lode, J. R. Lonks, L. Mandell, J. Ramirez, and V. Yu Guidelines for Empiric Antimicrobial Prescribing in Community-Acquired Pneumonia Chest, May 1, 2004; 125(5): 1888 - 1901. [Abstract] [Full Text] [PDF]
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I. Morrissey and G. Tillotson Activity of gemifloxacin against Streptococcus pneumoniae and Haemophilus influenzae J. Antimicrob. Chemother., February 1, 2004; 53(2): 144 - 148. [Abstract] [Full Text] [PDF]
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Y. Otsu, K. Yanagihara, Y. Fukuda, Y. Miyazaki, K. Tsukamoto, Y. Hirakata, K. Tomono, J.-i. Kadota, T. Tashiro, I. Murata, et al. In Vivo Efficacy of a New Quinolone, DQ-113, against Streptococcus pneumoniae in a Mouse Model Antimicrob. Agents Chemother., December 1, 2003; 47(12): 3699 - 3703. [Abstract] [Full Text] [PDF]
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A. P. Johnson, C. L. Sheppard, S. J. Harnett, A. Birtles, T. Harrison, N. P. Brenwald, M. J. Gill, R. A. Walker, D. M. Livermore, and R. C. George Emergence of a fluoroquinolone-resistant strain of Streptococcus pneumoniae in England J. Antimicrob. Chemother., December 1, 2003; 52(6): 953 - 960. [Abstract] [Full Text] [PDF]
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R. Canton, M. Morosini, M. C. Enright, and I. Morrissey Worldwide incidence, molecular epidemiology and mutations implicated in fluoroquinolone-resistant Streptococcus pneumoniae: data from the global PROTEKT surveillance programme J. Antimicrob. Chemother., December 1, 2003; 52(6): 944 - 952. [Abstract] [Full Text] [PDF]
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R. Reynolds, J. Shackcloth, D. Felmingham, A. MacGowan, and on behalf of the BSAC Extended Working Party on Re Antimicrobial susceptibility of lower respiratory tract pathogens in Great Britain and Ireland 1999-2001 related to demographic and geographical factors: the BSAC Respiratory Resistance Surveillance Programme J. Antimicrob. Chemother., December 1, 2003; 52(6): 931 - 943. [Abstract] [Full Text] [PDF]
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P. Grohs, S. Houssaye, A. Aubert, L. Gutmann, and E. Varon In Vitro Activities of Garenoxacin (BMS-284756) against Streptococcus pneumoniae, Viridans Group Streptococci, and Enterococcus faecalis Compared to Those of Six Other Quinolones Antimicrob. Agents Chemother., November 1, 2003; 47(11): 3542 - 3547. [Abstract] [Full Text] [PDF]
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A. M. Nilius, L. L. Shen, D. Hensey-Rudloff, L. S. Almer, J. M. Beyer, D. J. Balli, Y. Cai, and R. K. Flamm In Vitro Antibacterial Potency and Spectrum of ABT-492, a New Fluoroquinolone Antimicrob. Agents Chemother., October 1, 2003; 47(10): 3260 - 3269. [Abstract] [Full Text] [PDF]
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E. J. C. Goldstein, D. M. Citron, C. V. Merriam, Y. A. Warren, K. L. Tyrrell, and H. T. Fernandez In Vitro Activities of ABT-492, a New Fluoroquinolone, against 155 Aerobic and 171 Anaerobic Pathogens Isolated from Antral Sinus Puncture Specimens from Patients with Sinusitis Antimicrob. Agents Chemother., September 1, 2003; 47(9): 3008 - 3011. [Abstract] [Full Text] [PDF]
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M.-I. Morosini, E. Loza, R. del Campo, F. Almaraz, F. Baquero, and R. Canton Fluoroquinolone-Resistant Streptococcus pneumoniae in Spain: Activities of Garenoxacin against Clinical Isolates Including Strains with Altered Topoisomerases Antimicrob. Agents Chemother., August 1, 2003; 47(8): 2692 - 2695. [Abstract] [Full Text] [PDF]
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T. A. Davies, R. Goldschmidt, S. Pfleger, M. Loeloff, K. Bush, D. F. Sahm, and A. Evangelista Cross-resistance, relatedness and allele analysis of fluoroquinolone-resistant US clinical isolates of Streptococcus pneumoniae (1998-2000) J. Antimicrob. Chemother., August 1, 2003; 52(2): 168 - 175. [Abstract] [Full Text] [PDF]
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K. Drlica The mutant selection window and antimicrobial resistance J. Antimicrob. Chemother., July 1, 2003; 52(1): 11 - 17. [Abstract] [Full Text] [PDF]
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R. Cha and M. J. Rybak Linezolid and Vancomycin, Alone and in Combination with Rifampin, Compared with Moxifloxacin against a Multidrug-Resistant and a Vancomycin-Tolerant Streptococcus pneumoniae Strain in an In Vitro Pharmacodynamic Model Antimicrob. Agents Chemother., June 1, 2003; 47(6): 1984 - 1987. [Abstract] [Full Text] [PDF]
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J. M. Chaitram, L. A. Jevitt, S. Lary, and F. C. Tenover The World Health Organization's External Quality Assurance System Proficiency Testing Program Has Improved the Accuracy of Antimicrobial Susceptibility Testing and Reporting among Participating Laboratories Using NCCLS Methods J. Clin. Microbiol., June 1, 2003; 41(6): 2372 - 2377. [Abstract] [Full Text] [PDF]
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C. N. Johnson, W. H. Benjamin Jr., S. A. Moser, S. K. Hollingshead, X. Zheng, M. J. Crain, M. H. Nahm, and K. B. Waites Genetic Relatedness of Levofloxacin-Nonsusceptible Streptococcus pneumoniae Isolates from North America J. Clin. Microbiol., June 1, 2003; 41(6): 2458 - 2464. [Abstract] [Full Text] [PDF]
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I. Morrissey, D. J. Farrell, S. Bakker, S. Buckridge, and D. Felmingham Molecular Characterization and Antimicrobial Susceptibility of Fluoroquinolone-Resistant or -Susceptible Streptococcus pneumoniae from Hong Kong Antimicrob. Agents Chemother., April 1, 2003; 47(4): 1433 - 1435. [Abstract] [Full Text] [PDF]
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G. T. Hansen, K. Metzler, K. Drlica, and J. M. Blondeau Mutant Prevention Concentration of Gemifloxacin for Clinical Isolates of Streptococcus pneumoniae Antimicrob. Agents Chemother., January 1, 2003; 47(1): 440 - 441. [Full Text] [PDF]
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K. Weiss, G. S. Tillotson, and R. Guthrie Fluoroquinolones for Respiratory Infection : Too Valuable To Overuse (and Too Valuable To Misuse!) Chest, September 1, 2002; 122(3): 1102 - 1103. [Full Text] [PDF]
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G. A. Pankuch, B. Bozdogan, K. Nagai, A. Tambic-Andrasevic, S. Schoenwald, T. Tambic, S. Kalenic, S. Plesko, N. K. Tepes, Z. Kotarski, et al. Incidence, Epidemiology, and Characteristics of Quinolone- Nonsusceptible Streptococcus pneumoniae in Croatia Antimicrob. Agents Chemother., August 1, 2002; 46(8): 2671 - 2675. [Abstract] [Full Text] [PDF]
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E. Pestova, J. J. Millichap, F. Siddiqui, G. A. Noskin, and L. R. Peterson Non-PmrA-mediated multidrug resistance in Streptococcus pneumoniae J. Antimicrob. Chemother., March 1, 2002; 49(3): 553 - 556. [Abstract] [Full Text] [PDF]
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