This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Yokota, S.-i.
Right arrow Articles by Fujii, N.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Yokota, S.-i.
Right arrow Articles by Fujii, N.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, October 2002, p. 3311-3315, Vol. 46, No. 10
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.10.3311-3315.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Fluoroquinolone-Resistant Streptococcus pneumoniae Strains Occur Frequently in Elderly Patients in Japan

Shin-ichi Yokota,1 Kiyoshi Sato,1,2 Osamu Kuwahara,3 Satoshi Habadera,3 Naoyuki Tsukamoto,4 Hironori Ohuchi,4 Hirotsugu Akizawa,5 Tetsuo Himi,6 and Nobuhiro Fujii1*

Departments of Microbiology,1 Otolaryngology, Sapporo Medical University School of Medicine, Chuo-ku, Sapporo 060-8556,6 Hokkaido Wako Junyaku Co., Ltd., Kita-ku, Sapporo 001-0015,2 Sapporo Clinical Laboratory, Inc., Chuo-ku, Sapporo 060-0005,3 SRL Hokkaido, Inc., Chuo-ku, Sapporo 064-0919,4 Laboratory Medicine, Hokkaido University Medical Hospital, Kita-ku, Sapporo 060-8648, Japan5

Received 29 April 2002/ Returned for modification 3 June 2002/ Accepted 6 July 2002


arrow
ABSTRACT
 
We identified and genetically characterized seven fluoroquinolone-resistant Streptococcus pneumoniae strains among 293 clinical strains isolated from 1999 to 2001 in Japan. The resistant strains were isolated only from adults, and 7 of 31 isolates (22.6%) were from patients more than 20 years old. Resistant strains were not found in 262 isolates from children under age 10.


arrow
TEXT
 
It is now feared that multidrug resistant Streptococcus pneumoniae strains are becoming more prevalent, and fluoroquinolone resistance has also become more common over the last few years (7, 10, 12, 17). In Japan, the prevalence of fluoroquinolone-resistant S. pneumoniae is thought to be very low (27). Here we report emergence of fluoroquinolone-resistant strains among 293 S. pneumoniae strains isolated in 1999 to 2001 in the Hokkaido prefecture, Japan. The isolates were obtained from rhinorrhea (235 samples), sputum (23), otorrhea (15), throat swab (14), nasal mucous membrane (5), and articular fluids (1). Two hundred fourteen strains were from outpatients. Seventy-nine strains were isolated from hospitalized patients. Identification of the isolates was routinely carried out by MicroScan WalkAway40 (Dade Behring, Tokyo, Japan). We also confirmed isolates as S. pneumoniae by detection of the pneumolysin gene by PCR and optochin sensitivity. Isolates were grown at 37°C with 5% CO2 on Trypticase soy agar (Nippon Beckton-Dickinson, Tokyo, Japan) supplemented with 5% defibrinized sheep blood.

MICs of various fluoroquinolones were determined by the microdilution method using Müller-Hinton broth (Nippon Beckton-Dickinson) supplemented with 5% defibrinized sheep blood according to the standard method described by the Japan Society of Chemotherapy (14). Reagent powders of antimicrobial agents were provided from manufacturers as follows: ciprofloxacin (Bayer, Osaka, Japan), levofloxacin (Daiichi Pharmaceuticals, Tokyo, Japan), tosufloxacin (Dinabot, Osaka, Japan), sparfloxacin (Dainippon Pharmaceuticals, Osaka, Japan), and gatifloxacin (Kyorin Pharmaceuticals, Tokyo, Japan). We found that seven strains (2.4% of total strains tested) were resistant to ciprofloxacin and levofloxacin. Six of the seven strains were also resistant to tosufloxacin, sparfloxacin, and gatifloxacin (Table 1). Table 2 indicates the age distribution of patients harboring resistant strains. Interestingly, none of the children harbored fluoroquinolone-resistant strains. All the resistant strains were found in adults (22.6%, 7 of 31 strains). In particular, more than a quarter of patients older than 65, who are a group at high risk for pulmonary diseases, such as pneumonia, harbored such fluoroquinolone-resistant strains. Similar observations about the age distribution of patients carrying fluoroquinolone-resistant S. pneumoniae have been reported by Canadian (7) and Hong Kong (8) groups.


View this table:
[in this window]
[in a new window]
  		TABLE 1. Characterization of fluoroquinolone susceptibilities and the mutations in quinolone target gene QRDRs of seven resistant and five sensitive strainsa


View this table:
[in this window]
[in a new window]
  		TABLE 2. Relationship between patient age and prevalence of fluoroquinolone-resistant S. pneumoniae strains

Quinolone resistance is imparted by mutations in a particular domain designated the quinolone resistance-determining region (QRDR) of the principal target enzymes, DNA gyrase (an A2B2 complex encoded by the gyrA and gyrB genes) and/or topoisomerase IV (a C2E2 complex encoded by the parC and parE genes) (19). We determined the DNA sequences of the QRDRs in these four genes. Genomic DNA was isolated from a colony grown on an agar plate according to the method of Ubukata et al. (25) and used as a template for PCR analysis. PCR fragments containing QRDRs were amplified as described elsewhere (20) and directly sequenced by the dye termination method. The QRDR DNA fragment of parC could not be amplified in two (SR27 and SR179) of the seven resistant strains, and thus the full-length parC genes of these were amplified by another primer set (11) and sequenced by DNA walking with a combination of primers. The QRDR DNA sequences of the resistant strains were compared with sensitive strains, including strain R6 (GenBank accession no. NC 003098) as a standard strain and five strains obtained in our study (Table 1). In the resistant strains, mutations at the amino acid level were found in one or more of the QRDRs in the parC, gyrA, and parE genes, but not in gyrB. The mutation patterns varied between the strains except for SR27 and SR179. Among these mutations, two site ParC mutations (Ser79 [TCT] to Phe [TTT] or Arg [AGA], and Asp83 [GAT] to Tyr [TAT]), one site GyrA mutation (Ser81 [TCC] to Tyr [TAC] or Phe [TTC]), and one ParE mutation (Asp453 [GAC] to Asn [AAC]) have been previously reported to be frequent mutations contributing to fluoroquinolone resistance (3, 6, 15, 16, 21, 23, 26). It is unclear whether other mutations relate to fluoroquinolone resistance. The Ile460 (ATC) to Val (GTC) mutation on ParE observed in six of the resistant strains was also found in two fluoroquinolone-sensitive strains (SR4 and HU2), suggesting that it does not contribute to fluoroquinolone resistance. Pestova et al. also showed that this mutation is unrelated to resistance by a DNA recombination study (21). SR166, whose resistance to ciprofloxacin is imparted mainly by an efflux mechanism as shown below, bears an Asp83 (GAT) to Tyr (TAT) mutation in ParC. This mutation should be providing SR166 with the intermediate resistance to fluoroquinolones other than ciprofloxacin.

For determination of resistance originating with an efflux mechanism, MICs were determined in the presence and absence of reserpine (10 µg/ml; Daiichi Pharmaceuticals) (4, 5, 9, 18). SR166 showed complete susceptibility to ciprofloxacin in the presence of reserpine. MICs of ciprofloxacin for HU85, HU86, and SR69 were only partially affected. Reserpine did not markedly affect the resistance of any of the strains to the other agents, indicating the lack of efflux mechanisms, which are inhibited by reserpine, assisting resistance to these drugs.

Many nucleotide mutations, whose expressed amino acid residues were altered or not, were found in parC and gyrA QRDRs of SR27 and SR179, so we characterized the full DNA sequences of the gyrA and parC genes in these strains. The PCR fragments containing the entire coding region of the gyrA gene were obtained as described elsewhere (1). The nucleotide sequences of both genes were identical between the two strains. The two strains should be derived from the same clone. Randomly applied polymorphic DNA-PCR analysis confirms this observation (data not shown). Notably, SR27 and SR179 were isolated from the same hospital, suggesting the possibility of hospital infection. The sequence homologies of the parC and gyrA genes of SR27 and the S. pneumoniae standard strain R6 were 91.42 and 97.40%, respectively. The homology plot analysis (performed with DNASIS-Mac 3.5; Hitachi Soft Engineering, Tokyo, Japan) indicated that sequence dissimilarities of parC genes of SR27 and R6 were scattered throughout the whole coding region (Fig. 1). In contrast, the dissimilarities of the gyrA genes were concentrated on the 5'-terminal side of the gene. The failure of PCR amplification of the fragment containing the parC QRDR should be due to the sequence dissimilarity of parC genes in these strains.



View larger version (13K):
[in this window]
[in a new window]
  		FIG. 1. Homology plots comparing the DNA sequences of the entire parC and gyrA genes of the fluoroquinolone-resistant S. pneumoniae strain SR27 and the standard strain R6. The nucleotide sequence of strain R6 was taken from the GenBank database (accession no. NC 003098).

We performed phylogenetic tree analysis on the QRDRs in the parC and gyrA genes of S. pneumoniae strains and viridans streptococcus strains, including Streptococcus mitis, Streptococcus oralis, and Streptococcus sanguinis (Fig. 2). Horizontal transfer of various genes among S. pneumoniae and viridans streptococci has been previously reported (13, 22); the sequences used in the analysis were either the S. pneumoniae sequences we determined in this study or S. pneumoniae and viridans streptococcus sequences derived from the GenBank database. Multiple sequence alignment was performed with Clustal W version 1.5 (24). Phylogenetic analysis and tree construction were performed with DendroMaker ver.4.1 (developed by T. Horiguchi and T. Imanishi, Center for Information Biology, National Institute of Genetics, Mishima, Japan) available on the Internet at http://www.cib.nig.ac.jp/dda/timanish/dendromaker/home.html). Of the 12 strains examined in this study, only the parC and gyrA QRDR sequences of SR27 and SR179 showed a close phylogenetic relationship with sequences from some strains of viridans streptococci (Fig. 2). On the other hand, parE and gyrB QRDRs of all strains examined did not possess any mutations compared with the standard strain R6, except one, which results in an Ile460Val substitution as described above, in ParE. That horizontal transfer of these genes occurs between streptococcal strains had been previously suggested for strains 3180 and 3870 for both genes (11) and SPN1506 for parC (2), although the QRDR sequences differed from SR27 and SR179. In contrast, the parC and gyrA QRDR sequences of five other S. pneumoniae strains examined in this study are highly similar to the typical S. pneumoniae QRDRs. These observations suggest that while SR27 and SR179, which are identical, may have acquired fluoroquinolone resistance by spontaneous mutations together with horizontal gene transfer from viridans streptococci, the remaining five resistant strains gained resistance only from point mutations.



View larger version (24K):
[in this window]
[in a new window]
  		FIG. 2. Phylogenetic trees based on the nucleotide sequences of the parC and gyrA QRDRs of various Streptococcus spp. The 218-nucleotide parC sequence (positions 187 to 404) and the 170-nucleotide gyrA sequence (positions 190 to 359) were analyzed by the multiple-alignment program Clustal W 1.5 and expressed as a phylogenetic tree by Dendromaker 4.1. The DNA sequences of strains without an asterisk have been previously reported and were taken from the GenBank database. The sequences of strains indicated by asterisk(s) were determined in this study. The fluoroquinolone-sensitive and -resistant strains are marked by single and double asterisks, respectively. Sp, S. pneumoniae; Sm, S. mitis; So, S. oralis; Ss, S. sanguinis.

Ferrándiz et al. (11) have suggested that interspecies horizontal gene transfer between S. pneumoniae and viridans streptococci is a mechanism by which these bacteria gain fluoroquinolone resistance. Similar genetic exchange is well known for genes encoding penicillin binding proteins, and this process is thought to mainly contribute to the emergence and worldwide prevalence of ß-lactram resistance (22). However, that such recombination also largely contributes to fluoroquinolone resistance has been disputed by Bast et al. (2), who noted that strains sharing such chimeric quinolone target genes are rarely found. In support of this conjecture, we identified only two strains (SR27 and SR179), which are suggested to be derived from one clone, as showing a relationship between their parC and gyrA QRDRs and those of other viridans streptococci. Thus, interspecies horizontal gene transfer does not appear to be a major mechanism by which S. pneumoniae develops fluoroquinolone resistance.

In conclusion, we have found that fluoroquinolone-resistant S. pneumoniae strains occur frequently in the elderly. These strains showed high resistance to ciprofloxacin and levofloxacin and intermediate or high resistance to fluoroquinolones targeted for gram-positive bacteria, namely tosufloxacin, sparfloxacin, and gatifloxacin. Genetic analysis of QRDRs of target genes indicated that six distinct mutation patterns were identified among the seven resistant strains. This suggests that fluoroquinolone resistance occurs sporadically through acquired point mutations rather than by the spreading of a specific resistant mutant strain. The reason fluoroquinolone-resistant strains were not found in the children we tested may be that fluoroquinolones other than norfloxacin are not applicable to children in Japan. The usage of fluoroquinolones, including new-generation ones, against S. pneumoniae infection should merit more attention. This is also the case for ß-lactams and macrolides.

Nucleotide sequence accession numbers. The open reading frames of the gyrA and parC genes from strain SR27 have been assigned GenBank accession no. AF503576 and AF503577, respectively.


arrow
FOOTNOTES
 
* Corresponding author. Mailing address: South-1, West-17, Chuo-ku, Sapporo 060-8556, Japan. Phone: 81-11-611-2111. Fax: 81-11-612-5861. E-mail: fujii{at}sapmed.ac.jp. Back


arrow
REFERENCES
 
    1
  1. Balas, D., E. Fernandez-Moreira, and A. G. De La Campa. 1998. Molecular characterization of the gene encoding the DNA gyrase A subunit of Streptococcus pneumoniae. J. Bacteriol. 180:2854-2861.[Abstract/Free Full Text]
    2. 2
  2. Bast, D. J., J. C. de Azavedo, T. Y. Tam, L. Kilburn, C. Duncan, L. A. Mandell, R. J. Davidson, and D. E. Low. 2001. Interspecies recombination contributes minimally to fluoroquinolone resistance in Streptococcus pneumoniae. Antimicrob. Agents Chemother. 45:2631-2634.[Abstract/Free Full Text]
    3. 3
  3. Bast, D. J., D. E. Low, C. L. Duncan, L. Kilburn, L. A. Mandell, R. J. Davidson, and J. C. de Azavedo. 2000. Fluoroquinolone resistance in clinical isolates of Streptococcus pneumoniae: contributions of type II topoisomerase mutations and efflux to levels of resistance. Antimicrob. Agents Chemother. 44:3049-3054.[Abstract/Free Full Text]
    4. 4
  4. Beyer, R., E. Pestova, J. J. Millichap, V. Stosor, G. A. Noskin, and L. R. Peterson. 2000. A convenient assay for estimating the possible involvement of efflux of fluoroquinolones by Streptococcus pneumoniae and Staphylococcus aureus: evidence for diminished moxifloxacin, sparfloxacin, and trovafloxacin efflux. Antimicrob. Agents Chemother. 44:798-801.[Abstract/Free Full Text]
    5. 5
  5. Brenwald, N. P., M. J. Gill, and R. Wise. 1998. Prevalence of a putative efflux mechanism among fluoroquinolone-resistant clinical isolates of Streptococcus pneumoniae. Antimicrob. Agents Chemother. 42:2032-2035.[Abstract/Free Full Text]
    6. 6
  6. Broskey, J., K. Coleman, M. N. Gwynn, L. McCloskey, C. Traini, L. Voelker, and R. Warren. 2000. Efflux and target mutations as quinolone resistance mechanisms in clinical isolates of Streptococcus pneumoniae. J. Antimicrob. Chemother. 45(Suppl. 1):95-99.[Abstract/Free Full Text]
    7. 7
  7. Chen, D. K., A. McGeer, J. C. de Azavedo, and D. E. Low. 1999. Decreased susceptibility of Streptococcus pneumoniae to fluoroquinolones in Canada. Canadian Bacterial Surveillance Network. N. Engl. J. Med. 341:233-239.[Abstract/Free Full Text]
    8. 8
  8. Chiu, S. S., P. L. Ho, F. K. Chow, K. Y. Yuen, and Y. L. Lau. 2001. Nasopharyngeal carriage of antimicrobial-resistant Streptococcus pneumoniae among young children attending 79 kindergartens and day care centers in Hong Kong. Antimicrob. Agents Chemother. 45:2765-2770.[Abstract/Free Full Text]
    9. 9
  9. Coyle, E. A., G. W. Kaatz, and M. J. Rybak. 2001. Activities of newer fluoroquinolones against ciprofloxacin-resistant Streptococcus pneumoniae. Antimicrob. Agents Chemother. 45:1654-1659.[Abstract/Free Full Text]
    10. 10
  10. Felmingham, D., and J. Washington. 1999. Trends in the antimicrobial susceptibility of bacterial respiratory tract pathogens—findings of the Alexander Project 1992-1996. J. Chemother. 11(Suppl. 1):5-21.
    11. 11
  11. Ferrándiz, M. J., A. Fenoll, J. Linares, and A. G. De La Campa. 2000. Horizontal transfer of parC and gyrA in fluoroquinolone-resistant clinical isolates of Streptococcus pneumoniae. Antimicrob. Agents Chemother. 44:840-847.[Abstract/Free Full Text]
    12. 12
  12. Ho, P. L., T. L. Que, D. N. Tsang, T. K. Ng, K. H. Chow, and W. H. Seto. 1999. Emergence of fluoroquinolone resistance among multiply resistant strains of Streptococcus pneumoniae in Hong Kong. Antimicrob. Agents Chemother. 43:1310-1313.[Abstract/Free Full Text]
    13. 13
  13. Janoir, C., I. Podglajen, M. D. Kitzis, C. Poyart, and L. Gutmann. 1999. In vitro exchange of fluoroquinolone resistance determinants between Streptococcus pneumoniae and viridans streptococci and genomic organization of the parE-parC region in S. mitis. J. Infect. Dis. 180:555-558.[CrossRef][Medline]
    14. 14
  14. Japan Society of Chemotherapy. 1993. Method for the determination of minimum inhibitory concentration (MIC) of aerobic bacteria by microdilution method. Chemotherapy (Tokyo) 41:183-189. (In Japanese.)[CrossRef]
    15. 15
  15. Jorgensen, J. H., L. M. Weigel, M. J. Ferraro, J. M. Swenson, and F. C. Tenover. 1999. Activities of newer fluoroquinolones against Streptococcus pneumoniae clinical isolates including those with mutations in the gyrA, parC, and parE loci. Antimicrob. Agents Chemother. 43:329-334.[Abstract/Free Full Text]
    16. 16
  16. Jorgensen, J. H., L. M. Weigel, J. M. Swenson, C. G. Whitney, M. J. Ferraro, and F. C. Tenover. 2000. Activities of clinafloxacin, gatifloxacin, gemifloxacin, and trovafloxacin against recent clinical isolates of levofloxacin-resistant Streptococcus pneumoniae. Antimicrob. Agents Chemother. 44:2962-2968.[Abstract/Free Full Text]
    17. 17
  17. Linares, J., A. G. de la Campa, and R. Pallares. 1999. Fluoroquinolone resistance in Streptococcus pneumoniae. N. Engl. J. Med. 341:1546-1548.[Free Full Text]
    18. 18
  18. Markham, P. N. 1999. Inhibition of the emergence of ciprofloxacin resistance in Streptococcus pneumoniae by the multidrug efflux inhibitor reserpine. Antimicrob. Agents Chemother. 43:988-989.[Abstract/Free Full Text]
    19. 19
  19. Nakamura, S. 1997. Mechanisms of quinolone resistance. J. Infect. Chemother. 3:128-138.
    20. 20
  20. Pan, X. S., J. Ambler, S. Mehtar, and L. M. Fisher. 1996. Involvement of topoisomerase IV and DNA gyrase as ciprofloxacin targets in Streptococcus pneumoniae. Antimicrob. Agents Chemother. 40:2321-2326.[Abstract]
    21. 21
  21. Pestova, E., R. Beyer, N. P. Cianciotto, G. A. Noskin, and L. R. Peterson. 1999. Contribution of topoisomerase IV and DNA gyrase mutations in Streptococcus pneumoniae to resistance to novel fluoroquinolones. Antimicrob. Agents Chemother. 43:2000-2004.[Abstract/Free Full Text]
    22. 22
  22. Spratt, B. G. 1994. Resistance to antibiotics mediated by target alterations. Science 264:388-393.[Abstract/Free Full Text]
    23. 23
  23. Stewart, B. A., A. P. Johnson, and N. Woodford. 1999. Relationship between mutations in parC and gyrA of clinical isolates of Streptococcus pneumoniae and resistance to ciprofloxacin and grepafloxacin. J. Med. Microbiol. 48:1103-1106.[Abstract/Free Full Text]
    24. 24
  24. Thompson, J. D., D. G. Higgins, and T. J. Gibson. 1994. CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res. 22:4673-4680.[Abstract/Free Full Text]
    25. 25
  25. Ubukata, K., Y. Asahi, A. Yamane, and M. Konno. 1996. Combinational detection of autolysin and penicillin-binding protein 2B genes of Streptococcus pneumoniae by PCR. J. Clin. Microbiol. 34:592-596.[Abstract]
    26. 26
  26. Weigel, L. M., G. J. Anderson, R. R. Facklam, and F. C. Tenover. 2001. Genetic analyses of mutations contributing to fluoroquinolone resistance in clinical isolates of Streptococcus pneumoniae. Antimicrob. Agents Chemother. 45:3517-3523.[Abstract/Free Full Text]
    27. 27
  27. Yamaguchi, K., S. Miyazaki, F. Kashitani, M. Iwata, and L.-S. Group. 2000. Activities of antimicrobial agents against 5,180 clinical isolates obtained from 26 medical institutions during 1998 in Japan. Jpn. J. Antibiot. 53:387-408. (In Japanese.)[Medline]

Antimicrobial Agents and Chemotherapy, October 2002, p. 3311-3315, Vol. 46, No. 10
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.10.3311-3315.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Balsalobre, L., de la Campa, A. G. (2008). Fitness of Streptococcus pneumoniae Fluoroquinolone-Resistant Strains with Topoisomerase IV Recombinant Genes. Antimicrob. Agents Chemother. 52: 822-830 [Abstract] [Full Text]  
  • Hoshino, K., Inoue, K., Murakami, Y., Kurosaka, Y., Namba, K., Kashimoto, Y., Uoyama, S., Okumura, R., Higuchi, S., Otani, T. (2008). In Vitro and In Vivo Antibacterial Activities of DC-159a, a New Fluoroquinolone. Antimicrob. Agents Chemother. 52: 65-76 [Abstract] [Full Text]  
  • Yokota, S.-i., Ohkoshi, Y., Sato, K., Fujii, N. (2008). Emergence of Fluoroquinolone-Resistant Haemophilus influenzae Strains among Elderly Patients but Not among Children. J. Clin. Microbiol. 46: 361-365 [Abstract] [Full Text]  
  • Fukushima, K. Y., Hirakata, Y., Sugahara, K., Yanagihara, K., Kondo, A., Kohno, S., Kamihira, S. (2006). Rapid Screening of Topoisomerase Gene Mutations by a Novel Melting Curve Analysis Method for Early Warning of Fluoroquinolone-Resistant Streptococcus pneumoniae Emergence. J. Clin. Microbiol. 44: 4553-4558 [Abstract] [Full Text]  
  • Decousser, J.-W., Methlouthi, I., Pina, P., Collignon, A., Allouch, P., on behalf of the ColBVH Study Group, (2006). New Real-Time PCR Assay Using Locked Nucleic Acid Probes To Assess Prevalence of ParC Mutations in Fluoroquinolone-Susceptible Streptococcus pneumoniae Isolates from France.. Antimicrob. Agents Chemother. 50: 1594-1598 [Abstract] [Full Text]  
  • Varon, E., Houssaye, S., Grondin, S., Gutmann, L., the Groupe des Observatoires de la Resistance du P, (2006). Nonmolecular Test for Detection of Low-Level Resistance to Fluoroquinolones in Streptococcus pneumoniae. Antimicrob. Agents Chemother. 50: 572-579 [Abstract] [Full Text]  
  • Kasahara, K., Maeda, K., Mikasa, K., Uno, K., Takahashi, K., Konishi, M., Yoshimoto, E., Murakawa, K., Kita, E., Kimura, H. (2005). Clonal Dissemination of Macrolide-Resistant and Penicillin-Susceptible Serotype 3 and Penicillin-Resistant Taiwan 19F-14 and 23F-15 Streptococcus pneumoniae Isolates in Japan: a Pilot Surveillance Study. J. Clin. Microbiol. 43: 1640-1645 [Abstract] [Full Text]  
  • Croisier, D., Etienne, M., Bergoin, E., Charles, P.-E., Lequeu, C., Piroth, L., Portier, H., Chavanet, P. (2004). Mutant Selection Window in Levofloxacin and Moxifloxacin Treatments of Experimental Pneumococcal Pneumonia in a Rabbit Model of Human Therapy. Antimicrob. Agents Chemother. 48: 1699-1707 [Abstract] [Full Text]  
  • Otani, T., Tanaka, M., Ito, E., Kurosaka, Y., Murakami, Y., Onodera, K., Akasaka, T., Sato, K. (2003). In Vitro and In Vivo Antibacterial Activities of DK-507k, a Novel Fluoroquinolone. Antimicrob. Agents Chemother. 47: 3750-3759 [Abstract] [Full Text]  
  • Takemura, H., Terakubo, S., Yamamoto, H., Shimada, J., Nakashima, H. (2003). Susceptibilities of Fluoroquinolone-Resistant Haemophilus parainfluenzae Isolates from Japanese Patients with Respiratory Infections to Five Fluoroquinolones and Other Antimicrobial Agents. Antimicrob. Agents Chemother. 47: 3996-3997 [Full Text]  
  • Kawamura, Y., Fujiwara, H., Mishima, N., Tanaka, Y., Tanimoto, A., Ikawa, S., Itoh, Y., Ezaki, T. (2003). First Streptococcus agalactiae Isolates Highly Resistant to Quinolones, with Point Mutations in gyrA and parC. Antimicrob. Agents Chemother. 47: 3605-3609 [Abstract] [Full Text]  
  • Balsalobre, L., Ferrandiz, M. J., Linares, J., Tubau, F., de la Campa, A. G. (2003). Viridans Group Streptococci Are Donors in Horizontal Transfer of Topoisomerase IV Genes to Streptococcus pneumoniae. Antimicrob. Agents Chemother. 47: 2072-2081 [Abstract] [Full Text]  

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Yokota, S.-i.
Right arrow Articles by Fujii, N.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Yokota, S.-i.
Right arrow Articles by Fujii, N.

Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»