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J Infect Chemother (2005) 11:253–255 DOI 10.1007/s10156-005-0397-8 © Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases 2005 NOTE Kenji Suzuki · Toshiyuki Fujisawa · Mayuki Nakashima Risa Hamasaki Antimicrobial activities of tosufloxacin against Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella branhamella catarrhalis isolated from otolaryngological infectious diseases Received: January 5, 2005 / Accepted: June 29, 2005 Abstract In 2003, the Japan Society for Infectious Diseases in Otolaryngology conducted its third nationwide survey of clinical isolates from otolaryngological infectious diseases. We selected three primary causative organisms of otolaryngological infectious diseases, Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella Branhamella catarrhalis, and evaluated their sensitivities to tosufloxacin (TFLX), a new oral quinolone, because the survey revealed a rise in drug-resistant strains, suggesting potential problems with the antibiotics commonly used against these organisms. The minimum inhibitory concentration (MIC)90 values of TFLX against S. pneumoniae, H. influenzae, and M. catarrhalis were 0.25 mg/ml, £0.06 mg/ml, and £0.06 mg/ml respectively, and TFLX was shown to be as effective as or superior to other new quinolones. In addition, TFLX showed sufficient antimicrobial effects against frequently detected drug-resistant bacteria such as penicillin-resistant S. pneumoniae (PRSP) and b-lactamase-negative, ampicillin-resistant strains of H. influenzae (BLNAR). Furthermore, only a few strains of bacteria showed resistance to TFLX. Key words Otolaryngological infectious · Streptococcus pneumoniae · Haemophilus influenzae · Moraxella (Branhamella) catarrhalis · Susceptibility · Tosufloxacin (TFLX) The Japan Society for Infectious Diseases in Otolaryngology has conducted three nationwide surveys to gather data on clinically isolated bacteria and their sensitivities to antibacterial agents,1–4 and the results of the surveys have shown a rise in drug-resistant strains. Especially, the third survey, K. Suzuki (*) · T. Fujisawa · M. Nakashima · R. Hamasaki Department of Otolaryngology, Second Hospital, Fujita Health University School of Medicine, 3-6-10 Otobashi, Nakagawa-ku, Nagoya 454-8509, Japan Tel. +81-52-323-5647; Fax +81-52-331-6843 e-mail: [email protected] conducted in 2003, showed increases in penicillin-resistant Streptococcus pneumoniae (PRSP)/penicillin-intermediate resistant S. pneumoniae (PISP) strains among S. pneumoniae, and increases in b-lactamase-negative, ampicillinresistant Haeurophilus influenzae (BLNAR) strains among H. influenzae,4 indicating the clinical importance of antibiotics that have sufficient antibacterial activity against these resistant strains. In this study, we evaluated the strains of three primary causative organisms of otolaryngological infectious diseases; S. pneumoniae (156 strains), H. influenzae (191 strains), and Moraxella Branhamella catarrhalis (50 strains), isolated during the third nationwide survey conducted by the Japan Society for Infectious Diseases in Otolaryngology. These strains accounted for almost 60% of all clinical isolates found during the survey, and significant increases in resistant strains among these species were reported. This third survey was conducted from January 2003 to May 2003 in collaboration with a total of 137 medical institutions, including the otolaryngology departments of 31 universities, their affiliated facilities, and private clinics throughout Japan. The clinical isolates were collected from patients (aged 0 to 82 years) who visited participating institutions for the treatment of acute suppurative otitis media, acute sinusitis, acute tonsillitis, and peritonsillar abscess, excluding patients with a history of surgical treatment. The sensitivity of tosufloxacin (TFLX), a new quinolone antibiotic, was evaluated by measuring the minimum inhibitory concentration (MIC), using the standard method defined by the Japanese Society of Chemotherapy (broth microdilution test) so that the results could be directly compared with the results of the survey for the objective assessment of the antibacterial activity of TFLX. We compared the measured antibacterial activity of TFLX with the antibacterial activity of three new quinolones (ciprofloxacin [CPFX], levofloxacin [LVFX], and gatifloxacin [GFLX]) and one ketolide (telithromycin [TEL]) measured during the third survey. In addition, the antibacterial activity of TFLX was also compared with that of penicillin G (PCG) against S. pneumoniae and that of ampicillin (ABPC) against H. influenzae. 254 Table 1. Drug sensitivity of Streptococcus pneumoniae Antibiotics PCG TFLX CPFX LVFX GFLX TEL PSSP (63 strains) PISP (62 strains) PRSP (31 strains) Range MIC50 MIC90 Range MIC50 MIC90 Range MIC50 MIC90 ⬉0.06 0.12–0.5 0.5–4 0.5–2 0.25–1 ⬉0.06–1 ⬉0.06 0.25 2 1 0.5 ⬉0.06 ⬉0.06 0.25 2 2 0.5 0.125 0.125–1 ⬉0.06–0.25 0.25–2 0.25–2 0.06–0.5 ⬉0.06–2 0.5 0.25 1 1 0.5 ⬉0.06 1 0.25 2 2 0.5 0.25 2–4 0.12–0.25 0.5–2 0.5–2 0.25–1 ⬉0.06–0.5 2 0.12 1 1 0.5 0.125 2 0.25 2 2 0.5 0.25 PCG, penicillin G; TFLX, tosufloxacin; CPFX, ciprofloxacin; LVFX, levofloxacin; GFLX, gatifloxacin; TEL, telithromycin; PSSP, penicillinsusceptible S. pneumoniae (MIC of PCG, <0.063 mg/ml; PISP, penicillin-intermediate resistant S. pneumoniae (MIC of PCG, 0.125–1 mg/ml); PRSP, penicillin-resistant S. pneumoniae (MIC of PCG, >2 mg/ml) Table 2. Drug sensitivity of Haemophilus influenzae Antibiotics ABPC TFLX CPFX LVFX GFLX TEL BLNAS (95 strains) BLNAR (90 strains) BLPAR (6 strains) Range MIC50 MIC90 Range MIC50 MIC90 Range 0.125–0.5 ⬉0.06 ⬉0.06–0.5 ⬉0.06–1 ⬉0.06–0.5 0.5–8 0.25 ⬉0.06 ⬉0.06 ⬉0.06 ⬉0.06 2 0.5 ⬉0.06 0.125 0.125 0.125 4 1–32 ⬉0.06–0.5 ⬉0.06–1 ⬉0.06–1 ⬉0.06–0.5 0.5–8 2 ⬉0.06 ⬉0.06 ⬉0.06 ⬉0.06 2 8 ⬉0.06 ⬉0.06 ⬉0.06 ⬉0.06 4 64–256 ⬉0.06 ⬉0.06 ⬉0.06 ⬉0.06 1–2 ABPC, ampicilln; TFLX, tosufloxacin; CPFX, ciprofloxacin; LVFX, levofloxacin; GFLX, gatifloxacin; TEL, telithromycin; BLNAS, b-lactamasenegative, ampicillin-sensitive strains of H. influenzae (MIC of ABPC £ 0.5 mg/ml); BLNAR, b-lactamase-negative, ampicillin-resistant strains of H. influenzae (MIC of ABPC ≥ 1 mg/ml); BLPAR, b-lactamase-positive, ampicillin-resistant strains of H. influenzae (MIC of ABPC ≥ 1 mg/ml) Table 3. Drug sensitivity of Moraxella (Branhamella) catarrhalis Antibiotics TFLX CPFX LVFX GFLX TEL b-lactamase (+) (47 strains) b-lactamase (-) (3 strains) Range MIC50 MIC90 Range ⬉0.06 ⬉0.06–0.125 ⬉0.06–0.125 ⬉0.06 ⬉0.06–0.5 ⬉0.06 ⬉0.06 ⬉0.06 ⬉0.06 0.125 ⬉0.06 ⬉0.06 0.125 ⬉0.06 0.25 ⬉0.06 ⬉0.06 ⬉0.06 ⬉0.06 ⬉0.06–0.25 TFLX, tosufloxacin; CPFX, ciprofloxacin; LVFX, levofloxacin; GFLX, gatifloxacin; TEL, telithromycin; b-lactamase(+), production of b-lactamase; b-lactamase(-), irrespective of production of b-lactamase For the evaluation of antibacterial activity, the isolated S. pneumonia were classified into three groups, penicillinsusceptible S. pneumoniae (PSSP; MIC of PCG, £0.063 mg/ ml), PISP (MIC of PCG, 0.125–1 mg/ml), and PRSP (MIC of PCG, ≥2 mg/ml), as defined by the National Committee for Clinical Laboratory Standards (NCCLS).5 The results are summarized in Table 1. The MIC90 values of TFLX against PSSP, PISP, and PRSP were consistently around 0.25 mg/ml, and TFLX was shown to have the most powerful antimicrobial activity among these new quinolones. In addition, it was shown that the antibacterial activity of TFLX was equivalent to that of a ketolide, telithromycin. Furthermore, for the other new quinolones and TEL, there were strains with MIC90 values of 1–4 mg/ml and 2 mg/ml, respectively, indicating the presence of resistant strains, but there was no strain suggesting a decrease in the antibacterial activity of TFLX. The isolated H. influenzae were classified into three groups, b-lactamase-negative, ampicillin-sensitive strains of H. influenzae (BLNAS; MIC of ABPC, £0.5 mg/ml), BLNAR (MIC of ABPC, ≥1 mg/ml) and b-lactamasepositive, ampicillin-resistant strains of H. influenzae (BLPAR; MIC of ABPC, ≥1 mg/ml). The results are summarized in Table 2. The MIC90 values of TFLX against BLNAS, BLNAR, and BLPAR were consistently £0.06 mg/ ml, and it was shown that the antibacterial activity of TFLX was equivalent to that of the other new quinolones. The MIC90 values of TEL were 2–4 mg/ml, and it was shown that the antibacterial activity of TEL against H. influenzae was inferior to that of the new quinolones. The isolated M(B). catarrhalis were classified into two groups, according to the production of b-lactamase. The results are summarized in Table 3. The MIC90 values of TFLX against M(B). catarrhalis were £0.06 mg/ml for both 255 b-lactamase-producing and non-producing strains, and it was shown that the antibacterial activity of TFLX was equivalent to that of the other new quinolones. The MIC90 value of TEL was 0.25 mg/ml, slightly lower than that of the new quinolones. The MIC90 values of TFLX against the three above primary causative organisms for otolaryngological infectious diseases were the lowest among the antibacterial agents that were evaluated, and it was shown that TFLX had sufficient antibacterial activity against these three organisms. In addition, TFLX was shown to be the antibiotic with the leastresistant strains. Furthermore, the antibacterial activity of TFLX was shown to be one of the best among the quinolones used for respiratory infections. This is a very important factor for selecting a drug. The incidence of PRSP/PISP among S. pneumoniae increased from 50.9% in the second survey to 59.6% in the third survey, indicating the serious impact of these resistant strains on the clinical use of cephems and macrolides, which are frequently used to treat tympanitis and sinusitis. In fact, with the rise in the number of resistant strains, the number of antibiotics that one can use knowing that they work for sure is decreasing every year. Therefore, it is believed that agents such as TFLX, which was shown to be one of the most effective new quinolones and as effective as TEL against S. pneumoniae, will play a very important role clinically. TFLX is recommended as one of the first-line treatment drugs for tympanitis and sinusitis in adults, in the Prescription guidelines for antibiotics published by the Japanese Association for Infectious Diseases and the Japanese Society of Chemotherapy.5 The results of the present study demonstrate the powerful antimicrobial activity of TFLX and its suitability as an effective treatment drug, and the results support the use of TFLX as the first-line treatment drug. The development of new antibiotics has not kept up with the development of antibiotic-resistant strains, and now one cannot expect a steady supply of new antibiotics to fight these emerging resistant strains. Therefore, it is important for clinicians to evaluate the use of currently available antibiotics, not only to achieve optimal treatment effects but also to prevent drug-resistant strains from emerging. TFLX has potent antibacterial activity against primary causative organisms such as S. pneumoniae, H. influenzae, and M(B). catarrhalis, and there are only a few strains resistant to TFLX. These characteristics make TFLX a very useful agent for the treatment of infections with primary causative organisms, and TFLX should be considered as one of the first-line treatment drugs for these infections. References 1. Baba S, Ohyama M, Kataura A, Togawa K, Takasaka T, Ichikawa G, et al. First report on a nationwide survey of clinical isolates from patients with tympanitis and sinusitis: prevalence of isolates from patients with tympanitis and sinusitis (in Japanese). J Jpn Soc Infect Otolaryngol Dis 1996;14:70–83. 2. Baba S, Ohyama M, Kataura A, Togawa K, Takasaka T, Ichikawa G, et al. Second report of nationwide survey of clinical isolates from patients with tympanitis and sinusitis: sensitivity of isolates to oral antibiotics (in Japanese). J Jpn Soc Infect Otolaryngol Dis 1996; 14:84–98. 3. Suzuki K, Nishimura T, Baba S. Current status of bacterial resistance in the otolaryngology field: results from the Second Nationwide Survey in Japan. J Infect Chemother 2003;1:46–52. 4. Nishimura T, Suzuki K, Oda M, Kobayashi T, Yajin K, Yamanaka N, et al. Report of the results of the third nationwide survey of clinical isolates from patients with infectious otolaryngological diseases (in Japanese). J Jpn Soc Infect Otolaryngol Dis 2004;22:12–23. 5. Suzuki K. II-10 Otolaryngological infectious diseases. Prescription guidelines for antibiotics (in Japanese). (edited by The Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases) Tokyo: Kyowakikaku; 2001; p. 136–41.