Fumiaki Ikeda

Toho University, Edo, Tōkyō, Japan

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Publications (64)149.45 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The Centers for Disease Control and Prevention (CDC) now recommend combination therapy with ceftriaxone 250 mg plus azithromycin (AZM) 1 g as a first-line regimen for gonorrhea because the increase of Neisseria gonorrhoeae resistant to multiple antimicrobial agents. However, reports on the in vitro activity of antimicrobial combinations against clinical isolates of N. gonorrhoeae are very rare. In the present study, a checkerboard method was utilized to examine the in vitro activity of ceftriaxone (CTRX), cefodizime (CDZM), spectinomycin (SPCM), or gentamicin (GM) in combination with AZM against 25 clinical isolates of N. gonorrhoeae. The SPCM + AZM combination demonstrated the lowest mean fractional inhibitory concentration index (FICI) of 0.69, followed by the CDZM + AZM combination (mean FICI, 0.75), the CTRX + AZM combination (mean FICI, 0.81), and the GM + AZM combination (mean FICI, 0.83). Additivity/indifference effect was detected for the SPCM + AZM combination, the CDZM + AZM combination, the CTRX + AZM combination, and the GM + AZM combination, against 96 %, 72 %, 92 %, and 100 % of the isolates, respectively. There was no antagonism for any of the antimicrobial combinations against the 25 N. gonorrhoeae isolates. These results suggest that the antimicrobial combinations may be worthy of clinical evaluation as an alternative regimen for gonococcal infections caused by antimicrobial-resistant strains.
    Journal of Infection and Chemotherapy 04/2013; · 1.55 Impact Factor
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    ABSTRACT: Metallo-beta-lactamase (MBL) producing Serratia marcescens isolate was recovered from a study patient in September, 2007 in whom MBL non-producing S. marcescens had been isolated 2 months previously. Two S. marcescens isolates recovered from the study patient showed the same pulsed-field gel electrophoresis (PFGE) pattern. Seven S. marcescens isolates were recovered from other patients in our hospital during August, 2007 and November, 2007. Five of the seven isolates produced MBL. All of the MBL-producing isolates showed the same PFGE pattern and harbored plasmids of the same size and bla(IMP) genes. The bla(IMP) genes were easily transferred to Escherichia coli DH5alpha by transformation of a plasmid purified from the MBL-producing isolate. Those transformation experiments suggested that bla(IMP) genes were encoded by the plasmid. From these observations, it was speculated that the MBL non-producing S. marcescens isolate recovered from the study patient had acquired the plasmid which encoded bla(IMP) genes and a monoclone of MBL-producing S. marcescens spread horizontally in our hospital.
    Kansenshogaku zasshi. The Journal of the Japanese Association for Infectious Diseases 03/2013; 87(2):189-94.
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    ABSTRACT: A mechanism for the acquisition of high-level echinocandin resistance in Candida glabrata was investigated. FKS mutants were constructed to: determine whether clinically significant micafungin resistance requires a hot-spot mutation in FKS1 and a premature stop codon in FKS2, as was observed in a clinical isolate; select for variants with reduced susceptibility and locate mutations in FKS genes; and assess the roles of FKS1 and FKS2. A panel of FKS mutants was constructed using micafungin-susceptible parents by site-directed mutagenesis. Drug susceptibility, gene expression and glucan synthase activities were compared between mutants. Mutations acquired by selection were identified by DNA sequence analysis of FKS genes from selected variants. Single FKS deletants were constructed and their phenotypes examined. Introduction of the hot-spot mutation in FKS1 alone conferred an intermediate reduction in susceptibility, and the premature stop codon in FKS2 alone had no effect on susceptibility, while severely reduced susceptibility equivalent to that of the clinical isolate required both mutations. Exposure of susceptible strains to micafungin yielded variants with an intermediate reduction in susceptibility that possessed a hot-spot mutation in FKS1. Further exposure to micafungin yielded variants with severely reduced susceptibility that acquired various single mutations in FKS2. The phenotypes of Δfks1 and Δfks2 mutants indicate that the two FKS genes are functionally redundant, while deletion of both FKS1 and FKS2 conferred synthetic lethality. In the laboratory mutants of C. glabrata, clinically significant reduced susceptibility to micafungin required single nucleotide changes in both FKS1 and FKS2, and both genes encoded β-1,3-glucan synthase catalytic subunits.
    Journal of Antimicrobial Chemotherapy 04/2012; 67(7):1666-76. · 5.34 Impact Factor
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    ABSTRACT: The antimicrobial susceptibility of 93 Acinetobacter baumannii complex isolates from clinical specimens collected nationwide between May and October 2009 were measured by microdilution antimicrobial susceptibility testing based on CLSI M100-S20. Beta-lactamase genes, including classes B and D and ISAbal in meropenem nonsusceptible, including intermediate or resistant isolates, were detected using PCR. Rates of isolates nonsusceptible to meropenem were 18%, to ciprofloxacin 41% and to amikacin 14%. L7-L8: The rate of multidrug-resistant Acinetobacter (MDRA) isolates which were resistant to all 3 antimicrobial agents was 4.3%. MDRA isolates were classified into ST92 by multilocus sequence typing. No metallo-beta-lactamase producer was seen among the 17 meropenem nonsusceptible isolates. The blaoxa-51-like carbapenemase gene and ISAbal were detected in all 17 isolates. ISAba1 upstream presence of the blaOXA-51-like gene was observed in 7 of 17 isolates and the blaOXA-23 like gene in 5 of 17. Consistent with overseas reports, our results confirm the existence of MDRA isolates and isolates harboring OXA carbapenemase genes in Japan. While resistance rates were lower than reports elsewhere, it is clear that resistance trends must be carefully monitored.
    Kansenshogaku zasshi. The Journal of the Japanese Association for Infectious Diseases 09/2011; 85(5):501-7.
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    ABSTRACT: In a nationwide antimicrobial susceptibility survey of 494 Nesseria gonorrhoeae isolates collected from February 2008 to December 2009 in 3 regions of Japan, 112 (22.7%) were collected from western Japan (Kinki, Chugoku, Shikoku, and Kyushu), 277 (56.1%) from mid-eastern Japan (Kanto), and 105 (21.1%) from eastern Japan (Tokai, Hokuriku, Koushinetsu, Tohoku, and Hokkaido). Resistance to ciprofloxacin (CPFX) was 72.8%, to penicillin G (PCG) 19.8%, and to tetracycline (TC) 18.2%. Intermediate resistance to CPFX was 1.8%, to PCG 73.7%, and to TC 43.7%. These results indicate that both types of resistance to the 3 agents were very high. Intermediate resistance to cefixime (CFIX) was 38.1% and to cefozidim (CDZM) 13.4%. Resistance to CFIX was only 0.4% and to CDZM 0%. Susceptibility to azithromycin was 96.6%, to ceftriaxone 99.8%, and to spectinomycin 100%. No significant difference in resistance was seen to different antimicrobial agent classes tested in the 3 regions, although intermediate resistance to CFIX in western Japan was significantly higher than in mid-eastern Japan.
    Kansenshogaku zasshi. The Journal of the Japanese Association for Infectious Diseases 07/2011; 85(4):360-5.
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    ABSTRACT: A high rate of resistance (49.5 to 72.7%) to amoxicillin (AMX) was observed in Helicobacter pylori after two or three unsuccessful eradication attempts. Unsuccessful eradication regimens significantly increase resistance to not only clarithromycin (CLR) and metronidazole (MNZ) but also AMX.
    Antimicrobial Agents and Chemotherapy 06/2011; 55(6):3012-4. · 4.57 Impact Factor
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    ABSTRACT: Although metronidazole (Mtz) is an important component of Helicobacter pylori eradication regimens, it has been pointed out that the increasing use of Mtz may result in increase in the incidence of Mtz-resistant strains. The present study was designed to examine the initial mechanism of resistance acquisition of H. pylori to Mtz. After 10 Mtz-susceptible strains were cultured on plates containing sub-inhibitory concentrations of Mtz, the MIC of Mtz for 9 of the 10 strains increased to levels of the Mtz-resistant strains. In the Mtz-resistance-induced strains, the expression of the TolC efflux pump (hefA) was significantly increased under Mtz exposure, without the reduction of the Mtz-reductive activity. Our finding suggests that overexpression of hefA may be the initial step in the acquisition of Mtz resistance in H. pylori.
    Biochemical and Biophysical Research Communications 01/2011; 404(2):656-60. · 2.28 Impact Factor
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    ABSTRACT: In vitro activity of sitafloxacin (STFX) and various oral antimicrobial agents against bacterial isolates recovered from clinical specimens between January and December 2009, at different healthcare facilities in Japan was evaluated. A total of 1,620 isolates including aerobic and anaerobic organisms was available for the susceptibility testing using the microbroth dilution methods recommended by Clinical Laboratory Standard Institute. The minimum inhibitory concentration of STFX at which 90% of isolates (MIC90) was 0.06 microg/mL for methicillin-susceptible Staphylococcus aureus and was equal to that of garenoxacin (GRNX), 2 times lower than that of moxifloxacin (MFLX), and 8 times lower than that of levofloxacin (LVFX). STFX inhibited the growth of all the isolates of Streptococcus pneumoniae at 0.06 microg/mL or less. The MIC90s of STFX ranged from 0.03 to 0.06 microg/mL and were 1 to 2 times lower than those of GRNX, 2 to 4 times lower than those of MFLX, and 16 to 32 times lower than those of LVFX. Against Streptococcus pyogenes, the MIC90 of STFX was 0.06 microg/mL and was 2 times lower than that of GRNX, 4 times lower than that of MFLX, and 32 times lower than that of LVFX. The MIC90 of STFX was 0.25 microg/mL for Enterococcus faecalis, and was 2 times lower than those of GRNX and MFLX, and 8 times lower than that of LVFX. The MIC90 of STFX for E. coli was 2 microg/mL, and the MIC90s of other 10 species of Enterobacteriaceae which were the lowest values of the quinolones tested ranged from 0.03 to 1 microg/mL. The MIC90 of STFX for Pseudomonas aeruginosa isolates recovered from urinary infections was 8 microg/mL and was 16 times lower than those of GRNX, MFLX and LVFX. The MIC90 of STFX for P aeruginosa isolates recovered from respiratory infections was 2 microg/mL and was 32 times lower than those of GRNX and MFLX, and 16 times lower than that of LVFX. STFX inhibited the growth of all the isolates of Haemophilus influenzae at 0.004 microg/mL or less, and was 2 to 4 times lower than those of GRNX, 8 times lower than those of MFLX, and 4 times lower than those of LVFX. The MIC90 of STFX was 0.008 microg/mL for Moraxella catarrhalis, and was 2 times lower than that of GRNX, 8 times lower than those of MFLX and LVFX. The MIC90s of STFX ranged from 0.015 to 0.12 microg/mL for all the species of anaerobic bacteria and were the lowest values of all the antimicrobial agents tested. In conclusion, the activity of STFX against Gram-positive cocci was comparable or superior to those of GRNX, MFLX and LVFX. STFX showed the most potent activity against Gram-negative bacteria and anaerobic bacteria of all the antimicrobial agents tested in this study.
    The Japanese journal of antibiotics 12/2010; 63(6):411-30.
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    ABSTRACT: In recent years, increased isolation of extended-spectrum beta-lactamase (ESBL)-producing Proteus mirabilis has been reported in Japan. We undertook an investigation to determine the prevalence of ESBL-producing P. mirabilis isolated in Japan and to characterise the genotype. Seventy-four P. mirabilis isolates recovered from specimens at 54 hospitals in Japan between March and October 2006 were included in the study. Of the 74 P. mirabilis isolates examined, 28 (37.8%) were ESBL-producers. The bla(CTX-M-2) gene was found in 27 isolates, whilst 1 isolate possessed bla(CTX-M-3). Amongst the 28 ESBL-producers, 25 (89.3%) were non-susceptible to ciprofloxacin, whilst 11 (23.9%) of 46 ESBL-non-producing isolates were non-susceptible to ciprofloxacin. Pulsed-field gel electrophoresis (PFGE) analysis of the 28 ESBL-producing isolates from 19 hospitals revealed 17 clusters. The same PFGE type was observed in two or more hospitals especially in the greater Tokyo area, suggesting possible clonal spread and the need for monitoring to determine whether emergence of a dominant clone occurs. Our results show that in Japan there is a high prevalence of CTX-M-type beta-lactamase-producing P. mirabilis. Moreover, these isolates are characterised by reduced susceptibility to fluoroquinolones.
    International journal of antimicrobial agents 10/2010; 36(4):340-2. · 3.03 Impact Factor
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    ABSTRACT: We report the appearance of Candida glabrata strains with reduced sensitivity during treatment with the echinocandin drug micafungin (MCF). Four C. glabrata strains were isolated from sputum, gastric juice, and blood taken from a patient during hospitalization. Two of these strains, one of which was obtained after treatment with MCF for suspected Candida pneumonia and the other of which was obtained during MCF treatment for candidemia, were isolated from blood and found to have a reduced susceptibility to MCF. These two clinical isolates showed a high minimum inhibitory concentration (MIC) for MCF, with this change in MIC being unique for MCF among established antifungal drugs. To further investigate the mechanism underlying this reduced sensitivity, an in vivo mouse infection model and in vitro enzymatic analysis were performed. MCF had little effect in the mouse disseminated infection model and enzymatic analysis showed the low affinity of MCF to the 1,3-Beta-D-glucan synthase of the clinical isolates, although the enzymes of both clinical isolates and control strain were noncompetitively inhibited by MCF. Taken together, this low affinity of MCF for the enzymes is likely to cause the reduced sensitivities. These data further indicate that MCF could induce acquired MCF-resistant strains during clinical use.
    Japanese journal of infectious diseases. 09/2010; 63(5):332-7.
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    ABSTRACT: To determine the mechanism of intermediate- and high-level echinocandin resistance, resulting from heterozygous and homozygous mutations in GSC1 (FKS1), in both laboratory-generated and clinical isolates of Candida albicans. The DNA sequences of the entire open reading frames of GSC1, GSL1 (FKS3) and RHO1, which may contribute to the beta-1,3-glucan synthase of a micafungin-susceptible strain and a resistant clinical isolate, were compared. A spontaneous heterozygous mutant isolated by selection for micafungin resistance, and a panel of laboratory-generated homozygous and heterozygous mutants that possessed combinations of the echinocandin-susceptible and -resistant alleles, or mutants with individual GSC1 alleles deleted, were used to compare levels of echinocandin resistance and inhibition of glucan synthase activity. DNA sequence analysis identified a mutation, S645P, in both alleles of GSC1 from the clinical isolate. GSL1 had two homozygous amino acid changes and five non-synonymous nucleotide polymorphisms due to allelic variation. The predicted amino acid sequence of Rho1p was conserved between strains. Reconstruction of the heterozygous (S645/S645F) and homozygous (S645F/S645F) mutation showed that the homozygous mutation conferred a higher level of micafungin resistance (4 mg/L) than the heterozygous mutation (1 mg/L). Exposure of the heterozygous mutant to micafungin resulted in a loss of heterozygosity. Kinetic analysis of beta-1,3-glucan synthase activity showed that the homozygous and heterozygous mutations gave echinocandin susceptibility profiles that correlated with their MIC values. A homozygous hot-spot mutation in GSC1, caused by mutation in one allele and then loss of heterozygosity, is required for high-level echinocandin resistance in C. albicans. Both alleles of GSC1 contribute equally and independently to beta-1,3-glucan synthase activity.
    Journal of Antimicrobial Chemotherapy 03/2010; 65(5):842-52. · 5.34 Impact Factor
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    ABSTRACT: ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
    ChemInform 01/2010; 32(22).
  • [Show abstract] [Hide abstract]
    ABSTRACT: ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
    ChemInform 01/2010; 33(14).
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    ABSTRACT: Sitafloxacin showed MICs of less than or equal to 0.5 microg/ml against 105 isolates of Helicobacter pylori, including 44 isolates with mutations in the gyrA gene. The highest MICs for garenoxacin and levofloxacin were 8 and 64 times, respectively, higher than the highest MICs observed for sitafloxacin.
    Antimicrobial Agents and Chemotherapy 05/2009; 53(7):3097-9. · 4.57 Impact Factor
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    ABSTRACT: As the most common cause of neonatal sepsis, Lancefield Group B Streptococcus (GBS) must be diagnosed as early as possible in pregnant women is prevent neonatal infection. A selective enrichment broth medium has been widely recommended to optimally recover GBS from genital and anorectal samples. To establish a culture suitable for screening vaginal swab specimens, we compared subcultures of three selective enrichment media to direct culture on agar medium. Vaginal swab samples were inoculated directly onto 5% sheep blood agar and into New Granada medium (Eiken), Lim broth (Becton, Dickinson, and Company), and Todd Hewitt broth with gentamicin and nalidixic acid (Becton, Dickinson, and Company, Todd). Of the 288 specimens tested, GBS was recovered from 43 samples (14.9%) on direct agar media, with 82 (28.5%), positive on New Granada medium subculture, 67 (23.3%) on Lim broth subculture, and 61 (21.2%) on Todd, subculture. These results demonstrates that selective enrichment broth media provides more superior sensitivity than direct agar media for detection of GBS colonization in vaginal specimens, underscoring the usefulness of selective enrichment broth media in GBS screening for vaginal swabs in pregnant woman.
    Kansenshogaku zasshi. The Journal of the Japanese Association for Infectious Diseases 02/2009; 83(1):52-5.
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    ABSTRACT: Background: Sitafloxacin is a recently developed fluoroquinolone with wide spectrum activity ranging from gram positive cocci to gram negative bacilli. We studied the influence of mutations in the QRDR of gyrA of Helicobacter pylori on the antimicrobial activity of sitafloxacin (STFX). Methods: A total of 105 H. pylori isolates recovered from patients with peptic ulcer in Japan between 2004 and 2005 were screened for susceptibility to STFX and levofloxacin (LVFX) by agar dilution method according to CLSI guidelines. The QRDR of gyrA was amplified by PCR and the amplicon was sequenced. The sequences were compared to the wild type strain. Results: STFX exhibited excellent antibacterial activity against 105 H. pylori isolates with all isolates having a MIC less of than 0.5 μg/mL. Compared to LVFX, the activity of STFX was 8 to 32-fold greater. Of the 105 H. pylori isolates examined, mutations in the QRDR of gyrA were observed in 44 isolates. Of these isolates, the STFX MIC50 and MIC90 were 0.12 μg/mL and 0.25 μg/mL, respectively, which represents 32 to 64-fold greater activity compared to LVFX. Of the 44 isolates with mutations in the gyrA, the following changes were observed: Asn87 to Lys or Ile (14 isolates); Asp91 to Gly, Tyr or Asn (25 isolates); multiple mutations involving Asn87 or Asp91 and another region (7 isolates). With respect to mutations involving Asn87 and Asp91, the mean LVFX MIC was 9.75 μg/mL and 3.89 μg/mL, respectively, compared to 0.19 and 0.11 μg/mL, respectively, for STFX. Conclusions: STFX in comparison to other fluoroquinolones is less affected by gyrA mutations and exhibits superior MICs even in the presence of mutations. Our data suggests that STFX may be an effective antibiotic in H. pylori eradication therapy.
    Infectious Diseases Society of America 2008 Annual Meeting; 10/2008
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    ABSTRACT: Background: The antifungal natural product sordarin inhibits protein synthesis by a mechanism involving selective targeting of translation elongation factor 2 in fungi. Because of the weak antifungal activity and poor pharmacokinetic profile of sordarin itself, however, in vivo antifungal activity is negligible. We have discovered a novel derivative, FR290581 (FR), by chemical modification of sordaricin, the aglycone unit of sordarin. We report herein the superior antifungal activities of FR in vitro and in vivo. Methods: In vitro antifungal activity against pathogenic fungi was evaluated according to CLSI M27-A2, M38-A, and using animal serum. Therapeutic activity against Candida albicans (C.a)- infected ICR mouse models and Pneumocystis jirovecii (P.j)-infected SCID mouse model was evaluated orally. Results: FR displayed potent in vitro activity against C.a, C. tropicalis, and C. kefyr, which was comparable to fluconazole (FLCZ), but showed only negligible activity against C. parapsilosis, C. neoformans, and A. fumigatus. In a mouse systemic candidiasis model of C.a, FR had a comparable survival effect to FLCZ and had fungicidal activity against kidney fungal burden whereas FLCZ had only a fungistatic effect. In mouse oropharyngeal candidiasis, FR had a similar mycological effect in tongue as compared with FLCZ. FR also had more potent in vivo activities against P.j as compared with sulfamethoxazole-trimethoprim (ST). (see table) Conclusions: FR had potent in vivo activity against C.a and P.j compared with existing drugs. The antifungal profile of FR suggests it may be useful for AIDS patients. Number of P.j cysts and histological changes in mouse lung Group No. of cysts (x 103) Pneumonia (positive) Mononuclear cell infiltration Control - 1187.5±628.9 8/8 impossible for analysis FR 5mg/kg 0.6±1.6* 0/8 2/8 20mg/kg 0* 0/8 1/8 ST 120mg/kg 1.1±1.9* 0/8 8/8 *: significantly difference from the control (p<0.01)
    Infectious Diseases Society of America 2008 Annual Meeting; 10/2008
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    ABSTRACT: Background: In recent years, the increased isolation of extended spectrum beta-lactamase (ESBL)-producing Proteus mirabilis in Japan has been reported. We undertook an investigation to determine the prevalence of ESBL-producing P. mirabilis isolated in Japan and to characterize genotype and transferability of the ESBL. Methods: Seventy-four P. mirabilis isolates recovered from urine and sputum specimens in Japan between March and October of 2006 were included in the study. The CLSI double-disk method using CAZ/CVA and CTX/CVA were employed as screening tests for ESBL-producing isolates with confirmation on the basis of PCR using appropriate primer pairs and sequencing. Genomic DNA of isolates producing ESBL was analyzed by PFGE after digestion with Sfi I. Results: Of the 74 P. mirabilis isolates examined, 28 (37.8%) were ESBL-producers of which all produced a CTX-M-2-type ESBL. The molecular characterization of the isolates containing CTX-M-2 by PFGE showed great genomic diversity among them. The 28 isolates gave 17 major patterns. The CTX-M-2carrying plasmids were transferred from P. mirabilis to non-CTX-M-2 possessing E. coli and P. mirabilis at a frequency of 10-4/donor. Conclusions: P. mirabilis isolates in Japan harboring plasmids encoded CTX-M-2 gene which can be transferred to other organisms beyond P. mirabilis. The rapid emergence CTX-M-2 producing P. mirabilis and easy transferability of the plasmid to other Enterobacteriaceae point to the need for increased monitoring activities and aggressive infection control prevention.
    Infectious Diseases Society of America 2008 Annual Meeting; 10/2008
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    ABSTRACT: Background: In disk diffusion susceptibility testing of Haemophilus influenzae to amoxicillin/clavulanic acid (AMPC/ CVA; AMC), a double zone of inhibition is occasionally observed around the AMC disk. This double zone is expressed at a high frequency in ß-lactamase positive, AMC-resistant (BLPACR) strains. We studied the double zone in BLPACR H. influenzae strains as well as antimicrobial susceptibilities and associated mutations in the fts I gene coding for PBP 3. Methods: One hundred-eleven ß-lactamase positive, H. influenzae isolates with MICs to AMC of greater than 1.0/0.5 μg/mL were included in this study. Disk diffusion test were performed using the CLSI recommended Haemophilus Test Medium (HTM) procedure as well as Mueller Hinton chocolate agar (MHC). MICs to AMC were performed according to the CLSI broth microdilution method. The mutations in fts I was analyzed according to PCR. Results: Of the 111 H. influenzae isolates, 105 had mutations in the fts I gene (Asn526 to Lys and / or Ser385 to Thr). With respect to AMC disk diffusion testing, double zones were observed with 106 (95%) and 87 (78%) of the isolates using HTM and MHC, respectively. The zone diameters on the basis of the outer zone of inhibition using HTM and MHC were correlated with the MIC values by CLSI broth microdilution method for 58 (52%) and 84 (76%) of the isolates, respectively. Disk susceptibilities using HTM and MHC produced very major errors with 44% and 14%, respectively. When double zones are observed around the AMC disks, the use of the outer zone of inhibition may result in a failure to detect BLPACR isolates. Conclusions: The use of HTM in AMC disk diffusion testing produces a high rate of double zones of inhibition with BLPACR isolates. When double zones of inhibition are observed, additional workup such as MIC determinations and examination for mutations in the gene encoding PBP3 are indicated.
    Infectious Diseases Society of America 2008 Annual Meeting; 10/2008
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    ABSTRACT: In vitro susceptibility assays of antifungal activity do not always accurately predict in vivo efficacy. As well as having a clear clinical importance, the ability to predict efficacy is also essential for effective screening of novel drug compounds. Initial screening of novel compounds must often be based on in vitro data. The present report describes the use of serum-MIC, an in vitro test of antifungal susceptibility, to accurately predict in vivo efficacy of echinocandin drugs in a mouse model of disseminated candidiasis. The basis of the serum-MIC method was to measure the inhibitory activity of a test compound against Candida albicans hyphal growth in the presence of pooled mouse serum. For 13 previously uncharacterized echinocandin compounds, as well as for the known echinocandin drugs, micafungin and caspofungin, serum-MIC determinations were shown to give better correlation to efficacy in the animal model than conventional, CLSI standard, in vitro antifungal susceptibility tests. The most accurate prediction of efficacy was obtained when the serum-MIC was adjusted in relation to the serum concentration at 30 min post-treatment. Furthermore, when the efficacy of micafungin was determined by measuring C. albicans kidney burden in the mouse model of infection, the adjusted serum-MIC consistently reflected the effective serum concentrations. Our data indicate that determination of serum-MIC values will facilitate prediction of the in vivo potency of new antifungal compounds such as novel echinocandins.
    Microbiology and Immunology 09/2008; 52(8):383-91. · 1.55 Impact Factor

Publication Stats

1k Citations
149.45 Total Impact Points

Institutions

  • 1986–2013
    • Toho University
      • • Department of Infection Control and Prevention
      • • Department of Microbiology
      Edo, Tōkyō, Japan
  • 2011
    • Fukuoka University
      • Department of Urology
      Hukuoka, Fukuoka, Japan
  • 2006–2008
    • Astellas Pharmaceutical
      • Pharmacology Research Laboratories
      Northbrook, IL, United States
    • National Institute of Infectious Diseases, Tokyo
      Edo, Tōkyō, Japan
  • 2001
    • Nagasaki University
      Nagasaki, Nagasaki, Japan
  • 1998
    • Osaka Medical Center for Cancer and Cardiovascular Diseases
      Ōsaka, Ōsaka, Japan