Increasing Prevalence of Ampicillin- Resistant, Non-Beta-Lactamase-Producing Strains of &lt;i&gt;Haemophilus influenzae&lt;/i&gt; in Children in Japan

Seki, Hidetoshi; Kasahara, Yoshihito; Ohta, Kunio; Saikawa, Yoshiro; Sumita, Ryou; Yachie, Akihiro; Fujita, Shin-ichi; Koizumi, Satoshi

doi:10.1159/000007160

Cited by 47 publications

(40 citation statements)

References 21 publications

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“…Interestingly, in the United States and Europe, the BLNAR strains were uncommon and represented less than 1 to 2% of H. influenzae strains until the early 1990s, with their prevalence gradually increasing from 2.5% in 1994 to 10.1% 1995 (4)(5)(6)16). In Japan, the BLNAR strains were not identified before 1984 and then had a prevalence of only 2.1% in 1988 and 5.0% in 1991 (32). The strains with MICs for AMP of 1.0 g/ml then increased from 23.1% to 37.8% from 1996 to 1999 (32).…”

Section: Discussionmentioning

confidence: 99%

“…In Japan, the BLNAR strains were not identified before 1984 and then had a prevalence of only 2.1% in 1988 and 5.0% in 1991 (32). The strains with MICs for AMP of 1.0 g/ml then increased from 23.1% to 37.8% from 1996 to 1999 (32). Furthermore, a prospective prevalence study in Japan in 1999 showed that 55.1% of the H. influenzae strains were BLNAS, 3% were BLPAR, 26.4% were intermediateresistant strains, and 13.2% were BLNAR (35).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, a prospective prevalence study in Japan in 1999 showed that 55.1% of the H. influenzae strains were BLNAS, 3% were BLPAR, 26.4% were intermediateresistant strains, and 13.2% were BLNAR (35). The increase in the percentage of BLNAR strains has led to serious problems in the treatment of infectious disease in Japan (26,(31)(32)(33). Unfortunately, there is still limited information about the precise prevalence and dissemination of antimicrobial-resistant pathogens.…”

Section: Discussionmentioning

confidence: 99%

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Genetic Characteristics and Clonal Dissemination of β-Lactamase-Negative Ampicillin-ResistantHaemophilus influenzaeStrains Isolated from the Upper Respiratory Tract of Patients in Japan

Hotomi

Fujihara

Billal

et al. 2007

Antimicrob Agents Chemother

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We evaluated the recent prevalence of antimicrobial-resistant Haemophilus influenzae isolated from the upper respiratory tracts (URT) of patients in Japan. Mutations in the ftsI gene, which encodes penicillin binding protein 3 (PBP3), and the clonal dissemination of the resistant strains were also investigated. A total of 264 H. influenzae isolates were collected from patients with URT infections. According to the criteria of the Clinical and Laboratory Standards Institute for the susceptibility of H. influenzae to ampicillin (AMP), the isolates were distributed as follows: 161 (61.0%) susceptible strains (MIC < 1 g/ml), 37 (14.0%) intermediately resistant strains (MIC ‫؍‬ 2 g/ml), and 66 (25.0%) resistant strains (MIC > 4 g/ml). According to PCR-based genotyping, 172 (65.1%) of the isolates had mutations in the ftsI gene and were negative for the ␤-lactamase (bla) gene. These 172 isolates were thus defined as genetically ␤-lactamase-negative ampicillinresistant (gBLNAR) strains. The ftsI mutant group included 98 (37.1%) strains with group I/II mutations in the variable mutated region (group I/II gBLNAR) and 74 (28.0%) strains with group III mutations in the highly mutated region (group III gBLNAR). Eighty-seven (33.0%) of the isolates were genetically ␤-lactamasenegative ampicillin-susceptible (gBLNAS) strains. The group III gBLNAR strains showed resistance to ␤-lactams. Only five strains (1.9%) were positive for a bla gene encoding TEM-type ␤-lactamase. The three clusters consisting of 16 strains found among the 61 BLNAR strains (MIC > 4 g/ml and without the bla gene) showed identical or closely related DNA restriction fragment patterns. Those isolates were frequently identified among strains with a MIC to AMP of 16 g/ml. The current study demonstrates the apparent dissemination and spread of a resistant clone of H. influenzae among medical centers in Japan. The gBLNAR strains show a remarkable prevalence among H. influenzae isolates, with the prevalence increasing with time. This fact should be taken into account when treating URT infections.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Genetic Characteristics and Clonal Dissemination of β-Lactamase-Negative Ampicillin-ResistantHaemophilus influenzaeStrains Isolated from the Upper Respiratory Tract of Patients in Japan

Hotomi

Fujihara

Billal

et al. 2007

Antimicrob Agents Chemother

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“…To date, there are many types of oral antimicrobial agents such as ␤-lactams, fluoroquinolones, and penems with broad antibacterial activities. Recently, there has been an increase in the incidence of community-acquired respiratory tract infections caused by penicillin-resistant Streptococcus pneumoniae, penicillinase-producing Haemophilus influenzae, and ␤-lactamase-nonproducing ampicillin-resistant H. influenzae (3,13,18). In addition, the incidence of infections caused by fluoroquinolone-resistant organisms also seems to have increased (1,5,14).…”

Section: L-084 (A Prodrug Of Ljc 11036 [L-036]) Is a New Oral Carbapmentioning

confidence: 99%

In Vitro and In Vivo Antibacterial Activities of L-084, a Novel Oral Carbapenem, against Causative Organisms of Respiratory Tract Infections

Miyazaki

Hosoyama

Furuya

et al. 2001

Antimicrob Agents Chemother

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L-084 (a prodrug of LJC 11,036 [L-036]) is a new oral carbapenem.Here we compared the in vitro and in vivo antibacterial activities of L-036 with those of imipenem, faropenem, ceditoren-pivoxil, cefdinir, amoxicillin, and levofloxacin. The MICs at which 90% of the isolates were inhibited of L-036 against methicillinsusceptible staphylococci, Streptococcus pneumoniae including penicillin-resistant organisms, Escherichia coli, Klebsiella pneumoniae, Haemophilus influenzae including ampicillin-resistant organisms, Legionella pneumophila, and Moraxella catarrhalis were equal to or less than 1 g/ml. In pharmacokinetics studies of L-084 in lungs of mice, the maximum concentration in serum, half-life, and area under the concentration-time curve of this drug were 9.09 g/g of tissue, 6.18 h, and 31.0 g ⅐ h/ml, respectively. In murine respiratory infection models of penicillin-susceptible and -resistant S. pneumoniae and H. influenzae, the efficacies of L-084 were better than those of reference drugs. Our results indicate that the in vitro high potency and good distribution in the lungs might be the underlying mechanisms of its efficacy in the murine model of pneumonia.Carbapenems such as imipenem, meropenem, and panipenem, which are commercially available parenteral drugs, have broad-spectrum activity against both gram-positive and gram-negative bacteria. To date, there are many types of oral antimicrobial agents such as ␤-lactams, fluoroquinolones, and penems with broad antibacterial activities. Recently, there has been an increase in the incidence of community-acquired respiratory tract infections caused by penicillin-resistant Streptococcus pneumoniae, penicillinase-producing Haemophilus influenzae, and ␤-lactamase-nonproducing ampicillin-resistant H. influenzae (3,13,18). In addition, the incidence of infections caused by fluoroquinolone-resistant organisms also seems to have increased (1,5,14). These conditions highlight the need for novel antimicrobial agents active against these problematic pathogens. At present, various oral carbapenems such as GV118819X, CS-834, DZ-2640, and CL191,121 remain under development (12, 15, 16, 19, 20).hept-2-ene-2-carboxylate, is a novel oral carbapenem synthesized at the Medical Research Laboratories, Lederle (Japan), Ltd., Saitama, Japan. In the study described here, we evaluated the in vitro antibacterial properties of LJC 11,036 (L-036) and the in vivo activities of L-084 (a prodrug of L-036) by using models of murine bronchopneumonia caused by H. influenzae and pneumonia caused by S. pneumoniae. We also compared the potency of this drug with those of faropenem, imipenem, levofloxacin, cefditoren-pivoxil (a prodrug of cefditoren), cefdinir, and amoxicillin. MATERIALS AND METHODSAntimicrobial agents. The following antimicrobial agents, used in this study, were obtained from the indicated sources: L-036 and L-084, Wyeth Lederle Japan, Tokyo, Japan; faropenem, Suntory, Tokyo, Japan; imipenem, Banyu Pharmaceutical Co., Tokyo, Japan; levofloxacin, Daiichi Pharmaceutical Co., Tokyo, J...

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“…H. influenzae is known to acquire antibiotic resistance by two different mechanisms: the production of ␤-lactamases (TEM-1 or ROB-1 type) (19,41) and mutations in the penicillin-binding protein (PBP) gene. In Japan, the prevalence of ␤-lactamase-positive ampicillin (AMP)-resistant (BLPAR) H. influenzae is not high, with such isolates constituting less than 6% of all clinical H. influenzae isolates (11,13,34), while recent studies have shown that H. influenzae strains with mutations in the PBP gene, such as ␤-lactamase-negative AMP-resistant (BLNAR) H. influenzae and ␤-lactamase-positive amoxicillin-clavulanic acid-resistant (BLPACR) H. influenzae, are increasing (12,30). Ubukata et al (37,38) have discovered several mutations in the ftsI gene, which encodes PBP 3, in clinically isolated H. influenzae strains.…”

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confidence: 99%

Nasopharyngeal Haemophilus influenzae Carriage in Japanese Children Attending Day-Care Centers

Hashida¹,

Shiomori²,

Hohchi³

et al. 2008

J Clin Microbiol

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We conducted a prospective bacteriological survey to investigate antibiotic resistance-related genetic characteristics and the turnover of nasopharyngeal Haemophilus influenzae carriage in healthy children in day-care centers (DCCs). A total of 363 nasopharyngeal mucus samples were collected from children aged 0 to 6 years attending two DCCs in the summer of 2004 (n ‫؍‬ 184) and the following winter (n ‫؍‬ 179). We obtained 172 H. influenzae isolates and analyzed them by antimicrobial susceptibility testing, PCR for bla TEM-1 and the penicillin-binding protein (PBP) gene, and pulsed-field gel electrophoresis (PFGE). The overall carriage rate was 47.4% (172/363), and 37.2% of the isolates (64/172) were ampicillin (AMP) resistant. All the resistant isolates had a PBP mutation(s), while only three isolates had TEM-1. The carriage rate was significantly higher in the winter than in the summer (56.4% and 38.6%, respectively), owing to the increase in the numbers of AMP-susceptible H. influenzae isolates in the winter. Children aged <3 years showed a higher rate of carriage of H. influenzae isolates with an AMP resistance gene(s) than those aged >4 years (21.9% and 12.6%, respectively). Forty-two strains with different PFGE patterns were obtained from among the 172 isolates. Only five strains were observed in both seasons. None of the strains isolated in the summer was isolated from the same carrier in the winter. Twenty-seven strains (64.3%) were isolated from two or more children, and 25 of these were each isolated from children belonging to the same DCC. These results indicate the spread of H. influenzae, particularly those with a PBP mutation(s), and the highly vigorous genetic turnover and substantial horizontal transmission of this pathogen in healthy children attending DCCs in Japan.

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Increasing Prevalence of Ampicillin- Resistant, Non-Beta-Lactamase-Producing Strains of <i>Haemophilus influenzae</i> in Children in Japan

Cited by 47 publications

References 21 publications

Genetic Characteristics and Clonal Dissemination of β-Lactamase-Negative Ampicillin-ResistantHaemophilus influenzaeStrains Isolated from the Upper Respiratory Tract of Patients in Japan

Genetic Characteristics and Clonal Dissemination of β-Lactamase-Negative Ampicillin-ResistantHaemophilus influenzaeStrains Isolated from the Upper Respiratory Tract of Patients in Japan

In Vitro and In Vivo Antibacterial Activities of L-084, a Novel Oral Carbapenem, against Causative Organisms of Respiratory Tract Infections

Nasopharyngeal Haemophilus influenzae Carriage in Japanese Children Attending Day-Care Centers

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