influenzae at a university hospital in Okinawa, the southernmost part of Japan, and found that 27 strains were BLNAR, while 24 strains were β-lactamase-producing. Our group determined the MICs of 160 clinical isolates of H.
Randomly amplified polymorphism DNA fingerprinting of clinical isolates of BLNAR strains showed genetic heterogeneity of the strains, suggesting that the prevalence of BLNAR in this region was a result of the emergence of multiple clones of this phenotype.Ībstract = "Recently, the instance of β-lactamase-negative ampicillin (AMP)-resistant (BLNAR) strains of Haemophilus influenzae has exhibited a marked increase in Japan. Multiple substitutions in the amino acid sequence seemed to be closely related with extended resistance against β-lactams, including third-generation cephems. These substitutions were located around the penicillin binding sites of PBP3. Furthermore, changes from Asp-350 to Asn-350 and from Ser-357 to Asn-357 were also found in most BLNAR strains. In addition, some BLNAR strains had an additional three residues (Met-377, Ser-385, and Leu-389) in ftsI replaced with Ile, Thr, and Phe, respectively. Deduced amino acid sequence analyses of BLNAR strains showed that three residues (Asn-526, Val-547, and Asn-569) were replaced with Lys, Ile, and Ser, respectively. The sequences of ftsI, the gene encoding transpeptidase domain of PBP 3A and/or PBP 3B, were determined, and it was found that sequences of the ftsI gene of BLNAR strains were heterogeneous mutations. The competitive affinity assay using biotinylated AMP for penicillin-binding protein (PBP) showed that the binding of cefotiam to PBP 3A/3B of BLNAR strain C2163 was lower than that of the AMP-susceptible strain, while bindings to other PBPs were not changed. BLNAR strains were shown to be more resistant to cephems than non-BLNAR strains. Among the latter, 2 strains were resistant to AMP/clavulanic acid.
Recently, the instance of β-lactamase-negative ampicillin (AMP)-resistant (BLNAR) strains of Haemophilus influenzae has exhibited a marked increase in Japan.
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