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Antimicrob Agents Chemother. 2019 Nov 18. pii: AAC.01500-19. doi: 10.1128/AAC.01500-19. [Epub ahead of print]

In vitro Derivation of Fluoroquinolone-resistant Mutants from Multiple Lineages of Haemophilus influenzae and Identification of Mutations Associated with Fluoroquinolone Resistance.

Author information

1
Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, Sapporo, Japan.
2
Department of Microbiology, Sapporo Medical University School of Medicine, Sapporo, Japan.
3
Department of Microbiology, Sapporo Medical University School of Medicine, Sapporo, Japan sato.t@sapmed.ac.jp.
4
Division of Laboratory Medicine, Sapporo Medical University Hospital, Sapporo, Japan.
5
Division of Bioresources, Hokkaido University Research Center for Zoonosis Control, Sapporo, Japan.
6
Global Station for Zoonosis Control, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, Sapporo, Japan.
7
Department of Infection Control and Laboratory Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.

Abstract

Haemophilus influenzae is a pathogenic bacterium that causes respiratory and otolaryngological infections. The increasing prevalence of β-lactamase-negative high-level ampicillin-resistant H. influenzae (high-BLNAR) is a clinical concern. Fluoroquinolones are alternative agents to β-lactams. However, the emergence and increasing prevalence of fluoroquinolone-resistant H. influenzae have been reported. The current risk of fluoroquinolone resistance in H. influenzae (especially in high-BLNAR) has not yet been evaluated. Here, we examined the development of fluoroquinolone resistance in fluoroquinolone-susceptible clinical H. influenzae isolates in vitro during passaging in the presence of moxifloxacin (from 0.03 to 128 mg/L). Twenty-nine isolates were examined. Seventeen isolates (58.6%) showed reduced moxifloxacin susceptibility, and 10 of these 17 isolates (34.5% of all isolates) exceeded the Clinical and Laboratory Standards Institute breakpoint for moxifloxacin (MIC>1 mg/L) after repeat cultivation on moxifloxacin-containing agar. Seven of these ten isolates were high-BLNAR representing multiple lineages. We identified 56 novel mutations in 45 genes induced during the development of fluoroquinolone resistance, except the defined quinolone resistance-determining regions (Ser84Leu and Asp88Tyr/Gly/Asn in GyrA, and Gly82Asp, Ser84Arg, and Glu88Lys in ParC). Glu153Leu and ΔGlu606 in GyrA, Ser467Tyr and Glu469Asp in GyrB and ompP2 mutations, were novel mutations contributing to fluoroquinolone resistance in H. influenzae In conclusion, H. influenzae clinical isolates from multiple lineages can acquire fluoroquinolone resistance by occuring multiple novel mutations. The high rate of derivation of fluoroquinolone-resistant H. influenzae from high-BLNAR than BLNAS (p=0.01) raises the possibility of the emergence and spread of fluoroquinolone-resistant high-BLNAR in the clinical setting.

PMID:
31740553
DOI:
10.1128/AAC.01500-19

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