Case Report: Whole-Genome Sequencing of Serially Collected Haemophilus influenzae From a Patient With Common Variable Immunodeficiency Reveals Within-Host Evolution of Resistance to Trimethoprim-Sulfamethoxazole and Azithromycin After Prolonged Treatment With These Antibiotics.

Abstract

We report within-host evolution of antibiotic resistance to trimethoprim-sulfamethoxazole and azithromycin in a nontypeable Haemophilus influenzae strain from a patient with common variable immunodeficiency (CVID), who received repeated or prolonged treatment with these antibiotics for recurrent respiratory tract infections. Whole-genome sequencing of three longitudinally collected sputum isolates during the period April 2016 to January 2018 revealed persistence of a strain of sequence type 2386. Reduced susceptibility to trimethoprim-sulfamethoxazole in the first two isolates was associated with mutations in genes encoding dihydrofolate reductase (folA) and its promotor region, dihydropteroate synthase (folP), and thymidylate synthase (thyA), while subsequent substitution of a single amino acid in dihydropteroate synthase (G225A) rendered high-level resistance in the third isolate from 2018. Azithromycin co-resistance in this isolate was associated with amino acid substitutions in 50S ribosomal proteins L4 (W59R) and L22 (G91D), possibly aided by a substitution in AcrB (A604E) of the AcrAB efflux pump. All three isolates were resistant to aminopenicillins and cefotaxime due to TEM-1B beta-lactamase and identical alterations in penicillin-binding protein 3. Further resistance development to trimethoprim-sulfamethoxazole and azithromycin resulted in a multidrug-resistant phenotype. Evolution of multidrug resistance due to horizontal gene transfer and/or spontaneous mutations, along with selection of resistant subpopulations is a particular risk in CVID and other patients requiring repeated and prolonged antibiotic treatment or prophylaxis. Such challenging situations call for careful antibiotic stewardship together with supportive and supplementary treatment. We describe the clinical and microbiological course of events in this case report and address the challenges encountered.

• Authors: Paul Christoffer Lindemann, Haima Mylvaganam, Oddvar Oppegaard, Inger Lill Anthonisen, Nermin Zecic, Dagfinn Skaare
• Journal: Frontiers in cellular and infection microbiology (Front Cell Infect Microbiol) Vol. 12 Pg. 896823 ( 2022) ISSN: 2235-2988 [Electronic] Switzerland
• PMID: 35719354 (Publication Type: Case Reports, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 Lindemann, Mylvaganam, Oppegaard, Anthonisen, Zecic and Skaare.

Chemical References

• Anti-Bacterial Agents
• Trimethoprim, Sulfamethoxazole Drug Combination
• Azithromycin
• Dihydropteroate Synthase

Topics

• Anti-Bacterial Agents (metabolism, pharmacology, therapeutic use)
• Azithromycin (pharmacology, therapeutic use)
• Common Variable Immunodeficiency
• Dihydropteroate Synthase (genetics, metabolism)
• Haemophilus Infections (drug therapy, microbiology)
• Haemophilus influenzae
• Humans
• Microbial Sensitivity Tests
• Trimethoprim, Sulfamethoxazole Drug Combination (pharmacology, therapeutic use)