Authors: Francesca McDonagh 1, Elaine K. Murray 2, Brian Hallahan 3, Georgios Miliotis 1,4

Affiliations: 1 Antimicrobial Resistance and Microbial Ecology Group, School of Medicine, University of Galway, Galway, Ireland. 2 Personalised Medicine Centre, School of Medicine, C-TRIC, Altnagelvin Hospital, Ulster University, Derry, United Kingdom. 3 Discipline of Psychiatry, School of Medicine, University of Galway, Galway, Ireland. 4 Centre for One Health, Ryan Institute, University of Galway, Galway, Ireland.

Background/ Introduction: Antipsychotic drugs, the primary drug treatment for schizophrenia, are increasingly being recognised to contribute to an increased risk in infection. Additionally, antipsychotics have been identified as a contributing factor in microbiome dysbiosis, creating opportunities for pathobiont colonisation. Clozapine, a second generation antipsychotic used for treatment resistant schizophrenia (TRS), has been associated with an increased risk of pulmonary infection. This study characterises pathobionts colonising the salivary microbiome of patients prescribed the antipsychotic clozapine.

Material & Methods: Following informed consent, saliva samples from individuals with TRS prescribed clozapine were collected and cultured on selective media. Study participants completed a questionnaire on their oral health and general medical history. An age- and sex- matched control cohort was also recruited. Isolates positively identified as Enterobacteriaceae or Moraxellaceae by MALDI-ToF mass spectrometry were retained for further analysis. Antimicrobial susceptibility testing was conducted to determine phenotypic resistance profiles while bioinformatic analyses were carried out to identify features of interest including virulence factors (VFs), antimicrobial resistance genes (ARGs), biosynthetic gene clusters (BGCs) and determine genomic relatedness among isolates.

Results: Colonisation was observed in 78% of the clozapine cohort participants, of which 47% were identified to be multi-colonised. In contrast, a colonisation rate of approximately 10% was observed in the control cohort. Twenty-one Enterobacteriaceae species and four Moraxellaceae species were identified. All genomes exhibited a virulent genotype with a mean of 57 VFs per genome. However, low phenotypic resistance to antimicrobials was noted across all isolates. Six distinct strains were observed to co-occur across seven different unrelated participants, suggestive of a potential shared reservoir associated with clozapine use.

Conclusion: This study found that clozapine use in patients with TRS is associated with oral pathobiont colonisation. Consequently, enhanced surveillance of patients on clozapine may be warranted to minimise the associated pulmonary infection risk.