# qacA is a key factor in heteroresistance to vancomycin in sequence type 5 methicillin-resistant Staphylococcus aureus isolates from pneumonia patients

## TL;DR

The study finds that the gene qacA plays a key role in making some MRSA strains less responsive to vancomycin in pneumonia patients.

## Contribution

The study identifies qacA as a novel independent predictor of hVISA in ST5-MRSA through genetic and experimental validation.

## Key findings

- qacA is a significant predictor of hVISA in ST5-MRSA isolates from pneumonia patients.
- ST5-MRSA strains with qacA exhibit a high hVISA detection rate compared to ST764-MRSA.
- Acquisition of the qacA plasmid transforms VSSA strains into hVISA phenotypes.

## Abstract

The presence of heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) among methicillin-resistant Staphylococcus aureus (MRSA) strains has been associated with vancomycin treatment failure, especially in cases of MRSA pneumonia. This study aimed to analyze the molecular characteristics and risk factors for hVISA among MRSA strains isolated from pneumonia patients and to validate the most important risk factors. All the MRSA clinical isolates were collected in a multicenter, prospective, observational clinical trial from July 2012 to June 2020. The hVISA strains were verified via a modified population analysis profile–area under the curve method, and the prevalence of hVISA in hospitalized pneumonia patients was 53.5% (61/114). Sequence type 5 (ST5)-MRSA, the dominant hVISA strain, and ST764-MRSA, the dominant vancomycin-susceptible S. aureus (VSSA) strain, exhibited comparable incidences (27.2% vs 36.8%) but with different hVISA detection rates (90.3% vs 21.4%, P < 0.001). Furthermore, the efflux pump gene qacA was identified by multivariate logistic regression analysis as an independent significant predictor of hVISA occurrence in ST5-MRSA (P < 0.001). This association was confirmed when both the recipient ST5-MRSA and ST764-MRSA strains that acquired the qacA-borne plasmid exhibited phenotypic transformation from VSSA to hVISA. This study provides evidence that the acquisition of qacA by the VSSA strain is associated with the formation of hVISA in MRSA isolates from hospitalized pneumonia patients.

Methicillin-resistant Staphylococcus aureus (MRSA) is among the leading causes of pulmonary infections, and currently, vancomycin use remains an effective intervention. The irrational use of vancomycin has increased the prevalence of heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA)/vancomycin-intermediate S. aureus strains in pneumonia patients infected with MRSA, but the underlying molecular characteristics remain unknown. This study focused on the evidently high detection rates of hVISA strains from pneumonia patients from a prospective observational study in China and investigated the predictive risk factors for the dominant hVISA strain sequence type 5 (ST5)-MRSA. Multivariate logistic regression analysis of variables identified as significant for host, pathogen, and genetic characteristics revealed that qacA was a significant independent predictor of the development of hVISA in ST5-MRSA, which was confirmed by plasmid-based experiments. This study provides new insights and an improved understanding of the decreased vancomycin susceptibility of MRSA in pneumonia patients and provides evidence-based support for optimizing clinical treatment plans from an innovative perspective to maintain the efficacy of vancomycin.

This study is registered with the China Clinical Trials Registry as ChiCTR-OPC-16007920 and ChiCTR-OPC-17012567 .