Prevalence and risk factors for recurrent Staphylococcus aureus small-colony variants in people with cystic fibrosis followed at the Tuscan Regional Reference Center

Purpose: This study aimed to determine the prevalence of Staphylococcus aureus small colony variants (SCV) in people with cystic fibrosis (pwCF), evaluate the clinical differences of single versus multiple detections of SCVs in respiratory cultures, and assess antibiotic resistance. Methods: This monocentric retrospective study included pwCF colonised by S. aureus SCVs between January 1, 2017, and December 31, 2023, at the CF centre of Florence, Italy. Clinical data were collected, and patients with single versus recurrent SCV detections were compared to identify risk factors for recurrent SCVs. Results: Among 154 pwCF (62 children, 92 adults), SCV was detected in 38.31%. Univariate analysis identified lower percent predicted forced expiratory volume in the first second (ppFEV1) (OR: 0.49, p = 0.04), prior trimethoprim-sulfamethoxazole (TMP-SMX) use (OR: 2.639, p = 0.005), chronic azithromycin (OR: 2.228, p = 0.020), and chronic/intermittent Pseudomonas aeruginosa colonisation (OR: 2.107, p = 0.049) as risk factors for recurrent SCVs. In multivariate analysis, prior TMP-SMX use was the sole independent risk factor for recurrent SCVs (OR: 2.280, p = 0.028). A significant decline in respiratory function over time (p = 0.025) was observed in patients with recurrent SCVs, but not in those with a single SCV episode. Resistance to TMP-SMX was observed in nearly all isolates tested (231/234) with available antibiotic susceptibility testing results. SCV detection frequency decreased over the study period (19.06% in 2017 vs. 5.83% in 2023, p < 0.00001), probably due to the increased use of elexacaftor-tezaxaftor-ivacaftor. Conclusions: S. aureus SCVs were highly prevalent in pwCF, although their frequency declined over time with the widespread use of elexacaftor–tezacaftor–ivacaftor. Recurrent SCV detections, but not single episodes, were associated with a progressive decline in respiratory function. Prior TMP-SMX exposure was identified as an independent risk factor for recurrent SCV detections. The clinical implications of these findings require further investigation to clarify causality and guide management strategies.