Antibiotic co-resistance phenotypes as predictors of methicillin resistance in Staphylococcus aureus: a multi-study analysis of transportability, lineage dependence and model explanations

Methicillin-resistant Staphylococcus aureus (MRSA) frequently carries resistance to non-β-lactam antibiotics, but it is unclear how reproducibly these phenotypes indicate methicillin status across settings. From all laboratory-derived S. aureus susceptibility records in BV-BRC (45,876), we analysed 2,245 isolates from six studies with both MRSA and methicillin-susceptible S. aureus, defining MRSA by mecA/mecC carriage (714 isolates); an audit against source publications found 99 mecA-positive isolates recorded as susceptible in one collection. We estimated study- and lineage-stratified associations, compared a ciprofloxacin-only rule with logistic regression and XGBoost under leave-one-study-out validation, and compared SHAP attributions with label-based importance measures. Ciprofloxacin, erythromycin and clindamycin resistance were positively associated with MRSA in every evaluable study (study-adjusted odds ratios 14.0, 11.3 and 9.2), but effect sizes were heterogeneous (I² 90–98%) and fell 57–73% after stratification by sequence type. Within three of five evaluable sequence types, ciprofloxacin was uninformative. In pooled cross-validation, XGBoost reached an AUC of 0.93 and a model given only which antibiotics had been tested 0.71. In held-out studies, ciprofloxacin alone reached AUCs of 0.88–0.98 in collections dominated by healthcare-associated lineages but 0.58 in a collection mainly from retail food; multivariable models did not consistently outperform it and were poorly calibrated. SHAP and all label-based measures ranked ciprofloxacin first, but lower SHAP ranks were unstable and partly reflected testing practice. Co-resistance phenotypes mark the MRSA lineages present in a sample, which depend on how it was collected; they are not transportable predictors of methicillin resistance and cannot substitute for cefoxitin testing.