Case Commentary: The hidden side of oxacillin resistance in Staphylococcus aureus

ABSTRACT

Acquisition of PBP2a (encoded by the mec gene) is the key resistance mechanism to β-lactams in Staphylococcus aureus. The mec gene can be easily detected by PCR assays; however, these tools will miss mec-independent oxacillin resistance. This phenotype is mediated by mutations in cell wall metabolism genes that can be acquired during persistent infections under prolonged antibiotic exposure. The complex case presented by Hess et al. (Antimicrob Agents Chemother 67:e00437-23, 2023, https://doi.org/10.1128/aac.00437-23) highlights the diagnostic and therapeutic challenges in the management of mec-independent oxacillin resistance.

INTRODUCTION

Resistance to anti-staphylococcal β-lactams (flucloxacillin, oxacillin, and methicillin) is the most important antibiotic resistance feature in Staphylococcus aureus (1). It is associated with less favorable clinical outcomes (2) and dramatically limits treatment choices (3). Given its importance, detection of oxacillin resistance is a central step in the phenotypic characterization (oxacillin or cephoxitin testing) of S. aureus in clinical laboratories (4); however, molecular detection of the mec gene [encoding penicillin-binding protein 2 a (PBP2a)] has been increasingly employed (5). Its main advantage is the rapid turnaround time which may allow to avoid vancomycin when initiating treatment for severe infections such as S. aureus bacteremia (SAB) and endocarditis (6).

Both phenotypic and molecular detection of oxacillin resistance have blind spots that have important clinical consequences and can point to intriguing patho-adaptive mechanisms in S. aureus (7). On one hand, mec-positive strains can appear oxacillin susceptible due to heteroresistance (8) or mutations in the mec gene or its promoter (9). On the other hand, low-level oxacillin resistance [minimum inhibitory concentration (MIC) 2–8 mg/L] can arise in the absence of PBP2a [mec-independent oxacillin non-susceptible S. aureus (MIONSA)] (10). Such resistance is missed by molecular detection methods relying on mec detection, potentially leading to ineffective antibiotic treatment if an antistaphylococcal β-lactam is used.

Hess et al. report a case of recurrent SAB and endocarditis, with the emergence of MIONSA at recurrence. Several features of this case are noteworthy: (i) it is a “textbook example” of complicated SAB combining recurrence, endocarditis, and the presence of an intravascular implant (11); (ii) recurrence was preceded by a nearly 2-year treatment with β-lactams; (iii) the oxacillin resistance phenotype was initially missed due to inconsistent phenotypic testing and negative mec PCR and PBP2a lateral flow assay; (iv) antibiotic treatment in such cases is not standardized; here, source control and β-lactam-gentamicin combinations seemed to have been sufficient to obtain negative blood cultures; however, the long-term outcome is not provided.

The clinical features of this case fittingly reflect the recent appreciation that MIONSA is an adaptive phenotype that can arise in response to prolonged antibiotic exposure (10). It is associated clinically with complex, high-inoculum infections, in particular, when source control is delayed, incomplete, or impossible, leading to prolonged antibiotic treatments (12). In the laboratory, MIONSA isolates are easily selected upon exposure to oxacillin in vitro, but at the price of slower growth (10) and sometimes a small colony phenotype, another hallmark of chronic S. aureus infections (13). These evolutionary trade-offs explain the observation of the frequent emergence of MIONSA clades of limited size in population genomic studies (14). While this suggests limited spreading potential, MIONSA transmission in special settings, such as dermatologic wards, has been reported (15).

Over the last decade, bacterial whole-genome sequencing has triggered a paradigm shift in our view of the genetic landscape of MIONSA. While it was traditionally believed that non-mec-medicated oxacillin resistance was driven by β-lactamase hyperproduction or penicillin-binding protein (PBP) modifications (16), bacterial genomic studies have emphasized the importance of adaptive mutations in core genes related to cell-wall metabolism, the most important being the c-di-AMP phosphodiesterase gdpP. GdpP truncations were described in sequencing studies of clinical strains with acquired oxacillin resistance (10, 17) and in a bacterial genome-wide association study (GWAS) (18) and confirmed through mutagenesis (10, 19). Other core genes such as the molecular chaperon clpX or the peptidoglycan transferase sgtB have been linked to non-mec-mediated oxacillin resistance (20).

Overall, the clinical, phenotypic, and genetic features of MIONSA are reminiscent of the classical description of vancomycin-intermediate S. aureus (VISA) (21). Similar to VISA, the key prevention strategies are avoidance of prolonged antibiotic exposure and aggressive source control, but an optimal treatment approach has not been established. Based on the appraisal that the MIONSA phenotype is an antibiotic adaptation, it would seem logical to switch the antibiotic regimen to a non-β-lactam or at least to a cephalosporin. However, cross-resistance to other cell-wall active antibiotics might complicate this choice (10). On the other hand, a recent study by the authors of the current case challenge suggests that at least at low-oxacillin MIC and in uncomplicated cases (i.e., MIONSA detected at baseline), β-lactam or cefazolin does not lose their efficacy (22). While we wait for more data, it is reasonable to switch antibiotic when MIONSA emerges during treatment and to be mindful of potential cross-resistance when selecting the salvage regimen. Potential choices reported in the literature and, in this case, include vancomycin (12, 23), daptomycin, or linezolid (10). It is unclear whether combination therapy improves treatment success.

In conclusion, MIONSA should be considered in complex, persistent, or recurrent mec-negative (MSSA) infections. It can be heralded by laboratory features such as subtle increases in oxacillin MIC, slower growth, or small colonies. In the future, bacterial whole-genome sequencing might provide a more holistic picture of the hidden side of oxacillin resistance.