Cryptic susceptibility to penicillin/β-lactamase inhibitor combinations in emerging multidrug-resistant, hospital-adapted Staphylococcus epidermidis lineages

• Published in: Nature communications Vol. 14; no. 1; p. 6479
• Main Authors: Ba, Xiaoliang, Raisen, Claire L., Restif, Olivier, Cavaco, Lina Maria, Vingsbo Lundberg, Carina, Lee, Jean Y. H., Howden, Benjamin P., Bartels, Mette D., Strommenger, Birgit, Harrison, Ewan M., Larsen, Anders Rhod, Holmes, Mark A., Larsen, Jesper
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14.10.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 45/23; 631/326/41/2530; 64/60; 692/699/255/1318; Acid resistance; Amides; Amoxicillin; Amoxicillin - pharmacology; Amoxicillin - therapeutic use; Anti-Bacterial Agents - pharmacology; Anti-Bacterial Agents - therapeutic use; Antibiotic resistance; Antibiotics; beta-Lactamase Inhibitors - pharmacology; Clavulanic acid; Clavulanic Acid - pharmacology; Clavulanic Acid - therapeutic use; Clinical trials; Drug resistance; Health services; Hospitals; Humanities and Social Sciences; Humans; Inhibitors; MecA protein; Methicillin; Microbial Sensitivity Tests; multidisciplinary; Multidrug resistance; Multidrug resistant organisms; Penicillin; Penicillins - pharmacology; Penicillins - therapeutic use; Rifampin; Science; Science (multidisciplinary); Staphylococcal Infections - drug therapy; Staphylococcus epidermidis; Thigh; Vancomycin; β Lactamase; β-Lactam antibiotics
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-42245-y

Global spread of multidrug-resistant, hospital-adapted Staphylococcus epidermidis lineages underscores the need for new therapeutic strategies. Here we show that many S . epidermidis isolates belonging to these lineages display cryptic susceptibility to penicillin/β-lactamase inhibitor combinations under in vitro conditions, despite carrying the methicillin resistance gene mecA . Using a mouse thigh model of S . epidermidis infection, we demonstrate that single-dose treatment with amoxicillin/clavulanic acid significantly reduces methicillin-resistant S . epidermidis loads without leading to detectable resistance development. On the other hand, we also show that methicillin-resistant S . epidermidis is capable of developing increased resistance to amoxicillin/clavulanic acid during long-term in vitro exposure to these drugs. These findings suggest that penicillin/β-lactamase inhibitor combinations could be a promising therapeutic candidate for treatment of a high proportion of methicillin-resistant S . epidermidis infections, although the in vivo risk of resistance development needs to be further addressed before they can be incorporated into clinical trials. Staphylococcus epidermidis can cause invasive infections that are difficult to treat due to multi-resistance to most clinically relevant drugs, including methicillin and other β-lactam antibiotics, vancomycin, and rifampicin. In this work, the authors use in vitro assays and a mouse infection model to explore cryptic susceptibility and development of resistance to penicillin/β-lactamase combinations.