US FDA-Approved Antibiotics During the 21st Century

Abstract

There is an urgent need to develop new antibiotics for the treatment of difficult-to-treat bacterial infections, caused by pathogens such as Mycobacterium tuberculosis, Gram-positive methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), and Clostridioides difficile, Gram-negative Pseudomonas aeruginosa and carbapenem-resistant Enterobacteriaceae (CRE), as well as multi-drug resistant Acinetobacter baumannii and Neisseria gonorrhoeae. Thirty-five antibiotics have been approved by US FDA since 2000. These new antibiotics include new chemotype antibacterial classes such as oxazolidinone (linezolid and tedizolid phosphate), lipocyclopeptide (daptomycin), anti-difficile macrolide (fidaxomicin), the cephalosporin-siderophore conjugate antibiotic (cefiderocol), and antitubercular agents diarylquinoline and nitroimidazooxazine (bedaquiline and PA-824, respectively). The remaining advanced antibiotics, developed on the basis of existing antibacterial chemical classes, include carbapenem (ertapenem and doripenem), nitroimidazoles (tinidazole and secnidazole), fluoroquinolones (gemifloxacin mesylate, besifloxacin, delafloxacin, and finafloxacin), ketolide (telithromycin), rifamycin (rifaximin and rifamycin SV), tetracycline and/or glycylcycline (tigecycline, eravacycline, omadacycline, and sarecycline), pleuromutilins (retapamulin and lefamulin), lipoglycopeptides (telavancin, oritavancin, and dalbavancin), cephalosporin (ceftaroline fosamil), aminoglycoside (plazomicin), four β-lactam/β-lactamase inhibitor combinations (ceftolozane/tazobactam, ceftazidime/avibactam, meropenem/vaborbactam, and imipenem/cilastatin/relebactam with a renal dehydropeptidase inhibitor), along with three monoclonal antibodies (mAbs) (raxibacumab, obiltoxaximab, and bezlotoxumab). The chemical class, physiochemical property, mechanism of action, route of administration and dosing frequency, pharmacokinetic profiles (e.g., Tmax, t1/2, bioavailability, protein binding, metabolism, excretion, etc.), as well as clinical indications and adverse effects of each antibiotic are reviewed and discussed in detail.