Newer Antibacterial Agents

Newer Antibacterial Agents

1. Why "newer" antibacterials — the resistance-driven rationale

• The antibacterial pipeline of the last two decades is almost entirely a response to acquired resistance, not to a need for new targets: each new agent is engineered to evade (e.g. ceftaroline binding the altered PBP of MRSA) or to neutralize (β-lactamase inhibitors) an existing resistance mechanism rather than to act on a novel pathway (G&G 14e Ch.58, p.1147).
• β-Lactams remain "the single most important antibacterial class" by virtue of broad spectrum, potent bactericidal killing and favourable tolerability; resistance has "steadily increased, requiring development of new agents" — this sentence frames the entire newer-β-lactam programme (G&G 14e Ch.58, p.1147).
• The clinically dominant resistance threats these agents target are extended-spectrum β-lactamase (ESBL)-producers, AmpC over-expressers, and above all carbapenemase-producing carbapenem-resistant Enterobacterales (CRE) — the last being potentially "resistant to all or almost all antibacterials in clinical use" (G&G 14e Ch.58, p.1148).
• Of particular concern are carbapenemases: β-lactamases capable of hydrolyzing carbapenems as well as penicillins and cephalosporins; the two clinically pivotal families named are the Klebsiella pneumoniae carbapenemase (KPC) type and the metallo-β-lactamases (MBLs) (G&G 14e Ch.58, p.1148).
• The failure of the "traditional antibacterial pipeline … to adequately address the antimicrobial drug resistance crisis" is also driving renewed interest in non-conventional modalities — the revival of old polymyxins and the re-emergence of bacteriophage therapeutics ("living antibiotics") (G&G 14e Ch.59, pp.1172, 1174).
• A unifying theme of every newer agent below: most are positioned as reserve / last-line agents for pathogens "resistant to all or almost all other alternative antibiotics," which makes antimicrobial stewardship intrinsic to their place in therapy (G&G 14e Ch.58, pp.1158, 1159; Ch.59, p.1172).

Mechanistic map — where the newer agents act

• Cell-wall synthesis (PBP transpeptidase) → newer cephalosporins (ceftaroline, ceftolozane, cefiderocol) ± β-lactamase inhibitors (avibactam, vaborbactam, relebactam); carbapenem/BLI combinations (G&G 14e Ch.58, pp.1147, 1157–59).
• d-Ala-d-Ala cell-wall precursor + membrane → lipoglycopeptides (telavancin, dalbavancin, oritavancin) (G&G 14e Ch.58, p.1160).
• 30S ribosome (A-site tRNA) → newer tetracycline derivatives — glycylcycline (tigecycline), fluorocycline (eravacycline), aminomethylcycline (omadacycline) (G&G 14e Ch.60, pp.1179–80).
• 50S ribosome (P-site / 23S rRNA initiation) → oxazolidinones (tedizolid) (G&G 14e Ch.60, p.1186).
• 50S ribosome (peptidyl-transferase A/P site) → pleuromutilin (lefamulin) (G&G 14e Ch.60, p.1187).
• 30S ribosome (modified aminoglycoside) → plazomicin (G&G 14e Ch.59, p.1168).
• Outer / inner membrane disruption → polymyxins (colistin, polymyxin B) — revived against MDR gram-negatives (G&G 14e Ch.59, pp.1172–73).