LACTAM ANTIBIOTICS THIENAMYCIN MONOBACTAMS LACTAM INHIBITORS 1 Thienamycin

β-LACTAM ANTIBIOTICS THIENAMYCIN MONOBACTAMS β-LACTAM INHIBITORS

1. Thienamycin Merck 1976 • Isolated from Streptomyces cattleya • Potent and wide range of activity vs Gram +ve and Gram -ve bacteria • Active vs. Pseudomonas aeruginosa • Low toxicity • High resistance to b-lactamases • Poor stability in solution (ten times less stable than Pen G)

1. Thienamycin analogues used in the clinic Imipenem Meropenem Ertapenem(2002)

2. Monobactams Nocardicins (Fujisawa 1975) Nocardicin A • Monocyclic b-lactam ring • Moderately active in vitro vs narrow group of Gram -ve bacteria • Active vs. Pseusomonas aeruginosa • Inactive vs. Gram +ve bacteria • Different spectrum of activity from penicillins • Thought to operate by a different mechanism from penicillins • Low toxicity

2. Monobactams Clinically useful monobactam Aztreonam • Administered by intravenous injection • Can be used for patients with allergies to penicillins and cephalosporins • No activity vs. Gram +ve or anaerobic bacteria • Active vs. Gram -ve aerobic bacteria

3. b-Lactamase Inhibitors Clavulanic acid (Beechams 1976) • Isolated from Streptomyces clavuligerus • Weak, unimportant antibacterial activity • Powerful irreversible inhibitor of b-lactamases – suicide substrate • Used as a sentry drug for ampicillin • Augmentin = ampicillin + clavulanic acid • Allows less ampicillin per dose and an increased activity spectrum • Timentin = ticarcillin + clavulanic acid

3. b-Lactamase Inhibitors Clavulanic acid - mechanism of action 2 1 NH 2 OH 3 4 5

3. b-Lactamase Inhibitors Penicillanic acid sulfone derivatives Sulbactam Tazobactam • Suicide substrates for b-lactamase enzymes • Sulbactam has a broader spectrum of activity vs b-lactamases than clavulanic acid, but is less potent • Unasyn = ampicillin + sulbactam • Tazobactam has a broader spectrum of activity vs b-lactamases than clavulanic acid, and has similar potency • Tazocin or Zosyn = piperacillin + tazobactam

COMPULSORY READING FROM TEXTBOOK – WILSON AND GISVOLD • PAGES - 274 – 278 • EXAMPLES: CLAVULANATE POTASSIUM, SULBACTAM, TAZOBACTAM, THIENAMYCIN, MEROPENEM [PAGES 274 – 278]

COMPULSORY READING FROM TEXTBOOK – PATRICK • THE ENTIRE SECTION ON b – LACTAMASE INHIBITORS AND ANTIBIOTICS IN CHAPTER 19