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

2. Monobactams Nocardicin A Nocardicins (Fujisawa 1975) 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 Aztreonam Clinically useful monobactam 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 O H N 2 1 2 N H 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