Chapter 11

Antibiotics and synthetic antimicrobial agents: their properties and uses

2 -Lactam Antibiotics
2.1 Penicillin Naturally occurring Semisynthetic Low toxicity PROBLEM: Allergic reactions (benzylpenicillin and ampicillin) Orally administered penicillins can cause: o Diarrhea o Pseudomembranous colitis (rare) Excreted in urine Some penicillins have considerable activity against Gram-negative and Grampostive bacteria (BROAD SPECTRUM ANTIBIOTIC) Penicillioc acid Not antibacterial Produced at alkaline pH or at neutral pH, but at acid pH a molecular rearrangement occurs, giving penillic acid Susceptible to hydrolysis Cannot be formulated as aqueous products Oral syrups manufactured as dry granules for resuspension in water Injections freeze dried in vials or in ampoules Aqueous solutions of penicillins lose 10% or more of their activity in 24 hours at room temperature At pH 1.3 and 35C: Zylpenicillin o Halfe-life: less than 5 minutes o Not administered orally Ampicillin o Half-life: 600 minutes o Suitable for oral use o -lactamase sensitive o Possession of amino group: much broader spectrum of activity than benzylpenicillin -Lactamases Enzyme produced by many bacteria Inactivates penicillin by opening -Lactam ring Staph. aureus o Only clinically significant -lactamae produced by Gram (+) species Ampicillin and Amoxicillin Effective against many Gram-negative bacteria including: o Haemophilus influenza o Escherichia coli o Samonella o Shigella o Proteus Not effective against Pseudomonas aeruginosa

Carbenicillin First penicillin showing antipseudomonal activity Replaced by ticarcillin Meticillin Only available as an injection Replaced by flucloxacillin (orally active) 2.2 Cephalosphorins Several of these act as good inducers of -lactamases First generation drugs o Moderate antimicrobial activity o Resistance to staphylococcal, but not Gram-negative, lactamases o Primary alternative antibiotics for treatment of staphylococcal infections o Rarely first-choice therapy Second generation drugs o Possession of good resistance to both staphylococcal and Gramnegative -lactamases o Improved potency towards H. influenza and enterobacteria Third generation drugs o Higher activity towards Gram-negative bacteria o Some have little or no value in treatment of staphylococcal infections o Parentally administered cephalosporins: Cefotaxime Ceftazidime Both are sometimes used with gentamicin or other aminoglycosides o Spread of strains produce extended-spectrum lactamases Fourth generation drugs o Treats extended spectrum -lactamases 2.2.1 Structure-activity relationships PSEs Penicillin-Sensitive Enzymes PBPs Penicillin Binding Proteins Cephamycins molecules possessing a 7-methoxy group 2.3 -Lactamase inhibitors Co-amoxiclav Consists of amoxicillin plus clavulanic acid Reserved for infections known, or likely, to be due to amoxicillinresistant -lactamase-producing strains o Not always used in this manner Clavulanic acid Used to protect ticarcillin from -lactamase attack Isolated from Streptomyces clavuligerus

Affords some protection against enzymes that are primarily active against cephalosporins rather than penicillins Sulbactam and tazobactam Penicillanic acid sulphones protect it 2.4 Carbapenems and aztreonam Penicillin or cephalosphorin derivatives in which the sulfur atom has been replaced with a carbon Carbapenems o Generic term for which the group includes olivanic acids and thienamycins Imipenem o N-formimidoyl derivative of thienamycin o In vitro stability o Broad spectrum Meropenem o More stable than imipenem to depeptidase o May be administered without cilastatin Monobactams o Naturally occurring antibiotics Aztreonam o Marketed in 1986 o Highly active against most Gram-negative bacteria o Intravenous injection 2.5 Hypersensitivity Patients sensitive to penicillin will be sensitive to all others because it is the basic penicillin structure that is responsible for hypersensitivity Benzylpenicillin and ampicillin o Most likely to cause anaphylaxis and skin allergy 10% patients allergic to penicillins will also be sensitive to cephalosphorins

3 Tetracyclines