Pharmacology Week 6 ANTIMICROBIAL AGENTS

Pharmacology Week 6 ANTIMICROBIAL AGENTS

Mechanisms of antimicrobial action

Mechanisms of antimicrobial action Bacteriostatic - Slow or stop bacterial growth, needs an immune system to finish off the microbe Bactericidal - Results in bacterial death

Mechanisms of antibiotic resistance

Beta - lactam antibiotics Penicillins Bacteriocidal All have a beta lactam ring that binds to D-ala-D-ala of a penicillin binding protien and therefore interferes with transpeptidisation of the bacterial cell wall As a result - the cells lyse Only kills cells that are growing

Classification of Penicillins Penicillin - greatest activity against gram positive, gram -ve cocci and non beta lacatamase producing anaerobes Susceptible to hydrolysis by betalactamases Benzylpenicillin Antistaphylacoccal penicillins Resistant to staphylacoccal beta lactamases Active against staph and strep but not eneteroccoi, anaerobic bacteria and gram -ve rods and cocci Extended spectrum penicillins e.g. ampicillin Improved activity against gram -ve organisms but susceptible to beta lactamases

Penicillin Mechanism of action Inhibition of cell wall synthesis Cell wall is unique to bacteria Mechanism of resistance Formation of beta lactamases Modification of target Increased Efflux

Penicillins Pharmacokinetics: A: Absorption differs greatly for different penicillins Dicloxacillin, Ampicillin and Amoxicillin are acid stable and well absorbed Absorption of most oral penicillins are impaired by food D: Widely distributed in body fluids and tissues Concentration in most tissues is equal to serum with poor penetration into eye, CNS With active meningeal infections - the BBB is disrupted and so the penetration is improved E: Rapidly excreted by the kidneys Prolonged half life in renal failure

Penicillin Clinical Use Penicillin - Strep, Meningoccal, Enterococci, Staph Penicillin resistant to Staph. beta lactamase (Methicillin) - indicated for beta lactamase Extended spectrum penicillins aminopenicillins greater activity against gram -ve bacteria carboxypenicillin - TICARCILLIN

Penicillin Remarkably non toxic Most serious is hypersensitivity All are cross sensitising and cross reacting <1% of people who have had a penicillin in the past develop a new allergy Anaphylaxis is more serious (0.05%) Serum sickness reactions Desensitisation can be used if necessary Given that it is really excreted - if high doses are given in renal failure can cause seizures

Cephalosporins

Cephalosporins Similar to penicillin but more stable to beta lactam activity - BROADER SPECTRUM Not active against enterococci and listeria Four major families

First Generation CEPHAZOLIN, CEPHALEXIN Pharmacokinetics Oral - A: Cephalexin absorbed from the gut to varying degrees D: Urine concentrations are high, but varying tissue penetration M: E: Excretion by GFR and Tubular secretion Probenecid blocks tubular secretion and may increase serum levels substantially Dose modification in renal impairment Parenteral - Cephazolin is the only 1st gen still in use A: 100% D: Low Vd M: E: Renal excretion

First Generation Clinical uses: UTI Staph, strep infections (Cellulitis) Cephazolin is drug of choice in surgical prophylaxis Does not penetrate CSF therefore not used in meningitis

Second Generation CEFALCOR Active against organisms resistant to first generation drugs - extended gram -ve coverage, NO activity against pseudomonas Pharmacokinetics A: Ceflacor and cefuroxime can be given orally, well absorbed D:? M:? E: Renally excreted Clinical uses Effective against beta lactamase producing H.influenzae or Moraxella Primarily used to treat sinusitis, otitis media or LRTI

Third Generation CEFOTAXIME, CEFTAZADINE, CEFTRIAXONE Antimicrobial activity - Expanded gram -ve coverage Some are able to cross BBB Pharmacokinetics A: IV Administration D: Large Vd, penetrate body tissues well All penetrate the CSF M/E: Ceftriaxone is secreted in biliary tract and so does not need adjustment with renal failure, but the remainder of the 3rd generation cephalosporins do need adjustment Clinical use: Ceftriaxone and Cefotaxime are approved for treatment of meningitis Fever on unknown origin in immune competent hosts

Fourth Generation cefepime - Good activity against Pseudomonas, enterobacter, staph and pneumococcus Pharmacokinetics A: IV D: Penetrate well into CSF M: halflife of 2 hours E: Renally cleared

Cephalosporins Adverse reactions: Allergy - 5-10% cross reactivity, don't give if anaphylactic Toxicity - Local irritation and pain after IM and IV injection Renal toxicity AIN and ATN

MONOBACTAMS Aztreonam - well tolerated in penicillin allergic individuals Relatively resistant to beta lactamases, active against gram -ve rods Pharmacokinetics A: PO, well absorbed D: M: E: Renally excreted

Beta lactamse inhibitors Calvulanic acid, Sulbactam, Tazobactam Inhibitors of many but not all bacterial beta lactamases and can protect penicillins that would otherwise be hydrolysed from these enzymes Activity against Staph, Haemophillus, Nisseria gonhorea, salmonella, shigella, E coli and Klebsiella Little therapeutic difference between the three

CARBEPENAMS Structurally related to beta lactam antibiotics Used for treatment of enterobacter infections and ESBL producing gram -ve, gram +ve and anerobic organisms ERTAPENEM, IMIPENEM, MEROPENEM Pharmacokinetics A: Intravenous administration D: Penetrate tissues well including CSF M: E: Renally excreted and must be dose adjusted in renal failure Adverse reactions Nausea Vomiting Diarrhoea Rash

Vancomycin Exclusive gram +ve activity Bacteriocidal Pharmacokinetics: A: Poorly absorbed orally - only administered for C.Diff D: CSF levels are about 30% of serum levels M: E: 90% really excreted, accumulation in renal failure Anephric patients have a half life of 8-10 days NOT removed by HD Clearance is directly proportional to Cr Clearance Mechanism of Action: Inhibits cell wall synthesis by binding to D-ALA-D-ALA and resistance is due to modification of this binding site Clinical Use: MRSA, enterococcal endocarditis in a patient with penicillin allergy,

Vancomycin Adverse Reactions Nephrotoxicity is uncommon Red man and Red neck syndromes - infusion related flushing caused by histamine release, which is overcome by slowing of the infusion