Beta- Lactamase Inhibitors

1. Beta-Lactamase Inhibitors • Clavulanic acid, Tazobactam, Sulbactam • Drug Class: inhibitors of beta-lactamase • Trade Names: • Augmentin ® (Amoxicillin + Clavulanate) • Zosyn ® (Piperacillin + Tazobactam) • Timentin ® (Ticarcillin + Clavulanate) • Mechanism of Action: • these three substances resemble β-lactam molecules & are potent inhibitors of “most” plasmid-mediated beta-lactamases. • Sulbactam has intrinsic activity against Acinetobacter & may be used against MDR strains. • Indications: • used in fixed combination with specific penicillins: ampicillin, amoxicillin or ticarcillin • penicillin-β-lactamase inhibitor combinations are used for empirical therapy against a wide range of potential pathogens including treatment of aerobic & anaerobic infections (e.g. intra-abdominal infections). • The β-lactam inhibitor merely extends the activity of the combined penicillin

2. Penicillins Resistant to Staph Beta-LactamaseExtended Spectrum Penicillins • Ampicillin (po, im, iv) • Drug Class:Semisynthetic Penicillin • Mechanism of Action: • Same as Pen G, but greater activity against gram negative bacteria due to enhanced ability to penetrate the gram negative outer membrane. • Side Effects: • skin rash, esp. if patient has mononucleosis. • Diarrhea & Superinfections are common. • Pharmacokinetics: • oral, i.m. or i.v. administration • acid resistant & well absorbed afer oral administration. • Significant biliary excretion (hence effective against Salmonella infections in the biliary tract). Half-life is 1.3 hours.

3. Amoxicillin • Drug Class:Semisynthetic Penicillin • Mechanism of Action: • Same as Pen G, but greater activity against gram negative bacteria due to enhanced ability to penetrate the gram negative outer membrane. • Side Effects: • hypersensitivity (like other penicillins) • Pharmacokinetics: • absorbed better than ampicillin upon oral administration.

4. Ticarcillin - Clavulanic Acid Combo • Trade Names:Timentin ® • Drug Class:Semisynthetic Penicillin • Mechanism of Action: • Same as Penicillin G, but greater activity against gram negative bacteria due to enhanced ability to penetrate the gram negative outer membrane. • Almost always given as a combined medication with clavulanic acid (Timentin ®) for inhibition of beta-lactamases. • Pharmacokinetics: • parental (i.m. or i.v.) use. Acid unstable.

5. Piperacillin - Tazobactam Combo • Drug Class:SemisyntheticPenicillins • Mechanism of Action: • Same as Penicillin G, but greater activity against gram negative bacteria due to enhanced ability to penetrate the gram negative outer membrane. • Piperacillin is combined with tazobactam to provide protection against beta-lactamase inactivation. • Pharmacokinetics: • given parentally

6. Cephalosporins • Cephalosporin discovery credited to Brotzu in 1945 in sewer water off coast of Sardinina • Several compounds isolated from mold Acremoniumchrysogenum with cephalosporin C as basic nucleus for future drugs • First introduced into clinical use in 1964 (cephalothin) • Cephalosporins are the second major group of beta-lactam antibiotics.

7. Cephalosporins • Cephalosporins are a family of antibiotics originally isolated in 1948 from the fungus Cephalosporium, their -lactam structure very similar to that of the penicillins , cephalosporins resemble penicillins in inhibiting the transpeptidation reaction during • peptidoglycan synthesis. • They are broad-spectrum drugs frequently given to patients with penicillin allergies. • Many cephalosporins are in use • First-generation cephalosporins are more effective against gram-positive than gram-negative pathogens. • Secondgeneration drugs act against many gram-negative as well as grampositive • pathogens. • Third-generation drugs are particularly effective against gram-negative pathogens, and often also reach the central nervous system.

8. Cephalosporins • Bicyclic ring structure • beta-lactam ring (in common with penicillins) • 6 membered sulfur containing dihidrothiaizine ring • Changes in side chain R groups gives changes in spectrum of activity, pharmacokinetics, etc.

9. Mechanism of action: binds to penicillin binding proteins and inhibition of formation of cell wall • Mechanisms of resistance: • Changes in drug target of penicillin binding proteins  - methicillin-resistantStaphyloccocusaureus • Efflux pumps – MexAB-OprM efflux pump in Pseudomonas aeruginosa • Decreased permeability of cell wall – less common for cephalosporins • Alteration of drug itself by hydrolysis by beta-lactamases • Numbers and types of beta-lactamases increasing • Can be chromosomally or extra-chromosomally (more easily transmitted to other organisms) mediated • Resistance to one cephalosporin can result in resistance others depending on mechanism • Resistance to cephalosporins can confer resistance to other beta-lactam drugs like penicillins as well

10. Different classes • Divided into “generations” for convenience but many drugs in same “generation” not chemically related and different spectrum of activity • Currently four generations of cephalosporins but which generation a particular drug belongs often a matter of debate • Generalization that with increasing “generation” activity in vitro against Gram positive organisms decreases while activity against Gram negatives increases (but an oversimplification)

11. Diff classes • 1st Generation - Narrow Spectrum • Cephalexin, Cefazolin • 2nd Generation - Intermediate Spectrum • Cefaclor,Cefotetan,Cefoxitin,Cefuroxime • 3rd Generation - Broad Spectrum • Cefotaxime, Ceftriaxone • Cefixime • 4th Generation - Broad Spectrum • Cefepime

12. Cephalosporins • First generation • Oral and intravenous forumlations • Activity against E. coli, Klebsiella, Proteus • In general, FDA approved for skin and soft tissue infections, urinary tract infections, respiratory tract infections • Second generation • Oral and intravenous - cefuroximeaxetil • Anti-anaerobic activity (cephamycins) - cefoxitin • Third generation • Non-anti-pseudomonal – ceftriaxone, cefotaxime • Anti-pseudomonal – ceftazidime • Fourth generation – cefepime

13. Glycopeptide antibiotics are a class of antibioticdrugs. • The class is composed of glycosylated cyclic or polycyclic nonribosomal peptides. • Significant glycopeptide antibiotics include vancomycin, teicoplanin, 

14. Vancomycin • Vancomycin is a glycopeptide antibiotic produced by Streptomyces orientalis. • It is a cup-shaped molecule composed of a peptide linked to a disaccharide. • The antibiotic blocks peptidoglycan synthesis by inhibiting the transpeptidation step that cross-links adjacent peptidoglycan strands. • The resulting peptidoglycan is mechanically weak and the cells osmoticallylyse. • Vancomycin’s peptide portion binds specifically to the D-alanine-D-alanine terminal sequence on the pentapeptide portion of peptidoglycan. • This complex blocks transpeptidase action. • The antibiotic is bactericidal for Staphylococcus and some • members of the genera Clostridium, Bacillus, Streptococcus, and • Enterococcus. • It is given both orally and intravenously, and has • been particularly important in the treatment of antibiotic resistant staphylococcal and enterococcal infections. • Vancomycin-resistant strains of Enterococcus have become widespread and recently a few cases of resistant Staphylococcus aureus have appeared.

15. Teicoplanin • Teicoplanin is a glycopeptide antibiotic from Actinoplanesteichomyceticus • is similar in structure and mechanism of actiontovancomycin. • It is active against staphylococci, enterococci, streptococci, clostridia, Listeria, and many other grampositivepathogens. This antibiotic presently is used in Europe and elsewhere, but not in the United States.

16. Bacitracin •  is a polypeptide antibiotic produced by Bacillus species. • It prevents cell wall growth by inhibiting the release of the subunits of peptidoglycan from the lipid carrier molecule that carries the subunit to the outside of the membrane • Teichoic acid synthesis, which requires the same carrier, is also inhibited. • Bacitracin has a high toxicity which precludes its systemic use. • It is present in many topical antibiotic preparations, and since it is not absorbed by the gut, it is given to "sterilize" the bowel prior to surgery