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Beta-Lactamase Inhibitors

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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-Lactamase Extended 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: Semisynthetic Penicillins 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 Acremonium chrysogenum 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 Mechanisms of resistance:
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-resistantStaphyloccocus aureus 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 Second generation Third 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 - cefuroxime axetil 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 antibiotic drugs.
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 osmotically lyse. 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 Actinoplanes teichomyceticus is similar in structure and mechanism of actionto vancomycin. It is active against staphylococci, enterococci, streptococci, clostridia, Listeria, and many other grampositive pathogens. 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

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