Presentation on theme: "Beta-Lactamase Inhibitors"— Presentation transcript:
1 Beta-Lactamase Inhibitors Clavulanic acid, Tazobactam, SulbactamDrug Class: inhibitors of beta-lactamaseTrade 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 ticarcillinpenicillin-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 PenicillinMechanism 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. administrationacid 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 PenicillinMechanism 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 PenicillinsMechanism 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 CephalosporinsCephalosporin discovery credited to Brotzu in 1945 in sewer water off coast of SardininaSeveral compounds isolated from mold Acremonium chrysogenum with cephalosporin C as basic nucleus for future drugsFirst introduced into clinical use in 1964 (cephalothin)Cephalosporins are the second major group of beta-lactam antibiotics.
7 CephalosporinsCephalosporins 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 duringpeptidoglycan synthesis.They are broad-spectrum drugs frequently given to patients with penicillin allergies.Many cephalosporins are in useFirst-generation cephalosporins are more effective against gram-positive than gram-negative pathogens.Secondgeneration drugs act against many gram-negative as well as grampositivepathogens.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 ringChanges 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 wallMechanisms of resistance:Changes in drug target of penicillin binding proteins - methicillin-resistantStaphyloccocus aureusEfflux pumps – MexAB-OprM efflux pump in Pseudomonas aeruginosaDecreased permeability of cell wall – less common for cephalosporinsAlteration of drug itself by hydrolysis by beta-lactamasesNumbers and types of beta-lactamases increasingCan be chromosomally or extra-chromosomally (more easily transmitted to other organisms) mediatedResistance to one cephalosporin can result in resistance others depending on mechanismResistance to cephalosporins can confer resistance to other beta-lactam drugs like penicillins as well
10 Different classesDivided into “generations” for convenience but many drugs in same “generation” not chemically related and different spectrum of activityCurrently four generations of cephalosporins but which generation a particular drug belongs often a matter of debateGeneralization that with increasing “generation” activity in vitro against Gram positive organisms decreases while activity against Gram negatives increases (but an oversimplification)
12 Cephalosporins First generation Second generation Third generation Oral and intravenous forumlationsActivity against E. coli, Klebsiella, ProteusIn general, FDA approved for skin and soft tissue infections, urinary tract infections, respiratory tract infectionsSecond generationOral and intravenous - cefuroxime axetilAnti-anaerobic activity (cephamycins) - cefoxitinThird generationNon-anti-pseudomonal – ceftriaxone, cefotaximeAnti-pseudomonal – ceftazidimeFourth 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 VancomycinVancomycin 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 somemembers of the genera Clostridium, Bacillus, Streptococcus, andEnterococcus.It is given both orally and intravenously, and hasbeen 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 TeicoplaninTeicoplanin is a glycopeptide antibiotic from Actinoplanes teichomyceticusis 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 Europeand 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 membraneTeichoic 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