Lec 19. Cell Wall Synthesis Inhibitors I, Dr. Panavelil- FS PDF

Beta lactam antibiotics Penicillins, Cephalosporins, Carbapenems, Monobactams ANTIBACTERIAL Other Inhibitors of Cell Wall CELL WALL SYNTHESIS AND Synthesis and Cell Wall DISRUPTION Disrupting agents (Non-beta DRUGS lactams)...

Beta lactam antibiotics Penicillins, Cephalosporins, Carbapenems, Monobactams ANTIBACTERIAL Other Inhibitors of Cell Wall CELL WALL SYNTHESIS AND Synthesis and Cell Wall DISRUPTION Disrupting agents (Non-beta DRUGS lactams) Vancomycin, Bacitracin, Cycloserine, Polymyxins, Fosfomycin (Phosphonomycin) etc.  Structure Beta lactam antibiotics have a unique 4-membered ring in their structure called beta-lactam ring attached to the thiazolidine ring. The beta lactam ring carries a secondary amino group (RNH). Substituents can be attached to the amino group. Cephalosporins are also beta lactam antibiotics but have a 6- membered ring in place of thiazolidine ring. R1 and R2 groups determine therapeutic activity and toxicity (see figure). Cephalosporins will be discussed separately in detail.  Penicillin classes Penicillins are classified into basically three classes. They are: 1) Natural penicillins (penicillin G) 2) Gm positive or Antistaphylococcal penicillins (Eg: nafcillin) 3) Extended spectrum penicillins (Ampicillin Amoxicillin and the gram negative or antipseudomonal penicillins)  Mechanism of Action (MOA) Penicillins inhibit the cross-linking step in the synthesis of bacterial cell wall. They combine with and inactivate a transpeptidase which is normally responsible for cross-linking the linear glycopeptide strands of bacterial cell walls. Since this action causes cell lysis and death, penicillins are bactericidal antibiotics. They need rapidly growing organisms for their action, with peptidoglycan cell walls. Mycobacteria, fungi, protozoa, virus etc. do not have these structures therefore beta lactams are usually inactive against these organisms. There are three distinct steps that were discovered in the process of cell wall disruption by penicillins: Penicillins do their action by binding to enzymes involved in the cell wall synthesis called penicillin-binding proteins (PBPs). Some PBPs are transpeptidases that help in cross-linking the cell wall chains. Penicillins by its binding to these transpeptidases thus blocks cross-linking. Gram-positive cocci, produce degradative Mechanism enzymes called autolysins, that help in the remodeling of the cell wall. Penicillins have also been found to activate these autolysins for the self-destruction of the bacterial cell wall. For gram-positive bacteria, cell walls are easily traversed by penicillins. For gram-negative bacteria due to the lipopolysaccharide outer membrane, lipid filled channels (porins) are needed for the entry of penicillins. Penicillins differ in their capability for their entry. Penicillin G (benzylpenicillin): parenteral for treponemal and clostridium infections Chain, Florey and their associates produced significant quantities of penicillin 60 years ago. They have good activity against gram- positive organisms. They are used for treatment against gram + cocci and gram + bacilli, Gram – cocci, and Spirochetes (Drug of choice for Natural Treponema pallidum, gram-negative bacteria once considered anaerobic penicillins: and now it is known that that they can use glucose oxidatively). Many oral anaerobes also are susceptible. Penicillin G is susceptible to betalactamases. They are unstable at acidic pH and gastric environment inactivates penicillin G and only 30% absorbed from the duodenum. Drug of choice for ‘gas gangrene’ usually due to Clostridium perfringens. (in combination with clindamycin) Used in diphtheria for acute and chronic carrier states.  Also used in anthrax (B. anthracis, aerobic gram positive), actinomycosis (caused by actinomyces, anaerobic gram-positive bacilli) and Listeria (gram-positive facultatively anaerobic bacillus) infections. Highly active against Treponema pallidum with no resistance. In the US, Syphilis is treated with benzathine penicillin (i.m. 2.4 million units) and doxycycline (orally 4 weeks) in Penicillin penicillin allergic patients. Upon Subcutaneous or Intra-muscular administration of crystalline penicillin G, peak G…….. concentration achieves in 15 minutes. Penicillin G when administered at doses 18-24 million units is inhibitory for enterococci, but the simultaneous administration of an aminoglycoside is necessary to achieve a bactericidal effect that is necessary when treating enterococcal endocarditis. Repository forma of penicillin (insoluble salts) such as procaine penicillin G and Benzathine penicillin G etc. provide duration of action 12-24 hours. Benzathine penicillin G can provide effective blood levels for up to a week.  Penicillin V Amoxicillin substitutes this drug in almost all cases Penicillin V is more stable in acidic environment and is the oral form of penicillin. It is used for oral infections against anaerobes. Indicated only in minor infections because of poor bioavailability, four times a day dosing, and narrow bacterial spectrum. Has high minimal lethal concentration, therefore not good a choice in bacteremia. General comments on penicillin G and penicillin V Since food interferes with absorption, Penicillin V and Penicillin G should be administered at least 1 hour before meals or 2-3 hours after meals. The simultaneous administration of probenecid prolongs the duration of penicillin in the body due proximal renal tubule mechanism. 99% of penicillin G and penicillin V are eliminated via the kidney. Prophylactic uses of penicillins: Streptococcal infections Rheumatic fever recurrences Gonorrheal ophthalmia in neonates Surgical procedures in patients with valvular disease Dental extractions, tonsillectomy, and intestinal and genitourinary operations. Bacteremia is not totally prevented by using prophylactic penicillin  Antistaphylococcal (gram-positive cocci) penicillins These drugs are resistant to staphylococcal beta lactamases. They are active against staphylococci and streptococci but inactive against enterococci, anaerobic bacteria, and gram- negative cocci and rods. Methicillin (not in the US because better drugs are available), Nafcillin (Nallpen, i.v.), Oxacillin, Cloxacillin (available only off market, Teva and Bristol Myers) and Dicloxacillin (oral) are examples of these beta-lactamase resistant drugs. Therefore, they are indicated against staphylococci that are penicillinase producing.  Points on individual antistaphylococcal penicillins: Methicillin is nephrotoxic (interstitial nephritis) and is rarely used. Methicillin has poor oral absorption. Not available in the US Oxacillin can be given orally because it is acid stable. It is 8 times potent than methicillin. Gram positive Nafcillin can be given via all routes. Nafcillin can cause neutropenia and penicillins…. phlebitis Dicloxacillin is highly resistant to penicillinase and is very effective orally. For serious systemic staphylococcal infections, oxacillin or nafcillin is given by intermittent intravenous infusion Remember: Resistant strains of bacteria that are usually of nosocomial origin are usually susceptible to vancomycin.  Extended spectrum penicillins Ampicillin and Amoxicillin They are called extended spectrum because while retaining the antibacterial spectrum of penicillins, they are also effective against gram negative bacilli. But they are destroyed by beta-lactamases. For aerobic (also facultatively anaerobic) gram positive bacilli Listeria, ampicillin is the drug of choice. Amoxicillin is given orally only (achieves higher blood levels and lower incidence of diarrhea than penicillin). Amoxicillin is employed prophylactically by for patients with abnormal heart valves, who are to undergo oral surgery. Ampicillin is acid stable, but not penicillinase resistant. Due to plasmid mediated penicillinases, organisms like E. coli and H. influenzae usually develop resistance. Beta lactamase inhibitors like clavulanic acid, sulbactam etc are used to protect these drugs from hydrolysis (Eg. Augmentin is amoxicillin-clavulanic acid combination, Unasyn is ampicillin-sulbactam combination and Zosyn is piperacillin- tazobactam combination) Use of ampicillin and sulbactam (Unasyn) in treating intra-abdominal and gynecological infections are common.  Carbenicillin (parenteral no longer available), Anti- ticarcillin, piperacillin azlocillin and mezlocillin are examples that are active pseudomonal against Pseudomonas aeruginosa therefore sometimes called anti-pseudomonal penicillins: penicillins. Carbenicillin Carbenicillin and Ticarcillin are similar to ampicillin and, in addition, are effective (oral only in against indole-positive Proteus and Pseudomonas. US), Ticarcillin Azlocillin, Mezlocillin and Piperacillin are (Timentin with ureido-penicillins. Piperacillin is the most potent. clavulanate, Piperacillin can cause platelet dysfunction and Ticar both Mezlocillin and Piperacillin are active against Klebsiella pneumoniae (facultative gram- i.v. only), negative rod). Piperacillin Piperacillin/tazobactam treats serious nosocomial polymicrobial infections, (with especially when Pseudomonas is involved tazobactam, as Carbenicillin indanyl is acid-stable and is administered orally. Zosyn as i.v.) Carbenicillin is oral only in the us, but piperacillin is considered a better option for coverage Ticarcillin I.V. replaces carbenicillin I.V. for pseudomonas infections  Clavulanic acid Sulbactam Betalactamase Tazobactam inhibitors Prevent penicillinase (beta-lactamase) mediated drug hydrolysis/breakdown.  Penicillins and aminoglycosides work synergistically. But, they cannot be given in the same IV Synergism fluid because aminoglycosides are positively charged and penicillins are negatively charged! Causes for resistance to penicillins Impermeable cell walls Those that lack peptidoglycan cell walls Plasmid mediated resistance Chromosome and Plasmid mediated beta lactamases Decreased permeability Altered penicillin binding proteins – Eg. methicillin resistant Staph.  Given intramuscular (many) and oral (amoxicillin + clavulanic acid, example). Procaine penicillin G and benzathine penicillin G are IM depot forms (absorbed over a long period of time) usually for beta hemolytic streptococcal infections. Kinetics (all Amoxicillin has great oral absorption. penicillins): Penicillin G absorption affected by food. Penicillins cross placental barrier, but no teratogenic effect. Penetration to cerebrospinal fluid is possible only with inflammation! Primary excretion is through kidney. Probenecid inhibits secretion of penicillins.  Adverse effects (all penicillins): Hypersensitivity in 5 – 25% patients, especially the metabolite penicilloic acid. Skin rashes, and in severe cases Steven-Johnson syndrome (bullous form of erythema multiforme). The highest incidence is with ampicillin. Diarrhea, potential interstitial nephritis, neurotoxicity to the extent of seizures, platelet dysfunction (carbenicillin, ticarcillin, piperacillin), cation toxicity due to Na+ and K+. Drug induced fever disappears after 36 hours of administration. Eosinophilia, serum sickness, angioedema (subcutaneous or mucosal edema) are other adverse effects. One in 50,000 patients treated in the US with penicillin dies from an anaphylactic reaction. Also superinfection observed with extended spectrum penicillins such as ampicillin and carbenicillin. Penicillin reactive patients have occasional allergic reactions to cephalosporins.