Beta-Lactam Antibiotics Lecture Notes PDF

BETA-LACTAM ANTIBIOTICS Dr. Sahand K Arif  Classification of antibiotics Inhibitors of cell wall synthesis Penicillins Cephalosporins Carbapenems and monobactams Glycopeptides Protein synthesis inhibitors acting on ribosomal subunits 30S Aminoglycosides...

BETA-LACTAM ANTIBIOTICS Dr. Sahand K Arif  Classification of antibiotics Inhibitors of cell wall synthesis Penicillins Cephalosporins Carbapenems and monobactams Glycopeptides Protein synthesis inhibitors acting on ribosomal subunits 30S Aminoglycosides Tetracyclines Protein synthesis inhibitors acting on ribosomal subunits 50S Macrolides and azalides Chloramphenicols Lincosamides Antibiotics which disturb functions of nucleic acids Rifampicins Antibiotics which disturb structure and functions of cell membranes Polienes Cyclic polypeptides (polymyxins). Characteristics of beta lactam antibiotics: 1- All beta lactams have the same mode of action (inhibit cell wall synthesis). 2- Bactericidal (except against Enterococcus sp.).? 3- Time-dependent killers. 4- Cross hypersensitivity. 5- All beta-lactams lack activity against atypical organisms such as Mycoplasma pneumoniae and Chlamydophila pneumoniae. ? 6- Nearly all currently available beta-lactams lack activity against MRSA.  MOA (Mechanism of action) Bacteria are unique Don’t have osmotic regulating mechanism Cell wall controls osmotic changes. Cell wall is composed of Peptidoglycans Cross linked by peptide chains. NAM – NAG ( N-acetyl muramic acid and N- acetyl glucosamine) Cross linked by a Pentaglycine cross bridge (Extending from the L-lysine residue of one peptide chain to the D-alanine residue of another peptide chain). Cross bridging is transpeptidation reaction. Transpeptidase (Penicillin Binding Proteins) are used for making cross linkage. Cross linking provides stability, strength. https://www.youtube.com/watch?v=qBdYnRhdWcQ  β-Lactams inhibit Transpeptidase leading to Damage of cross linking Weakening of cell wall Swelling of cell due to Endosmosis Bacterial membrane bursts Bacterial lysis Additional mechanism – Activation of autolysing enzymes (Murein Hydrolase and Autolysins) More lethal during active multiplication Penicillin Binding Proteins are of three types PBP-1- involved in peptidoglycan synthesis during elongation PBP-2- is carboxypeptidase. It hydrolyses the terminal D-ala residue present on the adjacent pentapeptide chain to promote further cross linking at that site. Its inhibition leads to spherical cells (Instead of rod shaped bacilli) PBP-3 is endopeptidase. It splits cross linking involved in septum formation during cell division. (Inhibition leads to filamentation wherein cells cannot separate from one another during cell division.)  Bactericidal activity of penicillin is more against Gram positive. (Difference in organization of cell wall) In gram positive Thick layer of Peptidoglycans and teichoic acid (a polyol phosphate polymer) surrounds the membrane. Peptidoglycans layer is easily accessible to Beta lactam antibiotics In gram negative Two membranes are present. (The cytoplasmic membrane and an outer membrane with thin layer of Peptidoglycans sandwiched between the two). The outer membrane consists of lipopolysaccharides with narrow porin channels which function as a barrier to permeability of antibiotics Penicillins which are hydrophilic in nature (Ampicillin and Amoxicillin) can diffuse through porin channels and show activity against negative. Pseudomonas lacks porins due to which even Ampicillin and amoxicillin can’t act against them. Aminoglycosides addition is synergistic  Why selective against bacteria ( and different types of bacteria) Peptidoglycans cell wall is unique to bacteria. In gram positive cell wall is entirely made by Peptidoglycans with extensive cross linking ( More effective in +ve) In gram negative cell wall consists of lipoprotein and Peptidoglycans with less cross linking ( Less effective in –ve) Penicillin binds with PBPs and every organism has different proteins with different affinity for penicillin. Gram negative bacteria have porins of specific proteins located in outer membrane. Permeability of different beta-lactam antibiotics through these channels differs leading to variable action.  Resistance against Penicillin Natural Target enzymes and PBPs are deeply located (Lipoprotein barrier in –ve) PBPs of organisms have low affinity for penicillin Acquired Production of Penicillinase (Beta-Lactamase) enzyme, (>300 subtypes). Common organisms producing Beta-Lactamase are Staphylococcus Bacillus subtilis Gonococci E. coli Enterococci Haemophilus influenza Loss or alteration of Porin channels in gram negative Modification of penicillin binding proteins (PBPs)- having low affinity. Activation of antibiotic efflux mechanism- Some gram negative bacteria  Side effects of penicillins The main hazard with the penicillins is allergic reaction. These include itching, rashes, fever, and angioedema, and rarely anaphylactic shock which can be fatal. Allergies are least likely when penicillins are given orally. Metabolic opening of the β-lactam ring creates a highly reactive penicilloyl group which polymerizes and binds with tissue proteins to form the major antigenic determinant. The anaphylactic reaction involves specific IgE antibodies which can be detected in the plasma of susceptible persons. There is a cross-allergy between all the various forms of penicillin due to their common structure and to the degradation products common to them all. Partial cross-allergy exists between penicillins and cephalosporins (a maximum of 10%). Carbapenems and monobactams have a much lower risk of cross- reactivity. An intradermal test for allergy may be performed; appearance of a flare and wheal reaction indicates a positive response. Only about 10% of patients with a history of “penicillin allergy” respond positively.  Nonallergic side effects include diarrhoea due to alteration in normal intestinal flora which may progress to Clostridium difficile-associated diarrhoea (for wide spectrum penicillins). Neutropenia is a risk if penicillins or other β-lactams which are used in high dose and longer than 10 days. Rarely penicillins cause anemia, and thrombocytopenia or interstitial nephritis. Extremely high plasma penicillin concentrations cause convulsions. Co-amoxiclav, flucloxacillin, or oxacillin given in high doses for prolonged periods in the elderly may cause hepatic toxicity. A-NARROW SPECTRUM PENICILLIN 1-Biosynthetic (natural) penicillins 2-Antistaphylococcal (beta-lactamase resistant penicillins) B-BROAD SPECTRUM PENICILLINS 1-Aminopenicillins 2-Antipseudomonal penicillins Carboxypenicillins Ureidopenicillins 1-Biosynthetic (natural) penicillins ▼Benzylpenicillin (Penicillin G) is a drug of choice for infections caused by streptococci meningococci enterococci, penicillin- susceptible pneumococci non-β-lactamase-producing staphylococci T. pallidum and many other spirochetes, clostridium species actinomyces other Gram- positive rods non-β-lactamase-producing Gram- negative anaerobic organisms.  ▼Phenoxymethylpenicillin Potassium (Penicillin-V) the oral form of penicillin, is indicated only in minor infections (e.g. tonsillitis) because of its poor bioavailability, short action and narrow antibacterial spectrum ▼Benzathine penicillin and Procaine Penicillin G maintain low but prolonged drug levels bioavailability, short action and narrow antibacterial spectrum Benzathine benzylpenicillin G (BPG) is recommended as secondary prophylaxis to prevent recurrence of acute rheumatic fever and subsequent rheumatic heart disease (RHD). Following intramuscular injection, BPG is hydrolysed to benzylpenicillin (3-4 weeks). A single IM injection is an effective treatment for β-hemolytic streptococcal pharyngitis, 2.4 million units IM once a week for 1–3 weeks, is effective in the treatment of syphilis.  2-Antistaphylococcal penicillins Also called “Penicillinase-resistant” penicillins Isoxazolyl penicillins Cloxacillin, Dicloxacillin Flucloxacillin, Oxacillin others Methicillin Nafcillin These semisynthetic penicillins are indicated for infection by : beta-lactamase-producing staphylococci, although penicillin-susceptible strains of streptococci and pneumococci are also susceptible. An isoxazolyl penicillin (cloxacillin, dicloxacillin, or oxacillin), 250–500 mg orally every 4 to 6 h is suitable for the treatment of mild to moderate localized staphylococcal infections. All are relatively acid-stable but food interferes with their absorption.  2. BROAD-SPECTRUM PENICILLINS 1-Aminopenicillins Ampicillin, Amoxicillin These penicillin analogs have an amino side group that increases their hydrophilicity, allowing them to permeate through porins of some gram-negative bacteria (e.g. E. coli, P. mirabili & Shigella spp.) the addition of a hydroxyl group (−OH) to amoxicillin increased acid stability, which allows for improved oral absorption. Commonly used to treat listeria meningitis & enterococcal infections They share the same vulnerability to beta-lactamases as the natural penicillins, and hence are commonly combined with a beta-lactamase inhibitor, e.g. ampicillin + sulbactam (Unasyn ®) amoxicillin + clavulanic acid (Augmentin ®) Narrow-spectrum against gram-positive bacteria but with increased gram-negative spectrum 2-Antipseudomonal penicillins Extended-Spectrum Penicillins The side groups of these penicillin analogs allow for greater penetration into gram-negative bacteria compared to aminopenicillins. These agents are also generally more resistant to many (but not all) gram- negative beta-lactamases They are more active against Pseudomonsa aeruginosa These drugs achieve their fullest antimicrobial potential when combined with β-lactamase inhibitors, and have activity against many aerobic gram- positive, gram-negative bacteria, and nearly all anaerobic bacteria except C. difficile For example, the drug combination of extended spectrum penicillins with β-lactamase inhibitors are useful in treating infections caused by many β-lactamase producing strains of E. coli, Klebsiella spp, Bacteroides spp & Enterobacter spp. Carboxypenicillins Carbenicillin Ticarcillin Ureidopenicillins Azlocillin Mezlocillin Piperacillin  Resistance to penicillins and other beta-lactams due to one of some general mechanisms: (1) inactivation of the antibiotic by beta-lactamase; (2) modification of the target PBPs; (3) impaired penetration of the drug to the target PBPs; (4) efflux of the drug from bacterial cells. Beta-lactamase production is the most common mechanism of resistance. Many hundreds of different beta-lactamases have been identified. Some, such as those produced by Staphylococcus aureus, Haemophilus spp., and Escherichia coli, are relatively narrow in substrate specificity, preferring penicillins to cephalosporins. They are called penicillinase and cephalosporinases. Other β-lactamases produced by P. aeruginosa and Enterobacter spp., and extended-spectrum beta-lactamases, hydrolyze both cephalosporins and penicillins. Carbapenems are highly resistant to hydrolysis by penicillinases and cephalosporinases but they are hydrolyzed by metallo-beta-lactamase and carbapenemases.  Ampicillin, amoxicillin, ticarcillin, and piperacillin are also available in combination with one of several beta-lactamase inhibitors: clavulanic acid, sulbactam, or tazobactam. The addition of a beta-lactamase inhibitor extends the activity of these penicillins to include beta-lactamase-producing strains of S. aureus as well as some beta-lactamase-producing Gram-negative bacteria (E. coli, K. pneumoniae, P. aeruginosa, Proteus, H. influenzae). THE PENICILLINS CATEGORY PARENTERAL AGENTS ORAL AGENTS Natural Penicillins Penicillin G Penicillin V Antistaphylococcal Penicillins Nafcillin, Oxacillin, (Methicillin*) Dicloxacillin Aminopenicillins Ampicillin Amoxicillin, Ampicillin Aminopenicillins + Ampicillin-sulbactam Amoxicillin-clavulanate β-lactamase inhibitors Extended-spectrum Penicillins Piperacillin, ticarcillin Extended-spectrum + Piperacillin-tazobactam, Ticarcillin- β-lactamase inhibitors clavulanate