Antimicrobial Agent 2 - Beta Lactam Antibiotics PDF

Antimicrobial Agent 2 : Betalactam antibiotics Dr. Nazmun Nahar Alam Specific Learning outcomes At the end of the lecture, students should be able to ▪ Describe the mechanism of action, therapeutic uses, adverse effects and limitations of crystalline penicillin / penicillin G. ▪ List the long...

Antimicrobial Agent 2 : Betalactam antibiotics Dr. Nazmun Nahar Alam Specific Learning outcomes At the end of the lecture, students should be able to ▪ Describe the mechanism of action, therapeutic uses, adverse effects and limitations of crystalline penicillin / penicillin G. ▪ List the long acting penicillins with their duration of action and uses. ▪ List different groups of semisynthetic penicillins with examples, advantages over penicillin G and uses. ▪ List and describe the role of betalactamases inhibitors in the treatment of bacterial infections. ▪ List the different generations of cephalosporins with 2 examples for each and state their mechanism of action, uses and adverse effects. 11/2/2024 Dr. Nazmun@ Aimst 2  Antimicrobial agents (AMA) – Classification based on Chemical group Penicillins – Penicillin G, Amoxicillin β-lactam antibiotics Cephalosporins – Cephalexin, Cefotaxime Macrolides – Erythromycin, Azithromycin Aminoglycosides – Streptomycin, Gentamicin Tetracyclines – Doxycycline, Minocycline Fluoroquinolones – Ciprofloxacin, Ofloxacin Others – Sulphonamides, Trimethoprim, Rifampicin, Metronidazole 11/2/2024 Dr. Nazmun@ Aimst 3  β-Lactam antibiotics β-Lactam antibiotics – Contain β-lactam ring, Penicillins Cephalosporins Carbapenems Monobactams β-lactam ring in the antibiotic is hydrolysed by the enzyme betalactamase leading to inactivation of the antibiotic. Betalactamase / penicillinase is produced by some bacteria resistant to β- Lactam antibiotics. 11/2/2024 Dr. Nazmun@ Aimst 4  Penicillin Penicillin sources: Penicillium notatum & P. chrysogenum Structure: 6-aminopenicillanic acid = β-lactam ring + thiazolidine ring 6-aminopenicillanic acid is the active nucleus of penicillin. Opening of the β-lactam ring by β-lactamase inactivates penicillin. Penicillin is a bactericidal antibiotic. 6-aminopencillanic acid 11/2/2024 SiteAimst Dr. Nazmun@ of cleavage by betalactamase 5  Structure of Penicillin Unique structure of 6- Aminopenicillanic Acid contains two rings- β - lactam ring and Thiazolidine ring β - lactam ring is responsible for antibacterial effect Modification at the side chain with different groups gives different penicillin 11/2/2024 Dr. Nazmun@ Aimst 6  Classification of Penicillin ❑Narrow Spectrum penicillin Benzylpenicillin (Penicillin G) Phenoxymethyl penicillin (PenicillinV) Antistaphylococcal penicillin/ Beta-lactamase resistance penicillin: - Flucloxacillin - Cloxacillin ❑ Broad Spectrum Penicillin - Amoxicillin - Ampicillin ❑ Extended Spectrum/(Antipseudomonal) penicillin - Ticarcillin - Carbenicillin 11/2/2024 Dr. Nazmun@ Aimst 7 - Piperacillin  Penicillins Natural penicillin: Penicillin G / Benzyl penicillin/ Xlline penicillin Repository penicillins: Procaine penicillin, Benzathine penicillin Semisynthetic penicillins Acid resistant penicillin: Phenoxymethylpenicillin (Pencillin V) Penicillinase-resistant penicillins: Cloxacillin, Dicloxacillin, Methicillin Extended spectrum penicillins Aminopenicillins: Ampicillin, Amoxicillin Antipseudomonal penicillins Carboxypenicillins: Carbenicillin, Azlocillin Ureido-penicillins: Ticarcillin, Piperacillin 11/2/2024 Dr. Nazmun@ Aimst 8  Beta Lactams(Penicillins) 11/2/2024 Dr. Nazmun@ Aimst 9  Penicillin – Mechanism of action Peptidoglycan component of the bacterial cell wall provides rigid mechanical stability to the cell wall. Transpeptidation is the last step in the synthesis of peptidoglycans, in which peptide bridges cross link the polymer chains making the cell wall rigid & bacterium viable. All β-lactam antibiotics inhibit transpeptidation reaction in the bacterial cell wall making the cell wall weak, increase its permeability resulting in bursting of the bacterium. All β-lactams are bactericidal & act only on multiplying bacteria. 11/2/2024 Dr. Nazmun@ Aimst 10  Penicillin G - Spectrum of activity ▪ Gram-positive & Gram-negative cocci ▪ Gram-positive bacilli ▪ Anaerobs ▪ Spirochaetes 11/2/2024 Dr. Nazmun@ Aimst 11  Penicillin G limitations 1. Acid sensitivity - cannot be given orally. Needs to be given parenterally, as IM or IV injection 2. Penicillinase susceptibility – Infections by penicillinase producing bacteria cannot be treated. 3. Narrow spectrum – Not effective against G-ve infections, Semisynthetic penicillins overcome these limitations. 4. Short duration of action – Repeated administration is necessary requiring hospitalization. 11/2/2024 Dr. Nazmun@ Aimst 12  Penicillin G limitations – Method to overcome 11/2/2024 Dr. Nazmun@ Aimst 13  Penicillin G – Indication/uses Prophylactic uses: Activity of penicillin G is expressed in units while the activity of semisynthetic penicllin is expressed by weight. Benzathine penicillin: Injection every 3-4 weeks 1. Prophylaxis of beta-hemolytic streptococcal infections. 2. To prevent recurrence of rheumatic fever. 3. in syphilis contacts. Therapeutic uses: Procaine benzyl penicillin Administered once a day. Syphilis, in various infections caused by susceptible bacteria 11/2/2024 Dr. Nazmun@ Aimst 14  Penicillin- Indication/ uses Penicillin G IM or IV is preferred for acute infections and in critically ill patients. 1. Pneumococcal meningitis – iv penicillin G in high doses. 2. Meningococcal meningitis – Penicillin G is the drug of choice (DOC) 3. Pneumococcal pneumonia 4. Syphilis – highly effective 5. Anaerobic infections 6. Streptococcal pharyngitis 7. Diphtheria – to eliminate carrier state. 11/2/2024 Dr. Nazmun@ Aimst 15  Semisynthetic Penicillins 6-aminopenicillanic acid can be isolated by separation of the side chain by enzyme amidase. By the addition of various side chains to the amino group of 6- aminopenicillanic acid, a series of semisynthetic penicillins are made. 11/2/2024 Dr. Nazmun@ Aimst 16  Semisynthetic Penicillins (1) Limitations of Semisynthetic penicillin- Examples (Limitations) Penicillin G Advantage over penicillin G 1. Acid sensitivity Acid resistant penicillin – Penicillin V (inactivated in effective orally (Narrow spectrum, stomach) penicillinase susceptible, short duration) 2. Inactivated by Penicillinase resistant Cloxacillin, Dicloxacillin, bacterial penicillins – active against β- Methicillin penicillinase lactamase producing bacteria (Narrow spectrum, short (penicillinase e.g. Staphylococci duration) susceptible) 11/2/2024 Dr. Nazmun@ Aimst 17  Semisynthetic Penicillins (2) Limitations of SS penicillin- Examples (Limitations) Penicillin G Advantage over penicillin G 3. Narrow Broad spectrum Ampicillin, Amoxicillin spectrum penicillins / Extended Carbenicillin,Ticaricillin, spectrum penicillins Piperacillin, (short duration, penicillinase susceptible) 11/2/2024 Dr. Nazmun@ Aimst 18  Penicillins ADME of Penicillins: Acid resistant penicillins - Penicillin V, amoxicillin, cloxacillin, dicloxacillin absorbed orally. ▪ Penicillins are distributed well reaching higher concentrations in inflamed tissues e.g.: meningitis. ▪ Penicillin mostly is excreted by kidney in active form - filtration (10%) – secretion (90%). ▪ Probenecid inhibits the secretion & maintains high plasma concentration and for longer time. ▪ Urine has high concentrations of the antibiotic. 11/2/2024 Dr. Nazmun@ Aimst 19  Penicillins Half life of penicillin is 30 – 90 min Excreted in small quantities in milk, may lead to allergy in baby. Penicillin in cow’s milk may cause allergy in community. Activity of penicillin G is expressed in units while the activity of semisynthetic penicillin is expressed by weight. Resistance to Penicillins: Many staphylococci, gonococci, Heamophilus influenzae are resistant by producing penicillinase. 11/2/2024 Dr. Nazmun@ Aimst 20  Adverse effects of Penicillin ADR: Remarkably low toxicity. Hypersensitivity (in 0.7% to 1.0% patients). Enquire about previous exposure & allergy. Amoxicillin causes skin rash. Penicillin G injection – Anaphylactic shock Superinfections e.g. Fungi – Candida, psudomembranous enterocolitis Diarrhoea: Common with ampicillin due to incomplete absorption from GIT. Less with amoxicillin due to almost complete absorption from GIT. 11/2/2024 Dr. Nazmun@ Aimst 21  Penicillinase resistant Penicillins The penicillinase-resistant penicillins are resistant to hydrolysis by staphylococcal penicillinase. E.g. Oxacillin, cloxacillin, dicloxacillin Route: oral and parenteral Penicillinase producing staphylococcal infections. Methicillin Resistant Staphylococcus Aureus (MRSA) – are resistant to pencillinase resistant penicillins and also to cephalosporins. 1. Bone and joint infections (Staphylococcal infections) 2. Staphylococcal meningitis 11/2/2024 Dr. Nazmun@ Aimst 22  Extended spectrum Penicillins – Aminopenicillins Active against Gram +ve and some Gram –ve organisms. With penicillinase inhibitors, the spectrum is extended to pencillinase producing organisms H. influenzae, E. coli, Klebsiella, Proteus etc. Ampicillin and Amoxicillin – oral. Amoxicillin is almost completely absorbed & has less GI side effects, longer duration of action compared to ampicillin, given thrice a day. Ampicillin is given 4 times a day due to its incomplete absorption. 11/2/2024 Dr. Nazmun@ Aimst 23  Extended spectrum Penicillins – Aminopenicillins Uses 1.Otitis media, Bronchitis, Pneumonia, UTI 2.Endocarditis due to enterococci: Amoxicillin with aminoglycosides 3.Gonorrhea: amoxicillin with probenecid - plasma amoxicillin concentration is maintained high and sustained by probenecid which decreases its renal secretion. 11/2/2024 Dr. Nazmun@ Aimst 24  Extended spectrum Penicillins – Antipseudomonl penicillins Carboxypenicillins: Carbenicillin, carbenicillin indanyl (oral) Azlocillin Ureido-penicillins: Ticarcillin, Piperacillin Active against Gram +ve and Gram –ve organsims including pseudomonas. Extend activity against pencillinase producing organisms by combining with penicillinase inhibitors. Piperacillin has got the broadest antibacterial spectrum. Uses in infections with Psuedomonas aeruginosa: Intra abdominal, skin & soft tissue infections, nosocomial pneumonia, UTI 11/2/2024 Dr. Nazmun@ Aimst 25 etc.  β-lactamase inhibitors Clavulanic acid, Sulbactam, Tazobactam Suicide inhibitors, as they combine with betalactamases to form inhibitory products. No antibacterial activity of their own & no ADR. They form a synergistic combination with betalactam antibiotics as they protect them against inactivation by betalactamase & extend their antibacterial spectrum. Clavulanic acid + Amoxicillin / any other penicillin Sulbactam + Ampicillin / any other penicillin Indications: with betalactamase susceptible AMA against betalactamase producing Haemophilus influenzae etc. 11/2/2024 Dr. Nazmun@ Aimst 26  Penicillin with Aminoglycosides ▪ Penicillin acts by interfering with cell wall synthesis & integrity. ▪ Aminoglycoside inhibits bacterial protein synthesis by acting on ribosomes. Aminoglycosides have to enter the cell by an energy dependent process which is rate limiting. ▪ Following the cell wall damage by penicillin, aminoglycosides enter the bacterium in larger amounts. ▪ Both antibiotics together exert a synergistic action in inhibiting the bacteria by facilitating each other. ▪ The combination of penicillin & aminoglycoside is used in endocarditis caused by streptococcus viridans & enterococci (e.g., enterococcal endocarditis). 11/2/2024 Dr. Nazmun@ Aimst 27  Cephalosporins β-lactam antibiotics, inhibit cell wall synthesis. Effective against G+ve & G-ve bacteria. More resistant to the action of Β-lactamase than penicillins. 4 generations of cephalosporins are available. From 1st to 4th generation they are more effective against Gram –ve than Gram +ve bacteria are more resistant to β-lactamases. cross easily BBB – more suitable to treat meningitis 11/2/2024 Dr. Nazmun@ Aimst 28  Cephalosporins First generation cephalosporins: Cephalexin, Cefazolin, Cephalothin, Cephradine – Active against streptococci and staphylococci, most E.coli, Proteus mirabilis and Klebsiella pneumoniae Uses: as alternative to penicillin in penicillin allergic individuals. Second generation cephalosporins : Cefaclor, Cefamandole, Cefuroxime Uses: Streptococcal, Staphylococcal & H.influenzae infections 11/2/2024 Dr. Nazmun@ Aimst 29  Cephalosporins Third generation cephalosporins: Ceftriaxone, Ceftazidime, Cefotaxime Enterobacteriaceae and H. influenzae Third generation cephalosporins are beta lactamase resistant Good CSF concentration Uses: meningitis and nosocomial pneumonia Fourth generation: Antipseudomonal cephalosporins Cefepime, Cefpirome Extended spectrum Good activity against P aeruginosa, Enterobacteriaceae, S aureus, S pneumoniae, Hemophilus etc. Highly resistant to hydrolysis byDr.β-lactamases 11/2/2024 Nazmun@ Aimst 30  Cephalosporins – Pharmacokinetics: Most by IV or IM route and oral route. Distribute very well into body fluids, 3rd & 4th generation cross well into CSF – suitable to treat meningitis. Safe during pregnancy. Cephalosporins – ADR: Hypersensitivity reactions, especially in those who are hypersensitive to penicillin. Disulfiram- like effects – Cefamandole etc. when taken with alcohol. Bleeding- due to platelet dysfunction. 11/2/2024 Dr. Nazmun@ Aimst 31  Cephalosporins - Uses 1. Surgical prophylaxis 2. Septicemia 3. Skin and Soft tissue infections 4. Meningitis 5. Urinary tract infection - especially in pregnancy or in patients unresponsive to other drugs. 6. Sinusitis 7. Gonorrhea 8. CAP - Community acquired pneumonia 9. Pseudomonas infections 11/2/2024 Dr. Nazmun@ Aimst 32  Monobactams Monobactams – Aztreonam Active against Gram-negative bacteria especially to treat penicillin allergic patients. Nosocomial infections – pneumonia, UTI, maningitis etc. They have no activity against gram-positive bacteria or anaerobes. Route: parenteral Occasional skin rashes and elevations of serum aminotransferases occur during administration of aztreonam.  Carbapenems Carbapenems – Imipenem, Meropenem Have broader spectrum of activity than other betalactams Imipenem with cilastatin Cilastatin, inhibits the degradation of imipenem by renal tubular enzyme - dehydropeptidases. Cross into CNS Route: IV, broadest antibiotic spectrum Uses: Effective against many bacteria, including Anaerobes. UTI, Lower respiratory infections; meningitis. Skin, soft tissue, bone and joint infections. 11/2/2024 Dr. Nazmun@ Aimst 34  Reference Katzung, B.G., 2023.Basic and Clinical Pharmacology, 16th Edition. Lange Medical Books. Whalen, K., 2018. Lippincott® illustrated reviews: pharmacology. Wolters kluwer india Pvt Ltd. 11/2/2024 Dr. Nazmun@ Aimst 35