Untitled Quiz

Antimicrobial Agent 2: Beta-lactam antibiotics

• Beta-lactam antibiotics contain a beta-lactam ring.
• Penicillins, Cephalosporins, Carbapenems, and Monobactams are examples of beta-lactam antibiotics.
• The beta-lactam ring in an antibiotic is hydrolysed by the enzyme beta-lactamase, leading to inactivation of the antibiotic.
• Betalactamases/penicillinase are produced by some bacteria resistant to beta-lactam antibiotics.
• 6-aminopenicillanic acid is the active nucleus of penicillin.
• Opening of the beta-lactam ring by beta-lactamase inactivates penicillin.
• Penicillin is a bactericidal antibiotic.
• Penicillin sources include Penicillium notatum & P. chrysogenum.

Specific Learning Outcomes

• Students should be able to describe the mechanism of action, therapeutic uses, adverse effects, and limitations of crystalline penicillin (penicillin G).
• Students should be able to list long-acting penicillins, their duration of action, and uses.
• Students should be able to list and describe different groups of semisynthetic penicillins, advantages over penicillin G, and uses.
• Students should be able to list and describe the role of beta-lactamases inhibitors in the treatment of bacterial infections.
• Students should be able to list different generations of cephalosporins with examples, mechanisms of action, uses, and adverse effects.

Classification of Antimicrobial Agents

• Penicillins (Penicillin G, Amoxicillin)
• Cephalosporins (Cephalexin, Cefotaxime)
• Macrolides (Erythromycin, Azithromycin)
• Aminoglycosides (Streptomycin, Gentamicin)
• Tetracyclines (Doxycycline, Minocycline)
• Fluoroquinolones (Ciprofloxacin, Ofloxacin)
• Others (Sulphonamides, Trimethoprim, Rifampicin, Metronidazole)

Beta-lactam Antibiotics

• Penicillins contain a beta-lactam ring.
• Cephalosporins
• Carbapenems
• Monobactams

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, where peptide bridges cross-link polymer chains, making the cell wall rigid and the bacterium viable.
• All beta-lactam antibiotics inhibit the transpeptidation reaction in the bacterial cell wall.
• This weakens the cell wall, increases its permeability, and results in the bursting of the bacterium.
• All beta-lactams are bactericidal and act only on multiplying bacteria.

Penicillin G - Spectrum of activity

• Gram-positive & Gram-negative cocci
• Gram-positive bacilli
• Anaerobes
• Spirochaetes

Penicillin G - Limitations

• Acid sensitivity - cannot be given orally. Needs to be given parenterally (IM or IV injection).
• Penicillinase susceptibility - Infections by penicillinase-producing bacteria cannot be treated.
• Narrow spectrum - Not effective against G-ve infections.
• Short duration of action - Repeated administration is necessary.

Penicillin G - Method to Overcome Limitations

• Repository penicillins (long-acting penicillins) - Procaine penicillin (24 h), Benzathine penicillin (2-3 wk).

Penicillin G-Indication/uses (Prophylactic & Therapeutic)

Penicillin - Indications/Uses

• Pneumococcal meningitis - IV penicillin G in high doses.
• Meningococcal meningitis-Penicillin G is the drug of choice (DOC).
• Pneumococcal pneumonia
• Syphilis - highly effective
• Anaerobic infections
• Streptococcal pharyngitis
• Diphtheria - eliminate carrier state

Semisynthetic Penicillins

• 6-aminopenicillanic acid can be isolated by separating the side chain by enzyme amidase.
• Adding various side chains to the amino group of 6-aminopenicillanic acid produces various semisynthetic penicillins.
• Penicillin V
• Methicillin, Cloxacillin, Dicloxacillin,

Semisynthetic Penicillin (Advantages over Penicillin G)

• Acid-resistant penicillin - effective orally.
• Penicillinase-resistant penicillins - active against beta-lactamase bacteria. Examples: Staphylococci

Semisynthetic Penicillins (Broad Spectrum, Extended Spectrum/Antipseudomonal)

ADME Properties of Penicillins

• Acid-resistant penicillins (Penicillin V, amoxicillin, cloxacillin, dicloxacillin) are absorbed orally.
• Penicillins are well distributed in inflamed tissues.
• Penicillin is mostly excreted by the kidneys in active form (filtration 10%, secretion 90%).
• Probenecid inhibits secretion and maintains high plasma concentration.

Half-Life of Penicillins & Resistance

Adverse effects of Penicillin

• Remarkably low toxicity (0.7%–1.0% patients).
• Hypersensitivity reactions
• Amoxicillin causes skin rash
• Penicillin G injection - Anaphylactic shock, Superinfections (e.g., Fungi – Candida, psudomembranous enterocolitis).
• Diarrhoea (common with ampicillin, less with amoxicillin)

Penicillinase-Resistant Penicillins

• Resistant to hydrolysis by staphylococcal penicillinase. Examples: oxacillin, cloxacillin, dicloxacillin.
• Route: oral and parenteral
• Methicillin Resistant Staphylococcus Aureus (MRSA) are resistant to penicillinase resistant penicillins and also to cephalosporins.
• Infections: bone and joint infections (Staphylococcal), staphylococcal meningitis

Extended Spectrum Penicillins (Aminopenicillins)

• Active against Gram+ve and some Gram−ve organisms
• Combine with penicillinase inhibitors to extend spectrum to penicillinase-producing organisms (H. influenzae, E. coli, Klebsiella, Proteus).
• Ampicillin & Amoxicillin (oral).
• Amoxicillin absorbed almost completely, fewer side effects and longer duration of action. Ampicillin given more frequently due to incomplete absorption.

Extended Spectrum Penicillins (Aminopenicillins)- Uses

Extended Spectrum Penicillins (Antipseudomonal)

• Carboxypenicillins: Carbenicillin, carbenicillin indanyl (oral), Azlocillin.
• Ureido-penicillins: Ticarcillin, Piperacillin.
• Active against Gram+ve, Gram−ve, including pseudomonas.
• Extend activity against penicillinase-producing organisms.
• Piperacillin broadest activity.
• Infections: Intraabdominal, skin & soft tissue, nosocomial pneumonia, UTI, etc.

Beta-lactamase Inhibitors

• Suicide Inhibitors that combine with beta-lactamases and form inhibitory products.
• No antibacterial activity of their own.
• Synergistic combination with beta-lactam antibiotics to protect against inactivation and to extend the antibacterial spectrum.
• Examples: clavulanic acid, sulbactam, tazobactam

Penicillin with Aminoglycosides

• Penicillin interferes with cell wall synthesis/integrity.
• Aminoglycosides interrupt bacterial protein synthesis by influencing ribosomes.
• Aminoglycosides need energy-dependent process for entry into cells, rate limiting process.
• Cell wall damage created by penicillin allows greater penetration of aminoglycosides into bacteria.

Cephalosporins

• Beta-lactam antibiotics that inhibit cell wall synthesis.
• Effective against both G+ve and G−ve bacteria.
• More resistant to beta-lactamase action than penicillins.
• Four generations available.
• 1st to 4th generations more effective against Gram-negative than Gram-positive bacteria.
• More resistant to beta-lactamases
• Cross BBB more easily - suitable for treating meningitis

Cephalosporins - Pharmacokinetics & ADR

• Primarily administered IV or IM, some oral formulations also available.
• Good distribution throughout body fluids, including CSF.
• Safe during pregnancy.
• ADR: Hypersensitivity reactions (especially in those with penicillin allergy), Disulfiram-like effects (with alcohol), bleeding due to platelet dysfunction.

Cephalosporins - Uses

Monobactams

• Active against Gram-negative bacteria.
• Treat patients allergic to penicillin.
• Nosocomial infections (pneumonia, UTI, meningitis).
• No activity against Gram-positive bacteria or anaerobes.
• Route: parenteral
• Occasional skin rashes, elevated serum aminotransferases

Carbapenems

• Broader spectrum of activity than other beta-lactams.
• Imipenem with cilastatin (inhibits degradation by renal enzymes).
• Crosses the blood-brain barrier.
• Broadest spectrum, including anaerobes.
• Routes: IV
• Uses: UTI, Lower respiratory infections, meningitis, skin soft tissue, bone and joint infections.