Here is a list of various Beta-Lactam antibiotics.
1. Penicillins:
(i) Sir Alexander Fleming discovered in 1928.
(ii) The mold belongs to Penicillium notatum.
(iii) White crystalline substance, benzyl penicillin, soluble in water.
(iv) Benzyl penicillin has a five membered thiazolidine ring and a four membered β-lactam ring.
(v) Biosynthetic penicillins (Penicillin V) result from altering the medium for growth of penicillins.
(vi) Semisynthetic Penicillins result from the separation of the benzyl side chain from the 6-aminopenicillanic acid nucleus.
(vii) Unit of penicillin is the specific activity contained in 0.6 µg of the crystalline sodium salt of penicillin G.
(viii) The semisynthetic penicillins are expressed in terms of weight (mg/kg body weight).
(ix) Penicillins are classified according to spectrum of antibacterial activity.
Penicillin G (Benzyl penicillin) and Phenoxymethyl Penicillin (Penicillin V):
(a) Pharmacology:
(i) Penicillin G is broken-down by gastric acid but penicillin V is resistant to gastric acid.
(ii) Absorbed very rapidly from parenteral injection sites.
(iii) Adequate blood level achieved within 30 min by I/M injection.
(iv) Half life very short 20 min.
(v) Half life be increased by using procaine or benzathine with penicillin.
(vi) Procaine penicillin G maintain therapeutic blood conc. for 24 hr.
(vii) Benzathine penicillin G lasts for 7 days following single I/M injection.
(viii) Penicillins are excreted through urine by glomerular filtration and active tubular secretion. The tubular secretion could be blocked by probenecid to raise serum level of penicillin.
(ix) Minimum blood concentration required is 0.02-0.03 jug /ml.
(x) Benzyl penicillin does not cross blood brain barrier, placental barrier and intestinal barrier.
(xi) 80% excreted through urine as active form within 6hr, small amount with bile and saliva.
(b) Antibacterial Spectrum and Usage:
(i) Mastitis, systemic and local infections in all species (Streptococci, Staphylococci and corynebacterium pyogenes). Dose: 3 lakhs unit of each affected quarter at 24 hr interval.
(ii) Pyelonephritis in cattle (Corynebacterium renale).
(iii) Swine erysipelas (Erysipelothrix rhusiopathiae). Dose: 4000 IU/kg at 24 hr. interval.
(iv) Lumpy jaw in cattle (Actinomyces bovis).
(v) Tetanus, pulpy kidney, lamb dysentery (Clostridia).
(vi) Leptospiral nephritis, Vibrionic abortion (Leptospira canicola).
(vii) Anthrax Bacillus anthracis).
Dose: 1 lakh unit/kg at 12 hr. interval.
(c) Adverse Effect:
(i) Few toxicity problem.
(ii) Allergic skin reactions in small animals and horses.
(iii) Diarrhoea due to overgrowth with Clostridium difficile.
(d) Resistance:
(i) Production of β-lactamase by some bacteria causes opening of the β-lactam ring which leads to inactivation of penicillin G.
(ii) Gram negative bacilli are generally resistance.
Phenoxymethyl Penicillin (Penicillin V):
(i) Acid stability and available in oral form.
(ii) Absorption relatively low.
(iii) Antibacterial spectrum is similar to penicillin G.
(iv) Dose: 8 mg/kg b.w.
b-Iactamase (Penicillinase) Resistant Penicillin:
1. Cloxacillin, dicloxacillin and oxacillin.
(i) Active against Penicillin G resistant staphylococci.
(ii) Stable in gastric acid.
(iii) Administered orally or parenterally.
(iv) Rapid and effective absorption of cloxacillin than oxacillin.
(v) Partly metabolised in the body.
(vi) Antibacterial activity of metabolite of cloxacillin similar to parent compound.
(vii) Sodium cloxacillin for mastitis in lactating animal.
(viii) Benzathine penicillin for treatment and prevention of mastitis in dry period.
(ix) Less effective against gm.(-) bacteria.
(x) Side effects like rash, hypersensitivity, hepatitis.
2. Nafcillin and Flucloxacillin:
(i) Similar to cloxacillin and oxacillin.
(ii) Intramammary administration.
(iii) Excreted primarily by liver attaining high concentration in bile.
3. Methicillin:
(i) Parenteral use due to poor oral absorption.
(ii) Ineffective against gm.(-) bacteria.
(iii) Side Effects: reversible bone marrow depression, allergic reaction, phlebitis, interstitial nephrites.
Broad Spectrum Penicillins:
A. Ampicillin:
(i) Same as penicillin G but in addition active against gm. (-) bacteria which is comparable with that of chloramphenicol and tertracycline.
(ii) Oral and parenteral preparation available.
(iii) Stable in acid.
(iv) Peak serum concentration obtained about 2 hr. after oral dosing.
(v) Elimination half life 1-1.5 hr.
(vi) Distribute throughout the body tissue.
(vii) The concentration in bile 40 times higher than plasma level.
(viii) Very high dose given over a long period without producing toxic reaction.
Antibacterial Spectrum and Usage:
(i) Respiratory infection- Streptococcus pneumonae, H. influenza, Strep. Pyogenes.
(ii) Urinary tract infection-E. coli. Streptococcus, Proteus.
(iii) Meningitis-H. influenza, streptococcus pneumonae, N. meningitidis.
(iv) Typhoid fever-Salmonella.
(v) Bacillary dysentery-Shigella.
(vi) Listeria infections.
Side Effects:
(i) Similar to penicillin G.
(ii) Patients with history of type I hypersensitivity to penicillin not be given ampicillin.
B. Amoxicillin:
(i) Close analogue to ampicillin.
(ii) Acid stable and well absorbed from the gut.
(iii) Higher peak serum level than ampicillin after similar oral dose.
(iv) Rapid excretion in the urine after I/V route.
(v) Elimination half life 90 min in dog and calf.
(vi) Antibacterial spectrum similar to ampicillin.
(vii) Diarrhoea as a side effect uncommon in animals.
Antipseudomonal Penicillins:
1. Carbenicillin:
(i) Administered by parenteral route.
(ii) Rapidly exereted in the urine.
(iii) Antibacterial spectrum similar to ampicillin.
(iv) Good activity against strains of Proteus and against Enterobacter.
(v) Mainly indicated in Pseudomonas aeruginosa infection.
(vi) Inactivated by Penicillinase enzyme.
(vii) Side effects and toxicity-hypokalemia, bleeding due to platelet dysfunction, sodium overload, occasional hypersensitivity reaction.
2. Ticarcillin:
(i) Properties similar to carbenicillin but with greater activity against Pseudomonas.
(ii) Used in combination with gentamicin.
(iii) Used parenterally.
(iv) Inactivated by Penicillinase.
3. Mezlocillin:
(i) More active against Klebsiella and Pseudomonas than carbenicillin.
(ii) Used parenterally.
(iii) Excreted in bile to a significant degree.
4. Piperacillin:
(i) Similar activity to mezlocillin.
Mechanism of Antibacterial Action:
The cell walls of bacteria are essential for their normal growth and development. Peptidoglycan provides rigid mechanical stability. In gram positive microorganisms, the cell Wall is 50 to 100 molecules thick but it is only 1 or 2 molecule thick in gram negative bacteria.
The peptidoglycan consists of alternating N-acetyl glucosamine and N-acetyl muramic acid units, from which project a stem peptide, and in the peptidoglycan network, cross linkages occur between the stem peptides to form the rigid cell wall, as explained by fig. 26.1.
The terminal glycine residue of the pentaglycine bridge is linked to the fourth residue of the pentapeptide (D- ala), releasing the fifth residue (also D-ala), through a trans peptidase reaction. The PBP is therefore, a vital factor in the cell wall formation and its inhibition by penicillins will result in either abnormal cell growth leading to filamentous forms of bacteria, or a spheroplast and cell death.
Dosage:
2. Cephalosporins:
(i) Originated from species Cephalosporium
(ii) β-lactam ring present, affected by β-lactamase
(iii) More resistant to break down than penicillin (except β-lactamase resistant penicillins)
(iv) Changes at position 3, affect pharmacokinetic behaviour.
(v) Substitution of various side chains resulted cephalosporin with a broad spectrum activity.
(vi) The mechanism of antibacterial action similar to that of penicillin i.e. inhibition of bacterial cell wall synthesis.
(vii) Ineffective against bacteria producing cephalosporinase.
(viii) Used in upper respiratory tract, urinary tract, skin and soft tissue infections by Staphylococcus aureus, systemic infections by sensitive gm. (+) and gm. (-) bacteria, and life threatening infections before specific organism identified.
(ix) Excreted by the kidney through glomerular filtration and tubular secretion.
(x) Only cefoperazone eliminated (80%) by biliary excretion.
(xi) Minimal metabolism.
(xii) Side effects and toxicity-rash, eosinophilia, cross reactivity to cephalosporins in those hypersensitive to penicillins, elevated liver function tests, diarrhoea, hypoprothrombinemia and nephrotoxicity.
(xiii) Adding different side chain to the basic molecule of cephalosporin resulted a number of semisynthetic compounds divided into three generations given in the following table:
β-lactamase Inhibitors:
A. Clavulanic Acid:
(i) Contain β-lactam ring.
(ii) Isolated from Streptomyces clavuligerus.
(iii) Irreversible inhibition of the β-lactamase.
(iv) Clavulanic acid also destroyed, the enzyme permanently inactivated-“Suicide inhibition”.
(v) A combination formulation of potassium clavulanate with amoxicillin- “Clavulanate-potentiated amoxicillin”.
(vi) This combination useful in skin and enteric infection.
(vii) Dosage: 2.5 mg/kg in combination with amoxicillin (10mg/kg) twice daily.
B. Sulbactam:
(i) Similar spectrum to that of the clavulanic acid, but less potent inhibitor.
(ii) Less able to penetrate cells than clavulanic acid.
(iii) A combination formulation of sulbactam with ampicillin in human.
Other β-lactam Antibiotics:
A. Carbapenems: Imipenem.
(i) Isolated from Streptomyces Cattleya.
(ii) Inhibit cell wall synthesis of bacteria.
(iii) Broadest spectrum β-lactam.
(iv) Active against gm.(+) and gm.(-) bacteria including Pseudomonas aeruginosa and anaerobes.
(v) Side effects-allergic reaction, nausea, diarrhoea, seizures.
B. Monobactams: Aztreonam:
(i) A single β-lactam ring in the structure.
(ii) Interfere cell wall synthesis.
(iii) Only effective against gm.(-) enteric bacilli.
(iv) No cross sensitivity with penicillin.