Compare and contrast benzylpenicillin with ceftriaxone (a third generation cephalosporin).

Outline:

·        Chemical structure and mechanism of action.

·        Pharmacokinetics.

·        Spectrum of activity.

·        Adverse effects.

Suggested Answer:

Both benzylpenicillin and ceftriaxone are beta-lactam anti-microbials, the structure of which contains a beta-lactam ring. They are bactericidal and acts by inhibiting bacterial cell wall synthesis which protects the bacterium from its environment. Benzylpenicillin consists of a 6-aminopenicillanic acid which is made up of a thiazolidin ring and a beta-lactam ring. In contrast, ceftriaxone consists of a 7-aminocephalosporanic acid nucleus made up of a dihydrothiazine ring and a beta-lactam ring.

Benzylpenicillin is destroyed by gastric acid and is unsuitable for oral use. It may be given i.m. or i.v. Its plasma half-life is 0.5h. It is distributed mainly in the body water and enter well into the CSF if the meninges are inflamed. Being an organic acid, benzylpenicillin is secreted into the renal tubular fluid by the anion transport mechanism in the kidney. Like benzylpenicillin, ceftriaxone is not appreciably absorbed from the GI tract and must be given parenterally. Following i.m. or i.v. administration, ceftriaxone is widely distributed into body tissues and fluids including the gallbladder, lungs, bone, heart, bile, pleural and synovial fluids. Ceftriaxone generally diffuses into the CSF following i.m. or i.v. administration of the drug, penetrating adequately to treat Gram-negative meningitis. However, CSF concentrations of the drugs are still higher in patients with inflamed meninges than in those with uninflamed meninges. Ceftriaxone is over 90% bound to plasma albumin. It crosses the placenta and is distributed into amniotic fluid.

Benzylpenicillin is highly active against Streptococcus pneumoniae and the Lancefield group A, b-haemolytic streptococci. Viridans streptococci are usually sensitive. Benzylpenicillin is the drug of choice for infections due to Neisseria meningitidis (meningococal meningitis), Bacillus anthracis (anthrax), Clostridium perfringens (gas gangrene) and Clostridium tetani (tetanus), Corynebacterium diphtheriae (diphtheria), Treponema pallidum (syphilis), Leptospira spp.(leptospirosis) and Actinomyces israelii (actinomycosis). It is also the drug of choice for Borrelia burgdorferi (Lyme disease) in children.

Like other third-generation cephalosporins, cetriaxone has wide activity against Gram-megative bacilli but less activity against Gram-positive cocci. This is in contrast to benzylpenicillin which are generally active against Gram-positive cocci but less so against Gram-negative bacilli. Ceftriaxone is active in vitro against most gram-positive aerobic cocci including penicillinase-producing and nonpenicillinase-producing strains of Staphylococcus aureus and S. epidermidis; Streptococcus pneumoniae; S. pyogenes (group A beta-hemolytic streptococci); S. agalactiae (group B streptococci); viridans streptococci (including the S. milleri group [S. anginosus, S. constellatus, S. intermedius]); and nonenterococcal group D streptococci. Staphylococci resistant to penicillinase-resistant penicillins also generally are resistant to ceftriaxone. Enterococci, including E. faecalis (formerly S. faecalis), generally are resistant to ceftriaxone. Ceftriaxone is active against the following enterobacteriaciae: E. coli, Enterobacter, Klebsiella pneumoniae, Proteus mirabilis, Serratia, Salmonella, Shigella and Citrobacter. Pseudomonas aeruginosa is generally resistant to ceftriaxone. Ceftriaxone is the drug of choice for the treatment of infections caused by Haemophilus influenzae, Borrelia burdgoferi and Neisseria gonorrhoea.

Benzylpenicillin and ceftriaxone shares many similar adverse effects probably due to their similar chemical structure. Partial cross-allergy exists between both of them (10%).

The main hazard with benzylpenicillin is allergic reactions. These include itching, rashes (eczematous or urticarial), fever and angioneurotic edema. Rarely there is anaphylactic shock which can be fatal. Other rare adverse effects are diarrhoea, anaemia and neutropenia. Neurotoxicity manifesting as lethargy, confusion, convulsions and myoclonic jerks can occur after parenteral high doses of benzylpenicillin.

Hematologic effects are among the most frequent adverse effects reported with ceftriaxone. These include anaemia, leukopenia, eosinophilia and neutropenia. Diarrhea has generally been reported in 2 –4% of patients receiving ceftriaxone. Nausea, vomiting, dyspepsia, abdominal pain and flatulence have also been reported. Clostridium difficile – associated diarrhea and colitis has been rarely reported in patients receiving ceftriaxone. Allergic reactions such as rash, fever, itching, chills, bronchospasm and anaphylaxis are found with the use of ceftriaxone. Ceftriaxone has been found to increase concentrations of blood urea nitrogen and serum creatinine. Local reactions, including pain, ecchymosis and tenderness at the injection site have been reported in 1-2% of patients receiving i.m. ceftriaxone.