Benzylpenicillin (penicillin G)
Benzylpenicillin (t1/, 0.5 h) is used when high plasma concentrations are required. The short t'/2 means that reasonably spaced doses have to be large to maintain a therapeutic concentration. Fortunately, the unusually large therapeutic ratio of penicillin allows the resulting fluctuations to be tolerable.2 Benzylpenicillin is eliminated by the
2 Is it surprise at the answer that reduces most classes of students to silence when asked the trough:peak ratio for a drug given 6-hourly with a t1/ of 0.5 h? (answer: 212 = 4096).
kidney, with about 80% being actively secreted by the renal tubule and this can be blocked by probenecid, e.g. to reduce the frequency of injection for small children or for single dose therapy as in gonorrhoea.
Uses (see Table 11.1, p. 211). Benzylpenicillin is highly active against Streptococcus pneumoniae and the Lancefield group A, ß-haemolytic streptococcus (Streptococcus pyogenes). Viridans streptococci are usually sensitive unless the patient has recently received penicillin. Enterococcus faecalis is less susceptible and, especially for endocarditis, penicillin should be combined with an aminoglycoside, usually gentamicin. This combination is synergistic unless the enterococcus is highly resistant to the aminoglycoside; such strains are becoming more frequent in hospital patients and present major difficulties in therapy. Benzylpenicillin used to be active against most strains of Staphylococcus aureus, but now over 90% are resistant in hospital and domiciliary practice. Benzylpenicillin is the drug of choice for infections due to Neisseria meningitidis (meningococcal meningitis and septicaemia), Bacillus anthracis (anthrax), Clostridium perfringens (gas gangrene) and 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. The sensitivity of Neisseria gonorrhoeae varies in different parts of the world and, in some, resistance is rife.
Adverse effects are in general uncommon, apart from allergy (above). It is salutary to reflect that the first clinically useful true antibiotic (1942) is still in use and is also amongst the least toxic. Only in patients with bacterial endocarditis, where the requirement for high doses can co-exist with reduced clearance due to immune complex glomerulonephritis, does a risk of dose related toxicity (convulsions) arise.
Preparations and dosage for injection. Benzyl-penicillin may be given i.m. or i.v. (by bolus injection or by continuous infusion). For a sensitive infection, benzylpenicillin3 600 mg 6-hourly is enough. This is obviously inconvenient in domi ciliary practice where a mixture of benzylpenicillin and one of its long-acting variants may be preferred (see below).
For relatively insensitive infections and where sensitive organisms are sequestered within avascular tissue (e.g. infective endocarditis) 7.2 g are given daily i.v. in divided doses. When an infection is controlled, a change may be made to the oral route using phenoxymethylpenicillin, or amoxicillin which is more reliably absorbed in adults.
Procaine penicillin, given i.m. only, is a stable salt and liberates benzylpenicillin over 12-24 h, according to the dose administered. Usually this is 360 mg 12-24-hourly. There is no general agreement on its place in therapy, and it is no longer available in a number of countries. It is best to use benzylpenicillin in the most severe infections, especially at the outset, as procaine penicillin will not give therapeutic blood concentrations for some hours after injection and peak concentrations are much lower.
Preparations and dosage for oral use. Phenoxymethylpenicillin (penicillin V), is resistant to gastric acid and so reaches the small intestine intact where it is moderately well absorbed, sometimes erratically in adults. It is less active than benzylpenicillin against Neisseria gonorrhoeae and meningitidis, and so is unsuitable for use in gonorrhoea and meningococcal meningitis. It is a satisfactory substitute for benzylpenicillin against Streptococcus pneumoniae and Streptococcus pyogenes, especially after the acute infection has been brought under initial control by intravenous therapy. The dose is 500 mg 6-hourly.
All oral penicillins are best given on an empty stomach to avoid the absorption delay caused by food.
Certain bacteria produce (^-lactamases which open the ^-lactam ring that is common to all penicillins, and thus terminate the antibacterial activity. P-lactamases vary in their activity against different P-lactams, with side chains attached to the P-lactam
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