Penicillin-G (Benzyl Penicillin)

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Chapter: Essential pharmacology : Betalactam Antibiotics

PnG is a narrow spectrum antibiotic; activity is limited primarily to gram-positive bacteria and few others.


PENICILLIN-G (BENZYL PENICILLIN)

 

Antibacterial Spectrum

 

PnG is a narrow spectrum antibiotic; activity is limited primarily to gram-positive bacteria and few others.

 

Cocci: Streptococci (except viridans, group D or enterococci) are highly sensitive, so are many pneumococci. Staph. aureus, though originally very sensitive, has acquired resistance to such an extent that it must be counted out of PnG spectrum. Gram negative cocci—Neisseria gonorrhoeae and N. meningitidis are susceptible to PnG, though increasing number of gonococci have developed partial and others high degree resistance.

 

Bacilli: Gram-positive bacilli—majority of B. anthracis, Corynebacterium diphtheriae, and practically all Clostridia (tetani and others), Listeria are highly sensitive, so are spirochetes (Treponema pallidum, Leptospira, and others), but Bacteroides fragilis is largely resistant.

 

Actinomyces israelii is only moderately sensitive. Majority of gram-negative bacilli (except a few E. coli, Proteus), Mycobacterium tuberculosis, rickettsiae, chlamydiae, protozoa, fungi and viruses are totally insensitive to PnG.

 

Bacterial Resistance

 

Many bacteria are inherently insensitive to PnG because in them the target enzymes and PBPs are located deeper under lipoprotein barrier where PnG is unable to penetrate or have low affinity for PnG. The primary mechanism of acquired resistance is production of penicillinase.

 

Penicillinase: It is a narrow spectrum βlactamase which opens the βlactam ring and inactivates PnG and some closely related congeners. Majority of Staphylococci and some strains of gonococci, B. subtilis, E. coli, H. influenzae and few other bacteria produce penicillinase. The gram-positive penicillinase producers elaborate large quantities of the enzyme which diffuses into the surroundings and can protect other inherently sensitive bacteria. In gram-negative bacteria, penicillinase is found in small quantity, but is strategically located in-between the lipoprotein and peptidoglycan layers of the cell wall. Staphylococcal penicillinase is inducible, and methicillin is an important inducer; while in gram-negative organisms, it is mostly a constitutive enzyme.

 

Penicillinase has been successfully used to destroy PnG in patient’s blood sample so that it does not interfere with bacterial growth when such blood is cultured.

 

Some resistant bacteria become penicillin tolerant and not penicillin destroying. Their target enzymes are altered to have low affinity for penicillin, e.g. highly resistant pneumococci isolated in some areas have altered PBPs. The methicillin-resistant Staph. aureus (MRSA) have acquired a PBP which has very low affinity for βlactam antibiotics. Some penicillin resistant pneumococci and enterococci have altered PBPs. The low level penicillin-resistant gonococci are less permeable to the drug, while high degree resistant ones produce penicillinase, as do highly resistant H. influenzae. Both these appear to have acquired the penicillinase plasmid by conjugation or transduction and then propagated by selection.

 

The gram-negative bacteria have ‘porin’ channels formed by specific proteins located in their outer membrane. Permeability of various βlactam antibiotics through these channels differs: ampicillin and other members which are active against gram-negative bacteria cross the porin channels much better than PnG. Some gram-negative bacteria become resistant by loss or alteration of porin channels.

 

Pharmacokinetics

 

Penicillin G is acid labile—destroyed by gastric acid. As such, less than 1/3rd of an oral dose is absorbed in the active form. Absorption of sod. PnG from i.m. site is rapid and complete; peak plasma level is attained in 30 min. It is distributed mainly extracellularly; reaches most body fluids, but penetration in serous cavities and CSF is poor. However, in the presence of inflammation (sinovitis, meningitis, etc.) adequate amounts may reach these sites. About 60% is plasma protein bound. It is little metabolized because of rapid excretion.

 

The pharmacokinetics of PnG is dominated by very rapid renal excretion; about 10% by glomerular filtration and the rest by tubular secretion. The plasma t½ of PnG in healthy adult is 30 min. Neonates have slower tubular secretion—t½ is longer; but approaches adult value at 3 months and then is even shorter during childhood. Aged and those with renal failure excrete penicillin slowly. Tubular secretion of PnG can be blocked by probenecid—higher and longer lasting plasma concentrations are achieved. Probenecid also decreases the volume of distribution of penicillins.

 

Preparations and dose

 

1. Sod. penicillin G (crystalline penicillin) injection 0.5–5 MU i.m./i.v. 6–12 hourly. It is available as dry powder in vials to be dissolved in sterile water at the time of injection. BENZYL PEN 0.5, 1 MU inj.

 

Repository penicillin G injections These are insoluble salts of PnG which must be given by deep i.m. (never i.v.) injection. They release PnG slowly at the site of injection, which then meets the same fate as soluble PnG.

 

1. Procaine penicillin G inj. 0.5–1 MU i.m. 12–24 hourly as aqueous suspension. Plasma concentrations attained are lower, but are sustained for 12–24 hours; PROCAINE PENICILLING 0.5, 1 MU dry powder in vial.

 

Fortified procaine penicillin G inj: contains 3 lac U procaine penicillin and 1 lac U sod. penicillin G to provide rapid as well as sustained blood levels. FORTIFIED P.P. INJ 3+1 lac U vial.

 

2. Benzathine penicillin G 0.6–2.4 MU i.m. every 2–4 weeks as aqueous suspension. It releases penicillin

extremely slowly—plasma concentrations are very low but remain effective for prophylactic purposes for up to 4 weeks:

 

PENIDURELA (long acting), LONGACILLIN, PENCOM, 0.6, 1.2, 2.4 MU as dry powder in vial.

 

Adverse Effects

 

Penicillin G is one of the most nontoxic antibiotics; up to 100 MU (60 g) has been injected in a day without any direct toxicity.

 

Local Irritancy And Direct Toxicity Pain at i.m. injection site, nausea on oral ingestion and thrombophlebitis of injected vein are doserelated expressions of irritancy.

 

Toxicity to the brain may be manifested as mental confusion, muscular twitchings, convulsions and coma, when very large doses (> 20 MU) are injected i.v.; especially in patients with renal insufficiency. Bleeding has also occurred with such high doses due to interference with platelet function. Intrathecal injection of PnG is no longer recommended because it has caused arachnoiditis and degenerative changes in spinal cord.

 

Accidental i.v. injection of procaine penicillin produces CNS stimulation, hallucinations and convulsions due to procaine. Being insoluble, it may also cause microembolism.

 

Hypersensitivity These reactions are the major problem in the use of penicillins. An incidence of 1–10% is reported. Individuals with an allergic diathesis are more prone to develop penicillin reactions. PnG is the most common drug implicated in drug allergy, because of which it has practically vanished from use in general practice.

 

Frequent manifestations are—rash, itching, urticaria and fever. Wheezing, angioneurotic edema, serum sickness and exfoliative dermatitis are less common. Anaphylaxis is rare (1 to 4 per 10,000 patients) but may be fatal.

 

All forms of natural and semisynthetic penicillins can cause allergy, but it is more commonly seen after parenteral than oral administration. Incidence is highest with procaine penicillin: procaine is itself allergenic. The course of

penicillin hypersensitivity is unpredictable, i.e. an individual who tolerated penicillin earlier may show allergy on subsequent administration and vice versa.

 

There is partial cross sensitivity between different types of penicillins; an individual who has exhibited immediate type of hypersensitivity—urticaria, angioedema, bronchospasm, anaphylaxis or serum sickness with one penicillin should not be given any other type of penicillin. However, if the earlier reaction had been only a rash, penicillin may be given cautiously—often no untoward effect is seen. History of penicillin allergy must be elicited before injecting it. A scratch test or intradermal test (with 2–10 U) may be performed first. On occasions, this itself has caused fatal anaphylaxis. Testing with benzyl-penicilloyl-polylysine is safer. However, a negative intradermal test does not rule out delayed hypersensitivity. It should also be realised that presence of antibodies to penicillin does not mean allergy to it, because practically everyone who receives penicillin develops antibodies to it.

 

For the development of antibodies, penicillin or a product of it (mostly penicilloyl moiety— major determinant) acts as a hapten. There are many minor determinants as well.

 

Topical use of penicillin is highly sensitizing (contact dermatitis and other reactions). Therefore, all topical preparations of penicillin (including eye ointment) have been banned, except for use in eye as freshly prepared solution in case of gonococcal ophthalmia.

 

If a patient is allergic to penicillin, it is best to use an alternative antibiotic. Hyposensitization by the injection of increasing amounts of penicillin intradermally at hourly intervals may be tried only if there is no other choice.

 

Superinfections These are rare with PnG because of its narrow spectrum; though bowel, respiratory and cutaneous microflora does undergo changes.

 

Jarisch-Herxheimer Reaction Penicillin injected in a syphilitic patient (particularly secondary syphilis) may produce shivering, fever, myalgia, exacerbation of lesions, even vascular collapse. This is due to sudden release of spirochetal lytic products and lasts for 12–72 hours. It does not recur and does not need interruption of therapy.

 

Aspirin and sedation afford relief of symptoms.

 

Uses

 

Penicillin G is the drug of choice for infections caused by organisms susceptible to it, unless the patient is allergic to this antibiotic. However, use has declined very much due to fear of causing anaphylaxis.

 

1. Streptococcal Infections Like pharyngitis, otitis media, scarlet fever, rheumatic fever respond to ordinary doses of PnG given for 7–10 days. For subacute bacterial endocarditis (SABE) caused by Strep. viridans or faecalis high doses (10–20 MU i.v. daily) along with gentamicin given for 2–6 weeks is needed.

 

2. Pneumococcal Infections PnG is not used now for empirical therapy of pneumococcal (lobar) pneumonia and meningitis because many strains have become highly penicillin resistant. However, PnG 3–6 MU i.v. every 6 hours is the drug of choice if organism is sensitive.

 

3. Meningococcal Infections are still mostly responsive; meningitis and other infections may be treated with intravenous injection of high doses.

 

4. Gonorrhoea PnG has become unreliable for treatment of gonorrhoea due to spread of resistant strains.

 

The treatment of ophthalmia neonatorum due to sensitive N. gonorrhoeae consists of saline irrigation + sod. PnG 10,000–20,000 U/ml 1 drop in each eye every 1–3 hours. In severe cases, give 50,000 U i.m. BD for 1 week in addition.

 

5. Syphilis T. pallidum has not shown any resistance and PnG is the drug of choice. Early and latent syphilis is treated either with daily injection of 1.2 MU of procaine penicillin for 10 days or with 1–3 weekly doses of 2.4 MU benzathine penicillin. For late syphilis, benzathine penicillin 2.4 MU weekly for 4 weeks is recommended. Cardiovascular and neurosyphilis requires 5 MU i.m. 6 hourly of sod. PnG. For 2 weeks followed by the above regimen.

Leptospirosis: PnG 1.5 MU injected i.v. 6 hourly for 7 days is curative.

 

6. Diphtheria Antitoxin therapy is of prime importance. Procaine penicillin 1–2 MU daily for 10 days has adjuvant value and prevents carrier state.

 

7. Tetanus And Gas Gangrene Antitoxin and other measures are more important; PnG 6–12 MU/day is used to kill the causative organism and has adjuvant value.

 

8. Penicillin G is the drug of choice for rare infections like anthrax, actinomycosis, trench mouth, rat bite fever and those caused by Listeria monocytogenes, Pasteurella multocida.

 

9. Prophylactic Uses

 

a) Rheumatic fever: Low concentrations of penicillin prevent colonization by streptococci responsible for rheumatic fever. Benzathine penicillin 1.2 MU every 4 weeks till 18 years of age or 5 years after an attack, whichever is more.

 

b) Bacterial endocarditis: Dental extractions, endoscopies, catheterization, etc. cause bacteremia which in patients with valvular defects can cause endocarditis. PnG can afford protection, but amoxicillin is preferred now.

 

c) Agranulocytosis patients: Penicillin may be used alone or in combination with an aminoglycoside antibiotic to prevent respiratory and other acute infections.

 

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