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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