Benzathine Penicillin
A white powder. Benzathine penicillin 900 mg is approxi-
mately equivalent to 720 mg of benzylpenicillin (1.2 million
units).
Very slightly soluble in water; slightly soluble in alcohol:
freely soluble in dimethylformamide and in formamide: prac-
tically insoluble in ether. The pH of a 0.05% solution of the
tetrahydrate in equal quantities of water and dehydrated alco-
hol is 4.0 to 6.5. Store at a temperature not exceeding 30Β° in
airtight containers.
Adverse Effects, Precautions & Interactions as for Benzylpenicillin.
BENZYL PENICILLIN SODIUM : (Penicillin G Sodium.)
Units
The second International Standard Preparation
(1952) of benzylpenicillin sodium contained 1670
units of penicillin per mg but was discontinued in
1968 since penicillin can now be characterised com-
pletely by chemical tests. Despite this, doses of ben-
zylpenicillin are still expressed in units in some
countries.
Benzylpenicillin potassium 600 mg or benzylpeni-
cillin sodium 600 mg have generally been consid-
ered to be approximately equivalent to I million
units ( I mega unit).
Adverse Effects
The most common adverse effects of benzylpenicil-
lin are hypersensitivity reactions, especially skin
rashes: anaphylaxis occasionally occurs and has
sometimes been fatal. Other adverse effects have
generally been associated with large intravenous
doses of benzylpenicillin; patients with impaired re-
nal function are also at increased risk. These adverse
effects include haemolytic anaemia and neutrope-
nia, both of which might have some immunological
basis; prolongation of bleeding time and defective
platelet function; convulsions and other signs of
CNS toxicity (encephalopathy has followed intrath-
ecal administration and can be fatal); and electrolyte
disturbances because of the administration of large
amounts of potassium or sodium when benzylpeni-
cillin potassium or sodium, respectively, are admin-
istered.
Hepatitis and cholestatic jaundice have been report-
ed rarely with some penicillins, notably penicilli-
nase-resistant penicillins such as flucloxacillin and
oxacilln. and also combinations of amoxycillin or
ticarcillin with clavulanic acid. _
Nephropathy and interstitial nephritis, which may
have some immunological basis, has been especially
associated with methicillin, but may be produced by
other penicillins.
Some patients with syphilis and other spirochaete
infections may experience a Jarisch-Herxheimer re-
action shortly after starting treatment with penicil-
lin, which is probably due to the release of
endotoxins from the killed treponemes and should
not be mistaken for a hypersensitivity reaction.
Symptoms include fever, chills, headache, and reac-
tions at the site of the lesions. The reaction can be
dangerous in cardiovascular syphilis or where there
is a serious risk of increased local damage such as
with optic atrophy.
Gastro-intestinal effects like diarrhoea and nausea
are the most common adverse effects following oral
administration of benzylpenicillin: a sore mouth or
tongue or a black hairy tongue have occasionally
been reported. Pseudomembranous colitis has been
associated with the use of most antibiotics: of the
penicillins, ampicillin or amoxycillin have been im-
plicated most frequently (see Antibiotic-associated
Colitis).
Hypersensitivity. The overall incidence of allergic
reactions to penicillin has been reported to vary
from about I to 10% although some patients may
have been incorrectly labelled 'allergic to penicil-
lin'. Anaphylactic reactions occur in about 0.05% of
patients, usually after parenteral administration but
they have also been reported after taking penicillin
by mouth.
Hypersensitivity to penicillin gives rise to a wide va-
riety of clinical syndromes. Immediate reactions in-
clude anaphylaxis, angioedema, urticaria. and some
maculopapular rashes. Late reactions may include
serum sickness-like reactions and haemolytic anae-
mia. Reactions are considered to be due mainly to
breakdown products (produced in vitro before ad-
ministration) or metabolites of penicillin, and possi-
bly penicillin itself, acting as haptens which when
combined with proteins and other macromolecules
produce potential antigens. As the hypersensitivity
is related to the basic penicillin structure, patients
who are genuinely allergic to benzylpenicillin must
be assumed to be allergic to all penicillins: sensi-
tised patients may also react to the cephalosporins
and other beta-lactam antibiotics. For comment on
crossreactivity with penicillamine. see under Peni-
cillamine, Precautions.
Tests for hypersensitivity' may be used to determine
those patients most likely to develop serious allergic
reactions to penicillins. Skin tests are used to evalu-
ate the current risk of immediate or accelerated lgE-
mediated reactions, the most serious being anaphy-
laxis. Both the major and minor determinants of
penicillin hypersensitivity should be used: the major
determinant is available as penicilloyl-polylysine
(p. 1616) and a minor-determinant mixture consist-
ing of benzylpenicillin and its derivatives, including
penicilloic acid and benzylpenicilloylamine can be
used. although if this is not available a solution of
benzylpenicillin may be substituted. Adrenaline
should be available in case an anaphylactic reaction
develops. The results of skin tests are unreliable if a
significant time has elapsed before beginning thera-
py. A number of in-vitro tests including the radioal-
lergosorbent test (RAST) have been developed.
Desensitisation may be attempted in patients aller-
gic to penicillin when treatment with penicillin is
considered essential. It involves the administration
of very small doses of penicillin given at relatively
short intervals of 15 minutes or more. and gradually
increased to therapeutic concentrations. However.
desensitisation may be hazardous and should only
be carried out if the patient can be monitored contin-
uously and adrenaline and resuscitation equipment
are immediately available. Desensitisation should
be regarded as temporary, and allergic reactions may
recur during the next exposure to penicillin.
Neutropenia. Neutropenia has been widely report-
ed in patients receiving high doses of beta-lactams
and an incidence of from 5 to more than 15% has
been reported in patients treated for 10 days or more.
Warning signs include fever, rash, and eosinophilia.
Monitoring of the leucocyte count is recommended
during long-term treatment with high doses. Some
have proposed a direct toxic effect whereas others
have postulated an immune mechanism.
Precautions
Patients known to be hypersensitive to penicillins
should be given an antibacterial of another class.
However, sensitised patients may also react to the
cephalosporins and other beta-lactams. Desensitisa-
tion may be necessary if treatment with a penicillin
is essential (see Adverse Effects, above). Penicillins
should be given with caution to patients with a his-
tory of allergy. especially to drugs.
Care is necessary if very high doses of penicillins
are given, especially if renal function is poor.
because of the risk of neurotoxicity. The intrathecal
route should be avoided. Care is also necessary if
large doses of the potassium or sodium salts are giv-
en to patients with impaired renal function or heart
failure, and high doses of benzylpenicillin potassi- <
um should be used with caution in patients receiving
potassium-containing drugs or potassium-sparing -
diuretics. Renal and haematological status should be
monitored during prolonged and high-dose therapy.
Because of the Jarisch-Herxheimer reaction, care is
also necessary when treating patients with spirocha-
etc infections, particularly syphilis.
Contact with penicillin should be avoided since skin
sensitization may occur.
Penicillin therapy changes the normal bacterial flora
and can lead to supra-infection with penicillin-re-
sistant organisms including Pseudomonas or Cand-
ida, particularly with prolonged use.
Penicillins may interfere with some diagnostic tests
such as those for urinary glucose using copper sul-
phate. direct antiglobulin (Coombs') tests, and some
tests for urinary or senim proteins. Penicillins may
interfere with tests that use bacteria, for example the
Guthrie test for phenyiketonuria using Bacillus sub-
tilis organisms.
Interactions
Probenecid prolongs the half-life of benzylpenicil-
lin by competing with it for renal tubular secretion
and may be used therapeutically for this purpose.
Benzylpenicillin may also interact with bacteriostat-
cyclines (see under Antimicrobial Action, below)
and may be incompatible in vitro with other drugs
including a number of other antibacterials (see
above).
The possibility of a prolonged bleeding time follow-
ing oral treatment with a broad-spectrum drug like
ampicillin should be borne in mind in patients re-
ceiving anticoagulants.
Antimicrobial Action
Benzylpenicillin is a beta-lactam antibiotic and has
a bactericidal action against Gram-positive bacteria.
Gram-negative cocci, some other Gram-negative
bacteria, spirochaetes, and actinomycetes.
Mechanism of action. It exerts its killing action on
growing and dividing bacteria by inhibiting bacteri-
al cell-wall synthesis, although the mechanisms in-
volved are still not precisely understood. Bacterial
cell walls are held rigid and protected against osmot-
ic rupture by peptidoglycan. Benzylpenicillin inhib-
its the final cross-linking stage of peptidoglycan
production by binding to and inactivating
transpeptidases. penicillin-binding proteins on the
inner surface of the bacterial cell membrane.
How-ever , it is now realised that other earlier stages in
cell-wall synthesis can also be inhibited. Other
mechanisms involved include bacterial lysis by the
inactivation of endogenous inhibitors of bacterial
autolysins.
Its action is inhibited by penicillinase and other
beta-lactamases that are produced during the growth
of certain micro-organisms.
Many Gram-negative organisms are intrinsically re-
sistant by virtue of the inability of benzylpenicillin
to penetrate their outer membranes. Intrinsic resist-
ance can also be due to structural differences in the
target penicillin-binding proteins. See under Resist-
ance, below, for reference to acquired resistance.
ganisms are usually sensitive to benzylpenicillin:
Gram-positive aerobes and anaerobes including
Bacillus anthracis, Clostridium perfringens, Cl.
tetani, Corynebacterium diphfheriae, Ery'sipelo-
thrix rhusiopafhiae, Listeria monocytogenes, Pcpto-
streptococcus spp., non-beta-lactamase-producing
coccus agalactiae (group B), Str. pneumoniae
(pneumococci), Str. pyogenes (group A), and some
viridans streptococci: enterococci are relatively in-
- sensitive.
Gram-negative cocci including Neisseria meningi-
tidis (meningococci) and Neisseria gonorrhoeae
(gonococci).
Gram-negative bacilli including Pasteurella mulfoc-
ida. Streplobacillus moniliformis, and Spirillum mi-
nus (or minor)', most Gram-negative bacilli,
including Pseudomonas spp. and Enterobacter-
iaceae, are insensitive although some strains of Pro-
teus mirahilis and Escherichia coli may be inhibited
by high concentrations of benzylpenicillin.
Gram-negative anaerobes including Prevotella
(non-fragilis Bacteroides) and Fusobacterium spp.
Other organisms including Actinomyces and the spi-
rochaetes, Borrelia, Leptospira, and Treponema
spp.
Mycobactena, fungi, mycoplasmas, and nckettsias
are not sensitive.
Minimum inhibitory concentrations (MICs) of ben-
zylpenicillin for the most sensitive organisms
(gonococci, meningococci, non-beta-lactamase-
producing staphylococci. and streptococci) have
been reported to 'range from 0.005 to 0.05 ng
mL; the maximum bactericidal effect is at cone
trations about 4 times the MIC.
Activity with other antimicrobials : Benzylpenicillin
may exhibit synergy with other antimicrobials par-
ticularly the aminoglycosides and such combina-
tions have been used against enterococci and other
relatively insensitive bacteria. Its activity may be en-
hanced by clavulanic acid and other beta-lactamase
inhibitors, and both enhancement and antagonism
have been demonstrated for beta-lactam combina-
tions. Antagonism has been reported to occur with
some bacteriostatic drugs, such as chloramphenicol,
that interfere with active bacterial growth necessary
for benzylpenicillin to achieve its effect.
Resistance. Susceptible Gram-positive bacteria ac-
quire resistance to beta-lactams mainly through the
induction of beta-lactamases. including penicilli-
nases. These enzymes are liberated extracellularly
and hydrolyse the beta-lactam ring. This resistance
is usually plasmid-mediated and can be transferred
from one bacterium to another. Gram-negative bac-
teria produce beta-lactamases within their cell mem-
branes which may be chromosomally or plasmid-
mediated; all Gram-negative species probably con-
tain small amounts of beta-lactamases. Resistance in
Gram-negative species may also be due to changes
in their outer membrane resulting in the failure of
beta-lactams to reach their target penicillin-binding
proteins. Changes in the binding characteristics of
penicillin-binding proteins may also result in resist-
ance in Gram-positive and Gram-negative bacteria.
Most strains of Staphylococcus aureus are now re-
sistant to benzylpenicillin. Streptococcus pneumoni-
ae with reduced susceptibility or complete
resistance to benzylpenicillin have increasingly
been reported. Strains of Neisseria meningitidis
with reduced sensitivity to benzylpenicillin have
been identified. Penicillinase-producing Neisseria
gonorrhoeae are widespread; reduced sensitivity of
gonococci to benzylpenicillin may also result from
alterations in penicillin-binding proteins. Resistant
strains of other species usually sensitive to ben-
zylpenicillin have emerged among Bacillus anthra-
cis and Cornebacterium diphtheriae. Most strains
of Haemophilus influenzae and Moraxella (Branha-
mella) catarrhalis are now resistant.
Some organisms, usually Gram-positive cocci such
as staphylococci or streptococci, may develop toler-
ance and are inhibited but not killed by benzylpeni-
cillin: in such cases the minimum bactericidal
concentration (MBC) is much greater than the min-
imum inhibitory concentration (MIC).
BENZATHINE PENICILLIN :
Non-allergic (embolic-toxic) reactions similar to
those reported after administration of procaine pen-
icillin, have been reported rarely with benza-
thine penicillin.
Benzathine penicillin should not be injected intra-
vascularly since ischaemic reactions may occur.
Pharmacokinetics
When benzathine penicillin is given by intramuscu-
lar injection, it forms a depot from which it is slowly
released and hydrolysed to benzylpenicillin. Peak
plasma concentrations are produced in about 24
hours and are lower than those following an equiva-
lent dose of benzylpenicillin potassium or sodium.
However, depending on the dose, benzylpenicillin is
usually detectable in plasma for up to 4 weeks (but
see below).
Distribution into the CSF is reported to be poor.
Due to the slow absorption from the site of injection,
benzylpenicillin has been detected in the urine for
up to 12 weeks after a single dose.
Benzathine penicillin is relatively stable in the pres-
ence of gastric juice, but absorption from the gastro-
intestinal tract is variable. Plasma concentrations of
benzylpenicillin achieved following an oral dose are
lower than those from the same dose of a soluble
penicillin: peak concentrations are also produced
less rapidly, but may persist for longer.
Plasma concentration : Benzathine penicillin has been
given every 4 weeks for secondary prophylaxis against rheu-
matic fever, although some advocate administration every 3
weeks to ensure adequate plasma concentrations of ben-
zylpenicillin. Typical concentrations achieved after a single
intramuscular injection of benzathine penicillin 900 mg have
been cited as about O.I. 0.02, and 0.002 ng per mL on days 1.
14, and 32 respectively. In one study' adequate concentra-
tions (defined as 0.02 ng or more per mL) were seen in more
than 80% of senim samples at 3 weeks, but in only 36% at 4
weeks. In a further study in which single doses of 900 mg,
1.35 g and 1.8 g were compared, it appeared that doses higher
than the 900-mg dose of benzathine penicillin usually recom-
mended might prolong the duration of protective plasma con-
centrations of benzylpenicillin (defined as above 0.025 micro gm per
mL) and improve the efficacy of dosing every 4 weeks for
prophylaxis against rheumatic fever.
Pregnancy. The pharmacokinetics of benzathine penicillin
appear to be altered in late pregnancy. Of 10 healthy pregnant
women given benzathine penicillin 1.8 g intramuscularly be-
fore caesarean section, only 4 achieved adequate serum con-
centrations of benzylpenicillin (for syphilis, at least 0.018 microgm
per mL) for 7 days.'
Uses and Administration
Benzathine penicillin has the same antimicrobial ac-
tion as benzylpenicillin to which it is hydro-
lysed gradually following deep intramuscular
injection. This results in a prolonged effect, but
because of the relatively low blood concentrations
of benzylpenicillin produced, its use should be re-
stricted to micro-organisms that are highly suscepti-
ble to benzylpenicillin. In acute infections, and
when bacteraemia is present, the initial treatment
should be with benzylpenicillin by injection.
Infections treated with benzathine penicillin include
diphtheria (asymptomatic carriers), pharyngitis
(Streptococcus pyogenes: Arcanobacterium {Co-
rynebacterium) haemolyticum), rheumatic fever
(primary and secondary prophylaxis), and syphilis
(including non-venereal treponematoses). For de-
tails of these infections and their treatment, see un-
der Choice of Antibacterial .
Administration and dosage. Benzathine penicillin is
administered by deep intramuscular injection,
sometimes in association with procaine penicillin. It
has been given by mouth for mild infections, al-
though phenoxymethylpenicillin is usually pre-
ferred.
For early syphilis, a single dose of benzathine peni-
cillin 1.8 g by deep intramuscular injection is given.
usually as 2 injections at separate sites. In late syph-
ilis. 1.8 g is given at weekly intervals for 3 consecu-
tive weeks. Benzathine penicillin is not usually
recommended for the treatment of neurosyphilis
because of reports of inadequate penetration into the
CSF. Infants up to 2 years of age may be given a
single intramuscular dose of 37.5 mg per kg body-
weight for the treatment of congenital syphilis pro-
vided mere is no evidence of infection in the CSF.
For the treatment of other treponemal infections.
such as yaws. pinta, and endemic syphilis (bejel), a
single intramuscular dose of benzathine penicillin
900 mg is given, or 450 mg in children.
For streptococcal pharyngitis and the primary pre-
vention of rheumatic fever the adult dose is a single
intramuscular injection of 900 mg; children under
30 kg body-weight may be given 450 to 675 mg. To
prevent recurrences of acute rheumatic fever
900 mg is given intramuscularly every 3 or 4 weeks;
a dose of 450 mg has been recommended for chil-
dren under 30 kg body-weight.