CURRENT D R U G THERAPY

Penicillin therapy-Newer semisynthetic penicillins

It is obvious that the perfect penicillin has not been developed as yet.
There is need for an acid-stable, highly absorbable, .lwnicillinase-resistant, hroad-
spectrum penicillin. Progress, so far, has been exciting and most promising. Many
agents are now heing studied, and many more will soon be available.
Acid-resistant peniciUins
One serious drawback to the usefulness of penicillin G is its instability in
acid media. This makes it less effective and erratic in hehavior when given by
mouth. The development of acid-resistant penicillins was, therefore, an important
advance. There are now six commercially available acid-resistant penicillins;
it is possihle to obtain good to excellent drug blood levels by their oral admin-
istration. Although they all have acid resistance in common, they vary in uses.
Therefore, a discussion of each and its role in therapy wiII he helpful in leading
the physician to the selection of the proper agent.

Phenoxymethyl penicillin
Phenoxymethyl penicillin (Pen-Vee-K, Compocillin-VK, V-Cillin-K), pro-
duced in 1953, was the first of the acid-resistant penicillins discovered. It still
remains one of thc most effective of the series and is widely used clinically when
oral penicillin therapy is desirable. .
Phenoxymethyl penicillin differs from penicillin G in having a phenoxymethyl
in place of a henzyl side chain.

o H S
;=\, -O-CH2-G-N-~H-7H
'L-' I!' / "
C (CH3) 2

CO-l\'~-CH-C-OH

"o

Pharmllcology. Phenoxymethyl penicillin has essentially thc same antibac-

terial action as penicillin G. It is insoluble and acid stahle in gastric juice but
dissolves readily in the alkaline medium of the duodenum. It is weil, hut not
completely, absorhed in the upper small boweI. In comparable doses, it gives
blood levels 3 to 5 times greater than those with penicillin G. Distribution after
ahsorption is similar to that of penicillin G, and it is excreted hy the kidney in a
similar mann er. Allergic reactions are altogether similar to those of penicillin G.
Furthermore, there is cross sensitivity with penicillin G.
The usual dose is 250 mg. every 6 hours (250 mg. is e(luivalent to 400,000
llnits of penicillin G). In more severe infections, doses as high as 3 or 4 Gm. a
706
Volumc 7 Ne/cer semisynthctic lJCnicillills 707
.'\/lim/)('r;')

day or more may bc given. Usually, in scvere infcction, parelüpral penicillin G

is preferable, and, as the infection is brought under control, adequate doses of
oral phenoxymethyl penicillin can he used as continuation therapy, if desired.
Oral phenoxymethyl penicillin may he used dfectively in most infections r('-
sponsive to penicillin G, such as streptococcaL pncnmococcal, and nonpenicil-
linase, nonresistant staphylococcal infections.
Phenoxymethyl penicillin is mon; expensive than penicillin C.

Phenoxyethyl penicillin
Phenethicillin (Chemipen, Darcil, Dramcillin, \Iaxipcn, Semopen, Syn-
cillin), a eIose relative of phenoxymethyl penicillin, was introduced in 1960. lt
is also acid resistant and effective hy mouth.
Phenoxyethyl penicillin differs from penicillin G hy having a plll'noxyethyl
in pI ace of the benzyl side chain,' and from phenoxymethyl penicillin hy having
an additional methyl group.

eH30 S
j\
~-o-eH-e-:'\H-~H-eH
. 11 / "
e (CH:)) 2

co-:\- CH-C-Oll
~
o

Phannacology. Phenoxyethyl penicillin eIosdy rescmhks phenoxynwthyl

penicillin in all characteristics.
Dose and administration. Phenoxyethyl penicillin is giwn in the sanw dose
and manner and for the same infections as phcnoxymethyl penicillin. It, too,
is more expensive than penicillin G.

Oxacillin
Oxacillin (Prostaphlin, Resistopen ), discovered in 1961 differs considcrahly
in the side chain stmcture from the above two acid-resistarlt penicillins. It has
the additional virtue of being penicillinase resistant. Unfortunatdy, it is a potent
penicillinase inducer.
Oxacillin differs frorn penicillin G hy having a .5 methyl-.3-phenyl-4 isoazolyl
in pI ace of the henzyl side chain.

s
j\
'L!-~-r-NH-C,.H-IH
/ " CI' (CH.') 2

N
"/,,
o
C I
CH.' CO-N-- CH-CONa
H20

11
o

Pharmacology. Oxacillin is relatively stable in acid media and strongly re-

sistant to penicillin ase. It is given orally, but owing to its somewhat erratic ah-
sorption, and not being entirely resistant to acid, blood levels are not predictablc.
Approxirnately 50 to 60 per cent is absorbed. About 80 per cent is l)Ound to
708 Friend Clinica! Pharmaco!ogl/
,md Thcrapcutics

plasma pruteilI. This binding, however, does not sccm to impair the effectiveness
of the dmg.
OxaciIlin is excreted mainly by the kidney, but not as rapidly as penicillin
G. In the presence of renal failure, cIearance of the dmg is markedly reduced
and more is eliminated in the bile.
Toxie effeets. Neutropenia and impaired liver functions have been reported.
Superinfection may be more likely than with penicillin G.
Dose and administration. OxaciIlin is given orally and, for the best resuIts,
on an empty stomach to insure better absorption, less acid destmction, and more
effective and stable blood levels. A dose of 0.5 Gm. every 6 hours is usually
effective. If larger doses are given, nausea, indigestion, gas, and mild diarrhea
are prone to develop but are usually not severe enough to force discontinuance
of the dmg. Oxacillin is not a substitute for penicillin G. It is useful in controlling
penicillinase-producing organisms when penicillin in G is ineffective. Its expense,
erratie absorption, and reduced effectiveness do not make it the agent of first
ehoice as a primary therapeutic penicillin.

C loxacillin
Cloxacillin (Tegopen) is dosely related to oxacillin and possesses all the
virtues of oxacillin. It is better absorbed than oxacilIin, more predictable blood
levels are attained, and absorption is not influenced by food. H, like oxacillin, was
discovered in 1961.
Cloxacillin differs from oxacillin by having chlorine in the 3-0-phenyl posi-
tion of the side chain. It is 5 methyl-3-chlorphenyl-4-isoxazolyl penicillin.

CI
/ s

V1J,N"Tl" rem)
/ '

o CH3
/ "'-

CO-l\'--CH-CONa
2 H20

"o
Pharmacology. Like oxacillin, doxacillin is penicillinase resistant and rela-
tively acid stable. It is absorbed bettel' than oxacillin, and its absorption is not
impaired by food, which gives it an advantage over oxacillin. It is metabolized
by the liver, and approximately 38 per cent is excreted by the kidney.
The spectmm of antibacterial activity is similar to that of oxacillin. Although
more expensive than penicillin G, it does not differ much in price from other
orally eHective compounds and is cheaper than erythromycin. Because of the
dmg's eHectiveness by mouth and resistance to penicillinase, some prefer to start
treatment with this agent in gram-positive infections, especially in hospital pa~
tients, until the infecting organism can be identified.
Toxie effects. Cross sensitivity to penicillin G and other penicillins does
occur. Eosinophilia and allergie reactions have been seen. Liver function tests
may show slight abnormalities in some patients.
Dose and administration. These are the same as for oxacillin.
V()tumc 7 N cu'cr scmisyntllClic penicillins 709
!\lurnber 5

Dicloxacillin
This penicillin (not commercially available in the U .S.A.) is a derivative
of oxacillin. It is significantly more active against penicillinase-producing staphy-
lococci than oxacillin and cloxacillin. It is also as effective as its homologues
against Group A streptococci, and the decreased activity of cloxacillin against
pneumococci is not exhibited by dicloxacillin, making it one of the most effective
of the acid-stable, penicillinase-resistant penicillins.
Dicloxacillin differs from cloxacillin by having an additional chlorine in the
phenyl ring side chain. It is 5 methyl-3-dichlorphenyl-4-isoxazolyl penicillin.

CI
/ s
j=\ /"-
L)-C~rNH-CIH-CIH CI' (CH3) 2
H20
"-Cl "-0/"-CH3 CO-N--CH-CONa
11
o

Plwrmacology. Dicloxacillin is very effective against penicillinase-producing

staphylococci. It is weIl absorbed orally, giving semm levels 4 times those seen
with oxacillin and twice those with cloxacillin. These higher semm levels are
not entirely due to hetter ahsorption but may, to some degree, result from slower
metabolism and, perhaps, lessened renal excretion. Semm binding is the same
as for oxacillin and cloxacillin. Although semm binding approaches 95 to 100 per
cent, it does not appear to interfere with antibacterial activity. Dicloxacillin is
partially metabolized by the liver and partially excreted by the kidney.
Dicloxacillin has a similar spectmm of activity as cloxacillin, but it is more
effective against penicillinase-producing staphylococci. It has also been found
to be effective against methicillin-resistant, coagulase-positive staphylococci. It
is nearly as active as oxacillin against pneumococci and far more active than
cloxacillin against this organism. These superior qualities make dicloxacillin
highly useful in staphylococcal infections and an effective agent against other
penicillin-sensitive organisms.
Toxie effects. Although not much is known as yet, mild gastrointestinal dis-
tress has been observed. It is reasonable to believe that the same effects as seen
from oxacillin, cloxacillin, and penicillin may be seen as use of dicloxacillin is
extended.
Dose and administration. When high hlood levels of dmg are needed, as in
severe infections, 0.5 to 1.0 Gm. every 6 hours, as for oxacillin, is recommended.
Because lower dos es give excellent blood levels in milder infections, 250 mg.
every 4 to 6 hours may be satisfactory.
Nafcillin (Unipen)
This semisynthetic penicillin is also acid and penicillin ase resistant and
effective orally. As the soluble sodium salt, it can also be given intramuscularly
and intravenously, thus offering in a single agent these various routes of admin-
istration.
 Clinical Pllannacologll
710 Fricncl (",d Thcropeutic$

Nafcillin has Cl unique side chain which differs considerahly from others in
the serics. It is 6-2 ethoxy-l-naphthamide penicillin.

~
\/ /\ H H H S CH,
1 1/" /
~--------N-~ C
" O-C,H,
II
O=C-N--C-COOH
I"CH,
H

Pharmacology. Nafcillin is absorbed from the gastrointestinal tract somewhat

irregularly and is, to some extent, inactivated by acid. It is stable in solution
even at a lower pR than the 7.2 to 7.4 range of methicillin, a distinct advantage.
After ingestion, peak blood levels occur in lh to 1 hour. When given intramuscu-
larly, 0.5 Gm. gives blood levels equivalent to 1.0 Gm. by mouth. About 60 to 70
per cent is bound to serum protein. Some believe nafcillin is capable of achieving
higher tissue levels than in the blood, and, therefore, serum levels may not he a
tme index of the effectiveness of this drug. Approximately 90 per cent is elimi-
nated in the bile and 10 per cent in the urine. It is erereted by the kidney some-
what more slowly than methicillin. In the presenee of liver impairment, very
high levels can be rapidly attained. Recirculation through the bile and reabsorp-
tion from the gut greatly prolong elimination.
Nafcillin approaches penicillin G in effectiveness against susceptible staphylo-
cocci and is superior to penicillin G, methicillin, and oxacillin against resistant
staphylococci. It is particularly effective against Staphylococcus aureus. Strains
resistant to oxacillin are usually susceptible to nafcillin. It is also effective against
penicillin G-susceptible pneumococci and streptococci. It is not, however, the
agent of first choice against organisms susceptible to penicillin G since it is more
expensive and less effective.
Adverse effects. Nafcillin should not be given to patients who have had a
reaction to penicillin G. Thrombophlebitis has followed intravenous administra-
tion.
Dose alld administration. Nafcillin may be given by mouth, intramuscularly,
or intravenously. Parenteral therapy should be employed in the presence of
severe infections. In the latter, 0.5 to 1.0 Gm. every 4 hours, intravenously, is
needed. It may be dissolved in 150 C.C. normal saline solution and given as a
drip at a rate of 100 or so drops aminute. Intravenous therapy should be changed
to intramuscular therapy as soon as possible, certainly after 24 hours. A dose of
500 mg. may be given every 4 to 6 hours, depending on the severity of infection.
Orally, 250 to 500 mg. every 4 to 6 hours, taken 1 to 2 hours before meals
and in the fasting state, is satisfactory for milder infections. More severe in fec-
tions require 1.0 Gm. every 4 to 6 hours.

Ampicillin (Omnipen, Penbritin, Polycillin)

This agent differs from others of the group in its wider spectrum of action.
It is active against certain gram-negative organisms. Unfortunately, it is not
penicillinase resistant. It is, however, acid stabil' and can be given orally.
Va/U1Ue 7 711
:Vuml}('r .')
Nelcer semisy"thetic pCllicillins

Ampicillin has an a-amino henzyl group in place of thc benzyl side chain
of penicillin G.

H H H H S CH:3

1/~\\-C--X-C-C
I ! I 1/ '" /
C

~ I
NH2
I:
O=C-:\--C-COOH
I'tH3
H

Pharmacolo{!.y. Ampicillin is acid stabil' and absorbed when given orally.

Food retards absorption somewhat. Aftt'r ingestion, peak blood levels of the
dmg oecur in approximately 1 to 2 hours, and some dmg may persist in the
semm for 6 hours. A dose of 2.50 mg. gives blood levels of about 2 fJ.g per milli-
liter. Most of the dmg is excreted uI1changed in the urine. About 20 per cent is
bound to semm protein. It is also concentrated in bile, where levels far higher
than those in the blood are found. This faetor has made it a useful agent in
treating infection of the hiliary system and, in particnlar, the elimination of the
typhoid carrier statt'. It diffuses poorly into the cerebrospinal fluid nonnally, hut
higher levels are found during infection.
Ampicillin is active against II emaphilus influenzae, Salmollella shigella.
Escherichia ('ali, and ProteIls mimhilis. ~·Iost Klehsiella and At'rohaeter, and
all Pseudomonas, are resistant. It is probahle in most situations that amphicillin
is no more effective than penicillin G, if the latter is given in sufficiently high
dose. It does have an advantage over penicillin G in heing effective against
many strains of Streptococcus faecalis and enterococci and is also advantagcous
because of its heavy concentration in the biliary traC't.
Adverse eflect. Liver fnnetion, as detennined hy serum glutamic oxalo-
acetic transaminase, has lwen disturbed in a few instances, but no adverse effeet
of consequence developed. Cross allergy with penicillin G has been ohserved.
Dose amI administration. Ylilder infections of the respiratory traC't respond
to 250 mg. orally, every 6 hours. rvlore serious infeetions, genitourinary and
gastrointcstinal infections should be treated with 500 mg., or more, ever)' 6 hours.
Typhoid carriers should he given 100 mg. per kilogram daily for 4 weeks.
Children weighing less than 20 kilograms should be given 50 to 100 mg. per
kilogram, depending on thc loeation and severity of infection. Those weighing
more than 20 kilograms should he given the usual adult dose. Sodium ampieillill
is available for parenteraillse in vials containing 2.50 or 500 mg.

Non-acid resistant penicillin: Methicillin (Dimocillin-RT, Staphcillin)

This agent was the first of the penicillinase-resistant penicillins. It was de-
scribed in 1960. ~ethicillin lacks the acid stability of the other acid penieillinase-
resistant penicillins. It cannot be given by mouth and is unstable in aqueous
solution. It induces penicillinase aetivity in staphylococei. Resistance to it de-
velops, and it is less potent than the other penicillins of the series. It should not
be used carelessly.
~ethicillin has a 2,6, dimethoxyphenyl side grollp in place of thc henzyl
group of penicillin G.
 Friend C/i"iclll Pl",rmacolollY
712 alld Therap('utics

-O-CH3 .s CH3
~ 11 H H/ , , /
1/ \\---N-C-C C

""=I-O~H3 II
C-N---C~OOH
I 'cH3

11 I
o H

Pharmacology. Methicillin is unstable in acid media; aqueous solutions are

unstable. Acid solutions lose 50 per cent of their activity at room temperature in
30 minutes. Solutions must, therefore, be adjusted to pH 7.2 to 7.4 for continuous
intravenous infusion, or the drug may be freshly made just before administration
and given in 20 to 50 c.c. amounts over a 5 minute period. About 20 per cent is
bound to serum protein. It is excreted unchanged in the urine. High levels can
quickly develop if there is renal impairment or in infants whose renal excretion
is not fully developed. Normally, 60 per cent or better of a dose is eliminated in
4 hours.
It does not penetrate into cerebrospinal fluid in sufficient amounts to be
dependable for treatment of meningeal infections~ It appears in the precordial,
ascitic, and pleural fluids in nearly the same concentrations as in the blood.
MethicilIin was the first penicillin found effective against penicillin ase-
resistant staphylococci, and as such has enjoyed wide use. Now, more effective
and more stahle penicillins are replacing it. It should not be used for penicillin
G-sensitive infections, since the latter is far more effective and less expensive.
When methicillin is used, there is little or no virtue in giving penicillin G with it.
Adverse effects. Cross sensitivity to penicillin G has heen observed. An ex-
tremely high blood level may develop rapidly, if there is renal impairment. At
least one reported patient with renal failure and a blood urea nitrogen level of
140 mg. per (-ent had a drug plasma level of 250 p.g per milliliter. Blood dyscrasias
have been r.eported. .
Dose and administration. Methicillin must be given parenterally. Solutions
must be given immediately or deterioration will inactivate much of the drug.
Intravenous solutions given by drip must be at pH 7.2 to 7.4 to prevent deteriora-
tion. Many dissolve the dose in 20 to 50 c.c. saline solution and give it immedi-
ately to prevent loss. A dose of 6 to 12 Gm. daily, depending on the severity
of the infection, is recommended. Many failures in the treatment of staphylo-
coccal infections with methicillin have occurred because inadequate doses were
given.
DALE G. FRIEND, M.D.
Senior Associate in Medicine
Peter Bent Brigham Hospital
Assistallt Professor in Medicine
Harvard Medical School
I