ANTI-BACTERIAL ANTIBIOTICS

CATEGORY Generic Chemical Name Description R Group or Other Uses

Name Structure Names
PENICILLINS Penicillin G Benzylpenicillin It was first made available as the water the most popular
soluble salts of K, Na, and Ca. These salts of penicillin
penicillin are inactivated by the gastric juice In fact, with the
and are not effective when administered exception of
orally unless antacids, such as patients allergic
Ca carbonate, Al hydroxide, and Mg to it, penicillin G
trisilicate; or a strong buffer, such as Na remains the
citrate, is added. agent of choice
Penicillin is absorbed poorly from the for the
intestinal tract; oral doses must be very treatment of
large, about 5x the amount necessary with more different
parenteral administration. kinds of bacterial
The water-soluble K and Na salts are used infection than
orally and parenterally to achieve high any other
plasma concentrations of penicillin G rapidly. antibiotic.
The more water-soluble K salt usually is
preferred when large doses are required.
Situations in which hyperkalemia is a
danger, however, as in renal failure, require
use of the Na salt; the K salt is preferred for
patients on salt-free diets or with congestive
heart conditions.
Penicillin G The first widely used amine salt of penicillin Crysticillin,
Procaine G was made with procaine. Duracillin,
This can be made readily from penicillin G Wycillin
sodium by treatment with procaine
hydrochloride.
Penicillin G N,N_- the salt of a diamine,2 moles of penicillin are Bicillin,
Benzathine dibenzylethylened available from each molecule. It is very Permapen),
iamine insoluble in water, requiring about 3,000 mL
dipenicillin G to dissolve 1 g. This property gives the
compound great stability and prolonged
duration of effect. At the pH of gastric juice,
it is quite stable, and food intake does not
interfere with its absorption
Penicillin V Phenoxymethylpe it has enjoyed wide use because of its Pen Vee, V-
nicillin resistance to Cillin)
hydrolysis by gastric juice and its ability to
produce uniform
concentrations in blood (when administered
orally) For parenteral
solutions, the potassium salt is usually used.
This salt is very
soluble in water. Solutions of it are made
from the dry salt
at the time of administration. Oral dosage
 forms of the
potassium salt are also available, providing
rapid, effective
plasma concentrations of this penicillin. Its
high water insolubility
makes it a desirable compound for aqueous
suspensions
used as liquid oral dosage forms.
Methicillin 2,6- the second penicillin produced as Staphcillin has been
Sodium Dimethoxyphenyl a result of the research that developed introduced for
penicillin synthetic analogs, was use in the
introduced for medicinal use. treatment of
is particularly resistant to inactivation staphylococcal
by the penicillinase found in staphylococci infections caused
and somewhat by strains
more resistant than penicillin G to resistant
penicillinase from to other
Bacillus cereus. Methicillin and many other penicillins. It is
penicillinaseresistant recommended
penicillins induce penicillinase formation, an that it not be
observation used in general
that has implications concerning use of these therapy, to avoid
agents in the treatment of penicillin G- the possible
sensitive infections. widespread
Clearly, the use of a penicillinase-resistant development of
penicillin should organisms
not be followed by penicillin G. resistant to it.
The incidence of interstitial nephritis, a
probable hypersensitivity
reaction, is reportedly higher with methicillin
than with other penicillins.
Nafcillin 2-Ethoxy-1- is another semisynthetic penicillin that Unipen Nafcillin sodium
naphthylpenicillin resulted may be used in
from the search for penicillinase-resistant infections caused
compounds. Like solely by
methicillin, nafcillin has substituents in penicillin G-
positions ortho to resistant
the point of attachment of the aromatic ring staphylococci or
to the carboxamide when
group of penicillin. streptococci are
nafcillin is stable enough in acid to present also.
permit its use by oral administration. When it Although it is
is given recommended
orally, its absorption is somewhat slow and that it be used
incomplete, exclusively for
but satisfactory plasma levels may be such resistant
achieved in about infections,
1 hour. Relatively small amounts are nafcillin is also
excreted through effective against
the kidneys; most is excreted in the bile. pneumococci and
 Even though group
some cyclic reabsorption from the gut may A _-hemolytic
occur, nafcillin streptococci.
given orally should be readministered every Because, like
4 to 6 hours. other penicillins,
This salt is readily soluble in water and may it may cause
be administered allergic side
intramuscularly or intravenously to obtain effects, it should
high be administered
plasma concentrations quickly for the with care.
treatment of serious
infections.
Oxacillin (5-methyl3- is the salt of a semisynthetic Prostaphlin The use of
Sodium phenyl-4- penicillin that is highly resistant to oxacillin and
isoxazolyl)penicilli inactivation by other
n penicillinase. isoxazolylpenicilli
sodium Oxacillin sodium, which is available in ns
monohydrate capsule form, is should be
reasonably well absorbed from the restricted to the
gastrointestinal (GI) treatment of
tract, particularly in fasting patients. infections caused
Effective plasma levels by staphylococci
of oxacillin are obtained in about 1 hour, but resistant to
despite extensive penicillin G.
plasma protein binding, it is excreted rapidly Although their
through spectrum of
the kidneys. Oxacillin experiences some first- activity is similar
pass metabolism to that of
in the liver to the 5-hydroxymethyl penicillin G, the
derivative. isoxazolylpenicilli
This ns are, in
metabolite has antibacterial activity general, inferior
comparable to that of to it and the
oxacillin but is less avidly protein bound and phenoxymethylpe
more rapidly nicillins for the
excreted. The halogenated analogs treatment of
cloxacillin, dicloxacillin, infections
and floxacillin experience less 5-methyl caused by
hydroxylation. penicillin G-
sensitive
bacteria. Because
isoxazolylpenicilli
ns
cause allergic
reactions similar
to those
produced by
other penicillins,
they should be
used with
 great caution in
patients who are
penicillin
sensitive.
Cloxacillin 5-Methyl-3-(2- The chlorine atom ortho to the position of Tegopen
Sodium chlorophenyl)-4- attachment of the
isoxazolylpenicilli phenyl ring to the isoxazole ring enhances
n the activity of
this antibiotic
Dicloxacillin 5-Methyl-3-(2,6- The substitution of chlorine atoms on both (Dynapen, Its medicinal
dichlorophenyl)-4- carbons ortho Pathocil, properties and
isoxazolylpenicilli to the position of attachment of the phenyl Veracillin) use are the
n ring to the isoxazole same as those of
[3-(2,6- ring is presumed to enhance further the cloxacillin
dichlorophenyl)-5- stability of sodium.
methyl-4- the oxacillin congener dicloxacillin sodium,
isoxazolyl]penicilli
n sodium
monohydrate
Ampicillin D-- meets another goal of the research on Penbritn, Ampicillin is not
Aminobenzylpenic semisynthetic penicillinsan antibacterial Polycillin, resistant to
illin spectrum broader Omnipen, penicillinase, and
6-[D-_- than that of penicillin G. This product is Amcill, it produces
aminophenylaceta active against the Principen the allergic
mido]penicillanic same Gram-positive organisms that are reactions and
acid susceptible to other other untoward
penicillins, and it is more active against effects
some Gram-negative found in
bacteria and enterococci than are other penicillin-
penicillins. sensitive
Obviously, the _-amino group plays an patients. Because
important role in the such reactions
broader activity, but the mechanism for its are relatively
action is rare, however, it
unknown. It has been suggested that the may be used to
amino group confers treat infections
an ability to cross cell wall barriers that are caused by Gram-
impenetrable negative bacilli
to other penicillins. D-(_)-Ampicillin, prepared for which a
from D-(_)- broad-spectrum
_-aminophenylacetic acid, is significantly antibiotic, such
more active than as a tetracycline
L-(_)-ampicillin. or
chloramphenicol,
may be indicated
but not preferred
because of
undesirable
reactions or lack
of bactericidal
effect.
Ampicillin is not
so widely active,
however, that it
should
be used as a
broad-spectrum
antibiotic in the
same manner
as the
tetracyclines. It is
particularly useful
for the treatment
of acute urinary
tract infections
caused by E. coli
or
Proteus mirabilis
and is the agent
of choice against
Haemophilus
influenzae
infections.
Ampicillin,
together
with probenecid,
to inhibit its
active tubular
excretion, has
become a
treatment of
choice for
gonorrhea in
recent years.
_-Lactamase
producing strains
of Gram-negative
bacteria
that are highly
resistant to
ampicillin,
however, appear
to be
increasing in the
world population.
The threat from
such resistant
strains is
particularly great
with H.
 influenzae and
N. gonorrhoeae,
because there
are few
alternative
therapies
for infections
caused by these
organisms.
Incomplete
absorption
and excretion of
effective
concentrations in
the
bile may
contribute to the
effectiveness of
ampicillin in the
treatment of
salmonellosis and
shigellosis.
Amoxicillin D- -Amino- semisynthetic Amoxil, Its antibacterial
phydroxybenzylpe penicillin introduced in 1974, is simply the p- Larotid, spectrum is
nicillin hydroxy Polymox), nearly identical
analog of ampicillin, prepared by acylation of with that of
6-APA with phydroxyphenylglycine. ampicillin, and
like ampicillin, it
Amoxicillin is a fine, white to off-white, is resistant to
crystalline acid, susceptible
powder that is sparingly soluble in water. It is to alkaline and _-
available in lactamase
various oral dosage forms. Aqueous hydrolysis, and
suspensions are stable weakly protein
for 1 week at room temperature. bound. Early
clinical reports
indicated that
orally
administered
amoxicillin
possesses
significant
advantages over
ampicillin,
including more
complete GI
absorption to
give higher
plasma and urine
levels, less
 diarrhea, and
little or no effect
of food on
absorption.50
Thus, amoxicillin
has largely
replaced
ampicillin for the
treatment of
certain systemic
and urinary tract
infections
for which oral
administration is
desirable.
Amoxicillin is
reportedly less
effective than
ampicillin in the
treatment of
bacillary
dysentery,
presumably
because of its
greater GI
absorption.
Cyclacillin 1-
Aminocyclohexylp
enicillin
Carbenicilli semisynthetic penicillin released Geopen, Carbenicillin has
n Carboxybenzylpen in the United States in 1970, which was Pyopen), been effective in
Disodium, icillin introduced in the treatment of
Sterile disodium _- England and first reported by Ancred et al.52 systemic
carboxybenzylpen in 1967. and urinary tract
icillin Carbenicillin is not stable in acids and is infections caused
inactivated by by P. aeruginosa,
penicillinase. It is a malonic acid derivative indole-producing
and, as such, decarboxylates Proteus spp., and
readily to penicillin G, which is acid labile. Providencia spp.,
Solutions of the disodium salt should be all of
freshly prepared but, which are
when refrigerated, may be kept for 2 weeks. resistant to
It must be administered ampicillin. The
by injection and is usually given low toxicity of
intravenously. carbenicillin,
with the
exception of
allergic
sensitivity,
permits the
 use of large
dosages in
serious
infections. Most
clinicians
prefer to use a
combination of
carbenicillin and
gentamicin
for serious
pseudomonal and
mixed coliform
infections. The
two antibiotics
are chemically
incompatible,
however, and
should never be
combined in an
intravenous
solution.
Carbenicilli 5-indanyl ester Clinical trials with indanyl carbenicillin Geocillin), Indanyl
n Indanyl carbenicillin revealed a relatively carbenicillin thus
Sodium indanyl, high frequency of GI symptoms (nausea, provides an
6-[2-phenyl-2-(5- occasional orally active
indanyloxycarbon vomiting, and diarrhea). It seems doubtful alternative for
yl)acetamido]peni that the high the treatment of
cillanic doses required for the treatment of serious carbenicillinsensit
acid ( systemic infections ive
could be tolerated by most patients. Indanyl systemic and
carbenicillin urinary tract
occurs as the sodium salt, an off-white, bitter infections caused
powder by
that is freely soluble in water. It is stable in Pseudomonas
acid. It should be spp., indole-
protected from moisture to prevent positive Proteus
hydrolysis of the ester. spp., and
selected
species of Gram-
negative bacilli.
Ticarcillin -Carboxy-3- is an isostere of carbenicillin in which the Ticar),
Disodium, thienylpenicillin phenyl group is replaced
Sterile _-carboxy-3- by a thienyl group. This semisynthetic
thienylpenicillin penicillin
derivative, like carbenicillin, is unstable in
acid and, therefore,
must be administered parenterally. It is
similar to
carbenicillin in antibacterial spectrum and
pharmacokinetic
 properties. Two advantages for ticarcillin are
claimed:
(a) slightly better pharmacokinetic
properties, including
higher serum levels and a longer duration of
action; and
(b) greater in vitro potency against several
species of Gramnegative
bacilli, most notably P. aeruginosa and
Bacteroides
fragilis. These advantages can be crucial in
the treatment of
serious infections requiring high-dose
therapy.
Piperacillin -(4-Ethyl-2,3- Piperacillin is destroyed rapidly by stomach Pipracil) is the most
dioxo-1- acid; therefore, generally useful
piperazinylcarbon it is active only by intramuscular or of the extended-
ylamino) intravenous spectrum
benzylpenicillin administration. The injectable form is acylureidopenicilli
provided as the white, ns. It is more
crystalline, water-soluble sodium salt. Its active than
pharmacokinetic mezlocillin
properties are very similar to those of the against
other acylureidopenicillins. susceptible
strains of Gram-
negative
aerobic bacilli,
such as Serratia
marcescens,
Proteus,
Enterobacter,
Citrobacter spp.,
and P.
aeruginosa.
Mezlocillin -(1- an acylureidopenicillin with an antibacterial Mezlin)
Sodium, Methanesulfonyl- spectrum similar to that of carbenicillin and
Sterile 2- ticarcillin; however, there are some major
oxoimidazolidinoc differences. It is
arbonylamino) much more active against most Klebsiella
benzylpenicillin spp., P. aeruginosa,
anaerobic bacteria (e.g., Streptococcus
faecalis and
B. fragilis), and H. influenzae. It is
recommended for the
treatment of serious infections caused by
these organisms.
Mezlocillin is not generally effective against
_-
lactamaseproducing bacteria, nor is it
active orally. It is

CATEGORY
Beta-LACTAMASE Clavulanat
INHIBITORS e lacking the
Because these Potassium
inhibitors are also
substrates
for the enzymes that
they inactivate, they
are sometimes
referred to as suicide
substrates.
Because class I
inhibitors cause
prolonged inactivation
of
certain _-lactamases,
they are particularly
useful in combination
with extended-
spectrum, _-
lactamasesensitive
penicillins
to treat infections
caused by _-
lactamaseproducing
bacteria. Three such
inhibitors, clavulanic
acid, sulbactam,
and tazobactam, are
currently marketed in
the United States
for this purpose. A
class II inhibitor, the
carbapenem
derivative
imipenem, has potent
antibacterial activity in
addition to
its ability to cause
transient inhibition of
some _-lactamases.
Certain antibacterial
cephalosporins with a
available as a white, crystalline, water-
soluble sodium salt
for injection. Solutions should be prepared
freshly and, if
not used within 24 hours, refrigerated.
Generic Chemical Name Description R Group or Other Uses
Name Structure Names
1-oxopenam Combinations of amoxicillin and the Clavulanic acid
potassium salt exhibits
6-acylamino side of clavulanic acid are available (Augmentin) very weak
chain of penicillins in various antibacterial
but possessing a fixed-dose oral dosage forms intended for activity,
2- the treatment of comparable with
hydroxyethylidene skin, respiratory, ear, and urinary tract that of
moiety at C-2. infections caused 6-APA and,
by _-lactamaseproducing bacterial strains. therefore, is not
These combinations useful as an
are effective against _-lactamaseproducing antibiotic. It
strains of S. aureus, E. coli, K. pneumoniae, is, however, a
Enterobacter, potent inhibitor of
H. influenzae, Moraxella catarrhalis, and S. aureus _-
Haemophilus lactamase
ducreyi, which are resistant to amoxicillin and plasmid-
alone. The oral mediated _-
bioavailability of amoxicillin and potassium lactamases
clavulanate is elaborated by
similar. Clavulanic acid is acid-stable. It Gramnegative
cannot undergo penicillanic bacilli.
acid formation because it lacks an amide
side chain.
Potassium clavulanate and the extended-
spectrum penicillin
ticarcillin have been combined in a fixed-
dose, injectable
form for the control of serious infections
caused by
_-lactamaseproducing bacterial strains. This
combination
has been recommended for septicemia,
lower respiratory tract
infections, and urinary tract infections
caused by _-
lactamaseproducing Klebsiella spp., E. coli,
P. aeruginosa,
and other Pseudomonas spp., Citrobacter
spp., Enterobacter
spp., S. marcescens, and S. aureus. It also is
used in bone and
joint infections caused by these organisms.
The combination
leaving group at contains 3 g of ticarcillin disodium and 100
the C-3 position can mg of potassium
cause transient clavulanate in a sterile powder for injection
inhibition of _- (Timentin).
lactamases by forming Sulbactam penicillanic acid sulfone or 1,1-
stabilized acyl-enzyme dioxopenicillanic
intermediates. acid.
These are discussed This synthetic penicillin derivative is a potent
more fully later in this inhibitor
chapter. of S. aureus _-lactamase as well as many _-
lactamases
elaborated by Gram-negative bacilli.
Sulbactam has weak intrinsic
antibacterial activity but potentiates the
activity of
ampicillin and carbenicillin against _-
lactamaseproducing
S. aureus and members of the
Enterobacteriaceae family. It
does not, however, synergize with either
carbenicillin or ticarcillin
against P. aeruginosa strains resistant to
these agents.
Fixed-dose combinations of ampicillin sodium
and sulbactam
sodium, marketed under the trade name
Unasyn as
sterile powders for injection, have been
approved for use in
the United States. These combinations are
recommended for
the treatment of skin, tissue, intra-
abdominal, and gynecological
infections caused by _-lactamaseproducing
strains
of S. aureus, E. coli, Klebsiella spp., P.
mirabilis, B. fragilis,
and Enterobacter and Acinetobacter spp.
Tazobacta is a penicillanic acid sulfone that is
m
similar in
structure to sulbactam. It is a more
potent _-lactamase
inhibitor than sulbactam57 and has a
slightly broader spectrum
of activity than clavulanic acid. It
has very weak antibacterial
activity. Tazobactam is available in
fixed-dose, injectable
 combinations with piperacillin, a
broad-spectrum penicillin
consisting of an 8:1 ratio of
piperacillin sodium to tazobactam
sodium by weight and marketed
under the trade name Zosyn.
The pharmacokinetics of the two
drugs are very similar. Both
have short half-lives (t1/2 _1 hour),
are minimally protein
bound, experience very little
metabolism, and are excreted in
active forms in the urine in high
concentrations.
Approved indications for the
piperacillintazobactam
combination include the treatment
of appendicitis, postpartum
endometritis, and pelvic
inflammatory disease caused by
_-lactamaseproducing E. coli and
Bacteroides spp., skin and
skin structure infections caused by
_-lactamaseproducing
S. aureus, and pneumonia caused
by _-lactamaseproducing
strains of H. influenzae.
CARBAPENEMS
Thienam novel _-lactam antibiotic first
ycin isolated and
identified by researchers at Merck58
from fermentation of
cultures of Streptomyces cattleya.
Thienamycin displays outstanding
broad-spectrum antibacterial
properties in vitro.61 It is highly
active against
most aerobic and anaerobic Gram-
positive and Gramnegative
bacteria, including S. aureus, P.
aeruginosa, and
B. fragilis. Furthermore, it is
resistant to inactivation by
most _-lactamases elaborated by
Gram-negative and Grampositive
bacteria and, therefore, is effective
against many
strains resistant to penicillins and
cephalosporins. Resistance
to lactamases appears to be a
function of the _-1-
hydroxyethyl side chain because
this property is lost in the
6-nor derivative and
epithienamycins with S
stereochemistry
show variable resistance to the
different _-lactamases.
An unfortunate property of
thienamycin is its chemical
instability
in solution. It is more susceptible to
hydrolysis in
both acidic and alkaline solutions
than most _-lactam antibiotics,
because of the strained nature of its
fused ring system
containing an endocyclic double
bond. Furthermore, at its
optimally stable pH between 6 and
7, thienamycin undergoes
concentration-dependent
inactivation. This inactivation is
believed to result from
intermolecular aminolysis of the _-
lactam by the cysteamine side
chain of a second molecule.
Another shortcoming is its
susceptibility to hydrolytic
inactivation
 by renal dehydropeptidase-I (DHP-
I),62 which
causes it to have an unacceptably
short half-life in vivo.
Imipene Imipenem is N-
m formimidoylthienamycin, the most
Cilastati successful
n of a series of chemically stable
derivatives of thienamycin
in which the primary amino group is
converted to a nonnucleophilic
basic function.63 Cilastatin is an
inhibitor of DHPI.
The combination (Primaxin)
provides a chemically and
enzymatically
stable form of thienamycin that has
clinically
useful pharmacokinetic properties.
The half-life of the drug
is nonetheless short (t1/2 _1 hour)
because of renal tubular
secretion of imipenem. Imipenem
retains the extraordinary
broad-spectrum antibacterial
properties of thienamycin. Its
bactericidal activity results from the
inhibition of cell wall
synthesis associated with bonding
to PBPs 1b and 2.
Imipenem is very stable to most _-
lactamases. It is an inhibitor
of _-lactamases from certain Gram-
negative bacteria
resistant to other _-lactam
antibiotics (e.g., P. aeruginosa, S.
marcescens, and Enterobacter
spp.).
Imipenem is indicated for the
treatment of a wide variety of
bacterial infections of the skin and
tissues, lower respiratory
tract, bones and joints, and
genitourinary tract, as well as of
septicemia and endocarditis caused
by _-lactamaseproducing
strains of susceptible bacteria.
These include aerobic Grampositive
organisms such as S. aureus,
Staphylococcus epidermidis,
enterococci, and viridans
streptococci; aerobic Gramnegative
bacteria such as E. coli, Klebsiella,
Serratia,
Providencia, Haemophilus,
Citrobacter, and indole-positive
Proteus spp., Morganella morganii,
Acinetobacter and
Enterobacter spp., and P.
aeruginosa and anaerobes such as
B.
fragilis and Clostridium,
Peptococcus, Peptidostreptococcus,
Eubacterium, and Fusobacterium
spp. Some Pseudomonas
spp. are resistant, such as P.
maltophilia and P. cepacia, as are
some methicillin-resistant
staphylococci. Imipenem is
effective
against non_-lactamase-producing
strains of these and
additional bacterial species, but
other less expensive and
equally effective antibiotics are
preferred for the treatment of
infections caused by these
organisms.
The imipenemcilastatin
combination is marketed as a
 sterile powder intended for the
preparation of solutions for
intravenous
infusion. Such solutions are stable
for 4 hours at
25C and up to 24 hours when
refrigerated. The concomitant
administration of imipenem and an
aminoglycoside antibiotic
results in synergistic antibacterial
activity in vivo. The two
types of antibiotics are, however,
chemically incompatible
and should never be combined in
the same intravenous bottle.
NEWER
CARBAPEN
EMS