Symposium on Antimicrobial Agents-Part VI
The Penicillins
ALAN J. WRIGHT, M.D.
The penicillin family of antibiotics remains an important
part of our antimicrobial armamentarium. In general,
these agents have bactericidal activity, excellent distribu-
tion throughout the body, low toxicity, and efficacy against
infections caused by susceptible bacteria. The initial intro-
duction of aqueous penicillin G for treatment of strepto-
coccal and staphylococcal infections was an important
pharmacologic landmark. The emergence of penicillinase-
producing Staphylococcus aureus prompted the develop-
ment of the penicillinase-resistant penicillins (for example,
methicillin, oxacillin, and nafcillin), in which an acyl side
chain prevented disruption of the f3-lactamase ring. Sub-
sequently, the aminopeniciIlins (ampicillin, amoxicillin,
and bacampicillin) were developed because of the need for
gram-negative antimicrobial activity. Their spectrum ini-
tially included Escherichia coli, Proteus mirabilis, Shigella ,
T he discovery of penicillin is credited to Dr. Alexander
Fleming, who noted, in 1929, that a culture of Penicil-
lium notatum produced a substance that inhibited the
growth of Staphyloco ccus aureus. This substance was
called penicillin. Because of difficulties in production and
purification, penicillin was not used in the treatment of
infections until 1941, when Dr. Howard W. Florey and
coworkers in England were able to produce sufficient
quantities of penicillin for their initial human clinical trials.
In subsequent clinical trials conducted in the United States
at the Mayo Clinic and Yale University, penicillin was
successfully used to treat streptococcal and gonococcal
infections. Since then, penicillin has been widely used for
the treatment of various infections, and numerous penicil-
lins have been discovered or synthesized. Thus, the peni-
cillins have been one of the largest and most important
classes of antibiotics (Table 1).
Throughout the years, penicillin has remained a useful
antibiotic against many bacteria for which it was initially
introduced. The emergence of penicillinase-producing
staphylococci, however, prompted the development of the
penicillinase-resistant penicillins, which have an acyl side
chain that prevents disruption of the p-lactamase ring. Fur-
From the Division of Infectious Diseases and Internal Medicine ,
Mayo Clinic Rochester, Rochester , Minnesota.
Individual reprints of this article are not available. The entire Sym-
posium on Antimicrobial Agents will be available for purchase as a
bound booklet from the Proceedings Editorial Office at a later date .
Mayo Clin Proc 1999;74:290-307
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Salmonella, Listeria, Haemophilus, and Neisseria. The
search for a penicillin with additional antimicrobial ac-
tivity against the Enterobacteriaceae and Pseudomonas
aeruginosa led to the development of the carboxypen-
icillins (carbenicillin and ticarcillin) and the ureidopeni-
cillins (mezlocillin, azlocillin, and piperacillin). Finally,
the combination of a f3-lactamase inhibitor (c1avulanic
acid, sulbactam, or tazobactam) and an aminopenicillin,
ticarcillin, or piperacillin has further extended their anti-
bacterial spectra by inhibiting certain f3-lactamases (non-
group 1) of resistant bacteria. The development of an ideal
penicillin that is rapidly bactericidal, nonsensitizing, non-
toxic, bioavailable, and resistant to f3-lactamases and that
has a high affinity for penicillin. binding proteins remains
the goal.
Mayo Clin Proc 1999;74:290-307
ther changes in the side chains led to the discovery of
penicillins that have activity against gram-negative aerobic
bacteria, including Pseudomonas aeruginosa. These peni-
cillins included the aminopenicillins, carboxypenicillins,
ureidopenicillins, and penicillins combined with p-lac-
tamase inhibitors. In the development of these various
penicillins, the goal has been an ideal penicillin that would
be rapidly bactericidal, nonsensitizing, nontoxic, bioavail-
able, and resistant to p-lactamases and would have a high
affinity for penicillin-binding proteins. This article is an
overview of the various penicillins that are currently avail-
able for clinical use.
STRUCTURE AND MODE OF ACTION
The basic structure of penicillin (6-aminopenicillanic acid)
consists of a thiazolidine ring, an attached p-lactam ring,
and a side chain (Fig. 1). Manipulations of the side chain
have altered the antibacterial spectrum, p-Iactamase sus-
ceptibility, and pharmacokinetic properties. These changes
have resulted in an increased antibacterial spectrum against
gram-negative bacteria, including P. aeruginosa. Bacterial
p-lactamase may hydrolytically attack the p-lactam ring
and render the penicillin inactive. This process can be
prevented by adding certain acyl side chains that sterically
protect the p-lactam ring or by combining the penicillin
with a p-lactamase inhibitor (clavulanic acid, sulbactam, or
tazobactam) that inactivates certain of the bacterial ~­
lactamases. The structures of the various penicillins are
depicted in Figure 2.
290 © 1999 Mayo Foundation f or Medical Education and Research
Mayo Clin Proc, March 1999,Vol 74 The Penicillins 291

Although the mode of action of the penicillins has not Table I.-Classification of the Penicillins
been completely determined, it includes inhibition of syn-
Representative
thesis of the bacterial cell wall and activation of the endog- Type and generic name brand names
enous autolytic system.' The action of the penicillins ne-
Natural penicillins
cessitates the presence of a cell wall that contains Penicillin G (benzylpenicillin) Pfizerpen
peptidoglycans. In actively dividing bacteria, the penicil- Penicillin G procaine Wycillin
lins inhibit certain enzymes that create the cross-linkage Penicillin G benzathine Bicillin L-A
between the peptide chains and thereby prevent the devel- Phenoxymethyl penicillin
opment of the normal peptidoglycan structure. These (penicillin V) Pen·Vee K
enzymes (transpeptidase, carboxypeptidase, and endopep- Penicillinase-resistant penicillins
tidase), located beneath the cell wall, are termed the "peni- Methicillin* (Staphcillin)
Oxacillin Bactocill, Prostaphlin
cillin-binding proteins." The ability to penetrate the cell
Nafcillin Nafcil, Unipen
wall and the degree of affinity to these penicillin-binding Cloxacillin Cloxapen
proteins determine the activity of the penicillin on the Dicloxacillin Dynapen, Pathocil
bacterium. Various bacteria differ in their type and con- Aminopenicillins
centration of penicillin-binding proteins and the permeabil- Ampicillin Omnipen
ity of their cell walls to antibiotics; hence, they have differ- Amoxicillin Amoxil, Wymox
ing antibiotic susceptibilities. In addition, penicillins have Bacampicillin Spectrobid
been found to activate the endogenous autolytic system of Carboxypenicillins
bacteria, a process that initiates cell lysis and death.' Carbenicillin Geopen
Ticarcillin Ticar
PHARMACOLOGIC PROPERTIES Ureidopenicillins
Mezlocillin Mezlin
Many publications have reviewed the pharmacologic prop-
Azlocillin* (Azlin)
erties of the various penicillins. These properties and the Piperacillin Pipracil
usual recommended dosages for adult patients will be sum-
Penicillin plus f3-lactamase
marized herein and in Tables 2, 3, and 4. Because most of inhibitors
these drugs are destroyed by gastric acid, they are unsuit- Amoxicillin-clavulanic acid Augmentin
able for oral use and must be administered parenterally. Ampicillin-sulbactam Unasyn
Those agents that are not destroyed in the stomach are Ticarcillin-clavulanic acid Timentin
Piperacillin-tazobactam Zosyn
absorbed in the duodenum and reach peak levels in 1 to 2
hours. The presence of food often delays the peak levels *Discontinued in the United States.
and reduces the amount of drug absorbed. Penicillin bind-
ing to serum proteins is variable, ranging from 15% for the
aminopenicillins to 97% for dicloxacillin. The serum half- penicillins have a 20 to 30% rate of biliary excretion; thus,
life is short-approximately 30 minutes for penicillin G biliary levels are high, and less adjustment of the daily
and 60 minutes for the extended-spectrum penicillins. Be- dosage is needed for renal dysfunction. All penicillins
cause of this short half-life, the penicillins must be admin- have excellent penetration into most tissues except the
istered at short intervals, usually every 4 hours.
These drugs are not metabolized or only minimally
metabolized, and all but a few are excreted primarily by the
kidneys through glomerular filtration and tubular secretion.
o
II S CH3
Probenecid blocks renal excretion and thereby causes in- R1 -~H -+lC -HC ". ...... C::::: -
I 2 I 1 I O• '3
L
creased serum levels of penicillin. These antibiotics (ex- cfC-N-C-COOH
cept for the penicillinase-resistant penicillins) are removed
by both peritoneal dialysis and hemodialysis. In patients
with severe renal dysfunction, adjustments in the daily
1-thiazolidine ring
dosage are usually necessary to prevent excessive levels
and subsequent toxicity. The amount excreted by the liver 2-,8-lactam ring
is minimal for most penicillins, except nafcillin, oxacillin, ~-acyl side chain
and the ureidopenicillins. Because of their biliary excre-
tion, nafcillin and oxacillin do not necessitate dosage ad-
justments in patients with renal dysfunction. The ureido- Fig. 1. Basic chemical structure of penicillin.

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
292 The Penicillins Mayo Clin Proc, March 1999, Vol 74

the penicillin by various p-Iactamases. These enzymes

0 are excreted outside the cell wall by gram-positive bac-
R1-l!-NH-HC -Hc. ,s.... ~ teria and in the periplasmic space by gram-negative bac-
r!'b-N-o-<:oOH teria. These p-Iactamases inactivate penicillin by hydro-
Basicpenicillin structure Iytically disrupting the p-Iactarnase ring. An example of
this mechanism is the resistance of S. aureus to penicillin
R, R, R,

au ot
G or production of p-Iactamase by one of the members

c-
of the Enterobacteriaceae. Bacteria may also develop re-
- U I sistance to penicillin by decreasing the permeability of

t;a
'0 C~
Panic/lUnG Oxaclllln their cell walls to penicillins or by developing new pen-
icillin-binding proteins that have decreased affinity for
Oo-cH· O~H'H. CN-SOPH
MezIocillin • penicillins. Examples of the last-mentioned mecha-
PaniciliinV nism are the resistance of S. aureus to methicillin and
O~
Ampicillin
the increasing resistance of Streptococcus pneumoniae to
Oo-cH
- &.
HO~
- JH. to penicillin.
Phenethicillin AmoxielJlin ~y
QOC~ C NH
AzIocillin
NATURAL PENICILLINS
The natural penicillins were the first agents in the penicillin
'I '\
Or~o,Na family to be introduced for clinical use. Benzylpenicillin
Mathie;"in
~ -
Carbenicillin
O~NH or penicillin G, the parent drug of this family, has been used
extensively since its introduction. Penicillin G can be
bo
s~ ():
administered orally, intravenously, intrathecally, or as a
'I '\
(J-t S boNa
repository salt intramuscularly. The advantages ofpenicil-
lin G are its low cost, easy administration, excellent tissue
:-. /,
Nafcillin
Ticarcillin ~5 penetration , and favorable therapeutic index. In contrast ,
Piperacillin
the disadvantages are its degradation by gastric acid, its
destruction by bacterial p-Iactamases, and its association
Fig. 2. Chemical structures of the penicillin family of antimicro- with the development of an allergic reaction in about 10%
bial agents. of patients.

prostate, eye, and uninflamed cerebrospinal fluid. Ad-
equate penicillin levels in the cerebrospinal fluid are attain-
able when the meninges are inflamed . The variations in the
distribution of various penicillins throughout the body de-
pend on their molecular configuration and protein binding.
SP ECTRUM OF ACTIVITY AND INDICATIONS
In comparison with other families of antibiotics. the peni-
cillins have one of the widest spectrums of antibacterial
activity. This wide range of activity and the various infec-
tious organisms for which penicillins are a primary choice
are reflected in Table 5. Despite the proliferation of new
antibiotics , the penicillin family remains highly active
against many bacteria (Table 6) and is an important choice
for numerous infections. Over the years, however, the
penicillins have been replaced by other antibacterial agents
for some indications because of the development of bacte-
rial resistance.
BACTERIAL RESISTANCE
Bacteria may develop resistance to penicillins by several
mechanisms, the most important of which is inactivation of
Aqueous Crystalline Penicillin G
Aqueous crystalline penicillin G is often used for its
rapid effect and its high serum concentration. For serious
infections such as endocarditis or meningitis caused by
susceptible organisms. penicillin G should be administered
intravenously . A continuous intravenous infusion of 20 to
24 million U of aqueous penicillin G is the most cost-
effective intravenous treatment and yields high steady-state
serum levels. Less commonly , penicillin G is administered
intramuscularly and achieves a maximal plasma concentra-
tion within 30 to 60 minutes. The drug becomes undetect-
able in plasma within 3 to 6 hours, depending on the size of
the dose. Penicillin can be administered intramuscularly as
a repository salt (procaine or benzathine) to achieve a
longer duration (hours or days) of maximal levels. Penicil-
lin G can also be given orally, but because it is degraded by
gastric acid, only low serum concentrations are attained.
An oral preparation such as phenoxymethyl penicillin
should be used preferentially when an orally administered
natural penicillin is indicated.
Penicillin G has a half-life of approximately 30 minutes,
which increases to about 10 hours when severe renal failure

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Mayo Clin Proc, March 1999, Vol 74 The Penicillins 293

Table 2.-Comparison of Pharmacologic Properties and Costs of Penicillin, Aminopenicillins

With and Without ~-Lactamase Inhibitors, and Penicillinase-Resistant Penicillins'"
Oral Protein Half- Route Removal Dose
Type of absorption binding life of by change for Route of Cost per
penicillin (%) (%) (h) excretion dialysis renal failure administration daily doset
Penicillin G 45-68 0.5 Renal Yes Yes i.m.i i.v. $ 5.30-20 million U
Penicillin V 60-73 75-89 0.5 Renal Yes Minimal Oral $ 0.96-500 mg q.i.d.
Ampicillin 30-55 15-25 0.7-1.4 Renal Yes Yes Oral, i.m., i.v. $ 0.82-500 mg q.i.d,
$16.29-12 g i.v,
Ampicillin-
sulbactam 15-25 0.7-1.4 Renal Yes Yes i.m.,i.v. $55.88-12 g i.v.
Amoxicillin 75-90 17-20 0.7-1.4 Renal Yes Minimal Oral $ 0.89-500 mg q.i.d.
Amoxicillin-
clavulanic acid 75-90 17-20 0.7-1.4 Renal Yes Minimal Oral $12.95-500 mg q.i.d,
Cloxacillin 37-60 90-96 0.3-0.9 Renal, Minimal No Oral $ 1.11-500 mg q.i.d.
partially
hepatic
Dicloxacillin 35-76 95-97 0.3-0.9 Renal, Minimal No Oral $ 1.68-500 mg q.i.d,
partially
hepatic
Nafcillin Poor, erratic 70-90 0.5-1.5 Hepatic Minimal No i.rn., i.v, $47.42-12 g i.v.
Oxacillin 30-35 89-94 0.3-0.9 Hepatic Minimal No Oral, i.m., i.v, $68.10-12 g i.v,
Methicillin:j: Minimal, 30-50 0.3-0.9 Renal Minimal Yes i.m., i.v, :j:
acid labile
*Lm. = intramuscular; i.v. = intravenous; q.i.d, =four times a day.
t Average wholesale costs to pharmacy ("Red Book"), 1998.
:j:Discontinued in the United States.

or anuria develops. Although primarily excreted by the
kidneys, penicillin G is also excreted by the liver, as dem-
onstrated by near-zero clearance of the drug when severe
renal failure and hepatic failure coexist. Approximately
50% of penicillin G is bound to plasma proteins. Both
sodium and potassium penicillin G salts are available; they
provide 2.0 mEq of sodium or 1.7 mEq of potassium per 1
million U administered, respectively. These added
amounts of sodium or potassium must be considered in
patients with cardiac or renal dysfunction.

Table 3.-Comparison of Pharmacologic Properties and Costs of Carbenicillin, Ticarcillin,

Ticarcillin-Clavulanic Acid, Mezlocillin, Piperacillin, Piperacillin-Tazobactam, and Azlocillin'"

Accumulation Urinary
Sodium Protein Half- Distribution of drug excretion Biliary
Type of content binding life volume with renal in 24h excretion Route of Daily
penicillin (mEq/g) (%) (h) (L) dysfunction (%) (%) administration cost]
Carbenicillin:j: 4.7 50-60 1.1 12-16 Yes 90-95 0.2 p.o., i.m., i.v. :j:
Ticarcillin 5.2 50-60 1.2 14-16 Yes 80-90 3-5 i.m., i.v. $ 52.90§
Ticarcillin-
clavulanic
acid 5.2 50-60 1.2 14-16 Yes 80-90 3-5 i.v. $ 60.4Of
Mezlocillin 1.85 20-40 1.0 18-19 Minimal 50-70 20-30 i.m., i.v, $ 77.04§
Piperacillin 1.85 15-20 1.0 16-19 Minimal 60-80 20-30 i.m.i i.v. $107.00§
Piperacillin-
tazobactam 1.85 15-20 1.0 16-19 Minimal 60-80 20-30 i.v, $ 66.44~
Azlocillin:j: 2.17 20-40 1.0 18-19 Minimal 50-70 20-30 i.m., i.v. :j:
*Lm. = intramuscular; i.v, =intravenous; p.o. =perorally.
t Average wholesale costs to pharmacy ("Red Book"), 1998.
:j:Discontinued in the United States.
§Daily dose = 18 g.
fDaily dose = 12.4 g.
~Dosage = 3.375 g every 6 h.

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294 The Penicillins Mayo Clin Proc, March 1999, Vol 74

Table 4.-Usual Recommended Dosages of Penicillins for Adult Patients*

Route of administration
Agent Oral Intramuscular Intravenous
Penicillin G 250-500 mg q.i.d. 2-3 million U every 6 h 1-4 million U every 4 h
Penicillin G procaine 300 ,000-2 .4 million U
every 6-12 h
PhenoxymethyI
penicillin 250-500 mg q.i.d.
Cloxacillin 250-500 mg q.i.d.
DicloxacilJin 125-500 mg q.i.d.
Oxacillin 250-1,000 mg q.i.d. 500-1 ,000 mg every 6 h 1-2 g every 4-6 h
Nafcillin 250-500 mg every 6 h 1-2 g every 4-6 h
Ampicillin 500-1,000 mg q.i.d. 500-750 mg every 6 h 1-3 g every 4-6 h
Ampicillin-sulbactam 1.5-3 g every 6 h 1.5-3 g every 6 h
Amoxicillin 250-500 mg tj.d.
875 mg b.i.d,
Amoxicillin-clavulanic
acid 250-500 mg t.i.d,
Ticarcillin I g every 6 h 2-4 g every 4-6 h
Ticarcillin-clavulanic
acid 3.1 g every 4-6 h
Azlocillin 1-2 g every 6 h 2-4 g every 4-6 h
Mezlocillin 1-2 g every 6 h 2-4 g every 4-6 h
Piperacillin 1-2 g every 6 h 2-4 g every 4-6 h
Piperacillin-tazobactam 3.375-4.5 g every 4-6 h
*bj.d. = twice a day; q.i.d. = four times a day; t.i.d. = three times a day.

Penicillin G Procaine
Penicillin G procaine is used when serum levels of the
drug are needed for hours but the intravenous route is not
indicated or not available. Penicillin G procaine (an equal
molar mixture of penicillin and procaine) is administered
intramuscularly one to three times a day and is available in
600,000-, 1.2 million-, or 2.4 million-U cartridges. Penicil-
lin G procaine is available in two forms-aqueous crystal-
line salt or 2% aluminum monostearate-and is considered
less painful on administration than intramuscularly admin-
istered penicillin G. It is absorbed comparatively slowly
after intramuscular injection; maximal plasma concentra-
tions are achieved within 2 to 4 hours, and detectable levels
may be present for 24 hours. A dose of 600,000 U achieves
a peak level of 1.5 U/mL at 2 to 3 hours and 0.2 U/mL at 24
hours.
Penicillin G procaine is more likely to be allergenic than
is aqueous crystalline penicillin G. In the past, the main
indication for its use was the treatment of genitourinary
gonorrhea, for which a dose of 2.4 million U was admin-
istered in each buttock, along with 1 g of probenecid oral-
ly before the injections. Because of an increasing fre-
quency of penicillinase-producing Neisseria gonorrhoeae,
however, penicillin G procaine has been replaced by
ceftriaxone for empiric treatment of gonorrhea. Therefore,
penicillin G procaine should be used for treatment of gon-
orrhea only when results of susceptibility tests are known
and the p-lactamase test is negative. In the past, penicillin
G procaine was used for the treatment of uncomplicated
pneumococcal pneumonia in dosages of 300,000 U given
once or twice each day, but its use has decreased because of
the emergence of penicillin-resistant S. pneumoniae. Neu-
rologic adverse reactions have been noted with penicillin G
procaine when the procaine is unintentionally injected into
the bloodstream.' Penicillin G procaine is contraindicated
in patients with an allergy to procaine.
Penicillin G Benzathine
Penicillin G benzathine (benzathine penicillin, also
known as Bicillin L-A) is used when low levels of pen-
icillin are indicated for prolonged periods for treatment
of certain infections. This mixture of benzathine and peni-
cillin allows the slow release of drug from an intramus-
cular deposit, and low levels persist for 3 to 4 weeks. A
dose of 1.2 million U results in levels of 0.15 U/mL on
day 1, 0.03 U/mL on day 14, and 0.003 U/mL on day 32. It
is available in 600,000-, 1.2 million-, and 2.4 million-U
cartridges.
Benzathine penicillin is primarily indicated for treat-
ment of early and latent stages of syphilis, therapy for
streptococcal cellulitis or pharyngitis, and prophylaxis
against ~-hemolytic streptococci in patients with previous

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Mayo Clin Proc, March 1999, Vol 74 The Penicillins 295

rheumatic fever or recurrent streptococcal cellulitis. A Table 5.-Microorganisms for Which a Penicillin
commercial mixture of procaine and benzathine peni- Is a Drug of Choice*
cillin, known as Bicillin C-R, is administered by some Microorganism Penicillin
physicians in situations in which high levels followed by
low levels of penicillin are needed. Bicillin C-R is avail- Gram-positive cocci
Enterococcus faecalis Penicillin G, usually plus
able in 300,000-, 600,000-, 1.2 million-, and 2.4 million-U (nonpenicillinase strain) an aminoglycoside
cartridges. A dose of 2.4 million U of benzathine penicillin Ei faecium Penicillin G, usually plus
for early syphilis and three weekly doses of 2.4 million U (nonpenicillinase strain) an aminoglycoside
for late latent syphilis have proved successful. Staphylococcus aureus
Nonpenicillinase strain Penicillin G or V
Penicillinase strain Oxacillin, nafcillin
Phenoxymethyl Penicillin S. epidermidis
Phenoxymethyl penicillin is an oral form of penicillin Nonpenicillinase strain Penicillin G or V
that resists degradation by gastric acid. The potassium salt Penicillinase strain Oxacillin, nafcillin
of phenoxymethyl penicillin (penicillin VK) is commonly Streptococcus pyogenes
(group A, B, C, or G) Penicillin G or V
used and achieves levels about twice that of orally adminis-
Viridans streptococci Penicillin G
tered penicillin G. It is available in 125-,250-, and 500-mg S. bovis Penicillin G
tablets (125 mg is equivalent to 200,000 U). Penicillin VK Anaerobic streptococci or
is absorbed in the upper part of the small bowel and pro- peptostreptococci Penicillin G
duces peak serum levels within 60 minutes; levels are S. (Pneumococcus) pneumoniae,
maintained for approximately 4 hours. A 500-mg dose penicillin-susceptible
(MIC <0.1 J.1g/mL) Penicillin G or V
results in a peak level of 3 to 5 ug/ml., Oral penicillin
Gram-negative cocci
preparations should not be substituted for parenteral ad-
Neisseria meningitidis Penicillin G
ministration when serious infections are present or when
high levels of penicillin are needed. They are primarily Gram-positive bacilli
Bacillus anthracis (anthrax) Penicillin G
indicated for mild infections that involve the throat, respi- Clostridium perjringens Penicillin G
ratory tract, or soft tissue, for which 250 mg to 1 g is C. tetani Penicillin G
administered four times a day. Erysipelothrix rhusiopathiae Penicillin G
Listeria monocytogenes Ampicillin plus
PENICILLINASE·RESISTANT PENICILLINS: an aminoglycoside
METHICILLIN, OXACILLIN, NAFCILLlN, Gram-negative bacilli
Proteus mirabilis Ampicillin
CLOXACILLIN, AND DICLOXACILLIN
Eikenella corrodens Ampicillin
After the initial success of the natural penicillins in the Fusobacterium Penicillin G
treatment of staphylococcal infections, the emergence of Leptotrichia bucca lis Penicillin G
penicillinase-producing staphylococci rendered penicillin Pasteurella multocida Penicillin G
G ineffective. This situation led to the development of Pseudomonas aeruginosa Ureidopenicillin plus
semisynthetic penicillinase-resistant penicillins with an an aminoglycoside
Spirillum minus Penicillin G
acyl side chain that sterically inhibits the action of penicil- Streptobacillus moniliformis Penicillin G
linase by preventing the opening of the ~-lactam ring (Fig.
Other
1). Methicillin was the first member of this group, fol- Actinomyces israelii Penicillin G
lowed by oxacillin, nafcillin, and two drugs for oral use- Borrelia burgdorferi
cloxacillin and dicloxacillin. These agents have been (Lyme disease) Amoxicillin
widely used and were considered the mainstay in the treat- Leptospira Penicillin G
ment of Staphylococcus infections until the emergence of Treponema pallidum (syphilis) Penicillin G
T. pallidum subsp pertenue
methicillin-resistant Staphylococcus in the 1980s. These (yaws) Penicillin G
penicillinase-resistant penicillins have activity against both
Streptococcus and Staphylococcus species but no activity *MIC = minimal inhibitory concentration.
against gram-negative bacteria. Although on the basis of
data on minimal inhibitory concentrations these agents are lin in empiric therapy for presumed streptococcal infec-
less active than penicillin G against streptococci, the anti- tions is unnecessary when the latter is used.
bacterial activity is sufficiently high to eradicate all strepto- Over time, staphylococci resistant to these penicillinase-
cocci except the enterococci. Therefore, double coverage resistant penicillins have emerged. These bacteria are
with both penicillin G and a penicillinase-resistant penicil- called methicillin-resistant staphylococci. This resistance

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296 The Penicillins Mayo Clin Proc, March 1999,Vol 74

Table 6.-ln Vitro Susceptibility Results for Gram-Negative Bacteria

Comparing Various Penicillins (Mayo Clinic, 1997)
Strains inhibited (%) by breakpoint
minimal inhibitory concentration (J.Lg/mL)
Ticarcillin-
Strains Ampicillin- clavulanic Piperacillin-
tested Ampicillin Mezlocillin sulbactam acid tazobactam
Bacterial species (no.) (::>8) (::>16) (::>8/4) (::>16/2) (::>16/4)
Escherichia coli 3,486 69 74 87 82 99
Proteus mirabilis 4,337 95 98 99 99 100
Klebsiella pneumoniae 933 1 87 92 92 98
Citrobacter freundii 219 11 74 69 71 83
Serratia marcescens 205 1 92 8 90 94
Enterobacter cloacae 508 4 80 41 70 85
Pseudomonas aeruginosa 1,423 0 82 0 85 95
(::>64)* (::>64/2)* (::>64/4)*
Acinetobacter calcoaceticus 203 36 31 99 91 88
Stenotrophomonas maltophilia 265 0 8 0 58 31
*Minimal inhibitory concentration susceptibility cutoff levels used for P . aeruginosa isolates.

is based on the chromosomally mediated production of a
new penicillin-binding protein (2a) that has decreased af-
finity for these penicillins.' These resistant staphylococci
have become widespread throughout the United States and
have necessitated the use of vancomycin for empiric treat-
ment when their prevalence is known to be high. When the
results of susceptibility testing for a certain Staphylococcus
strain are known and sensitivity has been demonstrated to
either a penicillinase-resistant penicillin or penicillin G,
these antibiotics should be used preferentially over
vancomycin because of their more rapid killing, reduced
cost, and less toxicity.
Methicillin was the first of the semisynthetic penicillin-
ase-resistant penicillins to be introduced into clinical use.'
Because of inactivation by gastric acid, it was used only
parenterally. Methicillin has the lowest protein binding
(38%) of these agents and is excreted rapidly by the kid-
neys. The recommended dosage was 1 to 2 g every 4 hours
(maximal total daily dose, 12 g). Methicillin was highly
efficacious against staphylococcal infections, but because
of the occurrence of interstitial nephritis, its use has been
discontinued in the United States.
Nafcillin and oxacillin have replaced methicillin and
have been found to be similar in effectiveness. Both drugs
are highly protein bound (90% and 94%, respectively) and
primarily excreted through the liver. Dosages of 2 g every
4 to 6 hours are usually recommended for serious infec-
tions. Reduction in dosage for renal dysfunction is unnec-
essary because of their biliary excretion. No available
evidence supports one penicillinase-resistant penicillin
over another; thus, selection of an agent should be based on
cost and availability.
Oral administration is suitable for several of these peni-
cillinase-resistant penicillins-oxacillin, cloxacillin, and
dicloxacillin. Although oxacillin is absorbed orally, its
serum levels are only one-third to one-half those of
cloxacillin and dicloxacillin; hence, these last two antibiot-
ics are preferred. Cloxacillin and dicloxacillin are well
absorbed; their peak serum levels are 7 to 14 and 15 to 18
ug/ml., respectively, for a 500-mg dose. In general, the
recommended dosage is 250 to 1,000 mg four times a day,
depending on the type of infection being treated. These
orally administered penicillinase-resistant penicillins are
primarily indicated for mild infections that involve the skin
and soft tissue. Less commonly, these agents are used for
suppression of staphylococcal infections that have recently
been treated parenterally in clinical cases in which cure of
the infection seems unlikely.
EXTENOEO-5PECTRUM PENICILLINS
The need for penicillins with extended activity against
gram-negative bacilli prompted further manipulation of the
basic penicillin structure (Fig. 2). The result was the devel-
opment of the aminopenicillins, carboxypenicillins, and
ureidopenicillins. Initially, the aminopenicillins (for ex-
ample, ampicillin and amoxicillin) were developed, fol-
lowed by the extended-spectrum penicillins: carbenicillin,
ticarcillin, mezlocillin, azlocillin, and piperacillin. These
antibiotics do not resist the action of penicillinase produced
by staphylococci and are variably resistant to ~-lactamases
of gram-negative bacilli. Their added antimicrobial activ-
ity is derived from greater penetration through the outer
membrane of gram-negative bacteria and higher affinity
for penicillin-binding proteins.

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
Mayo Clin Proc, March 1999, Vol 74
Susceptibility data for gram-negative bacteria from
studies of ampicillin, mezlocillin, ampicillin-sulbactam,
ticarcillin-clavulanic acid, and piperacillin-tazobactam in
our Clinical Microbiology Laboratory are shown in Table
6. Of note, the susceptibility cutoff levels for the pen-
icillins may vary among laboratories and thereby yield
different percentages of strains inhibited. Susceptibility
results may also vary among institutions because of the
pattern of antibiotic usage, patient population, and endemic
bacterial strains. Clinicians must become familiar with the
susceptibility data at their institutions for the appropriate
selection of antibiotics for empiric treatment of serious
infections.
Aminopenicillins: Ampicillin, Amoxicillin, and
Bacampicillin
The first group of penicillins that had activity against
gram-negative bacteria was the aminopenicillins. These
agents not only extended the antimicrobial spectrum but
also served as a prototype for the development of other
penicillins (carboxypenicillins and ureidopenicillins) with
further wide-spectrum activity. Ampicillin was formulated
by the addition of an amino group to the basic benzyl-
penicillin molecule. Subsequently, two other aminopen-
icillins were developed-amoxicillin and bacampicillin.
Certain members of the aminopenicillin group are avail-
able in other countries but not in the United States
(hetacillin, cyclacillin, pivampicillin, talampicillin, and
epicillin).
After its introduction, ampicillin was found to have
more activity than penicillin G against enterococci and
Haemophilus influenzae but somewhat less activity against
S. pyogenes, S. pneumoniae, Neisseria species, and
Clostridium species. Unlike penicillin G, however,
ampicillin initially had activity against many gram-nega-
tive bacterial strains, including Escherichia coli, Proteus
mirabilis, Salmonella, Shigella, Listeria, and ~-lactamase­
negative H. influenzae. Ampicillin has little or no activity
against Klebsiella, Serratia, Enterobacter, and P.
aeruginosa. More recently, because of increasing bacterial
resistance, ampicillin has been shown to have less activity
against some strains of E. coli, Salmonella, Shigella, and N.
gonorrhoeae. Consequently, ampicillin is no longer the
drug of choice for the empiric treatment of childhood men-
ingitis, Salmonella or Shigella enteritis, and gonococcal
infections. Other antibiotics have now been recommended
to replace ampicillin for treatment of these infections-for
example, a third-generation cephalosporin for bacterial
meningitis, a quinolone for Salmonella or Shigella enter-
itis, and ceftriaxone for gonococcal infections. Because of
the low cost and safe profile of toxicity of ampicillin,
however, it can be used for treatment of some of these
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
The Penicillins 297
infections if the susceptibility tests have shown that the
infecting bacterial strain is sensitive.
Because ampicillin is stable in gastric acid and absorp-
tion is unaffected by food, it is suitable for oral use. After
oral administration of ampicillin, peak serum levels are
noted in approximately 2 hours but seldom exceed 6 Ilg/
ml.; thus, it is limited to treatment of mild infections. For
serious infections, ampicillin should be administered intra-
venously in a dosage of 2 to 3 g every 4 hours. Only
approximately 15 to 25% of ampicillin is protein bound,
and the drug is rapidly excreted through the kidneys. High
concentrations of the drug are found in urine and bile,
provided no obstruction or dysfunction is present.
Amoxicillin is closely related to ampicillin in both
chemical structure and antibacterial activity (Fig. 2).5 It is
administered only orally and has more complete absorption
than ampicillin; hence, the result is twice the serum level
for comparable doses. With this more complete absorp-
tion, less drug remains in the intestinal tract, and the fre-
quency of diarrhea is thereby decreased. Because of the
greater bioavailability, amoxicillin has been replacing
ampicillin when an orally administered aminopenicillin is
indicated. It is primarily used for treatment of infections of
the respiratory tract (such as otitis media, sinusitis, and
bronchitis) caused by susceptible bacteria, but amoxicillin
is also used for treatment of infections of the urinary tract
caused by sensitive strains of Enterobacteriaceae. Because
of the consistent absorption of amoxicillin, some physi-
cians have recently recommended it for clinical situations
in which orally administered penicillin G had been indi-
cated. An example of this application is the revised Ameri-
can Heart Association guidelines for the prevention of
bacterial endocarditis." These guidelines recommend the
administration of amoxicillin, 2 g orally 1 hour before
dental procedures, rather than penicillin VK.
Adverse effects from amoxicillin are similar to those
associated with ampicillin-primarily, hypersensitivity re-
actions and rash. The recommended dosage for amox-
icillin is usually 250 to 500 mg three times a day except for
endocarditis prophylaxis, for which a 2-g dose is indicated.
After administration of 250-mg and 500-mg tablets, peak
serum levels of 3.5 to 5.0 ug/ml, and 5.5 to 11.0 ug/ml.,
respectively, are achieved.
Bacampicillin is another aminopenicillin with efficacy
similar to that of ampicillin and amoxicillin, but it has not
been shown to have additional advantages. Bacampicillin
is in an inactive form that is hydrolyzed to ampicillin af-
ter absorption. When bacampicillin is used, serum levels
are about twice those of generic ampicillin and equal to
those of amoxicillin. Bacampicillin has been shown to be
effective in the treatment of bronchitis, sinusitis, and otitis
media.'
298 The Penicillins
Carboxypenicillins: Carbenicillin and Ticarcillin
With the emergence of more resistant gram-negative
bacilli and the increasing frequency of P. aeruginosa as a
nosocomial pathogen, penicillins with more antibacterial
activity were needed. Substitution of a carboxyl group for
the amino group on ampicillin produced carbenicillin (Fig.
2). Subsequently, substitutions on carbenicillin produced
ticarcillin, which further increased the activity against
gram-negative bacilli including P. aeruginosa. Both these
antibiotics are classified as carboxypenicillins and are ex-
tended-spectrum penicillins.
Both carbenicillin and ticarcillin have an antibacterial
spectrum that includes the activities of ampicillin; in addi-
tion, they have activity against indole-positive Proteus,
Enterobacter, Providencia, Morganella, and certain strains
of P. aeruginosa. Klebsiella and some strains of Serratia
are not inhibited by carbenicillin or ticarcillin and therefore
may overgrow during treatment. Unlike ampicillin, car-
benicillin and ticarcillin are not notably active against the
enterococci because of poor binding to their penicillin-
binding proteins. Although both carboxypenicillins have
activity against P. aeruginosa, ticarcillin is 2 to 4 times
more active than carbenicillin in vitro.
Both carbenicillin and ticarcillin can be administered by
either the intramuscular or the intravenous route. An oral
preparation of carbenicillin (carbenicillin indanyl sodium)
is available but has had limited clinical use because of low
serum levels, potential for developing bacterial resistance,
and availability of the fluoroquinolones. Serious infec-
tions should always be treated parenterally-preferably,
intravenously. Both carbenicillin and ticarcillin have a
short serum half-life (approximately 1 hour), are excreted
by the renal tubules, and have excellent tissue distribution.
Because aminoglycosides may be inactivated by high lev-
els of carboxypenicillins, they must not be mixed together
in the same solution but rather should be administered
separately.
With increased use of the carboxypenicillins, certain
toxicities became well known: a prolonged bleeding time
attributable to platelet dysfunction, hypokalemia, and so-
dium excess. These toxic effects were more common with
use of carbenicillin than ticarcillin primarily because of the
higher doses of carbenicillin needed for treatment of infec-
tions. Carbenicillin contains 4.7 mEq (108 mg) and
ticarcillin contains 5.2 mEq (120 mg) of sodium per gram
of drug administered. This added sodium load must be
carefully considered when a carboxypenicillin is selected
for treatment. Serum potassium levels must be carefully
monitored when these antibiotics are being administered.
Both carbenicillin and ticarcillin have been efficacious
for treatment of various infections including gram-negative
bacteremia, infections of the urinary tract, infections of the
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
Mayo Clin Proc, March 1999, Vol 74
respiratory tract, and osteomyelitis caused by sensitive or-
ganisms. The primary indication for use of the carboxy-
penicillins has been the treatment of P. aeruginosa in-
fections. The combination of an aminoglycoside with
carbenicillin or ticarcillin has been advocated for treatment
of severe Pseudomonas infections because many strains
are synergistically killed and use of this regimen will pre-
vent the emergence of resistance." Use of a carboxy-
penicillin alone for the treatment of Pseudomonas infec-
tions had often resulted in the development of resistance.
Superinfection with Klebsiella, S, marcescens, and Can-
dida may also occur during treatment. For treatment of
infections caused by non-Pseudomonas gram-negative
bacilli, lower dosages-6 to 12 g/day of ticarcillin and 12
to 18 g/day of carbenicillin-are recommended. For treat-
ment of P. aeruginosa infections, however, maximal dos-
ages of 18 to 24 g/day and 24 to 36 g/day have been
recommended for ticarcillin and carbenicillin, respectively.
Carbenicillin has certain disadvantages-lower activity
and thus need for high dosages, high sodium load, platelet
dysfunction, and hypokalemia-that decreased its use, and
the parenteral form is currently not available for use in the
United States. Replacement with ticarcillin or a ureido-
penicillin has avoided some of these problems and pro-
vided greater antibacterial activity.
Ureidopenicillins and Piperazine Penicillin:
Mezlocillin, Azlocillin, and Piperacillin
Although the carboxypenicillins have an extended spec-
trum of activity over the aminopenicillins, a need still
existed for further gram-negative bacterial activity, en-
hanced anti-Pseudomonas activity, and fewer adverse reac-
tions. Therefore, a piperazine penicillin and the ureido-
penicillins were developed. Included in this group of
antibiotics are mezlocillin (Mezlin), azlocillin (Azlin),
and piperacillin (Pipracil). These antibiotics are semisyn-
thetic penicillins derived from the ampicillin molecule with
acyl side-chain adaptations. These acyl side chains of
mezlocillin and azlocillin have a ureido- (urea) structure-
hence the name "ureidopenicillins" or, more specifically,
"acylureidopenicillins." Piperacillin, in addition to the
ureido- group, has a piperazine side chain attached to the
ampicillin parent molecule and, therefore, is more appro-
priately called an acylpiperazine penicillin. 10 Despite these
molecular differences, these three extended-spectrum peni-
cillins are known collectively as the ureidopenicillins.
Pharmacokinetics.-The ureidopenicillins are mono-
sodium salts that have a lower salt content per gram (1.85
to 2.17 mEq) than the disodium salts of carbenicillin (4.7
mEq) and ticarcillin (5.2 mEq) (Table 3). Because the
ureidopenicillins are not absorbed after oral administration,
they must be given parenterally. Pharmacokinetic studies
Mayo Clin Proc, March 1999, Vol 74 The Penicillins 299

have classified the ureidopenicillins in a first-order, two- Table7.-Summary of Adverse Reactions to Penicillins
compartment model. In comparison with carbenicillin and Adverse reaction Representative penicillin
ticarcillin, the ureidopenicillins have lower plasma protein
binding, shorter serum half-life, and greater volume of Allergic
Anaphylaxis Any penicillin
distribution (Table 3).11-13 They are minimally metabolized
Urticaria Any penicillin
(less than 10%) and are primarily excreted in an active Drugfever Any penicillin
form by glomerular filtration and tubular secretion. In Serumsickness Penicillin G
contrast to the carboxypenicillins, the ureidopenicillins Delayed hypersensitivity Any penicillin
have substantial biliary excretion (20 to 30%), which re- Electrolyte abnormalities
sults in high concentrations of antibiotic in the biliary tree. Sodium overload Carbenicillin
This biliary excretion results in a minimal increase of se- Hypokalemia Carbenicillin
rum half-life (from 1 to 4 hours) of the antibiotic during Gastrointestinal
renal dysfunction. During hemodialysis, 20 to 40% of a Nausea, vomiting Any penicillin
Diarrhea Any penicillin
dose is removed, a factor that must be considered when a Pseudomembranous colitis Any penicillin
ureidopenicillin is administered. The ureidopenicillins
Hepatic
penetrate tissues well and thus result in excellent tissue Increased transaminases Oxacillin, nafcillin,
concentrations, including in the cerebrospinal fluid in pa- carbenicillin
tients with inflamed meninges, and adequate levels in bone Cholestatic jaundice Ureidopenicillins
for treatment of osteomyelitis. Hematologic
The recommended dosages for the ureidopenicillins are Hemolytic anemia Any penicillin
similar to those for ticarcillin: 8 to 16 g/day for mild to Neutropenia Oxacillin, piperacillin, any
moderate infections and 18 to 24 g/day for severe to life- penicillin
Thrombocytopenia Piperacillin, any penicillin
threatening infections. Smaller dosages (1 to 2 g every 6 Platelet dysfunction Carbenicillin, any penicillin
hours) may be administered intramuscularly, but large
Neurologic
doses necessitate intravenous administration. The total Seizure Any penicillin
daily dosage is usually divided into 4- to 6-hour intervals. Dizziness, paresthesias Penicillin G procaine
Antibiotic levels measured 30 minutes after an intravenous Neuromuscular irritability Any penicillin
infusion of 1, 2, 3, and 5 g show concentrations of approxi- Renal
mately 40, 80, 110, and 230 flg/mL, respectively. Interstitial nephritis Any penicillin
An important pharmacokinetic property that must be Thrombophlebitis Nafcillin, oxacillin
kept in mind is the nonlinear dose-dependent feature of the
ureidopenicillins.":" Thus, increasing doses of these anti-
biotics result in nonlinear increased antibiotic levels and feature of these antibiotics. Specifically, the ureido-
decreased clearance. These findings are probably attribut- penicillins have in vitro activity against streptococci, en-
able to oversaturation of nonrenal clearance by the in- terococci, most Enterobacteriaceae, Pseudomonas, and
creased dosages. Excessive antibiotic levels can be many anaerobes, including Bacteroides fragilis, Fuso-
avoided by exercising caution when these agents are ad- bacterium, Clostridium, and peptostreptococci.P:" p-
ministered above the recommended dosages, especially in Lactamase-producing staphylococci or H. influenzae or-
those patients who have renal dysfunction. ganisms are resistant to the ureidopenicillins.
As with other members of the penicillin family, the In comparison with penicillin G or ampicillin, the
ureidopenicillins can cause adverse reactions (Table 7). ureidopenicillins are slightly less active against strepto-
These side effects are similar to those associated with cocci and enterococci but are more active against H.
carbenicillin and ticarcillin, but the frequency of hypo- influenzae or N. gonorrhoeae, which do not produce p-
kalemia, sodium overload, and prolonged bleeding time lactamase. Against the Enterobacteriaceae group, includ-
due to platelet dysfunction is less. ing most strains of Klebsiella, Enterobacter, and Serratia,
Antimicrobial Activity.-The ureidopenicillins have a the ureidopenicillins have greater activity and a wider spec-
wide spectrum of activity against many gram-positive and trum of activity in comparison with carbenicillin and
gram-negative bacteria. Their enhanced activity over other ticarcillin." Among the ureidopenicillins, piperacillin and
penicillins is attributable to their structure, which allows mezlocillin are more active against gram-negative bacilli
greater penetration of the cell wall and increased affinity than is azlocillin," but this finding may be clinically insig-
for penicillin-binding proteins. Preferential inhibitory ac- nificant. Because of significant resistance (approximately
tivity on the septum of dividing bacteria is another unusual 20 to 40%) by the Enterobacteriaceae;" use of the

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
300 The Penicillins
ureidopenicillins in single-drug empiric treatment of sep-
sis is questionable. Perhaps the major advantage of
the ureidopenicillins has been their enhanced activity
against P. aeruginosa. Piperacillin is more active than
azlocillin, which is more active than mezlocillin, against P.
aeruginosa.P-v-" In vitro studies against P. aeruginosa
demonstrated that piperacillin has activity that is twice that
of azlocillin, 4 times that of mezlocillin and ticarcillin, and
about 8 times that of carbenicillin. Although piperacillin
has more activity in vitro, the clinical significance of this
finding is unknown.
Two observed properties of the ureidopenicillins that
have caused some concern are the inoculum effect and the
reduced rate of killing. In vitro studies have demonstrated
that when a concentration of bacteria is increased from 103
to 107 colony-forming units per milliliter, the minimal in-
hibitory activity of the antibiotic increases substan-
tially.15.19.21 This inoculum effect has been consistently
noted with mezlocillin, piperacillin, and azlocillin when
tested against P. aeruginosa strains and also against some
strains of E. coli, Klebsiella, Enterobacter, and Mor-
ganella. This effect is probably related to the enhanced
sensitivity to ~-lactamase, which is produced in greater
amounts as the concentration of bacteria increases, or to
resistant subpopulations of bacteria that overgrow. The
second property of the ureidopenicillins that has caused
concern is the reduced rate of bactericidal activity. When
azlocillin and ticarcillin were tested with use of
morphologic studies, azlocillin produced elongated bacte-
rial forms with delayed or no lysis, whereas ticarcillin
caused only minimal cellular elongation and rapid lysis."
The clinical importance of both the inoculum effect and the
reduced rate of bacteriolytic activity is unclear.
Clinical Use.-The ureidopenicillins have an extended
spectrum of activity beyond the carboxypenicillins and
have certain advantages, including lower sodium load, less
frequent hypokalemia, reduced platelet dysfunction, mini-
mal dosage adjustment in patients with renal failure, and a
wider spectrum of antibacterial activity, especially against
Pseudomonas and Klebsiella. These advantages have con-
vinced many physicians to select the ureidopenicillins over
ticarcillin, but comparative clinical trials have not clearly
proved superiority.
As single agents, these antibiotics have been efficacious
in the treatment of pneumonia, bacteremia, infections of
the urinary tract, osteomyelitis, and soft tissue infec-
tions. 20 . 25 The ureidopenicillins are usually well tolerated;
however, bacterial resistance may develop in 10 to 15% of
patients during treatment. Although the ureidopenicillins
have more antibacterial activity than do the
carboxypenicillins, they have not shown clinical superior-
ity in the treatment of gram-negative infections. When the
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
Mayo Clin Proc, March 1999, Vol 74
ureidopenicillins have been used as single agents, treat-
ment failures have been noted in febrile patients with
neutropenia and in intra-abdominal infections.":" These
failures probably result from the incidence of primary re-
sistance (20 to 40%) among the Enterobacteriaceae for the
ureidopenicillins and their known inoculum effect. In
these two situations, a ureidopenicillin should be used in
conjunction with an aminoglycoside. This combination
has demonstrated in vitro synergistic inhibition against
gram-negative bacteria, including P. aeruginosa, and de-
creased development of bacterial resistance during treat-
ment. Like the carboxypenicillins, the ureidopenicillins
should not be directly mixed with an aminoglycoside but
rather administered at separate times. The primary indica-
tion for the ureidopenicillins in conjunction with an
aminoglycoside is for treatment of serious gram-negative
infections, especially those caused by P. aeruginosa. Nev-
ertheless, clinical studies in which the combination of
ticarcillin and amikacin was compared with the combina-
tion of piperacillin and amikacin in febrile patients with
neutropenia revealed no superior therapeutic efficacy."
Therefore, the selection of a ureidopenicillin (in conjunc-
tion with an aminoglycoside) should be based on the par-
ticular clinical situation, the results of in vitro susceptibility
tests, the cost of the antibiotic, and the pharmacokinetic
properties that may be advantageous. A narrow-spectrum
penicillin is usually preferred over an extended-spectrum
penicillin for treatment of an infection caused by a known
susceptible bacterium. Indiscriminate use of an extended-
spectrum penicillin will lead to excessive costs and antibi-
otic resistance and should therefore be avoided. Since the
development of third- and fourth-generation cephalospo-
rins and the fluoroquinolones, the use of extended-spec-
trum penicillins has decreased.
PENICILLINS PLUS ~-LACTAMASE INHIBITORS
Increasing the antibacterial spectrum of the penicillin de-
rivatives has long been a goal of antimicrobial research.
Because structural modification of the penicillin side chain
has had only limited success, new strategies for extending
the antibacterial spectrum of the penicillin family were
explored. Inasmuch as the primary mechanism of bacterial
resistance to the penicillins is through ~-lactamase produc-
tion, inactivation of these enzymes was the logical step.
Accordingly, a ~-lactamase inhibitor was combined with
certain penicillins. These ~-lactamase inhibitors act in two
ways: (I) by a high-affinity irreversible binding to the
catalytic site of the ~-lactamase (Fig. 3), which thereby
prevents the hydrolytic action on the penicillin," and (2) by
binding directly to the penicillin-binding proteins of the
bacteria, which increases the antibacterial activity of the
penicillin. Because these ~-lactamase inhibitors have only
Mayo Clin Proc, March 1999, Vol 74
OH
I
+ I
CH 2
",NH-CH-CO",
(3-lactamase inhibitor (3-lactamase
(clavulanic acid)
Fig. 3. Irreversible binding of ~-lactarnase inhibitor to ~-lactamase.
weak antibacterial activity by themselves, they should not
be used as single agents for treatment of infection. These
j3-lactamase inhibitors increase the antibacterial activity of
their companion penicillin only when the bacterial resis-
tance is primarily the result of j3-lactamase production but
not when bacterial resistance is mediated through cell wall
impermeability.
j3-Lactamase produced by bacteria can be classified by
the Bush system or the Richmond-Sykes classification.v-"
These j3-lactamase inhibitors primarily inhibit the plasmid-
encoded j3-lactamases and less frequently inhibit the
chromosomally encoded j3-lactamases. The plasmid-
produced j3-lactamases are Bush group 2 (or Richmond-
Sykes class III, IV, and V), whereas the chromosomally
produced j3-lactamases are Bush group 1 and 4 (or Rich-
mond-Sykes class Ia, Ib, and ld). The bacteria that pro-
duce these latter chromosomally encoded j3-lactamases
include certain species of Enterobacter, Citrobacter, Ser-
ratia, Pseudomonas, and Morganella. The j3-lactamases
of these bacteria are not inhibited by the j3-lactamase
inhibitors and therefore remain resistant to the com-
panion penicillin. Certain chromosomal j3-lactamases
produced by Legionella, Bacteroides, Moraxella, and
Klebsiella, however, are inhibited by j3-lactamase inhibi-
tors and are thereby inactivated. The j3-lactamase inhibi-
tors are most effective against S. aureus, H. influenzae, M.
catarrhalis, Bacteroides, E. coli, and other Enterobac-
teriaceae. Thus, the penicillin and j3-lactamase inhibitor
combinations are likewise most active and effective against
these bacteria.
Currently, three j3-lactamase inhibitors have been ap-
proved for combination with penicillins: clavulanic acid,
sulbactam, and tazobactam. Sulbactam and tazobactam are
penicillanic acid sulfonic derivatives with similar struc-
tures (Fig. 4). Each of these j3-lactamase inhibitors is
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
The Penicillins 301
..
Acyl enzyme complex
combined in a fixed amount with the individual penicillin.
These three j3-lactamase inhibitors penetrate tissues well,
have a half-life of about 1 hour, and are excreted by the
kidneys. Clavulanic acid and tazobactam are more potent
inhibitors of j3-lactamases; moreover, clavulanic acid in-
duces chromosomal j3-lactamase production, whereas
sulbactam and tazobactam do not." Despite these minor
differences in activity and pharmacologic properties, clini-
cally these j3-lactamase inhibitors are thought to be fairly
equivalent therapeutically. The primary antibacterial ac-
tivity of the penicillin and j3-lactamase inhibitor combina-
tion is mainly attributable to the activity of the penicillin in
the combination once the bacterial j3-lactamase has been
inhibited. Clinicians should remember, however, that the
in vitro antibacterial activity of these penicillin and 13-
lactamase inhibitor combinations may not be predictive of
the in vivo activity because the relative concentrations of
the j3-lactamase inhibitor and the penicillin in vivo may
differ from the in vitro concentrations.
Amoxicillin-Clavulanic Acid
The first oral combination of a penicillin and 13-
lactamase inhibitor was amoxicillin and clavulanic acid
(Augmentin), which became available in 1984. The addi-
tion of clavulanic acid to amoxicillin increased its antimi-
crobial activity to include j3-lactamase-producing strains of
S. aureus, H. influenzae, M. catarrhalis, N. gonorrhoeae,
E. coli, Proteus, Klebsiella, H. ducreyi, Bacteroides spe-
cies, and certain strains of Bnterobacteriaceae.v-"
Amoxicillin-clavulanic acid has little or no activity against
Pseudomonas, Serratia, Enterobacter, Citrobacter, and
methicillin-resistant S. aureus. This combination is also
not active against penicillin-resistant S. pneumoniae, which
has become an emerging bacterial resistance problem
throughout the world.
302 The Penicillins
a a
H a~ ~a
a /
P
H H
H H ~lSfCH
HWC~H
H CH3
a H caaH o N H
Clavulanic acid Sulbactam
Fig. 4. Chemical structures of various
Amoxicillin and clavulanic acid are both well absorbed
from the gastrointestinal tract and have a serum half-life of
about 1 hour. This combination has low protein binding
(18% and 25%), penetrates tissues and extravascular fluids
well, and is excreted by the kidneys. Amoxicillin-
clavu1anicacid is manufactured in a 250 mg/125 mg or 500
mg/125 mg combination and administered orally three
times a day. Peak: serum levels of amoxicillin are 5 ug/ml,
or 10 Ilg/mL after administration of a 250-mg or 500-mg
dose, respectively. The reported adverse effects are similar
to those of amoxicillin-primarily rashes, Candida super-
infection, gastrointestinal distress, and diarrhea. Adminis-
tration in conjunction with food does not decrease absorp-
tion but reduces the gastrointestinal symptoms.
Amoxicillin-clavulanic acid has been shown to be ef-
fective in the treatment of otitis media, sinusitis, bron-
chitis, urinary tract infections, and skin and soft tissue
infections." The prevalence of penicillin-resistant S.
pneumoniae in a specific area should be carefully consid-
ered when amoxicillin-clavulanic acid is prescribed for
outpatient treatment of otitis media and sinusitis; with
widespread prevalence of this strain, the result may be
treatment failure. Amoxicillin-clavulanic acid has also
been shown to be effective therapy for animal or human
bites because of its excellent activity against the p-
lactamase-producing aerobic and anaerobic bacteria that
are involved." Amoxicillin-clavulanic acid is more expen-
sive than amoxicillin alone and certain other orally admin-
istered antibiotics and therefore should not be used when
less expensive antibiotics are equally effective.
Ticarcillin-Clavulanic Acid
The first parenterally administered combination of a
penicillin and a ~-Iactamase inhibitor was ticarcillin-
clavulanic acid (Timentin), which was approved for use in
1985. The addition of clavulanic acid to ticarcillin in-
creases its antibacterial activity to include ~-lactamase­
producing strains of S. aureus, N. gonorrhoeae, H.
influenzae, M. catarrhalis, Klebsiella, Proteus,
Providencia, and Bacteroides species.t'-" Like other p-
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
Mayo Clin Proc, March 1999, Vol 74
H-1---t'YCH,-NV
F\
H H ~sf' CH3
3
coos ~~- coos
Tazobactam
~-lactamase inhibitors.
lactamase inhibitors, clavulanic acid does not increase the
activity of ticarcillin against those bacteria that are already
sensitive to it. Ticarcillin-clavulanic acid is inactive
against those resistant bacteria that produce Bush group 1
(Richmond-Sykes class I) p-Iactamases. These bacteria
include certain strains of Pseudomonas, Serratia,
Citrobacter, and Enterobacter. Methicillin-resistant staph-
ylococci are resistant to ticarcillin-clavulanic acid, and en-
terococci are moderately resistant. P. aeruginosa strains
that are resistant to ticarcillin as a result of reduced perme-
ability of their cell wall are also resistant to ticarcillin-
clavulanic acid."
The pharmacologic properties of ticarcillin-clavulanic
acid are the same as those for ticarcillin alone. The serum
half-life is about 1 hour for both ticarcillin and clavulanic
acid, excretion is through the kidneys, and both penetrate
tissues and extracellular fluids well. The combination of
ticarcillin-clavulanic acid is available as a 3.1-g or 3.2-g
dose, which contains 0.1 g or 0.2 g of clavulanic acid,
respectively. After an intravenous infusion of 3.1 g, the
peak serum levels of ticarcillin are 330 ug/ml, and of
clavulanic acid are 8.0 ug/ml., The adverse events from
ticarcillin-clavulanic acid are similar to those associated
with ticarcillin alone and include fever, rashes, nausea,
diarrhea, abnormal results of liver function tests, leuko-
penia, thrombocytopenia, anemia, false-positive Coombs'
test, infusion-related phlebitis, hypokalemia, salt and
fluid overload, inhibition of platelet aggregation, and
anaphylaxis.
In clinical trials, ticarcillin-clavulanic acid has been
shown to be effective therapy for many infections. These
conditions include bacteremia, urinary tract infections,
intra-abdominal or pelvic infections, osteomyelitis, and
skin and soft tissue infections." This drug combination,
when used in combination with an aminoglycoside such as
amikacin or tobramycin, has also proved to be effective
therapy for febrile neutropenia." No evidence has indi-
cated that ticarcillin-clavulanic acid is more efficacious
than other antibiotics when infections involving sensitive
bacterial strains are being treated. Its primary indication is
Mayo Clin Proc, March 1999, Vol 74
for treatment of polymicrobial infections involving resis-
tant bacteria that produce ~-lactamase because it can obvi-
ate the use of multiple drug regimens and thus contain the
cost. Ticarcillin-clavulanic acid is often active against
multiple drug-resistant Stenotrophomonas maltophilia and
can be used in combination therapy for infections caused
by this organism. Ticarcillin-clavulanic acid is usually
prescribed as a 3.I-g dose given intravenously every 4 to 6
hours. The 3.2-g dose is recommended every 8 hours for
treatment of urinary tract infections.
Ampicillin-Sulbactam
The second parenterally administered combination of
a penicillin and a ~-lactamase inhibitor was ampicillin-
sulbactam (Unasyn), which was approved in 1987.
The addition of sulbactam to ampicillin increases its spec-
trum to include ~-lactamase-producing strains of S. aureus,
H. influenzae, N. gonorrhoeae, M. catarrhalis, E. coli, H.
ducreyi, Klebsiella, Proteus, Providencia, and Bac-
teroidesr'-" Ampicillin-sulbactam is not active against
those bacteria that produce Bush group I (Richmond-
Sykes class I) ~-lactamases, including Pseudomonas,
Serratia, Citrobacter, and Enterobacter. Methicillin-resis-
tant S. aureus and vancomycin-resistant enterococci are
resistant to ampicillin-sulbactam. In comparison, imi-
penem and the third-generation cephalosporins are more
active than ampicillin-sulbactam against members of the
Enterobacteriaceae.
The combination of ampicillin-sulbactam is manufac-
tured in a 2: I ratio and is supplied as vials of 3 g (2 g of
ampicillin and I g of sulbactam) or 1.5 g (l g and 0.5 g).
Arnpicillin-sulbactam has a serum half-life of about 1 hour,
is excreted through the kidneys, and penetrates body fluids
and tissues well, including inflamed meninges. Peak serum
ampicillin levels after intravenous administration of 1.5 g
or 3 g every 6 hours are in the range of 40 to 70 ug/ml. or
110 to 150 ug/ml., respectively. Ampicillin-sulbactam is
usually well tolerated and has adverse effects similar to
those associated with ampicillin alone: rashes, nausea,
vomiting, diarrhea, and abnormal results of liver function
tests.
Ampicillin-sulbactam has demonstrated effectiveness in
the treatment of various infections, including skin and soft
tissue infections, intra-abdominal and pelvic infections,
urinary tract infections, and lower respiratory tract in-
fections.r':" Because ampicillin-sulbactam has no activ-
ity against certain members of the Enterobacteriaceae and
P. aeruginosa, it should not be used alone as empiric
treatment in febrile patients with neutropenia or critically
ill patients with probable bacteremia. Its primary indica-
tion is in the treatment of polymicrobial infections of mild
to moderate severity involving bacteria that do not pro-
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
The Penicillins 303
duce Bush group I ~-lactamases. Ampicillin-sulbactam
can be administered by either the intramuscular or the
intravenous route. The usual dosage is 1.5 or 3 g every 6
hours.
Piperacillin-Tazobactam
The third parenterally administered penicillin and ~­
lactamase inhibitor combination to become available was
piperacillin-tazobactam (Zosyn). This combination was
approved for use in 1993. The addition of tazobactam
extended the spectrum of piperacillin to include bacteria
that produce ~-lactamases, such as staphylococci and a
wide variety of anaerobic and certain aerobic gram-nega-
tive bacteria. Tazobactam, however, does not increase the
activity of piperacillin against those bacteria with resis-
tance due to altered cell wall permeability to piperacillin.
In general, piperacillin-tazobactam is active against most S.
aureus (except methicillin-resistant strains), Streptococcus
species, Enterococcus (except vancomycin-resistant
strains), many gram-negative aerobic bacteria including P.
aeruginosa, most anaerobic bacteria, and other gram-nega-
tive bacteria including N. gonorrhoeae, N. meningitidis, H.
injluenzae, and M. catarrhalis. Although tazobactam has
some inhibitory activity against chromosomally encoded
~-lactamases (class I), the combination of piperacillin
and tazobactam is usually not active against gram-nega-
tive bacteria that produce these ~-lactamases. Such bac-
teria include certain strains of Pseudomonas, Serratia,
Enterobacter, Citrobacter, and Morganella. Piperacillin-
tazobactam is also not active against methicillin-resistant S.
aureus, vancomycin-resistant E. faecium, penicillin-resis-
tant S. pneumoniae, Corynebacterium jeikeium, and those
gram-negative bacteria such as P. aeruginosa that have
altered cell wall permeability to piperacillin.
In comparison with other penicillin and ~-lactamase
inhibitor combinations, piperacillin-tazobactam is more
active than ticarcillin-clavulanic acid against gram-positive
and gram-negative bacteria and equivalent in activity to
ampicillin-sulbactam against gram-positive bacteria.
When tested in vitro against piperacillin- and ticarcillin-
resistant bacteria, piperacillin-tazobactam was much more
active than was ticarcillin-clavulanic acid.
Piperacillin and tazobactam are combined in an 8 to 1
ratio; thus, each I g of piperacillin is combined with 0.125
g of tazobactam. This amount of tazobactam results in
increased ~-lactamase at the site of infection for longer
periods in comparison with ticarcillin-clavulanic acid.
Piperacillin and tazobactam have similar pharmacologic
properties-that is, both are excreted by the kidneys, have a
half-life of 1 hour, and have 15 to 20% protein binding.
Hemodialysis removes about 30 to 40% of piperacillin and
tazobactam.
304 The Penicillins
The usual recommended dosage for most moderate to
severe bacterial infections is 3.375 g intravenously every 6
hours. For infections involving P. aeruginosa, an in-
creased dosage (4.5 g intravenously every 6 hours) is pre-
scribed, usually in combination with an aminoglycoside. A
dose of 3.375 g given intravenously during a 30-minute
period results in peak piperacillin and tazobactam levels of
240 ug/ml, and 24 ug/ml., respectively. When renal func-
tion is reduced below 40 mlzmin, an adjustment in admin-
istered dosage is recommended. When the creatinine clear-
ance is 20 to 40 mL/min, the dosage should be 2.25 g
intravenously every 6 hours; with creatinine clearance be-
low 20 mL/min, the dosage should be 2.25 g every 8 to 12
hours. When a patient is receiving hemodialysis, a dosage
of 2.25 g every 8 hours plus a supplemental dose of 0.75 g
after dialysis is advised.
Piperacillin-tazobactam is a safe antibiotic, without new
or unusual toxic effects reported. The adverse events that
have been described are similar to those for other penicil-
lins: gastrointestinal complaints (nausea or diarrhea),
rashes and pruritus, eosinophilia, fever, increased results of
liver function tests, thrombocytopenia, leukopenia,
azotemia, and coagulation abnormalities. In comparison
with other penicillin and ~-lactamase inhibitor combina-
tions, piperacillin-tazobactam has demonstrated similar ad-
verse reactions.
Piperacillin-tazobactam has been efficacious in the
treatment of a wide array of infections, including intra-
abdominal, pelvic, skin, soft tissue, and diabetes-related
foot infections, moderately severe community-acquired
pneumonia, osteomyelitis, and bacteremia in hosts with
neutropenia. In comparative trials, piperacillin-tazobactam
was equivalent to imipenem, I g intravenously every 8
hours," and comparable to clindamycin plus gentamicin"
for intra-abdominal infections, but it was superior to
imipenem at a dosage of 500 mg intravenously every 8
hours. 49•5o For treatment of skin and soft tissue infections in
a multicenter study, piperacillin-tazobactam and ticarcillin-
clavulanate were equally effective." For treatment of pel-
vic infections in hospitalized women, piperacillin-tazo-
bactam has been shown to be as effective as clindamycin
plus gentamicin." In comparison with ceftazidime,
piperacillin-tazobactam was superior for treatment of
nosocomial lower respiratory tract infections.P and when
compared in febrile patients with neutropenia, piperacillin-
tazobactam plus amikacin was superior to ceftazidime plus
amikacin.>'
The piperacillin-tazobactam combination is more ex-
pensive than most third-generation cephalosporins, but it is
less expensive than imipenem, meropenem, ticarcillin-
clavulanic acid, and certain combinations of two or three
antibiotics. Because of the broad spectrum of activity of
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
Mayo Clin Proc, March 1999, Vol 74
piperacillin-tazobactam against a wide variety of aerobic
and anaerobic bacteria, it is a useful combination antibiotic
for the treatment of polymicrobial infections. Piperacillin-
tazobactam, however, should not be used for infections
when a less expensive and equally efficacious antibiotic is
available. It should also not be used as monotherapy for
serious P. aeruginosa infections.
ADVERSE EFFECTS
Although the penicillins are considered relatively nontoxic,
many patients have adverse reactions (Table 7). Allergic or
hypersensitivity reactions are thought to be the most fre-
quent!y occurring side effect. An estimated 3 to 10% of the
general population are allergic to penicillin. The frequency
of an allergic reaction is least when the penicillin is admin-
istered orally, somewhat higher with intravenous adminis-
tration, and distinctly higher when penicillin is combined
with procaine and administered intramuscularly. Large
doses and prolonged administration seem to be associated
with more allergic reactions. Cross-allergenicity among
the semisynthetic and natural penicillins reflects their com-
mon 6-aminopenicillanic acid nucleus and sensitizing de-
rivatives. Patients allergic to one penicillin should be
considered allergic to the other members of the penicillin
family. Penicillin binds to proteins and acts as a hapten to
which antibodies develop. The major determinant of peni-
cillin allergy has been identified as benzylpenicillolyl, and
the minor determinants are benzylpenicillin, benzylpen-
icilloate, and benzylpenilloate. Both types of determinants
are involved in anaphylaxis, but the minor determinants are
more common. True anaphylactic reactions to penicillins
are infrequent, occurring in 0.004 to 0.015% of instances of
penicillin use (l in 7,000 to 25,000 cases), and mortality
from penicillin occurs once in every 50,000 to 60,000
treatment courses." The symptoms of anaphylaxis usually
begin within 10 to 20 minutes after administration of the
penicillin; hence, a patient should be observed for approxi-
mately 30 minutes after receiving an injection of penicillin.
Immediate treatment of anaphylaxis is imperative to pre-
serve life.
For anticipation of a possible allergic reaction, a history
of a previous adverse reaction to any penicillin must be
elicited before a penicillin is prescribed. Such a history,
however, does not necessarily predict subsequent occur-
rence because allergic reactivity may wane over time. The
prior oral or parenteral administration of an antihistamine
does not provide protection against an allergic reaction to
penicillin. A skin test may be used for predicting an
immediate hypersensitivity reaction, including anaphy-
laxis, when a history of a possible severe penicillin adverse
effect is unclear. Although negative results of a skin test do
not completely exclude the possibility of a reaction, most
Mayo Clin Proc, March 1999, Vol 74
physicians administer a small dose 0,000 to 2,000 U) of
penicillin and proceed to higher doses if no reaction occurs.
If the skin test result is positive, a penicillin should not be
used unless alternatives are not available (for example, in
the treatment of enterococcal endocarditis in a patient aller-
gic to both penicillin and vancomycin). Under these cir-
cumstances, desensitization by either an oral or a parenteral
protocol of slowly increasing doses of penicillin should be
performed under careful supervision.v-" Whenever pos-
sible, alternative antimicrobial agents should be used in
most patients who have a severe allergic reaction. Cross-
reactivity to the cephalosporins may occur in 3 to 5% of
patients and is of particular concern with severe allergic
reactions or immediate hypersensitivity reactions (such as
urticaria, angioedema, or anaphylaxis). Unfortunately, no
useful skin tests are available for predicting allergic reac-
tions to the cephalosporins or imipenem. Administration
of a cephalosporin is generally considered safe in a patient
with a history of a nonimmediate hypersensitivity reaction.
Various other allergic reactions have occurred after ad-
ministration of one of the penicillins: drug-induced fever,
serum sickness, cutaneous vasculitis, interstitial nephritis,
and rashes including urticaria and exfoliative dermatitis
(Table 7). In many patients who have infectious mono-
nucleosis, a macular or maculopapular erythematous rash
will develop after receiving ampicillin. This reaction, how-
ever, does not constitute a true allergy and does not prohibit
subsequent use of the drug. As with all other orally admin-
istered antimicrobial agents, penicillins may cause gas-
trointestinal irritation when administered orally. This side
effect may manifest as nausea, vomiting, abdominal pain,
or diarrhea but is usually not severe enough to discontinue
treatment. Neurologic adverse reactions may occur in
some patients who receive large intravenous doses of
penicillin, especially in those with concomitant renal dys-
function. These adverse effects may include irritability,
confusion, myoclonic jerking, visual or auditory hallucina-
tions, generalized seizures, or even coma. Permanent brain
damage has been reported in certain cases of neurologic
toxicity.
Although penicillin is not considered hematotoxic, rare
cases of penicillin-induced hemolytic anemia have been
described. Granulocytopenia has also been detected after
administration of methicillin, oxacillin, or piperacillin.
Thrombocytopenia has also been associated with the use
of piperacillin and, rarely, with other penicillins. Intersti-
tial nephritis and renal failure have ensued when large
doses of penicillin, ampicillin, or methicillin have been
administered. The initial manifestations may be fever,
eosinophilia, hematuria, proteinuria, or pyuria." A renal
biopsy specimen usually reveals damage to the renal tu-
bules and an interstitial mononuclear and eosinophilic
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
The Penicillins 305
cellular infiltration indicative of a hypersensitivity reac-
tion. Hepatotoxicity has occasionally developed during
therapy with oxacillin, nafcillin, and carbenicillin. The
extended-spectrum penicillins can considerably alter the
endogenous flora of the body and result in superinfection
with Klebsiella, Pseudomonas, or Candida. In addition, all
the penicillins have been associated with C. difficile
enterocolitis.
After an intramuscular injection of penicillin, localized
burning pain, induration, erythema, and heat may occur;
such reactions are seen most frequently with use of penicil-
lin G, ampicillin, nafcillin, and penicillin G benzathine.
Penicillin G procaine may cause neurologic symptoms if
the procaine portion gains entrance into the bloodstream
during injection.' The hypokalemia that has been de-
scribed during carbenicillin and ticarcillin therapy is a re-
sult of their acting as a nonreabsorbable anion and thereby
increasing excretion of potassium. Hypokalemia is less
commonly seen with use of the ureidopenicillins. The
platelet dysfunction that results from carbenicillin is due to
the binding to platelet adenosine diphosphate receptors.
Despite these various adverse reactions, the penicillin fam-
ily of antibiotics is usually thought to be well tolerated and
nontoxic.
CONCLUSION
The penicillin family is an important part of our antimicro-
bial armamentarium. Since the introduction of penicillin G
in 1941, millions of lives have been saved through its
bactericidal activity. Over the years, this family of antibi-
otics has grown, and the antimicrobial activity has ex-
panded to meet the challenge of new bacterial pathogens.
Nevertheless, the emergence of penicillin-resistant S.
pneumoniae, methicillin-resistant S. aureus, multidrug-
resistant Enterococcus, N. gonorrhoeae, and certain
Enterobacteriaceae that produce chromosomally encoded
p-lactamases has reduced their use against these isolates.
Despite the discovery of many new antibiotics, the penicil-
lin family has remained a primary choice for treatment of a
wide variety of bacterial isolates (Table 5).
Overall, the penicillins are bactericidal against sensitive
strains, are relatively nontoxic, have excellent tissue pen-
etration, are efficacious in the treatment of infections, and
are relatively inexpensive in comparison with other antibi-
otics. Whenever an antibiotic is chosen for treatment, use
of one of the penicillins should be considered because of
the excellent pharmacologic properties, therapeutic effi-
cacy, and low cost. In fact, other classes of antibiotics
have not been shown to be clinically superior to the penicil-
lins in the treatment of infections caused by sensitive or-
ganisms. Among the various members of the penicillin
family, the narrowest spectrum agent should be used, in
306 The Penicillins
order to prevent emergence of bacterial resistance and to
contain costs.
The search continues for the ideal penicillin that has
excellent penetration through the bacterial cell wall, high
stability to p-Iactamases, and considerable affinity for
penicillin-binding proteins. Until this search is completed,
the current members of the penicillin family will still pro-
vide excellent choices for antimicrobial therapy for a wide
variety of infections.
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