The penicillins share a common chemical nucleus (6-aminopenicillanic acid) that contains a -lactam ring essential to their biologic activity.
Antimicrobial Action & Resistance
The initial step in penicillin action is the binding of the drug
to receptorspenicillin-binding proteins. The proteins
of different organisms vary in number and in affinity for a given drug.
After penicillins have attached to receptors, peptidoglycan synthesis
is inhibited due to blockage of transpeptidation. The final bactericidal
action is the removal of an inhibitor of the autolytic enzymes in the
cell wall, which activates the enzymes and results in cell lysis.
Organisms that produce -lactamases (penicillinases)
are resistant to some penicillins because the -lactam
ring is broken and the drug is inactivated. Only organisms actively
synthesizing peptidoglycan (in the process of multiplication) are
susceptible to -lactam antibiotics. Nonmultiplying
organisms or those lacking cell walls are not susceptible.
Microbial resistance to penicillins is caused by four factors:
(1) Production of -lactamases, eg, by staphylococci,
gonococci, Haemophilus species, and coliform organisms,
including extended-spectrum -lactamaseproducing
bacteria; (2) lack of penicillin-binding proteins or decreased affinity
of penicillin-binding protein for -lactam antibiotic
receptors (eg, resistant pneumococci, methicillin-resistant staphylococci,
enterococci) or impermeability of cell envelope; (3) failure of
activation of autolytic enzymes in the cell wall"tolerance," eg,
in staphylococci, group B streptococci; and (4) cell wall-deficient
(L) forms or mycoplasmas, which do not synthesize peptidoglycans.
The natural penicillins include penicillin G for parenteral administration
(aqueous crystalline or benzathine penicillin G) or for oral administration
(penicillin G and phenoxymethyl penicillin [penicillin
V]). They are most active against gram-positive organisms
and are susceptible to hydrolysis by -lactamases.
They are used (1) for infections caused by susceptible and moderately susceptible
pneumococci, depending on the site of infection; (2) streptococci (including
anaerobic streptococci); (3) meningococci; (4) non-lactamase-producing
staphylococci; (5) Treponema pallidum and other
spirochetes; (6) Propionibacterium acnes and other
gram-positive rods; (7) non-difficile clostridia; (8) actinomyces;
and (9) most gram-positive anaerobes. See Table 304.
Pharmacokinetics & Administration
Penicillin has wide extracellular distribution after parenteral administration. Lower levels are present in the eye, prostate, and central nervous system. However, with inflammation of the meninges and with appropriate dosing, adequate penetration into the cerebrospinal fluid takes place.
Because benzathine penicillin allows for extended release of
penicillin, continuous blood and tissue levels are achieved.
Phenoxymethyl penicillin (penicillin V) is the oral penicillin
of choice because of its superior bioavailability. Penicillin is
renally eliminated; however, the majority is cleared by tubular
Most infections due to susceptible organisms respond to aqueous
penicillin G in daily doses of 12 million units administered
intravenously every 46 hours. For life-threatening infections
(meningitis, endocarditis), increased daily doses (1824
million units intravenously) every 4 hours are required.
Penicillin V is indicated in minor infections such as streptococcal
pharyngitis and cellulitis. Syphilis requires weekly injections
of benzathine penicillin, 2.4 million units intramuscularly for
13 weeks, depending on the stage of the disease (see Table 306).
The extended-spectrum group of penicillins includes the aminopenicillins:
ampicillin and amoxicillin and the ureidopenicillin piperacillin
(available only in combination with the -lactamase
inhibitor tazobactam). These drugs are susceptible to destruction
by staphylococcal (and other) -lactamases. While
this group of penicillins is more active against certain gram-negative
rods, they have approximately the same activity as natural penicillins against
Ampicillin and amoxicillin are active against most strains of Proteus
mirabilis, Listeria, and non-lactamase-producing
strains of Haemophilus influenzae but are inactive against
most gram-negative pathogens. Both drugs are effective against penicillin-susceptible
pneumococcus and Enterococcus faecalis; however,
ampicillin-resistant E faecalis has emerged.
Ticarcillin and piperacillin are no longer marketed. However, considering that piperacillin-tazobactam and ticarcillin-clavulanate are commercially available, it is important to know the spectrum of activity of piperacillin and ticarcillin.
Piperacillin is active against Pseudomonas aeruginosa and Klebsiella.
Similar to ampicillin, piperacillin is active against E
faecalis and pneumococci. The extended-spectrum penicillins
inhibit many but not all anaerobes. Ampicillin and amoxicillin are
not active against -lactamase-producing strains
of Bacteroides fragilisin contrast to piperacillin,
which is active against many of these isolates.
Pharmacokinetics & Administration
Ampicillin can be given orally or parenterally. Amoxicillin is
preferable to ampicillin in the oral treatment of infection because
of its improved oral bioavailability and less frequent dosage frequency.
An extended-release amoxicillin tablet (Moxatag) is approved
for once-daily use for streptococcal pharyngitis in children <
Piperacillin (in combination with tazobactam) is given intravenously
and increased doses (200300 mg/kg/d)
are required for treatment of infections due to P aeruginosa.
See eTable 306.1 for a summary
of dosage adjustments that are required in kidney disease.
Amoxicillin is given orally for minor infections, such as exacerbations of chronic bronchitis, sinusitis, or otitis. Ampicillin is administered intravenously for pneumonia, meningitis, bacteremia, or endocarditis.
Amoxicillin is also used as prophylaxis for endocarditis. Because
of the increased serum and respiratory secretion levels, this agent
is valuable in the treatment of susceptible and moderately penicillin-susceptible pneumococcus.
In general, if amoxicillin levels remain above the minimum inhibitory
concentration (MIC) of intermediately susceptible pneumococcus for
more than 40% of the dosing interval (which can be achieved
with a dose of 40 mg/kg/d in adults), bacteriologic
cure rates are optimal. An ambulatory 3-day course of amoxicillin, 8090
mg/kg/d in two doses, has been found to be equivalent
to parenteral antibacterials in the treatment of outpatient-treated community-acquired
Penicillins Combined with -Lactamase Inhibitors
The addition of -lactamase inhibitors (clavulanic
acid, sulbactam, tazobactam) prevents inactivation of the parent penicillin
by bacterial -lactamases. Products available are Augmentin
(amoxicillin, 250 mg, 500 mg, or 875 mg, plus 125 mg of clavulanic
acid); Augmentin XR (amoxicillin 1 g plus 62.5 mg of clavulanic
acid); Unasyn (ampicillin 1 g plus sulbactam 0.5 g, and ampicillin
3 g plus sulbactam 1 g); Timentin (3 g ticarcillin plus 100 mg clavulanate); and Zosyn (piperacillin 3 g plus tazobactam
0.375 g, and piperacillin 4 g plus tazobactam 0.5 g). Augmentin
is given orally and the others intravenously. In general, the -lactamase
inhibitors effectively inactivate -lactamases produced
by Staphylococcus aureus, H influenzae, Moraxella catarrhalis,
and B fragilis. In contrast, the -lactamase
inhibitors are variably and unpredictably effective against -lactamases
produced by certain aerobic gram-negative bacilli, such as Enterobacter. Of
the available parenteral drugs, Zosyn has the broadest spectrum
of activity. Like Unasyn, Zosyn is active against ampicillin-susceptible
enterococci. It has greater in vitro activity against P
aeruginosa, Serratia, and Klebsiella species when compared with Augmentin, Timentin or Unasyn. While Zosyn and Timentin are active in vitro, their efficacy has been inconsistent in the treatment of extended-spectrum -lactamase–producing organisms.
Augmentin, because of its increased cost, compared to amoxicillin,
and gastrointestinal intolerance, is limited to the treatment of
refractory cases of sinusitis and otitis and prophylaxis of infections
resulting from animal and human bites. The roles of Unasyn, Timentin, and Zosyn
include the treatment of polymicrobial infections such as peritonitis
from a ruptured viscus, osteomyelitis in a diabetic patient, or traumatic
As discussed previously, when Zosyn or Timentin is used to treat Pseudomonas infections,
dosages of 200300 mg/kg/d of the piperacillin (or ticarcillin)
component are used.
Piperacillin-tazobactam treatment of pseudomonal isolates with
reduced piperacillin-tazobactam susceptibility may be associated
with increased mortality. Nonpseudomonal infection can
be treated with lower doses (100200 mg/kg/d).
Oxacillin, cloxacillin, dicloxacillin, and nafcillin are relatively
resistant to destruction by -lactamases produced
by staphylococci. They are less active than natural penicillins against
nonstaphylococcal gram-positive bacteria; however, they are still
adequate in certain streptococcal infections, including those due
to group A streptococci in skin and soft tissue infections.
The primary route of clearance of the above agents is nonrenalthus,
no dosage adjustment is needed in kidney disease.
All penicillins are associated with allergic reactions, ranging
from serious IgE-mediated reactions, including anaphylaxis and bronchospasm,
to nonIgE-mediated reactions, such as macular papular
rash. All penicillins in excessive doses, particularly in kidney
disease, have been associated with seizures.
Of the oral penicillins, amoxicillin-clavulanate is most commonly
associated with diarrhea. Nafcillin administered at high doses is
associated with a modest leukopenia. Oxacillin may cause a higher
incidence of liver toxicity than other agents in this class. High
doses of penicillins, particularly piperacillin (with tazobactam),
inhibit platelet aggregation and produce hypokalemia due to binding
of potassium in the kidney.
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