The penicillins share a common chemical nucleus (6-aminopenicillanic acid) that contains a beta-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 beta-lactamases (penicillinases)
are resistant to some penicillins because the beta-lactam
ring is broken and the drug is inactivated. Only organisms actively
synthesizing peptidoglycan (in the process of multiplication) are
susceptible to beta-lactam antibiotics. Nonmultiplying
organisms or those lacking cell walls are not susceptible.
Microbial resistance to penicillins is caused by four factors:
(1) Production of beta-lactamases, eg, by staphylococci,
gonococci, Haemophilus species, and coliform organisms,
including extended-spectrum beta-lactamaseproducing
bacteria; (2) lack of penicillin-binding proteins or decreased affinity
of penicillin-binding protein for beta-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 beta-lactamases.
They are used (1) for infections caused by susceptible and moderately susceptible
pneumococci, depending on the site of infection; (2) other streptococci (including
anaerobic streptococci); (3) meningococci; (4) nonbeta-lactamase-producing
staphylococci; (5) Treponema pallidum and other
spirochetes; (6) Propionibacterium acnes and other
gram-positive anaerobic bacilli; (7) non-difficile clostridia; and (8) actinomyces. 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, allowing for the treatment of syphilis.
Phenoxymethyl penicillin (penicillin V) is the oral penicillin of choice because of its superior bioavailability. Penicillin is primarily renally eliminated by glomerular filtration and active tubular secretion.
Most infections due to susceptible organisms respond to aqueous penicillin G in daily doses of 1–2 million units administered intravenously every 4–6 hours. For life-threatening infections (meningitis, endocarditis), increased doses (3–4 million units intravenously every 4 hours) are required.
Penicillin V is the drug of choice in the treatment of streptococcal pharyngitis and cellulitis. Syphilis requires weekly injections of benzathine penicillin, 2.4 million units intramuscularly for 1–3 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 beta-lactamase inhibitor tazobactam). These drugs are susceptible to destruction by staphylococcal (and other) beta-lactamases. This group of penicillins is similar to the natural penicillins in its activity against gram-positive bacteria; however, these agents offer modest aerobic gram-negative coverage as well.
Ampicillin and amoxicillin are active against most strains of Proteus mirabilis, Listeria, and non–beta-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. Enterococcus faecium is likely to be resistant to ampicillin and piperacillin.
Ticarcillin and piperacillin are no longer marketed. However, considering that piperacillin-tazobactam and ticarcillin-clavulanate are commercially available, knowledge of the spectrum of activity of piperacillin and ticarcillin is important.
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 beta-lactamase–producing strains of Bacteroides fragilis—in 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 acute sinusitis or acute otitis media. 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 with amoxicillin when compared with penicillin, this agent is effective 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, 80–90 mg/kg/d in two doses, has been found to be equivalent to parenteral antibacterials in the treatment of outpatient-treated community-acquired pneumonia.
Penicillins Combined with Beta-Lactamase Inhibitors
The addition of beta-lactamase inhibitors (clavulanic acid, sulbactam, tazobactam) prevents inactivation of the parent penicillin by some, but not all, bacterial beta-lactamases. Marketed products include 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 beta-lactamase
inhibitors effectively inactivate beta-lactamases produced
by Staphylococcus aureus, H influenzae, Moraxella catarrhalis,
and B fragilis. In contrast, the beta-lactamase
inhibitors are variably and unpredictably effective against beta-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 is less clear in the treatment of extended-spectrum beta-lactamase–producing organisms.
Augmentin is generally used only for the treatment of refractory cases of otitis media and for prophylaxis of infections resulting from animal and human bites because of its gastrointestinal side effects and increased cost compared to amoxicillin. However, the Infectious Diseases Society of America (IDSA) considers Augmentin to be the drug of choice in the treatment of acute bacterial rhinosinusitis. 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 osteomyelitis.
As discussed previously, when Zosyn or Timentin is used to treat Pseudomonas infections, increased dosages (200–300 mg/kg/d of the piperacillin [or ticarcillin] component) should be 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). Continuous infusions of piperacillin-tazobactam may be superior to intermittent bolus dosing in the treatment of serious bacterial infection.
Oxacillin, cloxacillin, dicloxacillin, and nafcillin are resistant to degradation by beta-lactamases produced by staphylococci. They are less active than natural penicillins against nonstaphylococcal gram-positive bacteria; however, they are still effective in the treatment of certain streptococcal infections, including skin and soft tissue infections due to group A streptococci.
The primary route of clearance of the above agents is nonrenal—thus, no dosage adjustment is needed in chronic kidney disease.
All penicillins are associated with allergic reactions, ranging from serious IgE-mediated reactions, including anaphylaxis and bronchospasm, to non–IgE-mediated reactions, such as macular papular rash. Only a small minority of patients who claim allergy to penicillin will have a reaction with subsequent exposure to penicillins. All penicillins in excessive doses, particularly with decreased renal function, have been associated with seizures.
Of the oral penicillins, amoxicillin-clavulanate is more commonly associated with diarrhea. Nafcillin administered at high doses is associated with a modest leukopenia, and oxacillin has been linked with 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 and subsequent elimination by the kidney.
|Garbutt JM et al. Amoxicillin for acute rhinosinusitis. A randomized controlled trial. JAMA. 2012 Feb 15;307(7):685–92. [PMID: 22337680]|
|Kardos N et al. Penicillin: the medicine with the greatest impact on therapeutic outcomes. Appl Microbiol Biotechnol. 2011 Nov;92(4):677–87. [PMID: 21964640]|
|Rodríguez-Baño J et al. Beta-lactam/beta-lactam inhibitor combinations for the treatment of bacteremia due to extended-spectrum beta-lactamase-producing Escherichia coli: a post hoc analysis of prospective cohorts. Clin Infect Dis. 2012 Jan 15;54(2):167–74. [PMID: 22057701]|
|Wessels MR. Clinical Practice. Streptococcal pharyngitis. N Engl J Med. 2011 Feb 17; 364(7): 648–55.