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 receptors—penicillin-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 -lactamase (ESBL)–producing 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.

Natural Penicillins

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 (however, up to 30–35% of strains now demonstrate intermediate- or high-level resistance to penicillin); (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 30–4.

Pharmacokinetics & Administration

After parenteral administration, penicillin has wide extracellular distribution. 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 secretion.

Clinical Uses

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 daily doses (18–24 million units intravenously) 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 1–3 weeks, depending on the stage of the disease (see Table 30–10).

Extended-Spectrum Penicillins

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 gram-positive bacteria. With the availability of -lactamase inhibitor combinations, such as ampicillin-sulbactam and piperacillin-tazobactam, ticarcillin and piperacillin are no longer marketed in the United States.

Antimicrobial Activity

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, piperacillin, and the -lactam/-lactamase inhibitor ticarcillin-clavulanate are no longer marketed. However, considering that piperacillin-tazobactam is commercially available, it is important to know the spectrum of activity of piperacillin.

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 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) has been approved for once-daily use for streptococcal pharyngitis in children < 12 years.

Piperacillin (in combination with tazobactam) is given intravenously and increased doses (200–300 mg/kg/d) are required for treatment of infections due to P aeruginosa.

See Table 30–11 for a summary of dosage adjustments that are required in kidney disease.

Clinical Uses

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, 80–90 mg/kg/d in two doses, has been found to be equivalent to parenteral antibacterials in the treatment of community-acquired pneumonia.

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); 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 or Unasyn. While these agents are sometimes active in vitro, they are less useful clinically in the treatment of ESBL–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 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 is used to treat Pseudomonas infections, dosages of 200–300 mg/kg/d of the piperacillin 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 (100–200 mg/kg/d).

Antistaphylococcal Penicillins

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 nonrenal—thus, no dosage adjustment is needed in kidney disease.

Toxicity & Adverse Events

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 popular 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.