e1-01: Penicillins

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 binding to receptors, ie, penicillin-binding proteins. After attaching to receptors, penicillins inhibit peptidoglycan synthesis by blocking transpeptidation. The final bactericidal action is to remove an autolytic enzyme inhibitor in the cell wall, which results in cell lysis. Organisms that produce beta-lactamases (penicillinases) are resistant to some penicillins because the beta-lactam ring is broken. Only organisms actively synthesizing peptidoglycan (in the process of multiplication) are susceptible to penicillins and other beta-lactam antibiotics. Nonmultiplying organisms or those lacking cell walls are not susceptible.

Microbial resistance to penicillins is associated with five mechanisms: (1) production of beta-lactamases, (eg, by staphylococci, gonococci, Haemophilus species, and coliform organisms, including extended-spectrum beta-lactamase [ESBL]–producing 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); (3) impermeability of the cell envelope (eg, by Pseudomonas species); (4) failure to activate autolytic enzymes in the cell wall—“tolerance” (eg, in staphylococci, group B streptococci); and (5) cell wall-deficient (L) forms or mycoplasmas, which do not synthesize peptidoglycans.

The natural penicillins include penicillin G for parenteral administration (aqueous crystalline for intravenous or benzathine penicillin G for intramuscular administration) 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 at the site of infection; (2) other streptococci, such as Streptococcus pyogenes, (including anaerobic streptococci); (3) meningococci; (4) non–beta-lactamase-producing staphylococci; (5) Treponema pallidum and other spirochetes; (6) Cutibacterium (formerly Propionibacterium) acnes and other gram-positive anaerobic bacilli; (7) non-difficile clostridia; and (8) Actinomyces. See Table 30–4.

Pharmacokinetics & Administration

Penicillin has wide extracellular distribution with decreased levels in the eye, prostate, and cerebrospinal fluid. However, with inflamed meninges and appropriate dosing, sufficient penetration into the cerebrospinal fluid can be achieved.

Intramuscular administration of benzathine penicillin allows for extended release of penicillin, providing continuous therapeutic blood and tissue levels for the treatment of syphilis.

Phenoxymethyl penicillin (penicillin V) is the oral penicillin of choice because of its superior bioavailability compared with penicillin G. Penicillin is primarily eliminated by the kidney through both glomerular filtration and active 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 more serious infections (meningitis, endocarditis), increased doses (3–4 million units intravenously every 4–6 hours with normal kidney function) are required.

Penicillin V (or oral amoxicillin) is the medication of choice for the treatment of S pyogenes pharyngitis and cellulitis. Treatment of 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 30–6).

The extended-spectrum group of penicillins includes the aminopenicillins: ampicillin and amoxicillin. These medications are susceptible to destruction by staphylococcal (and other) beta-lactamases. The ureidopenicillin piperacillin is available only in combination with the beta-lactamase inhibitor tazobactam (piperacillin-tazobactam). 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.

Antimicrobial Activity

Ampicillin and amoxicillin are active against most strains of Proteus mirabilis, Listeria, and non–beta-lactamase-producing Haemophilus influenzae. They are inactive against most aerobic gram-negative pathogens. Both are predictably active against penicillin-susceptible pneumococcus and Enterococcus faecalis; however, ampicillin-resistant E faecalis has emerged. Enterococcus faecium is commonly resistant to both ampicillin and piperacillin.

Piperacillin is active against Pseudomonas aeruginosa and Klebsiella. Piperacillin and ampicillin have approximately equal activity against E faecalis and pneumococci. It inhibits many, but not all, anaerobes. Unlike ampicillin and amoxicillin, piperacillin is active against beta-lactamase–producing strains of Bacteroides fragilis.

Pharmacokinetics & Administration

Ampicillin can be administered orally or parenterally. Amoxicillin is preferable to ampicillin in the oral treatment of infection because of its improved oral bioavailability and more favorable dosing requirements. An extended-release amoxicillin tablet (Moxatag) is approved for once-daily use for streptococcal pharyngitis in children younger than 12 years.

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

Clinical Uses

Amoxicillin is given orally for minor upper respiratory tract infections, such as acute sinusitis or acute otitis media and uncomplicated, outpatient community-acquired pneumonia. Ampicillin is administered intravenously for hospitalized patients with community-acquired pneumonia (in combination with sulbactam), meningitis, bacteremia, or endocarditis.

Because of the increased serum and respiratory secretion levels with amoxicillin when compared with penicillin, amoxicillin is effective in the treatment of susceptible and moderately penicillin-susceptible pneumococcus. Maintenance of amoxicillin levels 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/day in adults) optimizes clinical and microbiologic outcomes. An ambulatory course of amoxicillin, 1 g three times daily, is recommended for treatment of uncomplicated, outpatient community-acquired pneumonia. Amoxicillin is also used as prophylaxis for endocarditis in at-risk patients.

The addition of beta-lactamase inhibitors (clavulanic acid, sulbactam, tazobactam) prevents inactivation of the parent penicillin by some, but not all, beta-lactamases. Marketed products include amoxicillin 250 mg, 500 mg, or 875 mg, plus 125 mg of clavulanic acid (tablet); amoxicillin 1 g plus 62.5 mg of clavulanic acid (extended-release tablet preparation); ampicillin 1 g plus sulbactam 0.5 g, and ampicillin 2 g plus sulbactam 1 g (vial for intravenous injection); and piperacillin 3 g plus tazobactam 0.375 g, and piperacillin 4 g plus tazobactam 0.5 g (vial for intravenous injection). Amoxicillin-clavulanic acid is given orally; ampicillin-sulbactam and piperacillin-tazobactam are administered intravenously. In Europe, amoxicillin-clavulanic acid is also available as a parenteral formulation. 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 penicillin–beta-lactamase inhibitor combinations, piperacillin-tazobactam has the broadest spectrum of activity. Like ampicillin-sulbactam, piperacillin-tazobactam is active against ampicillin-susceptible enterococci. It has greater in vitro activity against P aeruginosa, Serratia, and Klebsiella species when compared with amoxicillin-clavulanic acid or ampicillin-sulbactam. While piperacillin-tazobactam is active in vitro against ESBL-producing organisms, its clinical efficacy is less consistent when compared with other agents. Carbapenem antibiotics (see below) should be considered the first-line treatment of serious infection due to ESBL-producing bacteria.

Amoxicillin-clavulanic acid is recommended for the outpatient treatment of comorbid patients with community-acquired pneumonia, refractory cases of otitis media, and prophylaxis of infections resulting from animal and human bites. The Infectious Diseases Society of America (IDSA) considers amoxicillin-clavulanic acid to be the antibacterial of choice in the treatment of acute bacterial rhinosinusitis. The roles of the parenteral penicillin–beta-lactamase inhibitors include the treatment of polymicrobial infections such as peritonitis from a ruptured viscus, osteomyelitis in a patient with diabetes, or traumatic osteomyelitis.

When piperacillin-tazobactam is used to treat Pseudomonas infections, increased dosages (200–300 mg/kg/day of the piperacillin component) should be used.

Piperacillin-tazobactam treatment of pseudomonal isolates with reduced piperacillin-tazobactam susceptibility may be associated with increased mortality. Nonpseudomonal infections can be treated with lower doses (100–200 mg/kg/day of the piperacillin component). Taking advantage of pharmacokinetics and pharmacodynamics, extended infusions of piperacillin-tazobactam may be superior to intermittent bolus dosing in the treatment of serious bacterial infections and febrile neutropenia.

Oxacillin, cloxacillin, dicloxacillin, and nafcillin are resistant to degradation by beta-lactamases produced by staphylococci. They are superior to vancomycin in the treatment of serious infection due to methicillin-susceptible S aureus. They are less active in vitro 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 with decreased kidney function.

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. The incidence of anaphylaxis to penicillins is estimated to be 0.015–0.004%, with a fatality rate of 0.002–0.0015%. Only a small minority of patients who claim allergy to penicillin will have a true anaphylactic reaction with subsequent exposure to penicillins. It is important to distinguish “true” allergies to penicillin versus those reactions that are not life-threatening or represent antibiotic intolerance. Avoidance of beta-lactams in patients with reported allergy results in increased adverse events, increased risk for Clostridioides difficile superinfection, and decreased clinical efficacy. All penicillins in excessive doses, particularly with decreased kidney 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. The combination of piperacillin-tazobactam and vancomycin is associated with increased risk of nephrotoxicity when compared with other vancomycin–beta-lactam combinations. Dicloxacillin may decrease international normalized ratio levels in patients receiving warfarin.