Chapter: Modern Pharmacology with Clinical Applications: β-Lactam Antibiotics


The penicillins are a large group of bactericidal com-pounds. They can be subdivided and classified by their chemical structure and spectrum of activity.



The penicillins are a large group of bactericidal com-pounds. They can be subdivided and classified by their chemical structure and spectrum of activity. The struc-ture common to all penicillins is a β-lactam ring fused with a thiazolidine nucleus (Fig. 45.1). The antimicrobial activity of penicillin resides in the β-lactam ring. Splitting of the β-lactam ring by either acid hydrolysis or β-lactamases results in the formation of penicilloic acid, a product without antibiotic activity. Addition of various side chains (R) to the basic penicillin molecule creates classes of compounds with the same mechanism of action as penicillin but with different chemical and biological properties. For example, some analogues are resistant to hydrolysis by acid or β-lactamase; some have an extended the spectrum of antibacterial activity; and others show improved absorption from the intes-tinal tract.


Penicillins may be classified into four groups: natural penicillins (G and V), antistaphylococcal (penicillinase-resistant) penicillins, aminopenicillins, and antipseudo-monal penicillins. Natural penicillins have therapeutic ef-fects limited to streptococci and a few gram-negative organisms. The antistaphylococcal (penicillinase-resist-ant) penicillins treat infections caused by streptococci and staphylococci but do not affect MRSA. The amino-penicillins are effective against streptococci, enterococci, and some gram-negative organisms but have variable activity against staphylococci and are ineffective against P. aeruginosa. The antipseudomonal penicillins retain activity against streptococci and possess additional ef-fects against gram-negative organisms, including various Enterobacteriaceae and Pseudomonas.


Natural Penicillins


Penicillin G (benzylpenicillin) is an acid-labile com-pound having variable bioavailability after oral adminis-tration. Consequently, penicillin G is most appropriate for intramuscular or intravenous therapy. The drug dis-tributes to most tissues and serosa-lined cavities, al-though low concentrations appear in breast milk and cerebrospinal fluid. When the meninges are inflamed, cerebrospinal fluid concentrations of penicillin G ap-proximate 5% of the serum concentration. In inflamed joints, concentrations of the drug approach serum levels.


Penicillin G is excreted by the kidneys, with 90% of renal elimination occurring via tubular secretion and 10% by glomerular filtration. Probenecid blocks tubular secretion and has been used to increase the serum con-centration and prolong the half-life of penicillin G and other penicillins. Additional pharmacokinetic informa-tion can be found in Table 45.1.


The clinical uses of penicillin G include endocarditis caused by S. viridans (or Streptococcus bovis), pharyngi-tis (group A -hemolytic streptococci), cat bite cellulitis (Pasteurella multocida), and syphilis (Treponema pal-lidum).


Depot intramuscular formulations of penicillin G, including procaine penicillin and benzathine penicillin, have decreased solubility, delayed absorption, and a prolonged half-life. Drug concentrations are detectable 24 hours after injection of procaine penicillin, and low levels of benzathine penicillin (0.003 units/mL) are de-tectable 4 weeks after injection.


When prescribing one of the penicillin G depot for-mulations, practitioners must individualize treatment to clinical and microbial conditions. Some long-acting for-mulations may not maintain adequate plasma and tissue concentrations to treat specific organisms or infections. For acute streptococcal meningitis, the goal is rapid achievement of high antibiotic concentrations in the cerebrospinal fluid. Consequently, depot formulations are inappropriate for meningitis. Intravenous penicillin G is among the antibiotics of first choice for therapy of meningitis caused by susceptible S. pneumoniae. In con-trast, a depot formulation of benzathine penicillin G suffices for rheumatic fever prophylaxis.


Penicillin V is an orally administered phenoxy-methyl congener of penicillin G having an antibacterial spectrum of activity that is similar to that of penicillin G. Penicillin V is used to treat streptococcal infections when oral therapy is appropriate and desirable.


Antistaphylococcal (penicillinase-resistant) Penicillins


Nafcillin, oxacillin, cloxacillin, and dicloxacillin are more resistant to bacterial β-lactamases than is penicillin G. Consequently, these antibiotics are effective against streptococci and most community-acquired penicilli-nase-producing staphylococci. Methicillin, which is no longer marketed in the United States, is another peni-cillinase-resistant antibiotic similar to nafcillin and oxacillin. For historical reasons, staphylococci resistant to oxacillin or nafcillin are labeled methicillin resistant. Many hospitals are reservoirs for MRSA and methi-cillin-resistant Staphylococcus epidermidis (MRSE). These nosocomial pathogens are resistant in vitro to all β-lactam antibiotics.

For parenteral therapy, nafcillin and oxacillin offer comparable efficacy and antimicrobial spectra of activ-ity. Although both drugs undergo hepatic metabolism, only nafcillin requires dose adjustment in patients with combined hepatic and renal insufficiency. Other phar-macokinetic data for nafcillin and oxacillin appear in Table 45.1. Indications for nafcillin or oxacillin include severe staphylococcal infections like cellulitis, empyema, endocarditis, osteomyelitis, pneumonia, septic arthritis, and toxic shock syndrome.


For oral therapy, cloxacillin and dicloxacillin are comparable alternatives. Both undergo hepatic metabo-lism, and neither drug requires dose adjustment in pa-tients with hepatic insufficiency. Additional pharmaco-kinetic data are in Table 45.1. Indications for cloxacillin or dicloxacillin include clinically mild staphylococcal in-fections like impetigo.




The pharmacokinetics of ampicillin and amoxicillin are similar (Table 45.1). Both have good oral bioavailabil-ity; ampicillin is also bioavailable after intramuscular injection. Concomitant ingestion of food decreases the bioavailability of ampicillin but not amoxicillin. Consequently, oral doses of ampicillin should be given on an empty stomach. Ampicillin achieves therapeutic concentrations in the cerebrospinal fluid only during in-flammation. Therefore, ampicillin is effective treatment for meningitis caused by Listeria monocytogenes. Amoxicillin does not reach adequate concentrations in the central nervous system and is not appropriate for meningitis therapy. Other indications for ampicillin in-clude serious infections like enterococcal endocarditis and pneumonia caused by β-lactamase-negative H. in-fluenzae. Amoxicillin oral therapy is appropriate for clinically acute nonserious bacterial infections like otitis media and sinusitis. Amoxicillin also has use in mul-tidrug regimens for the eradication of Helicobacter py-lori in duodenal and gastric ulcers.



Antipseudomonal Penicillins


Mezlocillin, piperacillin, and ticarcillin are parenteral antibiotics formulated as sodium salts, so prescribers must consider the sodium content of these antibiotics when administering them to patients with congestive heart failure. During their distribution phase, an-tipseudomonal penicillins achieve only low concentra-tions in the cerebrospinal fluid. Consequently, an-tipseudomonal penicillins are not among the drugs of first choice for meningitis therapy.


The antipseudomonal penicillins undergo renal elimination (Table 45.1). Piperacillin and ticarcillin have minimal hepatic metabolism. In contrast, me-zlocillin has significant hepatic metabolism and requires dose adjustment in patients with hepatic insufficiency.

The antipseudomonal penicillins have comparable spectra of activity against many gram-positive and gram-negative pathogens, including most anaerobes. Mezlocillin, piperacillin, and ticarcillin have similar clin-ical outcomes in patients with known or suspected P. aeruginosa infections. Antipseudomonal penicillins are used to treat pneumonias associated with cystic fibrosis or mechanical ventilation.


Carbenicillin indanyl sodium is an antipseudomonal penicillin formulated for oral administration. The drug achieves negligible carbenicillin concentrations in the urine of patients with renal failure. Consequently, car-benicillin is not appropriate for patients with renal fail-ure. In patients with normal renal function, however, carbenicillin indanyl sodium is used to treat urinary tract infections caused by P. aeruginosa, Proteus spp., and Escherichia coli.


β-Lactamase Inhibitor Combinations


Several formulations combine a β-lactam antibiotic with a β-lactamase inhibitor (ampicillin-sulbactam [Unasyn], ticarcillin-clavulanic acid [Timentin], piper-acillin-tazobactam [Zosyn], and amoxicillin–clavulanic acid [Augmentin]). All of the β-lactamase inhibitor combinations except amoxicillin-clavulanic acid are parenteral formulations. Amoxicillin–clavulanic acid is the only combination drug with oral bioavailability. Elimination of the combination drugs occurs primarily by renal excretion. Therefore, all of the β-lactamase in-hibitor combinations require dose adjustments in pa-tients with renal insufficiency. The addition of the β-lactamase inhibitor significantly broadens the spectrum of antibacterial activity against β-lactamase-producing organisms. Consequently, these drugs have clinical use in treating infections with known or suspected mixed bacterial flora, such as biliary infections, diabetic foot ulcers, endomyometritis, and peritonitis.


β-Lactam Antibiotics in Pregnancy


All of the penicillin antibiotics are classified by the U. S. Food and Drug Administration (FDA) in pregnancy category B, that is, as drugs having either no fetal risk in animal studies but human trials are inadequate, or animal studies show adverse fetal effects but well-controlled human trials reveal no fetal damage. Obstetricians frequently prescribe ampicillin, penicillin G, and penicillin V because they are effective against the infections most frequently encountered in caring for pregnant women (e.g., upper respiratory and lower uri-nary tract infections).



Adverse Effects


While being associated with a low percentage of ad-verse reactions, the β-lactams are the most frequent source of troublesome allergic reactions among the an-tibiotics. The overall frequency of adverse effects asso-ciated with penicillin use is less than 10%, including al-lergic and other reactions. Anaphylaxis is a serious, rare allergic response with an occurrence rate between 0.004% and 0.015% of penicillin courses. Allergic reactions to penicillin are immediate immunoglobulin (Ig) E–mediated type I immune responses. Symptoms and signs of IgE-mediated reactions may include ur-ticaria, pruritus, bronchospasm, angioedema, laryngeal edema, and hypotension. Late onset immune-mediated reactions to β-lactam antibiotics may manifest as eosinophilia, hemolytic anemia, interstitial nephritis, or serum sickness. In contrast to the rare allergic reactions, nonallergic β-lactam rashes are common. For example, ampicillin is associated with nonurticarial rashes in 5 to 10% of recipients.


The incidence of nonallergic ampicillin eruptions is 40 to 100% in patients with concomitant Epstein-Barr virus (mononucleosis), cytomegalovirus, acute lympho-cytic leukemia, lymphoma, or reticulosarcoma. Non-allergic penicillin-associated rashes are characteristi-cally morbilliform (symmetrical, erythematous, confluent, maculopapular) eruptions on the extremities. The onset of typical nonallergic eruptions is more than 72 hours after β-lactam exposure. The mechanism for the nonurticarial ampicillin rash is not known and is not related to IgE or type I hypersensitivity. Penicillin skin tests are not useful in the evaluation of nonurticarial ampicillin rashes. Patients with a history of nonurticar-ial ampicillin rashes may receive other β-lactam antibi-otics without greater risk of subsequent serious allergic reactions.


Allergic cross-reactivity between β-lactam antibi-otics is significant. The frequency of allergic reactions to another β-lactam antibiotic is 5.6% among patients with a history of IgE-mediated hypersensitivity to one β-lactam antibiotic plus positive results from a peni-cillin skin test. In general, patients with a convincing his-tory of type I reaction to one β-lactam antibiotic should avoid all other β-lactam antibiotics except aztreonam. However, most patients give unreliable histories of penicillin allergy because of confusion with nonallergic penicillin rashes. Among patients who report penicillin allergies, 80 to 90% have negative results from peni-cillin skin tests, and 98% tolerate subsequent β-lactam antibiotic treatments. A careful history may discrimi-nate between nonallergic reactions and true penicillin allergy and permit safe β-lactam therapy.


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