Nafcillin (see Table 44-1) is highly resistant to penicillinase and has proven effective against infections caused by penicillinase-producing strains of S. aureus.

Pharmacological Properties

Nafcillin is slightly more active than oxacillin against penicillin G-resistant S. aureus. While it is the most active of the penicillinase-resistant penicillins for most microorganisms, it is not as potent as penicillin G.

Oral absorption of nafcillin is irregular, and injectable preparations should be used. Nafcillin is ~90% bound to plasma protein. Peak concentrations of nafcillin in bile exceed those found in plasma. Drug concentrations in CSF are adequate for therapy of staphylococcal meningitis.

Aminopenicillins: Ampicillin, Amoxicillin, and Their Congeners ANTIMICROBIAL ACTIVITY

Ampicillin and the related aminopenicillins are bactericidal for both gram-positive and gramnegative bacteria. The meningococci and L. monocytogenes are sensitive to this class of drugs.

Many pneumococcal isolates have varying levels of resistance to ampicillin. Penicillin-resistant strains should be considered ampicillin/amoxicillin-resistant. H. influenzae and the viridans group of streptococci exhibit varying degrees of resistance. Enterococci are twice as sensitive to ampicillin as they are to penicillin. From 30% to 50% of E. coli, a significant number of P. mirabilis, and practically all species of Enterobacter are insensitive. Resistant strains of Salmonella are recovered with increasing frequency. Most strains of Shigella, Pseudomonas, Klebsiella, Serratia, Acinetobacter, and indole-positive Proteus are resistant to this group of penicillins; these antibiotics are less active against B. fragilis than is penicillin G. Concurrent administration of ^-lactamase inhibitors markedly expands their spectrum of activity (see below).

ampicillin This drug is the prototype of the group (see structure in Table 44-1).

Pharmacological Properties Ampicillin (principen, others) is well absorbed after oral administration. Intake of food prior to ampicillin ingestion diminishes absorption. Severe renal impairment markedly prolongs the t1/2 of ampicillin in the plasma. Peritoneal dialysis does not remove the drug from the blood, but hemodialysis removes ~40% of the body store in 7 hours. Ampicillin doses must be decreased in the setting of renal dysfunction. Ampicillin undergoes enterohepatic circulation and is excreted in appreciable quantities in the feces.

amoxicillin This penicillinase-susceptible penicillin is closely related to ampicillin (Table 44-1). The drug is absorbed more rapidly and completely from the GI tract than is ampicillin. The antimicrobial spectrum of amoxicillin is essentially identical to that of ampicillin, except that amoxicillin is less effective for shigellosis.

Peak plasma concentrations of amoxicillin (amoxil, others) are twice those of ampicillin after oral administration of the same dose. Food does not interfere with absorption. Perhaps because of its more complete absorption, the incidence of diarrhea with amoxicillin is less than that with ampicillin. The incidence of other adverse effects is similar. While the t1/2 of amoxicillin is similar to that for ampicillin, effective concentrations of orally administered amoxicillin are detectable in the plasma for twice as long as with ampicillin because of its more complete absorption. About 20% of amoxicillin is protein-bound in plasma. Most of the antibiotic is excreted in an active form in the urine.

therapeutic indications for the aminopenicillins

Upper Respiratory Infections Ampicillin and amoxicillin are active against S. pyogenes and many strains of S. pneumoniae and H. influenzae, which are major upper respiratory pathogens. The drugs are effective for sinusitis, otitis media, acute exacerbations of chronic bronchitis, and epiglottitis caused by sensitive strains of these organisms. Amoxicillin is the most active of the oral f>-lactam antibiotics against both penicillin-sensitive and penicillin-resistant S. pneumoniae. Based on the increasing prevalence of pneumococcal resistance to penicillin, an increase in dose of oral amoxicillin (from 40-45 to 80-90 mg/kg/day) for empirical treatment of acute otitis media in children is recommended. Ampicillin-resistant H. influenzae also is a problem in many areas. The addition of a b-lactamase inhibitor (amoxicillin-clavulanate or ampicillin-sulbactam) extends the spectrum to b-lactamase-producing H. influenzae and Enterobacteriaceae. Bacterial pharyngitis should be treated with penicillin G or penicillin V because S. pyogenes is the major pathogen.

Urinary Tract Infections Most uncomplicated urinary tract infections are caused by Enterobac-teriaceae, and E. coli is the most common species; ampicillin often is an effective agent, although resistance is increasing. Enterococcal urinary tract infections are treated effectively with ampicillin alone.

Meningitis Ampicillin is not indicated for single-agent treatment of acute bacterial meningitis in children. Ampicillin has excellent activity against L. monocytogenes, which causes meningitis in immunocompromised persons. Thus, the combination of ampicillin and vancomycin plus a third-generation cephalosporin is a rational regimen for empirical treatment of suspected bacterial meningitis.

Salmonella Infections High doses of ampicillin (12 g/day for adults) are often effective, but resistance is common. The typhoid carrier state has been eliminated successfully in patients without gallbladder disease with ampicillin.

Antipseudomonal Penicillins: Carboxypenicillins and Ureidopenicillins

The carboxypenicillins, carbenicillin and ticarcillin, are active against some isolates of P. aerugi-nosa and certain indole-positive Proteus spp. that are resistant to ampicillin and its congeners. They are ineffective against most strains of S. aureus, Enterococcus faecalis, Klebsiella, and

L. monocytogenes. B. fragilis is susceptible to high concentrations of these drugs, but penicillin G is more active. The ureidopenicillins, mezlocillin and piperacillin, have superior activity against P. aeruginosa compared with carbenicillin and ticarcillin. Mezlocillin and piperacillin also are useful for Klebsiella infections. The carboxypenicillins and the ureidopenicillins are sensitive to destruction by ^-lactamases.

carbenicillin indanyl (geocillin)

This indanyl ester of carbenicillin is excreted rapidly in the urine; its only use is for the management of urinary tract infections caused by Proteus spp. other than P. mirabilis and by P. aeruginosa.

ticarcillin (ticar)

This semisynthetic penicillin (Table 44—1) is similar to carbenicillin but two to four times more active against P. aeruginosa. Ticarcillin is inferior to piperacillin for serious infections caused by



This ureidopenicillin is more active against Klebsiella than is carbenicillin; its activity against

Pseudomonas is similar to that of ticarcillin. It is more active than ticarcillin against E. faecalis.

Mezlocillin sodium (mezlin) has been discontinued in the U.S.

piperacillin (pipracil) Piperacillin (pipracil) extends the spectrum of ampicillin to include most strains of P. aeruginosa, Enterobacteriaceae (non-^-lactamase-producing), many Bacteroides spp. and E. faecalis. In combination with a ^-lactamase inhibitor (piperacillin-tazobactam, zosyn), it has the broadest antibacterial spectrum of the penicillins. Pharmacokinetic properties are reminiscent of the other ureidopenicillins. High biliary concentrations are achieved.

therapeutic indications Piperacillin and related agents are important drugs for the treatment of serious infections caused by gram-negative bacteria, including infections acquired in the hospital. These penicillins find their greatest use in treating bacteremias, pneumonias, infections following burns, and urinary tract infections owing to microorganisms resistant to penicillin G and ampicillin; the bacteria especially responsible include P. aeruginosa, indole-positive strains of Proteus, and Enterobacter spp. Since Pseudomonas infections are common in neutropenic patients, therapy for severe bacterial infections in such individuals should include a ^-lactam antibiotic such as piperacillin with good activity against these bacteria.

Untoward Reactions to Penicillins hypersensitivity reactions Hypersensitivity reactions complicate 0.7-4% of all treatment courses: rash, urticaria, fever, bronchospasm, vasculitis, serum sickness, exfoliative dermatitis, and anaphylaxis. Allergy to one penicillin increases the risk of reaction if another penicillin is given. Hypersensitivity reactions may appear in the absence of previous known exposure to the drug. in some cases, the reaction is mild and disappears even when the penicillin is continued; in others, immediate cessation of penicillin is required. in a few instances, it is necessary to interdict the future use of penicillin because of the risk of death, and the patient should be so warned.

Penicillins and their breakdown products act as haptens after covalent reaction with proteins. The most abundant breakdown product is the penicilloyl (major) moiety. A large percentage of IgE-mediated reactions are to this derivative, but at least 25% of reactions are to other breakdown products. The terms major and minor determinants refer to the frequency with which antibodies to these haptens appear to form rather than the severity of the reaction that may result, and anaphylactic reactions to penicillin usually are mediated by igE antibodies against minor determinants.

Antipenicillin antibodies are detectable in virtually all patients who have received the drug (and in many who deny previous exposure). Immediate allergic reactions are mediated by skin-sensitizing or IgE antibodies, usually of minor-determinant specificities. Accelerated and late urticarial reactions usually are mediated by major-determinant-specific skin-sensitizing antibodies. Some reactions may be due to toxic antigen-antibody complexes of major-determinant-specific IgM antibodies.

Rashes of all types may be caused by allergy to penicillin. Henoch-Schonlein purpura with renal involvement has been a rare complication. contact dermatitis is observed occasionally in pharmacists, nurses, and physicians who prepare penicillin solutions. Fixed-drug reactions also have occurred. More severe reactions involving the skin are exfoliative dermatitis and exudative erythema multiforme. The incidence of rashes appears to be highest following the use of ampicillin (~9%); rash follows the administration of ampicillin in nearly all patients with infectious mononucleosis.

The most serious hypersensitivity reactions produced by the penicillins are angioedema and anaphylaxis. Acute anaphylactic or anaphylactoid reactions to the penicillins constitute the most important immediate danger connected with their use. Among all drugs, the penicillins are most often responsible for this type of untoward effect. Anaphylactoid reactions to penicillins may occur at any age; their incidence is thought to be 0.004-0.04%. About 0.001% of patients treated with these agents die from anaphylaxis. Anaphylaxis most often has followed parenteral use but also has been observed after oral or intradermal administration. The most dramatic reaction is sudden hypotension and death. In other instances, bronchoconstriction with severe asthma; abdominal pain, nausea, and vomiting; extreme weakness; or diarrhea and purpuric skin eruptions have characterized the anaphylactic episodes.

Serum sickness reactions mediated by IgG antibodies can rarely appear after penicillin treatment has been continued for 1 week or more; they may be delayed until 1 or 2 weeks after the drug has been stopped and may persist for a week or longer.

Vasculitis may be related to penicillin hypersensitivity. The Coombs reaction frequently becomes positive during prolonged therapy, but hemolytic anemia is rare. Reversible neutropenia has been noted, occurring in up to 30% of patients treated with 8-12 g nafcillin for longer than 21 days. Eosinophilia occasionally accompanies other allergic reactions to penicillin.

Fever may be the only evidence of a hypersensitivity reaction to the penicillins. The febrile reaction usually disappears within 24-36 hours after drug administration is stopped but may persist for days. Penicillins rarely cause interstitial nephritis; methicillin has been implicated most frequently.

management of the patient potentially allergic to penicillin

Evaluation of the patient's history is the most practical way to identify patients at greatest risk of allergic reaction. Most patients with a history of penicillin allergy should be treated with another antibiotic. There is no totally reliable means to confirm a history of penicillin allergy. Skin testing using major and minor penicillin determinants is useful if available. Occasionally, desensitization is recommended for penicillin-allergic patients who must receive the drug. Gradually, increasing doses of penicillin are administered in the hope of binding all of the IgE without provoking anaphylaxis. When full doses are reached, penicillin should not be stopped and then restarted, as immediate reactions may recur. This procedure should be performed only in an intensive care setting, and its efficacy is unproven.

Patients with life-threatening infections (e.g., endocarditis or meningitis) may be continued on penicillin despite the development of a maculopapular rash, although alternative antibiotics should be used whenever possible. The rash often resolves as therapy is continued, perhaps owing to the development of blocking antibodies of the IgG class. Rarely, exfoliative dermatitis, with or without vasculitis, develops in these patients if therapy with penicillin is continued.

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