1

Mur NAc

0 L-Alanlne 0 D-Glutamate ® L-Lysine O Glycine O D-Alanine Mur NAc = N-Acetyl-muramic acid

FIGURE 44-2 Action of P-lactam antibiotics in Staphylococcus aureus. The bacterial cell wall consists of glycopeptide polymers linked via bridges between amino acid side chains. In S. aureus, the bridge is (Gly)5-D-Ala between lysines. The cross-linking is catalyzed by a transpeptidase, the enzyme that penicillins and cephalosporins inhibit.

FIGURE 44-2 Action of P-lactam antibiotics in Staphylococcus aureus. The bacterial cell wall consists of glycopeptide polymers linked via bridges between amino acid side chains. In S. aureus, the bridge is (Gly)5-D-Ala between lysines. The cross-linking is catalyzed by a transpeptidase, the enzyme that penicillins and cephalosporins inhibit.

readily in tissues and in many secretions. Penicillins do not significantly penetrate living phagocytic cells, and only low concentrations are found in prostatic secretions, brain, and intraocular fluid. Concentrations of penicillins in cerebrospinal fluid (CSF) are <1% of those in plasma when the meninges are normal. With inflammation, CSF concentrations may increase to 5% of the plasma value. Penicillins are eliminated rapidly by the kidney; their half-lives in the body are short (typically 30-90 minutes) and their urine concentrations are high.

Gram positive

Peptldo-

glycan layers

Gram negative

Specific Porin channel —, O Polysaccharide! Lipopoly-^ LipldAl^ande

Peptldo-

glycan layers

Penicillin Binding Protein (PBP) '

FIGURE 44-3 Comparison of the structure and composition of gram-positive and gram-negative cell walls.

Penicillin Binding Protein (PBP) '

Periplasms space

Phospholipid - Proteins

FIGURE 44-3 Comparison of the structure and composition of gram-positive and gram-negative cell walls.

Penicillin G and Penicillin V

antimicrobial activity The antimicrobial spectra of penicillin G (benzylpenicillin) and penicillin V (the phenoxymethyl derivative) are very similar for aerobic gram-positive microorganisms. Penicillin G is 5-10 times more active against Neisseria spp. and certain anaerobes.

Most streptococci (but not enterococci) are very susceptible to the drug. However, penicillin-resistant viridans streptococci and S. pneumoniae are increasingly seen. Penicillin-resistant pneu-mococci also are resistant to third-generation cephalosporins and are especially common in children. More than 90% of staphylococcal isolates are now resistant to penicillin G, as are most strains of S. epidermidis and many strains of gonococci. With rare exceptions, meningococci are quite sensitive to penicillin G.

Most anaerobic microorganisms, including Clostridium spp., are highly sensitive. Bacteroides fragilis is generally resistant to penicillins and cephalosporins by virtue of expressing a broad-spectrum cephalosporinase. Actinomyces israelii, Streptobacillus moniliformis, Pasteurella multocida, and L. monocytogenes are inhibited by penicillin G. Most species of Leptospira are moderately susceptible to the drug. Treponema pallidum is exquisitely sensitive. Borrelia burgdorferi, the organism responsible for Lyme disease, also is susceptible.

absorption

Oral Administration About one-third of an oral dose of penicillin G is absorbed from the GI tract under favorable conditions. Gastric juice at pH 2 rapidly destroys the antibiotic. Absorption is rapid, and maximal concentrations in blood are attained within 1 hour. Ingestion of food may interfere with GI absorption. Thus, oral penicillin G should be administered at least 30 minutes before or 2 hours after a meal, and oral therapy should be used only for infections in which clinical experience has proven its efficacy. The virtue of penicillin V in comparison with penicillin G is that it is better absorbed from the GI tract, yielding plasma concentrations two to five times greater than those provided by penicillin G.

Parenteral Administration of Penicillin G After intramuscular injection, peak concentrations in plasma are reached within 15-30 minutes. This value declines rapidly (t1/2 of 30 minutes). Repository preparations of penicillin G increase the duration of its effect. Such compounds include penicillin G procaine (wycillin, others) and penicillin G benzathine (bicillin l-a, permapen), which produce relatively low but persistent levels of penicillin in the blood.

Penicillin G procaine suspension combines procaine with penicillin in equimolar ratios; a dose of 300,000 units contains ~120 mgprocaine, which exerts local anesthetic effects when injected. If the patient is believed to be hypersensitive to procaine, a test dose of 0.1 mL of 1% solution of procaine should be injected first.

Penicillin G benzathine suspension is the aqueous suspension of the salt obtained by combining 1 mol of an ammonium base and 2 mol of penicillin G; this provides a very slow release. The persistence of penicillin in the blood after an intramuscular dose reduces cost, need for repeated injections, and local trauma. The average duration of demonstrable antimicrobial activity in the plasma is 26 days.

distribution Penicillin G is distributed widely, but the concentration differs in various fluids and tissues. Its apparent volume of distribution is ~0.35 L/kg. Approximately 60% of penicillin G in plasma is reversibly bound to albumin. Significant amounts appear in liver, bile, kidney, semen, joint fluid, and lymph.

Cerebrospinal Fluid Penicillin does not readily enter the CSF but penetrates more easily with meningeal inflammation. The concentration attained usually reaches 5% of the value in plasma and thus is therapeutically effective against susceptible microorganisms. Penicillin and other organic acids are secreted rapidly from the CSF into the bloodstream by an active transport process. In uremia, other organic acids compete with penicillin for secretion; the drug occasionally reaches toxic CNS concentrations that can produce convulsions.

excretion Normally, penicillin G is eliminated rapidly from the body, mainly by the kidney. Approximately 60-90% of an intramuscular dose of penicillin G in aqueous solution is eliminated in the urine, largely within the first hour after injection. The remainder is metabolized to penicilloic acid. The t1/2 for elimination of penicillin G is ~30 minutes in normal adults. Approximately 10% of the drug is eliminated by glomerular filtration and 90% by tubular secretion.

Clearance values are considerably lower in neonates and infants because of incomplete development of renal function; thus, penicillin persists in the blood for several times as long in premature infants as in children and adults. After renal function is fully established in young children, renal excretion is considerably more rapid than in adults.

Anuria increases the t1/2 of penicillin G to ~10 hours. The dose of the drug must be readjusted during dialysis and the period of progressive recovery of renal function. If hepatic insufficiency also is present, the t1/2 is prolonged even further.

therapeutic uses Pneumococcal Infections

Penicillin G is the drug of choice for infections caused by sensitive strains of S. pneumoniae, but resistance is an increasing problem. Thus, for pneumococcal pneumonia, a third-generation cephalosporin or high-dose penicillin G (i.e., 20—24 million units daily by continuous intravenous infusion or in divided boluses every 2-3 hours) should be used until sensitivities are determined. For parenteral therapy of sensitive isolates, penicillin G or penicillin G procaine is favored. Therapy should be continued for 7-10 days, including 3-5 days after the patient is afebrile. Similarly, pneumococcal meningitis initially should be treated with a combination of vancomycin and a third-generation cephalosporin until it is established that the infecting pneumococcus is penicillin-sensitive. Recommended therapy is 20-24 million units of penicillin G daily by constant intravenous infusion or divided into boluses given every 2-3 hours for 14 days.

Streptococcal Infections

Pharyngitis is the most common disease produced by S. pyogenes. Penicillin-resistant isolates of this organism have yet to be observed. The preferred oral therapy is with penicillin V 500 mg every 6 hours for 10 days. Equal results are produced by the administration of 600,000 units of penicillin G procaine intramuscularly once daily for 10 days or by a single injection of 1.2 million units of penicillin G benzathine. Parenteral therapy is preferred if there are questions of patient compliance. Penicillin therapy of streptococcal pharyngitis reduces the risk of subsequent acute rheumatic fever but not of post-streptococcal glomerulonephritis.

Streptococcal Toxic Shock and Necrotizing Fascitis

These life-threatening infections are best treated with penicillin plus clindamycin (to decrease toxin synthesis).

Streptococcal Pneumonia, Arthritis, Meningitis, and Endocarditis

These uncommon conditions should be treated with penicillin G; daily doses of 12-20 million units are administered intravenously for 2-4 weeks (4 weeks for endocarditis).

Infections Caused by Other Streptococci

Viridans streptococci, the leading cause of infectious endocarditis, increasingly are resistant to penicillin G; quantitative microbial sensitivities therefore should be determined in patients with endocarditis. Patients with penicillin-sensitive S. viridans endocarditis are treated successfully with 1.2 million units of procaine penicillin G four times daily for 2 weeks or with daily doses of 12-20 million units of intravenous penicillin G for 2 weeks, both regimens in combination with streptomycin or gentamicin.

Recommended therapy for penicillin- and aminoglycoside-sensitive enterococcal endocarditis is 20 million units of penicillin G or 12 g ampicillin daily administered intravenously in combination with low-dose gentamicin. Therapy usually should be continued for 6 weeks, but selected patients with a short duration of illness (<3 months) have been treated successfully in 4 weeks.

Infections with Anaerobes

Many anaerobic infections are polymicrobial, and most of the organisms are sensitive to penicillin G. An exception is the B. fragilis group, 75% of which may be resistant. Pulmonary and periodontal infections usually respond well to penicillin G. Mild-to-moderate infections at these sites may be treated with oral medication (either penicillin G or penicillin V 400,000 units four times daily). More severe infections should be treated with 12-20 million units of penicillin G intravenously. Brain abscesses also frequently contain several species of anaerobes, and most experts use high doses of penicillin G (20 million units per day) plus metronidazole or chloramphenicol.

Staphylococcal Infections

The vast majority of staphylococcal infections involve penicillinase-producing organisms. Patients with staphylococcal infection should receive penicillinase-resistant penicillins

(e.g., nafcillin or oxacillin). Staphylococcal infections increasingly involve methicillin-resistant staphylococci, which are resistant to penicillin G, all the penicillinase-resistant penicillins, and the cephalosporins. Vancomycin, linezolid, quinupristin-dalfopristin, and daptomycin are active against these bacteria (see Chapter 46).

Meningococcal Infections

Penicillin G is the drug of choice for meningococcal disease. Patients should be treated with high doses of penicillin given intravenously (see above). The rare penicillin-resistant strains should be considered in patients who are slow to respond to treatment. Penicillin G does not eliminate the meningococcal carrier state and is ineffective for prophylaxis.

Syphilis

Therapy of syphilis with penicillin G is highly effective. Primary, secondary, and latent syphilis of <1 year's duration may be treated with penicillin G procaine (2.4 million units per day intramuscularly), plus probenecid (1.0 g/day orally) to prolong the t122, for 10 days or with 1-3 weekly intramuscular doses of 2.4 million units of penicillin G benzathine (three doses in patients with HIV infection). Patients with neurosyphilis or cardiovascular syphilis typically receive intensive therapy with 20 million units of penicillin G daily for 10 days. Since there are no proven alternatives for treating syphilis in pregnant women, penicillin-allergic individuals must be acutely desensitized to prevent anaphylaxis.

Infants with congenital syphilis discovered at birth or during the postnatal period should be treated for at least 10 days with 50,000 units per kg daily of aqueous penicillin G in two divided doses or 50,000 units per kg of procaine penicillin G in a single daily dose.

Most patients with secondary syphilis develop the Jarisch-Herxheimer reaction, including chills, fever, headache, myalgias, and arthralgias occurring several hours after the first dose of penicillin. This is likely due to release of spirochetal antigens that induce a host reaction. Reactions usually persist for a few hours to days but do not recur with subsequent penicillin injections; penicillin therapy should not be stopped.

Other Infections

Penicillin G is the drug of choice for all forms of actinomycosis. The dose should be 12-20 million units of penicillin G intravenously per day for 6 weeks. Surgical drainage also may be needed.

Neither penicillin nor any other antibiotic alters the incidence of complications or the outcome of diphtheria; specific antitoxin is the only effective treatment. Penicillin G can eliminate the carrier state. The parenteral administration of 2-3 million units per day in divided doses for 10-12 days eliminates the diphtheria bacilli from the pharynx and other sites in ~100% of patients. A single daily injection of penicillin G procaine for the same period produces comparable results.

Penicillin G is the drug of choice for gas gangrene due to Clostridia; the dose is 12-20 million units per day given parenterally. Adequate debridement of the infected areas is essential. Antibiotics probably have no effect on the outcome of tetanus. Debridement and administration of human tetanus immune globulin may be indicated.

Gingivostomatitis, produced by the synergistic action of Leptotrichia buccalis and fusospiro-chetes that are present in the mouth, is readily treatable with penicillin. For simple "trench mouth," 500 mg penicillin V given every 6 hours for several days is usually sufficient.

The two microorganisms responsible for rat-bite fever, Spirillum minor and Streptobacillus moniliformis, are sensitive to penicillin G, the drug of choice. Since most cases due to Strepto-bacillus are complicated by bacteremia and often by infections of the synovia and endocardium, a daily dose of 12-15 million units given parenterally for 3-4 weeks is used.

Ampicillin (with gentamicin for immunosuppressed patients with meningitis) and penicillin G are the drugs of choice for infections with L. monocytogenes. The dose of penicillin G is 15-20 million units parenterally per day for at least 2 weeks. With endocarditis, treatment is for at least 4 weeks.

Severe Lyme disease may be treated with 20 million units of intravenous penicillin G daily for 14 days.The causative agent of erysipeloid, Erysipelothrix rhusiopathiae, is sensitive to penicillin. Uncomplicated infection responds to a single injection of 1.2 million units of penicillin G benza-thine. If endocarditis is present, penicillin G, 12-20 million units per day for 4-6 weeks is required.

prophylactic uses of the penicillins Streptococcal Infections

The administration of penicillin to individuals exposed to S. pyogenes protects against infection. The oral ingestion of 200,000 units of penicillin G or penicillin V twice a day or a single injection of 1.2 million units of penicillin G benzathine is effective. Indications for prophylaxis include outbreaks of streptococcal disease in closed populations (e.g., boarding schools or military bases).

The oral administration of 200,000 units of penicillin G or penicillin V every 12 hours markedly decreases the incidence of recurrences of rheumatic fever in susceptible individuals. Intramuscular injection of 1.2 million units of penicillin G benzathine once monthly also yields excellent results. Because acute rheumatic fever has been observed in the fifth decade, some advocate that prophylaxis should be continued for life.

Syphilis

Prophylaxis for a contact with syphilis consists of a course of therapy as described for primary syphilis. Serologies for syphilis should be tested monthly for at least 4 months thereafter.

Penicillinase-Resistant Penicillins

These penicillins resist hydrolysis by staphylococcal penicillinase. Their appropriate use is restricted to the treatment of infections that are known or suspected to be caused by staphylococci that elaborate the enzyme, including the vast majority of strains that are encountered clinically. These drugs are much less active than penicillin G against other penicillin-sensitive microorganisms.

The role of the penicillinase-resistant penicillins for most staphylococcal disease is decreasing with the increasing frequency of so-called methicillin-resistant microorganisms. Both S. aureus and S. epidermidis increasingly are resistant. Vancomycin is the drug of choice for serious infection caused by methicillin-resistant variants of these strains; rifampin is given concurrently when a foreign body is present.

isoxazolyl penicillins: oxacillin, cloxacillin, and dicloxacillin These semisynthetic penicillins are similar structurally and pharmacologically (Table 44-1). All are relatively stable in an acid medium and are absorbed adequately after oral administration. All are markedly resistant to cleavage by penicillinase. These drugs are not substitutes for penicillin G in the treatment of diseases amenable to it and are not active against enterococci or Listeria. Oral administration is not a substitute for the parenteral route in the treatment of serious staphylococcal infections.

Pharmacological Properties

The isoxazolyl penicillins potently inhibit the growth of most penicillinase-producing staphylo-cocci. Dicloxacillin is the most active. They are less effective against microorganisms susceptible to penicillin G and are not useful against gram-negative bacteria.

These agents are rapidly but incompletely absorbed from the GI tract (30-80%). As absorption is more efficient on an empty stomach, they ideally are administered 1 hour before or 2 hours after meals. Peak concentrations in plasma are attained by 1 hour. They all are highly bound to plasma albumin (>90%); none is removed from the circulation to a significant degree by hemodialysis.

The isoxazolyl penicillins are excreted rapidly by the kidney. Normally, ~50% of these drugs are excreted in the urine within 6 hours of an oral dose. They also are eliminated in the bile. Their half-lives are between 30 and 60 minutes. Intervals between doses are unchanged for patients with renal failure.

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