Whereas most strains of S. aureus were highly sensitive to penicillin G when this agent was first employed therapeutically, >90% of strains of staphylococci isolated from individuals inside or outside of hospitals are now resistant to penicillin G (and nearly half are methicillin-resistant). Most strains of S. epidermidis also are resistant to penicillin. Unfortunately, penicillinase-producing strains of gonococci that are highly resistant to penicillin G have become widespread. With rare exceptions, meningococci are quite sensitive to penicillin G.
Although the vast majority of strains of Corynebacterium diphtheriae are sensitive to penicillin G, some are highly resistant. The presence of chromosomally encoded β-lactamase in Bacillus anthracis is the reason that penicillin was not used for prophylaxis of anthrax exposure, although most isolates are susceptible. Most anaerobic microorganisms, including Clostridium spp., are highly sensitive. Bacteroides fragilis is an exception, displaying resistance to penicillins and cephalosporins by virtue of expressing a broad-spectrum cephalosporinase. Some strains of Prevotella melaninogenicus also have acquired this trait. Actinomyces israelii, Streptobacillus moniliformis, Pasteurella multocida, and L. monocytogenes are inhibited by penicillin G. Most species of Leptospira are moderately susceptible to the drug. One of the most exquisitely sensitive microorganisms is Treponema pallidum. Borrelia burgdorferi, the organism responsible for Lyme disease, also is susceptible. None of the penicillins is effective against amebae, plasmodia, rickettsiae, fungi, or viruses.
Oral Administration of Penicillin G. About one-third of an orally administered dose of penicillin G is absorbed from the intestinal tract under favorable conditions. Gastric juice at pH 2 rapidly destroys the antibiotic. The decrease in gastric acid production with aging accounts for better absorption of penicillin G from the gastrointestinal (GI) tract of older individuals. Absorption is rapid, and maximal concentrations in blood are attained in 30-60 minutes. The peak value is ~0.5 unit/mL (0.3 μg/mL) after an oral dose of 400,000 units (~250 mg) in an adult. Ingestion of food may interfere with enteric absorption of all penicillins, perhaps by adsorption of the antibiotic onto food particles. Thus, oral penicillin G should be administered at least 30 minutes before a meal or 2 hours after. Despite the convenience of oral administration of penicillin G, this route should be used only in infections in which clinical experience has proven its efficacy.
Oral Administration of Penicillin V. The virtue of penicillin V in comparison with penicillin G is that it is more stable in an acidic medium and therefore is better absorbed from the GI tract. On an equivalent oral-dose basis, penicillin V (K+ salt) yields plasma concentrations two to five times greater than those provided by penicillin G. The peak concentration in the blood of an adult after an oral dose of 500 mg is nearly 3 μg/mL. Once absorbed, penicillin V is distributed in the body and excreted by the kidney in a manner similar to that of penicillin G.
Parenteral Administration of Penicillin G. After intramuscular injection, peak concentrations in plasma are reached within 15-30 minutes. This value declines rapidly because the t1/2 of penicillin G is 30 minutes.
Many means for prolonging the sojourn of the antibiotic in the body and thereby reducing the frequency of injections have been explored. Probenecid blocks renal tubular secretion of penicillin, but it is used rarely for this purpose. More commonly, repository preparations of penicillin G are employed. The compound currently favored is penicillin G benzathine (bicillin l-a, permapen), which releases penicillin G slowly from the area in which it is injected and produces relatively low but persistent concentrations of antibiotic in the blood. Penicillin G benzathine suspension is the aqueous suspension of the salt obtained by the combination of 1 mol of an ammonium base and 2 mol of penicillin G to yield N,N′-dibenzylethylenediamine dipenicillin G. The salt itself is only 0.02% soluble in water. The long persistence of penicillin in the blood after a suitable intramuscular dose reduces cost, need for repeated injections, and local trauma. The local anesthetic effect of penicillin G benzathine is comparable with that of penicillin G procaine.
Penicillin G benzathine is absorbed very slowly from intramuscular depots and produces the longest duration of detectable antibiotic of all the available repository penicillins. For example, in adults, a dose of 1.2 million units given intramuscularly produces a concentration in plasma of 0.09 μg/mL on the first, 0.02 μg/mL on the fourteenth, and 0.002 μg/mL on the thirty-second day after injection. The average duration of demonstrable antimicrobial activity in the plasma is ~26 days. It is administered once monthly for rheumatic fever prophylaxis and can be given in a single injection to treat streptococcal pharyngitis.
Distribution. Penicillin G is distributed widely throughout the body, but the concentrations in various fluids and tissues differ widely. Its apparent volume of distribution is ~0.35 L/kg. Approximately 60% of the penicillin G in plasma is reversibly bound to albumin. Significant amounts appear in liver, bile, kidney, semen, joint fluid, lymph, and intestine.
Although probenecid markedly decreases the tubular secretion of the penicillins, this is not the only factor responsible for the elevated plasma concentrations of the antibiotic that follow its administration. Probenecid also produces a significant decrease in the apparent volume of distribution of the penicillins.
Penetration into Cerebrospinal Fluid. Penicillin does not readily enter the CSF when the meninges are normal. However, when the meninges are acutely inflamed, penicillin penetrates into the CSF more easily. Although the concentrations attained vary and are unpredictable, they are usually in the range of 5% of the value in plasma and are therapeutically effective against susceptible microorganisms.
Penicillin and other organic acids are secreted rapidly from the CSF into the bloodstream by an active transport process. Probenecid competitively inhibits this transport and thus elevates the concentration of penicillin in CSF. In uremia, other organic acids accumulate in the CSF and compete with penicillin for secretion; the drug occasionally reaches toxic concentrations in the brain and can produce convulsions.
Excretion. Under normal conditions, penicillin G is eliminated rapidly from the body mainly by the kidney but in small part in the bile and by other routes. 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. Renal clearance approximates the total renal plasma flow. The maximal tubular secretory capacity for penicillin in the normal adult male is ~3 million units (1.8 g) per hour.
Clearance values are considerably lower in neonates and infants because of incomplete development of renal function; as a result, after doses proportionate to surface area, the persistence of penicillin in the blood is several times as long in premature infants as in children and adults. The t1/2 of the antibiotic in children <1 week of age is 3 hours; by 14 days of age it is 1.4 hours. After renal function is fully established in young children, the rate of renal excretion of penicillin G is considerably more rapid than in adults.
Anuria increases the t1/2 of penicillin G from a normal value of 0.5 hour to ~10 hours. When renal function is impaired, 7-10% of the antibiotic may be inactivated each hour by the liver. Patients with renal shutdown who require high-dose therapy with penicillin can be treated adequately with 3 million units of aqueous penicillin G followed by 1.5 million units every 8-12 hours. The dose of the drug must be readjusted during dialysis and the period of progressive recovery of renal function. If, in addition to renal failure, hepatic insufficiency also is present, the t1/2 will be prolonged even further.
Pneumococcal Infections. Penicillin G remains the agent of choice for the management of infections caused by sensitive strains of S. pneumoniae. However, strains of pneumococci resistant to usual doses of penicillin G are being isolated more frequently in several countries, including the U.S. (Fiore et al., 2000).
Pneumococcal Pneumonia. Until it is highly likely or established that the infecting isolate of pneumococcus is penicillin-sensitive, pneumococcal pneumonia should be treated with a third-generation cephalosporin or with 20-24 million units of penicillin G daily by constant intravenous infusion. If the organism is sensitive to penicillin, then the dose can be reduced (Medical Letter, 2007). For parenteral therapy of sensitive isolates of pneumococci, penicillin G is favored. Although oral treatment with 500 mg penicillin V given every 6 hours for treatment of pneumonia owing to penicillin-sensitive isolates has been used with success in this disease, it cannot be recommended for routine initial use because of the existence of resistance. Therapy should be continued for 7-10 days, including 3-5 days after the patient's temperature has returned to normal.
Pneumococcal Meningitis. Until it is established that the infecting pneumococcus is sensitive to penicillin, pneumococcal meningitis should be treated with a combination of vancomycin and a third-generation cephalosporin (Catalan et al., 1994; John, 1994). Dexamethasone given at the same time as antibiotics was associated with an improved outcome (de Gans and van de Beek, 2002). Prior to the appearance of penicillin resistance, penicillin treatment reduced the death rate in this disease from nearly 100% to ~25%. The recommended therapy is 20-24 million units of penicillin G daily by constant intravenous infusion or divided into boluses given every 2-3 hours. The usual duration of therapy is 14 days.
Streptococcal Infections. Streptococcal Pharyngitis (Including Scarlet Fever). This is the most common disease produced by S. pyogenes (group A β-hemolytic streptococcus). Penicillin-resistant isolates have yet to be observed for S. pyogenes. The preferred oral therapy is with penicillin V, 500 mg every 6 hours for 10 days. Penicillin therapy of streptococcal pharyngitis reduces the risk of subsequent acute rheumatic fever; however, current evidence suggests that the incidence of glomerulonephritis that follows streptococcal infections is not reduced to a significant degree by treatment with penicillin.
Streptococcal Toxic Shock and Necrotizing Fascitis. These are life-threatening infections associated with toxin production and are treated optimally with penicillin plus clindamycin (to decrease toxin synthesis) (Bisno and Stevens, 1996; Brown, 2004).
Streptococcal Pneumonia, Arthritis, Meningitis, and Endocarditis. Although uncommon, these conditions should be treated with penicillin G when they are caused by S. pyogenes; daily doses of 12-20 million units are administered intravenously for 2-4 weeks. Such treatment of endocarditis should be continued for a full 4 weeks.
Infections Caused by Other Streptococci. The viridans group of streptococci are the most common cause of infectious endocarditis. These are nongroupable α-hemolytic microorganisms that are increasingly resistant to penicillin G (minimum inhibitory concentration [MIC] >0.1 μg/mL). Because enterococci also may be α-hemolytic, and certain other α-hemolytic strains may be relatively resistant to penicillin, it is important to determine quantitative microbial sensitivities to penicillin G in patients with endocarditis. Patients with penicillin-sensitive viridans group streptococcal endocarditis can be treated successfully with daily doses of 12-20 million units of intravenous penicillin G for 2 weeks in combination with gentamicin 1 mg/kg every 8 hours. Some physicians prefer a 4-week course of treatment with penicillin G alone.
Enterococcal endocarditis is one of the few diseases treated optimally with two antibiotics. The 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 a low dose of 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 (Wilson et al., 1984).
Infections with Anaerobes. Many anaerobic infections are caused by mixtures of microorganisms. Most are sensitive to penicillin G. An exception is the B. fragilis group, in which up to 75% of strains may be resistant to high concentrations of this antibiotic. Pulmonary and periodontal infections (with the exception of β-lactamase-producing Prevotella melaninogenica) usually respond well to penicillin G, although a multicenter study indicated that clindamycin is more effective than penicillin for therapy of lung abscess (Levison et al., 1983). Mild-to-moderate infections at these sites may be treated with oral medication (either penicillin G or penicillin V 400,000 units [250 mg] 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 authorities prefer to treat such disease with high doses of penicillin G (20 million units per day) plus metronidazole or chloramphenicol. Some physicians add a third-generation cephalosporin for activity against aerobic gram-negative bacilli.
Staphylococcal Infections. The vast majority of staphylococcal infections are caused by microorganisms that produce penicillinase (Swartz, 2004). Hospital-acquired methicillin-resistant staphylococci are resistant to penicillin G, all the penicillinase-resistant penicillins, and the cephalosporins. Isolates occasionally may appear to be sensitive to various cephalosporins in vitro, but resistant populations arise during therapy and lead to failure. Vancomycin, linezolid, quinupristin-dalfopristin, and daptomycin are active for infections caused by these bacteria, although reduced susceptibility to vancomycin has been observed. Community-acquired methicillin-resistant S. aureus (MRSA) in many cases retains susceptibility to trimethoprim-sulfamethoxazole, doxycycline, and clindamycin (Medical Letter, 2007).
Meningococcal Infections. Penicillin G remains the drug of choice for meningococcal disease. Patients should be treated with high doses of penicillin given intravenously, as described for pneumococcal meningitis. Penicillin-resistant strains of N. meningitides have been reported in Britain and Spain but are infrequent at present. The occurrence of 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 its administration thus is ineffective as a prophylactic measure.
Gonococcal Infections. Gonococci gradually have become more resistant to penicillin G, and penicillins are no longer the therapy of choice, unless it is known that gonococcal strains in a particular geographic area are susceptible. Uncomplicated gonococcal urethritis is the most common infection, and a single intramuscular injection of 250 mg ceftriaxone is the recommended treatment (Handsfield and Sparling, 2005).
Gonococcal arthritis, disseminated gonococcal infections with skin lesions, and gonococcemia should be treated with ceftriaxone 1 g daily given either intramuscularly or intravenously for 7-10 days. Ophthalmia neonatorum also should be treated with ceftriaxone for 7-10 days (25-50 mg/kg per day intramuscularly or intravenously).
Syphilis. Therapy of syphilis with penicillin G is highly effective. Primary, secondary, and latent syphilis of <1-year duration may be treated with penicillin G procaine (2.4 million units per day intramuscularly) plus probenecid (1.0 g/day orally) 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 late latent syphilis, neurosyphilis, or cardiovascular syphilis may be treated with a variety of regimens. Because the latter two conditions are potentially lethal and their progression can be halted (but not reversed), intensive therapy with 20 million units of penicillin G daily for 10 days is recommended. There are no proven alternatives for treating syphilis in pregnant women, so penicillin-allergic individuals must be acutely desensitized to prevent anaphylaxis (Centers for Disease Control and Prevention, 2006).
Infants with congenital syphilis discovered at birth or during the postnatal period should be treated for at least 10 days with 50,000 units/kg daily of aqueous penicillin G in two divided doses or 50,000 units/kg of procaine penicillin G in a single daily dose (Tramont, 2005).
Most patients (70-90%) with secondary syphilis develop the Jarisch-Herxheimer reaction. This also may be seen in patients with other forms of syphilis. Several hours after the first injection of penicillin, chills, fever, headache, myalgias, and arthralgias may develop. The syphilitic cutaneous lesions may become more prominent, edematous, and brilliant in color. Manifestations usually persist for a few hours, and the rash begins to fade within 48 hours. It does not recur with the second or subsequent injections of penicillin. This reaction is thought to be due to release of spirochetal antigens with subsequent host reactions to the products. Aspirin gives symptomatic relief, and therapy with penicillin should not be discontinued.
Actinomycosis. Penicillin G is the agent of choice for the treatment of all forms of actinomycosis. The dose should be 10-20 million units of penicillin G intravenously per day for 6 weeks. Some physicians continue therapy for 2-3 months with oral penicillin V (500 mg four times daily). Surgical drainage or excision of the lesion may be necessary before cure is accomplished.
Diphtheria. There is no evidence that penicillin or any other antibiotic alters the incidence of complications or the outcome of diphtheria; specific antitoxin is the only effective treatment. However, penicillin G eliminates 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 practically 100% of patients. A single daily injection of penicillin G procaine for the same period produces comparable results.
Anthrax. Strains of Bacillus anthracis resistant to penicillin have been recovered from human infections. When penicillin G is used, the dose should be 12-20 million units per day.
Clostridial Infections. Penicillin G is the agent of choice for gas gangrene; the dose is in the range of 12-20 million units per day given parenterally as an adjunct to the antitoxin. Adequate debridement of the infected areas is essential. Antimicrobial drugs probably have no effect on the ultimate outcome of tetanus. Débridement and administration of human tetanus immune globulin may be indicated. Penicillin is administered, however, to eradicate the vegetative forms of the bacteria that may persist.
Fusospirochetal Infections. Gingivostomatitis, produced by the synergistic action of Leptotrichia buccalis and spirochetes 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 to clear the disease.
Rat-Bite Fever. The two microorganisms responsible for this infection, Spirillum minor in the Far East and Streptobacillus moniliformis in America and Europe, are sensitive to penicillin G, the therapeutic agent of choice. Because most cases due to Streptobacillus are complicated by bacteremia and, in many instances, by metastatic infections, especially of the synovia and endocardium, the dose should be large; a daily dose of 12-15 million units given parenterally for 3-4 weeks has been recommended.
Listeria Infections. Ampicillin (with gentamicin for immunosuppressed patients with meningitis) and penicillin G are the drugs of choice in the management of infections owing to L. monocytogenes. The recommended dose of ampicillin is 1-2 g intravenously every 4 hours. The recommended dose of penicillin G is 15-20 million units parenterally per day for at least 2 weeks. When endocarditis is the problem, the dose is the same, but the duration of treatment should be no less than 4 weeks.
Lyme Disease. Although a tetracycline is the usual drug of choice for early disease, amoxicillin is effective; the dose is 500 mg three times daily for 21 days. Severe disease is treated with a third-generation cephalosporin or up to 20 million units of intravenous penicillin G daily for 10-14 days.
Erysipeloid. The causative agent of this disease, Erysipelothrix rhusiopathiae, is sensitive to penicillin. The uncomplicated infection responds well to a single injection of 1.2 million units of penicillin G benzathine. When endocarditis is present, penicillin G, 12-20 million units per day, has been found to be effective; therapy should be continued for 4-6 weeks.
Pasteurella multocida. Pasteurella multocida is the cause of wound infections after a cat or dog bite. It is uniformly susceptible to penicillin G and ampicillin and resistant to penicillinase-resistant penicillins and first-generation cephalosporins (Goldstein et al., 1988). When the infection causes meningitis, a third-generation cephalosporin is preferred because the MICs are slightly lower than for penicillin.
Prophylactic Uses of the Penicillins. The demonstrated effectiveness of penicillin in eradicating microorganisms was followed quickly and quite naturally by attempts to prove that it also was effective in preventing infection in susceptible hosts. As a result, the antibiotic has been administered in almost every situation in which a risk of bacterial invasion has been present. As prophylaxis has been investigated under controlled conditions, it has become clear that penicillin is highly effective in some situations, useless and potentially dangerous in others, and of questionable value in still others (Chapter 48).
Streptococcal Infections. The administration of penicillin to individuals exposed to S. pyogenes affords protection from 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 this type of prophylaxis include outbreaks of streptococcal disease in closed populations, such as boarding schools or military bases. Patients with extensive deep burns are at high risk of severe wound infections with S. pyogenes; "low-dose" prophylaxis for several days appears to be effective in reducing the incidence of this complication.
Recurrences of Rheumatic Fever. The oral administration of 200,000 units of penicillin G or penicillin V every 12 hours produces a striking decrease in the incidence of recurrences of rheumatic fever in susceptible individuals. Because of the difficulties of compliance, parenteral administration is preferable, especially in children. The intramuscular injection of 1.2 million units of penicillin G benzathine once a month yields excellent results. In cases of hypersensitivity to penicillin, sulfisoxazole or sulfadiazine, 1 g twice a day for adults, also is effective; for children weighing <27 kg, the dose is halved. Prophylaxis must be continued throughout the year. The duration of such treatment is an unsettled question. It has been suggested that prophylaxis should be continued for life because instances of acute rheumatic fever have been observed in the fifth and sixth decades. However, the necessity for such prolonged prophylaxis has not been established and may be unnecessary for young adults judged to be at low risk for recurrence (Berrios et al., 1993).
Syphilis. Prophylaxis for a contact with syphilis consists of a course of therapy as described for primary syphilis. A serological test for syphilis should be performed at monthly intervals for at least 4 months thereafter.
Surgical Procedures in Patients with Valvular Heart Disease. About 25% of cases of subacute bacterial endocarditis follow dental extractions. This observation, together with the fact that up to 80% of persons who have teeth removed experience a transient bacteremia, emphasizes the potential importance of chemoprophylaxis for those who have congenital or acquired valvular heart disease of any type and need to undergo dental procedures. Since transient bacterial invasion of the bloodstream occurs occasionally after surgical procedures (e.g., tonsillectomy and genitourinary and GI procedures) and during childbirth, these, too, are indications for prophylaxis in patients with valvular heart disease. Whether the incidence of bacterial endocarditis actually is altered by this type of chemoprophylaxis remains to be determined.
Detailed recommendations for adults and children with valvular heart disease have been formulated (Wilson et al., 2007).