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PENICILLIN G PENICILLIN V General Monograph, Benzylpenicillin Phenoxymethylpenicillin Antibiotic
 
Action And Clinical Pharmacology: Penicillins G and V, known as the natural penicillins, are bactericidal against susceptible organisms. Penicillins interfere with the synthesis of cell wall mucopeptides, resulting in the formation of defective cell walls that will lyse and eventually result in death of the organism.

The spectra of activity of penicillins G and V are similar. Penicillin G is more active against gram-negative organisms (i.e., Neisseria) and some anaerobes than is penicillin V. Penicillin G can also be given parenterally, enabling the attainment of high serum concentrations, and is used for the treatment of serious infections involving penicillin-susceptible bacteria. Penicillin V is more resistant to hydrolysis by acidic gastric secretions and is absorbed orally to a much greater extent than penicillin G; therefore, it is the preparation of choice for the treatment of penicillin-susceptible infections of mild to moderate severity, in which the oral route of administration is desirable.

The in-vitro spectrum of activity of the natural penicillins is as follows: Gram-positive Aerobic Bacteria: non-B-lactamase-producing staphylococci, streptococci Groups A, B, C, G, H, K, L and M, S. pneumoniae (increasingly not susceptible), nonenterococcal group D streptococci, viridans streptococci and some strains of enterococci, C. diphtheriae, L. monocytogenes, B. anthracis and E. rhusiopathiae.

Gram-negative Aerobic Bacteria: non-B-lactamase producing N. gonorrhoeae, N. meningitidis, non-beta-lactamase producing H. influenzae, H. parainfluenzae, B. pertussis, E. corrodens, P. multocida.

Gram-positive Anaerobic Bacteria: A. israelii, Bifidobacterium, C. tetani, C. perfringens, C. botulinum, Eubacterium, Lactobacillus, Peptococcus, Peptostreptococcus, Propionibacterium.

Gram-negative Anaerobic Bacteria: Fusobacterium, Veillonella; most Bacteroides species are resistant.

Spirochetes: T. pallidum, B. recurrentis, B. burgdorferi, Leptospira.

Pharmacokinetics: After oral administration, penicillin is absorbed mainly from the duodenum and upper jejunum. The extent of absorption depends on the presence of food in the gastrointestinal tract, gastric and intestinal pH and the relative acid-stability of the penicillin derivative. Both natural penicillins are hydrolyzed in the presence of acidic gastric secretions. Penicillin G is more acid-labile and should be taken on an empty stomach. Penicillin V is more stable in the presence of gastric acid and although it may be taken with meals, higher serum levels are achieved if it is taken on an empty stomach.

Peak serum levels are reached within 30 to 60 minutes and are 2 to 5 times higher with penicillin V than penicillin G. The oral form of penicillin G or V benzathine reaches a lower peak level when compared with other forms of oral penicillin but levels are sustained for a longer period of time.

Aqueous penicillin G (as the potassium or sodium salt) may be administered i.m. or i.v. Following i.m. injection of either salt, peak levels are attained within 15 to 30 minutes.

Repository preparations of penicillin G benzathine or penicillin G procaine are intended for deep i.m. injection and provide a tissue depot from which absorption takes place over several hours to several days. Penicillin G benzathine reaches its peak more slowly and is generally longer acting than penicillin G procaine.

The natural penicillins are readily distributed into ascitic, synovial, pleural and pericardial fluids. Distribution into tissues varies widely, with highest amounts in the kidney and lower concentrations in the liver, lungs, skin, intestines and muscle. Small amounts are found in all other body tissues and in the CSF. When the meninges are inflamed, the CSF concentration is about 5% of the serum concentration and can be therapeutic against sensitive organisms. Penicillins readily cross the placenta and are distributed into breast milk.

Penicillin V is more highly protein bound (75 to 89%) than penicillin G (45 to 68%).

In patients with normal kidney function, penicillin is excreted rapidly by filtration and active tubular secretion. The elimination half-life is about 30 minutes. In neonates and young infants and in individuals with impaired kidney function, excretion is considerably delayed, occasionally necessitating longer dosing intervals and smaller doses.

Penicillin G is removed by hemodialysis but only minimally removed by peritoneal dialysis. It is not known whether penicillin V is dialyzable.

Indications And Clinical Uses: Penicillin G is indicated for treatment of infections due to susceptible organisms (parenteral preparations for severe infections, oral preparations for less serious infections). Penicillin V is indicated for treatment of mild to moderately severe infections.

Both penicillin G and penicillin V are indicated in the treatment of: actinomycosis caused by Actinomyces species; anthrax caused by B. anthracis; bronchitis, acute otitis media, pharyngitis, sinusitis, skin and soft tissue infections caused by susceptible organisms; erysipelas caused by susceptible strains of group A streptococci; erysipeloid (including endocarditis and septicemia) caused by E. rhusiopathiae; acute, necrotizing, ulcerative gingivitis (Vincent's angina or "trench mouth") caused by anaerobes and spirochetes; P. multocida infections; rat-bite fever caused by S. moniliformis or S. minor; scarlet fever caused by group A streptococci; Lyme disease caused by B. burgdorferi. In addition, parenteral penicillin G is indicated for treatment of gonococcal arthritis caused by susceptible strains of N. gonorrhoeae; bone and joint infections, bacterial endocarditis, intra-abdominal infections, meningitis, pericarditis, pneumonia and septicemia caused by susceptible organisms; uncomplicated gonorrhea caused by susceptible strains (not a first-line agent); listeriosis caused by L. monocytogenes; tetanus; yaws caused by T. pallidum pertenue; tertiary and neurosyphilis; gas gangrene caused by Clostridium species; leptospirosis caused by Leptospira species.

Both penicillin G benzathine and penicillin G procaine are indicated for treatment of: bejel caused by T. pallidum endemicum; erysipeloid; pinta caused by T. carateum; yaws.

In addition, penicillin G procaine is indicated for treatment of the following infections involving sysceptible organisms: anthrax; bacterial endocarditis; erysipelas; acute necrotizing, ulcerative gingivitis; acute otitis media; pericarditis; pneumonia; rat-bite fever, scarlet fever; septicemia; skin and soft tissue infections; tertiary syphilis.

Penicillin G benzathine is also indicated for treatment of pharyngitis and for early or late benign syphilis (not neurosyphilis).

Penicillin G, penicillin V, penicillin G procaine and penicillin G benzathine are indicated in the prophylaxis of: diphtheria caused by C. diphtheriae, as an adjunct to antitoxin. Penicillins G and V are indicated in the prophylaxis of bacterial endocarditis but have been replaced by amoxicillin in the 1997 Recommendations by the American Heart Association for Prevention of Bacterial Endocarditis (see Endocarditis Prophylaxis in the Clin-Info section). Penicillin V and penicillin G benzathine are indicated in the prohylaxis of rheumatic fever caused by group A streptococci. Patients with a history of rheumatic fever who are receiving continuous prophylaxis may harbor penicillin-resistant organisms; use of another agent may be considered.

Contra-Indications: A clear history of penicillin allergy; infections caused by beta-lactamase producing organisms.

Oral penicillin should not be used as adjunctive prophylaxis for genitourinary instrumentation or surgery, lower intestinal tract surgery, sigmoidoscopy or childbirth, or for the active treatment of syphilis, gonorrhea, meningitis, bacterial endocarditis, diphtheria, gas gangrene or other severe infections due to penicillin-susceptible microorganisms.

Severe pneumonia, empyema, bacteremia, pericarditis, meningitis and septic arthritis should not be treated with oral penicillin during the acute stage.

Topical application of penicillin is contraindicated since hypersensitization is a frequent complication.

Penicillin G procaine is contraindicated in patients who are allergic to procaine. Hypersensitivity may be confirmed by injecting 0.1 mL of a 1 to 2% procaine HCl solution intradermally. Development of erythema, wheal, flare or eruption indicates procaine sensitivity.

Manufacturers' Warnings In Clinical States: Serious and occasionally fatal hypersensitivity reactions have been reported in patients receiving penicillin therapy. Although anaphylaxis is more frequent following parenteral therapy, it has occurred in patients receiving oral penicillin (see Overdose: Treatment).

Cross-sensitivity among B-lactam antibiotics such as penicillins, cephalosporins and carbapenems is known to occur. The precise incidence is unknown. The possibility of cross-sensitivity must be considered in all patients reporting an allergy to any B-lactam antibiotic.

Extreme care must be taken not to inject penicillin G procaine or penicillin G benzathine intravenously, intra-arterially or near a peripheral nerve or vessel as severe and/or permanent neurovascular damage may occur. Injections should be discontinued if sudden severe pain occurs at the injection site.

Precautions: Oral administration should not be relied upon in patients with severe illness, or with nausea, vomiting, gastric dilatation, cardiospasm or intestinal hypermotility.

Occasionally, certain patients will not absorb therapeutic amounts of orally administered penicillin.

In streptococcal infections, therapy should be given for a minimum of 10 days. Cultures should be taken following treatment to ensure eradication of streptococci.

Prolonged use of antibiotics may promote the overgrowth of nonsusceptible organisms, including fungi.

Patients with impaired renal function (ClCr <0.17 mL/sec) require modification of dose and interval.

High doses of intravenous penicillin G (>10 million units) should be administered slowly because of potential electrolyte imbalances resulting from the sodium or potassium load. This is particularly important in patients with impaired renal function.

The passage of any penicillin from blood into brain is facilitated by inflamed meninges and during cardiopulmonary bypass. In the presence of such factors, particularly in renal failure when high serum concentrations can be attained, CNS adverse effects including myoclonia, seizures and depressed consciousness can be expected.

Drug Interactions: Aminoglycosides: A synergistic bactericidal effect occurs in vitro against some strains of enterococci and against viridans streptococci when penicillin G is used in conjunction with aminoglycosides. This effect is used therapeutically to treat bacterial endocarditis.

Bacteriostatic Antibiotics (e.g., chloramphenicol, erythromycin, tetracycline): may decrease the effectiveness of penicillin.

Oral Contraceptives: Whether penicillins decrease the effectiveness of oral contraceptives is controversial. Some clinicians recommend adding an alternative method of contraception for the duration of the cycle when a penicillin is taken.

Probenecid: Decreases renal tubular secretion of penicillin leading to higher and more prolonged serum concentrations, higher CSF concentrations and an increased risk of toxicity.

Pregnancy: Usual doses appear to be safe in pregnant women.

Lactation: Penicillin does not appear in breast milk in sufficient quantities to treat infections in the infant but does appear in trace quantities which could lead to allergic sensitization or disruption of the gastrointestinal flora.

Adverse Reactions: Hypersensitivity: Hypersensitivity reactions are usually more severe following parenteral administration, however all degrees of hypersensitivity including fatal anaphylaxis have followed even oral administration of the drug. The most common manifestations of hypersensitivity are: skin eruptions (from mild rash to exfoliative dermatitis) with an overall incidence of approximately 2%, urticaria, chills, fever, edema, eosinophilia and anaphylaxis (overall incidence about 0.05%). A serum sickness-like reaction has been reported, characterized by fever, malaise, urticaria, arthralgia, myalgia, lymphadenopathy and splenomegaly.

Hematologic: eosinophilia (hypersensitivity), hemolytic anemia, transient neutropenia, leukopenia, thrombocytopenia and thrombocytopenic purpura. These reactions are more common with larger parenteral doses of penicillin.

Gastrointestinal: nausea, vomiting, epigastric distress, diarrhea, black hairy tongue, antibiotic associated pseudomembranous colitis.

Renal: Rarely, acute interstitial nephritis (fever, proteinuria and hematuria); high doses of parenterally administered penicillin sodium or potassium may result in electrolyte disturbances, especially in patients with poor renal function.

Hepatic: Hepatotoxicity may be associated with hypersensitivity.

CNS: Usually associated with administration of large parenteral dosages to patients with impaired renal function; manifested as hallucinations, confusion, lethargy, dysphasia, twitching, hyperreflexia, asterixis, localized or generalized seizures, coma or fatal encephalopathy.

Miscellaneous: Jarisch-Herxheimer Reaction: Frequently occurs 2 to 12 hours after penicillin is started to treat syphilis or other spirochetal infections and is thought to result from the phagocytized organism's release of endotoxins and/or other pyrogens. The reaction is characterized by headache, fever, chills, sweating, sore throat, myalgia, arthralgia, malaise, tachycardia, hypertension followed by hypotension. The reaction usually subsides within 24 hours.

Symptoms And Treatment Of Overdose: Symptoms: Hypersensitivity reactions including anaphylaxis may occur with any dosage. Oral ingestion of excessive amounts may cause nausea, vomiting, diarrhea, abdominal pain. Parenteral administration of high doses may lead to cardiovascular or electrolyte abnormalities or neurological effects such as drowsiness, seizures or coma. tag_Treatment

Treatment: Following oral ingestion, gastric decontamination, induction of emesis (if patient is not obtunded, comatose or experiencing seizures) and administration of activated charcoal with a cathartic may be of benefit. Patients must be observed for signs of a hypersensitivity reaction (see below). If seizures, cardiac arrhythmias or fluid or electrolyte disturbances occur following parenteral administration appropriate measures must be taken. Dialysis may be helpful in removing Penicillin G.

Anaphylaxis: Mild cases involving only urticaria may be managed with antihistamine therapy. Severe anaphylaxis may require oxygen supplementation, airway management, epinephrine administration, ECG monitoring and i.v. fluids.

Dosage And Administration: Oral therapy is generally used for the treatment of mild to moderately severe infections. Maximal absorption of both natural penicillins occurs on an empty stomach (1 hour before or 2 hours after meals). Parenteral administration is required for the treatment of severe infections including meningitis, endocarditis, syphilis, gonorrhea and clostridial infections.

Dosage must be individualized according to the causative organism, severity of the infection and host factors such as age and renal function.

Penicillin V 500 000 units is equivalent to 300 mg.

Penicillin G 500 000 units is equivalent to 312 mg.

Usual therapeutic dosages are as follows:

Penicillin G or V Oral: Adults and children >12 years: 500 000 units every 6 to 8 hours. Children <12 years: 25 000 to 90 000 units/kg/day in 3 to 6 divided doses.

Aqueous Penicillin G (Sodium or Potassium) I.M./I.V.: Adults and children >12 years: Dosage may range from 1 million units daily i.m. to 20 million units daily i.v. in 4 to 6 divided doses. Higher doses may be required for more serious infections. Intermittent i.v. infusions should be given over 1 to 2 hours.

Children 1 month to 12 years: 25 000 to 50 000 units/kg/day in 4 divided doses. Higher doses (100 000 to 400 000 units/kg/day, in divided doses every 4 to 6 hours) may be required to treat more severe infections. I.V. infusion should be given over 15 to 30 minutes.

Neonates 1 week to 1 month: 75 000 to 200 000 units/kg/day, in divided doses every 6 hours (if >2 kg) or every 8 hours (if <2 kg).

Neonates <1 week: 50 000 to 100 000 units/kg/day, in divided doses every 8 hours (if >2 kg) or every 12 hours (if 2 kg).

Dosage for meningitis caused by group B streptococci in neonates is 250 000 to 400 000 units/kg/day, in divided doses every 6 to 8 hours.

Dosage in renal failure: Patients with ClCr <0.17 mL/sec should receive approximately one half the usual dose at less frequent intervals (recommendations range from every 8 to every 18 hours).

Penicillin G Benzathine I.M.: Adults: single dose of 1 200 000 units by deep i.m. injection.

Children <27 kg: single dose of 300 000 to 600 000 units by deep i.m. injection; >27 kg: 900 000 units by deep i.m. injection. Extreme care must be taken to avoid injection into peripheral nerves or vessels. See Warnings.

Penicillin G Procaine I.M.: Adults and children >12 years: 600 000 to 1 200 000 units daily by deep i.m. injection.

Children <12 years: 25 000 to 50 000 units/kg once daily (not to exceed adult dose). Extreme care must be taken to avoid injection into or near peripheral nerves or vessels. See Warnings.

Rheumatic Fever Prophylaxis: Prevention of recurrent Group A beta-hemolytic streptococcal infections in patients who have had rheumatic fever and/or chorea: penicillin V 250 000 units orally twice daily on a continual basis.