National Toxicology Program

Selected toxicity information from HSDB, one of the National Library of Medicine's databases. ¹

Names (NTP)

• Penicillin VK
• (2S-(2ALPHA,5ALPHA,6BETA))-3,3-DIMETHYL-7-OXO-6((PHENOXYACETYL)AMINO)-4-THIA-1-AZABICYCLO(3.2.0)HEPTANE-2-CARBOXYLIC ACID MONOPOTASSIUM SALT (9CI)

Human Toxicity Excerpts

• A double blind, randomized study was undertaken in 52 children to compare the bacteriological efficacy and safety of oral sultamicillin (iosylate (I) to those of oral penicillin V potassium (II) in the treatment of childhood streptococcal pharyngitis for a period of 10 days. The dosage was determined by age & weight: patients under 5 yr were given 125 mg/dose and patients over 20 kg, 375 mg/dose. Recolonization did not occur in the II group. Adverse effects were self-limited. One child receiving II developed an elevated serum transaminase level. [Arnoff SC et al; J Antimicrob Chemother 14 (Sept): 261-5 (1984)]**PEER REVIEWED**
  
• Two patients (aged 24 and 34 yr) with penicillin V potassium induced anaphylaxis experienced cardiac disorders immediately after 5 ml of 1:10,000 epinephrine chloride (I) admin by slow IV. Within sec after the injection, ventricular premature beats and apparent accelerated idioventricular rhythm occurred in one patient and possible ventricular tachycardia occurred in the other. It was concluded that patients during anaphylaxis should be monitored and the potential hazards of admin I by IV route in this clinical setting should be emphasized. [Sullivan TJ; J Am Med Assoc 248 (Nov 5): 2161-2 (1982)]**PEER REVIEWED**
  
• However, seizures, myoclonus, and problems with mentation and level of consciousness have been reported, particularly with penicillins. Most often this toxicity is seen in the setting of renal failure, which may allow drug accumulation. The precise mechanism responsible for these neurologic side effects is unclear, but it is known that direct application of penicillin to the brain is associated with seizures. /Penicillins/ [Haddad, L.M., Clinical Management of Poisoning and Drug Overdose. 2nd ed. Philadelphia, PA: W.B. Saunders Co., 1990., p. 934]**PEER REVIEWED**
  
• In an epidemiologic study from Sweden, about half the cases of pseudomembranous colitis were associated with penicillins, about one third with cephalosporins, and about 14 percent with lincosamides (mostly clindamycin), reflecting the more frequent use of the penicillins and cephalosporins. The clustering of cases in some studies has suggested possible nosocomial transmission of C. difficile. /Penicillins and cephalosporins/ [Haddad, L.M., Clinical Management of Poisoning and Drug Overdose. 2nd ed. Philadelphia, PA: W.B. Saunders Co., 1990., p. 940]**PEER REVIEWED**
  
• Penicillins, which are cleared by both filtration and secretion /by the kidneys/, also accumulate in renal failure if dosages are not adjusted. The acylureidopenicillins are about 60-75 percent excreted by tubular secretion. This secretory mechanism is saturable, and at higher concn nonrenal elimination pathways may become important in their clearance. Thus, the half-lives of these drugs are dose dependent. /Penicillins/ [Haddad, L.M., Clinical Management of Poisoning and Drug Overdose. 2nd ed. Philadelphia, PA: W.B. Saunders Co., 1990., p. 941]**PEER REVIEWED**
  
• Glomerulonephritis caused by drug allergy is usually seen as part of a serum sickness. Deposition of antigen-antibody complexes occurs nonspecifically along the glomeruli. The nephrotic syndrome has occurred with drug allergy but is rarely associated with antimicrobials, except for penicillin. /Penicillins/ [Haddad, L.M., Clinical Management of Poisoning and Drug Overdose. 2nd ed. Philadelphia, PA: W.B. Saunders Co., 1990., p. 946]**PEER REVIEWED**
  
• Adverse cutaneous reactions to penicillins include morbilliform, macular, urticaria, Stevens-Johnson exfoliation, and angioedema/anaphylaxis. /Penicillins; from table/ [Haddad, L.M., Clinical Management of Poisoning and Drug Overdose. 2nd ed. Philadelphia, PA: W.B. Saunders Co., 1990., p. 948]**PEER REVIEWED**
  
• Hemolytic anemia is probably most frequently associated with the penicillins and the cephalosporins. ... A Coombs-positive reaction with or without hemolysis occurs with the penicillins. Specific IgG antibodies that react with penicillin-red blood cell complexes can be identified. This occurs in less than 1 percent of patients treated with penicillins. Coombs antibody is present in from 5-25 percent of patients treated with a cephalosporin, with rats depending on the particular cmpd studied. These antibodies are caused by binding of the cephalosporin with the red blood cell as well as by nonselective adsorption of plasma proteins such as immunoglobulins, complement, albumin, and fibrinogen to the red cell membrane. Hemolysis rarely occurs despite the frequency with which these antibodies are expressed ... . /Penicillins and cephalosporins/ [Haddad, L.M., Clinical Management of Poisoning and Drug Overdose. 2nd ed. Philadelphia, PA: W.B. Saunders Co., 1990., p. 949]**PEER REVIEWED**
  
• Drug-related immunologic destruction of granulocytes usually develops after the second wk of therapy but may be delayed and occur weeks or months into a course of therapy. It is characterized by a sudden fall in the peripheral neutrophil count; fever may be present. Absolute neutropenia can be severe and may place the patient at increased risk of infection. ... Drug-induced neutropenia may be due to antibodies to the neutrophil. ... The neutropenia seen with prolonged high-dose therapy with penicillins and cephalosporins is of uncertain etiology, but it may not have an immunologic basis as rechallenge is not associated with an accelerated recurrence of the neutropenia and the neutrophil count may fall more slowly. /Penicillins and cephalosporins/ [Haddad, L.M., Clinical Management of Poisoning and Drug Overdose. 2nd ed. Philadelphia, PA: W.B. Saunders Co., 1990., p. 949]**PEER REVIEWED**
  
• An antibody-induced immune thrombocytopenia has been described with the penicillins and cephalosporins. These are reversed quickly when the particular drug is discontinued. /Penicillins and cephalosporins/ [Haddad, L.M., Clinical Management of Poisoning and Drug Overdose. 2nd ed. Philadelphia, PA: W.B. Saunders Co., 1990., p. 950]**PEER REVIEWED**
  
• It has been estimated that up to 10 percent of patients treated with a penicillin will experience a hypersensitivity reaction to the drug. This figure may be up to 40 percent in those who have a prior history of an adverse reaction to penicillin. These reactions may vary from a minor rash to fatal anaphylaxis. In one series, 0.04 to 0.2 percent of all acute allergic reactions to penicillin were severe, and 0.001 percent of these had a fatal outcome. /Penicillins/ [Haddad, L.M., Clinical Management of Poisoning and Drug Overdose. 2nd ed. Philadelphia, PA: W.B. Saunders Co., 1990., p. 952]**PEER REVIEWED**
  
• Anaphylaxis presents clinically as the acute onset of peripheral vascular collapse and shock. This may begin minutes after contact with the precipitating allergen. It is the most feared and serious of the allergic reactions and carries with it a significant risk of death. Skin and mucosal lesions, including urticaria and angioedema, may immediately precede the onset of anaphylaxis. Nausea, vomiting, diarrhea, and bronchospasm may occur as part of the acute reaction to the drug. These end-organ responses are initiated by the release of histamine, serotonin, bradykinin and other vasoactive substances released by the basophils and mast cells. ... Penicillins, cephalosporins, and sulfonamides are the antimicrobials most often associated with anaphylactic reactions. /Penicillins and cephalosporins/ [Haddad, L.M., Clinical Management of Poisoning and Drug Overdose. 2nd ed. Philadelphia, PA: W.B. Saunders Co., 1990., p. 953]**PEER REVIEWED**
  
• Most experience with desensitization techniques has been with penicillin. Skin testing before initiating therapy may help indicate the likelihood of a persisting allergy. A commercial skin test called PrePen is available for penicillin but it must be combined with a test for the minor penicillin determinants because these may also mediate anaphylaxis. Even with a negative response to these skin tests, desensitization may be the safest way to administer penicillin or a related drug in a patient with a clear history of acute penicillin allergy. /Penicillins/ [Haddad, L.M., Clinical Management of Poisoning and Drug Overdose. 2nd ed. Philadelphia, PA: W.B. Saunders Co., 1990., p. 955]**PEER REVIEWED**
  
• Cross-reactivity between the cephalosporins and the penicillins occurs and may reflect the structural similarities (beta-lactam ring) of these classes of drugs. Up to 20 percent, but probably closer to 5-10 percent, of patients who are allergic to penicillin will be allergic to the cephalosporins. /Penicillins and cephalosporins/ [Haddad, L.M., Clinical Management of Poisoning and Drug Overdose. 2nd ed. Philadelphia, PA: W.B. Saunders Co., 1990., p. 955]**PEER REVIEWED**
  
• Serum sickness is a rare complication of antimicrobial therapy, caused by a delayed hypersensitivity reaction. It usually begins approx 7-10 days after the initiation of therapy. ... The rash associated with serum sickness may include urticaria and angioneurotic edema. Palpable skin lesions consistent with a vasculitis are often present and are very suggestive of the diagnosis. This IgG-mediated toxicity also may cause GI signs, pericarditis, myocarditis, polyneuritis, and rarely, myelitis. ... Fever is common, and red blood cell casts in the urine confirm the presence of a vasculitis. The offending drug should be stopped and avoided in the future. The penicillins ... are most frequently associated with serum sickness ... . /Penicillins/ [Haddad, L.M., Clinical Management of Poisoning and Drug Overdose. 2nd ed. Philadelphia, PA: W.B. Saunders Co., 1990., p. 955]**PEER REVIEWED**
  
• Erythema nodosum, distinguished by the presence of painful subcutaneous nodules predominately over the lower legs, has a prolonged course and is associated with systemic signs. An Arthus or mixed form of allergic reaction is suggested. ... Penicillins are associated with erythema nodosum reactions, as well as various viral and bacterial infections. /Penicillins/ [Haddad, L.M., Clinical Management of Poisoning and Drug Overdose. 2nd ed. Philadelphia, PA: W.B. Saunders Co., 1990., p. 956]**PEER REVIEWED**
  
• Drug fever is a common sign of drug allergy. It may occur alone or in combination with other signs of allergy, such as rash. Fever may precede the development of other more serious signs of drug allergy, such as serum sickness. The penicillins and cephalosporins lead the list of antimicrobial agents associated with drug fever. The mechanism of drug fever is uncertain. /Penicillins and cephalosporins/ [Haddad, L.M., Clinical Management of Poisoning and Drug Overdose. 2nd ed. Philadelphia, PA: W.B. Saunders Co., 1990., p. 957]**PEER REVIEWED**
  
• Electrolyte abnormalities may occur with antimicrobials that contain large salt loads. The penicillins may cause sodium overload with subsequent fluid retention. This may be very significant clinically, especially in the patient with underlying cardiac disease. Carbenicillin, for example, contains 4.7 mEq of sodium per gram of drug. When the dosage is 20 to 30 g/day, this drug may make a significant contribution to sodium metabolism ... . /Penicillins/ [Haddad, L.M., Clinical Management of Poisoning and Drug Overdose. 2nd ed. Philadelphia, PA: W.B. Saunders Co., 1990., p. 957]**PEER REVIEWED**
  
• Another side effect resulting from the electrolyte content of the penicillin salt is the rapid rise in serum potassium that may occur with a large iv bolus of the potassium salt of crystallin penicillin. Cardiac arrest has been precipitated by the rapid infusion of very large doses of aqueous penicillin potassium. In renal failure, the use of potassium penicillin is usually best avoided; even slow infusions here may result in rises of serum potassium to toxic levels. Using the sodium salt avoid this potentially severe side effect. /Penicillins/ [Haddad, L.M., Clinical Management of Poisoning and Drug Overdose. 2nd ed. Philadelphia, PA: W.B. Saunders Co., 1990., p. 958]**PEER REVIEWED**
  
• Hypokalemia may occur during penicillin therapy owing to competition of the penicillin at the distal renal tubule and excessive potassium excretion. /Penicillins/ [Haddad, L.M., Clinical Management of Poisoning and Drug Overdose. 2nd ed. Philadelphia, PA: W.B. Saunders Co., 1990., p. 958]**PEER REVIEWED**
  
• The GI complication of most concern is the development of pseudomembranous enterocolitis. Although this may begin without prior GI complaints, diarrhea in a patient on antimicrobial therapy must be followed closely. The acute development of fever and pain in a patient with copious diarrhea and bloody or mucous stools strongly suggests this diagnosis. Pseudomembranous enterocolitis is diagnosed when proctoscopic examination discloses pseudomembranes (small, yellow-white plaques) along the colonic mucosa. ... Various causes have been proposed, and multiple factors appear to be important. However, much data suggest that an alteration in bowel flora induced by the offending antimicrobial may allow the emergence of resistant organisms such as Clostridium difficile. Such organisms can produce cytotoxic substances that affect mucosal function and integrity. Overgrowth of staphylococci may be seen in the stool in some cases, and a toxin has been isolated from the staphylococci that is capable of causing tissue destruction and cell damage. /Antimicrobial agents/ [Haddad, L.M., Clinical Management of Poisoning and Drug Overdose. 2nd ed. Philadelphia, PA: W.B. Saunders Co., 1990., p. 938]**PEER REVIEWED**
  
• Although pseudomembranous colitis is most often associated with oral therapy, parenteral exposure also may be a predisposing factor. Most cases occur during parenteral exposure also may be a predisposing factor. Most cases occur during a course of antimicrobial therapy, often a week or two after therapy begins. However, cases have occurred up to 4 wk after discontinuation of an antimicrobial agent. /Antimicrobial agents/ [Haddad, L.M., Clinical Management of Poisoning and Drug Overdose. 2nd ed. Philadelphia, PA: W.B. Saunders Co., 1990., p. 939]**PEER REVIEWED**
  
• Antimicrobial agents frequently affect the hematopoietic system. These effects may be due to direct effects on stem cells in the bone marrow or on the formed cells in the blood stream. Thus, suppression of each of the three cell lines can occur independently or in combination. ... Most often suppression is reversible when the offending drug is discontinued. /Antimicrobial agents/ [Haddad, L.M., Clinical Management of Poisoning and Drug Overdose. 2nd ed. Philadelphia, PA: W.B. Saunders Co., 1990., p. 948]**PEER REVIEWED**
  
• Hematologic toxicity may include aplastic anemia and effects on the erythrocyte (RBC) which may include peripheral destruction - hemolysis due to immune mechanisms and to RBC abnormalities, and marrow suppression; effects on the leukocytes which may include antibody-mediated peripheral destruction and marrow suppression; and effects on the platelets which may include peripheral destruction, marrow suppression, and platelet dysfunction. /Antimicrobial agents; from table/ [Haddad, L.M., Clinical Management of Poisoning and Drug Overdose. 2nd ed. Philadelphia, PA: W.B. Saunders Co., 1990., p. 948]**PEER REVIEWED**
  
• Immunotoxic reactions include systemic: anaphylactic shock, serum sickness/vasculitis, and fever/eosinophilia; hematologic: hemolytic anemia, agranulocytosis, and thrombocytopenia; hepatic: hepatitis; renal: interstitial nephritis; respiratory: asthma and eosinophilic pneumonia; autoimmune reactions: SLE syndrome; and skin: maculopapular/maculovesicular rash, contact dermatitis, fixed drug eruptions, erythema multiforme, Stevens-Johnson syndrome, and phototoxicity/photoallergy. /Antimicrobial agents; from table/ [Haddad, L.M., Clinical Management of Poisoning and Drug Overdose. 2nd ed. Philadelphia, PA: W.B. Saunders Co., 1990., p. 953]**PEER REVIEWED**
  
• GI side effects of penicillins include diarrhea, epigastric/abdominal pain, and stomatitis/glossitis. /Penicillins; from table/ [Haddad, L.M., Clinical Management of Poisoning and Drug Overdose. 2nd ed. Philadelphia, PA: W.B. Saunders Co., 1990., p. 939]**PEER REVIEWED**
  
• Reversible, nonspecific liver enzyme elevations occur in from 1-4 percent of patients treated with the various penicillins, notably with the ureidepenicillins, carbenicillin, ticarcillin, and oxacillin, as well as with the new beta-lactams imipenem and aztreonam. Nonspecific mild elevations may also occur with many antimicrobials ... . /Antimicrobials, esp penicillins/ [Haddad, L.M., Clinical Management of Poisoning and Drug Overdose. 2nd ed. Philadelphia, PA: W.B. Saunders Co., 1990., p. 940]**PEER REVIEWED**
  
• Platelet dysfunction has been described with penicillins and is concn related. The penicillins, especially carbenicillin and ticarcillin, bind to adenosine diphosphate receptor sites on the platelet and can interfere with platelet aggregation. This effect is reversible, unlike the effect of aspirin on platelets. With very-high-dose therapy, significant bleeding may occur. /Penicillins/ [Haddad, L.M., Clinical Management of Poisoning and Drug Overdose. 2nd ed. Philadelphia, PA: W.B. Saunders Co., 1990., p. 950]**PEER REVIEWED**
  
• Acute neurotoxic effects of penicillin include visual, auditory hallucinations; encephalopathy; muscle hyperirritability; convulsions; and myoclonus. /Penicillins; from table/ [O'Donoghue, J.L. (ed.). Neurotoxicity of Industrial and Commercial Chemicals. Volume I. Boca Raton, FL: CRC Press, Inc., 1985., p. 123]**PEER REVIEWED**
  

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Non-Human Toxicity Excerpts

• DHHS/NTP; Toxicology & Carcinogenesis Studies of Penicillin VK in F344/N Rats and B6C3F1 Mice (Gavage Studies) Technical Report Series No. 336 (1988) NIH Publication No. 88-2592 Acute neurotoxic effects of penicillin include visual, auditory hallucinations; encepalopathy; muscle hyperirritability; convulsions; and myoclonus. /Penicillins; from table/ **QC REVIEWED**
  
• ... Conclusions: Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenic activity of penicillin VK for F344/N rats or for B6C3F1 mice administered 500 or 1,000 mg/kg penicillin VK in corn oil gavage, 5 days per week for 2 years. ... Decreased survival of low and high dose male rats and of high dose female rats reduced the sensitivity of the studies for determining the presence or absence of a carcinogenic response in this species. [Toxicology & Carcinogenesis Studies of Penicillin VK in F344/N Rats and B6C3F1 Mice (Gavage Studies). Technical Report Series No. 336 (1988) NIH Publication No. 88-2592 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709]**QC REVIEWED**
  

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Human Toxicity Values

• None found

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Non-Human Toxicity Values

• None found

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Absorption, Distribution and Excretion

• A dose of 1,000,000 units of the acid gives peak plasma levels of about 2 to 3 ug/ml, but the potassium salt will provide levels of 4.5 to 9 ug/ml. [Osol, A. (ed.). Remington's Pharmaceutical Sciences. 16th ed. Easton, Pennsylvania: Mack Publishing Co., 1980., p. 1142]**PEER REVIEWED**
  
• Penicillin VK provides faster and higher blood levels of antibiotic than Penicillin V. [Osol A, Hoover JE et al (eds); Remington's Pharmaceutical Sciences. 14th ed. Easton, PA: Mack Publishing Co., p. 1230 (1975)]**PEER REVIEWED**
  

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Metabolism/Metabolites

• None found

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TSCA Test Submissions

• None found

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Footnotes

¹ Source: the National Library of Medicine's Hazardous Substance Database, 10/28/2007.