Benzalkonium Chloride in Infant Twins
Poisoning
John T. Wilson, MD, Ian M. Burr, MD
\s=b\ Infant twins sustained severe circumoral and pharyngeal burns from a concentrated solution of benzalkonium (Zephiran) chloride prescribed for treatment of candidiasis. This report emphasizes the unnecessary hazard accompanying use of a potentially toxic drug\p=m-\especially when prepared in error by the pharmacist\p=m-\whena safer drug (nystatin) is available for treatment of oral candidiasis. Risks from use of a prescription drug for other than the intended patient are also highlighted by this episode of poisoning. (Am J Dis Child 129:1208-1209, 1975)
presence of an ever-increas¬ number of chemicals for
The ing medical, industrial,
household, and agricultural use enhances the risk for poisoning in children. Poisoning from drugs usually results from accidental ingestion of a toxic dose and less often from an error in drug formula¬ tion or miscalculation of drug dose. In general, the availability of drugs with a higher therapeutic index has en¬ couraged physicians to lay aside drugs with greater toxic potential. Further, formulation errors have been reduced by the availability of commercial, standardized dose forms for most medicines. Despite these trends, benzalkonium (Zephiran) chlo¬ ride is still used topically for oral moniliasis even though a more speReceived for publication May 10, 1974; accepted March 10, 1975. From the divisions of pediatric clinical pharmacology and pediatric endocrinology, departments of pediatrics, pharmacology, and physiology, Vanderbilt University School of Medicine, Nashville, Tenn. Reprint requests to Department of Pediatrics, Vanderbilt University School of Medicine, 1161 21st Ave S, Nashville, TN 37232 (Dr. Wilson).
cific and less toxic drug (nystatin) is available in dose forms not requiring formulation. We recently saw twin infants who sustained circumoral and pharyngeal chemical burns from a highly concentrated solution of ben¬ zalkonium chloride. REPORT OF CASES Benzalkonium chloride was prescribed in 1:50,000 dilution for treatment of oral candidiasis in the male member (patient 1) of 2%-month-old twins. Application of the drug (with a cotton-tipped stick) to the mouth of both children was followed imme¬ a
2 on day 4 and by patient 1 on day 10. Both children had normal esophagrams ten days after application of the drug. Drooling and increased salivation continued in both in¬ fants to the time of discharge (day 7 for patient 2 and day 14 for patient 1).
Laboratory evaluations disclosed leuko¬ cytosis (white blood cell count, 22,700 to 24,800/cu mm for both infants) that cleared within two days after admission. The following abnormal chemical values were found: serum uric acid level, > 12 and 9.2 mg/100 ml; alkaline phosphatase level, > 350
and
240
international
units
diately by sialorrhea, profuse bubbling of saliva, and crying. Subsequent anorexia, irritability, and fever prompted admission to the hospital within 24 hours of drug ad¬ ministration. Both infants had fever, de¬ hydration, circumoral erythema, and nu¬ merous oral and pharyngeal lesions that were gray-white on a hemorrhagic base and easily removed with a tongue blade (Figure). A red, dry, scaly diaper rash was present in both infants. Direct laryngoscopy showed no lesions in the posterior
area of the pharynx of either infant. Pa¬ tient 1 was febrile (40.4 C [105 F]) and was treated with acetaminophen and tepid wa¬ ter sponging. Drooling and an intermittent cough were noted in both twins. Patient 2, the female twin, had a normal chest roent¬ genogram, whereas patient 1 had roent¬ genographic evidence of pneumonitis that cleared within four days. Patient 1 re¬ ceived antibiotics for 13 days, and both infants were given nystatin and fluid therapy intravenously. Three days after admission there was substantial clearing of the oral lesions in patient 2, leaving a smooth, glistening appearance to the tongue. Patient 1, however, retained graywhite lesions on the anteroinferior aspect of the tongue that did not resolve until day 10. Oral feedings were tolerated by patient
Downloaded From: http://archpedi.jamanetwork.com/ by a University of Manitoba User on 06/11/2015
Facial view of infant twins. Circumoral and mouth region of patient 1 (top) and patient 2 (bottom), showing scaly erythe¬ ma around lips and patchy white lesions
(necrotic tissue) on tongue. Photographs were obtained approximately 36 hours af¬
ter administration of benzalkonium chlo¬
ride.
(IU)/liter;
lactic dehydrogenase level, 430 and 300 IU/liter; serum glutamic oxaloacetic transaminase level, 40 and 20 IU/liter, for patients 1 and 2, respectively. Within four days, the serum uric acid values had returned to normal following rehydration; no abnormalities of urine were noted. A telephone call to the pharmacist dis¬ closed that a 17% stock solution of ben¬ zalkonium chloride, diluted two parts to one part water, had been dispensed instead of the 1:50,000 dilution requested. An ali¬ quot of the prescription was analyzed and found to contain 11% benzalkonium chlo¬ ride, confirming the formulation error.
COMMENT
Benzalkonium chloride is a cationic detergent that has been associated with both local and systemic reac¬ tions. The caustic properties of this agent in concentrations greater than 1% on skin1·2 and mucous mem¬ branes3·4 and in the eye5 are well rec¬ ognized. Systemic effects from percu¬ taneous absorption are rare,6 but fatalities have followed parenteral7·8 and oral910 administration. When taken orally in concentrated form, it has produced oral pain, laryngeal edema,11 and ulcération of the stom¬ ach10 and small intestine.8 Both anticholinesterase and curare-like effects have been postulated1 but would not be expected from small amounts by the oral route. In our patients, the clinical findings were limited to local chemical burns of the circumoral area, mouth, and pharynx associated with anorexia, dehydration, fever, and pneumonitis. Esophageal lesions were not demonstrated. The excessive drooling in both infants could be explained by a localized anticholinesterase (or irritant) effect on the submandibular gland. Normal feeding activity and a return toward normal of laboratory values suggest that no permanent damage of a local or systemic nature followed the ini¬ tial acute episode. The choice of therapeutic agents must include an assessment of toxic
The human use of ben¬ zalkonium chloride for antisepsis of skin should be limited to dilutions of at least 1:1,000 or 1:750.12 Dilutions greater than 1:750 require prepara¬ tion by a pharmacist. Caustic action of the agent occurs with a prepara¬ tion diluted 1:2,000 or 1:5,000, with dilutions of at least 1:20,000 being suggested for use on mucous mem¬ branes.12·13 Although benzalkonium chloride is active against yeasts and its use in oral candidiasis has been ad¬
potential.
recipient of Research Career Award HD-K4-42-539. Dr. Burr is an investigator with the Howard Hughes Medical Institute. The benzalkonium chloride prescription was analyzed by Winthrop Laboratories, New York. Dr. Wilson is the
Development
Nonproprietary Name and Trademarks of Drug
chloride—Benasept, Benkosal, Germicin, Hyamine 3500, Pheneen,
Benzalkonium
Zephiran Chloride.
vocated,14 specific recommendations
about use or toxicity in treatment of oral candidiasis in children cannot be found,12·13·15 eg, no warnings are listed in the 1973 Physicians' Desk Refer¬ ence. In view of the availability (for¬ mulation not required), efficacy, and limited toxicity of nystatin in the management of oral candidiasis in in¬ fants,15 the use of benzalkonium chlo¬ ride appears unwarranted. Benzalkonium chloride in relatively concentrated form is unexpectedly available for accidental ingestion. Disposable moistened paper towels are commonly used for cleaning the diaper area and are found in mothers' handbags. One such product (Hands and Face, manufactured by HollandRantos Company, Inc.) contains ben¬ zalkonium chloride in a 1:750 concen¬ tration (approximate). Inquiry to Med-Pak Corporation disclosed that their paper towel product (Kleen Up) also contains a 1:750 aqueous ben¬ zalkonium chloride solution. The man¬ ufacturer of Wet Ones (Lehn & Fink Industrial Products) did not list ben¬ zalkonium chloride among the ingre¬ dients. A 1:750 concentration of this detergent may be quite irritating or caustic if ingested by young children. Mothers would be well advised to keep benzalkonium chloride-contain¬ ing paper towels out of reach of chil¬ dren. This investigation was supported in part by Public Health Service grant 15431 from the Pharmacology-Toxicology Center.
References 1. Gleason MN, Gosselin RE, Hodge HC, et al: Clinical Toxicology of Commercial Products, ed 3. Baltimore, Williams & Wilkins Co, 1969, p 167. 2. Bengmark S: Cytotoxic action of quaternary ammonium compounds with special reference to wound healing. Bull Soc Int Chir 27:56\x=req-\ 63, 1968. 3. Fisher AA, Stillman MA: Allergic contact sensitivity to benzalkonium chloride: Cutaneous, ophthalmic, and general medical implications. Arch Dermatol 106:169-171, 1972. 4. Fitzhugh OG, Nelson AA: Chronic oral toxicities of surface-active agents. J Am Pharm Assoc Sci Ed 37:29-32, 1948. 5. Draize JH, Kelley KA: Toxicity to eye mucosa of certain cosmetic preparations containing surface-active agents. Proc Sci Sect Toilet Goods Assoc, No. 17, May 1952. 6. Finnegan JK, Dienna JB: Toxicological observations on certain surface-active agents. Proc Sci Sect Toilet Goods Assoc, No. 20, December 1953. 7. Spann W: Uber die toxische wirkung von Zephirol auf den menschlichen Organismus. Arch Toxikol 15:196-201, 1955. 8. Wagner H-J: 3 Todesfalle durch Intoxikation (Invertseife) oder durch anaphylaktischen Schock (Rosskastanienextnakt)? Arch Toxikol
21:83-88, 1965. 9. Tiess D, Nagel KH: Beitrag
zur Morphologie and Analytic der Invertseifenintoxikation: Zwei akut-todliche Vergiftungen durch perorale
Aufnahme des Desinfektion mittels C4. Arch Toxikol 22:333-348, 1967. 10. Wolff F: Todliche Vergiftung durch Triken des Desinfektionsmittels "C4." Arch Toxikol 19:8\x=req-\ 14, 1961. 11. Kaye S: Handbook of Emergency Toxicology. Springfield, Ill, Charles C Thomas Publisher, 1970, p 385. 12. Goodman LS, Gilman A: The Pharmacologic Basis of Therapeutics, ed 4. New York, Macmillan Co, 1970, p 1052. 13. Physicians' Desk Reference. Oradell, NJ, Medical Economics Co, 1973, p 1555. 14. Gobba AH, Refai M: Therapeutic value of benzalkonium chloride in oral candidiasis. Mykosen 11:529-530, 1958. 15. AMA Drug Evaluations, ed 2. Acton, Mass, Publishing Sciences Group Inc, 1973, p 652.
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Poisoning
John T. Wilson, MD, Ian M. Burr, MD
\s=b\ Infant twins sustained severe circumoral and pharyngeal burns from a concentrated solution of benzalkonium (Zephiran) chloride prescribed for treatment of candidiasis. This report emphasizes the unnecessary hazard accompanying use of a potentially toxic drug\p=m-\especially when prepared in error by the pharmacist\p=m-\whena safer drug (nystatin) is available for treatment of oral candidiasis. Risks from use of a prescription drug for other than the intended patient are also highlighted by this episode of poisoning. (Am J Dis Child 129:1208-1209, 1975)
presence of an ever-increas¬ number of chemicals for
The ing medical, industrial,
household, and agricultural use enhances the risk for poisoning in children. Poisoning from drugs usually results from accidental ingestion of a toxic dose and less often from an error in drug formula¬ tion or miscalculation of drug dose. In general, the availability of drugs with a higher therapeutic index has en¬ couraged physicians to lay aside drugs with greater toxic potential. Further, formulation errors have been reduced by the availability of commercial, standardized dose forms for most medicines. Despite these trends, benzalkonium (Zephiran) chlo¬ ride is still used topically for oral moniliasis even though a more speReceived for publication May 10, 1974; accepted March 10, 1975. From the divisions of pediatric clinical pharmacology and pediatric endocrinology, departments of pediatrics, pharmacology, and physiology, Vanderbilt University School of Medicine, Nashville, Tenn. Reprint requests to Department of Pediatrics, Vanderbilt University School of Medicine, 1161 21st Ave S, Nashville, TN 37232 (Dr. Wilson).
cific and less toxic drug (nystatin) is available in dose forms not requiring formulation. We recently saw twin infants who sustained circumoral and pharyngeal chemical burns from a highly concentrated solution of ben¬ zalkonium chloride. REPORT OF CASES Benzalkonium chloride was prescribed in 1:50,000 dilution for treatment of oral candidiasis in the male member (patient 1) of 2%-month-old twins. Application of the drug (with a cotton-tipped stick) to the mouth of both children was followed imme¬ a
2 on day 4 and by patient 1 on day 10. Both children had normal esophagrams ten days after application of the drug. Drooling and increased salivation continued in both in¬ fants to the time of discharge (day 7 for patient 2 and day 14 for patient 1).
Laboratory evaluations disclosed leuko¬ cytosis (white blood cell count, 22,700 to 24,800/cu mm for both infants) that cleared within two days after admission. The following abnormal chemical values were found: serum uric acid level, > 12 and 9.2 mg/100 ml; alkaline phosphatase level, > 350
and
240
international
units
diately by sialorrhea, profuse bubbling of saliva, and crying. Subsequent anorexia, irritability, and fever prompted admission to the hospital within 24 hours of drug ad¬ ministration. Both infants had fever, de¬ hydration, circumoral erythema, and nu¬ merous oral and pharyngeal lesions that were gray-white on a hemorrhagic base and easily removed with a tongue blade (Figure). A red, dry, scaly diaper rash was present in both infants. Direct laryngoscopy showed no lesions in the posterior
area of the pharynx of either infant. Pa¬ tient 1 was febrile (40.4 C [105 F]) and was treated with acetaminophen and tepid wa¬ ter sponging. Drooling and an intermittent cough were noted in both twins. Patient 2, the female twin, had a normal chest roent¬ genogram, whereas patient 1 had roent¬ genographic evidence of pneumonitis that cleared within four days. Patient 1 re¬ ceived antibiotics for 13 days, and both infants were given nystatin and fluid therapy intravenously. Three days after admission there was substantial clearing of the oral lesions in patient 2, leaving a smooth, glistening appearance to the tongue. Patient 1, however, retained graywhite lesions on the anteroinferior aspect of the tongue that did not resolve until day 10. Oral feedings were tolerated by patient
Downloaded From: http://archpedi.jamanetwork.com/ by a University of Manitoba User on 06/11/2015
Facial view of infant twins. Circumoral and mouth region of patient 1 (top) and patient 2 (bottom), showing scaly erythe¬ ma around lips and patchy white lesions
(necrotic tissue) on tongue. Photographs were obtained approximately 36 hours af¬
ter administration of benzalkonium chlo¬
ride.
(IU)/liter;
lactic dehydrogenase level, 430 and 300 IU/liter; serum glutamic oxaloacetic transaminase level, 40 and 20 IU/liter, for patients 1 and 2, respectively. Within four days, the serum uric acid values had returned to normal following rehydration; no abnormalities of urine were noted. A telephone call to the pharmacist dis¬ closed that a 17% stock solution of ben¬ zalkonium chloride, diluted two parts to one part water, had been dispensed instead of the 1:50,000 dilution requested. An ali¬ quot of the prescription was analyzed and found to contain 11% benzalkonium chlo¬ ride, confirming the formulation error.
COMMENT
Benzalkonium chloride is a cationic detergent that has been associated with both local and systemic reac¬ tions. The caustic properties of this agent in concentrations greater than 1% on skin1·2 and mucous mem¬ branes3·4 and in the eye5 are well rec¬ ognized. Systemic effects from percu¬ taneous absorption are rare,6 but fatalities have followed parenteral7·8 and oral910 administration. When taken orally in concentrated form, it has produced oral pain, laryngeal edema,11 and ulcération of the stom¬ ach10 and small intestine.8 Both anticholinesterase and curare-like effects have been postulated1 but would not be expected from small amounts by the oral route. In our patients, the clinical findings were limited to local chemical burns of the circumoral area, mouth, and pharynx associated with anorexia, dehydration, fever, and pneumonitis. Esophageal lesions were not demonstrated. The excessive drooling in both infants could be explained by a localized anticholinesterase (or irritant) effect on the submandibular gland. Normal feeding activity and a return toward normal of laboratory values suggest that no permanent damage of a local or systemic nature followed the ini¬ tial acute episode. The choice of therapeutic agents must include an assessment of toxic
The human use of ben¬ zalkonium chloride for antisepsis of skin should be limited to dilutions of at least 1:1,000 or 1:750.12 Dilutions greater than 1:750 require prepara¬ tion by a pharmacist. Caustic action of the agent occurs with a prepara¬ tion diluted 1:2,000 or 1:5,000, with dilutions of at least 1:20,000 being suggested for use on mucous mem¬ branes.12·13 Although benzalkonium chloride is active against yeasts and its use in oral candidiasis has been ad¬
potential.
recipient of Research Career Award HD-K4-42-539. Dr. Burr is an investigator with the Howard Hughes Medical Institute. The benzalkonium chloride prescription was analyzed by Winthrop Laboratories, New York. Dr. Wilson is the
Development
Nonproprietary Name and Trademarks of Drug
chloride—Benasept, Benkosal, Germicin, Hyamine 3500, Pheneen,
Benzalkonium
Zephiran Chloride.
vocated,14 specific recommendations
about use or toxicity in treatment of oral candidiasis in children cannot be found,12·13·15 eg, no warnings are listed in the 1973 Physicians' Desk Refer¬ ence. In view of the availability (for¬ mulation not required), efficacy, and limited toxicity of nystatin in the management of oral candidiasis in in¬ fants,15 the use of benzalkonium chlo¬ ride appears unwarranted. Benzalkonium chloride in relatively concentrated form is unexpectedly available for accidental ingestion. Disposable moistened paper towels are commonly used for cleaning the diaper area and are found in mothers' handbags. One such product (Hands and Face, manufactured by HollandRantos Company, Inc.) contains ben¬ zalkonium chloride in a 1:750 concen¬ tration (approximate). Inquiry to Med-Pak Corporation disclosed that their paper towel product (Kleen Up) also contains a 1:750 aqueous ben¬ zalkonium chloride solution. The man¬ ufacturer of Wet Ones (Lehn & Fink Industrial Products) did not list ben¬ zalkonium chloride among the ingre¬ dients. A 1:750 concentration of this detergent may be quite irritating or caustic if ingested by young children. Mothers would be well advised to keep benzalkonium chloride-contain¬ ing paper towels out of reach of chil¬ dren. This investigation was supported in part by Public Health Service grant 15431 from the Pharmacology-Toxicology Center.
References 1. Gleason MN, Gosselin RE, Hodge HC, et al: Clinical Toxicology of Commercial Products, ed 3. Baltimore, Williams & Wilkins Co, 1969, p 167. 2. Bengmark S: Cytotoxic action of quaternary ammonium compounds with special reference to wound healing. Bull Soc Int Chir 27:56\x=req-\ 63, 1968. 3. Fisher AA, Stillman MA: Allergic contact sensitivity to benzalkonium chloride: Cutaneous, ophthalmic, and general medical implications. Arch Dermatol 106:169-171, 1972. 4. Fitzhugh OG, Nelson AA: Chronic oral toxicities of surface-active agents. J Am Pharm Assoc Sci Ed 37:29-32, 1948. 5. Draize JH, Kelley KA: Toxicity to eye mucosa of certain cosmetic preparations containing surface-active agents. Proc Sci Sect Toilet Goods Assoc, No. 17, May 1952. 6. Finnegan JK, Dienna JB: Toxicological observations on certain surface-active agents. Proc Sci Sect Toilet Goods Assoc, No. 20, December 1953. 7. Spann W: Uber die toxische wirkung von Zephirol auf den menschlichen Organismus. Arch Toxikol 15:196-201, 1955. 8. Wagner H-J: 3 Todesfalle durch Intoxikation (Invertseife) oder durch anaphylaktischen Schock (Rosskastanienextnakt)? Arch Toxikol
21:83-88, 1965. 9. Tiess D, Nagel KH: Beitrag
zur Morphologie and Analytic der Invertseifenintoxikation: Zwei akut-todliche Vergiftungen durch perorale
Aufnahme des Desinfektion mittels C4. Arch Toxikol 22:333-348, 1967. 10. Wolff F: Todliche Vergiftung durch Triken des Desinfektionsmittels "C4." Arch Toxikol 19:8\x=req-\ 14, 1961. 11. Kaye S: Handbook of Emergency Toxicology. Springfield, Ill, Charles C Thomas Publisher, 1970, p 385. 12. Goodman LS, Gilman A: The Pharmacologic Basis of Therapeutics, ed 4. New York, Macmillan Co, 1970, p 1052. 13. Physicians' Desk Reference. Oradell, NJ, Medical Economics Co, 1973, p 1555. 14. Gobba AH, Refai M: Therapeutic value of benzalkonium chloride in oral candidiasis. Mykosen 11:529-530, 1958. 15. AMA Drug Evaluations, ed 2. Acton, Mass, Publishing Sciences Group Inc, 1973, p 652.
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