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Nafcillin, pseudoproteinuria, and hypokalemic alkalosis
Volume 97 Number 5
trations below 50 /zg/ml? This is well above m a x i m u m concentrations predicted from doses which might be absorbed from colostrum and breast milk. Potential risk to the neonate who is hyperbilirubinemic, glucose-6-phosphate dehydrogenase deficient~ ill, stressed a n d / o r premature is more difficult to evaluate. Mothers of such infants who are breast-feeding should take alternate antimicrobial agents when possible.
Brief clinical and laboratory observations
841
2. O'Brien, TE: Excretion of drugs in human milk, Am J Hosp Pharm 31:844, 1974. 3. White M: Breastfeeding and drugs in human milk, La Leche League Internationall Inc., 1978, Franklin Park, Ill. 4. Rieder J: The simultaneous quantitative determination of total, active, acetylated, and conjugated sulfonarciides in biological fluids, Chemotherapy 22"84, 1976. 5. Oie S and Levy G: Interindividual differences in the effect of drugs on bilirubin plasma binding in newborn infants and in adults, Clin Pharmacol Ther 21:627, 1977.
REFERENCES
1. Hervada AR, Feit E, and Sagraves R: Drugs in breast milk, Perinatal Care 2:19, 1978.
Nafcillin, pseudoproteinuria, and hypokalemic alkalosis Sharon P. Andreoli, M.D., Martin B. Kleiman, M.D., Melvin R. Gliek, Ph.D., and Jerry M. Bergstein, M.D.,* Indianapolis, Ind. NAFC1LLIN is a semisynthetic penicillin useful for the treatment of infection due to penicillinase-producing strains of Staphylococcus aureus. Complications of nafcillin therapy have included hypersensitivity reactions, gastrointestinal disorders, a n d skin rash.' Renal complications of nafcillin therapy a r e rarely recognized. This report describes two children with rare but clinicallY important complications of n a f c i l l i n - h y p o k a l e m i c alkalosis and pseudoproteinuria. CASE REPORTS Patient 1. A 9-year-old boy was transferred for treatment of osteomyelitis of the left femur and pyogenic arthritis of the right hip. Blood cultures obtained at the referring hospital yielded a penicillin-resistant strain of Staphylococcus aureus. Treatment was begun with nafcillin 300 mg/kg/day intravenously. Upon admission to Riley Children's Hospital five days after nafeillin therapy was initiated, the serum sodium concentration was 139 mEq/1, potassium 3.0 mEq/1, chloride 99 mEq/1, bicarbonate 29 mEq/1, and venous pH 7.50. Nafcillin therapy was continued at a dose of 267 mg/kg/day. Normal diet and intravenous fluid therapy containing 50 gm/l of dextrose and 77 mEq/1 Of sodium chloride at a rate of 5 ml/hour was continued until the third Riley Hospital day, when peripheral parenteral alimentation (PA) containing 125 gm/1 of dextrose, 30 mEq/1 of sodium, and 25 mEq/1 of potassium was 'initiated as a supplement to oral feedings. This supplied an average daily potassium supplement of 50 mEq. The total daily intravenous fluid intake was 2,000 ml From the Departments of Pediatrics and Pathology, Indiana University School of Medicine. *Reprint address: James Whitcomb Riley Hospitalfor Children, 1100 West Michigan St., Indianapolis, IN 46223.
0022-3476/80/110841 +02500.20/0 9 1980 The C. V. Mosby Co.
and the urine output averaged 2.0 ml/kg/hour. On the sixteenth hospital day, PA was discontinued owing to adequate oral caloric Consumption, and intravenous fluid therapy containing 50 gm/l of dextrose and 30 mEq/1 of both sodium and of potassium was begun at the rate of 450 ml/day; the urine output now averaged 1.34 ml/kg/hour. Serum electrolyte values determined before, during, and after PA therapy consistently showed hypokalemia (range 2.5 to 3.5 mEq/1). During the period of hypokalemia, the urine potassium concentration was consistently greater than 50 mEq/1, suggesting renal potassium wasting. Five Weeks after admission, the nafcillin dosage was decreased to 15ff mg/kg/day. Within two days, the hypokalemic alkalosis resolved. Abbreviations used PA: parenteral alimentation TCA: trichloroacetic acid During investigation of the etiology of the hypokalemic alkalosis, a 24-hour urine collection revealed 1.15 gm of protein as measured by the trichloroacetic acid method. Although several urinalyses showed 3 + to 4 + protein reaction by sulfosalicylic acid testing, urine dipsticks were consistently negative for protein. Microscopic examination of the urine sediment, serum creatinine and BUN values, and creatinine clearance were Consistently normal. Serum protein electrophoresis was normal and electrophoresis of a urine c0flcentrate showed no proteinuria. Patient 2. An 18-year-old girl was admitted to Riley Children's Hospital with persistent fever, 20-pound weight loss, and increasing fatigue. At age 7 months, a Type I truncus arteriosus Was detected and, at age 13 years, the patient underwent corrective surgery with insertion of a Hancock prosthesis and a porcine valve. Although several blood cultures were sterile, treatment
8 42
Brief clinical and laboratory observations
with nafcillin, 100 mg/kg/day, gentamicin, 4 mg/kg/day, and ampicillin, 200 mg/kg/day, was begun for presumed bacterial endocarditis, l~our weeks after the initiation of antibiotic therapy, two 24-hour urine collections revealed 2.1 and 2.5 gm of protein, respectively (TCA method). Although several subsequent urinalyses showed no proteinuria by the dipstick technique, the sulfosalicylic acid reaction was consistently 3 + to 4+. Results of microscopic examination of the urine, and serum electrolyte, BUN, and creatinine concentrations were normal. Serum protein electrophoresis was normal and electrophoresis of a urine concentrate showed no proteinuria. A 24-hour urine specimen collected one week after discontinuing antibiotic therapy contained 95 mg of protein (TCA method). DISCUSSION The dipstick (Bili-Labstix, Ames, Elkhardt, Ind.) technique is a semiquantitative estimation primarily of urinary albumin concentration, whereas the sulfosalicylic and TCA methods quantitate total urinary protein/ Disagreement between the dipstick and both the sulfosalicylic and TCA protein determinations usually indicates nonalbuminous proteinuria (i.e., the loss of low molecular weight proteins in the urine). The serum protein electrophoretic pattern of both patients showed no evidence of abnormal proteins. Proteinuria was not detected following electrophoresis of a fiftyfold concentrate of urine from each patient. As described by others 3 and confirmed in our laboratory, the addition of nafcillin to protein-free urine produces positive sulfosalicylic acid and TCA reactions. These studies indicate that the "proteinuria" was, in reality, the result of an interaction between nafcillin and/or its metabolites and the quantitative reagents, and that true proteinuria did not exist. That TCA and sulfosalicylic acid form insoluble salts with proteins serves as the basis for their use in the nephelometric assay of protein concentration. Recently, it has been shown that methicillin and cephalothin yield false-positive results in the TCA assay by inducing turbidity in the test solution that is not the result of protein precipitation." A similar mechanism of interference is proposed for nafcillin (unpublished data). Hypokalemia may be caused by poor potassium intake, gastrointestinal and/or renal wasting, and maldistribution of potassium. When the urine potassium concentration is greater than 10 mEq/1 in the face of hypokalemia, renal potassium wasting exists? Other causes of renal potassium wasting, such as excess adrenal steroids, diuretic use,
The Journal of Pediatrics November 1980
excess licorice ingestion, acidosis, osmotic diuresis, and increased urine flow rate were not present in our patient. Although hypokalemia may be caused by intravenous infusion of solutions containing a high concentration of glucose, our patient's hypokalemia was present before and for two weeks after discontinuation of parenteral alimentation. Hypokalemia has been described previously in an adult who received high dose nafcillin (200 mg/kg/day) therapy;6 this complication has not been previously described in children. As in the adult patient, the serum electrolyte values in our patient returned to normal when the dosage of nafcillin was decreased. Although the precise mechanism of nafeillin-induced hypokalemia is unclear, it may act in the urine as a nonreabsorbable anion, increasing distal tubular potassium excretion by creating a negative transtubular electrical gradient/. 8 Usually, the findings of proteinuria or hypokalemic alkalosis require further etiologic evaluation. Recognition that nafcillin can cause reversible hypokalemic alkalosis and produce a false-positive quantitative test for proteinuria will spare patients unnecessary investigation and, perhaps, unwarranted therapy. REFERENCES
1. Weinstein L: Antimicrobial agents: Penicillin and cephalosporins, In Goodman LS, and Gilman A, editors: The pharmacological basis of therapeutics, New York, 1975, The Macmillan Company, pp 1130-1166. 2. Gyure WL: Comparison of several methods for semiquantitative determination of urinary protein, Clin Chem 23:876, 1977. 3. Line DE, Adler S, Fraley DS, and Burns FJ: Massive pseudoproteinuria caused by nafcillin, JAMA 235"1259, 19'76. 4. Muir A, and Hensley WJ: Pseudoproteinuria due to penicillins, in the turbidometric measurement of proteins with trichloroacetic acid, Clin Chem 25:1662, 1979. 5. Nardone DA, McDonald WJ, and Girard DE: Mechanisms in hypokalemia: clinical correlation, Medicine (Baltimore) $7:435, 1978. 6. Mohr JA, Clark RM, and Waack TC: Nafcillin-associated hypokalemia, JAMA 242:544, 1979. 7. Lipner HI, Ruzany F, Dasgupta M, et al: The behavior of carbenicillin as a nonreabsorbable anion, J Lab Clin Med 86:183, 1975, 8. Brunner FP, and Frick PG: Hypokalemia, metabolic alkalosis, and hypernatremia due to "massive" sodium penicillin therapy, Br Med J 4:550, 1968.
trations below 50 /zg/ml? This is well above m a x i m u m concentrations predicted from doses which might be absorbed from colostrum and breast milk. Potential risk to the neonate who is hyperbilirubinemic, glucose-6-phosphate dehydrogenase deficient~ ill, stressed a n d / o r premature is more difficult to evaluate. Mothers of such infants who are breast-feeding should take alternate antimicrobial agents when possible.
Brief clinical and laboratory observations
841
2. O'Brien, TE: Excretion of drugs in human milk, Am J Hosp Pharm 31:844, 1974. 3. White M: Breastfeeding and drugs in human milk, La Leche League Internationall Inc., 1978, Franklin Park, Ill. 4. Rieder J: The simultaneous quantitative determination of total, active, acetylated, and conjugated sulfonarciides in biological fluids, Chemotherapy 22"84, 1976. 5. Oie S and Levy G: Interindividual differences in the effect of drugs on bilirubin plasma binding in newborn infants and in adults, Clin Pharmacol Ther 21:627, 1977.
REFERENCES
1. Hervada AR, Feit E, and Sagraves R: Drugs in breast milk, Perinatal Care 2:19, 1978.
Nafcillin, pseudoproteinuria, and hypokalemic alkalosis Sharon P. Andreoli, M.D., Martin B. Kleiman, M.D., Melvin R. Gliek, Ph.D., and Jerry M. Bergstein, M.D.,* Indianapolis, Ind. NAFC1LLIN is a semisynthetic penicillin useful for the treatment of infection due to penicillinase-producing strains of Staphylococcus aureus. Complications of nafcillin therapy have included hypersensitivity reactions, gastrointestinal disorders, a n d skin rash.' Renal complications of nafcillin therapy a r e rarely recognized. This report describes two children with rare but clinicallY important complications of n a f c i l l i n - h y p o k a l e m i c alkalosis and pseudoproteinuria. CASE REPORTS Patient 1. A 9-year-old boy was transferred for treatment of osteomyelitis of the left femur and pyogenic arthritis of the right hip. Blood cultures obtained at the referring hospital yielded a penicillin-resistant strain of Staphylococcus aureus. Treatment was begun with nafcillin 300 mg/kg/day intravenously. Upon admission to Riley Children's Hospital five days after nafeillin therapy was initiated, the serum sodium concentration was 139 mEq/1, potassium 3.0 mEq/1, chloride 99 mEq/1, bicarbonate 29 mEq/1, and venous pH 7.50. Nafcillin therapy was continued at a dose of 267 mg/kg/day. Normal diet and intravenous fluid therapy containing 50 gm/l of dextrose and 77 mEq/1 Of sodium chloride at a rate of 5 ml/hour was continued until the third Riley Hospital day, when peripheral parenteral alimentation (PA) containing 125 gm/1 of dextrose, 30 mEq/1 of sodium, and 25 mEq/1 of potassium was 'initiated as a supplement to oral feedings. This supplied an average daily potassium supplement of 50 mEq. The total daily intravenous fluid intake was 2,000 ml From the Departments of Pediatrics and Pathology, Indiana University School of Medicine. *Reprint address: James Whitcomb Riley Hospitalfor Children, 1100 West Michigan St., Indianapolis, IN 46223.
0022-3476/80/110841 +02500.20/0 9 1980 The C. V. Mosby Co.
and the urine output averaged 2.0 ml/kg/hour. On the sixteenth hospital day, PA was discontinued owing to adequate oral caloric Consumption, and intravenous fluid therapy containing 50 gm/l of dextrose and 30 mEq/1 of both sodium and of potassium was begun at the rate of 450 ml/day; the urine output now averaged 1.34 ml/kg/hour. Serum electrolyte values determined before, during, and after PA therapy consistently showed hypokalemia (range 2.5 to 3.5 mEq/1). During the period of hypokalemia, the urine potassium concentration was consistently greater than 50 mEq/1, suggesting renal potassium wasting. Five Weeks after admission, the nafcillin dosage was decreased to 15ff mg/kg/day. Within two days, the hypokalemic alkalosis resolved. Abbreviations used PA: parenteral alimentation TCA: trichloroacetic acid During investigation of the etiology of the hypokalemic alkalosis, a 24-hour urine collection revealed 1.15 gm of protein as measured by the trichloroacetic acid method. Although several urinalyses showed 3 + to 4 + protein reaction by sulfosalicylic acid testing, urine dipsticks were consistently negative for protein. Microscopic examination of the urine sediment, serum creatinine and BUN values, and creatinine clearance were Consistently normal. Serum protein electrophoresis was normal and electrophoresis of a urine c0flcentrate showed no proteinuria. Patient 2. An 18-year-old girl was admitted to Riley Children's Hospital with persistent fever, 20-pound weight loss, and increasing fatigue. At age 7 months, a Type I truncus arteriosus Was detected and, at age 13 years, the patient underwent corrective surgery with insertion of a Hancock prosthesis and a porcine valve. Although several blood cultures were sterile, treatment
8 42
Brief clinical and laboratory observations
with nafcillin, 100 mg/kg/day, gentamicin, 4 mg/kg/day, and ampicillin, 200 mg/kg/day, was begun for presumed bacterial endocarditis, l~our weeks after the initiation of antibiotic therapy, two 24-hour urine collections revealed 2.1 and 2.5 gm of protein, respectively (TCA method). Although several subsequent urinalyses showed no proteinuria by the dipstick technique, the sulfosalicylic acid reaction was consistently 3 + to 4+. Results of microscopic examination of the urine, and serum electrolyte, BUN, and creatinine concentrations were normal. Serum protein electrophoresis was normal and electrophoresis of a urine concentrate showed no proteinuria. A 24-hour urine specimen collected one week after discontinuing antibiotic therapy contained 95 mg of protein (TCA method). DISCUSSION The dipstick (Bili-Labstix, Ames, Elkhardt, Ind.) technique is a semiquantitative estimation primarily of urinary albumin concentration, whereas the sulfosalicylic and TCA methods quantitate total urinary protein/ Disagreement between the dipstick and both the sulfosalicylic and TCA protein determinations usually indicates nonalbuminous proteinuria (i.e., the loss of low molecular weight proteins in the urine). The serum protein electrophoretic pattern of both patients showed no evidence of abnormal proteins. Proteinuria was not detected following electrophoresis of a fiftyfold concentrate of urine from each patient. As described by others 3 and confirmed in our laboratory, the addition of nafcillin to protein-free urine produces positive sulfosalicylic acid and TCA reactions. These studies indicate that the "proteinuria" was, in reality, the result of an interaction between nafcillin and/or its metabolites and the quantitative reagents, and that true proteinuria did not exist. That TCA and sulfosalicylic acid form insoluble salts with proteins serves as the basis for their use in the nephelometric assay of protein concentration. Recently, it has been shown that methicillin and cephalothin yield false-positive results in the TCA assay by inducing turbidity in the test solution that is not the result of protein precipitation." A similar mechanism of interference is proposed for nafcillin (unpublished data). Hypokalemia may be caused by poor potassium intake, gastrointestinal and/or renal wasting, and maldistribution of potassium. When the urine potassium concentration is greater than 10 mEq/1 in the face of hypokalemia, renal potassium wasting exists? Other causes of renal potassium wasting, such as excess adrenal steroids, diuretic use,
The Journal of Pediatrics November 1980
excess licorice ingestion, acidosis, osmotic diuresis, and increased urine flow rate were not present in our patient. Although hypokalemia may be caused by intravenous infusion of solutions containing a high concentration of glucose, our patient's hypokalemia was present before and for two weeks after discontinuation of parenteral alimentation. Hypokalemia has been described previously in an adult who received high dose nafcillin (200 mg/kg/day) therapy;6 this complication has not been previously described in children. As in the adult patient, the serum electrolyte values in our patient returned to normal when the dosage of nafcillin was decreased. Although the precise mechanism of nafeillin-induced hypokalemia is unclear, it may act in the urine as a nonreabsorbable anion, increasing distal tubular potassium excretion by creating a negative transtubular electrical gradient/. 8 Usually, the findings of proteinuria or hypokalemic alkalosis require further etiologic evaluation. Recognition that nafcillin can cause reversible hypokalemic alkalosis and produce a false-positive quantitative test for proteinuria will spare patients unnecessary investigation and, perhaps, unwarranted therapy. REFERENCES
1. Weinstein L: Antimicrobial agents: Penicillin and cephalosporins, In Goodman LS, and Gilman A, editors: The pharmacological basis of therapeutics, New York, 1975, The Macmillan Company, pp 1130-1166. 2. Gyure WL: Comparison of several methods for semiquantitative determination of urinary protein, Clin Chem 23:876, 1977. 3. Line DE, Adler S, Fraley DS, and Burns FJ: Massive pseudoproteinuria caused by nafcillin, JAMA 235"1259, 19'76. 4. Muir A, and Hensley WJ: Pseudoproteinuria due to penicillins, in the turbidometric measurement of proteins with trichloroacetic acid, Clin Chem 25:1662, 1979. 5. Nardone DA, McDonald WJ, and Girard DE: Mechanisms in hypokalemia: clinical correlation, Medicine (Baltimore) $7:435, 1978. 6. Mohr JA, Clark RM, and Waack TC: Nafcillin-associated hypokalemia, JAMA 242:544, 1979. 7. Lipner HI, Ruzany F, Dasgupta M, et al: The behavior of carbenicillin as a nonreabsorbable anion, J Lab Clin Med 86:183, 1975, 8. Brunner FP, and Frick PG: Hypokalemia, metabolic alkalosis, and hypernatremia due to "massive" sodium penicillin therapy, Br Med J 4:550, 1968.