Sulfisoxazole in human milk

Volume 99 Number 1

Editorial correspondence

In the general screening program, seven or eight infants with a low T , / T B G ratio and a normal TSH were normal, and an additional infant possibly had secondary hypothyroidism. The 2,386 infants with normal T . / T B G ratios were not evaluated, but were assumed to be normal, and the false-negative rate cannot be calculated. It was not demonstrated that the one infant "detected" was a true positive. Since the rate of congenital hypothyroidism in the series was one in 3,333 births, it would be quite possible for all of these 2,386 infants to be normal by chance alone, since the error rate in assuming normality without any testing is only 1:3,333. The major utility of a neonatal T B G assay would be to eliminate recall of euthyroid TBG-deficient infants. I find it suspicious that no such infants were detected, when the incidence of congenital T B G deficiency is at least one in 9,000 births? Since only two specimens with a serum TBG of less than 10/#g/ml were used to validate the assay, it was not demonstrated that this assay could reliably detect abnormally low concentrations of TBG. The author's screening strategy is not different from assuming that all infants with a low T4 and a normal TSH are normal, unless it can be demonstrated that the one infant had an actual pituitary problem. A proposed screening test must be reliable, sensitive, and specificY None o f these measures can be calculated from the data presented, and the use of the T4/TBG ratio in a neonatal screening program cannot be recommended without further evaluation of infants with normal and abnormal ratios. Daniel C Postellon, M.D. Assistant Professor of Pediatrics Wayne State University Children's Hospital of Michigan Detroit Medical Center 3901 Beaubien Blvd. Detroit, M I 48201

REFERENCES

1,

2. 3.

Robertson EF, Wilkins AC, Oldfield RK, and Polard AC: Blood spot thyroxine-binding globulin: A m e a n s to reduce recall rate in a screening strategy for neonatal hypothyroidism, J PEDIATR 971604, 1980. Frankenburg WK: Selection o f diseases and tests in pediatric screening, Pediatrics 541612, 1974. Fisher DA, Dussault JH, Foley TP, Klein All, LeFranchi S, Larson PR, Mitchell ML, M u r p h e y WH, and Walfish PG: Screening for congenital hypothyroidism: Results of screening one million North American infants, J PEDIATR 941700, 1979.

RepZy To the Editor: In relation to a neonatal screening test, "abnormals" requiring detection are those who have a significant abnormality of thyroid function requiring treatment. Subjects with T B G deficiency are not within this group, whether the deficiency arises from congenital deficiency of TBG or from another cause. This group can be expected to have a normal free thyroxine, and therefore normal

17 1

T J T B G ratio. Thus the data on the 20,000 infants screened would not be expected to show the incidence of TBG deficiency, and the absence of such data should not lead to the conclusion that no such infants were found. Neither the specificity nor the sensitivity o f the test can be calculated as yet; m u c h larger numbers will be required. However, calculation of a free thyroxine index using T B G h a s allowed us to reduce our recall rate. The few laboratories involved in thyroid function testing in this state, and the ready collaboration between them, together with the fact that all pediatricans have some connection with this hospital, allows us to be satisfied that any child with congenital hypothyroidism not detected by the screening program would be notified to us as a "missed" one. To follow-up all of 20,000 infants by serum thyroid function testing would not be practicable. There are choices. One could only follow-up infants with high TSH values, and ignore the large group whose thyroxine values are low and TSH normal (1.8% in our hands, 1.1% in the Quebec regional screening program). One could cause anxiety by following those infants with low T4 and normal TSH, most of whom have no abnormality of thyroid function of significance. Or one could use a strategy designed, (but not yet proven because of small numbers) to detect those infants in whom there is a high suspicion that there is significant abnormality because their free thyroxine index is low. Dr. E. F. Robertson Physician The A delaide Children "s Hospital Inc. North Adelaide South Australia 5006

Sulfisoxazole in human milk To the Editor: We read with interest Kauffman, O'Brien, and Gilford's ~ statements on the secretion of sulfisoxazole into h u m a n milk. Although we agree with their final statement regarding potential risk to the hyperbilirubinemic neonate, we disagree with the potential risk to a healthy neonate. The length of the study is inappropriately short; with a half-life of 5.2 + 0.3 hours, the plasma sulfisoxazole level in the mother barely achieves a steady-state plasma concentration d u r i n g the 24-hour study period. ~ The long-lived N4-acetyl sulfisoxazole (14.9 _+ 5.2 hours half-life) would require 80 hours to reach steady state and after 24 hours could, at best, achieve a plasma level 62.5% of the concentration seen during a ten-day course of antibiotic therapy. 2 The milk-to-serum ratios o f drug and metabolite will not change. However, the percentage of total drug excreted in the milk as parent and metabolite will change significantly as the level of N4-acetyl sulfisoxazole continues to rise to steady state. The steady-state concentration of the metabolite was not identified and its ability to bind to plasma proteins not addressed. T h o u g h claimed by the manufacturer to be approximately 30% protein bound, (personal communication: W. J. Humphreys,

l 72

Editorial correspondence

Roche Laboratories), its tendency to displace bilirubin in healthy or premature neonates has not been investigated. The N4-acetyl metabolite is more lipid soluble than the parent compound. The amount secreted into mother's milk may be significant and is probably greater than the 1% figure quoted for the parent compound. We find no rational basis for the statement that bilirubin displacement from albumin does not occur at sulfisoxazole levels below 50 ~g/ml, as extrapolated from Oie and Levy? The information appears to have been derived from a single graph addressing sulfisoxazole concentration vs binding o f bilirubin to albumin in normal healthy adults. Oie and Levy's study was an in vitro procedure. Drug metabolism did not occur and the level of N*-acetyl sulfisoxazole can be assumed to be zero. Therefore, the plasma concentration of sulfisoxazole-N*-acetyl sulfisoxazole necessary to displace bilirubin from plasma protein is still unknown. Although the authors' statements regarding sulfisoxazole alone may be completely true, the importance of the metabolite N4-acetyl sulfisoxazole in combination in the infant has been overlooked. The manufacturers continue to recommend against the use of sulfisoxazole in infants and nursing mothers. Physicians who use the drug in neonates and/or nursing mothers should realize they are using an FDA-approved drug for an unapproved use.

Gary T. Elliott, Pharm.D. Candidate Suzanne L. Quinn, Pharm.D. Department of Pharmacy Practice College of Pharmacy, University of Florida J. Hillis Miller Health Center Box J-4 Gainesville, FL 32610

REFERENCES 1. 2.

3.

Kauffman RE, O'Brien C, and Gilford P: Sulfisoxazole secretion into human milk, J P~C~AXP.97:839, 1980. Harvey SC: Drug absorption, action and disposition, in Hoover JE, editor: Remington's pharmaceutical sciences, Easton, Pa., 1975, Mack Publishing Company, p 702. Oie S, and Levy G: Interindividual differences in the effect of drugs on bilirubin plasma binding in newborn infants and adults, Clin Pharmacol Thor 32:627, 1977.

Repty To the Editor: The issues raised relate primarily to the question of whether a normal, term newborn infant who is breast-fed and whose mother is taking a therapeutic dose ofsulfisoxazole would receive a 24-hour dose of sulfisoxazole via breast milk sufficient to increase his/her risk of bilirubin toxicity. As we originally stated, mothers of hyperbilirubinemic, glucose-6-phosphate dehydrogenase deficient, i11, stressed, and/or premature infants should take alternate antimicrobial agents if breast-feeding. Our comments regarding potential risk to the normal, term neonate were based on our own data along with reported characteristics of sulfisoxazole and bilirubin binding to albumin in human serum or plasma.

The Journal of Pediatrics July 1981

Milk was collected in our study' during the 24 hours of dosing and for 24 hours thereafter. During this period we would expect to recover 97% (five half-lives) of drug excreted as sulfisoxazole and at least 62.5% (1.6 half-lives) o f drug eventually excreted as acetylated sulfisoxazole. A mean o f 0.45% of the 24-hour maternal dose was recovered in breast milk during the 48-hour collection period, including both sulfisoxazole and acetylated sulfisoxazole, not only parent compound. Even if one assumes that only 62.5% of the sulfisoxazole which might theoretically eventually be recovered from breast milk was recovered (an underestimation), the potential 24-hour dose to the infant would be only 0.7% of the maternal dose. Assuming the infant nurses six times during the 24-hour period, and the sulfisoxazole in breast milk is evenly divided among feedings (a questionable assumption), the dose every four hours to the infant would be approximately 5 mg, or 1.7 mg/kg for a 3.0 kg infant, two orders of magnitude less than the usual therapeutic dose. Assuming an apparent volume of distribution in infants for sulfisoxazole of 0.42 L/kg and instantaneous absorption and distribution of the dose, the anticipated serum concentration resulting from such a dose would be 4 mg/L or 1.5 x 10-'~M. All of the assumptions used in these calculations overestimate the serum concentration of sulfisoxazole in the infant. The basic question is whether the estimated concentration o f sulfisoxazole could increase the free bilirubin serum concentration in a normal, term neonate. The displacement of bilirubin from albumin by drugs is a complex phenomenon which is a function of albumin concentration, bilirubin concentration, drug concentration, and affinities of bilirubin and drug for the binding site(s). Oie and Levy ~ reported the apparent dissociation constant (Kd) of bilirubin for the primary binding site in plasma from newborn infants to be 1.07 • 10 L In contrast, the Ka for competitive binding of sulfisoxazole and acetyl-sulfisoxazole to the primary bilirubin binding site reported by Brodersen and Danielsen ~' were 2.8 x 10 ~ and 2.9 • 10 ~, respectively; i.e., the affinity of bilirubin is much greater than the affinity of either sulfisoxazote or acetyl-sulfisoxazole. The relative affinities of sulfisoxazole and bilirubin for the primary bilirubin-binding sites on albumin are consistent with the observations by Oie and Levy ~ that the ratio of free bilirubin fraction in plasma with and without sulfisoxazole did not increase until the plasma concentration of sulfisoxazole exceeded 50 rag/L, even in the presence of a plasma bilirubin concentration of 12 mg/dl; the relative displacing effect of sutfisoxazole was essentially the same with plasma from neonates and adults. Considering the apparent respective affinities of bilirubin and sulfisoxazole for the primary bilirubin-binding site and the low potential serum concentrations of sulfisoxazole and acetylsulfisoxazole in the nursing infant, it seems inappropriate to restrict use of the drug by the mother of a nonhyperbihrubinemic and otherwise normal infant.

Ralph E. Kauffman, M.D. Associate Professor of Pediatrics and Pharmacology Associate Director of Clinical Pharmacology Wayne State University Children's Hospital of Michigan 3901 Beaubien Blvd. Detroit, MI 48201