The Journal o f Pediatrics Edi tor ia l correspondence 1 6 9 Volume 123, Number 1

data from our study demonstrating a rapid plasma clearance of fluconazole in febrile neutropenic children carry potentially im- portant dosage implications for treatment of life-threatening my- coses. 9 If inhibitory levels of fluconazole disappear in the CNS of a child with Candida meningitis before the next dosage in a 24-hour cycle, then the organism may begin to regrow, particularly on a foreign body. The plasma levels in the patient of Dr. Epelbaum suggest that fluconazole was administered every 24 hours in this child, thus allowing for this possibility.

Intrinsic resistance of C. albicans to fluconazole in vivo is unusual, unless the isolate is derived from a patient receiving long- term suppressive therapy with this agent. In vitro susceptibility as- says of antifungal azoles have been notoriously difficult to stan- dardize. 1~ Differences in media, pH, inoculum, and standards of endpoint interpretation in different assays substantially influence the minimal inhibitory concentration (MIC). An organism inter- preted as being susceptible to an antifungal azole in one laboratory may be read as being resistant in another laboratory. Until suscep- tibility methods for antifungal azoles, including fluconazole, are standardized, routine determinations of MICs for this class of an- tifungal agents cannot be recommended.

Thus we suggest that, pending further studies, the initial treat- ment of choice for CNS candidiasis or cryptococcosis in children remains amphotericin B plus flucytosine. This combination is fun- gicidal against most isolates of C. albicans, and C. neoformans. Removal of foreign bodies such as ventricular shunts, when possi- ble, is an important adjunct to therapy in CNS mycoses refractory to treatment with amphotericin B plus flucytosine.

Thomas J. Walsh, MD Senior Investigator James W. Lee, MD Senior S ta f f Fellow

Infectious Diseases Section, Pediatric Branch National Cancer Institute

National Institutes o f Health Bethesda, MD 20892

Nita Seibel, MD Assistant Professor

Department o f Hematology and Oncology Children's National Medical Center

Washington, DC 20010

Philip A. Pizzo, MD Chief, Pediatric Branch

Head, Infectious Diseases Section National Cancer Institute

Professor o f Pediatrics Uniformed Services University o f the Health Sciences

National Institutes o f Health Bethesda, MD 20892

9/35/46456

R E F E R E N C E S

1. Walsh T J, Schlegel R, Moody MM, Costerton JW, Saleman M. Ventriculo-atrial shunt infection due to Cryptococcus neo-

formans." an ultrastructural and quantitative microbiological study. Neurosurgery 1986;18:373-5.

2. Perfect JR, Durack DT. Penetration of imidazoles and triaz- oles into cerebrospinal fluid in rabbits. J Antimicrob Chemother 1985;16:81-6.

3. Arndt CAS, Walsh T J, McCully CL, Balis FM, Pizzo PA, Poplack DG. Fluconazole penetration into cerebrospinal fluid: implications for treating fungal infections of the central ner- vous system. J Infect Dis 1988;157:178-80.

4. Walsh T J, Foulds G, Pizzo PA. Pharmacokinetics and tissue penetration of fluconazole in rabbits. Antimicrob Agents Chemother 1989;33:467-9.

5. Rakusan TA, Dreyer C, Rinaldi M. Use of oral fluconazole in treatment of coccidioidal meningitis in a child . Clin Res 1989;37:60A.

6. Brammer KW, Farrow PR, Faulkner JW. Pharmacokinetics and tissue penetration of fluconazole in humans. Rev Infect Dis 1990;12:318-26.

7. Moncino M, Gutman L. Sever systemic cryptococcal diseases in a child: review of prognostic indicators predicting treatment failure and an approach to maintenance therapy with oral flu- conazole. Pediatr Infect Dis J 1990;9:363-8.

8. Byers M, Chapman S, Feldman S, Parent A. Fluconazole pharmacokinetics in the cerebrospinal fluid of a child with Candida meningitis. Pediatr Infect Dis J 1992;11: 895-6.

9. Lee JW, Seibel NI, Amantea MA, Whitcomb P, Pizzo PA, Walsh TJ. Safety, tolerance, and pharmacokinetics of flucon- azole in children with neoplastic diseases. J PEDIATR 1992; 120:987-93. Kobayashi GS, Spitzer ED. Testing of organisms for suscep- tibility to triazoles: is it justified? Eur J Ctin Microbiol Infect Dis 1989;8:387-9.

10.

Effect of insulin-like growth factor I on IGF binding proteins

To the Editor." I read with interest the article by Walker et al. (J PED~ATR

1992;121:641-6) and was pleased that the authors were able to confirm our observation of long-term treatment of five children with Laron syndrome with recombinant insulin-like growth factor (IGF) I. 1

We have also found that long-term IGF treatment increased body and extremity length and also the head circumference, details not mentioned in the article by Walker et al. Thus IGF-I is a po- tent growth-promoting hormone and IGF binding proteins con- tribute to the long-term growth effect of IGF-I. Indeed, we found that IGF-I increased IGF binding proteins 1, 2, and even 3, which has been considered until now completely dependent on growth hormone.Z, 3

Z. Laron, MD Professor o f Pediatric Endocrinology

Endocrinology & Diabetes Research Unit Children's Medical Center o f lsrael

Petah Tikva 49 202, Israel 9/35/46452

1 7 0 Editorial correspondence The Journal of Pediatrics July 1993

REFERENCES

1. Laron Z, Anin S, Klipper-Aurbach Y, Klinger B. Effects of insulin-like growth factor on linear growth, head circumfer- ence and body fat in patients with Laron type dwarfism. Lan- cet 1992;339:1258-61.

2. Laron Z, Suikkari AM, Klinger B, et al. Growth hormone and insulin-like growth factor regulate insulin-like growth factor binding protein I in Laron type dwarfism, growth hormone de- ficiency and constitutional short stature. Acta Endocrinol 1992;127:351-8.

3. Kanety H, Karasik A, Klinger B, Silbergeld A, Laron Z. Long-term treatment of Laron type dwarfs with IGF-I in- creases serum IGFBP-3 in the absence of GH activity. Acta Endocrinol 1993;128:144-9.

Reply

To the Editor: The report of Dr. Laron and his colleagues was published after

our report was submitted to THE JOURNAL. The acceleration of growth in our patient and in others whom we have studied recently is indeed similar to that which he reports. In his letter, Dr. Laron alludes to the effects of insulin-like growth factor I (IGF-I) ther- apy on the insulin-like growth factor binding proteins (IGFBPs). Our investigations suggest that these effects vary among the different IGFBPs and that the regulatory mechanisms involved are complex.1 Six different IGFBPs have been identified in human be- ings-designated IGFBPs 1 to 6--and four are found in serum (IGFBPs 1 to 4). 2 Beyond their capacity to bind IGF-I and IGF- II, the precise biologic function of these proteins is not known. It is supposed that they might influence the biologic actions of IGF-I by impeding or facilitating transport from the circulation and by affecting binding to cell surfaces.

A complex 150,000-dalton (150K) molecule that contains IGFBP-3, IGF-I, and an acid-labile protein (acid labile subunit [ALS]) is the principal carrier of IGF-I in serum. IGFBP-3 is de- pendent on growth hormone (GH). Our patient, therefore, who cannot respond to GH, has a low IGFBP-3 concentration. The pro- portion of IGFBP-3 in the 150K circulating complex is decreased, probably because IGF-I suppresses ALS, creating a deficiency of one of the three components required for formation of the 150K complex. Our observations that IGFBP-3 is not increased by administration of IGF-I, therefore, differ from those of Dr. Laron.

In serum, IGFBP-1 is regulated more by insulin than by GH) IGFBP-1 rises during fasting and declines as insulin levels rise af- ter feeding. We find that the continuous intravenous infusion of 1GF-I leads to increased IGFBP-1. This is accompanied by suppression of insulin secretion; we assume that the reduced insu- lin is in part the mechanism for this suppression, Unlike Dr. Laron, we did not observe increased IGFBP-1 after subcutaneous injection of IGF-I, which caused minimal suppression of insulin secretion.

Serum concentrations of IGFBP-2 are increased in GH-deficient individuals, 4 and GH causes IGFBP-2 to decline. For reasons that are not clear, our patient, who is resistant to GH, did not have in- creased IGFBP-2, but understandably, GH treatment did not cause his IGFBP-2 to decline. In agreement with Dr. Laron's observa- tions, we also find that administration of IGF-I increases IGFBP-2. We assume that this is a direct effect of IGF-I.

In addition to showing that IGF-I promotes growth in children with growth hormone insensitivity, these studies have provided in- sights into the specific roles of GH and IGF-I in anabolism. 5 Be- cause patients with Laron syndrome represent a unique model for differentiating between the actions of GH and those of IGF-I, studies in these patients will also likely aid in efforts to understand the regulation and function of IGFBPs.

Louis E. Underwood, MD Department of Pediatrics

University of North Carolina School of Medicine Chapel Hill, NC 27599-7220

9/35/46451

REFERENCES

1. Walker JL, Baxter RC, Young S, Pucilowska J, Clemmons DR, Underwood LE. Effects of recombinant insulin-like growth factor I (IGF-I) on IGF binding proteins (IGFBPs) and the acid-labile subunit (ALS) in growth hormone insensi- tivity syndrome. Growth Regulation (in press).

2. Baxter RC. Physiological roles of IGF binding proteins. In: Spencer EM, ed. Modern concepts of insulin-like growth fac- tors. Amsterdam: Elsevier, 1991:371-80.

3, Suikkari AM, Koistinen VA, Rutanen EM, Jarvinen H, Karonen SL, Seppala M. Insulin regulates the serum levels of low molecular weight insulin-like growth factor binding pro- tein. J Clin Endocrinol Metab 1988;66:266-73.

4. Clemmons DR, Snyder DK, Busby WH Jr. Variables control- ling the secretion of insulin-like growth factor binding pro- tein-2 in normal human subjects. J Clin Endocrinol Metab 1991;73:727-33.

5. Walker JL, Ginalska-Malinowska M, Romer TE, Pucilowska JB, Underwood LE. Effects of the infusion of insulin-like growth factor-I in a child with growth hormone insensitivity syndrome (Laron dwarfism). N Engl J Med 1991;324:1483-8.

Idiopathic arterial calcification of infancy and pyrophosphate deficiency

To the Editor: Bellah et al. (J PEDIATR 1992;121:930-3) described the antena-

tal diagnosis of idiopathic infantile arteriat calcification in a pre- term infant at 29 weeks of gestation. Despite antenatal and post- natal treatment with disodium etidronate, refractory cardiorespi- ratory failure developed and the child died at 7V2 months of age.

We reported the unsuccessful treatment of this condition in two siblings; the condition was diagnosed in one of them by fetal ech- ocardiography. 1 Despite treatment with disodium etidronate (20 mg three times a day), both infants died of myocardial ischemia by 3 months of age. Although there is no identifiable abnormality of calcium metabolism in most children with idiopathic infantile ar- terial calcification, we noted a very low plasma concentration of pyrophosphate (0.6 #tool/L; normal range in adults, 1 to 6 ~mol/L) in one infant. Plasma pyrophosphate was not measured in the first sibli:Lg. Although the low pyrophosphate concentration may have been caused by calcium deposition, it is also possible that idiopathic