Chloramphenicol in paediatrics: current prescribing practice and the need to monitor

Two hundred and fifty-five neonates, infants and children, from 45 hospitals, who were receiving chloramphenicol therapy for serious infections were the subject of this study. Samples of serum and cerebrospinal fluid (CSF) were assayed for chloramphenicol and the patient's treatment regimens analysed. Less than 50% of neonates and 25% of infants received the recommended dose of chloramphenicol. In older children the recommended dose was used. Only 34% babies under 1 year of age and 50% older children had serum concentrations within the therapeutic range (15–25 mg/l). Thirty-one percent of neonates and infants had potentially toxic serum concentrations. Forty-three percent of neonates receiving chloramphenicol every 6h had subtherapeutic peak serum levels compared to 20% of those receiving the antibiotic every 12h. Concomitant administration of phenobarbitone or phenytoin had no effect on mean serum chloramphenicol levels. Serum concentrations of chloramphenicol were significantly higher in patients also receiving penicillin. CSF levels in 77 samples (39 patients) ranged from 1–60 mg/l. CSF from 44% patients contained less than 4 mg/l. Twelve neonates and infants (5.5%) suffered toxic side effects, four died. A further eight babies received an accidental 2- to 10-fold overdose and in three others an overdose was assumed following assay. No overdoses or toxic effects were reported in children over 1 year of age. Eight patients with impaired renal function had elevated serum levels and three showed toxic effects. In 22% patients dosage regimens were altered following assay. Even when the recommended dosage regimen for chloramphenicol is followed serum from all babies under 1 year of age should be assayed every 48–72 h if safe and effective levels are to be maintained.Abbreviations CSF cerebrospinal fluid - SAS statistical analysing system     

Urodynamics in boys after prenatally diagnosed vesicoureteric reflux

Over the years, several theories have been presented regarding the pathogenesis of vesicoureteral reflux (VUR) in children without neurological disease or posterior urethral valves. Primary VUR is one of many fetal uropathies detectable by prenatal sonography. Thirteen boys with a prenatal diagnosis of hydronephrosis and postnatally demonstrated VUR had a urodynamic evaluation carried out at the age of 1 to 26 weeks. The renal function was evaluated by renography and estimation of glomerular filtration rate. Maximum detrusor pressure at voiding was significantly higher in the group of patients with VUR and impaired renal function compared to: (1) reflux patients with bilateral normal renal function; and (2) normal controls. Patients with normal bilateral renal and bladder function had a low risk of urinary tract infection during the period of follow-up (1 to 6 years). Early urodynamic studies in infants with VUR are important in order to clarify the pathogenesis of reflux and plan treatment strategy.     

Phenytoin elimination kinetics in two children with drug intoxication

Two girls aged 6 and 10 years treated with anticonvulsants developed nystagmus and ataxia. The peak plasma concentrations of phenytoin were 42.6 and 46.6 g/ml, respectively, compatible with phenytoin toxicity. The decline in plasma phenytoin levels did not fit first order kinetics, but followed Michaelis-Menten kinetics.     

Peroxisomal β-oxidation defect with detectable peroxisomes: A case with neonatal onset and progressive course

A progressive demyelinating cerebral disorder is described in a normally-appearing female infant with neonatal seizures, progressive psychomotor deterioration, deafness, retinopathy, peripheral neuropathy and loss of myelin observed on magnetic resonance imaging (MRI) scanning. MRI also showed the absence of macroscopic neocortical dysplasia which is usually found in Zellweger syndrome (ZS). Adrenal cortical function was normal. The patient died at the age of 37 months. Extensive biochemical investigations of peroxisomal functions in the patient revealed an impairment of peroxisomal -oxidation resulting in elevated levels of very long (>C₂₂) chain fatty acids in plasma and fibroblasts. Moreover, elevated plasma levels of intermediates of bile acid biosynthesis such as tri- and dihydroxycholestanoic acid were found. Other peroxisomal functions were normal. Immunoblotting of the peroxisomal -oxidation enzyme proteins in liver from the patient revealed normal responses with antisera against acyl-CoA oxidase, bifunctional protein and thiolase respectively. From these data we conclude that the patient had a deficiency of a single peroxisomal -oxidation enzyme at the level of either the bifunctional protein or peroxisomal thiolase with retained immunoreactivity against these enzymes.     

Chromosome 22q11 Deletion in Patients with Truncus Arteriosus

The association between truncus arteriosus and chromosome 22q11 deletion is well recognized, but the frequency of a chromosome 22q11 deletion has not been characterized in a large series of patients with truncus arteriosus, and little is known about cardiovascular morphologic features associated with a chromosome 22q11 deletion in this group of patients. We prospectively enrolled 50 consecutive patients with truncus arteriosus who were admitted to The Childrens Hospital of Philadelphia between November 1991 and December 2001. Patients were studied for chromosome 22q11 deletion using fluorescence in situ hybridization. Correlations between anatomic features and chromosome 22q11 deletion were assessed. A chromosome 22q11 deletion was detected in 20 of the 50 patients (40%). Anatomic features that were significantly associated with a chromosome 22q11 deletion included a right-sided aortic arch, an abnormal aortic arch branching pattern, both abnormal sidedness and branching of the aortic arch, and the combined category of either abnormal sidedness or branching of the aortic arch. There was a trend toward the association of discontinuous pulmonary arteries with a chromosome 22q11 deletion. Interruption of the aortic arch and truncal valve morphology and function did not correlate significantly with the presence of a chromosome 22q11 deletion. In conclusion, a chromosome 22q11 deletion is common in patients with truncus arteriosus, and those with abnormal sidedness and/or branching of the aortic arch are significantly more likely to have a deletion. Clinically important anatomic variables, such as abnormalities of the truncal valve and interrupted aortic arch, were not associated with a chromosome 22q11 deletion in this series. Present address (D.B. McElhinney): Department of Cardiology, Childrens Hospital, Boston, MA     

Variable outcome of experimental interferon-γ therapy of disseminated Bacillus Calmette-Guerin infection in two unrelated interleukin-12Rβ1-deficient Slovakian children

Mycobacterium bovis Bacillus Calmette-Guerin (BCG) is an attenuated live vaccine that may cause life-threatening clinical disease in children with impaired immunity. In particular, patients with any of the nine known inherited disorders of the interleukin-12/23 interferon- (IL-12/23-IFN) axis are highly vulnerable to BCG. We describe two unrelated young Slovakian children suffering from disseminated BCG infection which developed shortly after routine BCG vaccination after birth. During treatment with selected anti-BCG antibiotics, resistance against several of these drugs developed. In both children, interleukin-12/23 receptor 1 (IL-12/23R1) deficiency was diagnosed. Thus, in addition to chemotherapy, immunomodulatory treatment with recombinant IFN- was performed as the pathogenesis of BCG disease in IL-12R1 deficiency involves impaired IL-12- and IL-23-dependent IFN- production by lymphocytes. One child responded to treatment and is presently doing well whereas the second patient died. Conclusion:The marked variability of outcome of disseminated Bacillus Calmette-Guerin disease in interleukin-12/23 receptor 1-deficient children sharing the same ethnic origin and exposed to a similar environment as presented in these case reports has to be taken into consideration for diagnosis and treatment of infections due to this genetic defect.T. Ulrichs and C. Fieschi, S. H. E. Kaufmann and J-L. Casanova contributed equally to this work     

Long-term functional results after perineal surgery for low anorectal anomalies

As part of a long-term follow-up review of anorectal anomalies treated at the Royal Children's Hospital, Melbourne, we examined 70 patients with translevator (low) anomalies treated by a perineal operation and assessed their anorectal function by four clinical scoring methods (Kelly, Templeton, Kiesewetter, and Wingspread). The results were compared qualitatively after conversion into three categories: good; fair; and poor. Over 90% of patients achieved socially acceptable anorectal control. The incidence of accidental defaecation was shown to be age-related, patients seen after 10 years of age having a lower incidence of soiling than younger children. The incidence of smearing or staining did not diminish with age. Prolonged management was required in 5 patients who continued to have a poor level of faecal continence. Anorectal function was not adversely affected by the anterior position of the anal orifice in most patients after simple perineal surgery. Offprint requests to: S. W. Beasley     

Inherited disorders of the IL-12-IFN-γ axis in patients with disseminated BCG infection

Disseminated BCG infection is a rare complication of vaccination that occurs in patients with impaired immunity. In recent years, a series of inherited disorders of the IL-12-IFN- axis have been described that predispose affected individuals to disseminated disease caused by BCG, environmental Mycobacteria, and non-typhoidal Salmonella. The routine immunological work-up of these patients is normal and the diagnosis requires specific investigation of the IL-12-IFN- circuit. We report here the first two such patients originating from and living in Iran. The first child is two years old and suffers from complete IFN- receptor 2 deficiency and disseminated BCG infection. He is currently in clinical remission thanks to prolonged multiple antibiotic therapy. The other, a 28-year-old adult, suffers from IL-12p40 deficiency and presented with disseminated BCG infection followed by recurrent episodes of systemic salmonellosis. He is now doing well. A third patient of Iranian descent, living in North America, was reported elsewhere to suffer from IL-12R1 deficiency. These three patients thus indicate that various inherited defects of the IL-12-IFN- circuit can be found in Iranian people. In conclusion we recommend to consider the disorders of the IL-12-IFN- circuit in all patients with severe BCG infection, disseminated environmental mycobacterial disease, or systemic non-typhoidal salmonellosis, regardless of their ethnic origin and country of residence.     

Renal tubular dysfunction following treatment with anti-epileptic drugs

To evaluate renal side-effects of anti-epileptic medication in children, we performed a cross-sectional study of various aspects of renal function. We studied 59 patients from our outpatient clinic. They had been on anti-epileptic monotherapy for at least 3 months. None had a history of renal disease. Twenty-three healthy children of the same age group served as controls. After collecting 24-h urine samples, glomerular function was derived from creatinine clearance and from the excretion of albumin. Proximal tubular function was investigated by the urinary excretion of 1-microglobulin and of the tubular enzymes N-acetyl-ß-D-glucosaminidase, alamine-amino-peptidase and fructose-1,6-di-phosphatase. Distal tubular function was examined by the 24-h excretion of Tamm-Horsfall protein. On treatment with carbamazepine (n=27) and phenytoin (n=8), the excretion of 1-microglobulin was significantly increased, as compared with the healthy controls. On valproate (n=20), ethosuximide (n=9) and phenytoin (n=8), therapies significantly increased excretion of N-acetyl-ß-D-glucosaminidase. This must be interpreted as an indication of a functional disturbance of the proximal tubulus. The other parameters, indicating function of the glomerulus, loop of Henle and distal tubules did not differ from normal.Patients on anti-epileptic treatment with therapeutic drug levels may demonstrate minor signs of tubular dysfunction. These are probably insignificant from a clinical standpoint, but they should be considered in drug overdose.     

Accumulation of pristanic acid (2, 6, 10, 14 tetramethylpentadecanoic acid) in the plasma of patients with generalised peroxisomal dysfunction

The plasma of some patients with biochemical evidence of a generalised peroxisomal dysfunction (GPD) show greatly increased levels of phytanic acid as well as its -oxidation product, pristanic acid (2, 6, 10, 14-tetramethylpentadecanoic acid). Increased amounts of 14- and 16- carbon branched chain fatty acids are also found in some of these patients. As pristanic acid is present in normal or near-normal amounts in classical Refsum disease and rhizomelic chondrodysplasia, two disorders characterised by deficiencies in phytanic acid oxidation, we speculate that its accumulation is not secondary to a defect in the -oxidation of phytanic acid, but is indicative of a block in the peroxisomal -oxidation of pristanic acid. The finding of phytanic acid, as well as a number of its metabolites in patients with inherited defects in peroxisomal biogenesis indicates that a number of the steps in phytanic acid degradation may be confined to peroxisomes.Abbreviations GPD generalised peroxisomal dysfunction - VLCFA very long chain fatty acids - THCA 3, 7, 12-trihydroxy-5-cholestan-26-oic acid - br branched chain fatty acid - ALD adrenoleukodystrophy - DHAPAT dihydroxyacetone phosphate acyltransferase     

Serum carnitine levels in patients with homozygous beta thalassemia: a possible new role for carnitine?

Carnitine (-hydroxy--trimethylaminobutyric acid) facilitates the transfer of activated long-chain fatty acids from the cytoplasm to the mitochondria, the site of their -oxidation. Carnitine deficiency results in a reduced usage of fatty acids in energy production and therefore the appearance of clinical symptoms such as myalgia and muscle weakness. In the present study, serum carnitine levels were measured in 45 children and 20 adults with homozygous beta thalassemia. A decrease in serum carnitine levels (total, free and acyl) was found, without any evidence of disorder in the process of mitochondrial -oxidation. The possible cause of this finding could be related to a reduced hepatic carnitine biosynthesis. Conclusion:In patients with homozygous beta thalassemia, the reduction of serum carnitine levels might play an important role in the appearance of muscular dysfunction. It is possible that l -carnitine administration in these patients might improve or even resolve the aforementioned symptom.     

Endocrine and molecular biological studies in a German family with Albright hereditary osteodystrophy

We examined a German family with five members affected by Albright hereditary osteodystrophy (AHO). The only patient with pseudohypoparathyroidism type Ia (PHP-Ia) presented clinically with latent tetany, mental retardation, round face, short stature, brachymetacarpia and calcifications of subcutaneous tissue, heart and brain, whereas all other four members with pseudopseudohypoparathyroidism (pseudo-PHP) showed only subcutaneous calcifications and brachymetaphalangia. The PHP-Ia patient exhibited hypocalcaemia, hyperphosphataemia, elevated immunoreactive parathyroid hormone (PTH), and a blunted response of cyclic adenosine monophosphate (cAMP) in plasma and urine to synthetic 1-38 hPTH. In addition, latent primary hypothyroidism was found. In contrast, all tested healthy family members as well as the patients with pseudo-PHP exhibited normal calcium metabolism including cAMP response to exogenous PTH. In Northern blot experiments all patients with AHO, regardless whether affected by PHP-Ia or pseudo-PHP, revealed significantly reduced mRNA levels coding for the subunit of the G protein that stimulates adenylyl cyclase (G_s), when compared with healthy family members. In contrast, there was no significant difference between healthy and affected subjects with regard to the levels of the mRNA coding for the subunit of G_i-2, the main inhibitory G protein of adenylyl cyclase. The results indicate that reduced expression of G_s is a useful genetic marker in some families with AHO, regardless whether patients are affected by PHP-Ia or by pseudo-PHP.     

Peritoneal dialysis in maple-syrup-urine disease: Studies on branched-chain amino and keto acids

We report biochemical data on a child with MSUD who underwent peritoneal dialysis for severe metabolic imbalance. In confirmation of earlier data, the BCKA/BCAA ratios in blood had been found to be fairly stable in this patient during long-term dietary therapy.The child became comatose at comparatively low levels of leucine and KICA (ca. 2 mM each). At this time the blood/cerebrospinal fluid ratio for BCAA's and BCKA's was markedly diminished. During peritoneal dialysis, peritoneal clearance was highest for KIVA, but less for MEVA and BCAA's (40–50% or urea clearance), and least for the allegedly most toxic metabolite, KICA. The differences for BCKA's may be due to their differential protein binding. Given these individual differences, 1.8 to 8.7 initial plasma volumes were cleared in 14h with 24.21 of dialysis fluid. In the same time, urinary excretion of BCAA's and BCKA's was much less efficient.The data are discussed with regard to the pathobiochemical significance of high tissue levels of branched chain acids. A quantitative comparison between peritoneal dialysis and exchange transfusion is not yet possible.Abbreviations BCAA's branched-chain -amino acids - BCKA's branched-chain -keto acids - KICA -keto-isocaproic acid - KIVA -keto-isovalerio acid - MEVA -keto--methyl-n-valeric acid - MSUD maple syrup urine disease With support of the Landesamt für Forschung des Ministeriums für Wissenschaft und Forschung des Landes Nordrhein-Westfalen. U.L. was supported by Deutsche Forschungsgemeinschaft, Bad Godesberg, G.F.R. (DFG La 201, Schwerpunkt Biochemische Humangenetik and SFB 33 Nervensystem und biologische Information)     

The oto-onycho-peroneal syndrome

Two male sibs exhibit peculiar dysplasia of the ears, partial aplasia of the nails, and aplasia or hypoplasia of the fibulae. Gross motor development is severely impaired due to contractures of the hip, knee and ankle joints. Minor craniofacial abnormalities and immobility of several interphalangeal joints are also noted in this new syndrome which may be due to a rare recessive allele, probably autosomal.This paper is dedicated to Prof. K. D. Bachmann, Münster, on the occasion of his 60th birthday     

The management of necrotizing enterocolitis by “patch,drain, and wait”

The operative management necrotizing enterocolitis continues to be associated with substantial mortality and many difficulties. A new approach is presented with illustrative cases. Neither resection nor enterostomy is a part of this approach, which emphasizes maximum salvage of compromised intestine. Major features of this method are prolonged hyperalimentation, gastrostomy, minimal bowel handling, transverse approximation (patching) of the upper and lower margins of a limited number of major perforations, and extensive and prolonged drainage of the peritoneal cavity by Penrose drains placed from both diaphragms to exit sites in the inferior aspects of both lower quadrants. Enteric fistulas developed in the majority of cases presented (4/5) and were captured by one or both of the Penrose drains with disappearing peritonitis and the formation of de facto enterostomies at one of the drainage sites (generally the left side). De facto enterostomies that did not close spontaneously were closed operatively. This approach may also be of value in the management of midgut volvulus with extensive vascular compromise of the midgut.     

Seatbelt induced chance fracture in an infant

Chance (seat belt) fractures of the lumbar spine are extremely rare in the pediatric population and virtually unheard of in infants. We report a case of a 14 month old boy sustaining an isolated Chance fracture to L1 without associated spinal subluxation, dislocation, neurologic or visceral injury. He was being breast fed with his back beneath the passenger side shoulder harness when the vehicular front end collision causing his injury occurred. Thus, he may actually have sustained a hyperextension distraction or Reverse Chance fracture.     

Zinc and copper in infants fed breast-milk or different formula

In 129 term infants at birth and at the age of 4 months, zinc and copper concentrations of plasma and urine were determined by graphite furnace atomic absorption spectrophotometry and the values correlated to other biochemical parameters and somatic data. Of the infants, 49 were exclusively breast-fed, 44 fed with various commercially available cow's milk formula, 35 fed with a hypollergenic formula (cows's milk whey hydrolysate, commercially available, supplemented with zinc and copper). Plasma zinc values declined from birth to the age of 4 months in all three groups (P<0.001). In formula fed children, 4 months old, the values (11.1±1.7 mol Zn/l) were significantly lower than in breast-fed (12.2±1.7 mol Zn/l;P=0.004) or babies on hypo-allergenic formula (12.4±1.6 mol Zn/l;P=0.0015). In accordance with the literature plasma copper and caeruloplasmin values increased significantly within the first 4 months of life, the plasma levels were similar in either feeding group, only urinary copper excretion was higher in male infants on hypoallergenic formula (P<0.03) at the age of 4 months. There were no correlations between zinc or copper values and alkaline phosphatase. In infants on hypo-allergenic formula there was a negative correlation between plasma zinc and weight or height increments. Despite different zinc and copper supply, presumedly different bioavailability, and different plasma zinc values, all infants thrived and weight and length increments were similar in each group.     

Association of increased numbers of peripheral blood double-negative T-lymphocytes with elevated serum lgG levels in severely handicapped children

CD3⁺4^–8^– double negative cells in peripheral blood lymphocytes were examined in 21 severely handicapped children divided into two groups according to serum IgG level. All children were bedridden and were taking multiple anticonvulsants and there were no apparent clinical differences between these two groups. Serum levels of IgG correlated well with percentages of CD3⁺4^–8^– double negative lymphocytes in patients of both groups. In comparisons between the two groups, the high IgG group had higher counts of CD3⁺4^–8^– double negative lymphocytes in peripheral blood than the normal IgG group. Two distinct types of double negative cells were identified in the patients with high IgG: one had T-cell antigen receptors of heterodimers, the other had receptors of chains on their surface. As double negative T-cells are reported to have an important role in defence against bacterial infections, the increased numbers of CD3⁺4^–8^– T-cells of both phenotypes in the high IgG patients may reflect exposure to repetitive bacterial stimuli or persistent subclinical infection which in many cases, may be undetectable clinically. Moreover, the hyperimmune states shown by the high serum IgG of these patients may result from the appearance of these unique lymphocytes because they are reported to have a helper function for IgG synthesis in vitro. Taken together, the increased numbers of double negative cells in patients with high IgG may reflect activated defence mechanisms and the development of hyperimmune status.     

Complement in cystic fibrosis

Complement components C3, C4, and C3A were estimated in 30 patients with cystic fibrosis aged 1 to 21 years (MF=1614) and were compared with results in 40 healthy, age-matched subjects. The influences of the clinical score, sputum microbiology, and the patients' sex were also investigated. In contrast to most previous communications, this paper shows that, compared to the control group, a significant decrease of C3 (P<0.001) and C4 (P<0.02) was observed whereas C3A levels were not altered. There were no increases in complement. Shwachman-scores above or below 70 did not influence the complement levels, nor did exacerbations of the disease change the levels. No influence of the patients' sex could be shown. Pseudomonas aer. in the sputum was clearly associated with complement defects (14/18). Alternative-pathway involvement of complement activation could be demonstrated in 32%. The results make complement activation due to pulmonary infection most likely. The defects observed probably represent secondary changes.Presented at the VIIth Annual Meeting of the European Working Group for Cystic Fibrosis, Dresden, June 20–21, 1977Dedicated to Professor E. Zweymüller on the occasion of his 60th birtday