Cerebrospinal fluid concentrations of ethionamide in children with tuberculous meningitis

Cerebrospinal fluid ethionamide concentrations were determined in 18 children (median age 26.5 months) with tuberculous meningitis complicated by raised intracranial pressure. Lumbar spinal fluid specimens were obtained before and after weekly hour-long monitoring of intracranial pressure. Thirty-five paired and four single specimens were evaluated. A dosage schedule of 15 mg/kg was used on 26 occasions, and a spinal fluid ethionamide concentration of 2.5 μg/ml, the in vitro minimal inhibitory concentration for Mycobacterium tuberculosis, was exceeded on only seven occasions (27%). A dosage of 20 mg/kg was administered on 13 occasions, and in only two instances (15%) was a concentration of 2.5 μg/ml not achieved. Ethionamide in a single daily dosage of 20 mg/kg should be considered for the initial treatment of tuberculous meningitis when the presence of isoniazid-resistant M. tuberculosis cannot be excluded.Articl

Stability of isoniazid, rifampin and pyrazinamide in suspensions used for the treatment of tuberculosis in children

The stability of monosuspensions, cosuspensions and multisuspensions of isoniazid (INH), pyrazinamide (PZA) and rifampin (RIF) has been evaluated by high pressure liquid chromatography over a period of 28 days both with and without the addition of vitamin C (20 μg/ml) and at ambient temperatures of 4°C, 24°C and 40°C. At the end of 28 days >90% of initial concentrations of INH, PZA and RIF in monosuspensions remained unchanged irrespective of ambient temperature as was the case with INH and PZA in cosuspension. The addition of RIF to either INH or PZA in cosuspension or together in multisuspension led to a marked fall in the concentration of one or more of the agents, an effect that was accentuated by the addition of vitamin C. In the case of a multisuspension of INH + RIF + PZA was vitamin C added, 41.7% (4°C), 24.1% (24°C) and 20.3% (40°C) of initial INH concentrations and 1.9% (4°C), 1.3% (24°C) and 0.0% (40°C) of initial RIF concentrations remained detectable after 28 days. The addition of vitamin C to monosuspensions of INH and PZA led to a marked decline in the amount of drug detectable and only in the case of RIF was >90% of initial concentrations of the drug detectable after 28 days. The dispensing of cosuspensions or multisuspensions of antituberculosis agents containing RIF is inadvisable as is the addition of vitamin C in any form.Articl

In vitro evaluation of ampicillin-gentamicin interactions

Ampicillin at a concentration of 100 μg/mL was combined in vitro with either gentamicin 10 μg/mL in serum, 0.01 mol/L phosphate-buffered saline at 37°C, or water at room temperature (25°C). At these concentrations, which represent the peak prophylactic serum concentrations likely to be achieved by a 70-kg person after parenteral administration of 1.5 mg/kg gentamicin and 2 g of ampicillin, no clinically significant inactivating effects of these antibiotics on each other were observed over a period of six hours.Articl

Effect of Ultrasound on Transdermal Permeation of Diclofenac

During the last two decades the effects of ultrasound on the transdermal permeability to a wide variety of drugs have been extensively investigated. There is still some uncertainty regarding the mechanisms involved in ultrasonic permeation enhancement, thus we investigated the effect of ultrasonic treatment on the transdermal permeation of the NSAID, diclofenac. Experiments were conducted over two phases, consisting of different time periods, using a continuous flow-through diffusion system. It is clear from the present study that ultrasound enhanced the permeability of human skin to diclofenac released from a commercially available gel. These results were in contrast to those obtained for ibuprofen in an in vitro study across human skin, but in agreement with those obtained in two in vivo studies of the latter NSAID. Steady state flux values of diclofenac remained approximately 1.26 times higher than those of controls during the 24 h of the experiment. These observations concurred with those made in two previous in vivo studies. It was concluded that the enhancement of diclofenac permeation by sonication could not be adequately explained primarily on a thermal basis. Furthermore, the in vitro flow-through diffusion model was shown to have predictive value as an in vivo method for sonophoresis

Drug treatment of tuberculosis meningitis in children. A practical guide

Treatment must be continued for a minimum of 6 months, but should be extended to 9 or 12 months if rifampicin cannot be used throughout and if pyrazinamide cannot be used for the first 2 months of treatment. Hydrocephalus and raised intracranial pressure frequently complicate stage II and stage m tuberculosis meningitis. In the presence of communicating hydrocephalus, confirmed on air encephalogram by the appearance of air in the ventricles, furosemide (frusemide) 1 mg/kg/day and acetazolamide 100 mg/kg/day given in 6- or 8-hourly divided doses will expedite the normalisation of intracranial pressure in the majority of cases. Ventriculo-peritoneal shunting should be brain but not in the ventricles, in those children with non-communicating hydrocephalus, demonstrated on air encephalogram by the presence of air at the base of the brain but not in the ventricles, and in those children who do not respond satisfac torily to medical management. Corticosteroids, in the form of prednisone or dexamethasone, have been shown to improve both morbidity and mortality in tuberculosis meningitis. These drugs should be given for the first month of treatment. Tuberculosis meningitis is the most serious extrapulmonary complication of tuberculosis and the commonest cause of death in childhood as a result of tuberculosis. Appropriate treatment must be started as soon as a diagnosis of tuberculosis meningitis is suspected. The main aims of the drug treatment of tuberculosis meningitis are the eradication of the causative organism Mycobacterium tuberculosis, the control of raised intracranial pressure, and modulation of the immune processes causing cerebral vasculitis and the associated exudate at the base of the brain. Isoniazid, rifampicin (rifampin) and pyrazinamide are essential drugs in the treatment of tuberculosis meningitis in dosages of 20 mg/kg/day, 20 mg/kg/day and 40 mg/kg/day, respectively. Lower dosages of isoniazid (10 mg/kg/day) and rifampicin (10 mg/kg/day) can be used if infectious hepatitis is a recognised problem in a particular geographical area, but a reduction in the dose of rifampicin may compromise its sterilising capacity. If it is possible that the disease is caused by drug-resistant organisms, the above regimen should be augmented by ethionamide 20 mg/kg/day or streptomycin 20 to 40 mg/kg/day.Revie

The association of age and elimination of isoniazid: An example of median regression with heteroscedasticity

The rate of elimination of the tuberculosis drug INH(k) varies from person to person, is characteristic of certain genotypes and has been thought to be age dependent. The data in this paper are subjected to a regression analysis of k on age, there being three genotypic groups of subjects. Median regression is used because the data clearly do not satisfy simple parametric assumptions about residual distributions.Articl

The pharmacogenetics of NAT2 enzyme maturation in perinatally HIV exposed infants receiving isoniazid

The roles of the NAT2 genotype and enzyme maturation on isoniazid pharmacokinetics were investigated in South African infants with perinatal HIV exposure enrolled in a randomized, double-blind, controlled trial of isoniazid for prevention of tuberculosis disease and latent infection. Plasma concentration-time measurements of isoniazid from 151 infants (starting at 3-4 months of age) receiving isoniazid 10 to 20 mg/kg/d orally during the course of the 24-month study were incorporated in a population analysis along with NAT2 genotype, body weight, age, and sex. The results showed a different NAT2 enzyme maturation profile for each of the 3 acetylation groups, with the 70-kg body weight-normalized typical apparent clearance for the fast and intermediate acetylators increasing from 14.25 L/h and 10.88 L/h at 3 months of age to 22.84 L/h and 15.58 L/h at 24 months of age, respectively, with no significant change in the apparent clearance of the slow group during this period. A hypothesis is proposed to explain the genotype-dependent enzyme maturation processes for the NAT2 enzyme. © 2012 The Author(s)

Massive posterior fossa tuberculous abscess developing in a young child treated for miliary tuberculosis: Possible role of very rapid acetylation of isoniazid

A 21-month-old infant presented with acute obstructive hydrocephalus due to a large tuberculous abscess in the posterior fossa 3 months after starting treatment for miliary tuberculosis. Insertion of a ventriculo-peritoneal shunt resulted in some clinical improvement but subsequent neurological deterioration occurred due to massive enlargement of the tuberculous abscess despite apparently adequate antituberculosis therapy. Repeated drainage procedures of the abscess eventually resulted in resolution and clinical improvement. As part of the workup for poor weight gain and the unusual clinical course, the patient's acetylation status for isoniazid was determined and found to be very rapid. Doubling the daily dose of isoniazid was followed by a dramatic weight increase and further clinical improvement. Decreasing the load of tuberculous antigen by draining the abscesses and increasing the pulse exposure of isoniazid is the best possible explanation for the clinical improvement finally seen in this patient.Articl

Distribution of acetylator genotypes in the coloured population of the Western Cape region of South Africa

Recent advances in molecular biology techniques for polymorphic N-acetyltransferase (NAT2) enzyme characterisation, involving polymerase chain reaction (PCR) multiplication and restriction enzyme cleavage of DNA, were used to determine the distribution of acetylator genotypes and their constituent alleles in the coloured population of the Western Cape region of South Africa. The frequency of slow acetylator individuals in the trial population was q2 = 0.286, indicating a frequency of slow acetylator alleles of q = 0.535. The trial population could be shown to be in Hardy-Weinberg equilibrium in accordance with a trimodal pattern of distribution of acetylator genotypes.Articl

Isoniazid pharmacokinetics, pharmacodynamics, and dosing in South African infants

ArticleAIMS: There are limited data on isoniazid (INH) pharmacokinetics in infants and young children and, therefore, uncertainty on appropriate dosing. METHODS: Pharmacokinetic data were obtained from perinatally HIV-exposed South African infants aged 3-24 months receiving INH 10-20 mg·kg·d orally for Mycobacterium tuberculosis prophylaxis. INH pharmacokinetic parameters were characterized using a population pharmacokinetic approach. Dosing simulations were performed to evaluate weight-based INH doses in children based on N-acetyltransferase 2 enzyme (NAT2) genotype, age, maximum concentrations (Cmax) ≥3 mg/L, and area under the curve (AUC0-24) ≥10.52 mg·h/L. RESULTS: In 151 infants (53% female, 48% HIV positive) receiving a mean INH dose of 14.5 mg·kg·d, mean (±SD) Cmax at 3, 6, and 23 months of age were 10.0 (3.5), 8.6 (2.6), and 9.3 (3.8) mg/L, respectively, mean (±SD) AUC0-24 were 53.6 (26.8), 42 (19.9), and 44 (30.7) mg·h/L, respectively, and mean (±SD) half-lives were 2.1 (0.7), 1.9 (0.6), and 1.8 (0.9) hours, respectively. A trimodal apparent oral clearance of INH as a function of the NAT2 genotype was apparent as early as 3 months. INH was well tolerated. At an average INH dose of 14.5 mg·kg·d, 99% of infants aged 3-24 months have an INH Cmax ≥3 mg/L, and 98% have an INH AUC0-24 ≥10.52 mg·h/L. CONCLUSIONS: INH at an average dose of 14.5 mg/kg once daily was well tolerated in infants and achieved INH Cmax values ≥3 mg/L and AUC0-24 values ≥10.52 mg·h/L. Copyright © 2012 by Lippincott Williams & Wilkins