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Pharmacokinetics of isoniazid formulation needs to be addressed
- Joseph F Standing (21 January 2007)
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Re: Pharmacokinetics of isoniazid formulation needs to be addressed
- Heather J Zar, H Simon Schaaf, Mark F Cotton (26 January 2007)
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HIV testing in TB patients, are we there yet
- Ismael Musa Balluz, Dr David Daniel, West middlesex university Hospital (20 September 2007)
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Joseph F Standing, Ph.D Student London School of Pharmacy, University of London, WC1N 1AX
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It is very encouraging to see that prescribing isoniazid can reduce tuberculosis in HIV infected children, yet 5/132 children randomised to isoniazid still developed tuberculosis (1). Despite the participants of this study being infants and young children, Zar et al (1) used tablets. Whilst Zar et al (1) report dosing of halved/quartered tablets to achieve a variability of just 20 percent (10mg/kg +/- 2mg/kg), no mention of the weight of split tablet fractions is made to confirm this. Halved tablet weights typically vary by greater than 20 percent (2), the weight of quartered tablets is likely to vary even more. Modified adult formulations of isoniazid have a significantly lower bioavailability than licensed liquid preparations in children (3). Zar et al (1) do not report how doses were administered, but it is well recognised that many children under 12 years are unable to swallow whole solid dose forms (4). If the halved/quartered tablets were crushed, patients are unlikely to have received the intended dose. When the amount of test drug received by participants cannot be ascertained on reading the published study, how is one to judge the validity or reliability of the findings? Logistic or cost concerns often mean tablets must be used for children in healthcare systems which lack resources, but reports of tablet fraction weights and basic pharmacokinetic data are still required. Whilst the results of this study suggest manipulated tablets of isoniazid reduce tuberculosis incidence, it is likely that further reduction could be made if formulation was optimised, perhaps by standardising the administration method and validating it with pharmacokinetic data. 1. Zar HJ, et al. Effect of isoniazid prophylaxis on mortality and incidence of tuberculosis in children with HIV: randomised controlled trial. BMJ 2007;334(7585):136-9. 2. Teng J, et al. Lack of medication dose uniformity in commonly split tablets. J Am Pharm Assoc 2002;42(2):195-9 3. Notterman DA, et al. Effect of dose formulation on isoniazid absorption in two young children. Pediatrics 1986;77(6):850-2. 4. Czyzewski DI, et al. Teaching and Maintaining Pill Swallowing in HIV- Infected Children. AIDS Read 2000;10(2):88-94. Competing interests: Researcher in paediatric pharmacokinetics |
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Heather J Zar, Associate Professor, School of Child and Adolescent Health Red Cross Children's Hospital, University of Cape Town, South Africa, 8001, H Simon Schaaf, Mark F Cotton
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Isoniazid (INH) tablets are the most widely used formulation for prophylaxis of tuberculosis (TB) in children and also form part of recommended treatment regimens for childhood TB. (1) While a syrup formulation may be more suitable for young children, it is not commercially available. Use of syrup is limited by the need for a pharmacist to make this up using a fairly complex recipe, the potential for variability in dosing, its higher cost compared to tablets, its stability for only a limited period and the potential for toxicity in recipes which use chloroform water or ethyl alcohol. (2) We were especially concerned about possible toxicity from chronic chloroform ingestion (which was the formulation our pharmacy could provide), as the study planned to investigate long term INH prophylaxis. While a suspension of INH can be made, it requires refrigeration and was therefore also unsuitable for our patients many of whom do not have access to a fridge. For these reasons, we chose not to use a syrup formulation. INH tablets were cut into halves or quarters according to the required dose and given uncrushed to children. Dosage recommendations for INH vary from 5 to 15mg/kg in different guidelines. (1,3) Since INH has a wide therapeutic index, an INH dose sufficient to achieve therapeutic plasma levels among fast acetylators (10 mg/kg) was given, as approximately 60% of people in this population are intermediate or fast acetylators. (4,5) As a measure of adherence, we also performed urine measurements of INH, which were positive in most children on INH, confirming absorption and metabolism of this drug in a tablet form. Moreover, all culture confirmed cases of TB occurred in children on placebo, further underlying the effectiveness of INH prophylaxis in preventing definite TB. (6) While we agree that pharmacokinetic data are lacking in children, the study suggests considerable impact of INH tablets in reducing mortality and TB incidence by more than 50% and 70% respectively. (6) We therefore believe that INH tablets which are widely available, safe and affordable offer a potentially effective means to reduce morbidity and mortality in HIV-infected children living in high TB prevalence areas. References 1. Guidance for national tuberculosis programmes on the management of tuberculosis in children. WHO 2006. WHO/HTM/TB/2006.371. 2. Seifart HI, Parkin DP, Donald PR. Stability of isoniazid, rifampin and pyrazinamide in suspension used for the treatment of tuberculosis in children. Pediatr Infect Dis J 1991;10:827-831 3. American Academy of Pediatrics. Tuberculosis. In: Pickering LJ, ed.Red Book: 2003 Report of the Committee on infectious Diseases. 26th ed.Elk Grove Village, IL: American Academy of Pediatrics; 2003:642-660. 4. Schaaf HS, Parkin DP, Seifart HI, Werely CJ, Hesseling PB, van Helden PD, Maritz JS, Donald PR. Isoniazid pharmacokinetics in children treated for respiratory tuberculosis. Arch Dis Child 2005;90:614-618 5. Parkin DP, et al. Trimodality of isoniazid elimination: phenotype and genotype in patients with tuberculosis. Am J Respir Crit Care Med 1997;155(5):1717-1722. 6. Zar HJ, et al. Effect of isoniazid prophylaxis on mortality and incidence of tuberculosis in children with HIV: randomised controlled trial. BMJ 2007;334(7585):136-9. Competing interests: None declared |
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Ismael Musa Balluz, SpR, GUM/HIV Chelsea and westminster Hospital, 369 Fulham Road, SW10 9NH, Dr David Daniel, West middlesex university Hospital
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HIV testing in TB patients. Are we there yet? According to WHO recommendations, HIV testing should be offered to all patients ` with Tuberculosis (TB) in settings where the HIV prevalence among TB patients exceed 5% . British Thoracic Society and London Regional office of communicable Disease Surveillance Centre (CDSC) recommended that HIV testing should be offered to all newly diagnosed TB patients (1&2). We audited the adherence of the Chelsea and Westminster Hospital, London (C&W) and the West Middlesex University Hospital, London (WMUH) to these guidelines between January 2006 and September, 2006 . Patient’s notes, HIV -test results from the computer and discussion with specialist TB nurses in both Hospitals were the sources of the data. This audit has shown that at C&W between Jan 2006 and Sep 2006 there were 55 (males 59% and females 41%) newly diagnosed TB patients. Average age was 35 and main ethnic group was black Africans (47%) followed by whites (22%). 6 patients were known HIV seropositive and 13 patients had recently been tested HIV seronegative and were excluded from further analysis.Out of the remaining 36 patients 22 (61%) were offered HIV testing and 19 (86.4%) took up the test and non was positive. However 5 (25%) of the 19 tested patients were admitted to Medical word diagnosed with TB then HIV and referred to Respiratory department thereafter. 9% of patient fall into paediatrics age (1-15 years) and these patients were not tested as they were considered as low risk group. The C&W –patient’s notes have a proforma for HIV testing which prompts doctors and nurses to offer HIV test and all TB patient’s notes are kept in the Respiratory department as this facilitates Audit process. At the WMUH 79 patients were diagnosed with TB. Average age was 45, males (68%) more than females (32%) and the main ethnic group was Indian (44%) followed by black African. Only 11 (14%) out of 79 patients were tested and 1 (1.1%) patient tested positive and it is not clear from the notes if any of the other patients were offered and declined HIV testing. Furthermore there was no evidence of risk assessment in spite of known increase prevalence in the ethnic groups encountered. This may be due to the absence of HIV testing proforma in patient’s notes. C&W carried out a similar Audit in 2005 and the figure of HIV testing in TB patients was below 50 % that indicates improvement not only due to the presence of proforma which they have for few years but also increased awareness of the issue. M Lipman et-al (3)had shown that HIV testing was offered to only 49% of TB patients at 2 central London Hospitals (Royal Free and Washington Hospitals) with a high prevalence of TB where 2% tested HIV positive and most of the patients tested were inpatients with similar results shown in the study by Warley et al (5) TB is a leading cause of morbidity and mortality among persons living with HIV or AIDS (4) and the rates of HIV/TB co-infection is increasing in UK. Our data are similar to other Metropolitan studies. It is clear that HIV testing in TB patients in Central London and University Hospitals in London is not in line with the recommendation and guidelines of WHO or CDSC. It is conceivable that healthcare workers might have discussed testing but not documented it in patient’s notes which can be overcome by implementing a data system (proforma) to accurately capture this information. Further education of the healthcare workers in General Medical setting to maximise HIV testing to ensure an early diagnosis of HIV and early access to Highly Active Anti Retroviral Therapy as shown by BHIVA-Audit (6) to improve morbidity and mortality in these patients. Finally, it appears the only way of ensuring 100% HIV testing in TB patients is to consider including it with the rourine tests on the patient's first visit. References 1. World Health Organisation. Treatment of tuberculosis, guidelines for national programmes. Geneva, Switzerland: WHO; 2003:24. 2. WHO. Interim policy on collaborative TB/HIV activities. Geneva, Switzerland: WHO; 2004:4-10. 3. M, Lipman et al HIV testing in TB clinics: a problem in practice. Thorax 2006;61:271-274. 4. World Health Organisation. Global health atlas. Geneva, Switzerland: WHO; 2006. Available at http://www.who.int/globalatlas/default.asp. 5. M, Warley A, Milburn H, et al. Tuberculosis and HIV seroprevalence in Lambeth, Southwark and Lewisham, an area of South London. Reps Med 2003, 97: 167-72. 6. Sabin, Caroline A a; Smith, Colette J a; Gumley, Helen b; Murphy, Gabrielle b; Lampe, Fiona C a; Phillips, Andrew N a; Prinz, Beth b; Youle, Mike b; Johnson, Margaret A b. Late presenters in the era of highly active antiretroviral therapy: uptake of and responses to antiretroviral therapy. AIDS. 18(16):2145-2151, November 5, 2004. Competing interests: None declared |
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