Isoniazid Plasma Concentrations in a Cohort of South African Children with Tuberculosis: Implications for International Pediatric Dosing Guidelines

McIlleron, Helen; Willemse, Marianne; Werely, Cedric J.; Hussey, Gregory; Schaaf, H. Simon; Smith, Peter J.; Donald, Peter R.

doi:10.1086/598192

Cited by 111 publications

(89 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The peak serum INH concentrations were comparable to those in our study and above the therapeutic minimum concentration of INH. In a previous study by our group, serum INH concentrations in children younger than 6 years of age receiving a dose of 4 to 6 mg/kg were significantly lower than in children prescribed a dose of 8 to 10 mg/kg (2.39 g/ml versus 5.71 g/ml) (21). The proportion of children with peak serum INH concentrations of Ͻ3 g/ml following an INH dose of 5 mg/kg was even higher than in the present study (70% versus 50%).…”

Section: Discussionmentioning

confidence: 52%

“…In contrast, at the previous WHO dosages, serum INH, PZA, and RMP concentrations were significantly lower and often below the recommended concentrations for anti-TB therapy. Serum INH concentrations in children are generally reported to be lower than in adults following the same mg/kg dose (3,21,34,41). Although INH is the most extensively studied anti-TB drug, we are aware of only two reports of INH pharmacokinetics that included only children younger than 3 years (19,30).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Pharmacokinetics of Isoniazid, Rifampin, and Pyrazinamide in Children Younger than Two Years of Age with Tuberculosis: Evidence for Implementation of Revised World Health Organization Recommendations

Thee

Seddon

Donald

et al. 2011

Antimicrob Agents Chemother

105

View full text Add to dashboard Cite

There was no difference in the t max values achieved. Children less than 2 years of age achieve target concentrations of first-line anti-TB agents using revised WHO dosage recommendations. Our data provided supportive evidence for the implementation of the revised WHO guidelines for first-line anti-TB therapy in young children.Isoniazid (INH), rifampin (RMP), and pyrazinamide (PZA) are routinely used to treat tuberculosis (TB) in children (23, 44). Recommendations for pediatric dosages are based on a small number of pharmacokinetic studies, few of which included children younger than 2 years of age. During early life, children experience significant changes in the relative sizes of their body compartments and their ability to absorb, metabolize, and excrete drugs (5, 17). These changes are greatest within the first 2 years of life (4). Most published studies on first-line anti-TB drugs in children have not analyzed differences between older and younger children or the effect of HIV coinfection. The pharmacokinetics of INH are further complicated by genetic polymorphisms of N-acetyltransferase type 2 (NAT2) in the metabolic pathway of INH, which influences INH concentrations (18,26,46).In the absence of pharmacodynamic data for children and therefore data that demonstrate an association between serum drug concentration and clinical outcome, optimal anti-TB therapy should aim to produce the targeted serum drug concentrations that have been determined in adult pharmacokinetic and pharmacodynamic studies. For INH, the proposed optimal maximum serum drug concentration (C max ) for therapy is 3 to 5 g/ml (15, 27). Target serum RMP concentrations in adults after a standard oral dose of 600 mg are in the range of 8 to 24 g/ml; serum RMP concentrations below 8 g/ml are considered low, and those below 4 g/ml are considered very low (28,29). There is more uncertainty regarding the optimal therapeutic serum PZA concentration. In adults, serum PZA concentrations are targeted at 20 to 60 g/ml (11, 28). However, in a recent study of adults, poor treatment outcome of pulmonary TB was associated with serum PZA concentrations of Ͻ35 g/ml (8).Optimal anti-TB therapy is important in all children but particularly in young children (Ͻ2 years of age) and those HIV infected, where there is a high risk of progression to severe

show abstract

Section: Discussionmentioning

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of Isoniazid, Rifampin, and Pyrazinamide in Children Younger than Two Years of Age with Tuberculosis: Evidence for Implementation of Revised World Health Organization Recommendations

Thee

Seddon

Donald

et al. 2011

Antimicrob Agents Chemother

105

View full text Add to dashboard Cite

show abstract

“…The docking result has predicted two database compounds and two analogues of ethambutol based on least energy score of rerank, moldock and H bond values as presen -ted in the Screening for alternative and effective drug is urgently needed to combat the drug resistance straings of M. tuburculosis (Burris, 2004;McIlleron, et al, 2009;Zhang, et al, 2014). The failure of ethambutol is another challenge.…”

Section: Resultsmentioning

confidence: 99%

“…Isoniazid and ethambutol have been used for the decades as frontline drugs to inhibit M. tuberculosis, but the rise of multi-drug resistant and extensively drug resistant strains poses a serious threat to present treatment of tuberculosis (Burris, 2004;McIlleron, et al, 2009;Zhang, et al, 2014). Ethambutol inhibits the synthesis of essential components of the mycobacterial cell wall.…”

Section: Introductionmentioning

confidence: 99%

Arabinosyl transferase inhibitor design against <i>Mycobacterium tuberculosis</i> using ligand based drug design approach

Kolita

Gogoi

Dutta

et al. 2014

Bangladesh J Pharmacol

View full text Add to dashboard Cite

Antibiotic resistance is a major challenge to combat tuberculosis. Several reports of antibiotic resistance strains of Mycobacterium tuberculosis is strongly demanding the need of new and alternative antibiotics for its inhibition. Therefore, current investigation is an attempt to screen few lead molecules for the inhibition of arbinosyl transferase enzyme of M. tuberculosis. The inhibition of this enzyme is an established target of many antibiotics especially ethambutol. Herein, we have considered the structure of ethambutol as a starting point to screen active compound then ethambutol. Similar compounds were searched in chemical database and six compounds were identified and considered as selective arbinosyl transferase inhibitor based on physiochemical properties, bioactivity and ADME with least docking score. The compounds viz. ZINC00388344, ZINC003884, Chemspider2057082, ZINC-00388344, ZINC0038846, Chemspider2057082, Etha17 (analog) and Etha10 (analog) were finally screened and recommended for in vitro investigation. Article Info

show abstract

“…33 Data on the pharmacokinetics of TB medicines among malnourished children are also needed, as differences have been reported. [34][35][36][37] Further research into anti-tuberculosis treatment in the setting of malnutrition can guide the development of recommendations for the optimal timing for the initiation of treatment, dosing, and follow-up of children with malnutrition and TB.…”

Section: Public Health Actionmentioning

confidence: 99%

Integration of childhood TB into guidelines for the management of acute malnutrition in high burden countries

Patel

Detjen

2017

public health action

View full text Add to dashboard Cite

T uberculosis (TB) is a major public health challenge, now surpassing human immunodeficiency virus (HIV) infection as a leading cause of death from infectious disease globally. With one million estimated cases, children aged <15 years accounted for approximately 10% of the 10.4 million incident TB cases in 2015, and 210 000 children died. 1 However, only 39% of child TB cases were reported, highlighting significant underdiagnosis and under-reporting of childhood TB. 1 Despite increased awareness within the TB community and the launch of a Roadmap for Childhood Tuberculosis in 2013, 2 there is a significant policy-practice gap in implementing guidelines, capacity building at the country level, and decentralization and integration of TB services into broader child health programs to better reach children where they access the health care system. 3 This means targeting programs and services at the community and primary health care level, and health care providers caring for those at high risk for TB. It also means actively engaging key stakeholders in child health and survival, including the nutrition sector. 4,5 TUBERCULOSIS AND MALNUTRITIONApproximately 45% of deaths in children aged <5 years are attributable to undernutrition, 6 which may be acute or chronic, and categorized as moderate or severe. Children with undernutrition are at increased risk of death from infectious diseases and, conversely, severe infectious diseases in early childhood can affect nutritional status. 6 Undernutrition increases the risk of TB and TB can cause or worsen undernutrition. 7 One study estimated that 26% of overall TB cases in 22 high-burden countries are attributable to undernutrition. 8 Data on TB prevalence among acutely malnourished children vary widely: 2-24% of acutely malnourished children in high TB burden settings have been diagnosed with TB. 9-13 The wide range observed between studies can be partly attributed to the use of varying screening strategies and access to TB diagnostics, as well as varying clinical capacity for childhood TB diagnosis and treatment among hospitalized children. Even at referral hospitals, access to diagnostic tests may be limited, 14 highlighting the need for improved access to services across all levels of the health care system, including appropriate referral pathways. These data also highlight the role of TB as a comorbidity among children with acute malnutrition, emphasizing the need to routinely screen for TB and manage those at risk of TB appropriately. Asking about contacts with persons with TB is included as part of the initial history for children with severe malnutrition, as outlined in the 1999 World Health Organization (WHO) manual on the management of severe malnutrition. 15 In the WHO 2013 update on the management of severe acute malnutrition (SAM), TB screening is mentioned in the context of HIV infection. 16 We performed a review of the guidelines on acute malnutrition from high TB burden countries to identify whether and how TB is integrated within nutrition guidelines. METHODS...

show abstract

Isoniazid Plasma Concentrations in a Cohort of South African Children with Tuberculosis: Implications for International Pediatric Dosing Guidelines

Abstract: Younger children require higher doses of isoniazid per kilogram of body weight to achieve isoniazid concentrations similar to those in adults. A daily isoniazid dose of 8-12 mg/kg should be recommended.

Cited by 111 publications

References 12 publications

Pharmacokinetics of Isoniazid, Rifampin, and Pyrazinamide in Children Younger than Two Years of Age with Tuberculosis: Evidence for Implementation of Revised World Health Organization Recommendations

Pharmacokinetics of Isoniazid, Rifampin, and Pyrazinamide in Children Younger than Two Years of Age with Tuberculosis: Evidence for Implementation of Revised World Health Organization Recommendations

Arabinosyl transferase inhibitor design against <i>Mycobacterium tuberculosis</i> using ligand based drug design approach

Integration of childhood TB into guidelines for the management of acute malnutrition in high burden countries

Contact Info

Product

Resources

About