Pharmacokinetics of anti-TB drugs in children and adolescents with drug-resistant TB: a multicentre observational study from India.

BACKGROUND: Drug-resistant tuberculosis (DR-TB) is one of the challenging forms of TB to treat, not only in adults but also in children and adolescents. Further, there is a void in the treatment strategy exclusively for children due to various reasons, including paucity of pharmacokinetic (PK) data on anti-TB drugs across the globe. In this context, the present study aimed at assessing the PK of some of the anti-TB drugs used in DR-TB treatment regimens. METHOD: A multicentre observational study was conducted among DR-TB children and adolescents (n = 200) aged 1-18 years (median: 12 years; IQR: 9-14) treated under programmatic settings in India. Steady-state PK (intensive: n = 89; and sparse: n = 111) evaluation of moxifloxacin, levofloxacin, cycloserine, ethionamide, rifampicin, isoniazid and pyrazinamide was carried out by measuring plasma levels using HPLC methods. RESULTS: In the study population, the frequency of achieving peak plasma concentrations ranged between 13% (for rifampicin) to 82% (for pyrazinamide), whereas the frequency of suboptimal peak concentration for pyrazinamide, cycloserine, moxifloxacin, levofloxacin and rifampicin was 15%, 19%, 29%, 41% and 74%, respectively. Further, the frequency of supratherapeutic levels among patients varied between 3% for pyrazinamide and 60% for isoniazid. In the below-12 years age category, the median plasma maximum concentration and 12 h exposure of moxifloxacin were significantly lower than that of the above-12 years category despite similar weight-adjusted dosing. CONCLUSIONS: Age significantly impacted the plasma concentration and exposure of moxifloxacin. The observed frequencies of suboptimal and supratherapeutic concentrations underscore the necessity for dose optimization and therapeutic drug monitoring in children and adolescents undergoing DR-TB treatment.

Vitamin D receptor genetic polymorphisms in severe and recurrent tuberculosis in children.

AIM: To analyze the genetic polymorphisms of vitamin D receptor FokI, TaqI, ApaI and BsmI gene polymorphisms in children with severe and recurrent tuberculosis (TB). METHODS: A prospective, observational study was conducted in 35 children with severe and recurrent TB referred to our Pediatric TB clinic at a tertiary referral center for children. The blood samples were analysed for genetic polymorphisms of Vitamin D receptor with respect to FokI, TaqI, ApaI and BsmI genotypes and their individual alleles and association of various clinical and laboratory parameters were analysed. RESULT: Ten (28.6%) children had recurrent TB and 26 (74.3%) had severe TB. The severity of TB was not associated with Ff and ff polymorphism of FokI (Odd's ratio 7.88) as compared to no FokI polymorphism. Absence of FokI polymorphism was associated with recurrent lymph node TB (Odds ratio 3.429). Presence of Tt polymorphism of TaqI (p = 0.04) and Fok1 Polymorphism [Odds ratio 7.88] were not associated with recurrent TB. CONCLUSION: Recurrent TB was absent in presence of Tt polymorphism of TaqI. Severe TB was not associated polymorphism of Vitamin D receptor polymorphisms.

Evaluation of constipation in children using high-resolution anorectal manometry.

This prospective, cross-sectional study, conducted from July 2018 to March 2019, aimed to determine the causes of constipation using high-resolution anorectal manometry. Among 33 children enrolled in the study, 31 (94%) children presented with complaints of constipation with mean duration of 2.3 ± 2.5 years and 12 (36.4%) children also had associated complaints of faecal incontinence with mean duration of 3.5 ± 2.8 years. Seven children (21.2%) had normal high-resolution anorectal manometry parameters; anal sphincter hypotonia with decreased squeeze in one child, anal sphincter hypertonia with other abnormal parameters were noted in 25 and absent recto-anal inhibitory reflex in two. The causes of constipation determined were functional constipation in 30 (91%) children, suspected Hirschsprung's disease in two and suspected dyssynergic defecatory disorder in one. Almost 90% had functional constipation of which anal hypotension and anal hypertension may be a part of chronic functional constipation.

Outcome of Tyrosinemia Type 1 in Indian Children.

AIM: The objective of this study was to determine the outcome of children with tyrosinemia type 1 from India. METHODS: A retrospective observational study was conducted on 11 patients diagnosed with type I tyrosinemia under our care. Age at symptoms, age at diagnosis, age at starting 2-nitro-4-trifluoromethylbenzoyl-1,3-cyclohexanedione (NTBC), duration between diagnosis and initiation of NTBC, dose given, total duration of NTBC, and outcomes were noted. RESULTS: Eleven children with a median age of 1.1 years (0.51-1.52) at onset of symptoms were included in the study. The median age at diagnosis was 1.76 years (0.95-2.43). Their current median age is 5.44 (2.36-8.80) years. Common clinical features at presentation were chronic liver disease in 8 (72.72%), rickets in 2 (18.18%), and fulminant liver disease in 1 (9.09%) patient. Hepatomegaly was observed in all children, growth retardation in 9 (81.81%), coagulopathy in 8 (72.72%), and abdominal distention in 6 (54.54%) patients. The median duration of NTBC therapy was 13.5 (7-21.25) months. The median dose of NTBC was 1 (0.77-1) mg/kg/day. One (9.09%) patient died due to liver cell failure. However, she had received NTBC only for a month. Another patient developed hepatocellular carcinoma (HCC) and underwent liver transplantation. He could receive NTBC only for 2 months, although he was diagnosed to have tyrosinemia for over a 1 year. Eight patients are on treatment with NTBC and are doing well, and 1 patient is not on NTBC and continues to have renal tubular acidosis. CONCLUSION: NTBC therapy is effective and improves the prognosis of tyrosinemia. A long-term follow-up is required to determine progression to HCC and need for liver transplantation.

Clinical profile and outcome of glycogen storage disease in Indian children.

We aimed to determine the clinical profile and outcome of Indian children with glycogen storage disorders. Ours was a retrospective study from 2005 to 2018 in 36 children diagnosed on the basis of a liver biopsy. Most (77.7%) presented with abdominal swelling but a quarter with convulsion, four of whom had documented hypoglycaemia associated, doll-like facies or developmental delay. Diarrhoea was found in four patients, ascites in two and portal hypertension in one. One child died, and over half were unfortunately lost to follow-up, though the rest had recurrent seizures, three more developed neutropenia, two recurrent infections, one portal hypertension with epistaxis, one nephrocalcinosis and liver adenoma. Liver function improved in six (37.5%) with normalisation of triglycerides, and four of serum transaminases.

Multi-Drug Resistant and Extensively-Drug Resistant Tuberculosis.

India is one of the high burden countries for tuberculosis (TB) including multi-drug resistant TB (MDR-TB) and extensively-drug resistant (XDR) TB. Drug-resistant (DR) TB has threatened the TB care and is a major health problem in many countries; treatment of DR TB has been difficult requiring use of reserve or second-line drugs, cost factors, has extensive side-effect profile and long duration of treatment. Treatment in MDR-TB are increasingly becoming individualised mainly due to preference for oral over injectable, results of drug susceptibility testing (DST), population resistance levels, history of previous TB treatment, drug tolerability and drug-to-drug interactions. Bedaquilline (BDQ) and delaminid (DLM) are new drugs available for treatment of these patients. World Health Organization (WHO) recommends use of BDQ in more than 15 y (>15 kg) patients only. Under Revised National Tuberculosis Control Programme (RNTCP) the use of this drug is recommended for patients older than 18 y only. Under RNTCP, the use of DLM is approved in children 6 y and above. Pediatric MDR/XDR TB treatment outcome with newer anti-TB drugs and regimen is lacking. Children when treated with individualized regimens have improved survival.