Mresistant to isoniazid and rifampin. The

CASE REPORT Zafar Iqbal*, Afsar Khan**, Arshad Javaid* *Department of Pulmonology, ** Programmatic Management of Drug Resistant TB Unit, Department of Pulmonology, Adress for correspondence: Dr. Zafar Iqbal Department of Pulmonology, ABSTRACT th Pakistan ranks at 4 number, in MDR-TB with estimated annual cases of 1300 among notified pulmonary TB cases. Unfortunately young children and infants are more at risk because of more attachment with elder and parents. We are reporting a rare case of MDR-TB in a 2 years boy. Key Words: MDR-TB; Child; Peshawar; Pakistan This case report may be cited as: Iqbal Z, Khan A, Javaid A. MDR-TB in a 2 years old boy. A Case Report. Pak J Chest Med 2015; 21(4): 155-59 INTRODUCTION ultidrug-resistant (MDR) tuberculosis is caused by Mycobacterium tuberculosis Mresistant to isoniazid and rifampin. The World Health Organization (WHO) estimated that there were 440 000 new MDR-tuberculosis cases worldwide 1 during 2008. Treatment outcomes are generally poor in adults, with favorable outcomes reported in only 2 60% of those receiving treatment. Even though childhood tuberculosis makes up 15% 20% of the 3 global tuberculosis burden, MDR-tuberculosis is poorly studied in children, the literature including 4-16 mainly case reports or small case series. The diagnosis of tuberculosis in young children is 17 challenging and often delayed. Symptoms and signs may be nonspecific, especially in children <3 years of age and in children infected with human immunodefi- 18 ciency virus (HIV). Because of the paucibacillary nature of childhood tuberculosis, a microbiological diagnosis is typically made in only 20% 40% of cases 19 with radiological evidence of intra thoracic disease. Because drug susceptibility testing (DST) is only possible following bacteriological confirmation, confirmed MDR-tuberculosis in children is infrequent. In the absence of a known MDR-tuberculosis source case, children are often initially treated for drugsusceptible tuberculosis, with MDR-tuberculosis treatment started only once treatment is failing, microbiological and DST results become available, or an MDR-tuberculosis source case is identified. Treating children with MDR-tuberculosis is complex. Few of the multiple drugs routinely used to treat MDRtuberculosis have been studied in children, and guidance on drug regimens, dosages, appropriate monitoring, and duration of therapy is frequently extrapolated from adult data. As young children metabolize drugs more rapidly than adults and 20 generally have paucibacillary disease, this may not always be appropriate. CASE REPORT A Two and half years kid who was fine and healthy till the age of one year. According to his literate parents and previous documents, one and a half years ago he developed axilliary and cervical lymph nodes swelling for which he was started in private sector on RHZ as st biopsy proven TB- lymph adenitis. After taking 1 line anti-tb drugs for more than one year, his condition deteriorated and lymph nodes started oozing pus. A Pediatrician added ciprofloxacin to RHZ which gave temporary relief in sense of lymph node swelling and oozing. But after one month again the swollen lymph nodes re appeared. We excised one of the lymph nodes and sent that tissue for AFB culture and sensitivity. AFB c/s report showed resistance to RHZ while Sensitivity to Ethambutol and all 2nd line anti-tb drugs. His HIV test was also non reactive. According to his parents, his two brothers and a sister have died at the age of 8, 6 & 2 years respectively, due to lymph adenopathy of different origins before his birth. Apart from this, no history of any type of PTB or ATT in the entire family. On receiving of this cute kid at our PMDT (programmatic management of Drug resistant TB) site, we enrolled him according to NTP (National TB control program) protocol and started on Cm (Capriomycine), 155

Z (Pyrazinamide), Lfx (Levofloxacine), Cs (Cycloserine), Eto (Ethionamide) along with Vit B6 (Pyridoxine) as a supportive drug. He is now under treatment and on his 2nd follow up he was much improved in sense of Lymph nodes swelling reduction, dryness and 2 kg weight gain. DISCUSSION MDR-TB treatment in children is guided by the same principles, using almost the same second-line drugs as in adults, with careful monitoring for adverse effects. Monitoring of a patient on second line anti tb therapy is essential not only from response to therapy but also to prevent adverse effects. Health workers should regularly check for common adverse effects such as rashes, gastrointestinal symptoms, psychiatric symptoms, jaundice, ototoxicity and peripheral neuropathy. Serum creatinine, potassium and hearing needs to be monitored monthly when giving an injectable agent. Thyroid function tests should be monitored if patient is on amino salicylic acid or a thionamide. Liver function tests need to be assessed for patients on Pyrazinamide. A check for myelosuppression should be done for patients on linezolid and eye examination is required for patients on Ethambutol. In principle, the duration of treatment in children is basically the same as for adults. Unfortunately there are only a limited number of reported cases documenting the use of second-line drugs in children over extended periods of time. The risks and benefits of each drug should be carefully considered when designing a regimen. An open discussion with family members is critical, especially at the outset of therapy. No anti-tuberculosis drugs are absolutely contraindicated in children, and the few cases available have reported that children with drug-resistant TB have generally tolerated second-line drugs rather positively. Although Fluoroquinolones have been shown to retard cartilage development in beagle puppies, experience with the use of Fluoroquinolones has not demonstrated similar effects in humans. The benefits of Fluoroquinolones in treating MDR-TB in children outweigh the risks, and Ethionamide, PAS, and Cycloserine have been shown both effective and well tolerated among pediatric patients. For older children who cannot swallow capsules, the capsules can be opened and dissolved in 10 ml water to aid administration.21 Among the group 4 drugs, thionamide and amino salicylic acid should not be given together in children due to increased incidence of hypothyroidism. In general, anti-tuberculosis drugs should be dosed according to body weight (see Table below; Pediatric dosage of second-line ant tuberculosis drugs). Monthly monitoring of body weight is therefore especially important in pediatric cases and dose adjustments should be made as healthy weight gain occurs. All drugs, including Fluoroquinolones, should be prescribed at maximum recommended dosage whenever possible, except Ethambutol which should be used at 15 mg/kg (not 25 mg/kg as sometimes used in adults with MDR-TB since it is more difficult to monitor for optic neuritis in children). In the above case Ethambutol has avoided due to the risk of optic neuritis though AFB C/s showed susceptibility. According to national and international guidelines Capreomycin is usually reserved for the treatment of XDR-TB. But as per decision of MDR expert panel (consist of mdr-tb physicians at every PMDT site) he was started on capriomycine instead of amikacine, due to less risk of ototoxicity. 156

In children who are not initially culture-positive or in extra pulmonary tb, treatment failure is difficult to assess. Persistent abnormalities on chest radiographs do not necessarily signify a lack of improvement. In children, weight loss, or more commonly failure to gain adequate weight, is of particular concern and often one of the first (or only). REFERENCES 8. Mendez EA, Baquero AF, Garcia MM, Rojo CP, Ballesteros DY, Rubio GB, et al. Multidrugresistant tuberculosis in the pediatric age group. Anales de Pediatria 2007; 67:206-11. 11. Pinon M, Scolfaro C,Bignamini E, Cordola G, Esposito I, Milano R, et al. Two pediatric cases of multidrug-resistant tuberculosis treated with linezolid and moxifloxacin. Pediatrics 2010; 126(5): e1253-6. 12. Fairlie L, Beylis NC, Reubenson G, Moore DP, Madhi SA. High prevalence of childhood multidrug resistant tuberculosis in Johannesburg, South Africa: a cross sectional study. BMC Infect Dis 2011; 11: 28. 1. World Health Organization (WHO). Multidrug and extensively drug-resistant: Global report on surveillance and response 2010. World Health 13. Thomas TA, Shenoi SV, Heysell SK, Eksteen FJ, Organization; 2010. Sunkari VB, Gandhi NR, et al. Extensively drugresistant tuberculosis in children with human 2. Orenstein EW, Basu S, Shah NS, Andrews JR, immunodeficiency virus in rural South Africa. Int J Friedland GH, Moll AP, et al. Treatment outcomes Tuberc Lung Dis 2010; 14: 1244-51. among patients with multidrug-resistant tuberculosis: systematic review and meta-analysis. The 14. Kjollerstrom P, Brito MJ, Gouveia C, Ferreira G, Lancet infectious diseases 2009; 9(3): 153-61. Varandas L. Linezolid in the treatment of multidrug-resistant/extensively drug-resistant 3. Van Rie A, Beyers N, Gie RP, Kunneke M, Zietsman tuberculosis in paediatric patients: experience of L, Donald PR. Childhood tuberculosis in an urban a paediatric infectious diseases unit. Scand J population in South Africa: burden and risk factor. Infect Dis 2011; 43: 556-9. Archives of disease in childhood 1999; 80(5): 433-7. 15. Tochon M, Bosdure E, Salles M, Beloncle C, Chadelat K, Dagorne M, et al. Management of 5. Drobac PC, Mukherjee JS, Joseph JK, Mitnick C, Furin JJ, del Castillo H, et al. Community-based therapy for children with multidrug-resistant tuberculosis. Pediatrics 2006; 117(6): 2022-9. 17. Beyers N, Gie RP, Schaaf HS, Van Zyl S, Nel ED, Talent JM, et al. Delay in the diagnosis, notifica- tion and initiation of treatment and compliance in children with tuberculosis. Tuber Lung Dis 1994; 7(4)5: 260-5. 6. Feja K, McNelley E, Tran CS, Burzynski J, Saiman L. Management of pediatric multidrug-resistant tuberculosis and latent tuberculosis infections in New York City from 1995 to 2003. Pediatr Infect Dis J 2008; 27: 907-12. 18. Marais BJ, Gie RP, Hesseling AC, Schaaf HS, Lombard C, Enarson DA, et al. A refined symp- tom-based approach to diagnose pulmonary tuberculosis in children. Pediatrics 2006; 118: e1350-9. 7. Padayatchi N,Bamber S, Dawood H, Bobat R. Multidrug-resistant tuberculous meningitis in children in Durban, South Africa. Pediatr Infect Dis J 2006; 25: 147-50. 9. Schluger NW, Lawrence RM,McGuiness G, Park M,Rom WN. Multidrug-resistant tuberculosis in children: two cases and a review of the literature. Pediatr Pulmonol 1996; 21: 138-42. 10. Suessmuth S, Bange FC, Gappa M. Multidrug resistant tuberculosis in a 6 year old child. Paediatr Respir Rev 2007; 8: 265-8. 4. Schaaf HS, Shean K, Donald PR. Culture confirmed multidrug resistant tuberculosis: diagnos- tic delay, clinical features, and outcome. Arch Dis Child 2003; 88: 1106-11. young children in contact with an adult with drugresistant tuberculosis, France, 2004 2008. Int J Tuberc Lung Dis 2011; 15: 326-30. 16. Mukherjee JS, Joseph JK, Rich ML, Shin SS, Furin JJ, Seung KJ, et al. Clinical and programmatic considerations in the treatment of MDR-TB in children: a series of 16 patients from Lima, Peru. Int J Tuberc Lung Dis 2003; 7(7): 637-44. 19. Marais BJ, Hesseling AC,Gie RP, Schaaf HS, Enarson DA, Beyers N. The bacteriologic yield in children with intrathoracic tuberculosis. Clin Infect Dis 2006; 42(8): e69-71. 20. Loebstein R,Koren G. Clinical pharmacology and therapeutic drug monitoring in neonates and children. Pediatr Rev 1998; 19: 423-8. 21. Management of Drug-Resistant Tuberculosis in Children: A Field Guide. 1st ed. Boston, USA: The Sentinel Project for Pediatric Drug-Resistant Tuberculosis; 2012. 157

PEDIATRIC DOSING OF SECOND-LINE ANTI-TUBERCULOSIS MEDICATIONS General Considerations; Anti-TB drugs should be dosed according to weight and adjusted regularly as weight increases during treatment. When a liquid formulation is available, it should be used for patients less than 15 kg. Most second-line TB drugs do not have pediatric liquid or tablet formulations, so it may be necessary to split the pills in order to approximate the correct dose. To split tablets into 0.75, it is suggested to split the tablet in half and then split a half tablet in half. Discard the smaller quarter tablet and give the child a half tablet plus the remaining quarter tablet. Doses of most anti-tb drugs have not been established for children below 5 kg, but often the potential benefit outweighs the risks. In such cases, the child should be dosed as close to the middle of the mg/kg range as possible 158

Group Drug Daily dose Maximum daily dose 1 isoniazid (H) rifampicin (R) If 100 mg tab. For 5 kg.5 tab. From 6-9 kg 1 tab. From 10-12 kg 1.5 tab. From 16-30 kg 2 tab. 7-15 mg/kg for less than 30 kg. 10-20 mg/kg once daily for patients less than 30 kg. For 150 mg tablet: Body weight 5-7 kg.5 tab. From 8-12 kg -1 tab. From 13-15 kg -1.5 tab.from 16-30 kg -300 mg -1 tab If 300 mg Tab, 1 tab daily maximum dose. Children with malnutrition, peripheral neuropathy should also use pyridoxine 5-10 mg/day 600 mg ethambutol (E) 15-25 mg/kg once daily 1200 mg pyrazinamide (Z) For 400 mg tab. 2000 mg 5 6 kg - 0.25 tab 7 9kg- 0.50 tab 10 11kg-.75 tab 12 18 kg-1 tab 19 25 kg- 1.5 tab 26 30 kg- 2 tab amikacin (Am) 15-30 mg/kg once daily 1000 mg 2 kanamycin (Km) 15-30 mg/kg once daily 1000 mg capreomycin (Cm) 15-30 mg/kg once daily 1000 mg Example: Injectable dose calculation for a child weighing 6.9 kg Calculate the low and high doses for the child s weight. For kanamycin: Low dose: 15 mg/kg x 6.9 kg = 103 mg High dose: 30 mg/kg x 6.9 kg = 207 mg Choose a convenient dose between the two numbers. Select a dose between the two numbers and toward the higher number. In this case, 200 mg is a convenient dose. Calculate the number of ml to draw up in the syringe based on the mg/ml concentration of the preparation. levofloxacin (Lfx) Less than 5 years 15-20 mg/kg twice daily Over 5 years 10-15 mg/kg once 3 daily. moxifloxacin (Mfx) 7.5-10 mg/kg once daily 400 mg Tab. 10 17 kg- 0.25 tab 18 30 kg 0.50 tab ethionamide (Eto)/ 15-20 mg/kg once daily 1000 mg 4 protionamide (Pto) cycloserine (Cs) 15-20 mg/kg once daily 1000 mg PAS (4 g sachet) 200-300 mg/kg two times daily 12 g 5 clofazimine (Cfz) 1 mg/kg once daily 200 mg co-amoxiclav (Amx/Clv) 80 mg/kg in 2 divided doses 4000 mg of Amx and 500 mg Clv Linezolid (Lzd) 10 mg/kg given three times daily (pyridoxine should also be given) 600 mg 159