Objective: To estimate proportion of off-label medication use in neonates and to evaluate evidence of efficacy and safety of these medications. Methods: Chart audit in neonatal intensive care units of two institutions in Chandigarh, India. Results: Among 568 prescriptions in 156 neonates, 286 (50%) were off-label. Of these, 56% drugs were not approved for use in neonatal age group and 26% prescriptions were off-label for frequency, dose, indication, route or rate. Most common off-label drugs were anti-infective and antiepileptic. Despite lack of regulatory approval, one-third off-label drugs had level I-II evidence of safety and efficacy for use in neonates. Conclusion: Use of off-label drugs is common in sick neonates.

Keywords: Audit, Neonate, Prescription, Treatment.

Complications of BCG vaccine are collectively known as BCG disease [1]. Local and regional complications (0.4-1/1000 vaccinees) develop irrespective of immune-competence status while distant/disseminated BCG disease is generally associated with well-defined immune-deficiencies [1,2]. An increase in the number of BCG-associated suppurative lymphadenitis has been reported in many countries in recent years [2-5]. Inherited disorders of INFg/Interleukin-12 (INFg/IL-12) axis have been increasingly reported in association with disseminated BCG disease [6,7], now known as Mendelian Susceptibility to Mycobacterial Diseases (MSMD). There is limited published data on clinical profile, outcome and immunological status of BCG disease in Indian literature. We undertook this study to describe the clinical profile, immunological status and outcome of BCG disease.

This observational study was conducted at a tertiary care hospital from April 2012 to August 2013. All infants with clinically suspected BCG disease were included in the study and classified as local, regional, distant or disseminated disease [1]. Children who were already on Anti-tubercular treatment (ATT) were excluded. Strain, dose and timing of BCG vaccine were documented. Fine needle aspiration cytology of the node (FNAC) and HIV antibody screening were planned in all children. Chest X-ray, gastric aspirate for Acid-fast bacilli (AFB) and mycobacterial cultures were performed on Infants with systemic symptoms and signs of distant disease. They were evaluated for underlying primary immunodeficiency by performing immunoglobulin assay, lymphocyte subset flow-cytometry, and neutrophil functions. If feasible, INFg/IL-12 axis defect assay was offered. Treatment was given as per protocol [1]. Local and regional diseases (non-suppurative adenitis) were observed and followed up. Infants with suppurative adenitis were subjected to therapeutic aspiration/ surgical excision. They were clinically followed up for signs of dissemination.

Six infants were classified clinically as suspected distant/disseminated disease at the onset. Signs of dissemination were noted at presentation in one and after a gap of 2-5 months in the rest. Hepato-splenomegaly (5) and failure to thrive (4) were common features. Gastric aspirate yielded positive AFB in 3 infants. M.bovis was isolated from blood in one infant (confirmed disseminated disease) and from gastric aspirate in another infant (confirmed distant disease). Both these infants were products of second degree consanguinity. All infants had normal immunoglobulin assays, flow cytometry and neutrophil functions. Genetic analysis of the infant with confirmed disseminated disease revealed a novel homozygous mutation in IFNg-R1 gene at P130H location. All these six infants received initially 2HRZEO/7HREO; four among 6 responded over 2-3 months. The mean duration of follow-up after treatment completion was 7 months with no recurrences. Though infants with confirmed distant/disseminated disease showed adequate response initially, they developed skeletal tuberculosis and increasing organomegaly over after 4-6 months. Currently, they are stable on amikacin, azithromycin and linezolid.

In the series, three-fourth of infants having BCG disease had local or regional involvement. All six children with suspected distant/disseminated BCG disease had normal immunological work-up; IFNg-R1 gene mutation was documented in one infant. Hesseling, et al. [1] reported dissemination in 32% of their infants with BCG disease [1]. They demonstrated HIV infection in 68% infants [1]. None of our infants were HIV-positive, similar to a report from Iran [9]. Primary immune-deficiencies like severe combined immune-deficiency and chronic granulomatous disease were diagnosed in 25-50% of children in these studies [1,8], but none in our study population.

TABLE I	Profile of Infants with Distant/Disseminated Disease 

9. Ritz N, Tebruegge M, Connell TG, Sievers A, Robins –Browne R, Curtis N. Susceptibility of Mycobacterium bovis BCG vaccine strains to anti tuberculous antibiotics. Antimicrob Chemotherapy. 2009;53:316-18.