Resistance acquired during treatment contributes to a substantial proportion of the drug-resistant (DR) tuberculosis (TB) burden in adults.1 Drug resistance is acquired after actual or functional monotherapy most often associated with poor treatment adherence or pharmacokinetic mismatch.1 Because of the paucibacillary nature of childhood TB, DR-TB in children is most often primary (transmitted) after infection with strains already DR, rather than resistance being acquired during treatment.2 Children with extensive TB disease with a large Mycobacterium tuberculosis bacillary load are at greater risk for acquiring drug resistance during inadequate treatment, although this is seldom described.
We report a young child with drug resistance acquired while receiving first-line directly observed treatment, and we highlight factors potentially contributing to this treatment failure and resistance acquisition.
Table (Supplemental Digital Content 1, http://links.lww.com/INF/B865) summarizes the clinical course and key microbiologic findings. A 25-month-old male presented to a rural hospital 5 months before admission to our hospital, with a 2-week history of cough, weight loss and decreased activity. His past medical history was significant for an episode of pneumonia 1 month earlier. He was HIV-unexposed and had received Bacille Calmette-Guérin vaccination at birth. His family of 2 adults and 2 children lived in a 1 room house visited regularly by a great uncle who had pulmonary TB susceptible to isoniazid (INH) and rifampin (RIF). Weighing 7.9 kg at initial presentation he was moderately underweight, with a weight-for-age z-score of <−2; he was tachypneic with crepitations on lung examination, but without neck stiffness. Chest radiography showed left-upper lobe opacification with cavities. A tuberculin skin test, nonreactive the previous year, now measured 12 mm induration. He was diagnosed with probable pulmonary TB and started on first-line 3-drug treatment with a fixed-dose combination containing INH 30 mg (3.8 mg/kg), RIF 60 mg (7.6 mg/kg) and pyrazinamide (PZA) 150 mg (19.0 mg/kg). Gastric aspirates were acid-fast bacilli smear negative on microscopy but culture positive for M. tuberculosis. Drug susceptibility testing was not done.
In follow up 2 months later, he was noted to have a weight of 7.85 kg and persistent abnormal chest signs. Repeat gastric aspirates were acid-fast bacilli smear negative and sent for mycobacterial culture. Despite persistent symptoms, he was changed to continuation phase treatment with INH-RIF. Since the child began TB treatment, medication administration had been directly observed by a nonfamily treatment supporter. The gastric aspirates subsequently grew M. tuberculosis resistant to INH with an inhA promoter region mutation, but susceptible to RIF by line probe assay (GenoType MTBDRplus, Hain Lifescience, Nehren, Germany), but the result was not communicated to the clinic.
He remained unwell, continued losing weight and was seen by multiple different health care providers (Table, Supplemental Digital Content 1, http://links.lww.com/INF/B865). Three months later, he was admitted to a secondary referral hospital where his mental status deteriorated. A lumbar puncture was done and the cerebrospinal fluid showed 1 neutrophil × 106/μL, 145 lymphocytes × 106/μL, a protein of 7.5 g/L and glucose of 1.8 mmol/L. The child was then referred to our hospital.
At Tygerberg Children’s Hospital, the patient had a Glasgow Coma Scale of 9/15. He was wasted, weighing 6.69 kg. An urgent computed tomography scan of the brain showed bilateral diffuse ring enhancing lesions with generalized edema, leptomeningeal and basal enhancement, hydrocephalus with bilateral periventricular hypodensities and hypodensities in the basal ganglia consistent with infarcts, all indicative of tuberculous meningitis. A ventriculoperitoneal shunt was placed, and cerebrospinal fluid was sent for bacterial and mycobacterial culture. A chest radiograph was consistent with cavitary pulmonary TB with bronchopneumonic spread. Gastric aspirates were acid-fast bacilli smear negative and cultures were requested. The previous culture was traced and because of INH resistance, recent treatment with INH-RIF only, and in light of disease progression he was started empirically on INH, RIF, PZA, ethambutol, ethionamide, ofloxacin, amikacin and terizidone for probable multidrug-resistant (MDR)-TB. After 2 weeks, his condition stabilized and he was transferred to Brooklyn Hospital for Chest Diseases for long-term management.
Cultures from these gastric aspirates grew M. tuberculosis resistant to both INH and RIF by line probe assay. The line probe assay identified both INH-resistant and INH- and RIF-resistant organisms. Spoligotyping of these MDR and previously identified INH-resistant, RIF-susceptible strains showed them to be Beijing strains of the same type making superinfection with a new MDR-strain unlikely. As part of a study of pharmacokinetics (PK) of anti-TB drugs, this child had PK investigations on 2 occasions, which showed very low maximum INH serum concentrations of 0.64 μg/mL and 2.2 μg/mL after exact oral doses of 20 mg/kg on 2 occasions. Genotyping of the arylamine N-acetyltransferase 2 (NAT2) gene as previously described,3 delineated the NAT2*4/2*7B genotype, which is consistent with heterozygous rapid acetylator genotype (FS).
The child completed 18 months of a standard MDR-TB treatment regimen after his first negative culture and had a successful treatment response. He showed substantial neurologic improvement and was walking unassisted at the time of discharge.
We describe a case of acquired drug resistance in a young child with extensive cavitating pulmonary TB receiving inadequate therapy. Cavitations on chest radiography in young children with TB, particularly those presenting late, are not rare, although may be because of breakdown in lobar or segmental consolidations rather than typical adult-type TB.4 As no drug susceptibility testing was done on the child’s initial sputum, we cannot definitively document that the child started treatment with a fully drug-susceptible strain. Considering the only identified source case had documented drug-susceptible TB, the high concordance of the isolates of young children with their source case and the well-documented potential for rapid emergence of INH resistance, this is most likely.2 If so, this child initially infected with drug-susceptible TB acquired first INH resistance followed by RIF resistance.
Although poor adherence is often postulated as the reason for acquired resistance, this child’s adherence was directly observed in the home by a treatment supporter. We hypothesize that under dosing, poor absorption and heterozygous rapid acetylation are responsible for resistance acquisition in this case, which is consistent with emerging evidence on the contribution of individual pharmacokinetic variability to acquired resistance.5 The initial dosages of INH 3.8 mg/kg, RIF 7.6 mg/kg and PZA 19.0 mg/kg were less than currently recommended dosages. Two-hour INH concentrations between 0.5 and 1.0 μg/mL have early bactericidal activity of 0.342,6 so even low concentrations as in this child, can assert a strong selective pressure. Based on published RIF PK in children, this RIF dosage was likely insufficient to prevent emergence of INH-resistant mutants.7 Because INH is the most bactericidal of the first-line anti-TB drugs, loss of its protective effect rapidly leads to further resistance acquisition against companion drugs, as was the case with this child. Despite his low INH dose, concentrations may still have been adequate in a slow acetylator to provide some activity and protection against acquiring RIF resistance considering the usual low-level INH resistance associated with inhA mutations.3,8 In a rapid or intermediate acetylator however, as this child was, the exposure could be inadequate to provide protection.
This case highlights additional important lessons for pediatric TB management. Anti-TB drug dosing in children is weight dependent and although standardized weight-banded dosing is widely used, misdosing in children may be common and this case illustrates the reasons for the recent changes in the recommended anti-TB drug doses for children. Children on anti-TB treatment who deteriorate or do not respond need investigation; failure to respond may be because of poor adherence, but a high index of suspicion for resistance is needed. This child had multiple interactions with the health system after starting documented adherent anti-TB treatment; despite worsening disease and loss of weight, neither additional investigations, treatment changes, nor possible drug resistance were considered. It is possible that early recognition of the poor treatment response may have averted this poor outcome.
Although cultures for M. tuberculosis were sent after 2 months of treatment, it seems that these results were not reported. He remained on his standard continuation phase INH-RIF, although INH resistance would have prompted a change in treatment. INH-resistant TB (ie, INH-resistant, RIF-susceptible) is the most common form of DR-TB, representing 4.6–7.7% of confirmed isolates in children in our setting9 and in adults, it has been associated with additional acquired resistance. Pediatric guidelines recommend treatment of INH-resistant TB with RIF, PZA and ethambutol for 6–9 months, with addition of a fluoroquinolone for extensive disease, although there is limited evidence for this recommendation.10 This case demonstrates the need for additional evidence on the most appropriate treatment of INH-resistant TB in children.
In conclusion, acquisition of drug resistance in young children with TB is possible. Addressing the clinical and programmatic challenges described here may help ensure the best possible outcomes for children with TB.
The mother of this child provided written informed consent for this case report and for the child’s participation in the PK study referenced here. Ethical approvals for this PK study and for this case report were provided by the Health Research Ethics Committee of the Faculty of Medicine and Health Sciences, Stellenbosch University.
The authors thank the Brooklyn Chest Hospital pediatric ward staff for their assistance with the care of this child and the Desmond Tutu TB Centre MDR PK study team for assistance with the pharmacokinetic studies.
1. Mitchison DA. How drug resistance emerges as a result of poor compliance during short course chemotherapy for tuberculosis
. Int J Tuberc Lung Dis. 1998;2:10–15
2. Schaaf HS, Van Rie A, Gie RP, et al. Transmission of multidrug-resistant tuberculosis
. Pediatr Infect Dis J. 2000;19:695–699
3. Schaaf HS, Parkin DP, Seifart HI, et al. Isoniazid pharmacokinetics in children
treated for respiratory tuberculosis
. Arch Dis Child. 2005;90:614–618
4. Schaaf HS, Marais BJ, Whitelaw A, et al. Culture-confirmed childhood tuberculosis
in Cape Town, South Africa: a review of 596 cases. BMC Infect Dis. 2007;7:140
5. Srivastava S, Pasipanodya JG, Meek C, et al. Multidrug-resistant tuberculosis
not due to noncompliance but to between-patient pharmacokinetic variability. J Infect Dis. 2011;204:1951–1959
6. Donald PR, Sirgel FA, Venter A, et al. The influence of human N-acetyltransferase genotype on the early bactericidal activity of isoniazid. Clin Infect Dis. 2004;39:1425–1430
7. Schaaf HS, Willemse M, Cilliers K, et al. Rifampin pharmacokinetics in children
, with and without human immunodeficiency virus infection, hospitalized for the management of severe forms of tuberculosis
. BMC Med. 2009;7:19
8. Cynamon MH, Zhang Y, Harpster T, et al. High-dose isoniazid therapy for isoniazid-resistant murine Mycobacterium tuberculosis
infection. Antimicrob Agents Chemother. 1999;43:2922–2924
9. Seddon JA, Hesseling AC, Marais BJ, et al. The evolving epidemic of drug-resistant tuberculosis
in Cape Town, South Africa. Int J Tuberc Lung Dis. 2012;16:928–933