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Discordance Between Fluoroquinolone Resistance Results on Xpert MTB/XDR Panel, Second-line Line Probe Assay and Phenotypic Drug Sensitivity Testing- How to Interpret?

Dhruv Gandhi, Ira Shah
Department of Pediatric Infectious Diseases, BJ Wadia Hospital for Children, Mumbai, India

Address for Correspondence: Dhruv Gandhi, 5B/13 Shyam Niwas, Breach Candy, Mumbai-400026, Maharashtra, India. Email: dhruvgandhi2610@gmail.com

Keywords: preXDR-TB, drug-resistant tuberculosis, microbiological diagnosis, antitubercular drugs, second-line antitubercular therapy, moxifloxacin resistance

Clinical Problem:
A 10-year-old boy presented in February 2024 with fever for 4 months. His older sister had a past history of pulmonary multidrug-resistant tuberculosis (MDR-TB), microbiologically diagnosed 5 years back, and who completed treatment after having received second-line antitubercular therapy (ATT) for 2 years. On presentation, his weight was 24 kg (10^th-25^th percentile according to Indian Academy of Pediatrics (IAP) charts) and height was 133.5 cm (25^th-50^th percentile according to IAP charts). General and systemic examinations were normal. Chest X-ray performed at another centre was suggestive of mediastinal lymphadenopathy. High-resolution computerized tomography thorax showed multiple enlarged pre- and paratracheal, pre- and subcarinal, and hilar lymph nodes, of which the largest measured 2.6 x 1.5 cm. Few mediastinal lymph nodes showed calcification and multiple discrete nodules were also visualized in the left lower lobe. Bronchoscopy showed no endobronchial involvement. Urine examination found 6-8 pus cells/high power field (HPF), 50-60 erythrocytes/HPF. Abdominal ultrasound was normal. Mediastinal lymph node biopsy Xpert MTB/Rif assay detected medium load rifampicin-resistant Mycobacterium tuberculosis (MTB) complex. Xpert MTB/XDR performed on the same sample revealed resistance to isoniazid and kanamycin. Other investigations of the patient are shown in Table 1. He was initially diagnosed with pulmonary and mediastinal lymph node MDR-TB and was started on steroids and a shorter oral second-line ATT regimen consisting of high-dose isoniazid, pyrazinamide, ethambutol, ethionamide, bedaquiline, moxifloxacin and clofazimine. Histopathological examination of the mediastinal lymph node showed granulomatous inflammation with Langhans giant cells, tissue first-line line probe assay (LPA) showed resistance to isoniazid, rifampicin, and second-line LPA showed resistance to fluoroquinolones. The mycobacterium growth indicator tube (MGIT) culture of the tissue sample grew MTB and subsequent phenotypic drug-sensitivity testing (DST) showed resistance to pyrazinamide and high-level moxifloxacin. Gastric lavage and sputum MGIT cultures were negative. He was diagnosed with pre-extensively drug resistant TB (preXDR-TB) and isoniazid, pyrazinamide, moxifloxacin and ethambutol were stopped. The patient was shifted onto a longer oral regimen consisting of bedaquiline, linezolid, clofazimine, cycloserine and ethionamide.

Table 1. Investigations of the patient.

Parameters	Patient’s Values	Reference Range
Hemoglobin (gm/dL)	9.5	11.5-15.5
TLC (cells/cumm)	6740	5000-13,000
ANC (cells/cumm)	3046	2000-8000
ALC (cells/cumm)	2501	1000-5000
Platelets (10⁶ cells/cumm)	3.70	1.50-4.50
ESR (mm/hr)	50	<15
ALT (IU/L)	35	<41
ALP (IU/L)	144	51-332
BUN (mg/dL)	9	5-18
Serum creatinine (mg/dL)	0.35	0.3-0.59
Serum total protein (gm/dL)	7.4	6.00-8.30
Serum albumin (gm/dL)	3.6	3.80-5.40
PT (sec)	13.7	10-14
INR	1.19	0.8-1.2
Serum C3 (mg/dL)	158	88-201
Serum TSH (IU/mL)	2.1	0.5-5.0
Serum free T3 (pg/mL)	1.46	2.7-5.2
Serum free T4 (pg/mL)	6.55	0.8-2.1
QTcF at baseline (ms)	380	<450
HIV ELISA	Non-reactive	-
ASO titres	Non-reactive	-
Sputum Xpert MTB/Rif	MTBC not detected	-
Gastric lavage Xpert MTB/Rif	MTBC not detected	-
BAL Xpert MTB/Rif	MTBC not detected	-

Note: TLC- Total leukocyte count, ANC- Absolute neutrophil count, ALC- Absolute lymphocyte count, ESR- Erythrocyte sedimentation rate, ALT- Alanine aminotransferase, ALP- Alkaline phosphatase, BUN- Blood urea nitrogen, PT- Prothrombin time, INR- International Normalized Ratio, TSH- Thyroid stimulating hormone, T3- Triiodothyronine, T4- Tetraiodothyronine, HIV- Human immunodeficiency virus, ELISA- Enzyme linked immunosorbent assay, ASO- Antistreptolysin O, BAL- Bronchoalveolar lavage, QTcF- QT interval.