Multidrug-resistant tuberculosis treatment with linezolid-containing regimen

Abstract

The following is a case of multidrug-resistant pulmonary tuberculosis (MDR-TB) that was treated successfully with a linezolid-containing regimen. It was found that linezolid is an efficient medicine for MDR-TB treatment with an acceptable side effect profile. Treatment was maintained for 18 months, and closely monitoring toxicities did not reveal evidence of any neurologic adverse effects. However, despite our expectation, thrombocytopenia was seen after 2 years follow-up.

Introduction

An estimated 9 million people are infected with tuberculosis (TB) worldwide [1]. In recent years, the epidemiology of TB has shown significant increases in developed countries because of immigration from countries with high prevalence as well as a rising incidence of TB and HIV infection [2]. As a result, an increase of multidrug-resistant (MDR)-TB is also anticipated over the next few years owing to population migration patterns [3]. MDR-TB signifies bacillary resistance to at least Isoniazid and Rifampicin [4]. Drug-resistant TB infection has presented since the beginning of the antibiotic era. Although genetic resistance to an anti-TB medication happens naturally, in consequence of chromosomal mutations that accompany mycobacterial replication, MDR-TB is a manmade phenomenon that has emerged owing to improper TB treatment [5,6]. The management of MDR-TB is challenging, requiring prolonged administration of second-line drugs which are more expensive, often less effective, and more toxic than first-line agents [7,8].

Linezolid, the first oxazolidinone approved for clinical use, has demonstrated excellent activity against drug-resistant strains of Mycobacterium tuberculosis (MTB) [7,9,10].

The following report describes a case of MDR-TB that was treated with a linezolid-containing regimen and discusses the challenges of long-term administration of linezolid in an adult with MDR-TB.

Case report

A 29-year-old Bhutanese refugee man was referred to the clinic for TB evaluation with positive tuberculin skin (PPD > 13 mm) and QuantiFERON-TB tests. He was living in a camp in Nepal for several years before moving to the United States. He complained of cough, fever, and weight loss for 9 months. His past medical history was not significant. The physical examination was remarkable for malnourishment (body mass index = 15.7), mildly tender bilateral cervical lymphadenopathies with maximum size of 2 cm and decreased breath sounds in left lower zone of the chest. The rest of the examination was normal. Hematological and biochemical parameters were within normal limits except mild anemia.

Imaging studies were performed and showed a mild left pleural effusion in the chest radiograph. A chest computed tomography showed nodular opacities in the right upper lobe, minimal scarring in the ligula, hilum lymph nodes with maximum size of 19 mm, and mild left side pleural effusion.

The sputum specimens were sent for the Acid Fast Bacilli smear, mycological culture and drug susceptibility test (DST). The patient underwent excisional biopsy of the cervical lymph nodes, which the pathological examination reported as chronic necrotizing granulomatosis inflammation consistent with TB. Anti-TB therapy was started empirically with a regimen including: isoniazid, rifampin, pyrazinamide, and ethambutol on direct observe therapy. Eight weeks later, the sputum and lymph node cultures reported mycobacterium tuberculosis complex, and DST confirmed the presence of a multiple drug-resistant strain, resistant to isoniazid, rifampin, pyrazinamide, ethambutol, streptomycin and para aminosalicylic sodium. The susceptibility results and molecular study provided by the Center for Disease Control are shown in Tables 1 and 2. The previous anti-TB regimen was switched to amikacin 1500 mg/week, moxifloxacin 400 mg/day, cycloserine 500 mg/day, linezolid 600 mg/day and ethionamide 500 mg/day. The patient responded well to anti-TB medications, although he experienced multiple anti-TB medication side effects, including thrombocytopenia, hearing loss and upper gastrointestinal discomfort. Consequently, his treatment was modified to linezolid 300 mg/day, cycloserine 500 mg/day, levofloxacin 750 mg/day and capreomycin 1300 mg/week (it was stopped 6 months after sputum conversion due to hearing loss).

Table 1.

Drug resistance results from sputum of MDR-TB patient.

Drugs	Percent resistance	Interpretation
Isoniazid 0.2 μg/ml	100	R
Isoniazid 1.0 μg/ml	100	R
Isoniazid 5.0 μg/ml	0	S
Rifampin 1.0 μg/ml	100	R
Ethambutol 5.0 μg/ml	50	R
Streptomycin 2.0 μg/ml	100	R
Rifabutin 2.0 μg/ml	100	R
Ciprofloxacin 2.0 μg/ml	100	R
Kanamycin 5.0 μg/ml	0	S
Ethionamide 10.0 μg/ml	0	S
Capreomycin 10.0 μg/ml	0	S
PAS 2.0 μg/ml	50	R
Ofloxacin 2.0 μg/ml	0	S
Amikacin 4.0 μg/ml	0	S
Pyrazinamide 100 μg/ml	100	R

Susceptibility testing method: indirect agar proportion, 7H10 medium; susceptibility is defined as <1% resistance compared with colonies that develop on drug-free media. Pyrazinamide was tested by the MGIT 960 method (Becton Dickinson).

Abbreviations: R, resistance; S, sensitive; PAS, para-aminosalicylate sodium; μg/ml, microliter.

Table 2.

Results for molecular detection of drug resistance in MDR-TB patient.

Anti-TB drug	Locus (region) examined	Result for mutation
Rifampin	rpoB-RRDR	TCG > TTG; Ser531Leu
Isoniazid	InhA (promoter) katG (ser315 codon)	No mutation AGC > ACC; Ser315Thr
Fluoroquinolones	gyrA (QRDR)	No mutation
Amikacin, Kanamycin, and Capromycin	rrs (1400 region)	No mutation
Kanamycin	eis (promoter)	No mutation
Capromycin	tlyA (entire ORF)	No mutation

rpoB, rpoB gene encoding the β-subunit of RNA polymerase; RRDR, rifampin resistance-determining region; InhA, InhA gene encoding InhA protein; katG, mycobacterial catalase-peroxidase; QRDR, quinolone resistance-determining regions; gyrA, DNA gyrase A gene; rrs, rrs gene of the 16S rRNA; eis, eis gene; tlyA, tlyA gene; ORF, open reading frame.

The anti-TB medicines were continued for 12 months after sputum conversion to negative (total duration of treatment was 18 months). The patient was free of symptoms and his cervical lymphadenitis subsided. He was closely followed up and no signs of relapse were observed up to 24 months after completion of treatment. Thrombocytopenia (platelet counts: 86 × 1000 per microliter) was seen even 24 months after stopping linezolid.

Discussion

Multidrug-resistant mycobacterium tuberculosis is a rising and alarming medical problem. The actual management and treatment regimens for MDR-TB are difficult, expensive, long-term, and linked with high rates of adverse effects and high morbidity and mortality [11,12]. Incomplete and inadequate treatment is the most significant factor leading to the development of MDR-TB [13].

Linezolid is a synthetic antibacterial agent that inhibits bacterial protein synthesis at an early stage of translation [14]. The oral bioavailability of linezolid is nearly 100%, with a high volume of distribution and high concentrations in alveolar macrophages [15]. Alternatively, various adverse drug reactions have been described with long-term use of linezolid, primarily bone marrow suppression and peripheral and/or optic neuropathy. Hematologic adverse reactions ensuing from the prolonged use of linezolid are dose dependent and reversible secondary to inhibition of mitochondrial protein synthesis, while peripheral neuropathy might be irreversible depending on the prolonged duration of the therapy rather than dosage; however, optic neuropathy appears to resolve after stopping linezolid [10,16]. In this case, treatment was maintained for 18 months and closely monitoring toxicities did not reveal evidence of any neurologic adverse effects. However, despite previous reports, thrombocytopenia was seen after 2 years of follow-up [17].

The optimal dose of linezolid for MDR-TB is not apparent. In this case, linezolid was given at a dose of 300 mg/day. This decision was directed by preliminary data regarding linezolid in the treatment of MDR-TB in adults being treated with 600 mg/day instead of 1200 mg/day, which is the Food and Drug Administration-approved dose for Gram-positive organisms [18]. In these studies, a daily 300 mg dose of linezolid was seen to be effective with less toxicity [19].

Conclusion

Specific strategies and measures should be engaged to prevent the propagation and dissemination of MDR-TB. Concerning MDR-TB treatment, risks and benefits of each medication should be deemed when tailoring a therapy. In this case, linezolid was found to be an effective drug available to treat MDR-TB. Although linezolid was efficacious in this study, randomized clinical trials are necessary to measure outcomes and permanent side effects of linezolid-containing regimens before the clinical role of linezolid as a treatment for MDR-TB can be recommended.