Treatment of Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis: Current Status and Future Prospects

Cheuk-Ming Tam; Wing-Wai Yew; Kwok-Yung Yuen

Expert Rev Clin Pharmacol. 2009;2(4):405-421.

Abstract and Introduction

Abstract

Drug resistance in Mycobacterium tuberculosis arises from the man-made selection of mutants that result from spontaneous chromosomal alterations. Preventing the development of drug-resistant TB through a good control program based on directly observed treatment, short-course, is of paramount importance. Established multidrug-resistant (MDR)-TB requires alternative specific chemotherapy, comprising drugs with higher cost and greater toxicity delivered on a programmatic basis. The development of new anti-TB drugs would help to prevent and treat MDR-TB. Notably, moxifloxacin and gatifloxacin are being tested for shortening treatment in Phase III trials, while three novel compounds, TMC-207, OPC-67683 and PA-824 are in Phase II studies for both drug-susceptible and drug-resistant disease. The roles of surgery and immunotherapy in the management of MDR-TB require further evaluation. The recent emergence of extensively drug-resistant TB poses a serious challenge to the global control of TB. In order to combat extensively drug-resistant TB, strengthening of directly observed treatment, short-course and drug-resistance programs, alongside other strategies, including the development of newer diagnostics and drugs, is mandatory.

Introduction

Since the discovery of effective anti-TB drugs in the middle of the last century, drug resistance has been one of the major challenges in the fight against TB. To tackle this problem, a number of measures and strategies have been adopted for the prevention and control of drug resistance. These include the use of combination chemotherapy, directly observed treatment, short-course (DOTS) strategy^[1,2] and its expanded form, DOTS-Plus,^[3] as well as the Stop-TB strategy introduced in 2006.^[4] Despite these efforts, drug-resistant TB continues to be a formidable problem. As a result, there has been increased interest in the development of new drugs and other forms of therapeutic modalities for TB in recent decades.

Among drug-resistant TB, multidrug-resistant (MDR)-TB denotes disease with bacillary resistance to at least isoniazid (INH) and rifampicin (RIF), the two most important first-line anti-TB drugs. Extensively drug-resistant (XDR)-TB is a subgroup of MDR-TB with additional bacillary resistance to any fluoroquinolone and at least one of the three injectables, kanamycin (KM), amikacin (AM) and capreomycin (CM). The importance of XDR-TB was first reported in early 2006^[5] and later widely publicized in the same year when a highly fatal epidemic occurred in South Africa.^[6] XDR-TB carries an ominous prognosis, with very high treatment failure and mortality rates. In October 2006, the WHO Global Task Force on XDR-TB called for an international response to the emerging XDR-TB crisis.^[7] According to the WHO, it has been estimated that approximately 500,000 MDR-TB and 40,000 XDR-TB cases emerge every year worldwide.^[8,9] The estimated global prevalence of MDR-TB may be as high as 1 million cases, posing a tremendous challenge to the control of TB.

Both failure in assuring an uninterrupted supply of a wide range of second-line drugs and inadequate management of MDR-TB patients can fuel the development of 'difficult-to-treat' fluoroquinolone-resistant MDR-TB. A step further in the faulty commitment would result in the emergence of XDR-TB, connoting bacillary resistance to both a fluoroquinolone and one or more of the second-line injectables. Genotypic fingerprinting has revealed the evolution from fully susceptible strains to MDR strains, and then to XDR strains over a period of approximately one decade.^[10] The common pathway is that drug-susceptible TB evolves into MDR-TB due to inadequate initial management, and that suboptimal use of second-line drugs leads to the development of XDR-TB, and perhaps even beyond.^[11] The alternative pathway in the development of fluoroquinolone-resistant TB may be related to the exuberant use of antimicrobials in the treatment of lower respiratory tract and other infections. TB patients could be mistakenly diagnosed as having pneumonia and treated with a fluoroquinolone.^[12,13] The escalating fluoroquinolone resistance in Mycobacterium tuberculosis (MTB) isolates/strains in different parts of the world does pose a significant cause for concern.^{[14,15,16,17]}

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Table 1. Categories of Anti-TB Drugs and Their Adverse Reactions
Drug	Adverse reactions
Drug	Common	Uncommon	Rare
*Category A: first-line oral drugs*
Isoniazid		Hepatitis Cutaneous hypersensitivity Peripheral neuropathy	Giddiness Convulsion Optic neuritis Mental symptoms Hemolytic anemia Aplastic anemia Lupoid reactions Arthralgia Gynecomastia
Rifampicin		Hepatitis Cutaneous hypersensitivity Gastrointestinal reactions Thrombocytopenic purpura Febrile reactions ‘Flu syndrome’	Shortness of breath Shock Hemolytic anemia Acute renal failure
Ethambutol		Retrobulbar neuritis Arthralgia	Hepatitis Cutaneous reactions Peripheral neuropathy
Pyrazinamide	Anorexia Nausea Flushing Photosensitization	Hepatitis Vomiting Arthralgia Cutaneous reactions	Sideroblastic anemia Gout
*Category B: injectable agents*
Streptomycin	Cutaneous hypersensitivity Giddiness Numbness Tinnitus	Vertigo Ataxia Deafness	Renal damage Aplastic anemia
Amikacin Kanamycin Capreomycin	Ototoxicity: hearing damage, vestibular disturbance Nephrotoxicity: deranged renal function tests	Clinical renal failure	Hypokalemia Hypocalcemia Hypomagnesemia
*Category C: fluoroquinolones*
Ofloxacin	Gastrointestinal reactions Insomnia Thrush	Anxiety Dizziness Headache Tremor	Convulsion Hemolysis Tendonitis/tendon rupture Arthropathy Colitis
Levofloxacin Moxifloxacin	Similar to those of ofloxacin, except less CNS dysfunction, and possibly more potential cardiotoxicity (moxifloxacin)
*Category D: oral bacteriostatic second-line agents*
Ethionamide Prothionamide	Metallic taste Salivation Gastrointestinal reactions	Hepatitis Peripheral neuropathy Headache	Convulsion Mental disturbances Impotence Menstrual disturbances Gynecomastia Hypothyroidism Hypoglycemia Alopecia
Cycloserine Terizidone	Dizziness Headache Depression Memory loss	Agitation Psychosis Convulsion	Sideroblastic anemia Stevens–Johnson syndrome
Para-aminosalicylic acid	Gastrointestinal reactions	Hepatitis Drug fever Cutaneous reactions	Hypothyroidism Hematological reactions Hypoakalemia Metabolic acidosis Sodium overload
*Category E: agents with efficacy that is not totally clear/certain (not recommended by the WHO for routine use in multidrug-resistant-TB patients generally)*
Clofazimine	Photosensitization Hyperpigmentation Cutaneous reactions	Gastrointestinal reactions Retinopathy	Intestinal obstruction
Amoxicillin clavulanate	Gastrointestinal reactions Cutaneous hypersensitivity	Headache Hematological reactions* Hypersensitivity vasculitis	Hepatitis* Colitis* Stevens–Johnson syndrome Convulsion
Thiacetazone	Gastrointestinal reactions Cutaneous hypersensitivity Vertigo Conjunctivitis	Hepatitis Erythema multiforme Exfoliative dermatitis Hemolytic anemia	Agranulocytosis*
Linezolid	Diarrhea Dyspepsia Headache	Thrombocytopenia* Aplastic anemia*	Colitis Peripheral and optic neuropathies*
Imipenem/cilastatin	Nausea	Diarrhea* Cutaneous reactions Thrush* Hepatitis* Neutropenia*	Colitis* Confusion Convulsion Arrhythmia
High-dose isoniazid	(See above)^‡
Clarithromycin	Nausea Giddiness Dryness of skin	Eye irritation Diarrhea	Taste disorder Colitis

*More common with prolonged administration.
^‡Hepatotoxicity and neurotoxicity may be more common.
Data from [25,31].

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