The Assessment and Treatment of Drug-Resistant Tuberculosis

September 20, 2009

The development of drug-resistant strains of Mycobacterium tuberculosis has increased morbidity and mortality associated with tuberculosis (TB) and has greatly increased the costs of care for patients with this disease.

Mycobacterium tuberculosis remains the most important infectious cause of morbidity and mortality among adults worldwide. Approximately 8 million persons are infected, and 1.6 million die of tuberculosis (TB) annually.1 Drug resistance has been a major challenge to the successful management of TB since the introduction of antituberculosis drugs. Streptomycin-resistant strains of M tuberculosis were identified within months of the introduction of streptomycin in the 1940s.2 Subsequently, resistance to all other medications used to treat TB has been reported and, over time, the rates of drug resistance have increased (Table 1).3-7

Drug-resistant (DR) strains arise spontaneously, and inappropriate treatment facilitates their selection.8 Multidrug resistance was first reported in the early 1980s and has become widespread, reaching epidemic proportions in the former Soviet republics and in areas of China.9

The World Health Organization (WHO) has reported rates of DR-TB over the past decade. Reports on TB and patterns of resistance were released in 1997 based on data from 35 countries, in 2000 based on data from 58 countries, and in 2004 based on data from 77 countries. The fourth report, released in February 2008, included data from 91,577 patients in 81 countries, representing 35% of the new smear-positive cases globally. The results of drug susceptibility testing performed in supranational reference laboratories were reported on specimens from 62,746 patients.9

In patients with newly diagnosed TB, rates of resistance to at least 1 antituberculosis drug- defined as monoresistance-range from essentially 0% in some Western European countries to 56% in Baku, Azerbaijan.9 Worldwide, the population-weighted means of drug resistance among new cases were 17% (95% confidence interval [CI], 13.6% - 20.4%) for resistance to any drug and 10.3% for isoniazid resistance.9

Rates of resistance are even higher in patients previously treated for TB, defined by the WHO as those who previously received antituberculosis drugs for a minimum of 1 month. Drug susceptibility test results were available for 12,977 previously treated patients. Resistance to at least 1 drug ranged from 0% in some Western European countries to 85.9% in Tashkent, Uzbekistan.9 Globally, the population-weighted means of resistance among new cases were 35% for resistance to any drug and 27.7% for isoniazid resistance.9

In response to this global TB epidemic, a series of initiatives to combat it have been funded; these initiatives are supervised by the WHO and include the supranational reference laboratories; the Global Fund to Fight AIDS, Tuberculosis and Malaria; and the Green Light Committee for Access to Second-line Anti-tuberculosis Drugs. The programs track the prevalence of TB and the prevalence and patterns of drug resistance, facilitate rapid testing for TB diagnosis and drug resistance, and subsidize the provision of medications and appropriate supervision of treatment through directly observed therapy programs.

Multidrug-Resistant TB
The development of multidrug- resistant (MDR) strains of M tuberculosis poses an even greater challenge to successful treatment. Multidrug resistance is defined as resistance to both isoniazid and rifampin.10 MDR strains may also be resistant to other drugs.11

MDR strains primarily affect the lungs but can also cause extrapulmonary disease, especially in patients coinfected with HIV.12-15 Cavitation is common in patients with MDR-TB.16 Those in whom MDR-TB developed during treatment have demonstrated a postprimary radiographic pattern, often with cavitation.17 However, patients infected with MDR M tuberculosis during an outbreak of the disease have presented with pleural effusions and a primary radiographic pattern without cavitation.17

The WHO estimates that 500,000 TB cases among the 8 million worldwide are MDR. Rates of multidrug resistance range from 0% to 22.3% (in Baku, Azerbaijan). The rates are lowest in the Americas, Central Europe, and sub-Saharan Africa. In 2006, it was estimated that MDR M tuberculosis accounts for 4.8% of all TB cases globally, with 50% occurring in India and China and 7% in the Russian Federation. Worldwide, 2.9% of new cases and 15.3% of previously treated cases were MDR. The rate of multidrug resistance in previously treated cases is 60% in Tashkent, Uzbekistan, and 56% in Baku, Azerbaijan.9

Extensively Drug-Resistant TB
In 2005, physicians in KwaZulu-Natal, South Africa, reported the rapid demise of some HIV-infected patients infected with strains of MDR M tuberculosis that were also resistant to fluoroquinolones and at least 1 injectable antibiotic and, in some cases, to other first- and second-line antibiotics.18-20 The importance of extensively drug-resistant (XDR) M tuberculosis is highlighted by the difficulty and expense of treatment and the high mortality rate in patients infected with these strains.21 It is estimated that the average cost of treating a case of XDR-TB in the United States is nearly $500,000, twice the average cost of treating a patient with MDR-TB.22

As of May 2008, it was recognized that XDR strains of M tuberculosis were present in at least 49 countries, including the United States.23-25

Conditions Associated With Drug Resistance
As resistance rates increase, the likelihood of being infected with a resistant strain increases.9 A study incorporating data from 11 countries found that prior ineffective treatment was strongly linked to the presence of drug resistance.26 The odds ratios (ORs), expressed as the mean and 95% CI, of resistance to 1, 2, 3, and 4 drugs in previously treated patients compared with patients undergoing treatment for the first time were 2.5 (2.1 - 3.0), 4.6 (3.7 - 5.6), 11.5 (8.6 - 15.3), and 18.5 (12.0 - 28.5), respectively.26

The duration of prior treatment also increased the risk of drug resistance, but this more likely reflected the results of treatment failure in patients with DR-TB. Infection with HIV was not an independent risk factor for the development of MDR-TB.26 A review of European reports found that previous treatment was the greatest risk factor for MDR-TB-the OR was 10.2.27

Multidrug resistance may also develop because of inappropriate therapy; this usually consists of not including 4 drugs in the initial regimen or not considering local patterns of resistance and not including a minimum of 2 drugs to which the organism is sensitive. Other factors that interfere with appropriate treatment include cost constraints, unavailability of medication, and prescription error on the part of the health care worker.26

Other common management errors include treating for an inadequate duration, especially in patients infected with DR strains that require longer treatment, and poor patient adherence to the prescribed regimen. Patient characteristics that predict poor adherence and therefore increase the risk of the development of DR strains include homelessness, alcohol or drug abuse, behavioral problems, psychiatric disorders, and a lack of social or family support.27-29

Other conditions that are suspected but not proved to contribute to multidrug resistance are imprisonment; recent immigration; HIV infection and other conditions associated with immunodeficiency, such as transplantation and diabetes; and host genetic susceptibility associated with the HLA-DR2 alleles, HLA-DRB1, and HLA-DQB1.30,31 Certain strains of M tuberculosis may be more invasive, including the Beijing family of genotypes that are frequently associated with drug resistance.32,33

A patient can acquire resistant organisms from contact with a patient with MDR-TB, or a patient who was previously successfully treated for TB may be reinfected with an MDR strain.34

Apart from differences in the selection of antituberculosis drugs and treatment duration, proper management of DR-TB encompasses the principles of good TB management, including prevention of infection, prompt diagnosis, appropriate and prompt initiation of therapy, drug susceptibility testing, and features to optimize adherence to prescribed therapy.35,36

Rationale for effective management. Inadequate TB treatment creates drug resistance, and patients who are inadequately treated remain infectious and may subsequently transmit disease, leading to outbreaks of DR-TB. This emphasizes the importance of treating TB properly from the beginning. To achieve this, adequate infrastructure and funding must be provided to prevent the generation of DR-TB and the resulting increased costs of treatment.

In general, properly supervised treatment for 6 months is adequate. Exceptions are conditions that increase the risk of treatment failure, including HIV coinfection treated with antiretroviral therapy, alcohol and drug use, anemia, low body mass index (BMI), older age, and more extensive resistance.37

Prevention: lessons from history. Disease prevention clearly reduces the likelihood of drug resistance. Between the mid-19th century and 1900, mortality from TB decreased from approximately 1000 per 100,000 population to 200 per 100,000. This is likely best explained by societal improvements, such as better living conditions with less overcrowding and better nutrition; the discovery of the tubercle bacillus by Robert Koch in 1882; and recognition of TB’s contagious nature and the importance of isolating infectious patients.38

Between 1900 and 1929, before the introduction of effective medications, the TB death rate fell from 200 to 69 per 100,000 population in the United States.39 Better identification of patients with TB by skin testing and chest radiographic surveillance contributed to the reduction in the infection rate.39 The rise of the sanitarium movement in the latter part of the 19th century provided the means to isolate infectious patients and decrease the spread of TB. The use of Mantoux skin testing to help remove infected cattle from the food supply also contributed to the reduction in TB.39

The emphasis on the isolation of infectious cases diminished with the introduction of effective drug therapy. The cure rate is 95% to 97% in adherent patients with drug-sensitive TB who are treated for 6 months with a directly observed therapy, short course (DOTS) program that includes isoniazid, rifampin, ethambutol, and pyrazinamide for the first 2 months.40 The number of sanitarium beds declined with the reduction in active TB cases, eventually leading to the closure of the sanitariums. Their closure led to the disappearance of health care workers with the skills to care for patients requiring respiratory isolation and the skills to protect themselves from nosocomial infection.41,42

The development of multidrug resistance, especially extensive drug resistance, has created the need for modern equivalents of the resources and skills that were available in the sanitarium era. Patients with infectious TB need to be isolated at home or in facilities with negative-pressure ventilation rooms. Since nosocomial transmission is a concern, appropriate precautions are necessary to protect patients and health care workers. Those who work with these patients have to be provided with appropriate masks or respirators and the training to use them properly. These resources may not be available in poorer countries, so options include greater ventilation to the outdoors, the use of ultraviolet light to kill airborne bacilli, and high-efficiency particulate air filtration.36

The importance of rapid diagnostic techniques. Delay in the diagnosis of DR-TB postpones the start of effective therapy. The belated initiation of appropriate therapy increases the extent of parenchymal lung damage and mortality, leads to greater bacterial loads, and increases the time that the patient remains infectious. Moreover, inappropriate treatment of DR-TB increases the risk of resistance to other first- and second-line medications.43

Traditionally, mycobacteria were plated on solid media and positive cultures underwent drug susceptibility testing, which took several months to complete. Several rapid diagnostic techniques have been developed to shorten the time to diagnosis. Microscopic observation drug susceptibility (MODS) is a method to rapidly identify MDR strains; this method was developed in Peru and is suitable and economical enough to be practical for use in the developing world.44M tuberculosis grows quickly and can be detected on liquid media, and isoniazid and rifampin can be incorporated into the MODS assay to allow drug susceptibility testing to these medications.45,46 Culture and susceptibility results are provided in about 7 days.44

Nucleic acid amplification techniques directed against the rpoB gene, a resistance gene, can identify rifampin-resistant strains in less than 2 hours. This mutation in mycobacterial RNA polymerase accounts for 95% of the cases of rifampin resistance.47 Since most rifampin-resistant strains are also resistant to isoniazid (83% in the United Kingdom), rifampin resistance is an effective surrogate for multidrug resistance.48

Two assays are commercially available. One is a reverse hybridization line-probe assay that can detect M tuberculosis and the rpoB gene; it has good sensitivity and specificity on isolates from culture, but it is less reliable with clinical specimens.49 The newer MDR M tuberculosis assay can also detect isoniazid resistance genes katG and inhA; it accurately detects rifampin resistance, but its sensitivity is less for isoniazid-resistant genes.49

Drug treatment of MDR-TB. The principles of MDR-TB management include the principles of proper TB management with some additional recommendations (Tables 2, 3, and 4). Sputum smear and culture should be monitored monthly to evaluate the response to treatment. It is important to also monitor patients for adverse effects of drugs to ensure adherence (Table 5).

There are no randomized controlled trials of the treatment of MDR-TB. Recommendations are based on retrospective cohort studies and expert opinion.50-53 Generally, regimens have been based on drug susceptibility testing, but such testing was not done consistently. In some reports, drug susceptibility testing was done to both first-line and second-line drugs, while in others, testing was done only to first-line drugs; in other reports, treatment was based on previous treatment or on drug susceptibility profiles in the community.

A fluoroquinolone and an injectable antibiotic formed the core of the regimen in most cases, and patients were treated with a median of 3.2 to 6.6 drugs.52 Generally, treatment was given for 18 to 24 months after the last positive culture. Since regimens were given for extended periods, adherence was often a problem, emphasizing the importance of directly observed therapy (DOT).2

In 2008, the WHO published an emergency update for the management of DR-TB.54 It suggested basing treatment on the history of drug therapy with the assumption that other drugs will be required, since the previous regimen failed. Resistance profiles to first- and second-line drugs in the local area should also be considered.51

Early detection and initiation of drug treatment of MDR-TB are important determinants of successful therapy. Regimens should include at least 4 drugs that are likely to be effective.51-53 Drug dosing should be adjusted by body weight. Pyrazinamide, ethambutol, and fluoroquinolones should be given once daily to attain high peak serum levels.51

Pyrazinamide can be given for the entire treatment period if it appears to be effective. The rationale is that patients with DR-TB have chronic inflammation producing the acidic environment in which pyrazinamide is active. If patients are doing well, pyrazinamide can be stopped at the end of the injectable phase as long as the patient continues to receive 3 other effective drugs.51

Cycloserine, p-aminosalicylic acid (PAS), and ethionamide/protionamide should be given in split doses to minimize adverse effects.51,53 To improve tolerance, these drugs should be started at half doses and increased to full doses over 2 weeks. Adverse effects should be dealt with promptly to minimize the risk of treatment interruptions.51,53 Injectable agents should be given for a minimum of 6 months and for at least 4 months after culture conversion; treatment should be continued with oral drugs for a minimum of 18 months after culture conversion. Each dose should be given as DOT.

Regimens should include any first-line oral agent (pyrazinamide and ethambutol) to which the MDR M tuberculosis strain is sensitive and an injectable agent other than streptomycin (amikacin, kanamycin, or capreomycin).51,53 There are high rates of resistance and a higher risk of ototoxicity with streptomycin. Include a fluoroquinolone; levofloxacin and moxifloxacin are preferred if ofloxacin resistance or extensive drug resistance is suspected.

Add second-line drugs, such as PAS, cycloserine, and ethionamide or protionamide, to have a regimen containing a minimum of 4 effective drugs. Consider adding other drugs if no 4 drugs from the above-described groups (clofazimine, linezolid, amoxicillin/clavulanate, imipenem/cilastatin, clarithromycin, high-dose isoniazid, or thiacetazone) are likely to be effective.52,53 Thiacetazone is contraindicated in HIV-infected patients. Occasionally, rifabutin is effective in patients with rifampin-resistant TB.51

Daily treatment is recommended during the intensive phase, and treatment no less than 3 times per week is recommended during the continuation phase.55 Even in countries with limited resources, treatment of MDR-TB with the provision of appropriate second-line drugs can be successful in 70% of newly and previously treated patients.56 Patients with MDR-TB need to be routinely monitored for adverse effects.

Role of daily observed therapy. DOT is an essential feature of therapy, because patients self-administering medications have low rates of treatment completion and are at greater risk for treatment failure and presumably for DR-TB. Programs aim for completion rates of 85% or greater. One study reported a median completion rate of 61% in unsupervised patients compared with 86% in patients receiving DOTS and 91% in patients receiving enhanced DOTS (including minor financial incentives).2 Countries with a DOTS strategy have lower rates of DR-TB.57

The use of DOTS is especially important to ensure that patients receiving short-course therapy are adequately treated. It minimizes the risk that drug resistance will develop in previously susceptible strains and that partially susceptible strains will become more resistant, which, in turn, reduces the risk of multi- drug resistance and extensive drug resistance.

The key components of an effective DOTS program are properly trained workers to administer DOTS; properly equipped laboratories to perform microscopy procedures to diagnose TB; a reliable supply of quality drugs (preferably at no cost to patients); accurate record keeping and a cohort analysis system to monitor case-finding, treatment, and outcomes; and sustained political commitment and funding.28 A DOTS program should also include education, address other health problems and dependency issues, and include enablers and incentives (alleviating poverty and social disadvantages) to enhance success.28

Governments focused on cost savings should recognize that although DOTS slightly increases the initial costs of TB treatment, it saves a substantial amount on the costs of re-treatment and acquired resistance, reduces the number of future cases, and reduces mortality.58,59

The use of DOTS decreases the incidence of TB, clustered cases of pulmonary TB, primary drug resistance, and multidrug resistance. An advantage of the DOT program for MDR-TB is that adverse drug effects are recognized promptly and regimens can be modified to improve treatment completion rates.60 The mortality rate is lower in patients infected with sensitive organisms than it is in those infected with MDR strains.61 Even with DOT, the cure rate of MDR-TB is approximately 60% and the relapse rate is 28%.28 In Latvia, a DOTS plus, or enhanced DOTS, program resulted in sputum cultures converting to negative in a median of 60 days in 77% of 167 patients with MDR-TB.62

Treatment of patients coinfected with HIV. There is a role for incorporating HIV testing into TB control programs. It is important to identify those with HIV coinfection so that they can be appropriately treated with highly active antiretroviral therapy (HAART) and other care, including prophylactic therapy for Pneumocystis jiroveci pneumonia (PJP).15

Conversely, efforts to diagnose TB in patients coinfected with HIV need to be intensified because TB is more severe in these patients, the risk of extrapulmonary disease (with its worse prognosis) is greater, and TB is a major contributor to the morbidity and mortality associated with HIV infection.15 Another consider- ation is that HIV coinfected patients are more likely to transmit MDR-TB to others.63 Treating latent TB is important in HIV-infected patients because of the high risk of progression to active TB.64 Treatment regimens must avoid potential interactions with HAART. Rifabutin induces cytochrome P-450 (CYP) 3A enzymes less than rifampin does and is a better choice in HIV-positive patients who are receiving HAART.

In patients with MDR-TB, it is important to treat both TB and HIV infection and to take measures to avoid immune reconstitution inflammatory syndrome (IRIS).65,66 Patients coinfected with MDR M tuberculosis and HIV are at a high risk for death; therefore, those who have a CD4+ cell count less than 200/µL should begin HAART and trimethoprim/sulfamethoxazole to prevent PJP as soon as possible. In a patient with a CD4+ cell count between 200/µL and 350/µL, HAART should be delayed until the patient has received 8 weeks of antituberculosis therapy, to reduce the risk of IRIS.15 If IRIS develops and MDR-TB is a concern, corticosteroid therapy should be used cautiously until the results of drug susceptibility testing are known.15

Consider empirical therapy with second-line drugs, ensure adequate infection control, and monitor patients for adverse effects from both HAART and antituberculosis ther- apy.67 Thiacetazone is not recommended for patients coinfected with HIV.15 There are limited data on interactions between the second-line antituberculosis drugs and HAART. The enteric-coated form of didanosine should be used to allow proper oral fluoroquinolone absorption.

Ethionamide and protionamide may be metabolized by the CYP3A pathway and have the potential for numerous interactions with protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs). Clarithromycin is also metabolized through the CYP3A pathway and has multiple interactions with PIs and NNRTIs.15

Treatment of MDR-TB in pregnancy. All women of childbearing age who have MDR-TB should undergo pregnancy testing at presentation.68 Birth control is recommended for nonpregnant women of child-bearing age. MDR-TB poses significant risks to both mother and fetus, so pregnancy is not a contraindication to therapy.69

Gestational age and the severity of the MDR-TB should be carefully evaluated. Each case has to be evaluated individually, with consider- ation of the extent of disease, severity of illness, the timing of the pregnancy, and the patient’s wishes after being informed of the risks and benefits to her and the fetus.68 Consider that the teratogenic effects are greatest in the first trimester and, in some situations, it may be appropriate to postpone therapy until the second trimester.

All aminoglycosides carry the risk of ototoxicity, but capreomycin is the drug of choice in pregnancy if an injectable drug is required.68 Ethionamide should be avoided because of its potential for teratogenicity; it also can aggravate nausea and vomiting.68

Lactating mothers with DR-TB should receive full-course therapy. Drug concentrations are relatively low in breast milk, but formula feeding is usually recommended.68

Treatment of MDR-TB in children. There is little information about the use of second-line therapy in children with MDR-TB. In general, treatment is similar to that in adults. All drugs are given in dosages at the higher end of the recommendations, except ethambutol because of the difficulty of monitoring optic neuritis in children.68

Treatment of MDR-TB and XDR-TB in contacts. Active TB that develops in close contacts, including those living in the same household and those sharing the same indoor space (such as coworkers), of patients with MDR-TB will most likely be MDR-TB. While all TB contacts require surveillance, MDR-TB contacts should be a priority, and they require close follow-up for at least 2 years. Currently, there is no evidence to recommend the use of second-line drugs for preventive therapy.70

Contact investigation of XDR-TB cases should be considered an emergency because of the risks of morbidity and mortality.22,71-74 Symptomatic contacts should undergo sputum culture and drug susceptibility testing. Pending susceptibility results or in their absence, an empirical regimen can be started based on the drug susceptibility profile of the index case or based on the most common pattern seen in the community.22

Management of XDR-TB. Clinical outcomes for patients with XDR-TB are worse than outcomes for patients with MDR-TB.75 The limited responsiveness of XDR-TB to available antibiotics is associated with a mortality rate similar to the rate during the preantibiotic era.9,18 For these patients, confinement to an airborne infection isolation room and prompt initiation of effective therapy are essential.22,72-74 Infection control strategies require administrative, environmental, and personal respiratory protection controls.75

Contact tracing of these patients is an emergency. They should be regularly monitored for at least 2 years, with treatment initiated if they become ill.22 Unfortunately, there are no effective treatments for latent infection caused by XDR M tuberculosis. Among the major challenges is the need for laboratories to properly handle specimens and to perform the appropriate drug susceptibility testing when extensive drug resistance is suspected.

It is essential that all cases of MDR-TB and XDR-TB are reported to the public health agencies. Enhanced surveillance is necessary in groups at high risk for DR-TB, such as those who are incarcerated, socially marginalized, or foreign-born from areas where DR-TB is prevalent.64

Treatment recommendations parallel those for MDR-TB.51,53 If the disease is localized, surgical resection may be the best option. Treatment strategies should include any effective drugs, aiming for the use of 4 to 6 potentially effective drugs, for at least 18 months after sputum culture conversion. Unfortunately, many patients do not respond to treatment, and best supportive measures will be necessary in an isolation environment for the protection of others.76

Surgery for DR-TB. A variety of surgical procedures were developed for the management of TB during the first half of the 20th century. These included various degrees of lung resection; pleural procedures designed to collapse the lung, including pneumothorax, oleothorax, and plombage; phrenic nerve crush and disruption to paralyze the hemidiaphragm; and chest wall procedures, such as thoracoplasty, to collapse part or all of the more affected lung.

Surgical treatment virtually disappeared by the early 1960s after the introduction of effective antituberculosis drug therapy.76 The development of drug resistance led to a renaissance of surgical management. The rationale is to remove destroyed areas of lung that have high concentrations of M tuberculosis.77,78 Other indications for surgery include DR lung disease, cultures that fail to convert to negative despite adequate and prolonged therapy, and complications that do not respond to drug therapy (such as hemoptysis).79,80

Consideration of resection should be limited to patients with pulmonary TB that is sufficiently localized to allow removal of most of the radiologically abnormal lung yet leave the patient with adequate lung function.81 Patients should receive drug therapy for at least 3 months before surgery. Ideally, preoperative cultures will be negative. It is important that the drugs be sufficiently effective to allow healing of the bronchial stump. If the resection margin involves an area of active infection, there is a risk of dehiscence and bronchopleural fistula. Bilateral disease is not an absolute contraindication to surgery. Staged sequential bilateral resections are possible.

Features associated with a poorer surgical outcome include a BMI of less than 18.5 kg/m2, fluoroquinolone resistance, and cavitary lung disease extending beyond the field of resection.

Resections can be performed with reasonably low perioperative mortality even in patients with MDR-TB or XDR-TB.82 Complications associated with surgery are not uncommon and include respiratory failure, bronchopleural fistula, infection (including empyema), wound bleeding or dehiscence, and recurrent laryngeal nerve palsy. Complications may require thoracoplasty, myoplasty, omentoplasty, or muscle flap transposition to achieve healing.83 The National Jewish Center group in Denver reported better survival in patients with MDR-TB with the aggressive use of surgery and treatment with fluoroquinolones.84

A variety of unproven treatments have been considered, including direct intrabronchial and intrapleural instillation of antituberculosis medications, plombage, pneumoperitoneum, and pneumothorax. Parenteral and inhaled cytokine therapy with interferon-g has been tried, but no trials with this therapy in patients with TB have been reported.85

Patients at risk for failure of MDR-TB treatment. Therapy is likely to fail in patients who have not improved after 4 months of treatment; patients who show clinical, radiographic, or bacteriological progression during therapy; and those whose disease reappears after 4 months of treatment.86 It is essential that patients in whom MDR-TB therapy fails undergo a complete review of their treatment. This should include a treatment card review to confirm adherence, and the health care worker should verify that the patient took all medications as prescribed. The DOTS worker should be interviewed to ensure that he or she has not been manipulated by the patient and, if that is a concern, consider switching to another DOTS worker.86

The treatment regimen should be reviewed in relation to the patient’s medical history, his contacts, and his drug susceptibility test reports. The bacteriological data should be reviewed to rule out the possibility of laboratory error, such as a single positive culture report due to laboratory error, especially if subsequent reports are negative.

Other illnesses, such as chronic diarrhea, may reduce absorption of the antituberculosis drugs, or immunosuppression, such as that associated with HIV coinfection, may interfere with the clinical response.

Patients with MDR-TB in whom therapy fails should be considered for surgical resection if disease is localized and resection is not precluded by pulmonary function abnormalities or comorbidities. If a treatment change is required, the new regimen should include at least 4 effective drugs.86

Indications for suspending therapy. Although suspending therapy in patients with a life-threatening condition is unconventional and may appear unethical, it is appropriate in some patients with MDR-TB. Suspension of drug therapy should be considered if the patient continues to have a persistently smear- or culture-positive sputum after 8 to 10 months of therapy, continues to deteriorate clinically (usually defined as ongoing weight loss and respiratory insufficiency), or has radiological progression or radiological changes that are bilateral and too extensive to consider surgery, or if the organism displays high-grade drug resistance (including extensive drug resistance) without the option of adding at least 2 effective drugs.86 Continue supportive care after active treatment is suspended.


Consideration should be given to suspending therapy if it is futile, because continuing treatment will not benefit the patient, will expose the patient unnecessarily to the adverse effects of medication, and will increase the risk of XDR-TB.86 Patients in whom therapy is suspended should not be abandoned and will continue to require proper nutritional support, regular medical visits, ancillary medications for symptom and pain relief, and measures for dyspnea control. This may require hospitalization or hospice care, which may include end-of-life supportive measures. Preventive and infection control measures to obviate the spread of infection to others need to be continued.86

Since the early 1980s, MDR-TB and, in the past few years, XDR-TB have become global problems. Drug resistance has the potential to increase the mortality from TB-a disease that already causes the most deaths from infection worldwide. Despite the suggestion that the threat from DR-TB is limited, the WHO and world governments should invest in effective TB programs that provide medications free of charge in DOTS programs.87 These have been shown to reduce the prevalence of TB and DR-TB and the associated morbidity and mortality.88 Moreover, these programs are cost-effective.

Rapid drug susceptibility testing is essential and should be promoted worldwide through the supranational reference laboratories program to allow the rapid identification and treatment of MDR-TB and XDR-TB. All TB programs should include DOT, enhanced with minor financial incentives where necessary, and provide antituberculosis medications and health care free of charge.2

In general, MDR-TB regimens should use all effective first-line drugs, an injectable agent, a fluoroquinolone, and other second-line and third-line drugs, aiming for a minimum of 4 effective drugs.51,53 XDR-TB regimens are more problematic because they require greater use of the less effective second-line drugs.

Surgery should be considered for all patients with MDR-TB or XDR-TB who have localized disease.84 Appropriate supportive care in a facility with proper respiratory isolation provisions should be available for patients in whom MDR-TB and XDR-TB treatment fails.


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