Multidrug-resistant tuberculosis

MYCOBACTERIAL INFECTIONS

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MULTIDRUG-RESISTANT TUBERCULOSIS Barbara J. Seaworth, MD

Multidrug-resistant tuberculosis (TB), strains resistant to at least isoniazid and rifampin,66 make the global TB problem even more serious. Multidrug-resistant TB is difficult to treat; treatment requires drugs that are expensive, toxic, and less effective. Multidrug-resistant TB is a serious threat to global TB control. Inadequately treated patients become chronic carriers and spread multidrug-resistant TB to their families and communities. GLOBAL EXTENT AND IMPACT OF DRUG RESISTANCE The World Health Organization (WHO) and the International Union Against Tuberculosis and Lung Disease’s global projects on antituberculosis drug resistance surveillance identified multidrug-resistant disease on five continents and in 40 of the 44 countries surveyed (Fig. 1). The full extent of the multidrug-resistant TB problem is unknown. The spreadof multidrug-resistant TB as HIV infection is introduced into areas with an already high incidence of multidrug-resistant TB is an enormous threat.107 Nosocomial outbreaks of multidrug-resistant TB have been reported in the United States and elsewhere and have had dramatic impacts on global TB control efforts.11 The main commitment of the WHO is to Directly Observed Therapy Short Course (DOTS) therapy, which is an inexpensive but effective

From the Tuberculosis Elimination Division and Tuberculosis Education Center, Texas Center for Infectious Diseases, San Antonio, Texas

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74 Figure 1. Prevalence of combined multidrug-resistant tuberculosis in countries and regions surveyed between 1994 and 1999. The designations employed and the presentation of material on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city, or area of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines represent approximate borderlines for which there may not yet be full agreement.

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treatment program. Guided by the axiom that ‘‘you cannot cure multidrug resistant TB as fast as you can create it,’’41 prevention of drugresistant disease by effective treatment of new cases remains the main thrust of global programs.61 In countries with a low incidence of multidrug-resistant TB, the standard treatment and retreatment regimens proposed by WHO have been successful.57 In countries with a high rate of multidrug-resistant TB, these policies, although justified by some because of economic and social realities and lack of secondary drug supplies, often serve as death sentences to those with multidrug-resistant TB. Resistant strains have contributed to poor outcomes when standard WHO regimens, even when administered by DOTS, have been used.27, 47, 71 Such regimens actually may cause further drug resistance by augmenting or amplifying the original resistance pattern.42, 71, 134 No programs or drugs exist to treat multidrug-resistant TB or even drugsusceptible TB in many areas of the world.53 Patients are condemned to the natural history of the disease, leading to death in 50% of patients over 5 years. These patients and those who remain relatively healthy and become chronic carriers continue to be infectious and transmit disease in their communities. Strong voices are insisting that the health care community cannot afford to ignore multidrug-resistant disease.7, 43, 64 The success in Peru of multidrug-resistant TB treatment regimens, the ethical dilemma posed by allowing people to die when successful treatment exists, the ability of multidrug-resistant TB to be transmitted within communities, and the growing recognition that a border does not protect against the importation of disease are influencing policy makers, international aid organizations and financiers to invest in the treatment of multidrug-resistant TB patients. Some worry that the time for action is running out.53, 65, 95, 114 In 1997, WHO recognized the need to address the multidrug-resistant TB epidemic and endorsed DOTS Plus treatment regimens for multidrugresistant TB.43, 131 Treatment of multidrug-resistant TB patients with DOTS Plus regimens is recommended only in those countries with wellfunctioning TB programs managing successful DOTS plus regimens.74

DRUG RESISTANCE IN THE UNITED STATES Multidrug-resistant TB threatens not only global TB control efforts but also the ability to eliminate TB in the United States. Although TB cases in both foreign-born and US-born residents are decreasing steadily, the rate of decline is less in the foreign-born. In 1998, foreign-born patients accounted for 42% of TB cases in the United States.121 This same population has a higher incidence of drug resistance and often reflects the drug susceptibility pattern prevalent in their countries of origin. Surveillance data from 1993 to 1998 show that approximately 66% of

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cases occurred in persons originally from Mexico, the Philippines, Vietnam, India, China, Haiti, and South Korea, all areas with high rates of drug resistance. Moore et al reviewed surveillance data reported to the Centers for Disease Control and Prevention (CDC) from 1993 to 1996 on trends in drug-resistant TB. They noted that when the duration of residence in the United States was 1 year or less, overall, 3.8% of patients from Mexico, 2.1% from the Philippines, and 2.3% from Vietnam had multidrug-resistant TB. Only 1.3% or less had multidrug-resistant TB when the duration of US residence was 1 year or longer.88 A history of prior treatment significantly increased the chance of multidrug-resistant TB in both populations (10.6% of foreign-born and 3.8% of US-born). The rates ranged from 5.4% of those born in India to 14.4% of those born in South Korea.88 There are more than 200 million legal northbound border crossings along the US-Mexico border each year, and a large number of undocumented individuals also enter the country.38 Large numbers of persons have migrated from south and central Mexico and Central and South America to US border counties and northern Mexican states. This has contributed to higher rates of TB and drug-resistant disease in these areas than in the states or countries as a whole79 (Fig. 2). Migration of farm workers across the US-Mexico border has been associated with identification of multidrug-resistant TB cases along all of the migrant streams (Fig. 3). Programs such as the Migrant Clinicians Network through TB Net and CURE TB help to track and provide migrant farm

Figure 2. Tuberculosis (TB) rates in US states and counties bordering Mexico in 1998. Only border counties with ⱖ10 TB cases/100,000 were included.

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Figure 3. Migration patterns of migrant farm workers. Restricted circuit (curved arrows): Many people travel throughout a season within a relatively small geographic area. Examples of this include the Central Valley in California, chili harvesting in the El Paso/Las Cruces/ Cuidad Juarez area, and migration that occurs in Nebraska along Interstate 80. Point-topoint: Another group of people will travel to the same place or series of places along a route during the course of a season. These people tend to live in homebase areas in Florida, Texas, Mexico, Puerto Rico, or California and travel for part of the year working in agriculture. The routes (dashed arrows) show just a few of the many regular routes that people travel during the season. Nomadic (solid lines): Still others travel away from home for a period of years working from farm to farm and crop to crop. Some of these people may eventually settle in an area to which they have migrated, while others eventually return to their homebase areas.

workers with consistent treatment and followups for a variety of medical problems.79 The movement of drug-resistant patients across the USMexican border impacts directly on the ability of states to control TB. Patients commonly have extensive families and many close contacts on both sides of the border. Efforts at collaboration in contact evaluation, especially household contacts involving young children and those likely to have the disease, have become more successful in recent years. This has been made possible by the CDC-supported Binational TB Projects and the cooperation of individual local health care providers along the

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border (Personal communication, Dr. Richard Wing, Medical Director, Grupo Sin Fronteras, Binational Tuberculosis Project).131 Multidrug-resistant TB also is acquired and spread within US borders. More than 300 cases of multidrug-resistant TB that primarily involved US residents were linked to the HIV epidemic in New York City. The cases were associated with high mortality rates in persons with HIV and involved the W strain. The W strain is usually resistant to seven antituberculosis agents.45 Cases caused by the multidrug-resistant TB W strain have been documented outside New York, both in other US cities and in other countries.10 Successful containment was achieved following an enhanced recognition of possible drug resistance, expedited susceptibility testing, extensive infection control measures, expanded use of DOTS and empiric use of six- and seven-drug regimens when multidrugresistant TB was suspected. The incidence of multidrug-resistant TB has declined significantly in New York in response to these measures, but the full extent of the consequences of these outbreaks is not known. Spread of multidrug-resistant TB has been detected in at least 42 states and the District of Columbia.88 Cases of latent TB infection (LTBI), which resulted from transmission during this period cannot be identified as having been caused by multidrug-resistant TB. They will not not be prevented by routine treatment with isoniazid (INH) and will only be detected when the infections break down and disease occurs. The implications and impact of outbreaks of multidrug-resistant TB, which occurred in the early 1990s, will be faced for years to come.45

DEFINITIONS Multidrug-resistant TB is caused by strains that are resistant to INH and rifampin,66 the very drugs essential to short-course treatment regimens. Acquired resistance to antituberculosis drugs occurs during selective multiplication of drug-resistant mycobacteria that have emerged spontaneously and flourished as a result of inadequate chemotherapy. Patients who develop drug resistance after an unsuccessful course of treatment were once categorized as having acquired drug resistance. Those found to have drug-resistant disease and no prior history of TB treatment were categorized as having primary drug resistance. It is difficult to obtain an accurate history of prior treatment. A patient in relapse may actually have initial, undetected, primary drug resistance, rather than acquired drug resistance. New terminology adopted by WHO recognizes the inherent difficulty in identifying resistance as acquired caused by past treatment and now uses the terms ’’resistance among new cases’’ and ’’resistance among previously treated cases.’’ The term ‘‘new cases’’ refers to TB patients who have never received antituberculosis drugs or have received them for no more than 1 month. ‘‘Previously treated cases’’ are those patients who have received at least 1 month of antituberculosis therapy.39

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MECHANISMS OF DRUG RESISTANCE Resistance to streptomycin was detected during the early treatment trials.40 In vitro studies demonstrated that depending on the antibiotic, resistant mutants arise spontaneously at a rate of 103 to 108 organisms. Mutations are much more likely with weak drugs such as thiacetazone, ethionamide, capreomycin, and cycloserine (103), intermediate for drugs such as isoniazid, streptomycin, ethambutol, kanamycin, and para-amino salicylic acid (106), and lowest for rifampin (108).5 Resistance most likely occurs within cavitary lesions containing large numbers of (108 to 10 9) organisms. Mutations are not linked and do not occur in blocks.14 The probability of multidrug resistance developing by chance alone is the product of the individual mutation rates. The probability of an isolate developing a spontaneous mutation conferring resistance to both isoniazid and rifampin, multidrug-resistant TB, is the product of the probability of resistance to isoniazid and the probability of resistance to rifampin (106 times 108 or one in 1014 ). The presence of an organism spontaneously resistant to both isoniazid and rifampin is unlikely even in cavitary lesions, and would be virtually impossible in areas of infiltration or granulomas, which contain only 102 to 104 bacilli.14 It is the exposure of a population of mycobacteria to a single antibiotic, monotherapy, which allows small numbers of resistant mutant organisms to multiply selectively, while the vast susceptible population is killed. Susceptible organisms in the population are eliminated, allowing the surviving drug resistant organisms to make up the entire population eventually. Monotherapy occurs when a single drug is prescribed or when only a single drug is taken, although multiple drugs are prescribed. Inadvertent monotherapy also occurs when only one drug in a combination has activity against a particular population of mycobacteria. This may happen when drug susceptibility studies are not done, the results of such studies are significantly delayed, or when standard four-drug treatment regimens are not prescribed. The sequential exposure of a population to various drugs, one at a time or in inadequate treatment regimens, may select eventually for multidrug resistant disease. During a treatment course, the patient may improve clinically and even convert sputum cultures to negative. If the resistant mycobacteria multiply, the patient will relapse with a recurrence of symptoms and positive cultures. This phenomenon was recognized and referred to by older phthisociologists as the ’’the fall and the rise’’ of TB.31 They knew that without a strong treatment regimen an initial clinical response did not assure a successful outcome. This premise forms the basis for today’s insistence that standard, well-devised regimens containing at least three drugs to which the organism is likely to be susceptible must be given and that inadequate regimens be changed even when physicians report that their patients are ‘‘doing well.’’ It is one instance when an initial response does not justify continuing a treatment plan.

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RECOGNIZING PATIENTS AT RISK FOR DRUGRESISTANT TUBERCULOSIS Any patient with signs or symptoms of TB who has a history of treatment failure or relapse has an increased risk of drug-resistant disease. Drug resistance is particularly more likely if the individual was not on treatment with either DOTS or a combination drug regimen. Those who are not able to provide details such as the names of medications, duration of therapy, or even the color and number of different tablets should be suspected of poor adherence to therapy and considered at risk for resistant disease. Patients treated in areas where drug supplies are inadequate and TB programs are weak are also at increased risk for drug resistance.53 Clinical suspicion of drug resistance should occur when review of treatment records identifies an inadequate regimen, serious errors in therapy, evidence of noncompliance, or intermittent medication ingestion. Failure of the patient to show at least a partial clinical response and persistence of fever after several weeks of a standard four-drug treatment regimen,108 failure to convert the sputum culture to negative within 2 months,21, 25, 70 and worsening radiographic disease after several weeks of therapy indicate possible drug resistance.83 Drug resistance in the absence of prior therapy is associated with a history of residence in a country with a high incidence of drug-resistant TB. The risk is greatest during the first few years after immigration and then decreases to that of the general population.86 Those who frequently return to their countries of origin or other high-incidence countries remain at increased risk.129 Households with guests from these countries who stay for extended visits are also more likely to be at risk for drugresistant disease. Drug resistance is more common in individuals who have resided in institutions lacking adequate infection control measures and serving populations harboring drug-resistant TB. Convergence of immunocompromised patients and persons with infectious TB led to the large nosocomial outbreaks of multidrug-resistant TB.45 Transmission of drugresistant disease has been associated with hospitals,18, 45 correctional facilities,19, 20 chronic care facilities, halfway houses, drug treatment facilities,28 residential facilities for persons with HIV, and homeless shelters.10, 88, 93, 94 Health care workers and staffs of these facilities are also at risk and have been diagnosed with the identical strains of drug-resistant TB as their clients or patients.45, 107 Persons infected in these places may infect their families and communities. Community transmission of multidrug-resistant TB has been documented.127 A study of six adult–child pairs confirmed transmission of multidrug-resistant TB in five of the six pairs by restriction fragment length polymorphism (RFLP) analysis.109 Rifampin-resistant disease was reported in children in New York City in the 1980s, suggesting primary transmission of drug-resistant TB.24 Combined with the loss of a viable TB program and the spread of the HIV epidemic, this phenomenon

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foreshadowed the city’s multidrug-resistant TB outbreak. Many individuals were linked epidemiologically to earlier and later drug-resistant patients.46 Transmission of multidrug-resistant TB was shown by RFLP analysis in 64% of patients in two neighboring communities in Cape Town, South Africa. None of the individuals studied were HIV-positive. Clustering was detected in 23 of 32 (72%) patients with histories of prior drug therapy and in 11 of 13 (85%) of those without treatment histories. This suggests significant transmission leading to new, previously untreated cases of multidrug-resistant TB.126

IMPACT OF MULTIDRUG-RESISTANT TUBERCULOSIS ON TREATMENT OUTCOMES Treatment outcomes among patients with multidrug-resistant TB vary widely. Response is related to the extent of pulmonary involvement, amount of fibrosis and lung destruction, the number of bactericidal drugs to which the patient remains susceptible, the resources of the community to deal with difficult TB patients, and the patient’s ability to tolerate and comply with long-term medical treatment. Early series reported treatment success rates at less than 60%,51 while intensive medical and surgical therapies have enabled ‘‘cure’’ in up to 95% of selected groups.45, 48, 67, 98, 120

ERRORS IN THERAPY Treatment errors may have serious consequences for patients. Inadequate treatment of drug susceptible disease can lead to multidrugresistant TB. Mahmoudi and Iseman found management errors in 28 of 35 (80%) multidrug-resistant TB patients admitted to National Jewish Center for Immunology and Respiratory Medicine between 1989 and 1990. An average of 3.93 errors per patient was noted. The most frequent errors included the addition of a single drug to a failing treatment regimen, inadequate primary treatment regimens, failure to recognize resistance, failure to recognize or ensure compliance, and inappropriate isoniazid preventive treatment. Treatment errors have been observed more often in patients cared for by private providers.73 Similar errors were reported by Byrd et al in 1977.13 A recent report in New Jersey described treatment errors by private practitioners including respiratory physicians. Nearly 50% of patients cared for outside the TB control program received regimens that deviated from the CDC and American Thoracic Society’s (ATS) guidelines (i.e., fewer than four drugs despite a local level of isoniazid resistance above 4%).78

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MANAGEMENT OF DRUG-RESISTANT TUBERCULOSIS Planning and Initiating Treatment for MultidrugResistant Tuberculosis An extensive evaluation of patients and their Mycobacterium tuberculosis isolates should be initiated before starting treatment when multidrug-resistant TB is documented or strongly suspected. This process is done most easily during an initial period of hospitalization and with the assistance of the health department and state or local experts in the care of drug-resistant TB.11, 113 These tasks are time-consuming and often involve the need for repeated interviews, requests for old clinical and TB program records, laboratory reports, and radiographs.105 All past treatment records and contacts with infectious TB patients possibly harboring drug-resistant organisms should be reviewed. Previous culture and susceptibility reports should be reviewed and correlated with treatment regimens and clinical outcomes. Consultation and coordination with the state TB laboratory usually is done by public health officials or the TB expert consultant. Baseline laboratory studies including a complete blood count, liver function levels, 24-hour creatinine clearance, and repeat chest radiographs, and often CT scans of the chest should be done and compared with earlier evaluations. Baseline assessment of the patient’s vision and hearing should be completed before the start of therapy. Evaluation of the patient’s risk factors, substance abuse problems, and coexisting medical and social problems, especially those with the potential to impact the ability to comply with therapy negatively, should be initiated. Addressing those problems that are remedial and providing substance abuse counseling will help a patient comply with and complete treatment. Educating patients extensively about their disease, modes of transmission, explaining the need for information to complete contact investigations, and discussing the duration of treatment, expected side effects, and possible lasting toxicity are all important. Prior to the initiation of therapy, patients should indicate a willingness to comply with the regimen and understand the consequences for failure to adhere to treatment. In the United States, the cornerstone for the detection and treatment of multidrug-resistant TB is drug susceptibility testing and crafting of individual treatment regimens based on these results.66 Three first morning specimens on 3 separate days should be submitted for culture and sensitivity levels. When drug resistance is found, susceptibility studies should be requested for the entire spectrum of agents that may be used in the treatment regimen. These should be requested when the initial report of resistance to isoniazid and rifampin is received. The potential loss of time, exposure of patients to drugs to which they are resistant, and initiation of inadequate retreatment regimens justify the additional expense. Conflicting reports of resistance can be received. This can be caused by sampling of various populations of bacilli, variations in

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laboratory techniques, or laboratory error.8, 90 A reference laboratory should help to resolve these differences. It is usually best to assume that any reported drug resistance indicates at least a small population of organisms with resistance to a given drug. Other investigators51 and the author strongly recommend that initiation of treatment for multidrug-resistant TB be undertaken in the hospital and in consultation with an expert in the management of multidrugresistant TB. In addition to simplifying the evaluation, an initial period of hospitalization removes an infectious patient from the community, interrupts disease transmission, lessens toxicity, allows early management of adverse reactions, and facilitates laboratory monitoring. To minimize toxicity, medications most likely to cause gastrointestinal upset are taken before bedtime. Interventions such as antiemetics or adjusting dosing regimens should be undertaken as soon as a problem is identified. These maneuvers help to prevent psychological intolerance to a medication. The patient also can benefit by having nutritional needs and other medical problems addressed. When hospitalization is not possible, an individual health care worker must take the responsibility for ensuring all the essential components involved in evaluation, treatment, and monitoring of the patient are addressed and completed. This person often will be a public health nurse. Directly observed therapy is essential for all patients with multidrug-resistant TB.16, 64 Treatment is difficult and prolonged, making even the most reliable of patients unlikely to fully comply. Many patients have acquired their disease because of noncompliance in the past. Treatment is likely to be a patient’s last chance for cure and should be approached as such. Problems that offer obstacles to treatment such as substance abuse and psychiatric illness may be overcome with DOTS. Dosing schedules usually need to be twice daily, placing a significant strain on resources. Despite the difficulties, the author feels it is imperative to give all medications by DOTS at least 5 days per week. Many programs allow self-medication over the weekend, as intermittent dosing schedules for multidrug-resistant TB do not exist nor do the resources for weekend DOTS delivery. Planning a Treatment Regimen Unless patients are HIV infected or immunosuppressed, the author prefers to wait until the results of susceptibility tests are known before initiating treatment for multidrug-resistant TB. Usually patients with a history of previous unsuccessful treatment of TB are chronically ill and have been so for an extended time. The main risk is usually continued transmission in the community while treatment is delayed. This can be offset by hospitalization, but economics usually do not allow such an approach unless specifically designed hospitals for such patients exist. When small children or immunocompromised persons do not live in the home of an inadequately treated, but stable, multidrug-resistant TB

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patient, a reasonable approach is to allow the person to remain on home isolation while susceptibilities are done and medical records reviewed. Other physicians and the author prefer to stop the current treatment66 to prevent further resistance. All HIV-infected patients with suspected multidrug-resistant TB must be recognized quickly and, following an assessment of the most likely susceptibility pattern, started on aggressive multidrug treatment. Mortality rates have been extraordinarily high in HIV-infected persons with multidrug-resistant TB who have delays in therapy. When multidrug-resistant TB is diagnosed early and treated appropriately, patients respond, and treatment prolongs their survival.45, 97, 107 Other immunosuppressed persons and those with severe respiratory symptoms, significant systemic toxicity, or hemoptysis require early treatment. Because it is imperative to initiate treatment because of HIV infection, immunosuppression, a deteriorating medical situation or serious infection control concerns, the author recommends a six- or seven-drug regimen. An adequate regimen must be designed to prevent the development of any additional drug resistance. Most, if not all of the remaining medications to which the person might be susceptible, should be prescribed. The empiric regimen should include enough drugs that an adequate regimen will remain even if several need to be stopped. When the results of susceptibility studies are known, the regimen can adjusted and the most toxic or weakest drugs can be withdrawn. Whenever possible, a regimen should be devised using drugs that have proven susceptibility and that have not been part of a previous unsuccessful treatment plan. Previous treatment with a drug has been associated with a reduced clinical response despite apparent ‘‘susceptibility’’ in vitro.29, 51 When retreatment regimens can be fashioned without the use of such drugs, they are usually avoided. If, despite earlier unsuccessful use, susceptibility persists in the laboratory, consideration to using the drug in a regimen can be given. This especially would be the case when limited agents for treatment remain or a drug such as pyrazinamide retains susceptibility. Some experts include pyrazinamide but do not ‘‘count’’ it. They would attempt to have, in addition, an adequate number of ‘‘definite’’ drugs. Too often, the reality is that all definite drugs and possibly effective drugs must be used to fashion a reasonable treatment plan.

Suggested Treatment Regimens Whenever possible, treatment should begin with six new drugs with proven susceptibility. Treatment should include at least three new drugs, two of which should be bactericidal drugs. Regimens recommended for multidrug-resistant TB usually include daily or 5 times weekly dosing of an aminoglycoside or capreomycin for at least the first 4 to 6 months.

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Others and the author then continue it 2 to 3 times weekly to complete 6 to 12 months of treatment after cultures convert to negative.51, 120 Several anecdotal cases of relapse associated with early discontinuation of the aminoglycoside have convinced the author to attempt therapy for 12 months after the culture is documented as negative. When treatment options are limited or disease is extremely severe, capreomycin can be given, along with an aminoglycoside. Some patients can tolerate this regimen with minimum toxicity for periods of up to a year. Four to five oral drugs should be given along with the aminoglycoside or capreomycin, and these agents should be continued for 24 months after the sputum culture converts to negative. The keystone of the oral regimen is a fluoroquinolone, which is given whenever possible and continued throughout the treatment course.45, 48, 68, 120 Resistance to the quinolones is uncommon but has been reported and may occur within a month of therapy.119 When susceptibility to first-line drugs exists, these usually are included in the planned treatment. Susceptibility to rifabutin will be present in 20% or more of rifampin-resistant patients.45 Rifabutin is as effective as rifampin in the treatment of drug-susceptible TB,52, 85 but data on its use in multidrugresistant TB are controversial and limited. When susceptibility to ethambutol and or pyrazinamide remains, these drugs may be included in the regimen if they have not been part of a previously failing regimen or when only a limited number of other agents are available. Ethambutol is initiated at a dose of 25 mg/kg until cultures convert and then decreased to 15 mg/kg. Pyrazinamide can be useful initially and as part of a continuation regimen for multidrug-resistant TB.59, 87 If possible, additional support drugs are included to bring the total number of drugs in the regimen to six. Ethionamide and clofazimine are weakly bactericidal and generally preferred over cycloserine and para-aminosalicylic acid (PAS). Individual drug selection is made based on the underlying medical condition of the patient and the presumed ability to tolerate a given drug. For instance, a person with a history of depression or mania would be unlikely to tolerate cycloserine, so another drug should be chosen. Careful attention also must be paid to renal and hepatic function during the selection of drug regimens; doses should be adjusted as necessary. Significant renal or hepatic dysfunction may limit the use of a medication. Treatment must be daily for most medications; there are no approved intermittent regimens for multidrug-resistant TB. A treatment regimen that consists of at least five drugs, includes both a fluoroquinolone and an aminoglycoside, and is continued for an adequate duration should have a high degree of success.23, 31, 45, 98 Iseman et al commonly include resectional surgery as part of the treatment plan and credit surgical intervention with improved outcomes. The other major change in their recent series is the near routine addition of a quinolone.68, 120 Farmer et al in Peru report good results using an individually tailored regimen based on drug susceptibilities. Their group also includes a quinolone and an aminoglycoside.43

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SELECTED SECOND-LINE ANTITUBERCULOSIS DRUGS Fluoroquinolones Considerable experience with the long-term efficacy and safety has been collected for the fluoroquinolones ciprofloxacin, ofloxacin, and levofloxacin.9, 68, 77, 99 These drugs are active against extracellular rapidly multiplying bacteria and intracellular nonmultiplying bacteria.49 The fluoroquinolones penetrate well into tissues, and their concentrations in tissue and body fluids are higher than or similar to serum concentrations.2, 76, 80 They are concentrated in respiratory tract tissues, fluids, and alveolar macrophages where they may reach levels more than five times those obtained in serum.49 The time to peak activity is about 2 hours and the half-life is long (5 to 8 hours for levofloxacin). This, combined with a significant presumed postantibiotic effect, allows once daily dosing for multidrug-resistant TB.80, 99 The initial experience with the use of fluoroquinolones was with ciprofloxacin and ofloxacin. Both have been associated with good outcomes in the treatment of drug susceptible disease,2, 72 and drug-resistant TB.82, 84, 97, 111 Levofloxacin is a pure L-enantiomer of ofloxacin, which is a racemic mixture. This property effectively doubles the antimicrobial potency of ofloxacin, because only the L-enantiomer form has antibacterial activity.128 Levofloxacin is highly bactericidal with minimal inhibitory concentrations (MIC) less than those of ciprofloxacin and ofloxacin.49, 102, 122 Because of its safety and activity, it is becoming the fluoroquinolone of choice, even though clinical studies of levofloxacin for the treatment of TB have not been done. Newer quinolones such as moxifloxacin have increased bactericidal activity and may offer new treatment benefits.117, 122 The therapeutic benefits of fluoroquinolones are related to the peak serum level and MIC. A trial of low-dose ofloxacin in combination with a standard retreatment regimen at 400 mg daily in multidrug-resistant TB was less effective (64% success rate) than a follow-up study using 600 mg daily (78% success rate). No relapses were seen in the high-dose group. Relapses were limited to 11% in the low-dose regimen. All relapses occurred early and were in those patients who had isolates resistant to ofloxacin at greater than 1.5 ␮g/mL prior to therapy. Resistance develops as a two-step process, and higher serum levels protect against selection of mutants.37 Resistance to fluoroquinolones develops rapidly when they are used as monotherapy.119 These drugs should always be protected by being given in combination with several other active agents.2 Rifabutin A small percentage of multidrug-resistant TB isolates retain sensitivity to rifabutin. Rifabutin is bactericidal. The MIC of rifabutin in multi-

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drug-resistant TB is regarded as susceptible if it is less than or equal to 2 ␮g. Although peak serum levels are less than one, the drug has excellent tissue penetration and activity, and tissue levels are significantly higher than serum levels. It is well concentrated in the lungs, where tissue levels are 5 to 10 times higher than in plasma.96 Rifabutin is used to replace rifampin in drug regimens for persons with HIV to avoid the drug interactions with protease inhibitors. Outcomes are similar to those patients treated with rifampin. The response to rifabutin in patients with multidrug-resistant TB is unclear. Most studies have not been able to select a patient group for reliable comparison of results. Some studies do not separate outcomes in patients with initial susceptibility to rifabutin from those with resistance.44, 81 A study of 11 patients with multidrug-resistant TB treated with rifabutin and other drugs noted: ‘‘Two patients had rifabutin-susceptible strains on admission to the study; their temporary responses were among the best and were associated with the emergence of rifabutin resistance, suggesting that rifabutin may have contributed to their response.’’60 When laboratory susceptibility is documented, rifabutin is included at a dose of 450 mg daily, and the author aims for a level at the higher end of the therapeutic range.

High-Dose Isoniazid The use of high-dose isoniazid, 1200 to 1500 mg three times weekly or 1000 to 1500 mg daily in the treatment of multidrug-resistant TB, is recommended by some physicians. A small study compared 50 retreatment patients given 1200 mg of isoniazid three times weekly with 50 receiving the standard 900 mg dose and found a similar incidence of mild side effects and no serious adverse events in either group.101 Although the numbers were too small to be significant, they noted a significant improvement in weight and a trend toward improved sputum conversion in the high-dose isoniazid group. Treatment outcome with high-dose isoniazid (1000 to 1500 mg daily), along with ethionamide and pyrazinamide was significantly better than the same regimen without the isoniazid in isoniazid-resistant patients.100 Moulding concluded that high-dose isoniazid may be most helpful in those patients who have low-level isoniazid resistance or who may have subpopulations of mycobacteria that remain susceptible. He suggested that those patients in developing countries may benefit the most, because isoniazid is inexpensive.90 Studies in a murine model lend support for use of high-dose isoniazid as combination therapy in patients with low-level resistance of 0.2 up to 5 ␮g/mL. Those patients with high-level resistance or who have had multiple treatment failures with an isoniazid-containing regimen would be unlikely to benefit from isoniazid, even at high doses.34, 45

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NEW OR ALTERNATIVE TREATMENT MODALITIES No new class of antituberculosis drug has been introduced since the development of rifampin and its release in the early 1970s. Rifapentine, a related compound with a similar spectrum but longer duration of activity, was approved for treatment of TB in 1998.4 Drugs without specific US Food and Drug Administration (FDA) approval often are used for multidrug-resistant TB. Amoxicillin/clavulanate has been used in several reports for treatment of multidrug-resistant TB. It is difficult to ascribe any direct benefit to this particular drug, however.22, 91, 133 It is active in vivo against multidrug-resistant TB. A recent study evaluating bactericidal killing by quantitative sputum culture suggested efficacy similar to other first-line drugs other than isoniazid, which was much more active. Most of the effect was present in the first 3 days of treatment and leveled off considerably at 1 week. The activity of the drug was related closely to dosing. A dose of 1000/250 mg three times daily was effective, but a dose of 500/125 mg three times daily was not. Another potential limit is that the drug does not penetrate and kill bacteria within macrophages. This is consistent with the early effect, which would allow killing of the large extracellular population. The role of amoxicillin-clavulanate remains unclear.69 Inhaled aminoglycosides have shown some promise in refractory cases, and the direct delivery to the pulmonary site increases local drug concentration and nearly eliminates toxicity. Seven of 12 patients with multidrug-resistant TB who were persistently smear and culture positive on therapy had conversion of the smear to negative, indicating a possible benefit as adjunctive therapy. Adverse events were limited to airway irritability.106 A new class of drugs, the oxazolidinones, the first of which is currently marketed as linezolid, has been introduced for the treatment of resistant gram-positive infections. Clinical studies in M. tuberculosis have not been done, but laboratory and murine data show some promise.6, 33 The nitroimidazoles are structurally similar to the antibiotic metronidazole, and a new drug in this class has been identified that possesses marked antituberculosis activity. Laboratory and murine studies found it to be highly bactericidal against M. tuberculosis and active against growing and stationary phase organisms.5, 36 Murine and guinea pig studies have shown activity similar to isoniazid at 25 mg/kg/day.118 Although metronidazole has been used for years, clinical trials on these new drugs are still pending, and unsuspected toxicity could occur. Both these drugs have shown activity against multidrug-resistant TB. The potential to use these two new highly active drugs along with a new quinolone in the future offers some hope to those suffering with multidrug-resistant TB. Systemic gamma interferon given to patients with severe disseminated infections caused by nontuberculous mycobacteria (NTM) resulted in symptomatic and clinical improvement in seven patients.58 The mecha-

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nism for interferon’s activity is most likely increased inhibition of mycobacterial growth by alveolar macrophages through enhanced production of reactive nitrogen species. An open-label trial of aerosol interferon gamma three times weekly for 1 month was given to five patients with multidrug-resistant TB refractory to treatment despite good adherence. Interferon was tolerated well, and sputum smears became negative. Time to a positive culture increased, and cavitary size was reduced in all patients. Cultures, however, continued to be positive, and all patients relapsed once treatment with interferon was discontinued.26 Interferon offers hope as an adjuvant therapy, and it is likely that further immunemodulating treatments will become available. Long-term treatment probably will be needed in addition to medical therapy. MONITORING AND MANAGING MEDICATION TOXICITY Treatment regimens for multidrug-resistant TB include drugs with significant toxicity (Table 1). Each patient should be warned to expect some adverse effects. The author routinely tells patients ‘‘the initial treatment is often worse than the disease.’’ The author reassures and encourages patients that once they can get through the treatment, they will get well and resume normal lives. The author commiserates with them, helps celebrate significant milestones in treatment, and congratulates them on the ability to take medications. It is the author’s experience that toxicity nearly always becomes tolerable and less severe as treatment progresses. The exception is auditory or vestibular toxicity, which usually progresses with continued treatment, is irreversible, and related to the total dose. An increase in the dosing interval can slow hearing loss and allow continuation of treatment. Vestibular toxicity necessitates discontinuation of the aminoglycoside or capreomycin. It is helpful to evaluate complaints of dizziness or ringing in the ears before attributing them to the aminoglycoside or capreomycin. The symptoms occasionally can result from cycloserine or the fluoroquinolone. A symptom screen should be done with each dose by those administering DOTS; any complaints should be noted and discussed with providers. Specific complaints related to signs or symptoms of hepatitis, behavioral changes including frank psychosis and depression (cycloserine), tendonitis (quinolones), and visual problems or eye pain should be addressed and an assessment of the need for medication changes made. Medications should be continued whenever possible. Replacement medications are usually not available, and discontinuation of a medication will impact on the effectiveness of most treatment regimens. An effort to identify potentially toxic drug levels, offer symptomatic treatment, or change dosing schedules usually should be attempted before discontinuing a medication.51 Significant elevation of liver enzymes, vestibular toxicity, acute renal failure,51 vision loss or uveitis, acute tendonitis or evidence of tendon rupture, seizures, psychosis, and serious depression require discontinuation of the offending medication in most situations.

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Table 1. CHARACTERISTICS OF SECOND-LINE DRUGS FOR MULTIDRUG-RESISTANT TUBERCULOSIS

Drug Streptomycin

Bactericidal

Minimum Inhibitory Concentration (MIC) (␮g/ml)

Serum Level

Yes

0.25 to 2.0

35 to 45

Dosing

Remarks

15 mg/kg/day 5 to 7 days/week

15 mg to 1 kg/day 5 to 7 days/week 20 to 25 mg/kg 2 to 3 days/week 15 mg/kg/day 5 to 7 days/week

Vestibular screen. Baseline audiogram Monitor creatine. Adjust dose and/or interval for renal insufficiency.

Amikacin

Yes

0.5 to 1.0

35 to 45

Capreomycin

Yes

1.25 to 2.5

35 to 45

Ciprofloxacin

Yes

0.5 to 2.0

4 to 6

750 to 1000 once daily

Poor central nervous system penetration. Adjust dose for creat cl ⬍50. May increase LFTs.

Ofloxacin

Yes

0.5 to 2.0

8 to 12

800 to 1200 once daily

L & D isomer (D-inactive)

Side Effects Class effects: Lichenoid eruptions, renal toxicity, giddiness, perioral numbness, hypersensitivity, vestibular toxicity/ ototoxicity (irreversible)6, 12, 50, 51, 55

Pain at injection site

Oxotoxicity—auditory vestibular, hypokalemia, hypocalcemia, hypomagnesemia, eosinophilia12, 50, 51 Class effect: Gastrointestinal (GI) upset, dizziness, hepatitis, hypersensitivity, photosensitivity, headaches, tendinitis, tendon rupture, insomnia, psychosis, agitation, depression, paranoia, seizures, thrush Sucraltate, antacids with Al, Mg, CaSo4 or FeSo4 inhibit absorption as may enteral supplements3, 9, 62, 75, 77, 80, 99, 104, 123, 128

Levofloxacin

Yes

0.5 to 1.0

8 to 12

Rifabutin

Yes

⬎2.0

0.3 to 0.9

Ethionamide

Weak

0.3 to 1.2

1 to 5

Para-aminosalicylate

No

8.0

500 to 1000 daily (usual 750) 450 to 600 mg daily

L & D isomer—All active drug Extensive drug interactions: Decreased white blood count, P-450 induction (less than decreased platelet count, rifampin) decrease levels arthralgia, renal of: protease inhibitors, impairment, methadone, oral hyperpigmentation, uveitis, contraceptives, diabetic discoloration of body medications, fluconazole, fluids, flushing, erythemia and others: see PDR.* of head and trunk, GI Concentrates in upset, hepatitis, ageusia52, 54, 56, 87, 89, 92 macrophages.

250 mg 2 or 3 times daily or 250 mg am/500 hs

Increase dose gradually, monitor liver function/ thyroid function. Increases effect of cycloserine

20 to 60 (6 hr) 4 gm 2 or 3 times daily

Peripheral neuropathy, nausea, vomiting, abdominal pain, hypothyroidism, salivation, metallic taste, hepatitis, giddiness, headache, hypersensitivity, alopecia, gyneocomastia, hypotension, impotence, mental disturbance, menstrual irregularity, hypoglycemia, photosensitivity3, 50, 51, 63, 116 Diarrhea improves with GI upset, diarrhea (self time; increase dose limiting), hypothyroidism, gradually, mix with acidic lichenoid eruptions, juice or apple sauce, hypokalemia, hepatitis, avoid diphenhydramine thrombocytopenia, increased acidosis in patient with renal failure50, 51, 55, 63, 116

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Table continued on following page

92 Table 1. CHARACTERISTICS OF SECOND-LINE DRUGS FOR MULTIDRUG-RESISTANT TUBERCULOSIS Continued

Bactericidal

Minimum Inhibitory Concentration (MIC) (␮g/ml)

Serum Level

Clofazamine

Weak

0.12

0.5 to 2.0

300 mg daily  2 mo then 100 mg daily

Skin problems limited by sunscreen, lubricants helpful

Cycloserine

No

N/A†

20 to 35

250 mg 2 times daily or 250 mg am/500 hs

Avoid in patients with Lichenoid eruption, agitation, seizures/psychotic psychosis, depression, disease or ethyl alcohol seizures, dizziness, abuse, check level before headache, slurred speech, increasing dose ⬎500 insomnia, Steven’s Johnson daily. Administer with syndrome1, 50, 51, 55, 112 pyridoxine 150 to 300 mg daily

Isoniazid (high-dose)

Yes

ⱕ5.0

N/A†

1200 mg 3 times weekly

Pyridoxine 150 mg daily interacts with phenytoin Only if MIC ⱕ5.0

Drug

Dosing

Remarks

Adapted from References 1, 3, 6, 9, 12, 30, 32, 34, 50, 51, 52, 54, 55, 56, 62, 63, 75, 77, 80, 87, 88, 89, 92, 99, 104, 112, 116, 123, 128 *PDR  Physicians Desk Reference †N/A  Not Available

Side Effects Hyperpigmentation, GI complaints, acne flare, retinopathy, ichthyosis, sunburn3, 30, 32

Optic neuritis, positive ANA rash, fever, jaundice, hepatitis, peripheral neuritis, anemia, agranulocytosis, decreased platelets, vasculitis34, 88

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Toxicity monitoring should include at least twice-monthly assessment of the serum creatinine initially; if significant changes are noted, a repeat 24-hour urine creatinine clearance should also be included. Liver function tests and a complete blood count should be done monthly. A significant percentage of patients on ethionamide and/or PAS will develop hypothyroidism. Thyroid function should be assessed after several months of treatment and then intermittently. Thyroid hormone replacement should be added when thyroid suppression is documented.116 Thyroid function returns to baseline after treatment after multidrugresistant TB is stopped, and supplements can be withdrawn.50 Monthly assessment of vestibular function and audiograms should be performed on patients treated with an aminoglycoside or capreomycin.50 Abnormalities on audiograms occur before clinical symptoms of hearing loss develop.12 Visual screens and attention to any evidence of uveitis are needed for patients on ethambutol or rifabutin.50, 56 Rare instances of visual toxicity caused by clofazimine have been noted.30, 32

MONITORING THE PATIENT DURING THERAPY Evaluating Treatment Response Sputum smears and cultures should be performed at least monthly. Sputum should be collected throughout the treatment course, as intermittent and late positive cultures can occur in patients with multidrugresistant TB.51 Susceptibility testing should be repeated on cultures that remain positive after 2 to 3 months of treatment to check for any additional evidence of resistance. Most patients will convert their sputum cultures within 3 months, although late conversions also have resulted in cure.51 Chest radiographs should be repeated at intervals of 3 to 6 months to assess new abnormalities and radiographic response. An end-of-treatment film should be done to serve as a baseline for followup. Most relapses occur within the first 24 months,59, 120 and the author follows patients during this time period and at any future time should they develop signs or symptoms of recurrent disease. Weight gain, sputum conversion, and resolution of respiratory and systemic symptoms are signs of clinical responses to treatment. These often precede the conversion of cultures to negative and are important to emphasize to patients in an effort to encourage them. The use of a care plan can help to assure essential components of the assessment are not neglected (Fig. 4). Other physicans and the author use a ‘‘drug o gram’’ (Fig. 5)113 to document details of therapy and bacteriological response. The author finds it extremely useful during therapy. It offers a quick review of the treatment course, highlights drug levels, doses, and duration of individual drugs, and breaks in therapy, if any.

94

Figure 4. Multidrug-resistant tuberculosis (MDR-TB) care plan.

95

96 Figure 5. Antimycobacterial drug history.

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97

THERAPEUTIC SERUM DRUG LEVEL MONITORING The routine use of serum therapeutic drug level monitoring should be considered for all patients with multidrug-resistant TB.11 The therapeutic indexes are narrow, and an attempt should be made to achieve the best peak serum drug level to MIC ratio. Successful outcomes and prevention of acquired drug resistance with fluoroquinolone therapy have been correlated with serum levels and doses.82, 84, 132 Monitoring drug levels allows the physician to ‘‘push a drug’’ and still limit toxicity. Serum levels may alert the clinician to a potentially harmful serum drug level before clinical evidence of toxicity occurs. This is especially true with the aminoglycosides where renal and auditory toxicities may be limited by decreasing the dose or interval. Levels of cycloserine are essential to minimize central nervous system adverse reactions and especially to prevent seizure activity. The author does not recommend increasing the dose of cycloserine over 250 mg twice daily until serum levels are checked. Therapeutic monitoring may alert the physician to an unsuspected problem with absorption, adherence, or a drug interaction. Persons with HIV or those with malabsorption especially should be targeted for therapeutic monitoring. SURGICAL INTERVENTION IN MULTIDRUGRESISTANT TUBERCULOSIS Iseman attributes the improved outcomes of patients with multidrug-resistant TB treated between 1984 and 1993 to surgical intervention.67-68 He and others recommended that surgical intervention be considered for patients with destruction of a lobe or entire lung and those with extensive disease including large or persistent cavities. Hemoptysis not controlled medically also may require surgical intervention. Persistence of organisms in devitalized pulmonary tissue and limited delivery of medication to the site because of the poor vascular supply may provide an opportunity for later relapse. Destroyed pulmonary tissue and old cavitary lesions may be sites for recurrent bacterial or fungal infections.124 The optimum timing of surgical intervention is following 3 to 4 months of therapy and mycobacterial eradication from the sputum. Patients who fail to convert their sputum to negative after 3 to 4 months of intensive chemotherapy may benefit from surgical intervention.68, 124–125 Therapy should be continued for at least an additional 18 to 24 months after surgery.68, 124 Surgical morbidity and mortality are infrequent, but complications including broncho-pleural fistula occur and may be devastating.124 INFECTION CONTROL Patients with multidrug-resistant TB are as infectious as any TB patient.115 Because treatment for LTBI is unproven in this group and has

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been associated with a high rate of adverse effects,62 every effort to prevent transmission of multidrug-resistant TB should be employed. Improvement of infection control measures in institutions has been credited with decreasing rates of multidrug-resistant TB in urban populations with HIV.45, 130 Patients with multidrug-resistant TB should be placed in respiratory isolation in single rooms. They should not share rooms with patients with drug-susceptible disease. The release of multidrug-resistant TB patients from respiratory isolation is frequently a controversial issue. Patients with multidrug-resistant TB should remain in respiratory isolation at least until they have three separate negative sputum cultures. Patients can develop positive cultures even after months of negative cultures.51 The CDC recommends continuing respiratory isolation throughout a hospital course, even when cultures are negative.15 Timing return to high-risk environments where patients could be exposed to young children or immunocompromised individuals is controversial, and decisions may need to be individualized after discussion with local health authorities. The decision may be more related to where these individuals can be discharged rather than whether they can be discharged.110 It is clear that they should not be regarded as noninfectious and returned to the community after 2 weeks of treatment and negative sputum smears. MANAGEMENT OF PERSONS EXPOSED TO MULTIDRUG-RESISTANT TUBERCULOSIS Persons who are identified as close contacts of patients with MDR TB are at risk of acquiring drug-resistant TB. They should be identified quickly and evaluated, as should all contacts of TB patients. The optimal management of these persons is a matter of some debate. No regimen has been proved effective, and it is unlikely that there will be a definitive study to evaluate the management of this population. Regardless of the decision to treat, it is important to follow all persons with presumed latent multidrug-resistant TB for 2 years following the exposure. Evaluation should include clinical and radiographic assessment every 3 months for persons with HIV or who are otherwise immunosuppressed and every 6 months for persons who are not at increased risk of developing active disease.17 Those who are tuberculin skin test-positive, are close contacts with a case of multidrug-resistant TB and have no prior history of a previously positive tuberculin test can be considered for treatment of latent multidrug-resistant TB. After discussion of the risks and benefits of treatment, a decision regarding treatment can be made by the patient and physician. Management of tuberculin skin test-negative high-risk contacts, especially infants and persons with HIV, varies. Some recommend empiric therapy after active disease is excluded and pending follow-up evaluation.17, 113 Most clinicians agree that medical treatment should be recom-

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mended for tuberculin skin test-positive immunosuppressed individuals with an exposure to multidrug-resistant TB. An assessment should include the risk of exposure to drug-susceptible TB and if present, isoniazid therapy might be preferred. The selection of agents should be guided by the susceptibility profile of the index case. One possible regimen is a combination of pyrazinamide (25 to 30 mg daily) and ethambutol (15 to 25 mg daily). If fluoroquinolone susceptibility is documented, a regimen that combines ciprofloxacin (750 mg), ofloxacin (800 mg), or levofloxacin (750 mg) daily with pyrazinamide can be used. A fluoroquinolone also can be combined with ethambutol. Some recommend quinolone monotherapy as a legitimate approach.113 SUMMARY Multidrug-resistant TB is a growing public health problem. Although control of the multidrug-resistant TB epidemic has been achieved in New York City, strains of multidrug-resistant TB are found in nearly every state. Much of the world faces a growing problem with no immediate solution. The treatment habits and policies that have led to this problem persist. New drug development has been almost nonexistent. The current tremendous global interest offers hope, as does the Global Alliance for Tuberculosis Drug Development supported by the Rockefeller Foundation and the Bill and Melinda Gates Foundation. Their mission is to accelerate the discovery and development of new antituberculosis drugs and put them on the market within 10 years, at prices affordable in less-developed countries. As Dr. Reichman notes, ‘‘this action will not address the main underlying cause of almost all drug resistance, non-adherence of patients and doctors to recommended regimens.’’ He calls for an equal commitment to improving the capacity of health care workers to use new and older agents correctly, so that they may continue to be effective in the future.103 Each year brings new, at-risk immigrants to the United States from all regions of the globe. They bring all the TB problems of their countries of origin with them. Foreign-born people will have a significant impact on TB control efforts in the next decade and beyond. TB elimination programs will need to incorporate systems that can adequately address TB within the United States and support national TB programs in developing countries to help them develop the capacity to successfully manage their own TB problems. A review of the drug resistance patterns isolated from foreign-born people should be adequate to convince even skeptics of the need to support global TB programs. ACKNOWLEDGMENTS The author acknowledges Araceli Santellanes for assistance with manuscript preparation, Stephanie Ott for developing figures and tables, and the Texas Department of Health

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nurses and physicians at the Texas Center for Infectious Disease and across the state for their dedicated care of patients with multidrug-resistant TB.

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