Management of MDR-TB
Michael D. Iseman, M. D.
Recently, "MDR-TB" has come to refer to cases in which the tuberculosis strain was resistant at least to isoniazid (INH) and rifampicin RIF. This situation is of special importance because INH and RIF are the most effective drugs in the contemporary armamentarium: they are the keystones to short-course chemotherapy. Given both drugs, a highly predictable, all oral curative regimens of 6 to 9 months duration is easily devised. Even with just one of the two, INH or RIF, curative regimens of similar duration can be devised although an injectable agent such as streptomycin or amikacin must be employed. But when both INH and RIF are lost to resistance, cure rates fall, the duration of treatment is more than doubled, and the likelihood of drug toxicity increases substantially.(1)
Factors Associated with MDR-TB
Resistance to the anti-tuberculosis medications is due to chromosomal mutations, not a mobile resistance factor such as seen with gram-negative bacilli. These mutations are unlinked and occur at low but predictable frequencies, in the range of 1 per 106-108 replications.
Because the mutations are unlinked, the use of multiple medications protects against acquired drug resistance through the following mechanism. Mutations resistant to drug A (e.g. INH) are killed by drug B (e.g. RIF) and mutations resistant to drug B (RIF) are killed by drug A (INH). And, because the mutations occur at a low frequency, it is highly improbable that a single organism would, without artificial selection, evolve spontaneous resistance to both drugs A and B.
Thus, in clinical practice, significant drug resistance is virtually always due originally to inadequate drug therapy. This inadequacy may be due to patient non-compliance (taking some, but not all medications), physician's error, lack of drug availability, or malabsorption. Acquired drug resistance is more commonly seen with cavity lung diseases in which large numbers of bacilli are proliferating rapidly. Once a patient acquires resistance to a single drug, they are more vulnerable to the acquisition of further resistance due to the probability of inadequate regimens. In this manner, strains may become sequentially resistant to several agents. Once drug resistance has been created within individuals, these patients may transmit that strain to others who then present with pre-formed or "primary" drug resistance; see below.
Epidemiology of Drug Resistance
A recent survey conducted by the World Health Organization (WHO) and the International and Lung Disease Union Against Tuberculosis (IUALTD) documented that both single-resistance and MDR-TB had reached alarming levels in certain areas, "Hot Zones", of the world (2). This survey was not universal; rather 39 nations or states/provinces were studied. Resistance was characterized as "primary", "acquired", or "combined"; see Table 1 for definitions. Data from this survey are displayed in figures 1, 2, and 3.
Analysis of factors to the levels of resistance showed that areas served by well-organized programs including the use of Directly Observed Therapy, Short-course (DOTS) had lower levels of resistance.
Historically, MDR-TB has gradually increased in prevalence. However, data from multiple sites (including New York (USA), Florida (USA), Illinois (USA), Argentina, Italy, and Spain) have demonstrated rapid epidemic spread in the setting of HIV infection and nosocomial transmission.
Impact of Drug Resistance on the Outcomes of Treatment
Among patients who were enrolled in British Medical Research Center short course trials, those with initial drug resistance to any of the first line agents were 88-fold more likely overall to experience treatment failure and a 2-fold higher risk of relapse after therapy was terminated (3). There were only 11 patients in the British Medical Research Council trials with resistance to INH and RlF; of these, only 27% enjoyed successful outcome. At the National Jewish Center, 171 patients with MDR-TB were treated from 1973-1983; these cases all involved resistance to INH, RIF, and multiple other drugs; the average patient in this study had TB resistant to 5.8 drugs (4). Among the patients, all of whom were HIV negative, only 56% enjoyed long term-cures. Only 9 of these patients underwent surgery.
During the subsequent decade, we have employed resectional surgery much more aggressively based on the high failure/relapse rates among the earlier group. Results of the recent surgical experience are noted below.
Management of Patients with MDR-TB
Medical Treatment
There are two distinct approaches to the management of patients with "drug resistant" tuberculosis. In many regions of the world where in vitro susceptibility tests are not available, "resistance" is inferred from failure to respond to initial or re-treatment regimens. By comparison, industrialized notions now generally recommend these susceptibility tests routinely for all patients undergoing chemotherapy; such tests directly identify and characterize drug resistance.
In the former case, where laboratory results are not available, empirical regimens have been advocated by the World Health Organization and the International Union Against Tuberculosis and Lung Disease. These recommended regimens are shown in Table 2.
