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Denver, CO
Dr. Peloquin is Director, Infectious Disease Pharmacokinetics Laboratory, National Jewish Medical and Research Center.
Correspondence to: Charles Peloquin, PharmD, Director, Infectious Disease Pharmacokinetics Laboratory, National Jewish Medical and Research Center, 1400 Jackson St, Denver, CO 80206; e-mail: peloquinc{at}njc.org
In this issue of CHEST (see page 1770), Li and colleagues describe their experience using therapeutic drug monitoring (TDM) in the management of patients with multidrug-resistant (MDR) tuberculosis (TB). The authors are to be commended for quantifying their experience.
In clinical settings, and especially in outpatient clinic settings, there are a number of logistical difficulties related to TDM to overcome. In the experience of Li et al, only 45% of the patients who were considered to be candidates for TDM actually had samples collected, and the likely reasons for this were cited in their article. Patients who had been treated longer or who had more extensive disease appeared more likely to have TDM. Blood samples were not always collected at the desired times, making the interpretation more challenging, and for some of these cases, unfamiliarity with the procedures likely played a role. Finally, when presented with concentrations that were out of range, not all physicians chose to adjust the doses. This was understandable for cases in which the patients already were tolerating the drugs poorly or for cases in which therapy with the drugs was about to be discontinued. For other cases, physicians may have been reluctant to exceed "maximum" doses, as listed in TB treatment guidelines.
Regarding the last point, I recommend avoiding use of the term maximum doses in treatment guidelines, since guidelines cannot anticipate every clinical circumstance. The maximum dose for any patient is the dose that produces the desired therapeutic effect with an acceptable degree of toxicity. Once the inadequacy of a drug dose has been documented using carefully timed TDM, a higher drug dose is justified, regardless of what was listed in the guidelines. For desperately ill patients, even more aggressive dosing may be required. Oncologists routinely have used drug doses that produce profound toxicity, since not doing so certainly would cost the patients their lives. Although the treatment of TB usually is not so extreme, clearly there are patients for whom one must "pull out all of the stops." Regarding the other logistical issues cited in the article by Li et al, each center considering routine TDM should appoint a "czar" who would be charged with establishing standard operating procedures for TDM, and then teaching others how to use these standard operating procedures. At many centers, pharmacists are the individuals who are charged with running the TDM service.
Compared to the early 1990s, TDM for TB patients has become more widely accepted, although a wide range of opinions still exist.1 The primary issue is selecting the best candidates for TDM, and, typically, these are sicker patients or patients who are slow to respond. In many ways, the question is similar to that posed in the old TV commercials for oil filters: "Pay me now, or pay me later." TB programs generally do not have extensive financial resources, and they are forced to be very careful with what they have. So, spending money on TDM is not embraced enthusiastically. Still, the cost of TDM pales in comparison with the costs of the retreatment of TB patients, and for MDR-TB patients there may be no retreatment options. Given that situation, TDM looks somewhat more appealing.
The details of how and why TDM should be performed have been published previously.234 More recently, larger clinical trials have noted that, in certain situations, low serum concentrations of the TB drugs are associated with worse treatment outcomes.56 Although not designed as TDM studies, they do point out that some minimum drug exposure is required for the drugs to be effective. Further, they show that certain patients, such as those with HIV, are particularly susceptible to adverse outcomes should their drug exposures be too low. As a first step, the Centers for Disease Control and Prevention no longer recommends intermittent treatment regimens for HIV-positive patients.7 It also may be time to consider higher initial doses for certain TB drugs, at least for selected patient populations, although such dose changes may require additional clinical trials for validation. Short of revising the guidelines, TDM performed early during treatment allows for timely dose adjustments that generally can overcome poor drug absorption. If TDM is performed early in treatment, poor clinical outcomes may be avoided. Clinical judgment is required to determine the patients to whom this approach should be applied. It has been the practice at certain centers, such as National Jewish Medical and Research Center and the A.G. Holley State Hospital (Lantana, FL) to perform TDM for nearly all TB patients. This reflects the difficult clinical problems facing many of these patients, including extensive drug resistance or multiple concurrent medical problems.89 Other centers, such as the Texas Center for Infectious Diseases (San Antonio, TX), San Diego TB Control (San Diego, CA), the Orange County Health Department (Westminster, CA), and Hennepin County Medical Center (Minneapolis, MN), use TDM in a substantial cohort of their TB patients. Like Li and colleagues, who are from New York City, it is likely that clinicians and laboratory investigators at these centers also would be willing to share their experiences with those at other centers who were interested in getting started with TB drug TDM.
A few "pearls" regarding TDM bear repeating. The timing of the doses and the blood draws needs to be coordinated in advance and carefully recorded. Ideally, two samples should be collected following the doses, so that the rate and completeness of drug absorption can be assessed. For many of the TB drugs, times of 2 h and 6 h postdose work reasonably well. Samples should be centrifuged, and the serum harvested and frozen promptly after collection. At the outset of treatment, a goal should be set for the desired serum concentrations, and this goal should be achieved with the greatest degree of precision possible.10 In some cases, doing so will require drug doses above the maximum doses listed in the guidelines. This is entirely justified in light of patient-specific data showing that the standard dose is inadequate.
Since serum concentrations are just one of several clinically relevant variables; alone they cannot predict treatment outcomes. However, combined with good clinical care, TDM allows physicians to maximize the probability of success for patients with TB and MDR-TB.
References
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