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DC-159a is a new fluoroquinolone with more potent in vitro activity than available fluoroquinolones against both drug-susceptible and fluoroquinolone-resistant Mycobacterium tuberculosis. Here, we report that DC-159a displays pharmacokinetics similar to those of moxifloxacin yet is more active than moxifloxacin during both the initial and continuation phases of treatment in a murine model. These results warrant further preclinical evaluation of DC-159a in selected drug combinations against drug-susceptible and fluoroquinolone-resistant tuberculosis. Fluoroquinolones are cornerstone agents in the treatment of multidrug-resistant (MDR) tuberculosis (TB). The most potent members of the class, moxifloxacin (MXF) and gatifloxacin, may be capable of shortening the treatment of drug-susceptible as well as MDR TB (1, 2, 11). However, the emergence of fluoroquinolone resistance in Mycobacterium tuberculosis threatens to undermine any such advances (4). Moreover, selection of fluoroquinolone resistance in other bacterial pathogens as a result of prolonged TB treatment is an increasing concern (13). DC-159a is a new 8-methoxyfluoroquinolone with an MIC 90 of 0.06 g/ml against M. tuberculosis, which is 4 and 8 times lower than that of MXF and levofloxacin (LVFX), respectively (3). With an MIC 90 of 0.5 g/ml against clinical MDR TB isolates which are resistant to other fluoroquinolones (e.g., MXF and LVFX MIC90 of 4 and 16 g/ml, respectively) (3), DC-159a may retain more activity than other fluoroquinolones against such MDR and extensively drug-resistant (XDR) TB isolates. Moreover, there is evidence that DC-159a is less likely than other fluoroquinolones to select for drug resistance in common bacterial pathogens other than mycobacteria (5, 7). Based on these promising in vitro data, we sought to compare the dose-ranging activity of DC-159a with that of MXF in a murine model of TB. Because fluoroquinolones may differ in their bactericidal activity against nonmultiplying or slowly multiplying M. tuberculosis in a fashion that may not be predicted from their activity against actively multiplying bacilli (6, 9), we compared the activities of MXF and DC-159a during the continuation phase as well as the initial phase of treatment. Because it measures a drug’s activity against a population of “persister” bacilli surviving 2 months of treatment with rifampin, isoniazid, and pyrazinamide (RHZ), the continuation phase assessment may provide greater insight into a drug’s treatment-shortening potential (8, 12).

The treatment of tuberculosis (TB) has remained mostly unchanged for the last 40 years. A renewed effort by public and private agencies around the world to slow the spread of the disease has led to an increased interest in finding a superior anti-TB drug regimen. The current doses recommended for first-line treatment of TB (isoniazid, rifampicin, pyrazinamide, ethambutol) may be inadequate for certain patients. Additionally, efforts are being made to reduce the length of treatment by utilizing other medications with activity against Mycobacterium tuberculosis, such as the fluoroquinolones. While the pharmacokinetic (PK) profile of a drug helps to explain a drug’s action in the body, equally important is the management of that drug’s PK profile clinically. Herein we review current PK questions being asked by leading researchers in the field and the role that therapeutic drug management may play in the treatment of TB.

The management of MDR-TB requires that the clinician become familiar with the "second-line" antimycobacterial agents. These drugs are generally less potent and frequently more toxic than isoniazid and rifampin. Because they are less active, innovative dosing schedules may allow us to take advantage of the few strengths that they possess. This approach will require further research into the dose-response relationships for each agent. Based on our current knowledge of these drugs, practical guidelines for their use have been described. These guidelines include the gradual escalation of the oral doses of PAS, cycloserine, and ethionamide over several days, and the intravenous administration of streptomycin and capreomycin. Both ciprofloxacin and ofloxacin may be used for the treatment of MDR-TB, but data from clinical trials are currently lacking. Finally, because patients with AIDS appear to develop antimycobacterial drug malabsorption over the course of their HIV infection, therapeutic drug monitoring can be used to verify drug absorption in the individual patient. This approach may improve therapy for that patient and prevent the selection of additional drug resistance.

Methodologies for preclinical animal model testing of drugs against Mycobacterium tuberculosis vary from laboratory to laboratory; however, it is unknown if these variations result in different outcomes. Thus, a series of head-to-head comparisons of drug regimens in three commonly used mouse models (intravenous, a low-dose aerosol, and a high-dose aerosol infection model) and in two strains of mice are reported here. Treatment with standard tuberculosis (TB) drugs resulted in similar efficacies in two mouse species after a low-dose aerosol infection. When comparing the three different infection models, the efficacies in mice of rifampin and pyrazinamide were similar when administered with either isoniazid or moxifloxacin. Relapse studies revealed that the standard drug regimen showed a significantly higher relapse rate than the moxifloxacin-containing regimen. In fact, 4 months of the moxifloxacin-containing combination regimen showed similar relapse rates as 6 months of the standard regimen. The intravenous model showed slower bactericidal killing kinetics with the combination regimens tested and a higher relapse of infection than either aerosol infection models. All three models showed similar outcomes for in vivo efficacy and relapse of infection for the drug combinations tested, regardless of the mouse infection model used. Efficacy data for the drug combinations used also showed similar results, regardless of the formulation used for rifampin or timing of the drugs administered in combination. In all three infection models, the dual combination of rifampin and pyrazinamide was less sterilizing than the standard three-drug regimen, and therefore the results do not support the previously reported antagonism between standard TB agents.

Objective An open-label, three-period pharmacokinetic study was conducted to investigate the drug interaction potential between fosamprenavir (FPV) and tenofovir disoproxil fumarate (TDF). Methods Thirty-six healthy subjects received TDF 300 mg once daily (qd) for 7 days (period 1), and then were randomized to 14 days of either FPV 1400 mg twice daily (bid) or FPV/ritonavir (RTV) 700/100 mg bid alone or with TDF (period 2). Subjects continued their randomized dose of FPV for 14 more days, adding or removing TDF based upon its receipt in period 2 (period 3). Twenty-four-hour pharmacokinetic sampling was carried out on day 7 of period 1 and on day 14 of periods 2 and 3. Steady-state plasma amprenavir (APV) and tenofovir (TFV) pharmacokinetics were assessed by noncompartmental analysis and parameter values observed with each regimen were compared using geometric mean ratios with 90% confidence intervals. Results After TDF coadministration, APV geometric mean minimum concentration (Cmin), maximum concentration (Cmax), and area under the plasma concentration–time curve (AUC) increased by 31, 3 and 7% above values observed with unboosted FPV alone; they also increased by 31, 4 and 16% above values observed with FPV/RTV alone. TFV Cmin, Cmax and AUC decreased by 12, 25 and 15% after FPV coadministration and by 9, 18 and 7% after FPV/RTV coadministration. No significant changes in RTV pharmacokinetics were observed. No differences were noted in adverse events among dosing periods. Conclusions In this evaluation of the interaction between FPV and TDF, increases in APV exposures and modest decreases in TFV exposures were observed. These were unlikely to be clinically significant.

Background. Human immunodeficiency virus (HIV)-associated tuberculosis is difficult to treat, given the propensity for drug interactions between the rifamycins and the antiretroviral drugs. We examined the pharmacokinetics of rifabutin before and after the addition of lopinavir-ritonavir. Methods. We analyzed 10 patients with HIV infection and active tuberculosis in a state tuberculosis hospital. Plasma was collected for measurement of rifabutin, the microbiologically active 25-desacetyl-rifabutin, and lopinavir by validated high-performance liquid chromatography assays. Samples were collected 2-4 weeks after starting rifabutin at 300 mg thrice weekly without lopinavir-ritonavir, 2 weeks after the addition of lopinavir-ritonavir at 400 and 100 mg, respectively, twice daily to rifabutin at 150 mg thrice weekly, and (if rifabutin plasma concentrations were below the normal range) 2 weeks after an increase in rifabutin to 300 mg thrice weekly with lopinavir-ritonavir. Noncompartmental and population pharmacokinetic analyses (2-compartment open model) were performed. Results. Rifabutin at 300 mg without lopinavir-ritonavir produced a low maximum plasma concentration (C max ) in 5 of 10 patients. After the addition of lopinavir-ritonavir to rifabutin at 150 mg, 9 of 10 had low C max values. Eight patients had dose increases to 300 mg of rifabutin with lopinavir-ritonavir. Most free rifabutin (unbound to plasma protein) C max values were below the tuberculosis minimal inhibitory concentration. For most patients, values for the area under the plasma concentration-time curve were as low or lower than those associated with treatment failure or relapse and with acquired rifamycin resistance in Tuberculosis Trials Consortium/US Public Health Service Study 23. One of the 10 patients experienced relapse with acquired rifamycin resistance. Conclusion. The recommended rifabutin doses for use with lopinavir-ritonavir may be inadequate in many patients. Monitoring of plasma concentrations is recommended.

The marked reduction in the potent early bactericidal activity of isoniazid during the initial phase of antituberculosis (anti-TB) therapy has been attributed not only to the depletion of logarithmically growing bacilli but also to the emergence of isoniazid resistance. We studied the anti-TB activity of isoniazid and its ability to select for drug-resistant mutant strains in guinea pigs, in which the histopathology of TB closely resembles that of human TB. Prior mouse passage did not appear to enhance the virulence of Mycobacterium tuberculosis in guinea pigs. The human-equivalent dose of isoniazid was determined to be 60 mg/kg. Although isoniazid therapy caused rapid killing of bacilli in guinea pig lungs during the first 14 days of administration and rescued guinea pigs from acute death, its activity was dramatically reduced thereafter. This reduction in activity was not associated with the emergence of isoniazid-resistant mutant strains but, rather, with the selection of phenotypically tolerant "persisters.".

This study evaluates the serum concentrations of rifampin (RMP), isoniazid (INH), and intestinal barrier function in patients with multidrug-resistant tuberculosis (MDR-TB), drug susceptible tuberculosis (DS-TB), and health volunteers (HC; controls). Peak serum concentrations of RMP were significantly lower in MDR-TB and DS-TB as compared with HC (odds ratio [OR] = 3.125, confidence interval [CI] [1.037-9.418] and OR = 4.025, CI [1.207-13.418], respectively). The INH peak serum concentration was not significantly different between MDR-TB versus DS-TB or DS-TB versus HC. The percent of mannitol excretion was significantly lower in the MDR-TB group compared with DS-TB (13.18 versus 16.03, analysis of covariance [ANCOVA], P = 0.0369) and compared with HC (13.18 versus 16.61, ANCOVA, P = 0.0291) the other study groups. These data suggested a lower peak serum concentration of RMP for both MDR-TB and DS-TB as compared with the HC group. The data also showed a lower intestinal area of absorption in patients with tuberculosis and even worse in MDR-TB.

Nineteen adults with pulmonary tuberculosis received linezolid (600 mg) once or twice daily in an early bactericidal activity trial. A one-compartment population model produced median values for the absorption rate constant, volume of distribution, and elimination rate constant of 1.5 h −1 , 29.6 liters, and 0.25 h −1 (once daily) and 2.7 h −1 , 32.1 liters, and 0.15 h −1 (twice daily). Linezolid administered twice daily produced higher values for free drug area under the concentration-time curve (AUC)/MIC and time above MIC. Both regimens achieved free AUC/MIC ratios > 100. Median times above the MIC for free drug were 100% (twice daily) and 63% (once daily).

Study Objective. To determine the feasibility of therapeutic drug monitoring for adjusting low serum antimycobacterial concentrations in patients with both tuberculosis and advanced human immunodeficiency virus (HIV). Design. Retrospective cohort study. Data Source. De-identified dataset from a tuberculosis clinic. Patients. Twenty-one patients (median age 38 yrs, range 25–68 yrs) with advanced HIV infection (CD4+ cell count < 100 cells/mm3) who received treatment for active tuberculosis between March 2002 and September 2007. Measurements and Main Results. We evaluated data based on the practices performed at the tuberculosis clinic. After the daily doses of isoniazid and rifamycins (rifampin or rifabutin) were ingested, serum concentrations were obtained at 2 hours for isoniazid and rifampin, at 3 hours for rifabutin, and, when possible, at 6 hours for all three drugs to detect delayed absorption. Antimycobacterial drug concentrations were compared with published reference levels, and dosages were adjusted to achieve desired concentrations. Costs of monitoring were recorded for all patients. Of the 21 patients, 18 (86%) had low serum concentrations of at least one drug 2 hours after ingestion: 2 (10%) had low isoniazid concentrations, 5 (24%) had low rifamycin concentrations, and 11 (52%) had low serum concentrations of both drugs. The median number of dosage adjustments to attain normal concentrations was 1 (range 0–4 adjustments). The median cost/patient for therapeutic drug monitoring was $619 (range $230–1948). The median final doses to achieve normal concentrations were isoniazid 600 mg/day (range 300–1500 mg/day), rifampin 1050 mg/day (range 600–1200 mg/day), and rifabutin 300 mg (range 150–450 mg) 3 times/week. No patient demonstrated any adverse effects attributed to these higher doses. Conclusion. Low serum concentrations of antituberculous drugs, which suggest malabsorption, are common among patients with advanced HIV who also have tuberculosis but can be overcome with higher doses. Therapeutic drug monitoring may be an effective tool to optimize therapy, but needs further study.

The treatment of tuberculosis (TB) is a mature discipline, with more than 60 years of clinical experience accrued across the globe. The requisite Multi-drug treatment of drug-susceptible TB, however, lasts 6 months and has never been optimized according to current standards. Multi-drug resistant TB and TB in individuals coinfected with HIV present additional treatment challenges.This article reviews the role that existing drugs and new compounds could have in shortening or improving treatment for TB. The key to treatment shortening seems to be sterilizing activity, or the ability of drugs to kill mycobacteria that persist after the initial days of multi-drug treatment.Among existing anti-TB drugs, the rifamycins hold the greatest potential for shortening treatment and improving outcomes, in both HIV-infected and HIV-uninfected populations, without dramatic increases in toxicity. Clinical studies underway or being planned, are supported by in vitro , animal and human evidence of increased sterilizing activity--without significant increases in toxicity--at elevated daily doses. Fluoroquinolones also seem to have significant sterilizing activity. At present, at least two class members are being evaluated for treatment shortening with different combinations of first-line drugs. However, in light of apparent rapid selection for fluoroquinolone-resistant mutants, relative frequency of serious adverse events and a perceived need to 'reserve' fluoroquinolones for the treatment of drug-resistant TB, their exact role in TB treatment remains to be determined. Other possible improvements may come from inhaled delivery or split dosing (linezolid) of anti-TB drugs for which toxicity (ethionamide) or lack of absorption (aminoglycosides and polypeptides) precludes delivery of maximally effective, oral doses, once daily. New classes of drugs with novel mechanisms of action, nitroimidazopyrans and a diarylquinoline, among others, may soon provide opportunities for improving treatment of drug-resistant TB or shortening treatment of drug-susceptible TB.More potential options for improved TB treatment currently exist than at any other time in the last 30 years. The challenge in TB pharmacotherapy is to devise well-tolerated, efficacious, short-duration regimens that can be used successfully against drug-resistant and drug-resistant TB in a heterogeneous population of patients.

HIV-infected pregnant women with undetectable plasma HIV RNA concentrations at delivery pose a minimal risk of vertical transmission. We studied the kinetics and the determinants of the virologic response to antiretroviral therapy in 117 consecutive pregnancies. Patients who initiated therapy during pregnancy had a VL decrease of 2 and 2.5log10after 4 and 24 weeks, respectively. Therapeutic drug monitoring (TDM) of the protease inhibitors administered in doses recommended for nonpregnant adults resulted in below-target concentrations in 29%, 35%, and 44% of 1st, 2nd, and 3rd trimester measurements, respectively, but low drug concentrations did not correlate with virologic failure. Demographic characteristics, antiretroviral experience prior to pregnancy, baseline VL, or use of specific antiretrovirals did not affect the virologic response. Adherence to≥95% of prescribed doses and utilization of psychosocial services were associated with undetectable plasma HIV RNA at delivery. In conclusion, the virologic responses of pregnant and nonpregnant adults share similar charactersitics.

A solid-phase extraction (SPE) method was developed to simplify the preparation of human serum prior to high-performance liquid chromatography of ethionamide (ETA). Octadecyl SPE columns were used. Serum constituents were removed from the column with water, and ETA was eluted with methanol. Samples were evaporated to dryness, reconstituted in mobile phase, and assayed. The method is reproducible, with a recovery of ETA of 64%, comparable to the more tedious liquid-liquid extraction method for ETA.

The study objective was to determine the minimum frequency of dosing for standard 4-g doses of p-aminosalicylic acid (PAS) granules. Two sequential six-patient pharmacokinetic studies are described, followed by clinical data from 40 subsequent patients. All patients had multidrug-resistant tuberculosis (MDR-TB). Serum was collected at two to three time points after dosing, and assayed by a validated high performance liquid chromatography (HPLC) assay. Data were analyzed using noncompartmental methods. In six patients, twice-daily dosing produced median serum concentrations at 4, 8, and 12 h post-dose of 25.8, 23.2, and 16.4 microgram/ml. In six patients, once-daily dosing produced median serum concentrations at 6, 12, and 24 h post-dose of 23.4, 3.7, and 0 microgram/ml. In 40 patients, twice-daily dosing produced median serum concentrations at 4 to 8 and 9 to 12 h post-dose of 24.8 and 20.6 microgram/ml. Unlike once-daily dosing, twice-daily PAS maintained serum concentrations in excess of 1 microgram/ml, the typical minimal inhibitory concentration against Mycobacterium tuberculosis, for the entire dosing interval. We now use twice-daily PAS granules for our patients with MDR-TB.

The macrolide antibiotic clarithromycin (CLARI) has a wide spectrum of activity and efficacy for Mycoplasma species. In addition, CLARI accumulates during re-dosing of Mojave desert tortoises (Gopherus agassizii). Here, we characterized plasma concentrations after a single dose, after 3.5 months of dosing, and after per rectum administration; all doses were 15 mg/kg. After a single dose, the median maximal plasma concentration (Cmax) was 1.69 mg/ml and occurred at a median of 6 h after administration, the estimated elimination half-life was 6.9 h, and the median accumulation index was 10%. Plasma concentrations after long-term dosing showed consistent intraturtle concentrations of at least 2 microg/ml, with 1 turtle showing increasing accumulation of CLARI at all 3 time points and the remaining 5 turtles showing increases by 3.5 mo. Compared with expected Cmax values, the median long-term values were approximately 3 times higher than expected in 4 of 6 turtles and approximately 2/3 of that expected in the remaining 2 turtles. Per rectum dosing caused antibiotic retention below target values. Together, these results support accumulation of CLARI after repeated oral dosing and indicate that stable concentrations are reached long-term. Either cystoenteric recycling of CLARI or large intestinal absorption of bypass CLARI may explain the observed cumulative increases. In addition, twice-weekly CLARI maintains target concentrations over time, and per rectum dosing will require higher doses or increased dose frequency to be successful. Based on this work, pharmacokinetic studies in exotic species should include multidose studies to verify initial kinetic estimates from single-dose trends.

Metronidazole, which is used for the treatment of infections caused by anaerobic organisms, was evaluated in Mycobacterium tuberculosis -infected guinea pigs. M. tuberculosis can adapt to hypoxia, which is present in the primary lesions of infected guinea pigs. Metronidazole treatment (for 6 weeks at 100 mg/kg of body weight) resulted in no reduction in the bacillary burden and significantly worsened lesion inflammation.

Background Availability of an ultra-short-course drug regimen capable of curing patients with tuberculosis in 2 to 3 mo would significantly improve global control efforts. Because immediate prospects for novel treatment-shortening drugs remain uncertain, we examined whether better use of existing drugs could shorten the duration of treatment. Rifapentine is a long-lived rifamycin derivative currently recommended only in once-weekly continuation-phase regimens. Moxifloxacin is an 8-methoxyfluoroquinolone currently used in second-line regimens. Methods and Findings Using a well-established mouse model with a high bacterial burden and human-equivalent drug dosing, we compared the efficacy of rifapentine- and moxifloxacin-containing regimens with that of the standard daily short-course regimen based on rifampin, isoniazid, and pyrazinamide. Bactericidal activity was assessed by lung colony-forming unit counts, and sterilizing activity was assessed by the proportion of mice with culture-positive relapse after 2, 3, 4, and 6 mo of treatment. Here, we demonstrate that replacing rifampin with rifapentine and isoniazid with moxifloxacin dramatically increased the activity of the standard daily regimen. After just 2 mo of treatment, mice receiving rifapentine- and moxifloxacin-containing regimens were found to have negative lung cultures, while those given the standard regimen still harbored 3.17 log10 colony-forming units in the lungs (p < 0.01). No relapse was observed after just 3 mo of treatment with daily and thrice-weekly administered rifapentine- and moxifloxacin-containing regimens, whereas the standard daily regimen required 6 mo to prevent relapse in all mice. Conclusions Rifapentine should no longer be viewed solely as a rifamycin for once-weekly administration. Our results suggest that treatment regimens based on daily and thrice-weekly administration of rifapentine and moxifloxacin may permit shortening the current 6 mo duration of treatment to 3 mo or less. Such regimens warrant urgent clinical investigation., Eric Nuermberger and colleagues found that after two months of treatment, mice with lung cultures positive for tuberculosis that received daily doses of rifapentine- and moxifloxacin-containing regimens converted to negative lung cultures. This finding could make possible the development of shorter treatment regimens for humans., Editors' Summary Background. Every year, nearly 9 million people develop tuberculosis—a bacterial infection most commonly of the lungs—and about 2 million people die from the disease. Tuberculosis is caused by Mycobacterium tuberculosis, bacteria that are spread in airborne droplets when people with active tuberculosis sneeze or cough. Most infected people never become ill—their immune system successfully contains the infection. However, the bacteria remain dormant within the body and can cause disease years later if host immunity declines. Active tuberculosis can be cured by taking several antibiotics daily (for tuberculosis treatments, daily may mean five or seven times a week) for at least 6 mo. Combinations of drugs are needed to prevent the bacteria from developing resistance to the treatment, but also because of the complex biology of M. tuberculosis. During active tuberculosis, there are rapidly multiplying bacteria in the lungs but also less rapidly multiplying and near-dormant bacteria elsewhere in the body. Effective treatments contain a “bactericidal” drug such as isoniazid to kill the actively multiplying bacteria, a drug to kill the less actively multiplying bugs (for example, pyrazinamide), and a sterilizing drug (the most potent of which is rifampin) to kill the near-dormant bacteria and thus prevent the disease from recurring. Why Was This Study Done? Unfortunately, many patients fail to complete this treatment because it is long and complicated and because the drugs may have unpleasant side effects. Poor adherence to treatment contributes to the emergence of drug resistance and means that people stay infectious for longer and are more likely to have relapses. Consequently, it is hampering global efforts to control tuberculosis. A shorter course of treatment might improve matters, but many researchers believe that this will require the development of new drugs and, although there are several promising candidates, it will be several years before they can be used in patients. In this study, therefore, the researchers asked whether better use of existing drugs could shorten treatment times. In particular, they studied tuberculosis in animals to investigate whether a long-lived rifampin-like drug called rifapentine combined with moxifloxacin (an alternative to isoniazid) might shorten treatment times. What Did the Researchers Do and Find? The researchers used several different courses (“regimens”) of treatment containing rifapentine, moxifloxacin, and pyrazinamide, and the standard daily short-course regimen containing rifampin, isoniazid, and pyrazinamide to treat mice infected with M. tuberculosis. For each regimen, they measured its bactericidal activity by counting how many bacterial colonies could be grown from the lungs of the mice at specific times during the treatment, and its sterilizing activity by assessing the proportion of mice with any live bacteria in their lungs (a culture-positive relapse) after treatment completion. After 2 mo of treatment, the mice receiving the rifapentine- and moxifloxacin-containing regimens had negative lung cultures, a point not reached with the standard regimen until after 4 mo of treatment. Three months of treatment with daily or thrice-weekly rifapentine- and moxifloxacin-containing regimens was sufficient to prevent any culture-positive relapses, whereas the standard daily regimen had to be continued for 6 mo to achieve cure. Testing of additional drug combinations revealed that rifapentine is the most important drug in the new regimen and that simply replacing rifampin with rifapentine and retaining isoniazid also is sufficient to shorten the duration of therapy to 3 mo in this experimental model. What Do These Findings Mean? These findings provide the first evidence that replacing rifampin with rifapentine might halve the length of therapy needed to cure tuberculosis. They also indicate that it might be possible to give the drugs thrice-weekly rather than daily as in the current therapy. The World Health Organization recommends that all tuberculosis treatment is supervised (so-called directly observed therapy) to ensure treatment adherence, so a regimen that requires only three doses a week for 3 mo would greatly reduce the resources needed to treat tuberculosis as well as potentially improving treatment adherence. However, it should be emphasized that the current study is experimental, and there may be important differences between how mice and people respond to the proposed drug regimens, both in terms of cure rates and side effects. Nevertheless, these results strongly suggest that the safety, tolerability, and efficacy of tuberculosis treatment regimens containing rifapentine and pyrazinamide, combined with either moxifloxacin or isoniazid, should be evaluated in people as soon as possible. Additional Information. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040344. The MedlinePlus encyclopedia contains a page on tuberculosis (in English and Spanish) The US National Institute of Allergy and Infectious Diseases provides information on all aspects of tuberculosis The US Centers for Disease Control and Prevention provide several fact sheets and other information resources about tuberculosis, including information for patients and caregivers about treatment adherence The World Health Organization provides a 2007 report on global tuberculosis control (in English with key findings in French and Spanish), information on the Stop TB initiative, and a recent bulletin on tuberculosis treatment (in English with an abstract in French, Spanish, and Arabic)

Study Objective. To characterize the bidirectional interaction between twice-daily nelfinavir and twice-weekly rifabutin and isoniazid in patients with tuberculosis and human immunodeficiency virus (HIV) infection. Design. Prospective cohort study. Setting. Three clinical research centers. Patients. Seven patients with HIV-related tuberculosis. Intervention. Rifabutin 300 mg and isoniazid 15 mg/kg (maximum dose 900 mg) twice/week were administered for at least 2 weeks during the continuation phase of tuberculosis treatment. Antiretroviral therapy with nelfinavir 1250 mg twice/day and two nucleoside reverse transcriptase inhibitors was then added. Measurements and Main Results. Patients underwent blood sampling for pharmacokinetic analysis during the continuation phase of tuberculosis therapy and after a median of 21 days after the addition of antiretroviral treatment. When rifabutin was coadministered with nelfinavir, its area under the concentration-time curve from 0–21 hours (AUC0–21) increased 22% (geometric mean 5.01 μg•hr/ml [90% confidence interval (CI) 3.25–7.71] with nelfinavir vs 4.10 μg•hr/ml [90% CI 3.18–5.27] without nelfinavir; geometric mean ratio 1.22 [90% CI 0.78–1.92]). Also, the AUC0–21 for the active metabolite, desacetylrifabutin, increased significantly (geometric mean ratio 3.46, 90% CI 1.84–6.47, p=0.009). In the presence of rifabutin, the pharmacokinetic parameters of nelfinavir and its principal metabolite M8 were similar to those of patients not taking rifabutin. No drug interaction between nelfinavir and isoniazid was detected. Conclusions. Coadministration of rifabutin and isoniazid without dosage adjustment during twice-weekly tuberculosis therapy with nelfinavir-based antiretroviral therapy resulted in rifabutin exposures within the acceptable ranges for safety and efficacy. Therefore, this combination is an appropriate option for the simultaneous treatment of tuberculosis and HIV infection when tuberculosis therapy is given twice weekly.

Background Reports of therapeutic drug monitoring (TDM) for second-line medications to treat multidrug-resistant tuberculosis (MDR-TB) remain limited. Methods A retrospective cohort from the Virginia state tuberculosis (TB) registry, 2009-2014, was analyzed for TDM usage in MDR-TB. Drug concentrations, measured at time of estimated peak (Cmax), were compared to expected ranges. Results Of 10 patients with MDR-TB, 8 (80%) had TDM for at least one drug (maximum 6 drugs). Second-line drugs tested were cycloserine in seven patients (mean C2hr, 16.6±10.2 µg/mL; 4 [57%] below expected range); moxifloxacin in five (mean C2hr, 3.2±1.5 µg/mL; 1 [20%] below); capreomycin in five (mean C2hr, 21.5±14.0 µg/mL; 3 [60%] below); para-aminosalicylic acid in five (mean C6hr, 65.0±29.1 µg/mL; all within or above); linezolid in three (mean C2hr, 11.4±4.1 µg/mL, 1 [33%] below); amikacin in two (mean C2hr, 35.3±3.7 µg/mL; 1 [50%] below); ethionamide in one (C2hr, 1.49 µg/mL, within expected). Two patients died: a 38-year-old woman with human immunodeficiency virus/acquired immune deficiency syndrome and TB meningitis without TDM, and a 76-year-old man with fluoroquinolone-resistant (pre-extensively drug-resistant) pulmonary TB and low linezolid and capreomycin concentrations. Conclusion Individual pharmacokinetic variability was common. A more standardized approach to TDM for MDR-TB may limit over-testing and maximize therapeutic gain.

The present study was conducted to identify any potential interaction between oral cimetidine and clarithromycin. Twelve healthy subjects were administered single doses of clarithromycin alone and with oral cimetidine dosed to steady state. Cimetidine prolonged the absorption of clarithromycin, as evidenced by decreased peak concentrations of both clarithromycin and 14-OH-clarithromycin (14OHC) in serum (46 and 43%, respectively), a delay in the formation of 14OHC (increase of 68%), and increases in both of their half-lives (75 and 82%, respectively), despite no changes in total oral clearance or area under the concentration-time curve for either compound. No mechanism for this interaction has been identified.

To investigate whether grapefruit juice inhibits the metabolism of clarithromycin, 12 healthy subjects were given water or grapefruit juice before and after a clarithromycin dose of 500 mg in a randomized crossover study. Administration of grapefruit juice increased the time to peak concentration of both clarithromycin (82 ± 35 versus 148 ± 83 min; P = 0.02) and 14-hydroxyclarithromycin (84 ± 38 min versus 173 ± 85; P = 0.01) but did not affect other pharmacokinetic parameters.

Low antimycobacterial drug concentrations have been observed in tuberculosis (TB) patients under treatment. The lactulose/mannitol urinary excretion test (L/M), normally used to measure intestinal permeability, may be useful to assess drug absorption. The objective of this research was to study intestinal absorptive function and bioavailability of rifampin and isoniazid in TB patients. A cross sectional study was done with 41 patients and 28 healthy controls, using the L/M test. The bioavailabilities of rifampin (R) and isoniazid (H) were evaluated in 18 patients receiving full doses. Urinary excretion of mannitol and lactulose, measured by HPLC, was significantly lower in TB patients. The serum concentrations of the drugs were below the expected range for R (8-24 mcg/mL) or H (3-6 mcg/mL) in 16/18 patients. Analyzing the drugs individually, 12/18 patients had low serum concentrations of R, 13/18 for H and 8/18 for both drugs. We suggest that there is a decrease in the functional absorptive area of the intestine in TB patients, which would explain the reduced serum concentrations of antituberculosis drugs. There is a need for new approaches to improve drug bioavailability in TB patients.

This study was undertaken to characterize the population pharmacokinetics (PK), therapeutic dose, and preferred route of administration for pyrazinamide (PZA) in elephants. Twenty-three African (Loxodonta africana) and Asian (Elephas maximus) elephants infected with or in contact with others culture positive for Mycobacterium tuberculosis were dosed under treatment conditions. PZA was dosed daily at 20-30 mg/kg via oral (fasting or nonfasting state) or rectal (enema or suppository) administration. Blood samples were collected 0-24 h postdose. Population PK was estimated using nonlinear mixed effect modeling. Drug absorption was rapid with T(max) at or before 2 h regardless of the method of drug administration. C(max) at a mean dose of 25.6 (+/-4.6) mg/kg was 19.6 (+/-9.5 microg/mL) for PZA given orally under fasting conditions. Under nonfasting conditions at a mean dose of 26.1 +/- 4.2 mg/kg, C(max) was 25% (4.87 +/- 4.89 microg/mL) and area under concentration curve (AUC) was 30% of the values observed under fasting conditions. Mean rectal dose of 32.6 +/- 15.2 mg/kg yielded C(max) of 12.3 +/- 6.3 microg/mL, but comparable AUC to PZA administered orally while fasting. Both oral and rectal administration of PZA appeared to be acceptable and oral dosing is preferred because of the higher C(max) and lower inter-subject variability. A starting dose of 30 mg/kg is recommended with drug monitoring between 1 and 2 h postdose. Higher doses may be required if the achieved C(max) values are below the recommended 20-50 microg/mL range.

Rationale:Treatmentoftuberculosiswithanefficaciousonce-weekly regimen would be a significant achievement in improving patient adherence. Currently, theonly recommended once-weekly continuation phase regimen of isoniazid plus rifapentine (10 mg/kg) is inferior to standard twice-weekly therapy with isoniazid plus rifampin and is, therefore, restricted to non–high-risk patients. The substitution of moxifloxacin, a new 8-methoxyfluoroquinolone, for isoniazid and an increase in the dose of rifapentine could augment the activity of once-weekly regimens. Methods: To test this hypothesis we evaluated the sterilizing activity of improved once-weekly rifapentine-based continuation phase regimens in a murine model that mimics the treatment of highrisk patients with tuberculosis. The bactericidal activity of standard daily therapy and standard intermittent therapy (“Denver” regimen) was also assessed to evaluate the effect of intermittent drug administration during the initial phase of therapy. Results: After 2 mo of treatment, lung colony-forming unit counts were 1 log10 lower in mice treated with standard daily therapy than with the Denver regimen. During the continuation phase, the sterilizing activity of once-weekly moxifloxacin plus rifapentine (15mg/kg) wassignificantlygreaterthanthatofthepredominantly twice-weekly Denver regimen of isoniazid plus rifampin. No significant difference in sterilizing activity was detected between onceweekly isoniazid plus rifapentine (15 mg/kg) and the Denver regimen. Conclusions: These results suggest that the efficacy of the onceweekly isoniazid plus rifapentine continuation phase regimen can be increased by substituting moxifloxacin for isoniazid and by increasing the dose of rifapentine to a clinically acceptable level of 15 mg/kg.

PURPOSE To evaluate the relationship between vitreous linezolid concentrations versus both time and serum concentrations after a single 600 mg oral dose. METHODS Two groups of six subjects undergoing a pars plana vitrectomy indicated by macular pucker or full thickness macular hole were given a single tablet of linezolid before surgery. The early group underwent vitrectomy at random times before the time of maximum serum linezolid concentration (i.e., 77 minutes) and the late group underwent vitrectomy at random times afterward. Each patient had a serum sample drawn shortly before and after vitrectomy and the vitreous specimen was sampled at the initiation of surgery. RESULTS The early group and late group had mean vitreous linezolid concentrations of 0.06 mcg/mL and 1.25 mcg/mL, respectively. The vitreous linezolid concentration showed a strong correlation to the interpolated serum concentration (R2 = 0.74, P < 0.01) at the time of vitrectomy. CONCLUSION The study demonstrates that linezolid penetrates the blood-retina barrier in noninflamed eyes. Because the vitreous concentrations appeared to exponentially trend upward with time and 33% of the late group achieved sufficient MIC90 levels for the common pathogens found in postoperative endophthalmitis, adequate concentrations might be achieved with an altered dosing regimen to achieve higher serum steady state levels. Further study is warranted.

BACKGROUND The pharmacokinetics of rifampin and ethambutol in HIV-infected patients with tuberculosis (TB) are incompletely characterized. We examined the pharmacokinetics of rifampin and ethambutol in a cohort of patients with HIV-related TB who were treated in the United States. METHODS Serum drug concentrations were determined 2, 6, and 10 h after dosing in 36 HIV-infected patients with TB who were taking rifampin and in 49 who were taking ethambutol. Observed serum concentrations were compared with published normal ranges and published data. RESULTS With daily dosing of rifampin (600 mg), 26 (77%) of 34 patients (95% confidence interval [CI], 59%-89%]) had a low maximum concentration of rifampin (

We recently described the clinical presentation and treatment of 18 elephants from six herds infected with TB. Treatment protocols and methods varied between herds to include both oral and rectal dosing using multiple drug doses and formulations. In this paper we present information regarding the pharmacokinetics (PK) of isoniazid (INH) in elephants and provide suggestions regarding initial treatment regimens. Forty-one elephants received INH daily by either oral or rectal administration with different formulations. Population PK analysis was performed using Non-linear Mixed Effect Modeling (NONMEM). Results of oral administration indicated that compared with premixed INH solution, the drug exposure was highest with a suspension prepared freshly with INH powder. When INH was concomitantly given as an admixture over food, Tmax was delayed and variability in drug absorption was significantly increased. Compared with oral administration, similar drug exposures were found when INH was dosed rectally. The data generated suggest that a starting dose of 7.5 mg/kg of INH is appropriate for initial TB treatment in elephants when premixed solution is administered directly into the oropharynx or rectal vault and 4 mg/kg are when INH is administered following immediate suspension from powdered form.

BACKGROUND: Linezolid is an oxazolidinone antimicrobial with excellent oral bioavailability and tissue penetration and is active against multidrug-resistant skin/soft tissue pathogens. OBJECTIVE: To study the pharmacokinetics and antibacterial activity of linezolid against selective skin/soft tissue pathogens in obese patients. METHODS: We obtained multiple serum samples from 7 obese patients (>50% over their calculated ideal body weight) receiving oral linezolid 600 mg every 12 hours for treatment of cellulitis. Following a minimum of 3 doses, serum concentrations of linezolid were measured in each subject prior to (trough) and 1 and 6 hours after a dose. These samples were then tested against clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) (linezolid minimum inhibitory concentrations [MICs] 1.0, 2.0, 4.0 μg/mL) and one strain each of vancomycin-resistant Enterococcus faecium (VRE) (MIC 2.0 μg/mL), Bacteroides fragilis (MIC 2.0 μg/mL), and Peptostreptococcus magnus (MIC 1.0 μg/mL). Serum inhibitory titers (SITs) and bactericidal titers (SBTs) were measured at each time point, and the median activity for these 7 patients was calculated. RESULTS: Mean linezolid serum concentrations were 4.2, 12.3, and 7.2 μg/mL at these respective time points. Median SITs for 12 hours (100% of the dosing interval) were observed against each organism with the exception of the least susceptible strain of MRSA (MIC 4.0 μg/mL); serum inhibitory activity was observed only at the one-hour time point against this isolate. Furthermore, prolonged (⩾6 h) median SBTs were observed against one isolate of MRSA (MIC 1.0 μg/mL) as well as the strain of VRE and P. magnus. CONCLUSIONS: Serum concentrations of oral linezolid in this patient population were diminished compared with those of healthy volunteers, but still provided prolonged serum inhibitory activity against common pathogens associated with skin/soft tissue infections. One treatment concern would be an obese patient receiving oral linezolid who was infected with a less susceptible (MIC ⩾4.0 μg/mL) strain of S. aureus. Bactericidal activity was also observed against selective pathogens.

Background Because of drug-drug interactions mediated by hepatic cytochrome P450, tuberculosis treatment guidelines recommend an increase in rifabutin from 300 mg to 450 or 600 mg when combined with efavirenz-based antiretroviral therapy. To assess this recommendation, rifabutin and efavirenz pharmacokinetic parameters were investigated. Methods Plasma concentrations of rifabutin were determined as a baseline control in 15 patients with tuberculosis and human immunodeficiency virus (HIV) infection who were treated with rifabutin 300 mg and isoniazid 15 mg/kg (up to 900 mg) twice weekly. Rifabutin, isoniazid, and efavirenz concentrations were determined after a median of 21 days (interquartile range, 20-34 days) of daily efavirenz-based antiretroviral therapy with twice-weekly rifabutin 600 mg and isoniazid 15 mg/kg. Results The mean rifabutin area under the concentration-time curve (AUC(0-24)) increased 20% from the baseline value (geometric mean, 5.0 vs. 4.2 microg.h/mL; ratio of geometric means, 1.2 [90% confidence interval, 1.0-1.4]). Also, the mean efavirenz AUC(0-24) in the 15 patients taking concomitant rifabutin 600 mg twice-weekly was 10% higher than that in 35 historical subjects with HIV infection who were not taking rifabutin. Efavirenz-based antiretroviral therapy was effective; HIV load decreased 2.6 log copies/mL, and the median CD4+ T cell count increased from 141 to 240 cells/mm3 after a median of 21 days of efavirenz-based antiretroviral therapy. No statistically significant differences in isoniazid pharmacokinetic parameters were found. Conclusions The rifabutin dose increase from 300 mg to 600 mg was adequate to compensate for the efavirenz drug interaction in most patients, and no drug interaction with isoniazid was detected. Efavirenz therapy administered at a standard 600-mg dose achieved adequate plasma concentrations in patients receiving intermittent rifabutin and isoniazid therapy, was generally well tolerated, and demonstrated potent antiretroviral activity.

Background. We conducted a pharmacokinetic study of antimycobacterial drugs involving a cohort of patients with pulmonary tuberculosis (TB) in Gaborone, Botswana, to assess the prevalence of and risk factors for low drug concentrations in serum. Methods. Adults participated if they had a history of cough 2 weeks, had abnormal chest radiograph findings, consented to testing for human immunodeficiency virus (HIV), had sputum cultures positive for Mycobacterium tuberculosis, and were receiving antituberculous therapy for 17 days. Observed maximum serum concentrations were compared with published normal ranges. Results. Of 91 patients enrolled, 89 (98%) were outpatients, and 59 (68%) of 87 patients tested had HIV infection. The following numbers of patients had low serum concentrations of the following drugs: isoniazid, 27 (30%) of 90; rifampin, 71 (78%) of 91; ethambutol, 37 (41%) of 91; and pyrazinamide, 1 (1%) of 91. Low serum concentrations of both isoniazid and rifampin occurred in 23 (26%) of 90 patients. Low serum concentrations of rifampin were found in both HIV-infected and non‐HIV-infected patients, and such patients were less likely to have 14 weeks of symptoms, more likely to have lymphadenopathy, and more likely to have low serum albumin levels ( for all). The associations with noncavitary pulmonary disease ( ) and HIV infection ( P ! .05 P p .12 P p ) did not reach statistical significance. Delayed absorption was most common with ethambutol, followed by .07 rifampin. Conclusions. These data, predominantly from HIV-infected patients with TB, suggest that low isoniazid, rifampin, and ethambutol concentrations are common in Botswana. In contrast, pyrazinamide usually is well absorbed.

We thank Coates and colleagues for their interest in our recent paper demonstrating in two pathologically distinct murine models of tuberculosis (TB) that rifapentine (RPT) is approximately 4 times more potent (on a mg/kg body weight basis) than rifampin (RIF) when used alone and in combination with

Background The occurrence of acquired rifamycin resistance despite use of directly observed therapy for tuberculosis is associated with advanced human immunodeficiency virus (HIV) disease and highly intermittent administration of antituberculosis drugs. Beyond these associations, the pathogenesis of acquired rifamycin resistance is unknown. Methods We performed a pharmacokinetic substudy of patients in a trial of treatment with twice-weekly rifabutin and isoniazid. Results A total of 102 (60%) of 169 patients in the treatment trial participated in the pharmacokinetic substudy, including 7 of 8 patients in whom tuberculosis treatment failure or relapse occurred in association with acquired rifamycin-resistant mycobacteria (hereafter, "ARR failure or relapse"). The median rifabutin area under the concentration-time curve (AUC(0-24)) was lower for patients with than for patients without ARR failure or relapse (3.3 vs. 5.2 microg*h/mL; P = .06, by the Mann-Whitney exact test). In a multivariate analysis adjusted for CD4+ T cell count, the mean rifabutin AUC(0-24) was significantly lower for patients with ARR failure or relapse than for other patients (3.0 microg*h/mL [95% confidence interval {CI}, 1.9-4.5] vs. 5.2 microg*h/mL [95% CI, 4.6-5.8]; P = .02, by analysis of covariance). The median isoniazid AUC(0-12) was not significantly associated with ARR failure or relapse (20.6 vs. 28.0 microg*h/mL; P = .24, by the Mann-Whitney exact test). However, in a multivariate logistic regression model that adjusted for the rifabutin AUC(0-24), a lower isoniazid AUC(0-12) was associated with ARR failure or relapse (OR, 10.5; 95% CI, 1.1-100; P = .04). Conclusions Lower plasma concentrations of rifabutin and, perhaps, isoniazid were associated with ARR failure or relapse in patients with tuberculosis and HIV infection treated with twice-weekly therapy.

Para-aminosalicylic acid (PAS), a tuberculostatic agent, was formulated into large porous particles for direct delivery into the lungs via inhalation. These particles possess optimized physical properties for deposition throughout the respiratory tract, a drug loading of 95% by weight and physical stability over 4 weeks at elevated temperatures. Upon insufflation in rats, PAS concentrations were measured in plasma, lung lining fluid and homogenized whole lung tissue. Systemic drug concentrations peaked at 15 min, with a maximum plasma concentration of 11+/-1 microg/ml. The concentration in the lung lining fluid was 148+/-62 microg/ml at 15 min. Tissue concentrations were 65+/-20 microg/ml at 15 min and 3.2+/-0.2 microg/ml at 3h. PAS was cleared within 3 h from the lung lining fluid and plasma but was still present at therapeutic concentrations in the lung tissue. These results suggest that inhalation delivery of PAS can potentially allow for a reduction in total dose delivered while providing for higher local and similar peak systemic drug concentrations as compared to those obtained upon oral PAS dosing. Similar particles could potentially be used for the delivery of additional anti-tuberculosis agents such as rifampicin, aminoglucosides or fluoroquinolones.

Objective To determine linezolid concentrations in peritoneal dialysis fluid after multiple oral doses of the drug in a 46-year-old man with vancomycin-resistant Enterococcus faecium peritonitis who was undergoing peritoneal dialysis. Methods After administration of oral linezolid 600 mg twice/day was started, peritoneal dialysis fluid was collected at the end of several 4- and 8-hour dwell times and submitted for analysis of linezolid concentration. Before linezolid therapy was begun, and immediately after several peritoneal dialysis exchanges, 30 ml of expended peritoneal dialysis fluid was collected in a sterile container and immediately frozen at -70 degrees C until analysis by high-performance liquid chromatography. Results Peritoneal dialysis concentrations of linezolid greater than 4 microg/ml were achieved after the first dose of linezolid and maintained after repeated doses. During the course of therapy, mean linezolid concentrations in peritoneal dialysis fluid tended to increase (mean 7.60 pg/ml, range 3.54-16.2 microg/ml). All assayed peritoneal dialysis samples demonstrated linezolid concentrations greater than 4 microg/ml at the end of 4- or 8-hour dwell times, except for one level after a missed dose on linezolid treatment day 3. Duration of dwell times did not appear to correlate with linezolid concentrations. Conclusion In this patient, linezolid 600 mg twice/day penetrated into peritoneal dialysis fluid at or above the concentrations necessary to treat common gram-positive bacteria. Linezolid therapy is likely to have a role in peritoneal dialysis-associated peritonitis based on its antimicrobial activity, pharmacokinetic properties, ease of administration, and tolerability.

Aminoglycoside use is limited by ototoxicity and nephrotoxicity. This study compared the incidences of toxicities associated with 2 recommended dosing regimens. Eighty-seven patients with tuberculosis or nontuberculous mycobacterial infections were prospectively randomized by drug to receive 15 mg/kg per day or 25 mg/kg 3 times per week of intravenous streptomycin, kanamycin, or amikacin. Doses were adjusted to achieve target serum concentrations. The size of the dosage and the frequency of administration were not associated with the incidences of ototoxicity (hearing loss determined by audiogram), vestibular toxicity (determined by the findings of a physical examination), or nephrotoxicity (determined by elevated serum creatinine levels). Risk of ototoxicity (found in 32 [37%] of the patients) was associated with older age and with a larger cumulative dose received. Vestibular toxicity (found in 8 [9%] of the patients) usually resolved, and nephrotoxicity (found in 13 [15%] of the patients) was mild and reversible in all cases. Subjective changes in hearing or balance did not correlate with objective findings. Streptomycin, kanamycin, and amikacin can be administered either daily or 3 times weekly without affecting the likelihood of toxicity.

Objective. To determine the linezolid clearance and serum concentrations in a critically ill man receiving continuous venovenous hemodiafiltration (CVVHDF). Methods. Intravenous linezolid 600 mg every 12 hours was administered to a critically ill, 85-year-old man with anuria who was receiving CVVHDF at a dialysate flow rate of 2000 ml/hour and a mean ultrafiltrate production rate of 775 ml/hour. Samples of blood and spent dialysate and ultrafiltrate were obtained at the time of linezolid peaks and troughs, and linezolid concentrations were determined. Results. The CVVHDF yielded a mean linezolid clearance of 36.5 ml/minute and an elimination half-life of 7.5 hours. The linezolid saturation coefficient ranged from 0.77‐0.81. Administration of intravenous linezolid 600 mg every 12 hours yielded suitable serum trough concentrations. Conclusion. Administration of intravenous linezolid 600 mg every 12 hours maintained therapeutic serum trough concentrations in this critically ill patient receiving CVVHDF.

In this issue of Clinical Infectious Diseases, Pasipanodya et al present a metaanalysis regarding the “pharmacokinetic variability hypothesis” for tuberculosis treatment outcomes, including acquired drug resistance [1]. We commend the authors for their in-depth analysis and for the substantial effort expended in collating the studies, performing the necessary statistical analyses, and interpreting the results. The power of metaanalysis lies in its ability to combine studies relating to a single topic. Its Achilles’ heel lies in the quality of the data available for the analysis. In this case, the authors provided a clear hypothesis and performed a systematic analysis. They focused on isoniazid, one of the most important tuberculosis drugs. Until now, it had been widely recognized that isoniazid acetylator status was associated with clinical and microbiological outcomes in older, once-weekly treatment regimens involving para-aminosalicylic acid and streptomycin. Beyond that, the “dogma” was that isoniazid acetylator status did not produce clinical significant differences in outcomes for fast versus slow acetylators. The work by Pasipanodya et al calls that dogma into question. For this analysis, a relatively limited number of acceptable studies were available. Furthermore, 9 of the 13 studies evaluated isoniazid within nonrifamycin regimens. Only 2 of the 4 remaining studies contained rifampin, the most commonly used rifamycin. Although the presence or absence of a rifamycin has no bearing on a patient’s acetylator status, nonrifamycin regimens last many more months, and they are associated with more microbiological failures. Thus, some caution should be exercised in generalizing these metaanalysis findings to rifamycin-based regimens. That said, some of the most compelling data come from those 4 rifamycin-based studies. Additionally, rifabutin-based studies also support the association between adequate drug concentrations and tuberculosis treatment outcomes [2, 3]. The authors briefly discuss the topic of pharmacokinetic mismatch and, in particular, the pairing of tuberculosis drugs with short versus long half-lives. Examples include the pairing of isoniazid (a drug with a short half-life) with either rifapentine or rifabutin (both with long half-lives), especially within intermittent regimens (once-, twice-, or thrice-weekly dosing). At least on the surface, this seems analogous to the situation with efavirenz and nucleoside reverse-transcriptase inhibitors; when discontinuing treatment with efavirenz (with its long half-life), it is widely accepted that one needs to continue taking nucleoside reverse-transcriptase inhibitors (with their short half-lives) for several days to prevent efavirenz resistance while efavirenz slowly leaves the body [4, 5]. For tuberculosis, with its slower rate of multiplication compared with human immunodeficiency virus (HIV), this area of research still is being explored. It is fair to say that there is growing concern about using intermittent tuberculosis regimens in general, and mismatched ones in particular, especially in HIV-positive patients and especially early in treatment. All of this can be summed up in one phrase: drug exposure. In the treatment of tuberculosis, our primary weapons are the drugs. Both mouse and human studies show that more drug exposure leads to more killing of tuberculosis and better treatment outcomes [6, 7]. It follows from this that it would be entirely reasonable to control and optimize tuberculosis drug exposures to facilitate these desired outcomes. We long have Received 15 March 2012; accepted 21 March 2012; electronically published 30 March 2012. Correspondence: Charles A. Peloquin, PharmD, FCCP, College of Pharmacy, and Emerging Pathogens Institute, University of Florida, 1600 SW Archer Rd, Room P4-33, PO Box 100486, Gainesville, FL 32610-0486 (peloquin@cop.ufl.edu). Clinical Infectious Diseases 2012;55(2):178–9 © The Author 2012. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. permissions@oup.com. DOI: 10.1093/cid/cis366

Methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium were exposed to linezolid (MIC of 2 mg/liter) under aerobic or anaerobic conditions in an in vitro pharmacodynamic model. Drug concentration and half-life were adjusted to simulate clinical dosing (600 mg twice daily) of linezolid. Linezolid produced a 2-log 10 killing at 24 h, and rates of killing against each of these facultative organisms as measured by mean survival time appeared similar under aerobic and anaerobic conditions.

Therapeutic drug monitoring (TDM) is a standard clinical technique used for many disease states, including many infectious diseases. As for these other conditions, the use of TDM in the setting of tuberculosis (TB) allows the clinician to make informed decisions regarding the timely adjustment of drug therapy. Such adjustments may not be required for otherwise healthy individuals who are responding to the standard, four-drug TB regimens. However, some patients are slow to respond to treatment, have drug-resistant TB, are at risk of drug-drug interactions or have concurrent disease states that significantly complicate the clinical situation. Such patients may benefit from TDM and early interventions may preclude the development of further drug resistance. It is not possible to collect multiple blood samples in the clinical setting for logistical and financial reasons. Therefore, one typically is limited to one or two time points. When only one sample can be obtained, the 2-hour post-dose concentrations of isoniazid, rifampin, pyrazinamide and ethambutol are usually most informative. Unfortunately, low 2-hour values do not distinguish between delayed absorption (late peak, close to normal range) and malabsorption (low concentrations at all time points). A second sample, often collected at 6-hour post-dose, can differentiate between these two scenarios. The second time point can also provide some information about clearance and half-life, assuming that drug absorption was nearly completed by 2 hours. TDM requires that samples are promptly centrifuged, and that the serum is promptly harvested and frozen. Isoniazid and ethionamide, in particular, are not stable in human serum at room temperature. Rifampin is stable for more than 6 hours under these conditions. During TB treatment, isoniazid causes the greatest early reduction in organisms and is considered to be one of the two most important TB drugs, along with rifampin. Although isoniazid is highly active against TB, low isoniazid concentrations were associated with poorer clinical and bacteriological outcomes in US Public Health Services (USPHS) TB Trial 22. Several earlier trials showed a clear dose-response for rifampin and pyrazinamide, so low concentrations for those two drugs also may correlate with poorer treatment outcomes. At least in USPHS TB Trial 22, the rifampin pharmacokinetic parameters were not predictive of the outcome variables. In contrast, low concentrations of unbound rifapentine may have been responsible, in part, for the worse-than-anticipated performance of this drug in clinical trials. The 'second-line' TB drugs, including p-aminosalicylic acid, cycloserine and ethionamide, are relatively weak TB drugs. Under the best conditions, treatment with these drugs takes over 2 years, as opposed to 6 to 9 months with isoniazid- and rifampin-containing regimens. Therefore, TB centres such as National Jewish Medical and Research Center in Denver, CO, USA, measure serum concentrations of the 'second-line' TB drugs early in the course of treatment. That way, poor drug absorption can be dealt with in a timely manner. This helps to minimise the time that patients are sputum smear- and culture-positive with multidrug-resistant TB, and may prevent the need for even longer treatment durations. Patients with HIV are at particular risk for drug-drug interactions. Because the published guidelines typically reflect interactions only between two drugs, these guidelines are of limited value when the patient is treated with three or more interacting drugs. Under such complicated circumstances, TDM often is the best available tool for sorting out these interactions and placing the patient the necessary doses that they require. TDM is only one part of the care of patients with TB. In isolation, it is of limited value. However, combined with clinical and bacteriological data, it can be a decisive tool, allowing the clinician to successfully treat even the most complicated TB patients.

Study Objective. To determine population pharmacokinetic parameters of pyrazinamide after multiple oral doses given to children and adults with tuberculosis. Design. Prospective, multiple-dose population pharmacokinetic study. Setting. Five hospitals in the United States. Patients. Sixty-seven adults and 23 children with active tuberculosis. Intervention. The 90 patients received multiple oral doses of pyrazinamide as part of their treatment, based on the best clinical judgment of the attending physicians and in keeping with standard clinical practices at each institution. The patients also received other antituberculosis drugs empirically or based on in vitro susceptibility data. Measurements and Main Results. Serum samples were collected over 12 hours after dosing and were assayed with a validated gas chromatography assay with mass selective detection. Concentration-time data were analyzed by using population methods. Pyrazinamide concentrations increased linearly with increasing oral doses (185–3550 mg). Median maximum serum concentration values were 41.0 μg/ml with daily dosing and 66.1 μg/ml with larger, twice-weekly dosing. Incomplete (18%) or delayed (30%) absorption was more common in children than in adults (1% for each). Pharmacokinetic parameters of pyrazinamide were independent of human immunodeficiency virus status and patient demographics, except for body weight. Population elimination half-life values in pediatric and adult patients were 3.5 and 6.0 hours, respectively. Median volume of distribution (L/kg) was 32% larger in children, and median clearance (L/hr/kg) was 106% larger in children, with a resultant median half-life 43% shorter in children. Conclusion. Pyrazinamide concentrations and most pharmacokinetic parameters were comparable to those previously published. Apparent half-life was somewhat shorter than that in previous reports. Compared with adults, absorption of pyrazinamide in children appeared more likely to be incomplete or delayed.

A thorough review of the clinical trial data combined with new in vitro experimental information may make the optimization of dosages of TB drugs possible. Several factors can affect the selection and dosage of TB drugs including hepatic and renal impairment, pregnancy, duration of disease before treatment, and extent of debilitation. Drug interactions and pharmacodynamics must be considered, and their roles are discussed.

OBJECTIVE: To determine the pharmacokinetics and relative bioavailability of para-aminosalicylic acid (PAS) granules. DESIGN: Phase I pharmacokinetics study. SETTING: University of Arizona School of Pharmacy. PARTICIPANTS: Sixteen healthy male and female volunteers aged 36 ± 8 years. INTERVENTIONS: Subjects received single doses of PAS granules (6 g) combined with cycloserine 500 mg, clofazimine 200 mg, ethionamide 500 mg, and pyridoxine 100 mg. Drugs were given on an empty stomach after an overnight fast (reference) with high-fat food, with orange juice, and with antacids. MEASUREMENTS AND RESULTS: Four subjects did not complete all four treatments due to adverse events or personal reasons. Plasma and urine samples were collected for 48 hours and measured by a validated HPLC assay. Pharmacokinetic data analysis was performed with WinNonlin using noncompartmental methods and a one-compartmental model. Bioequivalence testing was performed using the mean ratios of the maximum concentrations (Cmax) and AUC0-∞ of PAS, with 90% confidence intervals. Compared with the fasted condition, food increased Cmax 1.5–fold and AUC0-∞ 1.7-fold, and it doubled the time to maximum concentration (tmax). The least-squares mean ratios (treatment/reference) for Cmax were 0.90 (58% to 139% CI), 1.16 (75% to 179% CI), and 0.82 (52% to 127% CI) with orange juice, food, or antacid treatment, respectively. Corresponding ratios for AUC0-∞ were 1.05 (71% to 155% CI), 1.52 (103% to 224% CI), and 0.84 (57% to 125% CI), respectively. CONCLUSIONS: Food significantly enhanced the absorption of PAS, while orange juice and antacids had minor effects.