Rationale: Linezolid, the first oxazolidinone approved for clinical use, has effective in vitro and promising in vivo activity against Mycobacterium tuberculosis. Objectives: To evaluate the early and extended early bactericidal activity of linezolid in patients with pulmonary tuberculosis.Methods: Randomized open label trial. Thirty patients with newly diagnosed smear-positive pulmonary tuberculosis (10 per arm) were assigned to receive isoniazid (300 mg daily) and linezolid (600 mg twice daily or 600 mg once daily) for 7 days. Sputum for quantitative culture was collected for 2 days before and then daily during 7 days of study drug administration. Bactericidal activity was estimated by measuring the decline in bacilli during the first 2 days (early bactericidal activity) and the last 5 days of study drug administration (extended early bactericidal activity). Measurements and Main Results:The mean early bactericidal activity of isoniazid (0.67 log 10 cfu/ml/d) was greater than that of linezolid twice and once daily (0.26 and 0.18 log 10 cfu/ml/d, respectively). The extended early bactericidal activity of linezolid between Days 2 and 7 was minimal. Conclusions: Linezolid has modest early bactericidal activity against rapidly dividing tubercle bacilli in patients with cavitary pulmonary tuberculosis during the first 2 days of administration, but little extended early bactericidal activity. Clinical trial registered with www.clinicaltrials.gov (NCT00396084).

The World Health Organization recommends the use of artemisinin-based combination therapies (ACTs) for the treatment of uncomplicated malaria. The two most widely adopted ACT regimens are artemether (AR)-lumefantrine (LR) (the combination is abbreviated AL) and amodiaquine (AQ)-artesunate (AS). Pharmacokinetic (PK) data informing the optimum dosing of these drug regimens is limited, especially in children. We evaluated PK parameters in Ugandan children aged 5 to 13 years with uncomplicated malaria treated with AL (n ‫؍‬ 20) or AQ-AS (n ‫؍‬ 21), with intensive venous sampling occurring at 0, 2, 4, 8, 24, and 120 h following administration of the last dose of 3-day regimens of AL (twice daily) or AQ-AS (once daily). AS achieved an estimated maximum concentration in plasma (C max ) of 51 ng/ml and an area under the concentration-time curve from time zero to infinity (AUC 0-ؕ ) of 113 ng ⅐ h/ml; and its active metabolite, dihydroartemisinin (DHA), achieved a geometric mean C max of 473 ng/ml and an AUC 0-ؕ of 1,404 ng ⅐ h/ml. AR-DHA exhibited a C max of 34/119 ng/ml and an AUC 0-ؕ of 168/382 ng ⅐ h/ml, respectively. For LR, C max and AUC 0-ؕ were 6,757 ng/ml and 210 g ⅐ h/ml, respectively. For AQ and its active metabolite, desethylamodiaquine (DEAQ), the C max s were 5.2 ng/ml and 235 ng/ml, respectively, and the AUC 0-ؕ s were 39.3 ng ⅐ h/ml and 148 g ⅐ h/ml, respectively. Comparison of the findings of the present study to previously published data for adults suggests that the level of exposure to LR is lower in children than in adults and that the level of AQ-DEAQ exposure is similar in children and adults. For the artemisinin derivatives, differences between children and adults were variable and drug specific. The PK results generated for children must be considered to optimize the dosing strategies for these widely utilized ACT regimens.

Total eradication of HIV-1 is not yet achievable, in part because reservoirs of latent HIV-1 can develop within lymphoid tissue, the testes, and the central nervous system (CNS). The presence of HIV-1 in the CNS is clinically significant because of its association with the development of HIV dementia, which occurs in up to one fifth of untreated patients. This review summarizes current theory regarding HIV-1 infection within the CNS, describes physiologic and pharmacologic factors limiting CNS penetration of antiretroviral drugs used to treat HIV-1 infection, and reviews current treatment of CNS HIV-1 infection and HIV encephalopathy.

The treatment of tuberculosis (TB) is a mature discipline, with over 60 years of clinical experience accrued across the globe. The requisite multidrug treatment of drug-susceptible TB, however, lasts six months and has never been optimized according to current standards. Multi-drug resistant tuberculosis and tuberculosis 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 tuberculosis. The key to treatment shortening appears to be sterilizing activity, or the ability of drugs to kill mycobacteria that persist after the initial days of multidrug 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 appear to have significant sterilizing activity. At least two class members are currently under evaluation 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 and/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.