An Exposure-Response Perspective on the Clinical Dose of Pretomanid.

Pretomanid was approved by the U.S. FDA, via the limited population pathway for antibacterial and antifungal drugs, as part of a three-drug regimen with bedaquiline and linezolid for the treatment of extensively drug-resistant and treatment-intolerant or nonresponsive multidrug-resistant tuberculosis. The recommended dose of pretomanid is 200 mg once daily with food. The objective of this work was to retrospectively evaluate this recommended dose by means of exposure-response (E-R) modeling applied to outcomes of both efficacy and safety. Cox proportional-hazards modeling was used, with the steady-state average pretomanid concentration as the exposure metric. The efficacy outcome was time to sputum culture conversion (TSCC) to negative. The safety outcomes were times to the first occurrence of adverse events in classes selected from either pretomanid's investigator brochure or the new drug application (NDA) submission as recognized safety signals for pretomanid based on preclinical as well as clinical experience. Significant E-R relationships were found for TSCC and two adverse-event classes, vomiting (a single preferred term) and gastrointestinal (GI) symptoms (a collection of related terms). No significant E-R relationships were found for the single preferred terms nausea, alanine aminotransferase (ALT) increased, aspartate aminotransferase (AST) increased, and headache and for the collections hepatic disorders, transaminases increased, skin and subcutaneous tissue disorders, and headache. The results suggest that the recommended dose of pretomanid, 200 mg given in the fed state, is appropriate over the range of pharmacokinetic exposures.

Association between human leukocyte antigen class II alleles and genotype of Borrelia burgdorferi in patients with early lyme disease.

BACKGROUND: On the basis of a polymerase chain reaction-restriction fragment-length polymorphism analysis of the 16S-23S ribosomal DNA intergenic spacer, clinical isolates of Borrelia burgdorferi can be classified into 3 genotypes designated as RST1, RST2, and RST3. RST1 strains are the most pathogenic, and RST3 strains are the least pathogenic. METHODS: Human leukocyte antigen (HLA) class II alleles were determined for a group of culture-positive patients with Lyme disease-associated erythema migrans and were evaluated for an association with the genotype of the infecting B. burgdorferi strain. RESULTS: The DRB1*0101 allele carriage rate was higher in patients infected with RST3 strains (9/25 [36.0%]) than in patients infected with RST1 strains (2/28 [7.1%]) or RST2 strains (7/36 [19.4%]) (P=.010). The same relationship was found for carriage of the DRB1*0101-DQB1*0501 haplotype (P=.018), because of tight linkage disequilibrium. Similar associations could not be demonstrated for any of the other DRB1 and DQB1 alleles or haplotypes that were assessed. CONCLUSION: The DRB1*0101 allele and the DRB1*0101-DQB1*0501 haplotype may be relevant to the development of infection with strains from the least invasive genotypes of B. burgdorferi.

A randomized study of the use of fluconazole in continuous versus episodic therapy in patients with advanced HIV infection and a history of oropharyngeal candidiasis: AIDS Clinical Trials Group Study 323/Mycoses Study Group Study 40.

BACKGROUND: In human immunodeficiency virus (HIV)-infected patients, fluconazole prophylaxis is associated with reductions in the rate of fungal infection. However, concerns exist with regard to the use of fluconazole prophylaxis and the risk of development of fluconazole treatment-refractory infections. METHODS: We performed a randomized, open-label trial that compared oral fluconazole given continuously (200 mg 3 times weekly; the "continuous fluconazole arm") with fluconazole that was provided only for episodes of orophayngeal candidiasis (OPC) or esophageal candidiasis (EC) (the "episodic fluconazole arm") in HIV-infected persons with CD4+ T cell counts of <150 cells/mm3 and a history of OPC. The primary study end point was the time to development of fluconazole-refractory OPC or EC, which was defined as lack of response to 200 mg fluconazole given daily for 14 or 21 days, respectively. RESULTS: A total of 413 subjects were randomized to receive continuous fluconazole, and 416 were randomized to receive episodic fluconazole. After 42 months, 17 subjects (4.1%) in the continuous fluconazole arm developed fluconazole-refractory OPC or EC infections, compared with 18 subjects (4.3%) in the episodic fluconazole arm, with no difference between treatment arms with regard to the time to development of a fluconazole-refractory infection within 24 months (P=.88, by log-rank test) or before the end of the study (P=.97, by the log-rank test). Continuous fluconazole therapy was associated with fewer cases of OPC or EC (0.29 vs. 1.08 episodes per patient-year; P<.0001) and fewer invasive fungal infections (15 vs. 28 episodes; P=.04, by chi2 test), but not with improved survival, compared with episodic fluconazole therapy. CONCLUSION: Continuous fluconazole therapy is not associated with significant risk of fluconazole-refractory OPC or EC, compared with episodic fluconazole therapy, in HIV-infected patients with access to active antiretroviral therapy.

A case-control study to examine HLA haplotype associations in patients with posttreatment chronic Lyme disease.

In a comparison of 95 patients with systemic symptoms that persisted after antibiotic treatment for acute Lyme disease (posttreatment chronic Lyme disease) and 104 control subjects without such symptoms after antibiotic treatment, we sought associations between human leukocyte antigen class II (DRB1 and DQB1) markers and posttreatment chronic Lyme disease. No strong association between posttreatment chronic Lyme disease and any class II allele or genotype was found.

Relationship of peripheral arterial compliance and standard cardiovascular risk factors.

Abnormalities of peripheral arterial compliance are clinically useful markers of atherosclerosis and risk of vascular events. Local peripheral arterial compliance can be easily and accurately assessed in the clinic by computer-controlled pulse volume recordings (air plethysmography). The purpose of this study was to investigate the relationship between clinical cardiovascular risk factors, a surrogate of atherosclerotic burden, and peripheral arterial compliance in the thigh and calf determined by quantification of local pulse volume recordings in patients undergoing coronary angiography. Peripheral arterial compliance in the thigh and calf was measured in 346 patients undergoing diagnostic cardiac catheterization at 4 centers. Demographic and cardiovascular risk factor data were collected, and their relationship to local arterial compliance examined using a new device that assesses maximal local arterial volume change in an extremity segment. Pulse volume recordings detected decreased local arterial compliance in the thigh associated with a history of hypertension (p < 0.0001), diabetes mellitus (p = 0.0001), and hyperlipidemia (p = 0.0007). In the calf, this arterial compliance measure was associated with a history of hypertension (p < 0.0001) and diabetes mellitus (p = 0.002). Females had lower arterial compliance than males in the thigh (p = 0.003) and calf (p < 0.0001). Limited evidence of lower arterial compliance in the thigh was found for those with obesity (p = 0.07). This procedure also demonstrated that subjects with multiple cardiovascular risk factors had lower arterial compliance in the thigh than subjects with no or 1 risk factor (p = 0.0001). Peripheral arterial compliance determined by air plethysmography is strongly associated with standard cardiovascular risk factors. The noninvasive measurement of local arterial compliance by regional pulse volume recording may be a useful adjunct for cardiovascular risk stratification early in the course of the disease as well as for monitoring vascular response to therapy.