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Bedaquiline (BDQ) is an effective drug for the treatment of drug-resistant tuberculosis. Mutations in atpE , which encodes the target of BDQ, are associated with large increases in MICs. Mutations in Rv0678 that derepress the transcription of the MmpL5-MmpS5 efflux transporter are associated with smaller increases in MICs. However, Rv0678 mutations are the most common mutations that are associated with BDQ resistance in clinical isolates, and they also confer cross-resistance to clofazimine (CFZ).

Centrally necrotizing granulomas that harbor Mycobacterium tuberculosis (Mtb) are the hallmark of human tuberculosis (TB). New anti-TB therapies will need to effectively penetrate the cellular and necrotic, non-vascularized compartments of these lesions and reach sufficient concentrations to eliminate Mtb. BTZ‑043 is a novel antibiotic showing good bactericidal activity in humans in a phase IIa trial. Here, we report on the substantial efficacy of BTZ‑043 in the advanced pre-clinical model of interleukin-13-overexpressing mice, which mimic human TB pathology of pulmonary central granuloma necrosis. Accordingly, pulmonary BTZ‑043 concentrations were severalfold above the minimal inhibitory concentration in these mice. The detailed histological characterization of lung granulomas in combination with high resolution MALDI imaging revealed that BTZ‑043 diffuses and accumulates in the cellular compartment, and fully penetrates the necrotic center. In summary, this study is the first visualizing an efficient penetration, accumulation, and retention of a clinical-stage TB drug in human-like centrally necrotizing granulomas.

Despite known treatments, tuberculosis (TB) remains the world’s top infectious killer, highlighting the pressing need for new drug regimens. To prioritize the most efficacious drugs for clinical testing, we previously developed a PK-PD translational platform with bacterial dynamics that reliably predicted short-term monotherapy outcomes in Phase IIa trials from preclinical mouse studies. In this study, we extended our platform to include PK-PD models that account for drug-drug interactions in combination regimens and bacterial regrowth in our bacterial dynamics model to predict cure at end of treatment and relapse 6 months post-treatment. The Phase III trial STAND, testing new regimen pretomanid (Pa), moxifloxacin (M), and pyrazinamide (Z) (PaMZ), predicted to shorten treatment duration by 2 months was put on hold after a separate ongoing trial showed adding bedaquiline (B) to the PaMZ regimen (SimpliciTB) suggested superior efficacy. To forecast if the addition of B would indeed benefit the PaMZ regimen, we applied an extended translational platform to both regimens. We predicted currently available short- and long-term clinical data well for drug combinations related to BPaMZ. We predict the addition of B to PaMZ will shorten treatment duration by 2 months and be non-inferior compared to control HRZE, both at the end of treatment for treatment efficacy and 6 months after treatment has ended in relapse prevention. Using BPaMZ as a case study, we have demonstrated our translational platform can predict Phase II and III outcomes prior to actual trials, allowing us to better prioritize the regimens most likely to succeed.

BackgroundPhase 2a trials in tuberculosis typically use early bactericidal activity (EBA), the decline in sputum colony forming units (CFU) over 14 days, as the primary outcome for testing the efficacy of drugs as monotherapy. However, the cost of phase 2a trials can range from 7 to 19.6 million dollars on average, while more than 30% of drugs fail to progress to phase 3. Better utilizing preclinical data to predict and prioritize the most likely drugs to succeed will thus help accelerate drug development and reduce costs. We aim to predict clinical EBA using preclinical in vivo pharmacokinetic-pharmacodynamic (PKPD) data and a model-based translational pharmacology approach.Methods and FindingsFirst, mouse PK, PD and clinical PK models were compiled. Second, mouse PKPD models were built to derive an exposure response relationship. Third, translational prediction of clinical EBA studies was performed using mouse PKPD relationships and informed by clinical PK models and species-specific protein binding. Presence or absence of clinical efficacy was accurately predicted from the mouse model. Predicted daily decreases of CFU in the first 2 days of treatment and between day 2 and day 14 were consistent with clinical observations.ConclusionThis platform provides an innovative solution to inform or even replace phase 2a EBA trials, to bridge the gap between mouse efficacy studies and phase 2b and phase 3 trials, and to substantially accelerate drug development.

Tuberculosis (TB), the disease caused by Mycobacterium tuberculosis (Mtb), remains a leading infectious disease-related cause of death worldwide, necessitating the development of new and improved treatment regimens. Nonclinical evaluation of candidate drug combinations via the relapsing mouse model (RMM) is an important step in regimen development, through which candidate regimens that provide the greatest decrease in the probability of relapse following treatment in mice may be identified for further development. Although RMM studies are a critical tool to evaluate regimen efficacy, making comprehensive "apples to apples" comparisons of regimen performance in the RMM has been a challenge in large part due to the need to evaluate and adjust for variability across studies arising from differences in design and execution. To address this knowledge gap, we performed a model-based meta-analysis on data for 17 unique regimens obtained from a total of 1592 mice across 28 RMM studies. Specifically, a mixed-effects logistic regression model was developed that described the treatment duration- dependent probability of relapse for each regimen and identified relevant covariates contributing to interstudy variability. Using the model, covariate-normalized metrics of interest, namely, treatment duration required to reach 50% and 10% relapse probability, were derived and used to compare relative regimen performance. Overall, the model-based meta-analysis approach presented herein enabled cross-study comparison of efficacy in the RMM and provided a framework whereby data from emerging studies may be analyzed in the context of historical data to aid in selecting candidate drug combinations for clinical evaluation as TB drug regimens.

The Lancet Respiratory Medicine Commission on drug-resistant tuberculosis was published in 2017, which comprehensively reviewed and provided recommendations on various aspects of the disease. Several key new developments regarding drug-resistant tuberculosis are outlined in this Commission Update. The WHO guidelines on treating drug-resistant tuberculosis were updated in 2019 with a reclassification of second line anti-tuberculosis drugs. An injection-free MDR tuberculosis treatment regimen is now recommended. Over the past 3 years, advances in treatment include the recognition of the safety and mortality benefit of bedaquiline, the finding that the 9-11 month injectable-based 'Bangladesh' regimen was non-inferior to longer regimens, and promising interim results of a novel 6 month 3-drug regimen (bedaquiline, pretomanid, and linezolid). Studies of explanted lungs from patients with drug-resistant tuberculosis have shown substantial drug-specific gradients across pulmonary cavities, suggesting that alternative dosing and drug delivery strategies are needed to reduce functional monotherapy at the site of disease. Several controversies are discussed including the optimal route of drug administration, optimal number of drugs constituting a regimen, selection of individual drugs for a regimen, duration of the regimen, and minimal desirable standards of antibiotic stewardship. Newer rapid nucleic acid amplification test platforms, including point-of-care systems that facilitate active case-finding, are discussed. The rapid diagnosis of resistance to other drugs, (notably fluoroquinolones), and detection of resistance by targeted or whole genome sequencing will probably change the diagnostic landscape in the near future.

Background Tuberculosis is the leading killer of patients with human immunodeficiency virus (HIV) infection. Preventive therapy is effective, but current regimens are limited by poor implementation and low completion rates. Methods We conducted a randomized, open-label, phase 3 noninferiority trial comparing the efficacy and safety of a 1-month regimen of daily rifapentine plus isoniazid (1-month group) with 9 months of isoniazid alone (9-month group) in HIV-infected patients who were living in areas of high tuberculosis prevalence or who had evidence of latent tuberculosis infection. The primary end point was the first diagnosis of tuberculosis or death from tuberculosis or an unknown cause. Noninferiority would be shown if the upper limit of the 95% confidence interval for the between-group difference in the number of events per 100 person-years was less than 1.25. Results A total of 3000 patients were enrolled and followed for a median of 3.3 years. Of these patients, 54% were women; the media...

Since standardized rifampin-based first-line regimens and fluoroquinolone-based second-line regimens were used to treat tuberculosis (TB), unfortunately without timely modification according to the drug resistance profile, TB and drug-resistant disease are still important public health threats worldwide. Although the last decade has witnessed advances in rapid diagnostic tools and use of repurposed and novel drugs for better managing drug-resistant TB, we need an appropriate TB control strategy and a well-functioning health infrastructure to ensure optimal operational use of rapid tests, judicious use of effective treatment regimens that can be rapidly tailored according to the drug resistance profile and timely management of risk factors and co-morbidities that promote infection and its progression to disease. We searched the published literature to discuss (i) standardized versus individualized therapies, including the choice between a single one-size-fit-all regimen versus different options with different key drugs determined mainly by rapid drug susceptibility testing, (ii) alternative regimens for managing drug-susceptible TB, (iii) evidence for using the World Health Organization (WHO) longer and shorter regimens for multidrug-resistant TB and (iv) evidence for using repurposed and novel drugs. We hope an easily applicable combination of biomarkers that accurately predict individual treatment outcome will soon be available to ultimately guide individualized therapy.

Background Novel drug regimens are needed for tuberculosis (TB) treatment. New regimens aim to improve on characteristics such as duration, efficacy, and safety profile, but no single regimen is likely to be ideal in all respects. By linking these regimen characteristics to a novel regimen’s ability to reduce TB incidence and mortality, we sought to prioritize regimen characteristics from a population-level perspective. Methods and Findings We developed a dynamic transmission model of multi-strain TB epidemics in hypothetical populations reflective of the epidemiological situations in India (primary analysis), South Africa, the Philippines, and Brazil. We modeled the introduction of various novel rifampicin-susceptible (RS) or rifampicin-resistant (RR) TB regimens that differed on six characteristics, identified in consultation with a team of global experts: (1) efficacy, (2) duration, (3) ease of adherence, (4) medical contraindications, (5) barrier to resistance, and (6) baseline prevalence of resistance to the novel regimen. We compared scale-up of these regimens to a baseline reflective of continued standard of care. For our primary analysis situated in India, our model generated baseline TB incidence and mortality of 157 (95% uncertainty range [UR]: 113–187) and 16 (95% UR: 9–23) per 100,000 per year at the time of novel regimen introduction and RR TB incidence and mortality of 6 (95% UR: 4–10) and 0.6 (95% UR: 0.3–1.1) per 100,000 per year. An optimal RS TB regimen was projected to reduce 10-y TB incidence and mortality in the India-like scenario by 12% (95% UR: 6%–20%) and 11% (95% UR: 6%–20%), respectively, compared to current-care projections. An optimal RR TB regimen reduced RR TB incidence by an estimated 32% (95% UR: 18%–46%) and RR TB mortality by 30% (95% UR: 18%–44%). Efficacy was the greatest determinant of impact; compared to a novel regimen meeting all minimal targets only, increasing RS TB treatment efficacy from 94% to 99% reduced TB mortality by 6% (95% UR: 1%–13%, half the impact of a fully optimized regimen), and increasing the efficacy against RR TB from 76% to 94% lowered RR TB mortality by 13% (95% UR: 6%–23%). Reducing treatment duration or improving ease of adherence had smaller but still substantial impact: shortening RS TB treatment duration from 6 to 2 mo lowered TB mortality by 3% (95% UR: 1%–6%), and shortening RR TB treatment from 20 to 6 mo reduced RR TB mortality by 8% (95% UR: 4%–13%), while reducing nonadherence to the corresponding regimens by 50% reduced TB and RR TB mortality by 2% (95% UR: 1%–4%) and 6% (95% UR: 3%–10%), respectively. Limitations include sparse data on key model parameters and necessary simplifications to model structure and outcomes. Conclusions In designing clinical trials of novel TB regimens, investigators should consider that even small changes in treatment efficacy may have considerable impact on TB-related incidence and mortality. Other regimen improvements may still have important benefits for resource allocation and outcomes such as patient quality of life., Emily Kendall and colleagues simulate treatment regimens with differing characteristics and estimate the impacts on tuberculosis mortality and incidence., Author Summary Why Was This Study Done? Improvements in tuberculosis (TB) treatment are expected to play an important role in reaching the WHO goal of reducing TB deaths by 95%—that is, by more than 1.3 million deaths per year—between 2015 and 2035. Multiple aspects of existing treatment regimens have room for improvement, but it is unclear which types of improvement are most important. This study sought to prioritize different features of TB treatment regimens based on their potential to prevent TB deaths and new TB cases. What Did the Researchers Do and Find? The researchers developed a mathematical model to simulate the introduction of a novel regimen for the treatment of either drug-susceptible or multidrug-resistant (MDR) TB. They then compared regimens with different characteristics in terms of their ability to reduce TB deaths and new TB cases. Of the six characteristics modeled, regimen efficacy was the characteristic with the greatest potential to reduce TB cases and deaths, but other characteristics also had important effects (for example, shorter regimens could save health care resources). What Do These Findings Mean? It is important for developers of novel regimens to at least maintain the efficacy of existing regimens, and improvements in efficacy could prevent a large number of deaths. Other improvements, such as shorter duration and increased ease of adherence, may still have important effects by enabling more people with TB to receive appropriate and timely treatment.

The discovery of Streptomyces-produced streptomycin founded the age of tuberculosis therapy. Despite the subsequent development of a curative regimen for this disease, tuberculosis remains a worldwide problem, and the emergence of multidrug-resistant Mycobacterium tuberculosis has prioritized the need for new drugs. Here we show that new optimized derivatives from Streptomyces-derived griselimycin are highly active against M. tuberculosis, both in vitro and in vivo, by inhibiting the DNA polymerase sliding clamp DnaN. We discovered that resistance to griselimycins, occurring at very low frequency, is associated with amplification of a chromosomal segment containing dnaN, as well as the ori site. Our results demonstrate that griselimycins have high translational potential for tuberculosis treatment, validate DnaN as an antimicrobial target, and capture the process of antibiotic pressure-induced gene amplification.

Animal models have long played a crucial role in the preclinical and postmarketing evaluation of antimicrobial drug efficacy. With the alarming rise of antibiotic resistance in Streptococcus pneumoniae, such models have received increased attention as tools for deriving pharmacodynamic data and for determining the clinical significance of drug resistance. This information helps us to make therapeutic decisions to optimize efficacy and restrict the further promotion of drug resistance. Until now, however, insufficient attention has been paid to the special issues that arise in the evaluation of antimicrobials that are concentrated in tissue relative to serum or plasma. This article reviews the utility of animal models in the evaluation of these tissue-directed antibiotics, citing recent attempts to use murine models of pneumococcal pneumonia to determine the importance of macrolide resistance. A promising new, low-dose aerosol model of pneumonia is briefly presented, as is a discussion of the limitations of existing models.

Treatment of drug-resistant tuberculosis is hindered by the high toxicity and poor efficacy of second-line drugs. New compounds must be used together with existing drugs, yet clinical trials to optimize combinations of drugs for drug-resistant tuberculosis are lacking. We conducted an extensive review of existing in vitro, animal, and clinical studies involving World Health Organization–defined group 1, 2, and 4 drugs used in drug-resistant tuberculosis regimens to inform clinical trials and identify critical research questions. Results suggest that optimizing the dosing of pyrazinamide, the injectables, and isoniazid for drug-resistant tuberculosis is a high priority. Additional pharmacokinetic, pharmacodynamic, and toxicodynamic studies are needed for pyrazinamide and ethionamide. Clinical trials of the comparative efficacy and appropriate treatment duration of injectables are recommended. For isoniazid, rapid genotypic tests for Mycobacterium tuberculosis mutations should be nested in clinical trials. Further research focusing on optimization of dose and duration of drugs with activity against drug-resistant tuberculosis is paramount.

Presenting features A 40-year-old man with human immunodeficiency virus infection (CD4 count, 694/μL) and a history of sickle cell anemia was admitted for pain management after a right iliac wing fracture sustained in an assault. He denied recent fevers or respiratory symptoms. His medical history was remarkable for repeated vaso-occlusive crises and episodes of the acute chest syndrome, with resultant pulmonary hypertension and right-side heart failure. His physical examination was most notable for fever as high as 38.2°C, cervical and axillary adenopathy (2 cm), elevated jugular venous pressure, cardiomegaly, and hepatomegaly. His hematocrit was 19.5%, with a mean corpuscular volume of 91 fL; the platelet count was 176 000/μL; and the leukocyte count was 15 000/μL. He underwent a computed tomographic scan of the chest, abdomen, and pelvis (Figure 1), Figure 1Computed tomographic scan of the chest, abdomen, and pelvis revealing discrete lesions of low attenuation in the liver and autoinfarction of the spleen. which revealed discrete lesions of low attenuation in the liver, the largest being 4.5 cm in diameter, and autoinfarction of the spleen. What is the diagnosis?