Elderly patients with tuberculosis in a low-incidence country - Clinical characteristics, inflammation and outcome.

BACKGROUND: Susceptibility to respiratory infections increases with age. Diagnosing and treating tuberculosis in the elderly comes with the challenges of fewer specific symptoms and possibly more side effects of treatment. Much is unknown when it comes to tuberculosis in the elderly, especially in relation to inflammation, which may impact mortality. We, therefore, investigated a clinical cohort of elderly tuberculosis patients. METHODS: Patients aged ≥65 years, admitted to our tuberculosis reference center between 2005 and 2021, were retrospectively included in our cohort. Sociodemographic data, clinical characteristics, laboratory results, including inflammatory markers at baseline (monocyte, neutrophil, lymphocyte count, and CRP levels), and treatment outcomes were collected. They were compared to the National Dutch TB Registry and analyzed using descriptive statistics. Survival analysis was performed using univariate Cox regression analysis and a log-rank test. Results were visualized in Kaplan-Meier curves. RESULTS: 104 elderly tuberculosis patients, mostly European, with a mean age of 75 years, were included. None were HIV-infected. Miliary tuberculosis cases were overrepresented (14 %) compared to the National Dutch TB Registry (5 % in elderly, 2 % adults). Fever occurred in 77 % (57/74), and the duration of fever decreased with age. Innate immune markers, including monocyte/lymphocyte-ratio, moderately correlated with CRP. Overall mortality was 15 %, and highest (33 %) in patients with CRP levels >100 mg/mL. CONCLUSION: In elderly tuberculosis patients in a low-incidence setting, mortality rates are higher in comparison to younger patients. The overrepresentation of miliary tuberculosis may suggest waning immunity, with a subset of patients exhibiting strong inflammation associated with increased mortality.

Clofazimine Is a Safe and Effective Alternative for Rifampicin in Mycobacterium avium Complex Pulmonary Disease Treatment: Outcomes of a Randomized Trial.

BACKGROUND: Results of retrospective studies have suggested clofazimine as an alternative for rifampicin in the treatment of Mycobacterium avium complex pulmonary disease (MAC-PD). RESEARCH QUESTION: Is a treatment regimen consisting of clofazimine-ethambutol-macrolide noninferior to the standard treatment regimen (rifampicin-ethambutol-macrolide) in the treatment of MAC-PD? STUDY DESIGN AND METHODS: In this single-center, nonblinded clinical trial, adult patients with MAC-PD were randomly assigned in a 1:1 ratio to receive rifampicin or clofazimine as adjuncts to an ethambutol-macrolide regimen. The primary outcome was sputum culture conversion following 6 months of treatment. RESULTS: Forty patients were assigned to receive either rifampicin (n = 19) or clofazimine (n = 21) in addition to ethambutol and a macrolide. Following 6 months of treatment, both arms showed similar percentages of sputum culture conversion based on an intention-to-treat analysis: 58% (11 of 19) for rifampicin and 62% (13 of 21) for clofazimine. Study discontinuation, mainly due to adverse events, was equal in both arms (26% vs 33%). Based on an on-treatment analysis, sputum culture conversion following 6 months of treatment was 79% in both groups. In the clofazimine arm, diarrhea was more prevalent (76% vs 37%; P = .012), while arthralgia was more frequent in the rifampicin arm (37% vs 5%; P = .011). No difference in the frequency of QTc prolongation was seen between groups. INTERPRETATION: A clofazimine-ethambutol-macrolide regimen showed similar results to the standard rifampicin-ethambutol-macrolide regimen and should be considered in the treatment of MAC-PD. The frequency of adverse events was similar in both arms, but their nature was different. Individual patient characteristics and possible drug-drug interactions should be taken into consideration when choosing an antibiotic regimen for MAC-PD. CLINICAL TRIAL REGISTRATION: EudraCT; No.: 2015-003786-28; URL: https://eudract.ema.europa.eu.

Effect of seven anti-tuberculosis treatment regimens on sputum microbiome: a retrospective analysis of the HIGHRIF study 2 and PanACEA MAMS-TB clinical trials.

BACKGROUND: Respiratory tract microbiota has been described as the gatekeeper for respiratory health. We aimed to assess the impact of standard-of-care and experimental anti-tuberculosis treatment regimens on the respiratory microbiome and implications for treatment outcomes. METHODS: In this retrospective study, we analysed the sputum microbiome of participants with tuberculosis treated with six experimental regimens versus standard-of-care who were part of the HIGHRIF study 2 (NCT00760149) and PanACEA MAMS-TB (NCT01785186) clinical trials across a 3-month treatment follow-up period. Samples were from participants in Mbeya, Kilimanjaro, Bagamoyo, and Dar es Salaam, Tanzania. Experimental regimens were composed of different combinations of rifampicin (R), isoniazid (H), pyrazinamide (Z), ethambutol (E), moxifloxacin (M), and a new drug, SQ109 (Q). Reverse transcription was used to create complementary DNA for each participant's total sputum RNA and the V3-V4 region of the 16S rRNA gene was sequenced using the Illumina metagenomic technique. Qiime was used to analyse the amplicon sequence variants and estimate alpha diversity. Descriptive statistics were applied to assess differences in alpha diversity pre-treatment and post-treatment initiation and the effect of each treatment regimen. FINDINGS: Sequence data were obtained from 397 pre-treatment and post-treatment samples taken between Sept 26, 2008, and June 30, 2015, across seven treatment regimens. Pre-treatment microbiome (206 genera) was dominated by Firmicutes (2860 [44%] of 6500 amplicon sequence variants [ASVs]) at the phylum level and Streptococcus (2340 [36%] ASVs) at the genus level. Two regimens had a significant depressing effect on the microbiome after 2 weeks of treatment, HR20mg/kgZM (Shannon diversity index p=0·0041) and HR35mg/kgZE (p=0·027). Gram-negative bacteria were the most sensitive to bactericidal activity of treatment with the highest number of species suppressed being under the moxifloxacin regimen. By week 12 after treatment initiation, microbiomes had recovered to pre-treatment level except for the HR35mg/kgZE regimen and for genus Mycobacterium, which did not show recovery across all regimens. Tuberculosis culture conversion to negative by week 8 of treatment was associated with clearance of genus Neisseria, with a 98% reduction of the pre-treatment level. INTERPRETATION: HR20mg/kgZM was effective against tuberculosis without limiting microbiome recovery, which implies a shorter efficacious anti-tuberculosis regimen with improved treatment outcomes might be achieved without harming the commensal microbiota. FUNDING: European and Developing Countries Clinical Trials Partnership and German Ministry of Education and Research.

Drug interaction potential of high-dose rifampicin in patients with pulmonary tuberculosis.

Accumulating evidence supports the use of higher doses of rifampicin for tuberculosis (TB) treatment. Rifampicin is a potent inducer of metabolic enzymes and drug transporters, resulting in clinically relevant drug interactions. To assess the drug interaction potential of higher doses of rifampicin, we compared the effect of high-dose rifampicin (40 mg/kg daily, RIF40) and standard-dose rifampicin (10 mg/kg daily, RIF10) on the activities of major cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp). In this open-label, single-arm, two-period, fixed-order phenotyping cocktail study, adult participants with pulmonary TB received RIF10 (days 1-15), followed by RIF40 (days 16-30). A single dose of selective substrates (probe drugs) was administered orally on days 15 and 30: caffeine (CYP1A2), tolbutamide (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), midazolam (CYP3A), and digoxin (P-gp). Intensive pharmacokinetic blood sampling was performed over 24 hours after probe drug intake. In all, 25 participants completed the study. Geometric mean ratios (90% confidence interval) of the total exposure (area under the concentration versus time curve, RIF40 versus RIF10) for each of the probe drugs were as follows: caffeine, 105% (96%-115%); tolbutamide, 80% (74%-86%); omeprazole, 55% (47%-65%); dextromethorphan, 77% (68%-86%); midazolam, 62% (49%-78%), and 117% (105%-130%) for digoxin. In summary, high-dose rifampicin resulted in no additional effect on CYP1A2, mild additional induction of CYP2C9, CYP2C19, CYP2D6, and CYP3A, and marginal inhibition of P-gp. Existing recommendations on managing drug interactions with rifampicin can remain unchanged for the majority of co-administered drugs when using high-dose rifampicin. Clinical Trials registration number NCT04525235.

Recent advances in the treatment of tuberculosis.

BACKGROUND: Tuberculosis (TB) is a global health challenge and one of the leading causes of death worldwide. In the last decade, the TB treatment landscape has dramatically changed. After long years of stagnation, new compounds entered the market (bedaquiline, delamanid, and pretomanid) and phase III clinical trials have shown promising results towards shortening duration of treatment for both drug-susceptible (Study 31/A5349, TRUNCATE-TB, and SHINE) and drug-resistant TB (STREAM, NiX-TB, ZeNix, and TB-PRACTECAL). Dose optimization of rifamycins and repurposed drugs has also brought hopes of further development of safe and effective regimens. Consequently, international and WHO clinical guidelines have been updated multiple times in the last years to keep pace with these advances. OBJECTIVES: This narrative review aims to summarize the state-of-the-art on treatment of drug-susceptible and drug-resistant TB, as well as recent trial results and an overview of ongoing clinical trials. SOURCES: A non-systematic literature review was conducted in PubMed and MEDLINE, focusing on the treatment of TB. Ongoing clinical trials were listed according to the authors' knowledge and completed consulting clinicaltrials.gov and other publicly available websites (www.resisttb.org/clinical-trials-progress-report, www.newtbdrugs.org/pipeline/trials). CONTENT: This review summarizes the recent, major changes in the landscape for drug-susceptible and drug-resistant treatment, with a specific focus on their potential impact on patient outcomes and programmatic TB management. Moreover, insights in host-directed therapies, and advances in pharmacokinetics and pharmacogenomics are discussed. A thorough outline of ongoing therapeutic clinical trials is presented, highlighting different approaches and goals in current TB clinical research. IMPLICATIONS: Future research should be directed to individualize regimens and protect these recent breakthroughs by preventing and identifying the selection of drug resistance and providing widespread, affordable, patient-centred access to new treatment options for all people affected by TB.

Model-based analysis of bactericidal activity and a new dosing strategy for optimised-dose rifampicin.

BACKGROUND: Higher doses of rifampicin for tuberculosis have been shown to improve early bactericidal activity (EBA) and at the same time increase the intolerability due to high exposure at the beginning of treatment. To support dose optimisation of rifampicin, this study investigated new and innovative staggered dosing of rifampicin using clinical trial simulations to minimise tolerability problems and still achieve good efficacy. METHODS: Rifampicin population pharmacokinetics and time-to-positivity models were applied to data from patients receiving 14 days of daily 10-50 mg/kg rifampicin to characterise the exposure-response relationship. Furthermore, clinical trial simulations of rifampicin exposure were performed following four different staggered dosing scenarios. The simulated exposure after 35 mg/kg was used as a relative comparison for efficacy. Tolerability was derived from a previous model-based analysis relating exposure at day 7 and the probability of having adverse events. RESULTS: The linear relationship between rifampicin exposure and bacterial killing rate in sputum indicated that the maximum rifampicin EBA was not reached at doses up to 50 mg/kg. Clinical trial simulations of a staggered dosing strategy starting the treatment at a lower dose (20 mg/kg) for 7 days followed by a higher dose (40 mg/kg) predicted a lower initial exposure with lower probability of tolerability problems and better EBA compared with a regimen of 35 mg/kg daily. CONCLUSIONS: Staggered dosing of 20 mg/kg for 7 days followed by 40 mg/kg is predicted to reduce tolerability while maintaining exposure levels associated with better efficacy.

Protocol for a feasibility randomized controlled trial to evaluate the efficacy, safety and tolerability of N-acetylcysteine in reducing adverse drug reactions among adults treated for multidrug-resistant tuberculosis in Tanzania.

BACKGROUND: Adverse drug reactions (ADRs) frequently occur in patients using second-line anti-tuberculosis medicine for treatment of multidrug resistant tuberculosis (MDR-TB). ADRs contribute to treatment interruptions which can compromise treatment response and risk acquired drug resistance to critical newer drugs such as bedaquiline, while severe ADRs carry considerable morbidity and mortality. N-acetylcysteine (NAC) has shown promise in reducing ADRs for medications related to TB in case series or randomized controlled trials in other medical conditions, yet evidence is lacking in MDR-TB patients. TB endemic settings have limited capacity to conduct clinical trials. We designed a proof-of-concept clinical trial primarily to explore the preliminary evidence on the protective effect of NAC among people treated for MDR-TB with second-line anti-TB medications. METHODS: This is a proof-of-concept randomized open label clinical trial with 3 treatment arms including a control arm, an interventional arm of NAC 900 mg daily, and an interventional arm of NAC 900 mg twice-daily administered during the intensive phase of MDR-TB treatment. Patients initiating MDR-TB treatment will be enrolled at Kibong'oto National Center of Excellence for MDR-TB in the Kilimanjaro region of Tanzania. The minimum anticipated sample size is 66; with 22 participants in each arm. ADR monitoring will be performed at baseline and daily follow-up over 24 weeks including blood and urine specimen collection for hepatic and renal function and electrolyte abnormalities, and electrocardiogram. Sputum will be collected at baseline and monthly thereafter and cultured for mycobacteria as well as assayed for other molecular targets of Mycobacterium tuberculosis. Adverse drug events will be analysed over time using mixed effect models. Mean differences between arms in change of the ADRs from baseline (with 95% confidence intervals) will be derived from the fitted model. DISCUSSION: Given that NAC promotes synthesis of glutathione, an intracellular antioxidant that combats the impact of oxidative stress, it may protect against medication induced oxidative damage in organs such as liver, pancreas, kidney, and cells of the immune system. This randomized controlled trial will determine if NAC leads to fewer ADRs, and if this protection is dose dependent. Fewer ADRs among patients treated with MDR-TB may significantly improve treatment outcomes for multidrug regimens that necessitate prolonged treatment durations. Conduct of this trial will set the needed infrastructure for clinical trials. TRIAL REGISTRATION: PACTR202007736854169 Registered 03 July 2020.

High rifampicin peak plasma concentrations accelerate the slow phase of bacterial decline in tuberculosis patients: Evidence for heteroresistance.

BACKGROUND: Antibiotic treatments are often associated with a late slowdown in bacterial killing. This separates the killing of bacteria into at least two distinct phases: a quick phase followed by a slower phase, the latter of which is linked to treatment success. Current mechanistic explanations for the in vitro slowdown are either antibiotic persistence or heteroresistance. Persistence is defined as the switching back and forth between susceptible and non-susceptible states, while heteroresistance is defined as the coexistence of bacteria with heterogeneous susceptibilities. Both are also thought to cause a slowdown in the decline of bacterial populations in patients and therefore complicate and prolong antibiotic treatments. Reduced bacterial death rates over time are also observed within tuberculosis patients, yet the mechanistic reasons for this are unknown and therefore the strategies to mitigate them are also unknown. METHODS AND FINDINGS: We analyse a dose ranging trial for rifampicin in tuberculosis patients and show that there is a slowdown in the decline of bacteria. We show that the late phase of bacterial killing depends more on the peak drug concentrations than the total drug exposure. We compare these to pharmacokinetic-pharmacodynamic models of rifampicin heteroresistance and persistence. We find that the observation on the slow phase's dependence on pharmacokinetic measures, specifically peak concentrations are only compatible with models of heteroresistance and incompatible with models of persistence. The quantitative agreement between heteroresistance models and observations is very good ([Formula: see text]). To corroborate the importance of the slowdown, we validate our results by estimating the time to sputum culture conversion and compare the results to a different dose ranging trial. CONCLUSIONS: Our findings indicate that higher doses, specifically higher peak concentrations may be used to optimize rifampicin treatments by accelerating bacterial killing in the slow phase. It adds to the growing body of literature supporting higher rifampicin doses for shortening tuberculosis treatments.

Clinical implications of molecular drug resistance testing for Mycobacterium tuberculosis: a 2023 TBnet/RESIST-TB consensus statement.

Drug-resistant tuberculosis is a substantial health-care concern worldwide. Despite culture-based methods being considered the gold standard for drug susceptibility testing, molecular methods provide rapid information about the Mycobacterium tuberculosis mutations associated with resistance to anti-tuberculosis drugs. This consensus document was developed on the basis of a comprehensive literature search, by the TBnet and RESIST-TB networks, about reporting standards for the clinical use of molecular drug susceptibility testing. Review and the search for evidence included hand-searching journals and searching electronic databases. The panel identified studies that linked mutations in genomic regions of M tuberculosis with treatment outcome data. Implementation of molecular testing for the prediction of drug resistance in M tuberculosis is key. Detection of mutations in clinical isolates has implications for the clinical management of patients with multidrug-resistant or rifampicin-resistant tuberculosis, especially in situations when phenotypic drug susceptibility testing is not available. A multidisciplinary team including clinicians, microbiologists, and laboratory scientists reached a consensus on key questions relevant to molecular prediction of drug susceptibility or resistance to M tuberculosis, and their implications for clinical practice. This consensus document should help clinicians in the management of patients with tuberculosis, providing guidance for the design of treatment regimens and optimising outcomes.

Combined quantitative tuberculosis biomarker model for time-to-positivity and colony forming unit to support tuberculosis drug development.

Biomarkers are quantifiable characteristics of biological processes. In Mycobacterium tuberculosis, common biomarkers used in clinical drug development are colony forming unit (CFU) and time-to-positivity (TTP) from sputum samples. This analysis aimed to develop a combined quantitative tuberculosis biomarker model for CFU and TTP biomarkers for assessing drug efficacy in early bactericidal activity studies. Daily CFU and TTP observations in 83 previously patients with uncomplicated pulmonary tuberculosis after 7 days of different rifampicin monotherapy treatments (10-40 mg/kg) from the HIGHRIF1 study were included in this analysis. The combined quantitative tuberculosis biomarker model employed the Multistate Tuberculosis Pharmacometric model linked to a rifampicin pharmacokinetic model in order to determine drug exposure-response relationships on three bacterial sub-states using both the CFU and TTP data simultaneously. CFU was predicted from the MTP model and TTP was predicted through a time-to-event approach from the TTP model, which was linked to the MTP model through the transfer of all bacterial sub-states in the MTP model to a one bacterial TTP model. The non-linear CFU-TTP relationship over time was well predicted by the final model. The combined quantitative tuberculosis biomarker model provides an efficient approach for assessing drug efficacy informed by both CFU and TTP data in early bactericidal activity studies and to describe the relationship between CFU and TTP over time.

The accuracy of an electronic nose to diagnose tuberculosis in patients referred to an expert centre.

INTRODUCTION: An electronic nose (eNose) device has shown a high specificity and sensitivity to diagnose or rule out tuberculosis (TB) in the past. The aim of this study was to evaluate its performance in patients referred to INERAM. METHODS: Patients aged ≥15 years were included. A history, physical examination, chest radiography (CRX) and microbiological evaluation of a sputum sample were performed in all participants, as well as a 5-minute breath test with the eNose. TB diagnosis was preferably established by the gold standard and compared to the eNose predictions. Univariate and multivariate logistic regression analyses were performed to assess potential risk factors for erroneous classification results by the eNose. RESULTS: 107 participants with signs and symptoms of TB were enrolled of which 91 (85.0%) were diagnosed with TB. The blind eNose predictions resulted in an accuracy of 50%; a sensitivity of 52.3% (CI 95%: 39.6-64.7%) and a specificity of 36.4% (CI 95%: 12.4-68.4%). Risk factors for erroneous classifications by the eNose were older age (multivariate analysis: OR 1.55, 95% CI 1.10-2.18, p = 0.012) and antibiotic use (multivariate analysis: OR 3.19, 95% CI 1.06-9.66, p = 0.040). CONCLUSION: In this study, the accuracy of the eNose to diagnose TB in a tertiary referral hospital was only 50%. The use of antibiotics and older age represent important factors negatively influencing the diagnostic accuracy of the eNose. Therefore, its use should probably be restricted to screening in high-risk communities in less complex healthcare settings.

Tuberculosis Molecular Bacterial Load Assay Reveals Early Delayed Bacterial Killing in Patients With Relapse.

Bacterial killing in patients with tuberculosis (TB) relapse was compared to that in patients achieving cure, measured by TB molecular bacterial load assay (TB-MBLA) or mycobacteria growth indicator tube (MGIT) time to positivity (TTP). TB-MBLA in 4 relapsed patients was significantly different compared to 132 cured patients after 2 weeks of treatment; MGIT TTP showed a significant difference from week 8.

New and Repurposed Drugs for the Treatment of Active Tuberculosis: An Update for Clinicians.

Although tuberculosis (TB) is preventable and curable, the lengthy treatment (generally 6 months), poor patient adherence, high inter-individual variability in pharmacokinetics (PK), emergence of drug resistance, presence of comorbidities, and adverse drug reactions complicate TB therapy and drive the need for new drugs and/or regimens. Hence, new compounds are being developed, available drugs are repurposed, and the dosing of existing drugs is optimized, resulting in the largest drug development portfolio in TB history. This review highlights a selection of clinically available drug candidates that could be part of future TB regimens, including bedaquiline, delamanid, pretomanid, linezolid, clofazimine, optimized (high dose) rifampicin, rifapentine, and para-aminosalicylic acid. The review covers drug development history, preclinical data, PK, and current clinical development.

Building sustainable clinical trial sites in Sub-Saharan Africa through networking, infrastructure improvement, training and conducting clinical studies: The PanACEA approach.

INTRODUCTION: The Pan-African Consortium for the Evaluation of Anti-Tuberculosis Antibiotics (PanACEA) was designed to build tuberculosis (TB) trial capacity whilst conducting clinical trials on novel and existing agents to shorten and simplify TB treatment. PanACEA has now established a dynamic network of 11 sub-Saharan clinical trial sites and four European research institutions. OBJECTIVES: In 2011, a capacity development program, funded by the European & Developing Countries Clinical Trials Partnership (EDCTP), was launched with four objectives, aiming at strengthening collaborating TB research sites to reach the ultimate goal of becoming self-sustainable institutions: networking; training; conducting clinical trials; and infrastructure scaling-up of sites. METHODS: Assessment in six sub-Saharan TB-endemic countries (Gabon, Kenya, South Africa, Tanzania, Uganda and Zambia) were performed through a structured questionnaire, site visits, discussion with the PanACEA consortium, setting of milestones and identification of priorities and followed-up with evaluations of each site. The results of this needs-based assessment was then translated into capacity development measures. RESULTS: In the initial phase, over a four-year period (March 2011 - June 2014), the programme scaled-up six sites; conducted a monitoring training program for 11 participants; funded five MSc and four PhD students, fostering gender balance; conducted four epidemiological studies; supported sites to conduct five Phase II studies and formed a sustainable platform for TB research (panacea-tb.net). CONCLUSION: Our experience of conducting TB clinical trials within the PanACEA programme environment of mentoring, networking and training has provided a sound platform for establishing future sustainable research centres. Our goal of facilitating emergent clinical TB trial sites to better initiate and lead research activities has been mostly successful.

Interleukin-1 receptor antagonist anakinra as treatment for paradoxical responses in HIV-negative tuberculosis patients: A case series.

BACKGROUND: Paradoxical inflammatory responses can occur during microbiologically successful antituberculous therapy. Optimal treatment is unknown, but corticosteroids are used most often. It is likely that interleukin-1 (IL-1) plays a central role in the development of these paradoxical responses, and if corticosteroids fail or are undesirable because of adverse effects, anti-IL-1 therapy may therefore be a rational choice. METHODS: We present seven HIV-negative tuberculosis patients with paradoxical responses, two with exclusively pulmonary and five with extrapulmonary tuberculosis. All had received corticosteroids, with unsatisfactory effect. Patients were treated with the IL-1 receptor antagonist anakinra and monitored for reduction of fever and inflammatory markers, imaging evidence of stabilization or regression of lesions, and respiratory improvement. FINDINGS: Six patients had anemia and four patients had lymphopenia at the start of the antituberculosis treatment. Fever was present in six patients at the moment of paradoxical response. Anakinra resulted in the decrease of fever within days, followed by resolution of symptoms and radiological improvement in five patients. Anakinra induced neutropenia, necessitating its cessation in two patients, who recovered quickly afterward. CONCLUSION: Anakinra can be considered in HIV-negative tuberculosis patients with paradoxical responses when steroids fail or are undesired. Given its favorable safety profile and reversible side effects, it is conceivable that anakinra might also be used as first-line adjuvant treatment for paradoxical responses. FUNDING: A.v.L. and R.v.C. are supported by National Institutes of Health (R01AI145781).

Prediction of Moxifloxacin Concentrations in Tuberculosis Patient Populations by Physiologically Based Pharmacokinetic Modeling.

Moxifloxacin has an important role in the treatment of tuberculosis (TB). Unfortunately, coadministration with the cornerstone TB drug rifampicin results in suboptimal plasma exposure. We aimed to gain insight into the moxifloxacin pharmacokinetics and the interaction with rifampicin. Moreover, we provided a mechanistic framework to understand moxifloxacin pharmacokinetics. We developed a physiologically based pharmacokinetic model in Simcyp version 19, with available and newly generated in vitro and in vivo data, to estimate pharmacokinetic parameters of moxifloxacin alone and when administered with rifampicin. By combining these strategies, we illustrate that the role of P-glycoprotein in moxifloxacin transport is limited and implicate MRP2 as transporter of moxifloxacin-glucuronide followed by rapid hydrolysis in the gut. Simulations of multiple dose area under the plasma concentration-time curve (AUC) of moxifloxacin (400 mg once daily) with and without rifampicin (600 mg once daily) were in accordance with clinically observed data (predicted/observed [P/O] ratio of 0.87 and 0.80, respectively). Importantly, increasing the moxifloxacin dose to 600 mg restored the plasma exposure both in actual patients with TB as well as in our simulations. Furthermore, we extrapolated the single dose model to pediatric populations (P/O AUC ratios, 1.04-1.52) and the multiple dose model to children with TB (P/O AUC ratio, 1.51). In conclusion, our combined approach resulted in new insights into moxifloxacin pharmacokinetics and accurate simulations of moxifloxacin exposure with and without rifampicin. Finally, various knowledge gaps were identified, which may be considered as avenues for further physiologically based pharmacokinetic refinement.

Factors Associated with Unfavourable Treatment Outcomes in Patients with Tuberculosis: A 16-Year Cohort Study (2005-2020), Republic of Karakalpakstan, Uzbekistan.

Tuberculosis (TB) remains a public health burden in the Republic of Karakalpakstan, Uzbekistan. This region-wide retrospective cohort study reports the treatment outcomes of patients registered in the TB electronic register and treated with first-line drugs in the TB Programme of the Republic of Karakalpakstan from 2005-2020 and factors associated with unfavourable outcomes. Among 35,122 registered patients, 24,394 (69%) patients were adults, 2339 (7%) were children, 18,032 (51%) were male and 19,774 (68%) lived in rural areas. Of these patients, 29,130 (83%) had pulmonary TB and 7497 (>22%) had been previously treated. There were 7440 (21%) patients who had unfavourable treatment outcomes. Factors associated with unfavourable treatment outcomes included: increasing age, living in certain parts of the republic, disability, pensioner status, unemployment, being HIV-positive, having pulmonary TB, and receiving category II treatment. Factors associated with death included: being adult and elderly, living in certain parts of the republic, having a disability, pensioner status, being HIV-positive, and receiving category II treatment. Factors associated with failure included: being adolescent, female, having pulmonary TB. Factors associated with loss to follow-up included: being male, disability, pensioner status, unemployment, receiving category II treatment. In summary, there are sub-groups of patients who need special attention in order to decrease unfavourable treatment outcomes.

Treatment of severe Mycobacterium avium complex pulmonary disease with adjunctive amikacin and clofazimine versus standard regimen alone: a retrospective study.

Addition of intravenous amikacin and clofazimine to recommended rifamycin-ethambutol-macrolide regimens yields favourable outcomes in severe M. avium complex pulmonary disease (MAC-PD). This five-drug regimen should be considered in select MAC-PD patients. https://bit.ly/30dxdRj.