BACKGROUND: Nontuberculous mycobacteria are environmental organisms that are increasingly causing chronic and debilitating pulmonary infections, of which Mycobacterium avium complex (MAC) is the most common pathogen. MAC pulmonary disease (MAC-PD) is often difficult to treat, often requiring long-term multidrug antibiotic therapy.
OBJECTIVE: Is there an association between various guideline-based three-drug therapy (GBT) regimens and (1) therapy-associated adverse events or (2) regimen change/discontinuation, within 12 months of therapy initiation?
METHODS: In a retrospective cohort study, we examined tolerability outcomes of GBT regimens for MAC-PD in 4,626 US Medicare beneficiaries with bronchiectasis, who were prescribed a GBT as initial antibiotic treatment for presumed MAC-PD during 2006 to 2014. Using multivariable Cox proportional hazard regression, we estimated adjusted hazard ratios (aHRs) to compare the risk of adverse events and regimen change/discontinuations within 12 months of therapy initiation in various GBT regimens.
RESULTS: The cohort had a mean age ± SD of 77.9 ± 6.1 years at treatment start, were mostly female (77.7%), and were mostly non-Hispanic White (87.2%). The risk of regimen change/discontinuation within 12 months of therapy was higher for clarithromycin-based regimens than azithromycin-based regimens (aHR, 1.12; 95% CI, 1.04-1.20 with rifampin; aHR, 1.11; 95% CI, 0.93-1.32 with rifabutin as the companion rifamycin), and for rifabutin-containing regimens than rifampin-containing regimens (aHR, 1.49; 95% CI, 1.33-1.68 with azithromycin; aHR, 1.47; 95% CI, 1.27-1.70 with clarithromycin as the companion macrolide). The aHR comparing regimen change/discontinuation with clarithromycin-ethambutol-rifabutin and azithromycin-ethambutol-rifampin was 1.64 (95% CI, 1.43-1.64).
CONCLUSIONS: Overall, an azithromycin-based regimen was less likely to be changed or discontinued than a clarithromycin-based regimen, and a rifampin-containing regimen was less likely to be changed or discontinued than a rifabutin-containing regimen within 12 months of therapy start. Our work provides a population-based assessment on the tolerability of multidrug antibiotic regimens used for the treatment of MAC-PD.

BACKGROUND: The current World Health Organization (WHO) pediatric tuberculosis dosing guidelines lead to suboptimal drug exposures. Identifying factors altering the exposure of these drugs in children is essential for dose optimization. Pediatric pharmacokinetic studies are usually small, leading to high variability and uncertainty in pharmacokinetic results between studies. We pooled data from large pharmacokinetic studies to identify key covariates influencing drug exposure to optimize tuberculosis dosing in children.
RESULTS: We used nonlinear mixed-effects modeling to characterize the pharmacokinetics of rifampicin, isoniazid, and pyrazinamide, and investigated the association of human immunodeficiency virus (HIV), antiretroviral therapy (ART), drug formulation, age, and body size with their pharmacokinetics. Data from 387 children from South Africa, Zambia, Malawi, and India were available for analysis; 47% were female and 39% living with HIV (95% on ART). Median (range) age was 2.2 (0.2 to 15.0) years and weight 10.9 (3.2 to 59.3) kg. Body size (allometry) was used to scale clearance and volume of distribution of all 3 drugs. Age affected the bioavailability of rifampicin and isoniazid; at birth, children had 48.9% (95% confidence interval (CI) [36.0%, 61.8%]; p < 0.001) and 64.5% (95% CI [52.1%, 78.9%]; p < 0.001) of adult rifampicin and isoniazid bioavailability, respectively, and reached full adult bioavailability after 2 years of age for both drugs. Age also affected the clearance of all drugs (maturation), children reached 50% adult drug clearing capacity at around 3 months after birth and neared full maturation around 3 years of age. While HIV per se did not affect the pharmacokinetics of first-line tuberculosis drugs, rifampicin clearance was 22% lower (95% CI [13%, 28%]; p < 0.001) and pyrazinamide clearance was 49% higher (95% CI [39%, 57%]; p < 0.001) in children on lopinavir/ritonavir; isoniazid bioavailability was reduced by 39% (95% CI [32%, 45%]; p < 0.001) when simultaneously coadministered with lopinavir/ritonavir and was 37% lower (95% CI [22%, 52%]; p < 0.001) in children on efavirenz. Simulations of 2010 WHO-recommended pediatric tuberculosis doses revealed that, compared to adult values, rifampicin exposures are lower in most children, except those younger than 3 months, who experience relatively higher exposure for all drugs, due to immature clearance. Increasing the rifampicin doses in children older than 3 months by 75 mg for children weighing <25 kg and 150 mg for children weighing >25 kg could improve rifampicin exposures. Our analysis was limited by the differences in availability of covariates among the pooled studies.
CONCLUSIONS: Children older than 3 months have lower rifampicin exposures than adults and increasing their dose by 75 or 150 mg could improve therapy. Altered exposures in children with HIV is most likely caused by concomitant ART and not HIV per se. The importance of the drug-drug interactions with lopinavir/ritonavir and efavirenz should be evaluated further and considered in future dosing guidance.
BACKGROUND: ClinicalTrials.gov registration numbers; NCT02348177, NCT01637558, ISRCTN63579542.

In December 2022, based on the assessment of new evidence, the World Health Organization (WHO) updated its guidelines for the treatment of drug-resistant tuberculosis (TB). The evaluation of both, these recommendations, and the latest study data, makes it necessary to update the existing guidelines on the treatment of at least rifampicin-resistant tuberculosis for the German-speaking region, hereby replacing the respective chapters. A shortened MDR-TB treatment of at least 6 month using the fixed and non-modifiable drug combination of bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM) is now also recommended for Germany, Austria, and Switzerland under certain conditions. This recommendation applies to TB cases with proven rifampicin resistance, including rifampicin monoresistance. For treatment of pre-extensively drug resistant TB (pre-XDR-TB), an individualized treatment for 18 months adjusted to resistance data continues to be the primary recommendation. The non-modifiable drug combination of bedaquiline, pretomanid, and linezolid (BPaL) may be used alternatively in pre-XDR TB if all prerequisites are met. The necessary prerequisites for the use of BPaLM and BPaL are presented in this amendment to the S2k guideline for \'Tuberculosis in adulthood\'.
Im Dezember 2022 hat die Weltgesundheitsorganisation (WHO) die Empfehlungen für die Behandlung der medikamentenresistenten Tuberkulose (TB) aktualisiert. Die Bewertung dieser Empfehlungen und der neuen Studiendaten macht auch für den deutschsprachigen Raum eine Aktualisierung der Leitlinienempfehlungen zur Therapie der mindestens Rifampicin-resistenten Tuberkulose notwendig, welche die entsprechenden Kapitel ersetzt. Auch für Deutschland, Österreich und die Schweiz wird nun eine verkürzte, mindestens 6-monatige MDR-TB-Therapie unter Einsatz der festgelegten und nicht veränderbaren Medikamentenkombination Bedaquilin, Pretomanid, Linezolid und Moxifloxacin (BPaLM) empfohlen, wenn alle hierfür notwendigen Voraussetzungen erfüllt sind. Diese Empfehlung gilt für TB-Fälle mit nachgewiesener Rifampicin-Resistenz einschließlich der Rifampicin-Monoresistenz. Zur Behandlung der präextensiven (prä-XDR) TB wird weiterhin in erster Linie eine individualisierte, an die Resistenzdaten angepasste Therapie über 18 Monate empfohlen. Die nicht veränderbare Medikamentenkombination Bedaquilin, Pretomanid und Linezolid (BPaL) kann bei prä-XDR alternativ angewendet werden, wenn alle Voraussetzungen dafür erfüllt sind. Die notwendigen Voraussetzungen für den Einsatz von BPaLM und BPaL werden in diesem Amendment zur S2k-Leitlinie „Tuberkulose im Erwachsenenalter“ begründet dargestellt.

In September 2022, the World Health Organization (WHO) published a new guideline for the management of tuberculosis (TB) in children and adolescents. It included eight new recommendations. Xpert MTB/RIF Ultra (Xpert Ultra) has been designated as the preferred initial diagnostic test for pulmonary TB and detection of rifampicin resistance. But its place vis-à-vis the previously recommended GeneXpert has not been clarified. Further, the limited diagnostic accuracy of Xpert Ultra in some biological specimens like nasopharyngeal aspirates, and the inability to report the presence or absence of rifampicin resistance in \'trace\' reports has not been addressed. The guideline also recommends a shortened 4-mo treatment regimen for non-severe drug-susceptible TB. This is based on a single trial having several methodological issues that limit its applicability and generalizability. Interestingly, the criteria for designating \'non-severe\' TB in the trial is based on smear negativity, whereas the new WHO recommendation is to omit smear microscopy altogether. The guideline also recommends an alternative 6-mo intensive regimen for drug-susceptible TB meningitis, which needs more supportive evidence. The lower age limits for the use of bedaquiline and delamanid have been decreased to less than 6 and 3 y respectively. While this makes it feasible to treat drug resistant TB in children with oral medications, the resource implications need careful consideration. These concerns advocate caution before the WHO guideline recommendations can be universally implemented.

BACKGROUND: Infective endocarditis (IE) is still a severe disease with elevated morbidity and mortality. Nevertheless, the last European guidelines (GL) date back to 2015, and a recent survey described a diffuse suboptimal adherence to their recommendations. Here, we described a real-life scenario about adherence to IE treatment GL.
METHODS: This was a retrospective, multicentric, case-control study. All the cases of IE admitted to our wards from 2016 to 2020 were enrolled. Patients were divided into two groups, according to the non-adherence (group A, cases) or adherence (group B, controls) to 2015 ESC guidelines. Only targeted treatments were considered. Groups were compared for demographic, clinical, microbiological, and laboratory data and outcome. As a post hoc analysis, we analysed the characteristics of deviations from the guidelines and how these deviations affected mortality.
RESULTS: A total of 246 patients were enrolled, with 128 (52%) in group A and 118 (48%) in group B. Groups were homogeneous except for aetiologies: staphylococcal and blood-culture-negative IE were more frequent in group A, while streptococcal and enterococcal IE were more frequent in group B (p < 0.001). In-hospital mortality was comparable in the two groups. The most frequent causes of deviations from the guidelines were use of daptomycin, in addition to standard treatments and the missing administration of rifampin or gentamycin.
CONCLUSIONS: Adherence to 2015 ESC guidelines was limited but it did not affect mortality.

In December 2022 World Health Organization released a new treatment for multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB) guideline. The main novelty of this update is two new recommendations (i) a 6-month treatment regimen composed of bedaquiline, pretomanid, linezolid (600 mg), and moxifloxacin (BPaLM) is recommended in place of the 9-month or longer (18-month) regimens in MDR/RR-TB patients, now including extensive pulmonary TB and extrapulmonary TB (except TB involving central nervous system, miliary TB and osteoarticular TB); (ii) the use of the 9-month all-oral regimen rather than longer (18-months) regimen is suggested in patients with MDR/RR-TB and in whom resistance to fluoroquinolones has been excluded. Longer (18-month) treatments remain a valid option in all cases in which shorter regimens cannot be implemented due to intolerance, drug-drug interactions, extensively drug-resistant tuberculosis, extensive forms of extrapulmonary TB, or previous failure. The new guidelines represent a milestone in MDR/RR-TB treatment landscape, setting the basis for a shorter, all-oral, more acceptable, equitable, and patient-centered model for MDR/RR-TB management. However, some challenges remain to be addressed to allow full implementation of the new recommendations.

The cure rate of multidrug-resistant and rifampicin-resistant pulmonary tuberculosis in the world is about 60%, and timely surgical intervention can increase the cure rate to more than 85%. The treatment of multidrug-resistant and rifampicin-resistant pulmonary tuberculosis requires multidisciplinary involvement of tuberculosis department, thoracic surgery department, imaging department, laboratory department and other disciplines to significantly reduce its morbidity and mortality. Although the World Health Organization has defined the role and status of surgery in the treatment of multidrug-resistant and rifampicin-resistant pulmonary tuberculosis, there are significant differences in the cognition and diagnosis and treatment methods of domestic clinicians on multidrug-resistant and rifampicin-resistant pulmonary tuberculosis. Therefore, it is urgent to develop expert consensus on surgical treatment of multidrug-resistant and rifampicin-resistant pulmonary tuberculosis for clinicians to learn from in clinical diagnosis and treatment practice. The Chinese Society for Tuberculosis,Chinese Medical Association organized experts in tuberculosis thoracic surgery to write the first draft of consensus based on the expert suggestion on surgical diagnosis and treatment of multidrug-resistant pulmonary tuberculosis written by the European Office of the World Health Organization in 2014 and the 2019 version of China\'s multidrug-resistant and rifampicin-resistant pulmonary tuberculosis expert consensus, and combined with China\'s national situation. This consensus systematically elaborated seven aspects, including surgical indications, contraindications to surgery, conditions and timing of surgery, surgical methods and indications of various surgical procedures, preoperative and postoperative chemotherapy, treatment of surgical complications, and perioperative management of patients with multidrug-resistant and rifampin-resistant pulmonary tuberculosis. After discussion and voting by experts, six recommendations were formed, aiming to provide reference for clinicians in the treatment of multidrug-resistant and rifampin-resistant pulmonary tuberculosis and further improve the standardized diagnosis and treatment level of multidrug-resistant and rifampin-resistant pulmonary tuberculosis in China.
耐多药和利福平耐药肺结核（MDR/RR-PTB）治愈率在60%左右，外科的及时干预可将治愈率提高至85%以上。MDR/RR-PTB的治疗需要结核科、胸外科、影像科、检验科等多学科共同参与，才能明显降低其病死率。世界卫生组织虽已经明确外科手术在MDR/RR-PTB治疗中的作用和地位，但是国内临床医生对其认知和诊疗方法存在较大差异，因此亟须制定MDR/RR-PTB外科治疗专家共识，供临床医师在临床诊治实践中借鉴。中华医学会结核病学分会组织结核胸外科相关专家，基于2014年世界卫生组织欧洲工作处撰写的《耐多药肺结核外科诊疗专家建议》及《中国耐多药和利福平耐药结核病治疗专家共识（2019年版）》，结合我国国情共同撰写了本共识。本共识对MDR/RR-PTB的手术适应证、外科手术禁忌证、手术的条件和时机、手术方式及各种术式适应证、术前术后化疗、手术并发症的处理、患者围手术期管理等7个方面进行了系统的阐述，经专家讨论和投票，共形成6条推荐意见，旨在为临床医生治疗MDR/RR-PTB提供参考，进一步提高我国MDR/RR-PTB规范化诊疗水平。.

South Africa (SA) has the largest antiretroviral therapy programme in the world. While the majority of the country accesses healthcare in the public sector, 15.2% access private healthcare. In 2019, dolutegravir was introduced as first-line treatment for HIV. Dolutegravir has clinically significant interactions with numerous commonly used medicines, e.g. rifampicin and cation-containing medicines such as calcium and iron. They require dosage adjustments, detailed in public and private HIV guidelines.
To describe SA healthcare workers\' guideline access, training and knowledge of dolutegravir\'s interactions, focusing on differences between the public and private sectors.
A cross-sectional, descriptive study was done using an online survey of healthcare workers in the field of HIV in SA, conducted by the National HIV and TB Healthcare Worker Hotline. Convenience sampling was used, with electronic dissemination to users of the hotline and by relevant HIV-focused organisations. Simple descriptive statistics and statistical analyses were used.
A total of 1 939 surveys were analysed, with 22% from the private sector. Training on the dolutegravir guidelines was received by significantly fewer healthcare workers in the private sector v. the public sector: 42.4% (95% confidence interval (CI) 37 - 48) v. 67.5% (95% CI I 65 - 70), respectively. Significantly fewer healthcare workers in the private sector had access to the guidelines (63.8%; 95% CI 59 - 69 v. 78.8%; 95% CI 77 - 81). When asked if they were aware that dolutegravir has interactions, just over half (56.9%) of healthcare workers in the private sector responded \'yes\', 24.6% responded \'no\' and 18.5% did not answer. Of those who were aware that dolutegravir has interactions, 48.9% knew that dolutegravir interacts with calcium, 44.6% with iron and 82.0% with rifampicin. Private sector knowledge of dosing changes was lower for all interacting drugs, with the difference only significant for calcium and iron. Private sector healthcare workers reported significantly lower levels of counselling on dolutegravir use in all appropriate situations.
Private sector healthcare worker access to HIV training and guidelines requires attention. In a high-burden HIV setting such as SA, it is vital that healthcare workers across all professions, in both the public and private sector, know how to adjust antiretroviral dosing due to clinically significant interactions. Without these adjustments, there is a risk of treatment failure, increased mother-to-child transmission and morbidity and mortality.

Results from the STREAM stage 1 trial showed that a 9-month regimen for patients with rifampicin-resistant tuberculosis was non-inferior to the 20-month regimen recommended by the 2011 WHO treatment guidelines. Similar levels of severe adverse events were reported on both regimens suggesting the need for further research to optimise treatment. Stage 2 of STREAM evaluates two additional short-course regimens, both of which include bedaquiline. Throughout stage 2 of STREAM, new drug choices and a rapidly changing treatment landscape have necessitated changes to the trial\'s design to ensure it remains ethical and relevant. This paper describes changes to the trial design to ensure that stage 2 continues to answer important questions. These changes include the early closure to recruitment of two trial arms and an adjustment to the definition of the primary endpoint. If the STREAM experimental regimens are shown to be non-inferior or superior to the stage 1 study regimen, this would represent an important contribution to evidence about potentially more tolerable and more efficacious MDR-TB regimens, and a welcome advance for patients with rifampicin-resistant tuberculosis and tuberculosis control programmes globally.Trial registration: ISRCTN ISRCTN18148631 . Registered 10 February 2016.

BACKGROUND: We aimed to determine how emerging evidence over the past decade informed how Ugandan HIV clinicians prescribed protease inhibitors (PIs) in HIV patients on rifampicin-based tuberculosis (TB) treatment and how this affected HIV treatment outcomes.
METHODS: We reviewed clinical records of HIV patients aged 13 years and above, treated with rifampicin-based TB treatment while on PIs between1st-January -2013 and 30th-September-2018 from twelve public HIV clinics in Uganda. Appropriate PI prescription during rifampicin-based TB treatment was defined as; prescribing doubled dose lopinavir/ritonavir- (LPV/r 800/200 mg twice daily) and inappropriate PI prescription as prescribing standard dose LPV/r or atazanavir/ritonavir (ATV/r).
RESULTS: Of the 602 patients who were on both PIs and rifampicin, 103 patients (17.1% (95% CI: 14.3-20.34)) received an appropriate PI prescription. There were no significant differences in the two-year mortality (4.8 vs. 5.7%, P = 0.318), loss to follow up (23.8 vs. 18.9%, P = 0.318) and one-year post TB treatment virologic failure rates (31.6 vs. 30.7%, P = 0.471) between patients that had an appropriate PI prescription and those that did not. However, more patients on double dose LPV/r had missed anti-retroviral therapy (ART) days (35.9 vs 21%, P = 0.001).
CONCLUSIONS: We conclude that despite availability of clinical evidence, double dosing LPV/r in patients receiving rifampicin-based TB treatment is low in Uganda\'s public HIV clinics but this does not seem to affect patient survival and viral suppression.