Clinical Relevance of Rifampicin-Moxifloxacin Interaction in Isoniazid-Resistant/Intolerant Tuberculosis Patients.

Moxifloxacin is an attractive drug for the treatment of isoniazid-resistant rifampicin-susceptible tuberculosis (TB) or drug-susceptible TB complicated by isoniazid intolerance. However, co-administration with rifampicin decreases moxifloxacin exposure. It remains unclear whether this drug-drug interaction has clinical implications. This retrospective study in a Dutch TB center investigated how rifampicin affected moxifloxacin exposure in patients with isoniazid-resistant or -intolerant TB. Moxifloxacin exposures were measured between 2015 and 2020 in 31 patients with isoniazid-resistant or -intolerant TB receiving rifampicin, and 20 TB patients receiving moxifloxacin without rifampicin. Moxifloxacin exposure, i.e., area under the concentration-time curve (AUC0-24h), and attainment of AUC0-24h/MIC > 100 were investigated for 400 mg moxifloxacin and 600 mg rifampicin, and increased doses of moxifloxacin (600 mg) or rifampicin (900 mg). Moxifloxacin AUC0-24h and peak concentration with a 400 mg dose were decreased when rifampicin was co-administered compared to moxifloxacin alone (ratio of geometric means 0.61 (90% CI (0.53, 0.70) and 0.81 (90% CI (0.70, 0.94), respectively). Among patients receiving rifampicin, 65% attained an AUC0-24h/MIC > 100 for moxifloxacin compared to 78% of patients receiving moxifloxacin alone; this difference was not significant. Seven out of eight patients receiving an increased dose of 600 mg moxifloxacin reached the target AUC0-24h/MIC > 100. This study showed a clinically significant 39% decrease in moxifloxacin exposure when rifampicin was co-administered. Moxifloxacin dose adjustment may compensate for this drug-drug interaction. Further exploring the impact of higher doses of these drugs in patients with isoniazid resistance or intolerance is paramount.

Malnutrition assessment methods in adult patients with tuberculosis: a systematic review.

OBJECTIVES: Malnutrition is associated with a twofold higher risk of dying in patients with tuberculosis (TB) and considered an important potentially reversible risk factor for failure of TB treatment. The construct of malnutrition has three domains: intake or uptake of nutrition; body composition and physical and cognitive function. The objectives of this systematic review are to identify malnutrition assessment methods, and to quantify how malnutrition assessment methods capture the international consensus definition for malnutrition, in patients with TB. DESIGN: Different assessment methods were identified. We determined the extent of capturing of the three domains of malnutrition, that is, intake or uptake of nutrition, body composition and physical and cognitive function. RESULTS: Seventeen malnutrition assessment methods were identified in 69 included studies. In 53/69 (77%) of studies, body mass index was used as the only malnutrition assessment method. Three out of 69 studies (4%) used a method that captured all three domains of malnutrition. CONCLUSIONS: Our study focused on published articles. Implementation of new criteria takes time, which may take longer than the period covered by this review. Most patients with TB are assessed for only one aspect of the conceptual definition of malnutrition. The use of international consensus criteria is recommended to establish uniform diagnostics and treatment of malnutrition. PROSPERO REGISTRATION NUMBER: CRD42019122832.

Corticosteroid therapy for the management of paradoxical inflammatory reaction in patients with pulmonary tuberculosis.

BACKGROUND: Paradoxical reaction after the initiation of tuberculosis treatment is defined as increased inflammation following effective antimycobacterial treatment. This is a phenomenon that can severely complicate a patient's recovery, potentially leading to further morbidity and residual deficits. Paradoxical reaction remains poorly understood regarding its pathophysiology and management. Only a limited number of reports look critically at the available therapeutic options, with evidence of the efficacy of prednisolone therapy being primarily limited to extrapulmonary PR only. CASE: We describe two HIV negative patients who were admitted to our department with pulmonary tuberculosis, presenting with inflammatory patterns attributable to PR and their response to adjunctive steroid therapy. DISCUSSION AND CONCLUSIONS: The presented cases further highlight the need for immunological studies and randomized trials for corticosteroid therapy are needed to better understand this phenomenon as well as provide an evidence-base for anti-inflammatory treatment. Furthermore, by means of this case series, we are also able to highlight the potential variability in the symptomatology of the lesser known PR phenomenon, in which we observed a hypotensive shock-like syndrome not previously described in literature.

Targeting Krasg12c -mutant cancer with a mutation-specific inhibitor.

The RAS genes, which include H, N, and KRAS, comprise the most frequently mutated family of oncogenes in cancer. Mutations in KRAS - such as the G12C mutation - are found in most pancreatic, half of colorectal and a third of lung cancer cases and is thus responsible for a substantial proportion of cancer deaths. Consequently, KRAS has been the subject of exhaustive drug-targeting efforts over the past 3-4 decades. These efforts have included targeting the KRAS protein itself but also its posttranslational modifications, membrane localization, protein-protein interactions and downstream signalling pathways. Most of these strategies have failed and no KRAS-specific drugs have yet been approved. However, for one specific mutation, KRASG12C , there is light on the horizon. MRTX849 was recently identified as a potent, selective and covalent KRASG12C inhibitor that possesses favourable drug-like properties. MRTX849 selectively modifies the mutant cysteine residue in GDP-bound KRASG12C and inhibits GTP-loading and downstream KRAS-dependent signalling. The drug inhibits the in vivo growth of multiple KRASG12C -mutant cell line xenografts, causes tumour regression in patient-derived xenograft models and shows striking responses in combination with other agents. It has also produced objective responses in patients with mutant-specific lung and colorectal cancer. In this review, we discuss the history of RAS drug-targeting efforts, the discovery of MRTX849, and how this drug provides an exciting and long-awaited opportunity to selectively target mutant KRAS in patients.

Evaluation of Carbapenems for Treatment of Multi- and Extensively Drug-Resistant Mycobacterium tuberculosis.

Multi- and extensively drug-resistant tuberculosis (M/XDR-TB) has become an increasing threat not only in countries where the TB burden is high but also in affluent regions, due to increased international travel and globalization. Carbapenems are earmarked as potentially active drugs for the treatment of Mycobacterium tuberculosis To better understand the potential of carbapenems for the treatment of M/XDR-TB, the aim of this review was to evaluate the literature on currently available in vitro, in vivo, and clinical data on carbapenems in the treatment of M. tuberculosis and to detect knowledge gaps, in order to target future research. In February 2018, a systematic literature search of PubMed and Web of Science was performed. Overall, the results of the studies identified in this review, which used a variety of carbapenem susceptibility tests on clinical and laboratory strains of M. tuberculosis, are consistent. In vitro, the activity of carbapenems against M. tuberculosis is increased when used in combination with clavulanate, a BLaC inhibitor. However, clavulanate is not commercially available alone, and therefore, it is impossible in practice to prescribe carbapenems in combination with clavulanate at this time. Few in vivo studies have been performed, including one prospective, two observational, and seven retrospective clinical studies to assess the effectiveness, safety, and tolerability of three different carbapenems (imipenem, meropenem, and ertapenem). We found no clear evidence at the present time to select one particular carbapenem among the different candidate compounds to design an effective M/XDR-TB regimen. Therefore, more clinical evidence and dose optimization substantiated by hollow-fiber infection studies are needed to support repurposing carbapenems for the treatment of M/XDR-TB.

[Tuberculosis: from compulsory admission to compulsory treatment]. / Tbc: van gedwongen opname tot gedwongen behandeling.

Tuberculosis is still considered to be a threat to public health in the Netherlands. The Dutch Public Health Act enables the mandatory isolation of contagious patients who are not willing to be treated. However, this act does not mean that patients can be treated against their will. Another act, the Dutch Medical Treatment Act, regulates the contract between doctor and patient. According to this act, only patients who are mentally incompetent can be treated against their will. We describe two patients with contagious tuberculosis who are mentally incompetent. This article explains the steps which, in accordance with both acts, must be followed before starting appropriate treatment.

The assessment of field trials in GMO research around the world and their possible integration in field trials for variety registration.

Most regulations worldwide stipulate that a new genetically modified (GM) crop event has to be compared to its closest non-GM counterpart as a corner stone of the pre-market risk assessment. To this end the GM crop and its comparator should be grown in field trials for a phenotypic comparison as well as for subsequent detailed analysis of the composition of the two crop varieties. A more in-depth globally harmonised approach for the conduct of these field trials is lacking. Only a few countries have formulated detailed protocols for the set-up of GM field trials. In some countries, commercial non-GM reference varieties need to be included in a field study to compile reliable data that indicate the range of natural variation for the compounds tested at the specific location. Detailed analysis of pre-market assessment reports have so far not shown the added value of including these reference varieties in the field trials. In all cases where specific values were found to be outside of the range of the reference varieties, it proved possible to draw conclusions on the part of the pre-market risk assessment that relates to the compositional analysis, on the basis of already available compositional data. With the increasing quality of several databases on compositional data of a growing number of crop species, it seems unlikely that reference varieties will become more important on future occasions. It was furthermore investigated whether this part of the risk assessment can be related to field trial requirements for variety registration with the explicit intention of reducing the data burden on producers of new GM plant varieties. Field trials for variety registration so far include an assessment of phenotypic characteristics that do not cover safety aspects, with the exception of establishment of the glycoalkaloid content in potatoes in the Netherlands and Sweden. It may, however, under certain conditions be relatively easy to exchange data from compositional measurements between variety registration and GM testing procedures, thus laying a foundation for testing the feasibility of combining both pre-market assessment procedures in a single pre-market evaluation path.

Case Report: Carbapenemase-Producing Enterobacteriaceae in an Asylum Seeker with Multidrug-Resistant Tuberculosis.

A Syrian asylum seeker with multidrug-resistant tuberculosis (TB) developed a bronchopleural fistula after pneumonectomy. Although screening tests were negative on admission, carbapenemase-producing Enterobacteriaceae were cultured after a few months of TB treatment. Prevalence of multidrug-resistant organisms is reported to be increased in asylum seekers compared with the general Dutch population. Arduous conditions during transit and interrupted health care delivery in our patient led to multiple-resistant microorganisms that complicated treatment.

Correction to: New traits in crops produced by genome editing techniques based on deletions.

[This corrects the article DOI: 10.1007/s11816-017-0425-z.].

New traits in crops produced by genome editing techniques based on deletions.

One of the most promising New Plant Breeding Techniques is genome editing (also called gene editing) with the help of a programmable site-directed nuclease (SDN). In this review, we focus on SDN-1, which is the generation of small deletions or insertions (indels) at a precisely defined location in the genome with zinc finger nucleases (ZFN), TALENs, or CRISPR-Cas9. The programmable nuclease is used to induce a double-strand break in the DNA, while the repair is left to the plant cell itself, and mistakes are introduced, while the cell is repairing the double-strand break using the relatively error-prone NHEJ pathway. From a biological point of view, it could be considered as a form of targeted mutagenesis. We first discuss improvements and new technical variants for SDN-1, in particular employing CRISPR-Cas, and subsequently explore the effectiveness of targeted deletions that eliminate the function of a gene, as an approach to generate novel traits useful for improving agricultural sustainability, including disease resistances. We compare them with examples of deletions that resulted in novel functionality as known from crop domestication and classical mutation breeding (both using radiation and chemical mutagens). Finally, we touch upon regulatory and access and benefit sharing issues regarding the plants produced.

Simple strategy to assess linezolid exposure in patients with multi-drug-resistant and extensively-drug-resistant tuberculosis.

Linezolid is used increasingly for the treatment of multi-drug-resistant (MDR) and extensively-drug-resistant (XDR) tuberculosis (TB). However, linezolid can cause severe adverse events, such as peripheral and optical neuropathy or thrombocytopenia related to higher drug exposure. This study aimed to develop a population pharmacokinetic model to predict the area under the concentration curve (AUC) for linezolid using a limited number of blood samples. Data from patients with MDR-/XDR-TB who received linezolid and therapeutic drug monitoring as part of their TB treatment were used. Mw\Pharm 3.82 (Mediware, Zuidhorn, The Netherlands) was used to develop a population pharmacokinetic model and limited sampling strategy (LSS) for linezolid. LSS was evaluated over a time span of 6 h. Blood sampling directly before linezolid administration and 2 h after linezolid administration were considered to be the most clinically relevant sampling points. The model and LSS were evaluated by analysing the correlation between AUC12h,observed and AUC12h,estimated. In addition, LSS was validated with an external group of patients with MDR-/XDR-TB from Sondalo, Italy. Fifty-two pharmacokinetic profiles were used to develop the model. Thirty-three profiles with a 300 mg dosing regimen and 19 profiles with a 600 mg dosing regimen were obtained. Model validation showed prediction bias of 0.1% and r2 of 0.99. Evaluation of the most clinically relevant LSS showed prediction bias of 4.8% and r2 of 0.97. The root mean square error corresponding to the most relevant LSS was 6.07%. The developed LSS could be used to enable concentration-guided dosing of linezolid.

Neurological and functional recovery in tuberculosis patients with spinal cord injury in The Netherlands.

BACKGROUND: Spinal tuberculosis (TB) accounts for approximately 1% to 3% of all TB cases and it can cause a wide range of neurological symptoms, from none to a complete spinal cord injury (SCI), resulting in complete paraplegia or tetraplegia. OBJECTIVES: To describe the functional and neurological outcome of SCI caused by TB. METHODS: Retrospective data on the admission period was combined with prospectively collected data on long-term follow-up. Primary outcome was neurological outcome in terms of motor function. Secondary outcome measures were functional outcome in terms of level of independence and community participation. Results were compared to the outcome in patients with SCI due to trauma. RESULTS: Six TB patients with complete motor SCI (American Spinal Injury Association Impairment Scale (AIS) A or B) were compared to eighteen patients with traumatic SCI. Most TB patients regained almost full neurological function (median motor score improved from 50 to 100), and reached high levels of independence, whereas trauma patients did not improve neurologically (median motor score remained 50) and reached a plateau in level of independence. CONCLUSIONS: SCI due to tuberculosis in the Netherlands shows remarkable improvement in both neurological and functional outcome, especially compared with traumatic SCI.

Positive predictive value of ELISpot in BAL and pleural fluid from patients with suspected pulmonary tuberculosis.

BACKGROUND: The aim of this study was to evaluate the positive predictive value (PPV) of ELISpot in bronchoalveolar lavage (BAL) and pleural fluid for the diagnosis of active tuberculosis (TB) in real-life clinical practice, together with the added value of a cut-off >1.0 for the ratio between the extra-sanguineous and systemic interferon-gamma responses in positive samples. METHODS: A retrospective, single-centre study was performed. Patients with positive ELISpot in BAL and pleural fluid were included. RESULTS: The PPV for TB in patients with positive ELISpot in BAL (n = 40) was 64.9%, which increased to 82.6% for the ESAT-6 panel and 71.4% for the CFP-10 panel after the introduction of a cut-off >1.0 for the ratio between the BAL and blood interferon-gamma responses. In patients with positive ELISpot in pleural fluid (n = 16), the PPV for TB was 85.7%, which increased to 91.7% for the ESAT-6 panel and 92.3% for the CFP-10 panel after the introduction of a cut-off >1.0 for the ratio between the pleural fluid and blood interferon-gamma responses. CONCLUSIONS: This report describes the PPV of ELISpot in BAL and pleural fluid for the diagnosis of active TB in real-life clinical practice. The results indicate the possibility of an increase of the PPV using a cut-off >1.0 for the ratio between the extra-sanguineous and systemic interferon-gamma responses. Further studies are needed to underline this ratio-approach and to evaluate the full diagnostic accuracy of ELISpot in extra-sanguineous fluids like BAL and pleural fluid.