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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 centre 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/minimal inhibitory concentration (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.

ObjectivesMalnutrition 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.DesignDifferent 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.ResultsSeventeen 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.ConclusionsOur 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 numberCRD42019122832.

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 AUC(12h,observed) and AUC(12h,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 r(2) of 0.99. Evaluation of the most clinically relevant LSS showed prediction bias of 4.8% and r(2) 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. (C) 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

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.

Despite all our efforts, the disease burden of tuberculosis (TB) is not falling fast enough to reach the 2030 milestone of the End TB strategy [1]. Multidrug-resistant tuberculosis (MDR-TB) remains a public health crisis, with low treatment success rates [1]. The repurposed drug linezolid has emerged as a core drug in MDR-TB treatment regimens [2, 3], despite its toxicity, e.g. anemia, peripheral neuropathy and gastrointestinal disorders, optic neuritis, and thrombocytopenia [4, 5]. Currently, linezolid is used off-label, as part of Group A “Medicines to be prioritised” of the World Health Organization MDR-TB treatment guideline [2] and in several large trials [6], such as the NIX- TB and END-TB trials. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: Dr. Bolhuis has nothing to disclose. Conflict of interest: Dr. van der Werf has nothing to disclose. Conflict of interest: Dr. Kerstjens has nothing to disclose. Conflict of interest: Dr. de Lange has nothing to disclose. Conflict of interest: Dr. Alffenaar has nothing to disclose. Conflict of interest: Dr. Akkerman has nothing to disclose.

Exposure to moxifloxacin is low in patients with tuberculosis and diabetes comorbidity due to increased clearance of the drug. As low exposure may result in poor treatment outcomes, higher moxifloxacin doses may be required for treatment success.http://bit.ly/2Ynxdf7

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.

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.

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.

Rationale: Multidrug-resistant tuberculosis (MDR-TB) is a major burden to public health in Europe. Reported treatment success rates are around 50% or less, and cure rates are even lower.Objectives: To document the management and treatment outcome in patients with MDR-TB in Europe.Methods: We performed a prospective cohort study, analyzing management and treatment outcomes stratified by incidence of patients with MDR-TB in Europe. Treatment outcomes were compared by World Health Organization and alternative simplified definitions by the Tuberculosis Network European Trialsgroup (TBNET).Measurements and Main Results: A total of 380 patients with MDR-TB were recruited and followed up between 2010 and 2014 in 16 European countries. Patients in high-incidence countries compared with low-incidence countries were treated more frequently with standardized regimen (83.2% vs. 9.9%), had delayed treatment initiation (median, 111 vs. 28 d), developed more additional drug resistance (23% vs. 5.8%), and had increased mortality (9.4% vs. 1.9%). Only 20.1% of patients using pyrazinamide had proven susceptibility to the drug. Applying World Health Organization outcome definitions, frequency of cure (38.7% vs. 9.7%) was higher in high-incidence countries. Simplified outcome definitions that include 1 year of follow-up after the end of treatment showed similar frequency of relapse-free cure in low-(58.3%), intermediate-(55.8%), and high-incidence (57.1%) countries, but highest frequency of failure in high-incidence countries (24.1% vs. 14.6%).Conclusions: Conventional standard MDR-TB treatment regimens resulted in a higher frequency of failure compared with individualized treatments. Overall, cure from MDR-TB is substantially more frequent than previously anticipated, and poorly reflected by World Health Organization outcome definitions.

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.

Extensively drug-resistant (XDR) tuberculosis (TB) is defined by resistance to isoniazid, rifampicin, any fluoroquinolone and at least one of the three second line injectable drugs, such as amikacin. Drug toxicity and duration impair adherence to treatment and outcome is rather poor [1]. We report on a particularly challenging XDR-TB patient with persistent non-adherence to treatment and an exceptionally complex drug susceptibility pattern., Crossing borders by treating a patient with difficult to treat XDR-TB; highly individualised but holistic approach http://ow.ly/JyjK30ielsD

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.

We welcome the initiative by the Guideline Development Group (GDG) members to issue the 2016 update of World Health Organization (WHO) treatment guidelines for drug-resistant tuberculosis (TB) [1]. With one in two patients currently failing on treatment for multidrug-resistant (MDR)-TB, primarily as a result of the difficulties presented by cumulative drug toxicity, logistics, costs and subsequent poor adherence to therapy [2], a shorter regimen for selected patients would be a tremendous asset, even though the GDG argues that the recommendation is conditional, and the scientific evidence for the recommendation is low. Since the first reports on the efficacy of a regimen of only 9 months for MDR-TB [3, 4], two more studies have been published to support the concept of shorter regimens [5, 6] while the STREAM (Evaluation of a Standard Treatment Regimen of Anti-tuberculosis Drugs for Patients with MDR-TB) study is still enrolling [7]. However, shortening therapy would only apply for selected patients without prior use of or proven resistance to fluoroquinolones (group A) or second-line injectable agents (group B). At least five active drugs should be available for the intensive phase (4–6 months). Further exclusions are extrapulmonary TB, additional resistance to pyrazinamide (PZA) and pregnancy. Clofazimine [8] and linezolid [9] were regrouped as core agents in group C with ethionamide or prothionamide, while para-aminosalicylic acid was deferred to group D.

Dosage poorly predicts isoniazid and rifampicin drug exposure in TB patients; TDM advocated in certain patients http://ow.ly/37523023n23

Clarithromycin had a good tolerability and safety profile as assessed in MDR-TB patients receiving prolonged treatment http://ow.ly/r8Jh306Ac0u

Worldwide, tuberculosis (TB) is among the top five causes of death for women aged 15–44 years [1]. In 2014, an estimated 480 000 of newly reported TB cases were multidrug-resistant (MDR) TB [1]. Pregnancy is a risk factor for reactivation of TB, but data about multidrug-resistant (MDR)-TB in pregnant women are lacking. There are few data about the efficacy and safety of second-line anti-TB drugs during pregnancy for both the mother and the unborn child [2]. One study from Peru showed a mortality rate of 13% in 38 patients and 13% of these 38 patients were lost to follow-up. Five of the pregnancies ended in spontaneous abortions, and one child was stillborn. Data for pregnant women did not differ from the general MDR-TB population in Peru [2]. Pharmacokinetics of moxifloxacin and linezolid during and after pregnancy in an MDR-TB patient

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.

HIV-positive patients with MDR-TB demonstrate a very low proportion of relapse-free curehttp://ow.ly/r9sk30bqLBP

The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) substantially challenges TB control, especially in the European Region of the World Health Organization, where the highest prevalence of MDR/XDR cases is reported. The current management of patients with MDR/XDR-TB is extremely complex for medical, social and public health systems. The treatment with currently available anti-TB therapies to achieve relapse-free cure is long and undermined by a high frequency of adverse drug events, suboptimal treatment adherence, high costs and low treatment success rates. Availability of optimal management for patients with MDR/XDR-TB is limited even in the European Region. In the absence of a preventive vaccine, more effective diagnostic tools and novel therapeutic interventions the control of MDR/XDR-TB will be extremely difficult. Despite recent scientific advances in MDR/XDR-TB care, decisions for the management of patients with MDR/XDR-TB and their contacts often rely on expert opinions, rather than on clinical evidence. This document summarises the current knowledge on the prevention, diagnosis and treatment of adults and children with MDR/XDR-TB and their contacts, and provides expert consensus recommendations on questions where scientific evidence is still lacking., TBNET consensus statement on the management of patients with MDR/XDR-TB has been released in the Eur Respir J http://ow.ly/uizRD

Europe is facing a refugee crisis in which hundreds of thousands of displaced persons, often originating from tuberculosis (TB) high-endemic countries, risked their lives for a safer and better future in the European Union (EU) [1]. Among these asylum seekers a considerable proportion were accompanied or unaccompanied minors [2, 3]. Screening practices for TB and latent TB infection (LTBI) among refugees are highly variable in the EU [4, 5]. Details of practices, including mandatory radiographic screening for intrathoracic TB among children of all ages, and aggregate yield of TB entry screening among asylum seekers in the Netherlands from 2012 to September 2015 have been described [1, 6]. Entry screening for LTBI was not routine. We present the results of radiographic TB screening among >34 000 asylum seeker children in the Netherlands 2013–2017 (age groups suggested by the authors) and discuss options for policy changes. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: Dr. Wolters has nothing to disclose. Conflict of interest: Dr. Akkerman has nothing to disclose. Conflict of interest: Dr. Aartsma has nothing to disclose. Conflict of interest: Dr. de Lange has nothing to disclose. Conflict of interest: Dr. Scholvinck has nothing to disclose. Conflict of interest: Dr. van der Werf has nothing to disclose. Conflict of interest: Dr. Van Hest has nothing to disclose.

The use of linezolid for the treatment of multidrug-resistant tuberculosis is limited by dose-and time-dependent toxicity. Recently, we reported a case of pharmacokinetic drug drug interaction between linezolid and clarithromycin that resulted in increased linezolid exposure. The aim of this prospective pharmacokinetic study is to quantify the effect of clarithromycin on the exposure of linezolid.Subjects were included in an open-label, single-centre, single-arm, fixed-order pharmacokinetic interaction study. All subjects received 300 mg linezolid twice daily during the entire study, consecutively co-administered with 250 mg and 500 mg clarithromycin once daily. Steady-state serum curves of linezolid and clarithromycin were analysed using validated methods, and differences between pharmacokinetic parameters were calculated.Linezolid exposure increased by a median (interquartile range) of 44% (23-102%, p=0.043) after co-administration of 500 mg clarithromycin (n=5) compared to baseline, whereas 250 mg clarithromycin had no statistically significant effect. Co-administration was well tolerated by most patients; none experienced severe adverse effects. One patient reported common toxicity criteria grade 2 gastrointestinal adverse events.In this study, we showed that clarithromycin significantly increased linezolid serum exposure after combining clarithromycin with linezolid in multidrug-resistant tuberculosis patients. The drug drug interaction is possibly P-glycoprotein-mediated. Due to large interpatient variability, therapeutic drug monitoring is advisable to determine individual effect size.

Item does not contain fulltext Co-trimoxazole (SXT), a combination of sulfamethoxazole and trimethoprim, has shown in vitro activity against Mycobacterium tuberculosis. However, the pharmacokinetic and pharmacodynamic parameters of SXT in multidrug-resistant (MDR) tuberculosis (TB) are, thus far, lacking. Therefore, we evaluated its pharmacokinetics and drug susceptibility, along with its tolerability during treatment. Based on drug susceptibility testing, MDR-TB patients received SXT as a part of their MDR treatment. The pharmacokinetic parameters of sulfamethoxazole, the effective component of SXT against M. tuberculosis, were evaluated. The ratio of the area under the curve from 0 to 24 h (AUC0-24) to minimum inhibitory concentration (MIC) was used as the best pharmacokinetic/pharmacodynamic parameter to predict the efficacy of sulfamethoxazole. Adverse effects of SXT were also evaluated. 10 patients with MDR-TB (one of whom had extensively drug-resistant TB) received 480 mg of SXT with a median dosage of 6.5 mg.kg(-1) of SXT (range 6.1-6.8 mg.kg(-1)) once daily for a median treatment period of 381 days (range 129-465 days). In two patients, the dose was escalated to 960 mg. The free AUC0-24/MIC of sulfamethoxazole exceeded 25 in only one patient. SXT was safe and well-tolerated, except for one patient who had gastrointestinal side-effects after receiving 960 mg of SXT. Additional studies are needed to find the pharmacokinetic and pharmacodynamic targets, and consequently to set the optimal dose, of SXT for MDR-TB treatment. 01 augustus 2013

For 3 years, Europe has faced an increasing refugee crisis in which hundreds of thousands of displaced persons are risking their lives to seek a safer and better future in the European Union (EU). Many of these migrants originate from highly tuberculosis (TB)-endemic countries. Furthermore, their travel conditions are often poor, allowing potential transmission of infectious diseases, including TB. The Netherlands have observed an increased influx of asylum seekers since 2012 too, with fluctuating numbers every month, and a sharp increase in the summer of 2015, putting constraints on the process of registration, identification, application and accommodation, including mandatory radiographic screening for intrathoracic TB. We describe the impact of such migration on the Public Health TB Clinic of Groningen (responsible for nearly all TB entry screening for asylum seekers in the Netherlands), and our flexible and efficient practice model for daily radiographic TB screening. We report the yield of this intervention over the last 4 years, and reflect on issues concerning entry screening. The Dutch practice model for radiographic TB screening of asylum seekers has proved feasible

IntroductionThe current refugee crisis emphasizes the need for information on infectious diseases and resistant microorganisms in asylum seekers with possible consequences for public health and infection control.MethodsWe collected data from asylum seekers admitted to our university hospital or who presented at the Emergency Department (n = 273). We collected general and demographic characteristics including country of origin, the reason of presentation, and the screening results of multi-drug resistant organisms.Results67% of the patients were male with a median age of the study group of 24 years (IQR 15-33); 48% of the patients had an infectious disease-predominantly malaria with P. vivax or tuberculosis. Patients also reported with diseases which are less common-e. g. leishmaniasis, or even conditions rarely diagnosed in Europe-e. g. louse borne relapsing fever. A carriage rate of 31% for multi-drug resistant microorganisms (MDRO) was observed, with ESBL-expressing E. coli (n = 20) being the most common MDRO. No carriage of Carbapenemase Producing Enterobacteriaceae was found.ConclusionThe current refugee crisis in Europe challenges hospitals to quickly identify and respond to communicable diseases and the carriage of MDRO. A rapid response is necessary to optimize the treatment of infectious diseases amongst asylum seekers to maximize infection control.

Treatment of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) is becoming more challenging because of increased levels of drug resistance against second-line TB drugs. One promising group of antimicrobial drugs is carbapenems. Ertapenem is an attractive carbapenem for the treatment of MDR- and XDR-TB because its relatively long half-life enables once-daily dosing.A retrospective study was performed for all patients with suspected MDR-TB at the Tuberculosis Center Beatrixoord of the University Medical Center Groningen (Haren, the Netherlands) who received ertapenem as part of their treatment regimen between December 1, 2010 and March 1, 2013. Safety and pharmacokinetics were evaluated.18 patients were treated with 1000 mg ertapenem for a mean (range) of 77 (5–210) days. Sputum smear and culture were converted in all patients. Drug exposure was evaluated in 12 patients. The mean (range) area under the concentration–time curve up to 24 h was 544.9 (309–1130) h·mg·L−1. The mean (range) maximum observed plasma concentration was 127.5 (73.9–277.9) mg·L−1.In general, ertapenem treatment was well tolerated during MDR-TB treatment and showed a favourable pharmacokinetic/pharmacodynamic profile in MDR-TB patients. We conclude that ertapenem is a highly promising drug for the treatment of MDR-TB that warrants further investigation.

Introduction: Tuberculosis remains a global health problem and pharmacokinetic variability has been postulated as one of the causes of treatment failure and acquired drug resistance. New developments enable implementation of therapeutic drug monitoring, a strategy to evaluate drug exposure in order to tailor the dose to the individual patient, in tuberculosis treatment.Areas covered: Literature on pharmacokinetics and pharmacodynamics of anti-tuberculosis drugs was explored to evaluate the effect of drug exposure in relation to drug susceptibility, toxicity and efficacy. New, down-sized strategies, like dried blood spot analysis and limited sampling strategies are reviewed. In addition, molecular resistance testing of Mycobacteria tuberculosis, combining a short turn-around time with relevant information on drug susceptibility of the causative pathogen was explored. Newly emerging host biomarkers provide information on the response to treatment.Expert opinion: Therapeutic drug monitoring can minimize toxicity and increase efficacy of tuberculosis treatment and prevent the development of resistance. Dried blood spot analysis and limited sampling strategies, can be combined to provide us with a more patient friendly approach. Furthermore, rapid information on drug susceptibility by molecular testing, and information from host biomarkers on the bacteriological response, can be used to further optimize tuberculosis treatment.

Contains fulltext : 69075.pdf (Publisher’s version ) (Open Access) BACKGROUND: The clinical relevance of Mycobacterium szulgai isolates is unknown, and available literature focuses on case reports of M. szulgai disease. We assessed the clinical relevance of M. szulgai isolated from patients in The Netherlands. METHODS: We reviewed medical files for all 21 patients in The Netherlands from whom M. szulgai was isolated during 1999-2006, applying the diagnostic criteria of the American Thoracic Society for nontuberculous mycobacterial infection. Random amplified polymorphic DNA genotyping was performed using IS986, OPA-2, and OPA-18 as primers. RESULTS: Of the 21 patients, 16 (76%) met the American Thoracic Society diagnostic criteria and were thus likely to have M. szulgai disease. Pulmonary M. szulgai disease was the most common presentation, with extrapulmonary disease restricted to patients with an impaired systemic immunity. Although treatment regimens varied in content and duration, the outcomes were mostly favorable. Both overtreatment and undertreatment were noticed. Random amplified polymorphic DNA genotyping revealed a higher degree of interpatient variability, with limited intrapatient variability, suggesting persisting monoclonal infection and good reproducibility. No genotype was associated with clinical relevance. CONCLUSIONS: Clinical isolation of M. szulgai generally represents true disease and demands careful follow-up. Extrapulmonary disease occurs in patients with impaired immunity. Adherence to diagnostic guidelines can be improved.

Clinical isolation of M. xenopi represents true infection in 51% of cases; genotype is a major determinant., In the Netherlands, isolation of Mycobacterium xenopi is infrequent, and its clinical relevance is often uncertain. To determine clinical relevance and determinants, we retrospectively reviewed medical files of all patients in the Netherlands in whom M. xenopi was isolated from January 1999 through March 2005 by using diagnostic criteria for nontuberculous mycobacterial infection published by the American Thoracic Society. We found 49 patients, mostly white men, with an average age of 60 years and pre-existing pulmonary disease; of these patients, 25 (51%) met the diagnostic criteria. Mycobacterial genotype, based on 16S rRNA gene sequencing, was associated with true infection. Most infections were pulmonary, but pleural and spinal infections (spinal in HIV-infected patients) were also noted. Treatment regimens varied in content and duration; some patients were overtreated and some were undertreated.

Tuberculosis (TB), once considered as a disease of the past generally afflicting poor people, still claims 1.5 million lives annually [1]. Although 86% of patients with drug susceptible TB are cured with established first-line drugs, treatment is often longer than 6 months due to slow response, compliance problems or adverse drug reactions. In addition, emergence of drug-resistant Mycobacterium tuberculosis strains with an unacceptably low treatment success rate of 50% and TB–HIV co-infection have challenged the goals of global TB control and elimination [1]. Incorporating therapeutic drug monitoring into the WHO hierarchy of tuberculosis diagnostics

Bedaquiline, a diarylquinoline for the treatment of multidrug-resistant tuberculosis (TB), relies on exposure-dependent killing. As data on drug exposure in specific populations are scarce, pharmacokinetic studies may be of interest. No simple and robust validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method has been reported to date. Therefore, a new method using a quadrupole mass spectrometer was developed for analysis of bedaquiline and N -monodesmethyl bedaquiline (M2) in human serum, using deuterated bedaquiline as the internal standard. The calibration curve was linear over a range of 0.05 (lower limit of quantification [LLOQ]) to 6.00 mg/liter for both bedaquiline and M2, with correlation coefficient values of 0.997 and 0.999, respectively. The calculated accuracy ranged from 1.9% to 13.6% for bedaquiline and 2.9% to 8.5% for M2. Within-run precision ranged from 3.0% to 7.2% for bedaquiline and 3.1% to 5.2% for M2, and between-run precision ranged from 0.0% to 4.3% for bedaquiline and 0.0% to 4.6% for M2. Evaluation of serum concentrations in a patient receiving bedaquiline showed high levels at the end of treatment, reflecting accumulation of the drug. More observational pharmacokinetic data are needed to relate altered drug concentrations to clinical outcome or adverse drug effects. A simple LC-MS/MS method to quantify bedaquiline and M2 levels in human serum using a deuterated internal standard has been validated. This method can be used in clinical studies and daily practice.

Rifampin, together with isoniazid, has been the backbone of the current first-line treatment of tuberculosis (TB). The ratio of the area under the concentration-time curve from 0 to 24 h (AUC 0–24 ) to the MIC is the best predictive pharmacokinetic-pharmacodynamic parameter for determinations of efficacy. The objective of this study was to develop an optimal sampling procedure based on population pharmacokinetics to predict AUC 0–24 values. Patients received rifampin orally once daily as part of their anti-TB treatment. A one-compartmental pharmacokinetic population model with first-order absorption and lag time was developed using observed rifampin plasma concentrations from 55 patients. The population pharmacokinetic model was developed using an iterative two-stage Bayesian procedure and was cross-validated. Optimal sampling strategies were calculated using Monte Carlo simulation ( n = 1,000). The geometric mean AUC 0–24 value was 41.5 (range, 13.5 to 117) mg · h/liter. The median time to maximum concentration of drug in serum ( T max ) was 2.2 h, ranging from 0.4 to 5.7 h. This wide range indicates that obtaining a concentration level at 2 h ( C 2 ) would not capture the peak concentration in a large proportion of the population. Optimal sampling using concentrations at 1, 3, and 8 h postdosing was considered clinically suitable with an r 2 value of 0.96, a root mean squared error value of 13.2%, and a prediction bias value of −0.4%. This study showed that the rifampin AUC 0–24 in TB patients can be predicted with acceptable accuracy and precision using the developed population pharmacokinetic model with optimal sampling at time points 1, 3, and 8 h.

The incidence of tuberculosis in the Netherlands has dropped dramatically over the past 50 years. With declining experience of tuberculosis, misdiagnosis can easily happen. Laryngeal tuberculosis often presents as a tumorous mass that may initially be mistaken for cancer. As laryngeal tuberculosis is usually highly infectious, this poses a risk to the patient as well as his/her contacts including healthcare providers. We describe three patients with (suspected) laryngeal tuberculosis and discuss potential pitfalls. Pivotal for a correct diagnosis are thorough history-taking, physical examination and relatively simple radiological and laboratory tests. Risk groups have been identified for tuberculosis and this can provide a clue. Differentiation between tuberculosis and cancer can be difficult, and the two diseases may concur. Even in low-incidence settings for tuberculosis, knowledge of the disease remains necessary as it is curable and further spread can be prevented with simple measures.

Marieke G. G. Sturkenboom, Onno W. Akkerman, Mathieu S. Bolhuis, Wiel C. M. de Lange, Tjip S. van der Werf, Jan-Willem C. Alffenaar University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, The Netherlands; University of Groningen, University Medical Center Groningen, Pulmonary Diseases and Tuberculosis, Groningen, The Netherlands; University of Groningen, University Medical Center Groningen, Tuberculosis Center Beatrixoord, Haren, The Netherlands; University of Groningen, University Medical Center Groningen, Department of Internal Medicine, Groningen, The Netherlands

Wider use of TDM in complex TB cases could improve therapeutic management and prevent emergence of drug resistance http://ow.ly/CQx9j

Multidrug-resistant tuberculosis (MDR-TB) is a major global health problem. The loss of susceptibility to an increasing number of drugs behoves us to consider the evaluation of non-traditional anti-tuberculosis drugs.Clarithromycin, a macrolide antibiotic, is defined as a group 5 anti-tuberculosis drug by the World Health Organization; however, its role or efficacy in the treatment of MDR-TB is unclear. A systematic review of the literature was conducted to summarise the evidence for the activity of macrolides against MDR-TB, by evaluating in vitro, in vivo and clinical studies. PubMed and Embase were searched for English language articles up to May 2014.Even though high minimum inhibitory concentration values are usually found, suggesting low activity against Mycobacterium tuberculosis, the potential benefits of macrolides are their accumulation in the relevant compartments and cells in the lungs, their immunomodulatory effects and their synergistic activity with other anti-TB drugs.A future perspective may be use of more potent macrolide analogues to enhance the activity of the treatment regimen.

OBJECTIVE/BACKGROUND: Globally, approximately 50% of patients with multidrug-resistant tuberculosis (MDR-TB) experience treatment failure. MDR-TB treatment is hindered by adverse events, toxicity of the second-line anti-TB drugs, logistics and costs, especially in low-income countries, and problems with medication adherence. Pharmacokinetic variability is also attributed as one of the reasons contributing to treatment failure. In our reference Tuberculosis Center Beatrixoord (University Medical Center Groningen, Groningen, The Netherlands), we strive to individualize treatment of all MDR-TB patients based on drug-susceptibility testing using minimal inhibitory concentrations and pharmacokinetic parameters. The aim of this work is to give an overview of our efforts to individualize treatment of MDR-TB patients and to provide insights into practical tools that might be implemented in other clinical settings worldwide.METHODS: We critically looked at clinical practice guidelines implemented in our center to give an overview of practically applied tools to individualize treatment of MDR-TB patients. Furthermore, we selected studies carried out in our clinic on treatment individualization of MDR-TB patients and combined their results with recent studies in this area to suggest practical tools for implementation in other clinical settings.RESULTS: We regularly perform therapeutic drug monitoring (TDM) of several second-line anti-TB drugs, such as amikacin, kanamycin, linezolid, and moxifloxacin. New analyses of Group D and experimental drugs, such as co-trimoxazole (sulfamethoxazole/trimethoprim), bedaquiline, delamanid, and clarithromycin, have been or are being developed. By implementing TDM methods, variability in pharmacokinetics is often detected and treatment is adjusted, possibly preventing toxicity in patients with very high drug exposure or treatment failure, or resistance in patients with very low drug exposure. Over the past 10years in the Netherlands, 86% of 104 patients had a successful outcome using a median of six active drugs. Many studies were performed using dried blood spot (DBS) analysis of second-line TB drugs. These studies may be used to implement TDM worldwide, even in low-income countries. Furthermore, several studies are performed to determine limited sampling strategies (LSSs). By limiting the number samples required for adequate sampling, TDM will become easier to implement. Other examples of LSSs included development of oral fluid sampling methods or development of semiquantitative thin-layer chromatography methods.CONCLUSION: TDM is highly valuable to individualize and optimize treatment of complex MDR-TB patients. TDM is routinely applied in Tuberculosis Center Beatrixoord, and high success rates for treatment of MDR-TB patients have been achieved. DBS and LSS make implementation of TDM feasible, even in low- and middle-income countries.

Treatment of mycobacterial diseases such as tuberculosis (TB) entails long and intense antimicrobial therapy. TB patients are at risk of coinfection with other multidrug-resistant bacteria, such as those from Enterobacteriaceae family, because of antimicrobial selection pressure and nosocomial transmission during prolonged hospital admission. Here, we report on two patients treated for multidrug-resistant TB, who developed severe sepsis due to an extended spectrum beta-lactamase producing organism Diagnostic culture identified the venous access port as source, and upon surgical removal and antimicrobial therapy rapid clinical improvement was achieved. Increased awareness and knowledge on the prevalence of multi-resistant Enterobacteriaceae is needed, notably in TB centers, to provide a safe hospital environment to our patients.

Treatment of multidrug-resistant (MDR) tuberculosis (TB) is challenging because of the high toxicity of second-line drugs and the longer treatment duration than for drug-susceptible TB patients. In order to speed up novel treatment for MDR-TB, we suggest considering expanding the indications of already available drugs. Six drugs with antimicrobial activity (phenothiazine, metronidazole, doxycycline, disulfiram, tigecycline and co-trimoxazole) are not listed in the World Health Organization guidelines on MDR-TB treatment but could be potential candidates for evaluation against Mycobacterium tuberculosis. A systematic review was conducted to evaluate antituberculous activity of these drugs against M. tuberculosis. We searched PubMed, Google Scholar and Embase for English articles published up to December 31, 2012. We reviewed in vitro, in vivo and clinical antituberculous activity of these drugs in addition to pharmacokinetics and side-effects. Of the drugs effective against actively replicating M. tuberculosis, co-trimoxazole seems to be the most promising, because of its consistent pharmacokinetic profile, easy penetration into tissue and safety profile. For the dormant state of TB, thioridazine may play a potential role as an adjuvant for treatment of MDR-TB. A strategy consisting of pharmacokinetic/pharmacodynamic studies, dose finding and phase III studies is needed to explore the role of these drugs in MDR-TB treatment.

Dick Menzies and colleagues report findings from a collaborative, individual patient-level meta-analysis of treatment outcomes among patients with multidrug-resistant tuberculosis., Background Treatment of multidrug resistant tuberculosis (MDR-TB) is lengthy, toxic, expensive, and has generally poor outcomes. We undertook an individual patient data meta-analysis to assess the impact on outcomes of the type, number, and duration of drugs used to treat MDR-TB. Methods and Findings Three recent systematic reviews were used to identify studies reporting treatment outcomes of microbiologically confirmed MDR-TB. Study authors were contacted to solicit individual patient data including clinical characteristics, treatment given, and outcomes. Random effects multivariable logistic meta-regression was used to estimate adjusted odds of treatment success. Adequate treatment and outcome data were provided for 9,153 patients with MDR-TB from 32 observational studies. Treatment success, compared to failure/relapse, was associated with use of: later generation quinolones, (adjusted odds ratio [aOR]: 2.5 [95% CI 1.1–6.0]), ofloxacin (aOR: 2.5 [1.6–3.9]), ethionamide or prothionamide (aOR: 1.7 [1.3–2.3]), use of four or more likely effective drugs in the initial intensive phase (aOR: 2.3 [1.3–3.9]), and three or more likely effective drugs in the continuation phase (aOR: 2.7 [1.7–4.1]). Similar results were seen for the association of treatment success compared to failure/relapse or death: later generation quinolones, (aOR: 2.7 [1.7–4.3]), ofloxacin (aOR: 2.3 [1.3–3.8]), ethionamide or prothionamide (aOR: 1.7 [1.4–2.1]), use of four or more likely effective drugs in the initial intensive phase (aOR: 2.7 [1.9–3.9]), and three or more likely effective drugs in the continuation phase (aOR: 4.5 [3.4–6.0]). Conclusions In this individual patient data meta-analysis of observational data, improved MDR-TB treatment success and survival were associated with use of certain fluoroquinolones, ethionamide, or prothionamide, and greater total number of effective drugs. However, randomized trials are urgently needed to optimize MDR-TB treatment. Please see later in the article for the Editors' Summary., Editors' Summary Background In 2010, 8.8 million people developed tuberculosis—a contagious bacterial infection—and 1.4 million people died from the disease. Mycobacterium tuberculosis, the bacterium that causes tuberculosis, is spread in airborne droplets when people with the disease cough or sneeze and usually infects the lungs (pulmonary tuberculosis). The characteristic symptoms of tuberculosis are a persistent cough, weight loss, and night sweats. Tuberculosis can be cured by taking several powerful antibiotics regularly for at least 6 months. The standard treatment for tuberculosis comprises an initial intensive phase lasting 2 months during which four antibiotics are taken daily followed by a 4-month continuation phase during which two antibiotics are taken. However, global efforts to control tuberculosis are now being thwarted by the emergence of M. tuberculosis strains that are resistant to several antibiotics, including isoniazid and rifampicin, the two most powerful, first-line (standard) anti-tuberculosis drugs. Why Was This Study Done? Although multi-drug resistant tuberculosis (MDR-TB) can be cured using second-line anti-tuberculosis drugs, these are more expensive and more toxic than first-line drugs and optimal treatment regimens for MDR-TB have not been determined. Notably, there have been no randomized controlled trials of treatments for MDR-TB. Such trials, which compare outcomes (cure, treatment failure, relapse, and death) among patients who have been randomly assigned to receive different treatments, are the best way to compare different anti-tuberculosis drug regimens. It is possible, however, to get useful information about the association of various treatments for MDR-TB with outcomes from observational studies using a statistical approach called “individual patient data meta-analysis.” In observational studies, because patients are not randomly assigned to different treatments, differences in outcomes between treatment groups may not be caused by the different drugs they receive but may be due to other differences between the groups. An individual patient data meta-analysis uses statistical methods to combine original patient data from several different studies. Here, the researchers use this approach to investigate the association of specific drugs, numbers of drugs and treatment duration with the clinical outcomes of patients with pulmonary MDR-TB. What Did the Researchers Do and Find? The researchers used three recent systematic reviews (studies that use predefined criteria to identify all the research on a given topic) to identify studies reporting treatment outcomes of microbiologically confirmed MDR-TB. They obtained individual patient data from the authors of these studies and estimated adjusted odds (chances) of treatment success from the treatment and outcome data of 9,153 patients with MDR-TB provided by 32 centers. The use of later generation quinolones, ofloxacin, and ethionamide/prothionamide as part of multi-drug regimens were all associated with treatment success compared to failure, relapse or death, as were the use of four or more likely effective drugs (based on drug susceptibility testing of mycobacteria isolated from study participants) during the initial intensive treatment phase and the use of three or more likely effective drugs during the continuation phase. The researchers also report that among patients who did not die or stop treatment, the chances of treatment success increased with the duration of the initial treatment phase up to 7.1–8.5 months and with the total duration of treatment up to 18.6–21.5 months. What Do These Findings Mean? These findings suggest that the use of specific drugs, the use of a greater number of effective drugs, and longer treatments may be associated with treatment success and the survival of patients with MDR-TR. However, these findings need to be interpreted with caution because of limitations in this study that may have affected the accuracy of its findings. For example, the researchers did not include all the studies they found through the systematic reviews in their meta-analysis (some authors did not respond to requests for individual patient data, for example), which may have introduced bias. Moreover, because the patients included in the meta-analysis were treated at 32 centers, there were many differences in their management, some of which may have affected the accuracy of the findings. Because of these and other limitations, the researchers note that, although their findings highlight several important questions about the treatment of MDR-TB, randomized controlled trials are urgently needed to determine the optimal treatment for MDR-TB. Additional Information Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001300. The World Health Organization provides information on all aspects of tuberculosis, including MDR-TB; its guidelines for the programmatic management of drug-resistant tuberculosis are available The US Centers for Disease Control and Prevention has information about tuberculosis, including information on the treatment of tuberculosis and on MDR-TB The US National Institute of Allergy and Infectious Diseases also has information on all aspects of tuberculosis, including a drug-resistant tuberculosis visual tour MedlinePlus has links to further information about tuberculosis (in English and Spanish) TB & ME, a collaborative blogging project run by patients being treated for multidrug-resistant tuberculosis and Medecins sans Frontieres, provides information about MDR-TB and patient stories about treatment for MDR-TB The Tuberculosis Survival Project, which aims to raise awareness of tuberculosis and provide support for people with tuberculosis, also provides personal stories about treatment for tuberculosis

The nontuberculous or atypical mycobacteria (NTM) are a group of largely opportunistic pathogens, which are increasingly being detected in patients and being associated with clinical disease. Various host factors are responsible for this, such as the ageing population with the accompanying increase in the number of patients with chronic diseases, but NTM are also detected more often as a result of improvements in diagnostic laboratory techniques. The clinical relevance, i.e. the percentage of patients in whom the detected NTM is actually the cause of the clinical disease, differs enormously per species. Pulmonary NTM disease, which resembles pulmonary tuberculosis, is the most frequent, followed by lymphadenitis in children. Treatment of these infections is time-consuming, complicated and often ineffective. Therefore, prompt consultation with one of the specialized centres of expertise is warranted. We should also consider formulating national guidelines for diagnosis and treatment.

Contains fulltext : 80842.pdf (Publisher’s version ) (Closed access)

We present descriptions of two human Mycobacterium microti infections: one of a patient with pulmonary disease and one of a patient with osteomyelitis of the hip. Both patients had acid-fast bacilli and a positive Mycobacterium tuberculosis complex PCR from clinical specimens, but mycobacterial cultures remained negative. The microbiological diagnosis was established by molecular methods.

Contains fulltext : 79804.pdf (Publisher’s version ) (Open Access) Eighteen isolates of a nonchromogenic, slowly growing, non-tuberculous species of the genus Mycobacterium were cultured from respiratory specimens obtained over the last eight years from 17 patients in the Netherlands. These isolates were grouped because they revealed a unique 16S rRNA gene sequence and were related to Mycobacterium xenopi. None of the 17 patients met the American Thoracic Society diagnostic criteria for non-tuberculous mycobacterial disease, which distinguishes the novel isolates from the related species, M. xenopi. A polyphasic taxonomic approach, including identification by biochemical and phenotypical analysis, hsp65 gene sequencing and PCR restriction enzyme pattern analysis, and sequence analyses of the rpoB gene and 16S-23S internal transcribed spacer supported the separate species status of the novel isolates. The name Mycobacterium noviomagense sp. nov. is proposed for the novel strains. The type strain is NLA000500338(T) (=DSM 45145(T)=CIP 109766(T)). A more distinctive taxonomy of NTM is a prerequisite for the assessment of their clinical relevance.