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

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

A Dutch Case Report of Successful Treatment of Chronic Relapsing Urinary Tract Infection with Bacteriophages in a Renal Transplant Patient.

We report a case of a 58-year-old renal transplant patient who developed a recurrent urinary tract infection with an extended-spectrum ß-lactamase (ESBL)-positive Klebsiella pneumoniae strain in the first month posttransplant. Even though it tested susceptible to carbapenems and despite repeated meropenem treatment, his infection recurred. The infection eventually evolved into epididymitis that was successfully treated with meropenem and bacteriophages. This case demonstrates the difficulty of treating relapsing ESBL-positive Gram-negative infections in renal transplant patients.

A bedaquiline/clofazimine combination regimen might add activity to the treatment of clinically relevant non-tuberculous mycobacteria.

BACKGROUND: Non-tuberculous mycobacteria (NTM) infections are hard to treat. New antimicrobial drugs and smarter combination regimens are needed. OBJECTIVES: Our aim was to determine the in vitro activity of bedaquiline against NTM and assess its synergy with established antimycobacterials. METHODS: We determined MICs of bedaquiline for clinically relevant NTM species and Mycobacterium tuberculosis by broth microdilution for 30 isolates. Synergy testing was performed using the chequerboard method for 22 reference strains and clinical isolates of Mycobacterium abscessus (MAB) and Mycobacterium avium complex (MAC). Time-kill kinetics (TK) assays with resistance monitoring of bedaquiline alone and combined with clofazimine were performed for MAB CIP 104536 and M. avium ATCC 700898; bedaquiline/clarithromycin combinations were evaluated against M. avium ATCC 700898. Interactions were assessed for TK experiments based on Bliss independence. RESULTS: Bedaquiline had modest activity against tested NTM, with MICs between <0.007 and 1 mg/L. Bedaquiline showed no interaction with tested drugs against MAB or MAC. Lowest mean fractional inhibitory concentration index (FICI) values were 0.79 with clofazimine for MAB and 0.97 with clofazimine and 0.82 with clarithromycin for MAC. In TK assays, bedaquiline showed a bacteriostatic effect. Clofazimine extended the bacteriostatic activity of bedaquiline against MAB and yielded a slight bactericidal effect against M. avium. The bedaquiline/clofazimine combination slowed emergence of bedaquiline resistance for M. avium but promoted it for MAB. Relative to Bliss independence, bedaquiline/clofazimine showed synergistic interaction over time for MAB and no interaction for M. avium and bedaquiline/clarithromycin showed antagonistic interaction for M. avium. CONCLUSIONS: Following these in vitro data, a bedaquiline/clofazimine combination might add activity to MAB and MAC treatment. The bedaquiline/clarithromycin combination might have lower activity compared with bedaquiline alone for MAC treatment.

IgM Augments Complement Bactericidal Activity with Serum from a Patient with a Novel CD79a Mutation.

Antibody replacement therapy for patients with antibody deficiencies contains only IgG. As a result, concurrent IgM and IgA deficiency present in a large proportion of antibody deficient patients persists. Especially patients with IgM deficiency remain at risk for recurrent infections of the gastrointestinal and respiratory tract. The lack of IgM in the current IgG replacement therapy is likely to contribute to the persistence of these mucosal infections because this antibody class is especially important for complement activation on the mucosal surface. We evaluated whether supplementation with IgM increased serum bactericidal capacity in vitro. Serum was collected from a patient with agammaglobulinemia and supplemented with purified serum IgM to normal levels. Antibody and complement deposition on the bacterial surface was determined by multi-color flow cytometry. Bacterial survival in serum was determined by colony-forming unit counts. We present a patient previously diagnosed with agammaglobulinemia due to CD79A (Igα) deficiency revealing a novel pathogenic insertion variant in the CD79a gene (NM_001783.3:c.353_354insT). Despite IgG replacement therapy and antibiotic prophylaxis, this patient developed a Campylobacter jejuni spondylodiscitis of lumbar vertebrae L4-L5. We found that serum IgM significantly contributes to complement activation on the bacterial surface of C. jejuni. Furthermore, supplementation of serum IgM augmented serum bactericidal activity significantly. In conclusion, supplementation of intravenous IgG replacement therapy with IgM may potentially offer greater protection against bacterial infections, also in the context of increasing antibiotic resistance.

Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry Fails To Identify Nontuberculous Mycobacteria from Primary Cultures of Respiratory Samples.

We have assessed matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) identification (Bruker) of nontuberculous mycobacteria from newly positive liquid cultures of respiratory samples. Twelve (22%) of 54 isolates were identified directly from liquid medium. After subculture and with manual laser operation, this rose to 49/54 isolates (91%). MALDI-TOF MS is less promising than previously suggested.

Tailored anticoagulant treatment after a first venous thromboembolism: protocol of the Leiden Thrombosis Recurrence Risk Prevention (L-TRRiP) study - cohort-based randomised controlled trial.

INTRODUCTION: Patients with a first venous thromboembolism (VTE) are at risk of recurrence. Recurrent VTE (rVTE) can be prevented by extended anticoagulant therapy, but this comes at the cost of an increased risk of bleeding. It is still uncertain whether patients with an intermediate recurrence risk or with a high recurrence and high bleeding risk will benefit from extended anticoagulant treatment, and whether a strategy where anticoagulant duration is tailored on the predicted risks of rVTE and bleeding can improve outcomes. The aim of the Leiden Thrombosis Recurrence Risk Prevention (L-TRRiP) study is to evaluate the outcomes of tailored duration of long-term anticoagulant treatment based on individualised assessment of rVTE and major bleeding risks. METHODS AND ANALYSIS: The L-TRRiP study is a multicentre, open-label, cohort-based, randomised controlled trial, including patients with a first VTE. We classify the risk of rVTE and major bleeding using the L-TRRiP and VTE-BLEED scores, respectively. After 3 months of anticoagulant therapy, patients with a low rVTE risk will discontinue anticoagulant treatment, patients with a high rVTE and low bleeding risk will continue anticoagulant treatment, whereas all other patients will be randomised to continue or discontinue anticoagulant treatment. All patients will be followed up for at least 2 years. Inclusion will continue until the randomised group consists of 608 patients; we estimate to include 1600 patients in total. The primary outcome is the combined incidence of rVTE and major bleeding in the randomised group after 2 years of follow-up. Secondary outcomes include the incidence of rVTE and major bleeding, functional outcomes, quality of life and cost-effectiveness in all patients. ETHICS AND DISSEMINATION: The protocol was approved by the Medical Research Ethics Committee Leiden-Den Haag-Delft. Results are expected in 2028 and will be disseminated through peer-reviewed journals and during (inter)national conferences. TRIAL REGISTRATION NUMBER: NCT06087952.

Treatment and Outcome of Culture-Confirmed Mycobacterium marinum Disease.

Background: Mycobacterium marinum is a nontuberculous mycobacterium that causes skin and soft tissue infections. Treatment consists of multiple antibiotics, sometimes combined with surgical debridement. There is little evidence for the choice of antibiotics, the duration of treatment, and the role of susceptibility testing. Methods: We performed a retrospective cohort study of culture-confirmed M. marinum infections in the Netherlands in the 2011-2018 period. Clinical characteristics, in vitro susceptibility, extent of disease, treatment regimens, and outcomes were analyzed. Incidence was assessed from laboratory databases. Results: Forty cases of M. marinum infection could be studied. Antibiotic treatment cured 36/40 patients (90%) after a mean treatment duration of 25 weeks. Failure/relapse occurred in 3 patients, and 1 patient was lost to follow-up. Antibiotic treatment consisted of monotherapy in 35% and 2-drug therapy in 63%. Final treatment contained mostly ethambutol-macrolide combinations (35%). Eleven patients (28%) received additional surgery. We recorded high rates of in vitro resistance to tetracyclines (36% of isolates). Tetracycline resistance seemed correlated with poor response to tetracycline monotherapy. The annual incidence rate was 0.15/100 000/year during the study period. Conclusions: Prolonged and susceptibility-guided treatment results in a 90% cure rate in M. marinum disease. Two-drug regimens of ethambutol and a macrolide are effective for moderately severe infections. Tetracycline monotherapy in limited disease should be used vigilantly, preferably with proven in vitro susceptibility.

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

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

Failure of posaconazole therapy in a renal transplant patient with invasive aspergillosis due to Aspergillus fumigatus with attenuated susceptibility to posaconazole.

We report the case of a kidney transplant recipient with invasive aspergillosis due to Aspergillus fumigatus resistant to voriconazole and intermediately susceptible to posaconazole who failed posaconazole therapy. Plasma posaconazole concentrations indicated an unfavorable ratio of the area under the concentration-time curve over the MIC. Posaconazole should be used with caution for invasive aspergillosis caused by strains with attenuated posaconazole susceptibility, as drug exposure may be inadequate, resulting in therapeutic failure.

Effect of elevated levels of coagulation factors on the risk of venous thrombosis in long-distance travelers.

Risk of venous thrombosis is increased after long-distance travel. Identifying high-risk groups may provide a basis for targeted prevention. We assessed the effect of increased levels of coagulation factors and combinations of risk factors in travelers in a large case-control study. We calculated odds ratios (ORs) for 334 travelers (200 cases and 134 controls) with coagulation factors II (prothrombin), VII, VIII, and IX; fibrinogen, and von Willebrand factor (VWF) above the 80th percentile; for increasing numbers of risk factors; and for specific combinations. The risk was increased in travelers with high FII (OR, 2.2: 95% CI, 1.3-3.7) and FVIII (OR, 6.2, (95% CI, 3.6-10.5) compared with travelers with normal levels. High FIX and fibrinogen levels increased the risk in air travelers (FIX: OR, 3.2; 95% CI, 0.9-11.0; fibrinogen: OR, 2.0; 95% CI, 0.7-5.5) but not in other travelers. The ORs increased with the number of risk factors, and the risk was increased most in women with the combination of oral contraceptives and high FVIII (OR, 51.7; 95% CI, 5.4-498). We conclude that increased levels of FII and FVIII increase the risk of venous thrombosis in travelers. Furthermore, the risk is greatly increased if other risk factors are present as well.

Parenteral anticoagulation in patients with cancer who have no therapeutic or prophylactic indication for anticoagulation.

BACKGROUND: Anticoagulation may improve survival in patients with cancer through an antitumor effect in addition to the perceived antithrombotic effect. OBJECTIVES: To evaluate the efficacy and safety of parenteral anticoagulants in patients with cancer with no therapeutic or prophylactic indication for anticoagulation. SEARCH STRATEGY: A comprehensive search included (1) an electronic search (February 2010) of the following databases: Cochrane Central Register of Controlled Trials (CENTRAL) Issue 1, 2010, MEDLINE, EMBASE and ISI the Web of Science; (2) handsearch of conference proceedings; (3) checking of references of included studies; and (4) use of the 'related citation' feature in PubMed. SELECTION CRITERIA: Randomized controlled trials (RCTs) assessing the benefits and harms of parenteral anticoagulation in patients with cancer but no therapeutic or prophylactic indication for anticoagulation. DATA COLLECTION AND ANALYSIS: Using a standardized form we extracted in duplicate data on methodological quality, participants, interventions and outcomes of interest including all-cause mortality, symptomatic thromboembolism, major bleeding, minor bleeding and quality of life (QoL). MAIN RESULTS: Of 8187 identified citations, nine RCTs enrolling 2857 patients fulfilled the inclusion criteria. In all included RCTs the intervention consisted of heparin (either unfractionated heparin or low molecular weight heparin). Overall, the effect of heparin therapy on mortality was not statistically significant at 12 months (risk ratio (RR) 0.93; 95% CI 0.85 to 1.02) but it was statistically significant at 24 months (RR 0.92; 95% CI 0.88 to 0.97). Heparin therapy was associated with a statistically and clinically important reduction in venous thromboembolism (RR 0.55; 95% CI 0.37 to 0.82). There were no statistically significant effects on major bleeding (RR 1.30; 95% CI 0.59 to 2.88), minor bleeding (RR 1.05; 95% 0.75 to 1.46) or QoL. The quality of evidence was high for symptomatic venous thromboembolism, moderate for mortality, major bleeding and minor bleeding, and low for QoL. AUTHORS' CONCLUSIONS: Heparin was associated with a significant reduction of death at 24 months but not 12 months. It was also associated with a reduction in venous thromboembolism but based on the RCTs in this review it had no significant effect on major bleeding, minor bleeding or QoL. Future research should further investigate the survival benefit of different types of anticoagulants in patients with different types and stages of cancer. The decision for a patient with cancer to start heparin therapy for survival benefit should balance the benefits and downsides and integrate the patient's values and preferences.

Parenteral anticoagulation in patients with cancer who have no therapeutic or prophylactic indication for anticoagulation.

BACKGROUND: Anticoagulation may improve survival in patients with cancer through an antitumor effect in addition to the perceived antithrombotic effect. OBJECTIVES: To evaluate the efficacy and safety of parenteral anticoagulants in patients with cancer with no therapeutic or prophylactic indication for anticoagulation. SEARCH STRATEGY: A comprehensive search included (1) an electronic search (February 2010) of the following databases: Cochrane Central Register of Controlled Trials (CENTRAL) Issue 1, 2010, MEDLINE, EMBASE and ISI the Web of Science; (2) handsearch of conference proceedings; (3) checking of references of included studies; and (4) use of the 'related citation' feature in PubMed. SELECTION CRITERIA: Randomized controlled trials (RCTs) assessing the benefits and harms of parenteral anticoagulation in patients with cancer but no therapeutic or prophylactic indication for anticoagulation. DATA COLLECTION AND ANALYSIS: Using a standardized form we extracted in duplicate data on methodological quality, participants, interventions and outcomes of interest including all-cause mortality, symptomatic thromboembolism, major bleeding, minor bleeding and quality of life (QoL). MAIN RESULTS: Of 8187 identified citations, nine RCTs enrolling 2857 patients fulfilled the inclusion criteria. In all included RCTs the intervention consisted of heparin (either unfractionated heparin or low molecular weight heparin). Overall, the effect of heparin therapy on mortality was not statistically significant at 12 months (risk ratio (RR) 0.93; 95% CI 0.85 to 1.02) but it was statistically significant at 24 months (RR 0.92; 95% CI 0.88 to 0.97). Heparin therapy was associated with a statistically and clinically important reduction in venous thromboembolism (RR 0.55; 95% CI 0.37 to 0.82). There were no statistically significant effects on major bleeding (RR 1.30; 95% CI 0.59 to 2.88), minor bleeding (RR 1.05; 95% 0.75 to 1.46) or QoL. The quality of evidence was high for symptomatic venous thromboembolism, moderate for mortality, major bleeding and minor bleeding, and low for QoL. AUTHORS' CONCLUSIONS: Heparin was associated with a significant reduction of death at 24 months but not 12 months. It was also associated with a reduction in venous thromboembolism but based on the RCTs in this review it had no significant effect on major bleeding, minor bleeding or QoL. Future research should further investigate the survival benefit of different types of anticoagulants in patients with different types and stages of cancer. The decision for a patient with cancer to start heparin therapy for survival benefit should balance the benefits and downsides and integrate the patient's values and preferences.

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

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

Primary cutaneous melioidosis acquired in Nepal - Case report and literature review.

A 27 years-old Dutch male returning from Nepal presented with a painful abscess on the left forearm without fever or other systemic complications. Signs and symptoms consisted of culture of the abscess material revealed Burkholderia pseudomallei. Laboratory results, chest X-ray and CT scan of the abdomen were without abnormalities. The patient was initially treated with 2 weeks of ceftazidime and continued with a 6-week oral eradication phase with trimethoprim-sulfamethoxazole. The patient recovered without complications. Melioidosis is encountered relatively infrequently as an imported condition, mainly from Southeast Asia with focus on Thailand. Melioidosis from Nepal is a rarity and has previously been described in only four cases, with possible acquisition abroad in three of those.

Deciphering the genotype and phenotype of hairy cell leukemia: clues for diagnosis and treatment.

Introduction: Hairy cell leukemia (HCL) is a rare, indolent B-cell neoplasm. The classical variant of the disease is characterized by the BRAF V600E mutation, which is present in virtually all cases. How this mutation leads to the signs and symptoms of the disease is currently not known. Areas covered: This review explores the genetic background of HCL, especially the BRAF V600E driver mutation, but passenger mutations and their effects are also included. The clinical significance of BRAF mutations in other cancer types is discussed, as well as BRAF- induced senescence. An overview of the major forms of treatment of HCL (cytostatic drugs, specific BRAF inhibitors, B cell-specific antibodies) is given. Finally, possible mechanisms of the monocytopenia and hairy morphology so typical of this disease are discussed. Expert opinion: Although being a rare disease, HCL and its pathogenesis can yield important information about BRAF-related cancer metabolism. Many aspects of the disease are still unclear, but with the right resources, this could change. This can lead to a more efficient and specific treatment, thus leading to decreased morbidity.

Evaluation of Prolonged vs Short Courses of Antibiotic Prophylaxis Following Ear, Nose, Throat, and Oral and Maxillofacial Surgery: A Systematic Review and Meta-analysis.

Importance: Antibiotic prophylaxis is widely used after surgical procedures operating on the mucosal tissues of the aerodigestive tract, but the optimal duration of these prophylactic therapies is often unclear. Objective: To compare short-course antibiotic prophylaxis (≤24 hours) vs extended-course antibiotic prophylaxis (≥72 hours) after ear, nose, throat, and oral and maxillofacial surgery. Data Sources and Study Selection: Literature searches of PubMed were completed in October 2017 and included prospective trials that compared antibiotic prophylaxis courses of 24 hours or less vs 72 hours or more after ear, nose, throat, and oral and maxillofacial surgery. Some studies were also handpicked from reference lists of studies found with the initial search terms. All analysis was performed between September 2017 and October 2018. Data Extraction and Synthesis: All review stages were conducted in consensus by 2 reviewers. Data extraction and study quality assessment were performed with the Cochrane data extraction form and the Cochrane risk of bias tool. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were used for reporting. The fixed-effects Mantel-Haenszel method was used for meta-analysis. Main Outcomes and Measures: Relative risk (RR) of surgical site infections, microbial origins of surgical site infections, adverse events, duration of hospital stay, and treatment costs. Results: Included in the meta-analysis were 21 articles with a cumulative 1974 patients. In patients receiving 24 hours or shorter vs 72 hours or longer antibiotic prophylaxis regimens, no significant difference was found in the occurrence of postoperative infections in the pooled population (RR, 0.90; 95% CI, 0.67-1.19), or in the ear, nose, throat (RR, 0.89; 95% CI, 0.54-1.45), and oral and maxillofacial populations (RR, 0.88; 95% CI, 0.63-1.21), separately. No heterogeneity was observed overall or in the subgroups. Patients receiving extended-course antibiotic prophylaxis were significantly more likely to develop adverse events unrelated to the surgical site (RR, 2.40; 95% CI, 1.20-3.54). Conclusions and Relevance: No difference was found in the occurrence of postoperative infections between short-course and extended-course antibiotic prophylaxis after ear, nose, throat, and oral and maxillofacial surgery. Therefore, a short course of antibiotic prophylaxis is recommended unless documented conditions are present that would be best treated with an extended course. Using short-course antibiotics could avoid additional adverse events, antibiotic resistance development, and higher hospital costs. Future research should focus on identifying risk groups that might benefit from prolonged prophylaxis.

High-dose rifampicin in tuberculosis: Experiences from a Dutch tuberculosis centre.

BACKGROUND: Recent evidence suggests that higher rifampicin doses may improve tuberculosis (TB) treatment outcome. METHODS: In this observational cohort study we evaluated all TB patients who were treated with high-dose rifampicin (> 10 mg/kg daily) in our reference centre, from January 2008 to May 2018. Indications, achieved plasma rifampicin exposures, safety and tolerability were evaluated. RESULTS: Eighty-eight patients were included. The main indications were low plasma concentrations (64.7%) and severe illness (29.5%), including central nervous system TB. Adjusted rifampicin dosages ranged from 900 mg to a maximum of 2400 mg (corresponding to 32 mg/kg) per day. Patients with severe illness received high-dose rifampicin immediately, the others had a higher dosage guided by therapeutic drug monitoring. Four patients developed hepatotoxicity, of which two were proven due to isoniazid. Re-introduction of high-dose rifampicin was successful in all four. Eighty-seven patients tolerated high-dose rifampicin well throughout treatment. Only one patient required a dose reduction due to gastro-intestinal disturbance. CONCLUSION: High-dose rifampicin, used in specific groups of patients in our clinical setting, is safe and well-tolerated for the whole treatment duration. Measurement of drug exposures could be used as a tool/guide to increase rifampicin dosage if a reduced medication absorption or a poor treatment outcome is suspected. We suggest to administer high-dose rifampicin to patients with severe manifestations of TB or low rifampicin exposure to improve treatment outcome.