Abstract: The hollow-fibre system for tuberculosis (HFS-TB) is a preclinical model qualified by the European Medicines Agency to underpin the anti-TB drug development process. It can mimic in vivo pharmacokinetic (PK)–pharmacodynamic (PD) attributes of selected antimicrobials, which could feed into in silico models to inform the design of clinical trials. However, historical data and published protocols are insufficient and omit key information to allow experiments to be reproducible. Therefore, in this work, we aim to optimize and standardize various HFS-TB operational procedures. First, we characterized bacterial growth dynamics with different types of hollow-fibre cartridges, Mycobacterium tuberculosis strains and media. Second, we mimicked a moxifloxacin PK profile within hollow-fibre cartridges, in order to check drug–fibres compatibility. Lastly, we mimicked the moxifloxacin total plasma PK profile in human after once daily oral dose of 400 mg to assess PK–PD after different sampling methods, strains, cartridge size and bacterial adaptation periods before drug infusion into the system. We found that final bacterial load inside the HFS-TB was contingent on the studied variables. Besides, we demonstrated that drug–fibres compatibility tests are critical preliminary HFS-TB assays, which need to be properly reported. Lastly, we uncovered that the sampling method and bacterial adaptation period before drug infusion significantly impact actual experimental conclusions. Our data contribute to the necessary standardization of HFS-TB experiments, draw attention to multiple aspects of this preclinical model that should be considered when reporting novel results and warn about critical parameters in the HFS-TB currently overlooked.

Authors: Aguilar-Ayala D. A., Sanz-García F., Rabodoarivelo M. S., Susanto B. O., Bailo R. Eveque-Mourroux M. R., Willand N., Simonsson U. S. H., Ramón-García S., Lucía A.

Source: British Journal of Clinical Pharmacology

DOI: https://doi.org/10.1111/bcp.16068 

Abstract: The continuing spread of tuberculosis (TB) worldwide, especially drug-resistant TB, poses a major challenge to healthcare systems globally. Addressing this requires appraising the cost effectiveness of existing pharmacological interventions against TB to identify key drivers of cost effectiveness and value and guide pharmaceutical innovation and novel drug regimen development. Studies were identified from a search of six database: MEDLINE MEDLINE-In Process, MEDLINE Epub Ahead of Print, EMBASE, Cochrane Database of Systematic Reviews, and Econlit in July 2022. Two reviewers independently assessed all identified studies and reports using pre-defined inclusion/exclusion criteria. Study methodological quality was assessed, data were extracted in standard tables, and results were narratively synthesized. Overall, 991 studies and 53 HTA reports were identified with 20 studies and 3 HTA reports meeting the inclusion criteria. Quality assessment of the 20 studies identified 4 with minor limitations, while the remainder were assessed as having potentially or very serious limitations. Sixteen studies conducted cost-utility analyses, 6 conducted cost-effectiveness analyses, and 2 conducted cost-comparison analyses with some studies performing multiple analyses. The majority (n = 16) were model-based. Eleven studies analyzed the cost-effectiveness of bedaquiline, 6 compared shorter to longer/standard duration regimens, 2 assessed ethambutol, and 1 assessed delamanid. Key drivers of cost effectiveness were drug costs, the number of TB cases, the portion of cases with sputum culture conversion, treatment delivery costs, and treatment efficacy. Common value elements considered included adverse events, drug resistance, and improving treatment adherence. Our results suggest that out of the pharmacological treatments assessed, bedaquiline is likely a cost-effective addition to existing treatment regimens/background treatment regimens, while ethambutol is not likely to be. Newer shorter regimens, even if more costly, seem to be more cost-effective compared to longer regimens. These results illustrate the limited number of novel cost-effective pharmacological interventions and highlight a need to develop new drugs/regimens against TB to overcome resistance, taking into account the key drivers of cost effectiveness and other value attributes identified from this review.

Authors: Nagar S., Nicholss D., Dawoud D.

Source: Frontiers in Public Health, Health Economics

DOI: https://doi.org/10.3389/fpubh.2024.1201512



To prioritize healthcare investments, ranking of infections caused by antibiotic-resistant bacteria should be based on accurate incidence data.


We performed a systematic review to estimate frequency measures of antimicrobial resistance for six key bacteria causing bloodstream infections (BSI) in European countries.


We searched PubMed, Web of Science, Embase databases, and the ECRAID-Base Epidemiological-Network platform.


We included studies and surveillance systems assessing resistance-percentage, prevalence, or incidence-density of BSI because of carbapenem-resistant Pseudomonas aeruginosaAcinetobacter baumanniiKlebsiella pneumoniae, and Escherichia coli, third-generation cephalosporins-resistant E. coli and K. pneumoniae, vancomycin-resistant Enterococcus faecium, and methicillin-resistant Staphylococcus aureus.


Reviewers independently assessed published data and evaluated study quality with the modified Joanna Briggs Institute critical appraisal tool. Pooled estimates were determined using random effects meta-analysis. Consistency of data was assessed using random effects meta-regression (Wald test, p > 0.05).


We identified 271 studies and 52 surveillance systems from 32 European countries. Forty-five studies (16%) reported on BSI, including 180 frequency measures most commonly as resistance-percentage (88, 48.9%). Among 309 frequency measures extracted from 24 (46%) surveillance systems, 278 (89%) were resistance-percentages. Frequency measures of methicillin-resistant S. aureus and vancomycin-resistant E. faecium BSI were more frequently reported from Southern Europe and Western Europe (80%), whereas carbapenem-resistant P. aeruginosa BSI from Northern Europe and Western Europe (88%). Highest resistance-percentages were detected for carbapenem-resistant A. baumannii (66% in Central Eastern Europe) and carbapenem-resistant K. pneumoniae (62.8% in Southern Europe). Pooled estimates showed lower resistance-percentages in community versus healthcare-associated infections and in children versus adults. Estimates from studies and surveillance systems were mostly consistent among European regions. The included data was of medium quality.


Pathogen-specific frequency measures of antimicrobial resistance in BSI are insufficient to inform antibiotic stewardship and research and development strategies. Improving data collection and standardization of frequency measures is urgently needed.

Mupirocin resistance in S. aureus was infrequent in both blood and colonizing isolates. Furthermore, in the years 2003–2021, a decreasing trend in the annual rate of S. aureus bloodstream infections was observed. Targeted mupirocin-based decolonization of S. aureus carriers undergoing haemodialysis is a sustainable measure for preventing healthcare-associated infections.

Authors:Diletta Pezzani, M., Arieti, F., Babu Rajendran, N., Barana, B., Cappelli, E., De Rui, M. E., Galia, L., Hassoun-Kheir, N., Argante, L., Schmidt, J., Rodriguez-Bano, J., Harbarth, S., de Kraker, M., Primrose Gladstone, B., Tacconelli, E.

Source: ScienceDirect, Journal of Hospital Infection

DOI: https://doi.org/10.1016/j.jhin.2023.01.019

Abstract: Antimicrobial resistance (AMR) causes a high burden of disease. The European Centre for Disease Prevention and Control has estimated that in 2019, AMR caused 865 767 infections, 38 710 attributable deaths, and 1 101 288 disability-adjusted life years, in Europe []. Because increasing rates of AMR further reduce the effectiveness of last resort antibiotics, novel treatment strategies are urgently needed. According to Butler and Paterson [], between 2017 and 2021, 12 new antibiotics were approved, of which only vaborbactam belonged to a new class. Among 16 antimicrobial agents in phase III or under regulatory evaluation, only 4 have new modes of action. Vaccines and monoclonal antibodies (mAbs) could offer a promising alternative for prevention or treatment of infections []. The added advantage of vaccines is that they can reduce the need for antibiotic prescribing, through a reduction of the disease itself (bacterial vaccines) or a reduced number of bacterial superinfections (viral vaccines). Because antibiotic use is a key driver of AMR, a lower need for antibiotic prescribing can have knock-on benefits, slowing development, and spread of resistance in the population. In addition, evolution of vaccine resistance is less likely than AMR development, because vaccines have a multiplicity of targets and are mostly used prophylactically against invasive infection []. Serotype replacement, such as after the implementation of Streptococcus pneumoniae vaccination, might reduce vaccine sustainability []. However, this is a much slower process, and vaccine serotype coverage can be updated over time. For mAbs, antigenic escape could occur, but this can be overcome by using mAbs cocktails or bi-specific mAbs. Moreover, mAbs tend to have a long half-life, extending their clinical efficacy [].

Authors:Robotham, J. V., Tacconelli, E., Vella, V., de Kraker, M. E. A.

Source: ScienceDirect, European Society of Clinical Microbiology and Infectious Diseases

DOI: https://doi.org/10.1016/j.cmi.2023.10.004

Abstract: First-time-in-human (FTIH) trials are designed to generate information on the safety, tolerability, as well as the pharmacokinetic and pharmacodynamics profile of new drugs. To ensure the safety of participants, these trials need to be conducted at specifically equipped phase I clinical trial units (CTUs). In accordance with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Guideline for Good Clinical Practice (GCP) and the European Union (EU) regulatory guidelines, one of the aims of the European Regime Accelerator for Tuberculosis (ERA4TB) project is to collaboratively create a feasibility tool, through a partnership between public and private entities, for the validation of CTUs selected to conduct FTIH trials. A feasibility form, encompassing nine sections, was created to gather information on the unit in relation to key attributes of FTIH trials. Collaboratively, industry and academic partners defined the minimal criteria to ensure the adherence of CTUs to the principles of ICH GCP and regulations outlined by the European Medicines Agency (EMA) for the execution of FTIH trials. Subsequently, all CTUs available for the project were assessed for FTIH trial eligibility. The introduction of the certification procedure through the feasibility tool within ERA4TB resulted in the accreditation of the five academic CTUs, which are now prepared to carry out FTIH trials as part of the Consortium. The developed feasibility tool aims to establish open and widely used minimum requirements for the validation of academic CTUs as FTIH units, marking it as the inaugural tool for CTU validation resulting from the collaboration between industry and academia within the ERA4TB project. The established partnership has enabled an innovative and novel way of working.

Authors: Moraga, P., Prieto, P., Conradie, A., Benhayoun, M., Rousell, V., Davy, M., Fuhr, U., Arbos, R. A., Abad-Santos, F., Portolés, A., Van Duinen, J., Carcas, A. J., Borobia, A. M., Manganelli, R., Degiacomi, G., Recchia, D., Pasca, M. R., Simonsson, U., Ramón-García, S.

Source: American Society for Clinical Pharmacology & Therapeutics, Clinical and Translational Science

DOI: https://doi.org/10.1111/cts.13655



Antimicrobial resistance is a global threat, which requires novel intervention strategies, for which priority pathogens and settings need to be determined.


We evaluated pathogen-specific excess health burden of drug-resistant bloodstream infections (BSIs) in Europe.


systematic review and meta-analysis.


MEDLINE, Embase, and grey literature for the period January 1990 to May 2022.


Studies that reported burden data for six key drug-resistant pathogens: carbapenem-resistant (CR) Pseudomonas aeruginosa and Acinetobacter baumannii, third-generation cephalosporin or CR Escherichia coli and Klebsiella pneumoniae, methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium. Excess health outcomes compared with drug-susceptible BSIs or uninfected patients. For MRSA and third-generation cephalosporin E. coli and K. pneumoniae BSIs, five or more European studies were identified. For all others, the search was extended to high-income countries.


Paediatric and adult patients diagnosed with drug-resistant BSI.


Not applicable.


An adapted version of the Joanna-Briggs Institute assessment tool.


Random-effect models were used to pool pathogen-specific burden estimates.


We screened 7154 titles, 1078 full-texts and found 56 studies on BSIs. Most studies compared outcomes of drug-resistant to drug-susceptible BSIs (46/56, 82.1%), and reported mortality (55/56 studies, 98.6%). The pooled crude estimate for excess all-cause mortality of drug-resistant versus drug-susceptible BSIs ranged from OR 1.31 (95% CI 1.03–1.68) for CR P. aeruginosa to OR 3.44 (95% CI 1.62–7.32) for CR K. pneumoniae. Pooled crude estimates comparing mortality to uninfected patients were available for vancomycin-resistant Enterococcus and MRSA BSIs (OR of 11.19 [95% CI 6.92–18.09] and OR 6.18 [95% CI 2.10–18.17], respectively).


Drug-resistant BSIs are associated with increased mortality, with the magnitude of the effect influenced by pathogen type and comparator. Future research should address crucial knowledge gaps in pathogen- and infection-specific burdens to guide development of novel interventions.

Authors: Hassoun-Kheir, N., Guedes, M., Ngo Nsoga, M.-T., Arguante, L., Arieti, F., Gladstone, B. P., Kingston, R., Naylor, N. R., Pezzani, M. D., Pouwels, K. B., Robotham, J. V., Rodríguez-Baño, J., Tacconelli, E., Vella, V., Harbarth, S., de Kraker, M. E. A.

Source: ScienceDirect, European Society of Clinical Microbiology and Infectious Diseases

DOI: https://doi.org/10.1016/j.cmi.2023.09.001

Abstract: Tuberculosis (TB) is the historical leading cause of death by a single infectious agent. The European Regimen Accelerator for Tuberculosis (ERA4TB) is a public-private partnership of 30+ institutions with the objective to progress new anti-TB regimens into the clinic. Thus, robust and replicable results across independent laboratories are essential for reliable interpretation of treatment efficacy. A standardization workgroup unified in vitro protocols and data reporting templates. Time-kill assays provide essential input data for pharmacometric model-informed translation of single agents and regimens activity from in vitro to in vivo and the clinic. Five conditions were assessed by time-kill assays in six independent laboratories using four bacterial plating methods. Baseline bacterial burden varied between laboratories but variability was limited in net drug effect, confirming 2.5 μL equally robust as 100 μL plating. This exercise establishes the foundations of collaborative data generation, reporting, and integration within the overarching Antimicrobial Resistance Accelerator program.

Authors: van Wijk, R. C., Lucía, A., Sudhakar, P. K., Sonnenkalb, L., Gaudin, C., Hoffmann, E., Dremierre, B., Aguilar-Ayala, D. A., Dal Molin, M., Rybniker, J., de Giorgi, S., Cioetto-Mazzabò, L., Segafreddo, G., Manganelli, R., Degiacomi, G., Recchia, D., Pasca, M. R., Simonsson, U., Ramón-García, S.

Source: CellPress, iScience

DOI: https://doi.org/10.1016/j.isci.2023.106411


BACKGROUND: A critical step in tuberculosis (TB) drug development is the Phase 2a early bactericidal activity (EBA) study which informs if a new drug or treatment has short-term activity in humans. The aim of this work was to present a standardized pharmacometric model-based early bactericidal activity analysis workflow and determine sample sizes needed to detect early bactericidal activity or a difference between treatment arms.

METHODS: Seven different steps were identified and developed for a standardized pharmacometric model-based early bactericidal activity analysis approach. Non-linear mixed effects modeling was applied and different scenarios were explored for the sample size calculations. The sample sizes needed to detect early bactericidal activity given different TTP slopes and associated variability was assessed. In addition, the sample sizes needed to detect effect differences between two treatments given the impact of different TTP slopes, variability in TTP slope and effect differences were evaluated.

RESULTS: The presented early bactericidal activity analysis approach incorporates estimate of early bactericidal activity with uncertainty through the model-based estimate of TTP slope, variability in TTP slope, impact of covariates and pharmacokinetics on drug efficacy. Further it allows for treatment comparison or dose optimization in Phase 2a. To detect early bactericidal activity with 80% power and at a 5% significance level, 13 and 8 participants/arm were required for a treatment with a TTP-EBA0-14 as low as 11 h when accounting for variability in pharmacokinetics and when variability in TTP slope was 104% [coefficient of variation (CV)] and 22%, respectively. Higher sample sizes are required for smaller early bactericidal activity and when pharmacokinetics is not accounted for. Based on sample size determinations to detect a difference between two groups, TTP slope, variability in TTP slope and effect difference between two treatment arms needs to be considered.

CONCLUSION: In conclusion, a robust standardized pharmacometric model-based EBA analysis approach was established in close collaboration between microbiologists, clinicians and pharmacometricians. The work illustrates the importance of accounting for covariates and drug exposure in EBA analysis in order to increase the power of detecting early bactericidal activity for a single treatment arm as well as differences in EBA between treatments arms in Phase 2a trials of TB drug development.

Authors: Mockeliunas, L., Faraj, A., van Wijk, R. C., Upton, C. M., van den Hoogen, G., Diacon, A. H., Simonsson, U.

Source: Frontiers in Pharmacology, Section Pharmacology of Infectious Diseases

DOI: https://doi.org/10.3389/fphar.2023.1150243

Abstract: Despite being a preventable and curable disease, tuberculosis (TB) is still a major global health threat and the second leading cause of death due to an infectious agent worldwide. All the efforts invested to end TB have resulted overall in rather slow decreases in TB incidence and mortality rates, which have been further negatively affected by the ongoing coronavirus disease 2019 (COVID-19) pandemic. While the majority of targets of the End TB Strategy remain off track, and we have not yet overcome the disruptions caused by the COVID-19 pandemic, recent conflicts such as the ongoing war in Ukraine are threatening the decrease of the burden of TB even further. To get back on track and get closer to ending TB, we need urgent, global, well-structured and committed multi-sectoral actions that go beyond national and global TB programmes with the support of deep investments in research and facilitation of equitable and rapid implementation of innovation worldwide.

Authors: Villar-Hernández, R., Ghodousi, A., Konstantynovska, O., Duarte, R., Lange, C., Raviglione, M.

Source: European Respiratory Society, Breathe

DOI: https://doi.org/10.1183/20734735.0166-2022

Abstract: Mupirocin-based decolonization of Staphylococcus aureus carriers undergoing haemodialysis is not widely implemented due to concerns of mupirocin resistance. In our haemodialysis unit, a strategy combining universal S. aureus screening with targeted mupirocin-based decolonization was introduced two decades ago. In this study of haemodialysis patients, mupirocin resistance was assessed in blood and colonizing S. aureus isolates during two periods.

Mupirocin resistance in S. aureus was infrequent in both blood and colonizing isolates. Furthermore, in the years 2003–2021, a decreasing trend in the annual rate of S. aureus bloodstream infections was observed. Targeted mupirocin-based decolonization of S. aureus carriers undergoing haemodialysis is a sustainable measure for preventing healthcare-associated infections.

Authors: Hassoun-Kheir, N., Buetti, N., Olivier, V., Perez, M., Frossard, J., Renzi, G., Schrenzel, J., Saudan, P., Harbarth, S.

Source: ScienceDirect, Journal of Hospital Infection

DOI: https://doi.org/10.1016/j.jhin.2023.01.019