The inappropriate use of antibiotics is a key driver for the development of antibiotic resistance. In this regard, “older” marketing authorisations of antibiotics play a key role, as the current state of scientific knowledge on efficacy and the current resistance situation is only reflected to a limited extent in their product information texts.

Accordingly, BfArM advocated in the "Infectious Disease Working Party" (IDWP) of the European Medicines Agency (EMA) to review the marketing authorisations of important "older" antibiotics and, in particular, to re-evaluate the information on the authorised indications and the recommended dosage. BfArM is actively involved in these European procedures (re-evaluation procedures) in accordance with Article 30/31 of Directive 2001/83/EC in order to support the appropriate use of antibiotics and counteract possible resistance developments.

In one such procedure, BfArM took the lead (so-called co-rapporteurship) in the revision of the marketing authorisations of medicinal products containing fosfomycin, which was finalised in June 2020 (EMA/317719/2020). As a result, the authorised indications and dosages were adapted to the current state of scientific knowledge.

Likewise, the European Article 31 procedures for vancomycin (EMA/645879/2017) and colistin (EMA/785229/2014 corr1) took place with the active involvement of the BfArM in 2017 and 2014, as well as a series of European Article 30 procedures.

In addition, BfArM took the lead responsibility for the review of medicinal products containing azithromycin in November 2023.

In addition to the information on efficacy and safety, the information on the current resistance situation - based on available European data - is also updated. The review and re-evaluation of other "older antibiotics" is planned for the coming years.

Appropriate knowledge is a prerequisite for the proper use of antibiotics and the correct handling of multi-resistant pathogens. To this end, treating physicians need to have access to reliable national resistance data and need to be informed whether an antibiotic is effective against a specific pathogen at the appropriate dosage. Doctors can find this information in section 5.1 of the Summary of Product Characteristics (SmPC). Since 2006, all available and suitable data on the national resistance situation of antibiotics in Germany have been included there.

In 2005, BfArM launched a project that is unique in the EU: Centre for the Evaluation of Resistance Data for Antibiotics for Systemic Use, shortly Z.A.R.S.

Associations of the pharmaceutical industry, as well as the professional associations "German Society for Hygiene and Microbiology" and "Paul Ehrlich Society for Chemotherapy" (PEG), the Robert Koch Institute (RKI) as well as representatives of the German Network on Antimicrobial Resistance (GE-NARS) and the Competence Network for Community Acquired Pneumonia (CAPNETZ) were involved in its establishment.

Via Z.A.R.S, the resistance data of approximately 60 antibiotics for systemic use are evaluated at regular intervals and the corresponding resistance tables for section 5.1 of the SmPC are generated. Changes in the national resistance situation and possible consequences are discussed with BfArM at annual intervals.

The tables in section 5.1 of the SmPC provide treating physicians with important information on the resistance situation of pathogens in Germany to be expected for treatment. This up-to-date information is intended to help physicians to select a suitable antibiotic for a calculated therapy before the pathogen is identified and results of resistance testing are available.

https://www.resistenztabellen.de/login.php

In Germany, national antibiotic resistance data is collected, analysed and presented in section 5.1 of the Summary of Product Characteristics so that treating physicians can better assess whether an antibiotic is suitable for treating the bacterial infection in question before prescribing it. However, in daily practice, maintaining an overview on the current national resistance situation and treatment recommendations is challenging.

The aim of the project AntibioResDE (Antibiotic Resistance Germany) is to compile current and ongoing knowledge on the appropriate use of antibiotics in an electronic platform. In addition, this data is to be presented in a user-friendly manner to make it easier to use. The project, which is funded by the Federal Ministry of Health (BMG), was launched in 2023 and is realized jointly by BfArM and the Robert Koch Institute (RKI).

To this end, physicians are directly involved and interviewed on the use of resistance data. Based on this feedback, strategies are being developed to make the national data on antibiotic resistance even more usable. Thereafter, these suggestions will be used to develop an electronic platform that will speed up and simplify the analysis and visualisation of resistance data. After the trial phase with a few antibiotics (feasibility study), which should show whether such an electronic platform continuously provides valid and user-friendly data, this system could contribute to the prevention of resistance development and treatment failure in a more comprehensive manner.

As part of the Translational Infrastructure Product Development of the German Centre for Infection Research (DZIF), BfArM supports in particular academic research and development projects advancing the fight against antibiotic-resistant bacteria. The translation of (bio-) medical research into clinical use is of crucial importance in the fight against antibiotic resistance. More than 95 percent of newly developed substances already fail in the laboratory. Successful drug development requires scientific, regulatory and economic expertise. This is where BfArM and Paul Ehrlich Institute (PEI) come in since 2015, supporting the DZIF by addressing regulatory and scientific questions through the Office for Scientific and Regulatory Advice (OSRA). By the end of 2023, advice and support was provided to more than 40 academic projects in the field of product development.

These include projects on the development of novel antibiotics against methicillin-resistant Staphylococcus aureus and for the treatment of tuberculosis. Through a Federal Ministry of Education and Research (BMBF)-funded project and in collaboration with the DZIF, BfArM and PEI since 2019 also support the fight against antibiotic-resistant bacteria as a part of the CARB-X ("Combating Antibiotic-Resistant Biopharmaceutical Accelerator") initiative. This international public-private partnership aims to accelerate the development of innovative antibiotics and to develop other therapeutics, vaccines, rapid diagnostics and devices to combat drug-resistant bacterial infections. CARB-X supports more than 38 projects of small and medium-sized companies worldwide. Together, BfArM, PEI and DZIF provide advice to applicants and projects, particularly on scientific and regulatory questions and issues, impart regulatory knowledge through workshops and trainings and support researchers on their path to potential CARB-X funding.

For further information please visit

DZIF website: https://www.dzif.de/en  

DZIF, product development: https://www.dzif.de/en/infrastructure/product-development

CARB-X website: https://carb-x.org/

CARB-X, Global Accelerator Network website: https://carb-x.org/partners/global-accelerator-network/

Since 2021, an amendment to § 35a SGB V has enabled the Federal Joint Committee (G-BA) to exempt new antibiotics, which are referred to as reserve antibiotics within the meaning of the law, from the need for assessment of an additional benefit.

For antibiotics categorised as a reserve antibiotic by the G-BA in accordance with § 35a, the additional benefit compared to possible treatment alternatives is considered proven without the pharmaceutical company (PU) having to prove this through corresponding studies. The resulting financial and economic incentives are intended to promote the research, development and market launch of new antibiotics with efficacy against multi-resistant bacterial pathogens (MRE) ("push-pull mechanisms").

In collaboration with BfArM, the Robert Koch Institute (RKI) has developed criteria for classifying an antibiotic as a reserve antibiotic and created a non-exhaustive list of MRE for the first time in 2021 and updated it in 2024.

The non-exhaustive list of multi-resistant bacterial pathogens currently contains 25 multi-resistant bacterial pathogens or pathogen-resistance combinations that are considered as relevant for Germany.

The World Health Organisation's Pathogen Priority List (WHO PPL) served as basis for the selection of pathogens for the non-exhaustive pathogen list. In addition to the criteria used in the WHO PPL (such as treatability, mortality, transmissibility), national data from the Antibiotic Resistance Surveillance (ARS) database was used for the adaptation to the national context – focussing on the resistance situation (prevalence and trend) – in order to assess the relevance of the individual MRE for Germany.

The main criteria for classifying a new antibiotic as a reserve antibiotic were defined as its proven suitability for the treatment of serious bacterial infectious diseases caused by at least one of these relevant multidrug-resistant pathogens, with limited alternative, clinically equivalent treatment options at the same time.

As part of the 2024 update, the non-exhaustive list of pathogens was reviewed again using the latest available data and the requirements for the data to be submitted for classification by the G-BA were further specified using the list of criteria.

The non-exhaustive list of multi-resistant bacterial pathogens and the criteria for classifying an antibiotic as a reserve antibiotic in accordance with § 35a (1) SGB V as of 15 January 2025 can be found here:

Non-exhaustive list of multi-resistant bacterial pathogens and criteria for classifying an antibiotic as a reserve antibiotic in accordance with Section 35a (1) SGB V (as of 15 January 2025)

The development of new antibiotics is subject to complex regulatory and scientific requirements. Therefore, within its remit BfArM offers kick-off meetings. With this service, BfArM provides support on relevant aspects relating to potential ways to obtain a marketing authorisation, current regulatory requirements and necessary procedural steps at an early stage of product development.

As part of the scientific and procedural advice, applicants have the opportunity to address questions directly to BfArM related to administrative procedures for which BfArM is also responsible as the authorisation or supervisory authority.

https://www.bfarm.de/EN/BfArM/Tasks/Advice-procedures/_node.html

Bacteriophages (short form: phages) are viruses that kill bacteria within their reproduction cycle and are specific to one bacterial species. For this reason, bacteriophages represent a promising therapeutic approach for the treatment of bacterial infections - especially in the fight against multi-resistant pathogens. Although bacteriophages have been used medically for more than 100 years, the efficacy and safety of bacteriophages has not yet been demonstrated in a large randomised, controlled trial.

BfArM supports various academic and non-academic projects on the use of phages in different indications by providing scientific advice. One example is the BMBF-funded Phage4-Cure project (https://phage4cure.de/en/projekt/), which is developing an inhalation phage product for the treatment of Pseudomonas aeruginosa infections and is currently investigated in a first-in-human study. Similarly, a phage lysin is being developed within the DZIF, and has recently entered the clinical development stage. The phage protein HY-133 is intended to eliminate Staphylococcus aureus from the nose of patients before a surgery in order to reduce the risk of infection (https://www.dzif.de/en/new-active-agent-against-hospital-pathogens).

The National Antibiotics Susceptibility Testing Committee (NAK) has set itself the goal of

• establishing EUCAST (European Committee on Antimicrobial Susceptibility Testing) breakpoints for efficacy testing of antibiotics and antimycotics in Germany,
• evaluating breakpoints for antibiotics and antimycotics that are not taken into account by EUCAST,
• supporting the development of test methods, and
• helping to establish microbiological-infectiological quality standards.

In this way, the development of resistance is recognised at an early stage and the appropriate use of antibiotics and the correct handling of multi-resistant pathogens is ensured. BfArM is represented in the NAK by two representatives (NAK Plenum, NAK Steering Group) and is actively involved in the discussions and decisions.

https://www.nak-deutschland.org/nak-deutschland/index.html

The Commission for Antiinfectives, Resistance and Therapy (ART) at the Robert Koch Institute (RKI) was established based on the "Act amending the Infection Protection Law and other laws", which came into force on August 4th 2011, in accordance with § 23 (2) of the Infection Protection Law. The task of the ART Commission is to generate recommendations for standards for the diagnosis and treatment of infectious diseases in accordance with the current state of medical knowledge. On this basis, it carries out a medical-epidemiological benefit-risk assessment between weighing up the individual interest in effective treatment and the public interest in maintaining the effectiveness of anti-infectives and takes into account practical implementation concerns.

BfArM is represented in the ART Commission by a permanent guest and supports the Commission in its work both in terms of content and implementation.

https://www.rki.de/DE/Content/Kommissionen/ART/ART_node.html

The commission generates recommendations on the prevention of nosocomial infections and on operational-organisational and structural-functional hygiene measures in hospitals and other medical facilities. BfArM comments on KRINKO recommendations as part of consultation procedures and recommends additions with regard to regulatory aspects and from an authorisation perspective.