Every year, the World Health Organization (WHO) dedicates the week from 18 to 24 November to the awareness of antimicrobic resistance (AMR), a severe global problem that in 2019 directly caused 1,27 million deaths worldwide. Antibiotic resistance, which refers to the capacity of bacteria to survive the action of antibiotics, is the most well-known form of resistance to microorganisms.

Bacteria are called Multidrug Drug Resistant (MDR) when they acquire resistance to at least one agent in three or more antimicrobial categories. The treatment of infections caused by MDR organisms is challenging for both the patients and healthcare and associated to failure and health care cost increase.

In Europe, as stated by the surveillance report of ECDC in 2023, there is a decreasing gradient of severe infection caused by multidrug resistance bacteria from North to South and from West to East. This is very evident for two of the most threatening pathogens: third-generation cephalosporin and carbapenem resistance K. pneumoniae and Acinetobacter spp carbapenem resistance. Data show that problem is particularly severe in Italian and Greek hospitals and communities. In Italy, we also have high rate of circulation of other MDR organisms, such as methicillin-resistant Staphylococcus aureus, cephalosporin-resistant Enterobacteriales and glycopeptide-resistant Enterococci.

At IRCCS San Raffaele Scientific Institute, Doctor Daniela Maria Cirillo, Deputy Director of the Immunology, Transplantation and Infectious Diseases Division and head of the Emerging Bacterial Pathogen Unit, has been working for the last 20 years on the pathogenesis and molecular diagnostics of tuberculosis, the world leading cause of deaths from single infectious agent. Moreover, Doctor Cirillo’s group collaborates also with the WHO, the European Institution for bacterial breakpoint Definition (EUCAST) and the European Centre for Disease Control to define shared guidelines to properly tackle AMR.  Now she focuses on the process of early alignment of new antibiotics in phase IIB-III trials with proper diagnostics to address their future use and detect the emergence of resistance in surveillance programs.

Choosing the right antimicrobic requires an accurate diagnosis

“It is strongly recommendable to complement the development of new antimicrobics with that of diagnostic tests detecting the pathogen species, as well as whether and what kind of resistance it has already developed against the new drug. To this aim, there is a burgeoning field of molecular diagnostics based on whole genome and next generation sequencing techniques, enabling accurate identification of genetic characteristics that confer AMR. This is crucial for the definition of a personalized therapy, tailored on the specific pathogen species causing the infection, and for the monitoring of emergent AMR”, says Doctor Cirillo. “However, differences in market potential, costs and developmental timeline have made the complementary use of diagnostic tests and antimicrobics historically challenging.”

Developing new antimicrobics and antibiotics is financially disincentivized, given the costly initial investment and the time it takes to commercialization, which corresponds to about 10 years. Integrating the co-development of diagnostics into antimicrobics production increases the expense and the laboriousness of the process, eventually also enhancing the risk of marketing failure. However, the introduction of AMR diagnostics already at the level of phase IIB-III clinical trials could rapidly identify whether microorganisms have already developed resistance against the new drug, thus ruling out its use for the infection treatment. This, in turn, would provide AMR surveillance data and identify resistance trends useful to adapt treatment policies, potentially leading to decreased morbidity and mortality rates. In this context, the public sector should encourage partnerships between diagnostics developers and producers, for example by derisking the co-development of the two technologies and making the antimicrobic market contingent on an approved diagnostic test.

Preventing a severe global problem is key

“There should be concerted efforts involving clinicians, patients, and policymakers to eventually eradicate AMR. Clinicians should make very targeted pathogen diagnoses, in collaboration with the infectious disease specialist, to choose the right antimicrobic regimen. When the infection is caused by a bacterium, they should avoid the prescription of broad-spectrum antibiotics as much as possible, and they should train patients to strictly adhere to the therapeutic plan, which starts on the first day and ends at a very specific day. Patients, in turn, should prevent the spreading of infectious diseases through vaccination, when available, for example against bacteria causing pneumonia and meningitis. From the policymaker perspective, clear guidelines regulating antibiotic prescription and use must be made available and shared. These rules must concern not only the healthcare system, but also animal farming as well as water disposal”, continues Doctor Cirillo.

To this regard, we shall note that antibiotics are used also in veterinary medicine upon medical prescription. However, there are antibiotic analogs, classified as supplements, which do not need prescriptions and can be employed for instance in poultry farming, eventually reaching the human body through the diet. This can impact on the health of the microbiota, which is increasingly recognized as crucial for the health of the whole human body.

In addition to the unrestricted use of antibiotic analogs, there is the problem of correct disposal of waters coming from pharmaceutical production plants, which have been de-localized in countries outside the European Union, where the production cost is low, but the normative less stringent. “Those waters often contain antibiotic residuals that are still active and can reach animals and, eventually, humans, contributing to AMR development. In the end, it’s important to acknowledge that AMR is not only a problem of the human health, but it is a severe, global issue affecting the whole ecosystem”, concludes Doctor Cirillo