Antibiotic-resistance does not depend on the antibiotic administration mode

An international multicenter study coordinated by the San Raffaele Hospital has demonstrated how the continuous or intermittent administration of meropenem, an antibiotic used for the majority of gram-negative bacterial infections, belonging to the beta-lactam group and included in the WHO list of essential drugs, does not improve clinically relevant outcomes in critically ill patients with sepsis and sheds new light on the health policies to be adopted to direct human and economic resources to other specific more effective interventions.

The research, just published in the prestigious journal JAMA and supported by the Italian Medicines Agency, was coordinated by professors Alberto Zangrillo and Giovanni Landoni (UniSR Full Professors of Anesthesiology) and Giacomo Monti (UniSR Associate Professor of Anesthesiology) of the San Raffaele Hospital Center for Research in Anesthesia and Intensive Care Unit. It involved 26 hospitals in 4 different countries (Italy, Russia, Kazakhstan and Croatia), with a total of 607 patients, constituting the largest population included in a research project on this specific theme.

Antibiotic resistance, i.e. the ability of bacteria to become insensitive to the action of drugs capable of killing them, represents a health emergency of extraordinary importance. According to the World Health Organization, antibiotic resistance is one of the greatest threats to global health. In the United States, these particular bacteria are estimated to have caused more than 2.8 million infections in 2019 and contributed to the deaths of nearly 36,000 people.

For this category of antibiotics, beta-lactams, the administration mode, as well as the dose and the selection of the particular molecule, is a fundamental element in determining the effectiveness of the therapy and the risk of the onset of new infections.

Due to the outcome of previous scientific studies and pharmacological considerations, it has always been assumed that the "continuous" administration of these drugs, via continuous intravenous infusion, compared to the classic "intermittent" administration, always intravenous, offered an advantage in terms of better survival to the infection and a lower risk of the onset of multi-resistant bacteria to various antibiotics. However, this hypothesis had never found a confirmation, or a denial, within a large scientific study.

For these reasons, the working group coordinated by professors Zangrillo, Landoni and Monti, has developed, in a project that began over 10 years ago, an experimental research protocol capable of effectively answering this question: what is the best way to use meropenem in the most severe infections, affecting patients hospitalized in Intensive Care Units?

The result of the study was neutral, since both the intermittent and continuous administration produced the same result: the mortality after 90 days was found to be identical in the two groups, settling at 42%.

"With this study we have demonstrated that the method of administration of the antibiotic is not able to significantly modify mortality or the onset of new infections that are even more difficult to treat"

Giacomo Monti explains.

“During the study, no drug infusion-related side effects were observed in either mode, and this represents an important safety index for both delivery systems”

adds Alberto Zangrillo.

Finally, the research showed that there are no particular patient niches that could possibly benefit from one mode of administration over the other.

"The results of the research - continues Giovanni Landoni - therefore shift the attention to other aspects that must be taken into consideration in the management of the patient who shows serious bacterial infections in intensive care, evaluating the possibility of allocating human and economic resources to other specific interventions that could be more effective".

The study of dosages, which may have to be increased in the first hours, the duration of administration, which could be reduced in selected cases and the association of other antibiotics, are some of the important specifications that must be taken into consideration.

Professor Zangrillo concludes:

"We hope that the development of new technologies can help optimize the diagnosis of infections, anticipating them and making them more precise: thanks to the use of adjuvant drugs and techniques, we can improve the ability of the patients' immune system to react to infection, without amplifying the inflammatory response".