Continuous or intermittent administration of antibiotics does not reduce the growth of new resistant bacteria

For this category of antibiotics, beta-lactams, the manner in which they are administered, as well as the dose and selection of the particular molecule, are key elements in determining the efficacy of therapy and the risk of emergence of new infections or overinfection.

Due to the outcome of previous scientific studies and pharmacological considerations, it has always been hypothesized that “continuous” administration of these drugs, via continuous intravenous infusion, as opposed to the classical “intermittent” administration, also intravenous, offered an advantage in terms of better survival to infection and a lower risk of emergence of multi-resistant bacteria to various antibiotics. However, this hypothesis had never been confirmed, or disproved, within a major scientific study.

For these reasons, the working group coordinated by Professors Zangrillo, Landoni, and Monti, in a project started more than 10 years ago, developed an experimental research protocol that can effectively answer this question: what is the best way to use meropenem in the most severe infections, those that affect patients admitted to Intensive Care Units?

In the study, which was conducted blind, 607 patients with a particular form of severe infection (respiratory, gastrointestinal, or urinary) to the extent that it resulted in a picture of sepsis, a particular reaction of the body to infections that can cause death in 1 in 3 patients, were considered. Moreover, the very peculiarity of the infection from which they were suffering exposed them to a high risk of developing a new, even more severe infection, potentially sustained by bacteria with even worse resistance profiles, partly due to the antibiotic treatment itself.

Half of these patients were given meropenem as a continuous intravenous infusion, while the other half were given an intermittent intravenous infusion. The treatment administered with meropenem was quantitatively identical in the 2 groups, as well as the amount of drug administered overall. 

Patients who participated in the study were then followed up for the next 90 days to see if the treatment they received was able to change the disease course. Specifically, the primary goal of the project was to measure the number of patients who would go on to death or a new infection that was more difficult to treat with antibiotics during the observation period.

The infections that developed over the observation time frame were mainly caused by a particular type of bacteria, called gram negatives, those most often implicated in antibiotic-resistant bacterial infections, especially in Europe and Italy. These include Klebsiella, Pseudomonas and Acinetobacter, the genera most often identified and considered by WHO to be most at risk of developing drug resistance.

The result of the study was neutral. In both cases, both intermittent and continuous administration produced the same outcome: mortality after 90 days was identical in the 2 groups, standing at 42 percent. “With this study we have shown that the mode of antibiotic administration is not able to significantly modify mortality or the occurrence of new infections that are even more difficult to treat,” explains Giacomo Monti.

“During the study, no side effects related to infusion of the drug in either modality were observed, and this is an important indication of safety for both delivery systems,” adds Alberto Zangrillo.

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

“The results of the research,” Giovanni Landoni continues, “therefore shift the focus to other aspects that will have to be taken into account in the management of the patient presenting with severe bacterial infections in the ICU, considering whether human and economic resources can be allocated to other specific interventions that might be more effective."

The study of dosages, which may need to be increased in the first few hours, the duration of administration, which could be shortened in selected cases, and the combination of other antibiotics are some of the important specifics that need to be considered. 

But that's not all: the prevention of infections themselves, with the reduction of antibiotic use in the general population, also comes through the hand hygiene of healthcare workers. 

Professor Zangrillo concludes, “We hope that the development of new technologies can help optimize the diagnosis of infections, anticipating them and making them more accurate, and that through the use of adjuvant drugs and techniques, we can improve the ability of patients’ immune systems to respond to infection without amplifying the inflammatory response.”

The study was made possible through the support of AIFA.

Antibiotic resistance, or the ability of bacteria to become insensitive to the action of drugs that can kill them, is an extraordinarily important health emergency. According to the World Health Organization (WHO), the phenomenon of antibiotic resistance represents 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 thousand people.