Bacterial resistance threatens azithromycin, one of the best-selling drugs in the world – Health and Medicine

2023-12-13 13:29:22

The EU begins a review of the effectiveness of the antibiotic, invented 40 years ago by a small Croatian pharmaceutical company and a great contribution to medicine from Tito’s Yugoslavia.

Boxes of various medications that have azithromycin as the active ingredient.

On May 4, 1980, while Yugoslavia was burying its president, Josip Broz Tito, a team of researchers from the small pharmaceutical company Pliva in Zagreb finalized the development of what would be the country’s greatest contribution to world medicine: azithromycin. This broad-spectrum antibiotic, indicated for multiple bacterial infections, was soon converted by the American multinational Pfizer into one of the best-selling drugs in the world. Tito’s death opened a scenario full of uncertainties that would culminate 11 years later in the violent dismemberment of the country. Four decades later, humanity faces another war against superbugs that puts the lives of millions of people at risk and threatens to render most antibiotics ineffective.

“Azithromycin is a good example of the big problem we face. A very useful and safe tool against a large number of infections that in just 40 years is ceasing to be effective because bacteria have developed resistance to it due to its excessive and improper use,” José Miguel Cisneros, head of service, warned last week. of Infectious Diseases at the Virgen del Rocío Hospital (Seville) during the world awareness week on the use of antimicrobials.

The European Medicines Agency (EMA) announced on the 10th the start of a systematic review on azithromycin. “Bacterial resistance to azithromycin is increasing in the European Union. Therefore, and in view of the wide use of these medications, a reassessment of the benefits and risks in their multiple authorized uses is considered justified to optimize their use and minimize the risk of development of new resistance,” the agency then published in a release.

Several studies have warned in recent years of the growing loss of effectiveness of azithromycin, with resistance exceeding 30% in several strains of some bacteria. In a way, the reasons that are accentuating the problem are the same ones that led this antibiotic to success 40 years ago. “The most common prescription is to take it with one pill daily for three days. This makes it very comfortable and ensures good patient adherence. In addition, it has few side effects compared to other macrolide antibiotics, such as erythromycin, which frequently causes intestinal problems. And, finally, it is indicated in patients who are allergic to other antibiotics,” explains Francisco Zaragoza, professor of Pharmacology at the University of Alcalá de Henares and member of Teaching and Research of the General Council of Pharmaceutical Colleges of Spain.

Maite Jorge Bravo, family doctor at a health center in Valladolid and head of the Infectious Diseases Group of the Spanish Society of General and Family Physicians (SEMG), explains that the use of azithromycin is indicated for a limited number of respiratory infections. and sexually transmitted, among some others. “But in practice, it is prescribed many more times for all types of infectious processes, especially respiratory, in which no antibiotic should be used, because they are of viral origin, or there are others that are more suitable. I reviewed the prescriptions in the Valladolid area and 96% were out of indication,” she illustrates.

According to data from the specialized consulting firm Iqvia, during the year 2022, more than 7.7 million boxes of azithromycin were sold in Spain, of which there are more than a dozen presentations on the market, the vast majority generic. These data only include sales produced in pharmacies and not consumption in hospitals.

The experts consulted point to another reason that during the pandemic the consumption of this antibiotic in hospitals skyrocketed, which has just aggravated the problem of resistance. “It was one of the traps at the beginning of the crisis and something that, in addition, continued to be used for a while. As the presentation of pneumonia was atypical and to try to help the patient in the absence of therapeutic alternatives, azithromycin was often given. There was some study at the beginning of the pandemic that pointed to its usefulness, but then it became clear that it had no benefit,” says Cisneros.

According to data provided by the Spanish Agency for Medicines and Health Products (AEMPS), the initial belief that azithromycin could be useful against the coronavirus – it is an antibiotic, but some works pointed to an antiviral and anti-inflammatory effect – multiplied by 2.5 the consumption of macrolides (group of antibiotics to which azithromycin belongs) in Spanish hospitals.

Gabrijela Kobrehel, Gorjana Radobolja-Lazarevski, Zrinka Tamburašev and Slobodan Đokić are the names of the four scientists who invented azithromycin, a breakthrough they achieved by modifying the large molecule of erythromycin, which had been the first macrolide developed by the pharmaceutical industry, in this case after isolating it on land taken in the Philippines. “Eli Lilly was the pharmaceutical company that developed erythromycin in the 1950s. Despite the advantages it provided, it faced the notable problem of intestinal side effects and for many years attempts were made without success to make molecular modifications to remedy it. Until they achieved it in Yugoslavia,” says Zaragoza.

Research demonstrated a characteristic of azithromycin that would make it unbeatable compared to other macrolides: it remained in the body for longer hours than other molecules and was very easy to reach all tissues in the necessary concentrations. This was what made it possible to simplify its dosage to a single daily pill.

The legend of Pfizer

In 1981, Pliva filed a patent application for azithromycin, still in the development phase, in Yugoslavia. And in a decision that would later be key, he also patented the antibiotic worldwide shortly after. The book The legend of Pfizerpublished in 1999 by writer Jeffrey L. Rodengen, tells of the repercussions of the step taken by the small Croatian pharmaceutical company.

“Pfizer had been working since the mid-1970s on improving erythromycin. During the first 10 years of the project, a team of 30 scientists repeatedly modified the molecule without success. Finally, they learned that a Yugoslav company, Pliva, had managed to incorporate a nitrogen ring into the erythromycin molecule with an innovative technique. The result had enormous potential and Pfizer scientists then strove to obtain a compound for oral use,” the book states.

Once the objective was achieved, the American pharmaceutical company tried to patent its advances, but then discovered that Pliva had done so shortly before. Pfizer’s reaction was to withdraw its application and open negotiations with the Yugoslav company to become its global partner. Pliva maintained the marketing rights for azithromycin in central and eastern Europe, while Pfizer obtained them for the rest of the world in exchange for a percentage of the sales obtained.

Azithromycin was named Sumamed by Pliva and was launched in its markets in 1988. Pfizer opted for Zitromax and launched it in 1991 in the United States. The brand is still in use. The success was almost immediate and the drug soon became a blockbuster, the name given to medicines with sales of more than 1,000 million dollars or euros. Pfizer reached peak revenues in 2005—more than 2 billion euros—just before losing patent protection.

The millionaire income that the agreement also provided to Pliva allowed the Croatian company to become one of the largest pharmaceutical companies in Eastern Europe and enter into various business operations until, in 2008, it was acquired by another giant in the sector, Teva. Oriol Güell (EP)