New antibiotic buys medicine time in the never-ending fight against superbugs

After several decades fighting battles against superbugs, the medical world has accepted that it will be very difficult to win a war that every year causes more than 1.2 million deaths worldwide. The main reason is biological. No matter how effective the new treatments are, if they are used massively, natural selection will always push some strains of microorganisms to develop antibiotic resistance, which leads humanity to an endless fight where the goal is to buy time.

If new infections are avoided as much as possible — through prevention measures or new vaccines — the medical world buys itself time by reducing the use of antibiotics. If each infection is treated only with the indicated drug, more time is gained by slowing the development of resistance. And if enough time has been gained, when bacteria become immune to the available treatments, the next effective antibiotic will have already been developed. And in this way, medicine will be able to minimize the impact of superbacteria, perhaps not totally winning the war, but emerging victorious from multiple battles.

On April 22, the European Commission authorized a new antibiotic to fight these battles: Emblaveo, a medicine developed by the pharmaceutical companies Pfizer and Abbvie in cooperation with the European Union and the United States. The drug can be used to “treat complicated intra-abdominal and urinary tract infections, hospital-acquired pneumonia and infections caused by certain types of drug-resistant bacteria [Gram-negative bacteria],” according to the European Commission. “It will therefore contribute to tackling the serious problem of antimicrobial resistance and provide patients with treatment options where currently there are few or none.”

“It was a long-awaited antibiotic because it is active against strains of Klebsiella pneumoniae or Escherichia coli, among other enterobacteria, which have developed multi-resistance to antibiotics and have become some of the most difficult microorganisms to treat,” explains José Miguel Cisneros, head of the Infectious Diseases Department at the Hospital Virgen del Rocío in the Spanish city of Seville, and one of the academic leaders of the clinical trials of the drug, which will be administered intravenously in hospitals.

Emblaveo is, in fact, a new drug formed by combining two molecules already on the market. Aztreonam, marketed individually, and avibactam, an inhibitor of the enzymes that allow bacteria to develop resistance, which until now was sold in combination with ceftazidime, another antibiotic. Similar combinations have been developed in the past to fight against resistant infections, such as amoxicillin and clavulanic acid.

“The REVISIT trial has demonstrated that aztreonam-avibactam is effective and safe in the treatment of hospitalized adult patients with severe acute infections and stands out from other available antimicrobials because of its potent in-vitro activity against Gram-negative bacteria that produce metallobetalactamase [enzymes],” Cisneros adds.

Beta-lactamases are enzymes that bacteria use as a tool to deactivate antibiotics called b-lactams, such as carbapenems. Jordi Vila, head of the Microbiology Service at Hospital Clínic in Barcelona and director of the Antimicrobial Resistance Initiative at the Barcelona Institute for Global Health (ISGlobal), details the reasons that make the new antibiotic unique. “Avibactam is an inhibitor of some of these enzymes, of which there are four types [A to D]. Of these, the molecule is very effective against A and C, and also against some D, but not against the B. This was a major limitation of the ceftazidime-avibactam combination. Now we will be able to overcome it thanks to the fact that aztreonam is effective against almost all the bacteria that have class B enzymes,” he explains.

The biological causes that explain antibiotic resistance are not the only factor that has undermined the fight against superbugs. While administrations and physicians have been improving the use of available antibiotics, the pharmaceutical industry has been losing interest in developing new molecules. A 2020 article published in Nature, called Why Big Pharma Has Abandoned Antibiotics, analyzes how the poor business prospects of drugs intended to be used as little as possible have led to this result.

“To reverse this situation, the development of new antibiotics has been a priority for support and public financing by administrations in the European Union and the United States,” explains Jaime Espín, professor at the Andalusian School of Public Health in Spain and former advisor to the European Commission.

This type of incentive can be economic, with financial support, or non-economic. The latter group includes measures such as priority review vouchers, which are used in the United States by the FDA and speed up the evaluation of drugs. In a controversial (and still undefined) initiative, the EU has considered another model consisting of extending the patents of some drugs.

Emblaveo is the result of collaboration between the pharmaceutical companies Pfizer and AbbVie — which have jointly developed the drug — and the public sector. Pfizer has the marketing rights worldwide outside the United States and Canada (where AbbVie owns the rights). In Europe, most of the support has been channeled through the COMBACTE-CARE project of the Innovative Medicines Initiative (IMI, now renamed IHI, an alliance between the EU and industry). These collaborations provide for a public financial contribution and an “in kind” contribution from industry (personnel, equipment, etc.). The in-kind contribution from pharmaceutical companies has been valued at €59.8 million ($64.5 million). In the United States — where Emblaveo has not yet been approved — AbbVie has established collaborative agreements with the Department of Health and Human Services.

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