After several decades fighting battles against superbugs, medicine has assumed that it will be very difficult to win a war that causes more than 1.2 million deaths in the world every year. 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 resistance to survive, which leads humanity to an endless fight in which the objective is to buy time.
If new infections are avoided as much as possible – through prevention measures or new vaccines – time is saved 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 bought, when some bacteria have already become immune to the available treatments, the next effective antibiotic will have already been developed. And in this way, in a cycle doomed to repeat itself, medicine will be able to minimize the impact of superbacteria, perhaps without completely winning the war, but emerging victorious from multiple battles.
The The European Commission authorized on April 22 the commercialization of a new antibiotic to be able to face one of these battles. This is Emblaveo, developed by the pharmaceutical companies Pfizer and Abbvie in cooperation with the European Union and the United States (the first is the one that has the rights for Europe). The drug is indicated for “the treatment of complicated intra-abdominal and urinary infections, hospital-acquired pneumonia and infections caused by certain types of bacteria (Gram-negative aerobes)”, which constitute “a serious public health problem” against which there is “limited or sometimes non-existent treatment options”, according to the Spanish Agency for Medicines and Health Products (AEMPS).
“It was a long-awaited antibiotic because it is active against strains of Klebsiella pneumoniae either 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 service at the Virgen del Rocío Hospital (Seville) and one of the leaders academics of the clinical trials of the drug, which will be administered intravenously in hospitals.
After authorization by the European Commission, negotiations will now begin between the Ministry of Health and Pfizer to agree on the price and conditions to incorporate the treatment into public healthcare. This, however, will be affected by a global supply problem, which affects one of the molecules that make it up, aztreonam, according to industry sources. This incident could delay the availability of the drug until September, according to these sources.
Emblaveo is, in reality, a new medicine formed by the combination of two molecules already present on the market. Aztreonam, marketed individually, and avibactam, an inhibitor of the enzymes that allow bacteria to develop resistance that until now was sold in combination with ceftazidime, another antibiotic. Similar combinations have been developed in the past in the 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 for its potent activity.” in-vitro against gram-negative bacteria that produce [enzimas] metallobetalactamases,” adds Cisneros. The results of REVISIT were recently presented in Barcelona at the congress of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID Global).
Beta-lactamases are enzymes that bacteria use as a tool to deactivate some antibiotics called b-lactams, such as carbapenems. Jordi Vila, head of the Microbiology service at the Hospital Clínic 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 them, the molecule is very effective against A and C, and also against some D, but it is not effective against B. This was an important 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 bacteria that have class B enzymes,” he explains.
According to Vila, the percentage of bacteria that present these resistances against which Emblaveo will be effective is “relatively low in Spain, less than 5% in enterobacteria and depending on the type of bacteria,” compared to countries such as Italy or Greece, where It can be up to 10 times higher. “In any case, this antibiotic will be essential to treat this group of patients and in anticipation of a possible increase in resistance,” she says.
For Aurora Fernández, member of the Spanish Society of Hospital Pharmacy (SEFH) and a specialist in this service at the Vall d’Hebron Hospital (Barcelona), it is likely that this increase in resistance will end up occurring. “It is the natural result of the use of antibiotics. By eliminating sensitive bacteria, the drugs themselves accelerate the appearance of resistance because they create a favorable environment for microorganisms that have mechanisms to develop them. This is why it is so important that we use the new antibiotics appropriately,” he says.
The biological causes that explain the development of resistance are not, however, the only reason that has undermined the fight against superbacteria in recent decades. While administrations and physicians made progress in better use of available antibiotics, the pharmaceutical industry has been losing interest in developing new molecules. An article published in 2020 in the magazine Nature, titled Why have big pharma abandoned antibiotics?, analyzes how the poor business expectations of drugs intended to be used as little as possible and necessary have had this result.
“To reverse this situation, the development of new antibiotics has been a priority line of support and public financing by administrations in recent years in the European Union and the United States,” explains Jaime Espín, professor at the Andalusian School of Public Health and former advisor to the European Commission.
These types of incentives can be economic, with financial support, or non-economic. This last group includes measures such as the one used in the United States by the FDA, which speed up the evaluation of drugs and are known as priority review voucher (coupons for priority review). In a controversial initiative (and still pending definition), the EU has proposed another model consisting of extending the patents of some medicines.
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 worldwide marketing rights outside the United States and Canada (they belong to AbbVie there). In Europe, most of the aid has been channeled through the project COMBACTE-CARE of the Innovative Medicines Initiative (IMI, today renamed IHI, an alliance between the EU and industry). These collaborations establish a public financial contribution and another “in kind” from the industry (personnel, equipment…).
IMI’s public contribution amounts in this case to 23.9 million euros, which have been allocated to the public partners of the project to finance two clinical trials (REJUVENATE YOURSELF and REVISIT). The Spanish have been the Andalusian Health Service of Andalusia (3.7 million), ISGlobal (234,000 euros) and the Madrid Health Service (199,000). The in-kind contribution of pharmaceutical companies has been valued at 59.8 million. In the United States, where the drug has not yet been approved, AbbVie has established collaborative agreements with the Department of Health and Human Services.
Although the main objective of the IMI, its executive director, Niklas Blomberg, explains in writing to this newspaper, were more general with the objective of contributing to “overcoming bottlenecks in medical research” through “a broad collaboration of public actors.” and private”, in some specific cases the initiative also financed the development of medicines. Of them, two have reached the market: Emblaveo and the Janssen Ebola vaccine.
Public-private partnerships
José Chaves, medical director of Pfizer in Spain, recognizes that “there is an urgent need for new and innovative antimicrobials, but ensuring sustainable financing of the research and development of these drugs has been a challenge for the entire industry.” According to this position, strategies such as “public-private partnerships” are essential to develop new antibiotics and he gives COMBACTE-CARE as an example for its ability to “unite the knowledge and capabilities of the main experts in drug-resistant bacterial infections and the support of pan-European clinical and laboratory networks.
According to Espín, these contributions from the public sector raise an important question that becomes especially relevant given the upward escalation imposed by the sector in the prices of innovative treatments: How should they influence when setting the amounts that public systems must pay for the drugs they have helped develop?
“It is an issue that is not well resolved in most countries. In fact, only France and Italy explicitly include in their legislation that the public investment made is taken into account in the negotiation of drug prices, as we have found in an ongoing analysis on the subject with a research project funded by the EU. In Spain, although the Ministry of Health can enforce this public investment in price negotiations with pharmaceutical companies, it is not something that has been made explicit. Greater transparency about the criteria taken into account in the negotiations and about the costs of drug development would help shed light on this issue and avoid paying twice for the same thing, first for the research and then for the medicine,” he says. expert
Health sources assure that “public participation is taken into account when setting the price”, although they admit that the “Medicine Guarantees Law includes this aspect in a very general way and there has not been a royal decree that develops it specifically.” ”. Something that is planned to be “included in the reform of the Law underway, as well as in two royal decrees in preparation, the one on the evaluation of health technologies and the one on financing and pricing of medicines.”
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