The ABR threat is overblown.

We are living in a society of fear, where the objectivity in estimating risks is distorted by the media and the interested parties. During more than half of a century, the feeling of antibiotic resistance as an apocalyptic phenomenon able to push our society to the high mortality rates caused by infectious diseases in the dark pre-antibiotic ages has been steadily rising. However, at the current status of modern medicine, at least in the high-medium income countries, mortality by lack of efficacy of the antibiotic armamentarium in the therapy of infections is a problem, but not a catastrophe. The threat of antibiotic resistance has many other aspects than failures of therapy in the individual patient. Among them, the increase in the frequency of severe and potentially lethal infections, as bacteremia, the population biology alterations of the healthy microbiota, the global acceleration of bacterial evolution by selecting natural genetic tools mediating microbial interactions, and, most importantly, by modifying the equilibrium and composition of environmental microbial communities. All these threats have huge implications for human health as members of a Biosphere entirely rooted in a menaced microbiosphere.¶ Introduction¶ Along the last decades, research on bacterial antibiotic resistance has been steadily growing and now constitutes one of the fields with higher expansion in the frame of microbiological sciences. The main driver pushing research in that direction is the assumption of the urgency of solving a potentially catastrophic problem for human health. A curious epistemological problem is that scientific efforts are frequently directed to investigate and solve problems that have not been sufficiently scientifically dimensioned. Once science provide initial results, the door for new questions is opened, new knowledge opportunities are offered, and the unstoppable temptation of following the trend creates a powerful research stream that orientates the future of our endeavors. The case of antibiotic resistance fits with this view. In this opinionated updated review, recapitulating a previous dissertation (Baquero 2016), we are examining the risks associated with antibiotic resistance in a critical way and trying to evaluate the dimension of the burden of resistance as a homeostatic reaction of the microbial world to the anthropogenic aggression resulting from the industrial production and medical (human, veterinary, agricultural medicine) use of antibiotics, which can affect the health of humanity.¶ From ecstasy to fear¶ Few events in the history of microbiology have had such a wide impact in collective appreciation of the society as the discovery and extended use of antibiotics in the successful treatment of infectious diseases. Bacterial diseases were the highest cause of human mortality before the 40 s, probably including complications of viral diseases, as in the 1918’s influenza pandemic (Klugman et al. 2009), and that following the “tragedy of tuberculosis” killing so many young and romantic people along the nineteenth century. Suddenly, antibiotics, the “miracle drugs” (Moore 1999), sharply reduced morbidity and mortality and certainly contributed (by reducing complications) to the progress of advanced surgery, from war surgery in the 1940s–1950s to organ transplantation, anti-cancer immunodepressive therapy, and in general intensive care facilities. All of this was perceived by the society at large as a spectacular achievement of microbiological and chemical research.¶ The discovery of antibiotic resistance appeared as a disturbing storm-cloud in this clear sky. However, the 1940–1980 period offered a continuous wealth of new antibiotics, with a crucial participation of Spain, even in later periods (Mochales 1994). Interestingly, such a continuous progress in discovery was mostly fostered by the necessity of “fighting new antibiotic resistances,” following a kind of Red Queen dynamics, where the new discoveries compensated for the emergence of new resistances in bacterial pathogens. There is no doubt that the marketing activities of pharma companies contributed to a “replacement dynamics” to outcompete “older” drugs that could become inactive because of resistance. This strategy has strongly influenced the notion of “the unbearable threat of resistance,” and in fact many international surveys on antibiotic resistance in the world were financed by pharma companies, mostly in order to demonstrate the “superiority” of their new drugs over the old ones, but also providing an extremely useful body of knowledge on the epidemiology and ecology of antibiotic resistance. In parallel, the antibiotic “replacement strategy” was also boosted by launching less-toxic drugs, sometimes overstating few and transient, or controllable, toxic events of the “older” ones.¶ From the mid-1980s of the past century, the rhythm of discovery of novel antibiotics was gradually slowing, in part due to pharma investments being directed mostly to other drugs either much more expensive (as anticancer drugs) or prescribed for life (as anti-hypertensive, anti-cholesterolemic). Note that implicitly this indicates that most infections could be successfully treated in practice with the current antibiotic armamentarium, and the demand for new miracle anti-infectives had been weakened. However, the fear of a catastrophic return to all the horrors of a pre-antibiotic era has not only been maintained but has significantly increased, and all national and international organizations, including the WHO, situate antibiotic resistance among the top risks for public health (World Health Organization 2019); ad-hoc public–private research organizations have been created by the European Union, as ENABLE, within the IMI initiative, to stimulate research for new anti-infectives active on multi-resistant (“bad-bugs”) pathogens (Kostyanev et al. 2016).¶ Antibiotic resistance in the society of fear¶ In modern Western countries, in our developed world, a world of wonders, there is a dominant “culture of fear” which takes the form of the Alexis de Tocqueville (1805–1859) paradox: “plus tout va bien, plus on a peur” or “the better things are, the more fear we have.” Frank Furedi argues that most societal perceptions of risk, controversies over health, the environment, and technology have little to do with science or empirical evidence but are essentially shaped by cultural assumptions about human vulnerability, a kind of “kidulthood” of our society (Furedi 2007). Certainly, such a “kidulthood” favors the general manipulation of the society, either promising unfeasible “miracle” solutions or unnecessarily scaring our hopes of progress. The “threat” of antibiotic resistance is inserted in this global feeling of fear.¶ Of course, fear produces unwanted secondary effects. First, fear, as a cultural construct, tends to fix as proved the worse expectations. Second, it establishes a false equivalence, a fallacy, identifying situations to which we are scared of and those that are really dangerous. Third, the maintenance of a continuous fear without obvious solutions discredits scientific efforts; we have been speaking for too long (decades) about the urgent need to solve the problem of antibiotic resistance. Fourth, as a thought derived from the former, fear might convince us that “we are at the mercy of nature,” a deleterious thought for the societal appreciation of science. Fifth, and as suggested before, fear might be promoted, sustained, and exploited by interested parties, in the words (the parenthesis is mine) of one of my closest friends, “antibiotic resistance was a great career (and business) opportunity” (Levin 2017).¶ Fear has also positive aspects. First, it fosters the rapid analysis and counteractive responses of humans to confront microbial menaces, as occurred with AIDS, or currently with COVID-19 pandemics, but certainly it also contributed to open the golden age of antibiotic discovery. As early as in 1954, the British physician Lindsey W. Batten (1889–1981) declared: “We may come to the end of antibiotics. We may run clean out of effective ammunition, and then how the bacteria and moulds will lord it.” Second, the known interaction between emotion and creativity (Averill 2000) stimulates motivation and innovation in science. Third, fear improves social and organizational cooperation, and certainly fear to antibiotic resistance has significantly contributed to the interaction of scientists all around the world. Fourth, fear raises our awareness not to stop progress in any sense for the profit of a single humanity.¶ The apocalyptic landscape and the problem of public communication¶ Fear in antibiotic resistance has been amplified by the news in the media, worldwide known as passionate apocalyptic lovers. An indicative random selection of press titles is: “Antibiotic apocalypse: doctors sound alarm over drug resistance (The Guardian), “Antibiotic apocalypse warning” (BBC News Health), “Antibiotic resistance could be much worse than EBOLA” (Yorkshire Post). But not only the media, also serious institutions and journals: “Return to a pre-antibiotic era?” (The World Academy of Sciences), “A return to the pre-antimicrobial era? (Science). “War against superbugs” is a metaphor also forming part of this catastrophe discourse, which has been analyzed both in its rhetorical form, and in the implicit political, and professional function (Nerlich 2009). Metaphors used by the media are easily understood, but the resulting understanding can be deeply biased (Brossard 2013). Scientific communication is frequently obliged to a distortive simplification (Ortín and Uranga 2021), which in alliance with our innate human attraction for tragedy produce apocalyptic mental “monsters” (Francisco de Goya dixit).¶ The biased contribution of susceptibility testing, etiological attribution, and metagenomics¶ A main problem for the objective estimation of the consequences of a biological phenomenon is the accurateness of the methods measuring the biological parameters and criteria used to define the qualities of the system. Clearly, the burden of antibiotic resistance is estimated according to the definition of “resistance”. In vitro susceptibility testing provides “minimal inhibitory concentrations” (MICs), that, in practice, have been frequently taken as the single parameter for classifying a bacterial isolate into the “resistant” category. If the MIC is over a critical breakpoint, the organism is resistant. Therefore, the lower breakpoint, the higher the proportion of resistant strains in the species, and the feeling of “untreatable” bug. Of course, the advantage of establishing low breakpoints is to detect “first mutational steps” in the evolution of resistance, eventually preventing clinical resistance (Baquero 2001). But tagging such strains as resistant ones might have perverse consequences in the treatment of infections. In most cases infections caused by low-level resistant bacteria can be successfully treated with the antibiotic-in-case, and that obliged the international susceptibility testing agencies to “raise the breakpoint” to allow the use of the drug; typically, that has occurred for penicillins in Streptococcus pneumoniae with PBP mutations, or for carbapenems in Escherichia coli harboring carbapenemases.¶ A second problem was the common confusion (mostly for clinicians) between acquired resistance and natural antibiotic resistance. Many opportunistic non-commensal pathogens are intrinsically resistant to antibiotics, but, when they were listed among harmful human organisms, the feeling was that “antibiotic resistance” was widespread. In fact, in most cases these organisms have a low pathogenicity for patients but can be found in human mucosa, particularly in intensive care units where environmental members of the orders Pseudomonadales, Flavobacteriales, or Enterobacterales are present in water systems, not only from built environments (as sinks), but also medical equipment, as ventilators. The detection of these organisms in clinical samples is frequently a poor etiological value, but the alerted clinician might consider these (frequently intrinsically resistant) organisms at the time of therapy, increasing the awareness of “antibiotic resistance.”¶ Finally, the recent boom of microbial metagenomics has contributed to overstate the perception of a widespread antibiotic resistance, listing a number of resistance genes (genes whose loss increase susceptibility) probably approaching 10,000 in currently available curated databases. The ensemble of resistance genes in a microbiome is the “resistome,” accurately detectable by targeted capture metagenomics (Lanza et al. 2018). But resistance genes are simply everywhere and have been there for thousands of millions of years. The equivocal concept is “a bacterial organism carrying a resistance gene is a resistant organism.” The question is not “what is a resistance gene?” but “what is a resistance gene imposing a risk for therapy and public health?” (Martínez et al. 2015).¶ Back to the pre-antibiotic era?¶ This statement is simply an over exaggeration. History never comes back again, and we will never be back in the dark ages of deadly infections. Not only antibiotics are responsible for the decline in infectious diseases. In fact, infectious diseases started declining much before the discovery of antimicrobial agents, because of the progress of hygiene-ecology and social welfare (McKeown 2016). On the other hand, except in rare cases of organisms producing deadly poisoning toxins, bacteria “start a pathogenic process” that is generally amplified by the reactive host pathophysiology, as in the case of potentially deadly processes (septic shock) following the immunological recognition of molecules present in bacterial envelopes, as lipopolysaccharides or teichoic acids, without any microbial active intervention. Progresses in medicine are able to control in our days most of these host processes. In fact, many severe infectious diseases can now be cured without the need of antibiotics. A case-in-point is therapy of (once deadly) infectious diseases, as was cholera, where the lethality has almost disappeared just because of the introduction of oral rehydration therapy, without further need of antibiotics (Guerrant et al. 2003). At hospital level, progresses in the procedures of intensive care units care are able to compensate for most of the complications caused by either susceptible or resistant bacteria involved in severe infections. We will never be back in the pre-antibiotic era.