Emerging antibiotic resistance: carbapenemase-producing enterobacteria. New bad bugs, still no new drugs

Antimicrobial resistance (AMR) is recognized to be a global threat to health security, requiring action across government sectors and society. Many factors are involved in this phenomenon, overuse of antibiotics, incorrect antibiotic prophylaxis, and use of antibiotics for livestock purposes being the main causes of the increasing rate of multi-drug resistant (MDR) bacteria. The impact of resistance to antimicrobials is a major threat due also to the emergence of MDR Gram-negative bacteria resistant to carbapenems, and the lack of research to find new active molecules. The production of extended spectrum beta-lactamase enzymes was the first threatening mechanism for Gram-negative resistance to antibiotics, which prompted the development of new classes of antibiotics such as carbapenems. Unfortunately, resistance to carbapenems developed because of multiple mechanisms including efflux pumps, porin mutations and enzyme production, the latter being particularly relevant in terms of diffusion due to the genes located within plasmids that drive their horizontal diffusion. In this scenario, antimicrobial stewardship programs (ASP) are a mandatory resource in combating the spread of resistance. Reducing the total amount of antibiotics administration in the hospital setting and guiding prescribers in the correct administration of antibiotics for the shortest period possible, at the correct dosage, can be defined as the first goals of an ASP. That said, in an efficacious ASP, apart from antibiotic administration, efforts must be made to ensure the lowest probability of spreading MDR by efficacious measures of carrier isolation, and by offering tools for a rapid diagnosis of viral infections, thereby avoiding the administration of unnecessary antibiotics. A continuous audit of the ASP programs and correct assessment of the allergy to drugs such as penicillin should complete the program. Currently, few options are available for patients with an infection sustained by Gram-negative MDR bacteria. All the options currently available are based on the administration of colistin, an old drug whose real efficacy is reduced due to its high toxicity, or on the administration of recently proposed drugs such as ceftolozane-tazobactam, ceftazidime-avibactam and meropenem-vaborbactam. None of these new drugs have a novel mechanism of action and they have a limited spectrum in terms of activity against MDR bacteria. In conclusion, antimicrobial resistance is a global emergency and AMP is the most powerful tool currently available. Few options are available to treat infections due to Carbapenem-resistant Enterobacteria. Antimicrobial molecules with true novel mechanisms of action are needed to win the fight against antimicrobial resistance.