Antibiotic failure: Beyond antimicrobial resistance

Abstract

Despite significant progress in antibiotic discovery, millions of lives are lost annually to infections. Surprisingly, the failure of antimicrobial treatments to effectively eliminate pathogens frequently cannot be attributed to genetically-encoded antibiotic resistance. This review aims to shed light on the fundamental mechanisms contributing to clinical scenarios where antimicrobial therapies are ineffective (i.e., antibiotic failure), emphasizing critical factors impacting this under-recognized issue. Explored aspects include biofilm formation and sepsis, as well as the underlying microbiome. Therapeutic strategies beyond antibiotics, are examined to address the dimensions and resolution of antibiotic failure, actively contributing to this persistent but escalating crisis. We discuss the clinical relevance of antibiotic failure beyond resistance, limited availability of therapies, potential of new antibiotics to be ineffective, and the urgent need for novel anti-infectives or host-directed therapies directly addressing antibiotic failure. Particularly noteworthy is multidrug adaptive resistance in biofilms that represent 65 % of infections, due to the lack of approved therapies. Sepsis, responsible for 19.7 % of all deaths (as well as severe COVID-19 deaths), is a further manifestation of this issue, since antibiotics are the primary frontline therapy, and yet 23 % of patients succumb to this condition.

Keywords: Antibiotic resistance; Biofilm; Global health; Infectious Diseases; Sepsis.

Fig. 1.

Potential factors contributing to antibiotic failure. Antibiotic failure refers to situations where the administration of antibiotics does not lead to improved patient outcomes. While antimicrobial resistance (AMR), due to genetic exchange or mutation is a significant factor, other common causes of antibiotic failure include biofilm-associated infections, infections in immunocompromised patients (e.g., individuals with primary and secondary immunodeficiencies or with dysbiosis at the level of the microbiome), and the severe condition known as sepsis. Particularly, biofilm-grown bacteria resist antimicrobial treatment 1000 times more than planktonic forms, causing persistent infections like abscesses. Primary immunodeficiencies increase infection risk from birth, with most affected individuals succumbing to infections before one year of age, despite antibiotic treatment. Similarly, traumas that lead to secondary immunodeficiencies and compromised host defenses, induce intense inflammation, weakening immunity, and increasing vulnerability to sepsis and organ failure. The microbiome’s diverse microorganisms support digestion, produce vital metabolites, and shape the immune system, benefiting overall health and influencing pathogen susceptibility. Additionally, sepsis, a life-threatening condition due to uncontrolled infection response, is a major global cause of mortality. Early and appropriate antibiotic treatment is critical, as delays can increase mortality rates.

Fig. 2.

Potential strategies to address antibiotic failure. Several potential strategies are shown here, including the development of advanced diagnostic tools and specialized therapeutics tailored for situations where antibiotics prove ineffective. These approaches aim to tackle the complexities associated with antibiotic failure and offer innovative solutions to improve patient outcomes.