Antibiotic Failure – Beyond Antimicrobial Resistance

Written by: Loulou Cai, PhD Candidate, Côté Lab
Edited by: Marie-Soleil Smith, PhD Candidate, Côté Lab



Each year, millions of lives are lost annually to bacterial infections. While antibiotics have revolutionized medicine, improved quality of life, extended lifespans, and made complex medical procedures possible, antimicrobial resistance is on the rise. A recent review by the Hancock Lab delves into antimicrobial resistance, with topics that include contributors to antibiotic failure, how these may be alleviated by rapid diagnostics, and alternatives to antibiotics.

Factors Contributing to Antimicrobial Resistance

Potential factors contributing to antibiotic failure. (Fig. 1.)

Compromised immune and host defenses due to deficiencies in the innate or adaptive immune systems increase host susceptibility to frequent and/or recurrent infections. Antibiotics are often necessary for immunocompromised patients to prevent long-term complications; however, immunodeficiency increases the chances of antibiotic failure as the effectiveness of antibiotics often depend on cooperation with the host immune response. In addition, antibiotics often change the composition of the host microbiome, thereby increasing susceptibility to other infections.

Biofilms are colonies of bacteria that grow in large clumps that aggregate typically on a surface. In the context of antimicrobial resistance, they often grow on surfaces of medical devices and/or implants. These cluster formations are potentially a stress adaptation, as they exhibit distinct transcriptional and proteomic profiles that enable them to survive in harsh environments, contributing to their resilience. Biofilm bacteria are 10-1000-fold more resistant to most antibiotics than their non-adherent, non-aggregating, so-called planktonic counterparts. Although antibiotic resistant biofilms are one of the most prominent infections in human health, no specific treatments have been approved.

Looking Ahead – Countering Antimicrobial Resistance

It is widely appreciated that there is a general lack of understanding of underlying causes of antibiotic failure. Furthermore,  and the scarcity of simple model systems to enable screening and testing of microbials makes it challenging to gain new knowledge. One potential counter is rapid diagnostics of factors that contribute to antibiotic resistance. Initial therapy is often empiric, whereby health care professionals consider the region of infection, the most likely bacteria, and known resistance patterns. However, this has the downside of over prescription. Authors believe the need for rapid molecular diagnostics, such as PCR (polymerase chain reaction) to distinguish between viral and bacterial infections by differing host response or host markers and clinical symptomatology is required to counter resistance. New age methods such as multiplex PCR and other high-throughput molecular methods can detect most common classes of transmissible antibiotic resistance. While such methods are not yet in widespread practice, they can provide critical clinical information and therapeutic options that are faster than the traditional culturing of bacteria.

Potential strategies to address antibiotic failure. (Fig. 2.)

On the flipside, combination antibiotic therapies could help lower antibiotic resistance, as these may work in synergy and broaden the spectrum of action. Attacking multiple locations for bacterial replication and function in a simultaneous manner can offer a swift clearance. Other therapies include attenuating infection pathways or compensating for host immune deficiencies by boosting the innate or adaptive immune system. Despite the promise of these methods, they are more complex and expensive, requiring procedures such as exogenously supplied immunoglobulins, allogenic hematopoietic stem cell transplants, or injections of interfering RNA in conjunction with antibiotics.

Some non-medication-based alternatives to antibiotics can also aid in reducing antimicrobial resistance. In extreme low birth weight infants, dual-probiotic supplementation increased the eradication of Helicobacter pylori, decreased adverse events, and significantly reduced sepsis mortality. Prebiotic substances can also modify the gut microbiome and promote secretion of specific metabolites that facilitate proliferation of beneficial bacteria. Additionally, it has been noted that reversing anaerobicity of infectious sites by offering hyperbaric oxygen treatment can reduce bacterial load.

Non-antibiotic medicines for bacterial resistance are promising. Phage therapy, where the employment of viruses that specifically target certain bacteria is currently undergoing a phase III clinical trial to treat acute and non-complicated urinary tract infections. Treatment with lysins, enzymes that are synthesized by bacteriophages that disrupt the bacterial cell wall, is also promising, as this would provide high specificity, low risk of resistance development and minimal toxicity.

Overall, this review addresses several critical issues of antimicrobial resistance, emphasizing the importance of understanding contributors to antibiotic failure and exploring advanced diagnostics and alternative treatments. By adopting rapid molecular diagnostics and innovative therapies, mitigation of resistance and improvement of patient outcomes are possible.

Link to paper: