Progress and New Challenges in Combatting the Threat of Antimicrobial Resistance: Perspective From an Infectious Diseases Pharmacist

By the time the Centers for Disease Control and Prevention (CDC) released the first Antibiotic Resistance Threats report in 2013, it was clear that antimicrobial resistance (AMR) was a complex public health crisis with potentially catastrophic consequences [1]. The report identified 18 antimicrobial-resistant pathogens categorized as urgent, serious, and concerning threats, which were responsible for a minimum of 2 million infections and 23 000 deaths annually in the United States. Threats spanned a spectrum of commonly encountered human pathogens, including drug-resistant gram-positive and gram-negative bacteria, mycobacterium, fungi, and Clostridium difficile. Four core actions were proposed, including preventing infections, tracking AMR, improving use of antibiotics, and promoting the development of new antibiotics. Since publication, developments against gram-negative threats like carbapenem-resistant Enterobacterales (CRE) have become the paradigm for progress in AMR research. For example, in 2013, rates of CRE were rising on every continent, front-line treatment regimens often included highly toxic agents like aminoglycosides or polymyxins, rapid molecular diagnostics tests were not widely implemented, and mortality rates of infected patients typically exceeded 30%. Fast forward a decade and much has changed. Rates of serious and urgent antibiotic resistance threats like CRE, multidrug-resistant Pseudomonas aeruginosa (MDRPA), and carbapenem-resistant Acinetobacter baumannii (CRAB) have stabilized or down trended in the United States [2], rapid molecular tests have become standard of care at many hospitals and 8 new antibiotics with enhanced in vitro activity against CRE, MDRPA, and/or CRAB have been approved by the Food and Drug Administration (Table 1). Most importantly, treatment with newly developed antibiotics has contributed to an 18% reduction in deaths attributable to AMR pathogens in an updated report from the CDC [9]. Taken together, the AMR field has witnessed significant advances in the diagnosis, treatment, and prevention of the deadliest antibiotic resistance threats; however, if the past decade has taught us anything, it is that new challenges await.

The AMR crisis has been exacerbated during the course of the coronavirus disease 2019 (COVID-19) pandemic. As outlined in a special CDC report [10], rates of hospital-acquired CRE, MDRPA, and CRAB infections increased 35%, 32%, and 78%, respectively, from 2019 to 2020. During this time, hospital-based AMR surveillance systems were repurposed, antibiotics were overused, and infection control and prevention measures were overextended. The data serve as a sobering reminder that progress is fragile and reliant upon vigilance with ongoing efforts. Moreover, AMR threats are, and will continue to be, a public health priority. Recent epidemiological data underscore this point. In a systematic review of 471 million individual records from 204 countries, predictive statistical modeling approaches estimated that 4.95 million deaths were associated with bacterial AMR in 2019 [11]. Even more worrisome, across the 88 pathogen-drug combinations evaluated, 1.27 million deaths were directly attributable to AMR. Rates of death were highest in low- and middle-income countries where sanitation is poor and new diagnostics and therapeutics are generally not available. Importantly, AMR patterns vary geographically [11, 12], underscoring that locally tailored approaches for infection control and prevention, antimicrobial stewardship, and treatment are required. Health care systems must also reestablish active surveillance systems that are essential in recognizing shifts in the epidemiology of drug-resistant pathogens. To this end, the changing epidemiology of carbapenemase enzymes in the United States is cause for concern. Metallo-β-lactamase-producing (MBL) Enterobacterales have now been identified in at least 46 states and the overall prevalence is increasing [13]. MBLs escape inhibition from the newest β-lactamase inhibitors like avibactam, relebactam, and vaborbactam, thereby providing new challenges in treatment of CRE infections. The emergence of MBL-producing CRE has also been reported following the introduction of ceftazidime-avibactam at individual hospitals [14]. Guinea extended-spectrum (GES) β-lactamases are an emerging threat that mediates differential activity of new β-lactams against MDRPA [15, 16]. Of particular concern are single or double amino acid substitutions that result in GES variants capable of hydrolyzing carbapenems that are not routinely detected by commercially available molecular platforms. As recent history has indicated, new β-lactamases and/or β-lactamase variants will arise despite our advances in antibiotic development. Establishing novel classes of antimicrobial agents while developing the next generation of “ultrabroad” β-lactamase inhibitors are crucial objectives moving forward.

While antibacterial drug development has improved over the past decade, it is important to recognize that progress has been slow and significant obstacles remain [17]. The fundamental economic problem of incentivizing companies to develop antibiotics that are used infrequently persists [18]. Generation of meaningful efficacy data to support use of new agents against AMR pathogens has lagged behind regulatory approval and slowed clinical adoption [19]. Even when compared to an inferior treatment, randomized clinical trials of new antibiotics have not enrolled enough patients infected with drug-resistant pathogens to demonstrate survival advantages (Table 1 [4–8]). Thus, clinicians are left to fill data gaps by making decisions based on intuition, improved safety of the new agents, and imperfect, yet compelling, real-world evidence [20, 21]. To aid clinical translation of the available data, expert guidance documents and guidelines have been developed [3, 22]; however, comparative studies are still lacking. In fact, there is a dearth of clinical data available to help prescribers differentiate one new agent from another. This manifests in broad recommendations to select any of the new β-lactam agents that demonstrates in vitro activity against the targeted pathogen. To move forward, the field is in dire need of comparative-effectiveness studies that incorporate rapid molecular diagnostics and focus on differences in efficacy and cost-effectiveness of front-line treatment options. Observational reports have identified compelling distinctions between agents [23], yet practice-changing hypotheses have not been tested. It should be noted that designing such studies is extremely difficult due to the inherent biases of real-world studies. In addition, the margin to demonstrate superiority between treatment options has narrowed significantly because polymyxins are no longer recommended for any high-priority pathogen [3, 22].

Solutions to overcome the next wave of AMR challenges are multifaceted. Continued dedication to cornerstone measures in infection prevention and control are needed, as are renewed investments in alternative therapeutics, antibacterial drug discovery, and vaccine development. There is also an immediate need to optimize clinical use of the available treatment options. For this reason, antimicrobial stewardship programs play a pivotal role in preserving recent advances while defining the optimal therapeutic niche for each agent. Comparative-effectiveness studies of agents with overlapping in vitro activity would allow for more tailored approaches, and ideally slow the development of resistance to new agents. At the same time, innovative basic and translational research must meet the rapidly evolving challenges due to AMR. Foundational studies to better understand links between phenotypic and genotypic relationships are of paramount importance. Indeed, we have entered an era where optimal treatment against AMR pathogens is linked to the recognition of underlying resistance mechanisms [3], an approach that moves beyond treatment selection based entirely on traditional phenotypic testing. Furthermore, concepts like antibiotic heteroresistance and tolerance may have implications for treatment of AMR pathogens in clinical practice [24], but are poorly understood by clinicians, lack standardized definitions, and are not identified by routine microbiologic tests. Evidence is also mounting that bacterial infections are not caused by a single clone [25], but rather polyclonal populations that require metagenomic approaches to unravel. Other new tactics like inhibition of quorum sensing, immunotherapy, and gene editing are gaining traction in the field, but require further investigation. These new approaches may transcend bench to bedside principles and unlock a greater potential to combat the AMR crisis moving forward.

From a therapeutics perspective, novel preclinical in vitro and in vivo models are needed to fill knowledge gaps in the evolution of bacterial resistance, antibiotic dose optimization, and identification of new drug targets. Despite decades of research, the utility of rationally designed antibiotic combination strategies against AMR pathogens is still unknown. Identifying connections between in vitro synergy and patient outcomes has eluded researchers in the past; however, systems to study antimicrobial therapies in the laboratory have advanced, creating an opportunity to dispel the dogma of past endeavors. In the same light, alternative therapeutics like bacteriophages or antimicrobial peptides may play an increasing role as adjunctive therapy in the management of AMR pathogens. Over the course of the next decade, we are certain to see more conceptual innovation in the AMR field. For sustained progress, however, we must keep an eye towards the future to detect new threats and prioritize targeted interventions to mitigate them. Basic and translational research are critical to these objectives and limiting the global impact of AMR for future generations.

Notes

Financial support. No financial support was received for this work.

References

Author notes