Antimicrobial Resistance: Should We Still Be Concerned?

The Centers for Disease Control (CDC) reported that methicillin-resistant Staphylococcus aureus (MRSA) infections caused 20,000 deaths in the United States in 2017.¹ More than 2.8 million antimicrobial resistant (AMR) infections occur in the United States each year.¹ These resistant infections are due in larger part to antibiotic resistance.

AMR is defined as the ability of pathogens to become non-susceptible to treatments which would have previously eradicated them. The public health burden of AMR has resulted in an increase in morbidity and mortality in the United States and worldwide.¹ As reported by the CDC, the financial burden of AMR has been estimated to be upwards of $55 billion every year.¹ Recent data from the Global Research on AntiMicrobial Resistance (GRAM) project showed that deaths associated with AMR are the third leading cause of death globally.² The COVID-19 viral pandemic has highlighted the risks of spread of a difficult-to-treat infection. In addition, the initial use of various antibiotic combinations during the early days of the pandemic may have complicated and contributed to rising AMR numbers.³ The pandemic has also taken our attention away from the continued emerging risk of AMR, a threat which will exist perhaps long after the COVID-19 crisis has diminished.³

How Are Antibiotics Playing a Role in AMR Today?

Infectious disease providers have long identified increased antibiotic use with decreased bacterial susceptibility reported on their antibiograms.⁴ Antibiotic resistance is a type of AMR which focuses solely on antibiotics. Common reasons for the development of bacterial resistance are the increased use of antibiotics over the last few decades, poor patient adherence to antibiotic regimens, and the limited numbers of drugs under development to treat antibiotic resistant infections.⁵ In addition, inappropriate dosing of antibiotics, particularly when it results in subtherapeutic levels, provides pathogens an environment to facilitate resistance.⁵ The development of new antibiotic classes has been slow. An example is the development of the oxazolidinone class of antibiotics in the early 2000s; this class was the only new class of antibiotic on the market for 25 years prior to its introduction.⁵

There have been four mechanisms identified which contribute to antimicrobial resistance for most antibiotics. All four mechanisms below lead to the premature degradation and inactivation of drug:⁵

1. Active efflux pumps – proteins which remove drug from the cell. The protein is over-expressed by bacteria, removing the antibiotic from the cell. Active efflux pumps are a common mechanism for resistance with Pseudomonas aeruginosa and Acinetobacter spp. This can be seen clinically in patients with diabetic wound infections who may present with resistant Pseudomonas spp. causing broad spectrum beta-lactams to be ineffective.

2. Decreased uptake by changes in the outer membrane permeability or by presence of porins – (also known as the porin channel loss). These variations do not allow entrance of antibiotics.  This can be seen clinically in patients with surgical site infections due to gram-negative pathogens (ie, E coli, Klebsiella, Enterobacter, etc). These pathogens develop resistance via porin channel loss resulting in beta-lactam and fluroquinolone antibiotic classes becoming ineffective.  

3. Target site modification – antibiotics cannot bind to target, causing an antibiotic to become ineffective. An example of this is the tetracycline (TCN) class of antibiotics. Bacteria expresses a gene which encodes for protection proteins. These proteins attach to the ribosomal subunit which prevent tetracycline and doxycycline from binding and exerting their action. Patients presenting with wounds due to methicillin-resistant Staphylococcus aureus (MRSA) may not  respond to doxycycline due to this mechanism.

4. Enzymatic inactivation – production of an enzyme which breaks down an antibiotic, making it ineffective. For example, production of extended spectrum beta-lactamases (ESBLs) which result in beta-lactam antibiotics (penicillins, cephalosporins) losing their efficacy. ESBL-producing organisms may be present in wound infections with gram-negative organisms.

In 2019, the CDC updated their recommendations on Antimicrobial Resistance Threats in the United States. The report identified pathogens as urgent, serious, or concerning based on threat level.¹ Infections categorized as urgent were: carbapenem-resistant Acinetobacter; Candida auris; Clostridium difficile; carbapenem-resistant Enterobacterales (CRE); and drug-resistant Neisseria gonorrhoeae. Methicillin-resistant Staphylococcus aureus (MRSA) was categorized as a serious threat. These threats are highlighted more in depth in the CDC report and are expected to be areas of focus for antimicrobial stewardship teams nationwide.

The CDC report called for continued antimicrobial stewardship efforts to contain emerging resistance organisms.¹ Recommendations were classified as institutional or community-focused interventions. Institutional recommendations focused on preventing device and procedure-related infections, decreasing the spread of resistance organisms between institutions, and tracking and improving antibiotic use and infection prevention in non-hospital settings, such as nursing homes. Community recommendations emphasized widespread use of vaccines to prevent infections, routine tuberculosis and gonorrhea screening with rapid treatment, safe sexual behaviors, safe food preparation and handling, and improving antibiotic use everywhere.

In Conclusion

Despite significant advances in other therapeutic areas, antimicrobial resistance continues to be a major threat to human health. The Infectious Disease Society of America (IDSA) in its “Bad Bugs” policy report, proposed a three-prong legislative, regulatory, and funding approach to tackle AMR.⁶ There is also an urgent need for development of new antibiotic classes. This can be achieved by identifying novel antibiotic targets as well as exploring modalities to modify older drugs to overcome the looming threat of resistance. Podiatric practitioners can contribute to such antimicrobial stewardship through increased awareness of the mechanisms and repercussions of modern antimicrobial resistance.

Dr. Berrios-Colon is a Pharmacist and Board Certified Pharmacotherapy Specialist. She is currently a Medical Science Liaison for Paratek Pharmaceuticals, King of Prussia, PA.  

References
1.     CDC. Antibiotic resistance threats in the United States. Atlanta (GA), USA: CDC; 2019. Available at: https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf . Revised December 2019. Accessed July 5, 2022.
2.     Antimicrobial Resistance Collaborators. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet. 2022;399(10325):629-655. doi: 10.1015/S0140-6736(21)02724-0.
3.     Nieuwlaat R, Mbuagbaw L, Mertz D, et al. Coronavirus disease 2019 and antimicrobial resistance: parallel and interacting health emergencies. Clin Infect Dis. 2021;72(9):1657-1659.
4.     Madaras-Kelly, K. Optimizing antibiotic use in hospitals: the role of population-based antibiotic surveillance in limiting antibiotic resistance insights from the Society of Infectious Diseases Pharmacists. Pharmacotherapy. 2003;23(12):1627-1633.
5.     Annunziato G. Strategies to overcome antimicrobial resistance (AMR) making use of non-essential target inhibitors: a review. Int J Mol Sci. 2019;20(23):5844.
6.     Boucher HW. Bad bugs, no drugs 2002-2020: progress, challenges, and call to action. Trans Am Clin Climatol Assoc. 2020;131:65-71.