The Dawn of the Superbugs

The over- and improper use of antibiotics has resulted in an increasing number of pathogenic bacteria developing resistance to these drugs, leaving us with fewer and fewer treatment options. Antibiotics are the most powerful tool in our disposal to fight life-threatening bacterial infections and their discovery has tilted the balance favorably in the fight against bacterial infections in humans and animals. The uncontrolled emergence and spread of antimicrobial resistance have resulted in deadly untreatable infections in both the developed and the developing world.

The most menacing of all resistant bacteria are the so called "superbugs"- strains of bacteria that are resistant to several different classes of antibiotics or multidrug resistant. Globally, 1.27 million deaths are estimated to be caused by antibiotic resistant bacteria in 2019, with a total of 4.95 million deaths associated with bacterial antibiotic resistance¹. In the United States, each year antibiotic resistant bacteria cause more than 2.8 million infections resulting in more than 35,000 deaths². Some of these infections are caused by bacteria that are virtually resistant to all or all most all antibiotics available to treat infections. For example, in 2016 a patient in Nevada died of septic shock caused by an infection due to Klebsiella pneumoniae that was resistant to 26 different antibiotics².

Different types of superbugs

The Centers for Disease Control and Prevention (CDC) has classified antibiotic resistant pathogens infecting humans into different threat levels² such as urgent, serious, and concerning, based on their clinical and economic impact, current and projected incidence, transmissibility, availability of effective antibiotics to treat and barriers to prevent infection.

Pathogens posing public health threats that require urgent and aggressive action are considered as urgent threats. Some examples include Carbapenem-resistant Acinetobacter, Carbapenem-resistant Enterobacteriaceae, Clostridioides difficile etc.

Pathogens posing public health threats that require prompt and sustained action are considered as serious threats. Some examples include Drug-resistant Campylobacter, ESBL-producing Enterobacteriaceae, Multidrug-resistant Pseudomonas aeruginosa, Methicillin-resistant Staphylococcus aureus etc.

Pathogens posing public health threats that require careful monitoring and prevention action are considered as concerning threats. Some examples include Erythromycin-resistant group A Streptococcus and Clindamycin-resistant group B Streptococcus.

Similarly, the American Veterinary Medical Association (AVMA), based on the resistance patterns to antibiotic classes of Aminoglycosides, Carbapenems, Cephalosporins, Fluoroquinolones, Lincosamides, Macrolides, Penicillins and Tetracyclines, has identified Campylobacter jejuni, Enterobacterales, Enterococcus, Pseudomonas aeruginosa and Staphylococcus as pathogens of heightened concern for cats and dogs⁴.

Examples of some of the most clinically significant superbugs

Carbapenem-resistant Enterobacteriaceae (CRE): - Enterobacteriaceae area group of gram-negative pathogens including Escherichia coli, Klebsiella pneumoniae and Enterobacter spp. that cause a variety of serious infections. Carbapenems are a group of broad-spectrum antibiotics in the penicillin class that are reserved for treatment of serious infections caused by pathogens that are resistant to penicillins and 3^rd generation cephalosporins. Infections caused by CRE often are hospital acquired and shows an increasing trend in prevalence globally. CRE typically produce enzymes called carbapenemases that destroy the carbapenem antibiotics are transmissible between bacterial strains making it easy to spread globally through persons acting as carriers. Treatment options for CRE are very limited and polymyxins, fosfomycin, tigecycline and aminoglycosides are the most used drugs⁵.

Extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae: - Enterobacteriaceae producing ESBL are resistant to penicillins and cephalosporins due to the production of an enzyme that break down these antibiotics. While these bacterial can usually be treated with carbapenems or other classes of antibiotics, they are often multidrug resistant and carry large plasmids containing many antimicrobial resistance genes which are also easily transmissible between bacteria. As a result, these bacteria often cause difficult to treat infections.

Methicillin-resistant Staphylococcus aureus (MRSA): - MRSA are S. aureus that have developed resistance to most antibiotics in the penicillin class including penicillins, cephalosporins and carbapenems. Like many other superbugs they are also often multidrug resistant by acquiring many antimicrobial resistance genes. MRSA is often carried as a harmless commensal by many people in the skin, mouth and nasal passages. However, it can cause serious infections in immunocompromised patients or in infected wounds. Antibiotics like Sulfa-TMP, clindamycin, vancomycin and tetracycline can be used to treat MRSA infection based on susceptibility testing. Newer dugs like linezolid, daptomycin, telavancin and ceftaroline are also effective in treating MRSA⁶.

Vancomycin-resistant Enterococcus (VRE): - Enterococci are normal inhabitants of the intestinal tract but can cause life-threatening opportunistic infections like urinary tract infections, sepsis and endocarditis. They are naturally resistant to many antibiotics like penicillins and cephalosporins and rapidly acquire resistance to antibiotics such as vancomycin, linezolid and tigecycline following clinical introduction. About 30% of all healthcare-associated enterococcal infections are caused by VRE. VRE are often multidrug resistant, reducing the available drug options to treat them.

Impact of infections caused by superbugs and spread of antimicrobial resistance

The pace at which new antibiotic are developed and introduced into clinical practice has not kept up with that of the emergence and spread of antimicrobial resistance. In fact, introduction of new antibiotic is often followed immediately with development of resistance against them. As a result, there is a dire need for effective treatment options for infections caused by multidrug resistant bacteria. Even infections caused by bacteria that is resistant only to first-line therapeutics is also burdensome. The need to use second or third-line therapeutics can increase the cost of treatment, extend hospital stay or even expose the patient to drugs with significant side-effects. The threat of antimicrobial resistance can jeopardize other unrelated healthcare interventions such as organ transplants, joint replacements, or chemotherapy.

Antibiotic resistance is also a One Health challenge as the health of humans are closely intertwined with that of animals and the environment. These infections can also affect pets, zoo animals and food animals, thereby resulting in spread of difficult to treat infections through communities, food-supply chains, healthcare facilities and the environment and across the world.

Control of superbugs

Bacterial resistance to antibiotics stem from antibiotic use, therefore it is important that antibiotics are prescribed only when their use is absolutely warranted. Antimicrobials are routinely used to treat diseases in humans, pets, food-producing, zoo, and exotic animals. In this regard, the US FDA has recently promulgated policy restricting the use of medically important antibiotics in food-producing animals⁷. For therapeutic antibiotic use, following clinical and treatment guidelines when prescribing is essential to promote judicious antimicrobial use both in clinical and veterinary settings. Developing, implementing, and sustaining antimicrobial stewardship programsare vital to promote judicious antibiotic use and control antimicrobial resistance. While more than 75% of the acute care hospitals in the US have well established antimicrobial stewardship programs⁸, corresponding numbers in veterinary sector are unknown. Improving judicious antimicrobial use in the veterinary setting is essential in combating antimicrobial resistance due to the transmission of bacterial pathogens between humans and animals. Another important facet in controlling antimicrobial resistance is development and use of effective diagnostic tests that can provide information on pathogen ID and associated antimicrobial resistance patterns so that appropriate treatment decisions can made timely. The current gold standard method of culture and sensitivity takes 3-5 days to provide actionable results, forcing care-providers to start with empirical treatment that need to be modified when test results become available. The fight against antimicrobial resistance is further fortified by the availability of newer molecular methods like qPCR that target rapid detection of antimicrobial resistance genes, enabling clinicians to make evidence-based treatment decisions promoting judicious antibiotic use.

To learn more about Antimicrobial Resistance Stewardship, download our AMR Stewardship eBook

References:

1. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)02724-0/fulltext
2. https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf
3. https://www.cdc.gov/mmwr/volumes/66/wr/mm6601a7.htm
4. https://www.avma.org/sites/default/files/2020-10/AntimicrobialResistanceFullReport.pdf
5. https://www.frontiersin.org/articles/10.3389/fmicb.2019.00080/full#:~:text=Currently%2C%20antibiotic%20options%20for%20the,anti%2DCRE%20therapies%20is%20urgent
6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5204005/
7. https://www.fda.gov/animal-veterinary/safetyhealth/antimicrobialresistance#:~:text=The%20principles%20of%20FDA's%20judicious,to%20those%20that%20include%20veterinary
8. https://www.cidrap.umn.edu/news-perspective/2019/09/new-rule-requires-antibiotic-stewardship-programs-us-hospitals