Top 5 Superbugs That Current Antibiotics Soon Cannot Cure

Shin

Key microbial features that make them top the CDC’s priority list.

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The Present State of Superbugs

With antibiotics, bacterial infections are no longer the leading cause of reduced life expectancy in humans. Antimicrobial-resistant microbes — colloquially known as superbugs — have always been a problem soon after antibiotics invention. But pharmaceutical industries were actively pumping out new antibiotics during the 1960s to 1980s to fight superbugs.

After that, however, they realized antibiotics are not profitable compared to cancer drugs, for example. Microbial evolution also speeds up owing to antibiotics overuse. Existing antibiotics quickly became useless (see red bars in the figure below). And new ones are not readily available.

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Image source (CC BY): Tagliabue, A., & Rappuoli, R. (2018). Changing Priorities in Vaccinology: Antibiotic Resistance Moving to the Top. Frontiers in immunology, 9, 1068. https://doi.org/10.3389/fimmu.2018.01068

In 2015, superbugs re-emerged as a global threat to humans. In 2019, the Centers for Disease Control and Prevention (CDC) reported that superbugs infected more than 2.8 million people in the United States alone, of which over 35,000 died.

From an economic standpoint, antibiotic-resistant infections prolong hospitalization by about 13 days per case, amounting to extra 8 million days of hospitalization per year. Each instance of superbug infection costs about $29,000 with an annual loss being $35 billion in the United States.

Not every superbug evolved equally. Evolution is not predictable after all; Covid-19 is one example. Some superbugs are more ruthless than others. The CDC ranked them into four categories — urgent threats (5 microbes), serious threats (12), concerning threats (2), and watchlist (3). What makes the five superbugs, in no particular ranking order, earn their urgency status?

Urgency 1: Acinetobacter baumannii

The basic information the CDC provides:

  • A multidrug-resistant bacterium that infects the wound, bloodstream, urinary tract, and lungs.
  • Mainly affects hospitalized patients, especially those admitted to ICU and those using invasive medical devices such as ventilators or catheters, or having open wounds from surgery.
  • Infected 8,500 patients, of which 700 died, in the US in 2017.
  • Spread by contact with contaminated surfaces or hands.
  • Some are already resistant to all available antibiotics.

Acinetobacter baumannii resides in the soil, which was carried by soldiers to hospitals. It has remarkable persistence on the surfaces of objects. This bacterium is now responsible for about 20% of ICU infections with a mortality rate of 26% to 68%. Cases are more frequent in hot and humid climates and people with diabetes, chronic obstructive pulmonary disease (COPD), and regular smoking habits.

What makes it a severe superbug is its arsenal of antimicrobial-resistance techniques with about ten mechanisms identified so far, according to a 2017 review in the Frontiers in Cellular and Infection Microbiology. No wonder the CDC says it can be resistant to all existing antibiotics. “Recent interest about A. baumannii is mostly due to its seemingly endless capacity to acquire antibiotic resistance,” the review stated. “A. baumannii has almost all bacterial resistance mechanisms.”

“A. baumannii has almost all bacterial resistance mechanisms.” Even science’s last-resort antibiotic has to be combined with others to kill it.

For an antibiotic to work, it has to bypass all of its antibiotic-resistance mechanisms. The remaining treatment, although no success guaranteed, is colistin + other antibiotics. Colistin is science’s last resort; it is toxic to both microbes and human cells. Yet A. baumannii is already evolving resistance to colistin, so it must be combined with other antibiotics.

Urgency 2: Candida auris

The basic information the CDC provides:

  • A multidrug-resistant fungus identified rather recently in 2009 but has spread all over the globe.
  • Mainly affects hospitalized patients with severe medical issues.
  • Infected 323 patients in 2019 in the US (death cases not reported).
  • Spread via exposure to contaminated skin and hospital disinfectants are not very useful.
  • It is difficult to diagnose and prone to misidentification.
  • Some are already resistant to all three available classes of antifungals.

Candida auris is a fungal infection of the ear, wound or bloodstream. It kills about 30–72% of its human targets. The fungus appeared globally out of the blue; its origin still a mystery. “Somehow, it made a jump almost seemingly simultaneously and seemed to spread and it is drug-resistant, which is really mind-boggling,” remarked Snigdha Vallabhaneni, MD, a fungal expert and epidemiologist at the CDC. It had caused multiple hospital outbreaks in the last decade.

As this fungus is relatively new, diagnostics and prevention methods are lacking. Not to mention is it the only fungus that can be resistant to all accessible antifungals, so nobody knows how to treat it. “It’s pretty much unbeatable and difficult to identify,” said Lynn Sosa, MD, an epidemiologist at Yale School of Public Health in 2019. The only good news is that most (not all) cases are still responding to echinocandins, the only effective antifungal left.

Candida auris mysteriously appeared in hospitals around the globe in the past decade, spread easily, and “it’s pretty much unbeatable and difficult to identify.”

“It seemed hard to believe,” the CDC stated. “CDC fungal experts had never received a report describing a Candida infection resistant to all antifungal medications, let alone Candida that spreads easily between patients.” Yes, it has relatively high transmissibility. “The tendency of C. auris transmission within and between healthcare facilities is unique among Candida spp.,” explained a 2018 review in the Frontiers of Microbiology. “And is possibly promoted by virulence and pathogenicity factors that facilitate skin colonization and environmental persistence.”

Urgency 3: Clostridioides difficile

The basic information the CDC provides:

  • A multidrug-resistant bacterium that causes diarrhoea and colitis (inflamed gut).
  • Mainly occurs following antibiotics use that wipes out the gut microbiome.
  • Infected 223,900 patients, of which 12,800 died, in the US in 2017.
  • There has been a decrease in hospital cases owing to improved antibiotics usage, but community cases are rising.

C. difficile is a spore-forming bacterium that is naturally hard to kill and resistant to many common antibiotics. That’s why it proliferates following an antibiotic course that must have upset the gut microbiome that keeps C difficile at low levels. It produces high levels of toxins that kill cells of the large intestines. While C. difficile is part of the normal gut microbiome, it can be shed and transmitted via the faecal-oral route.

Spore-forming microbes often germinate or revive later; thus, it earns its name as recurrent C. difficile infection. About a third of recovered patient relapse within a few weeks. Each recurrence increases the risk for another and the risk of death. Risk factors for recurrent C. difficile infections are suppressed gastric acid (such as those taking proton pump inhibitors), gastrointestinal diseases, chemotherapy, long-term hospitalization or antibiotic usage, and low vitamin D status.

C. difficile diarrhoea often reappear multiple times. Antibiotics might not be reliable and medicine has to turn to gut microbiome restoration methods.

Current effective antibiotics are metronidazole, vancomycin, and fidaxomicin. Yet C. difficile is gaining resistance to all, particularly metronidazole. Hence, some cases of C. difficile cannot be treated by antibiotics, but by other unconventional means such as probiotics or faecal microbiota transplant (FMT). The aim is to restore the gut microbiome so that it can outcompete the C. difficile for space and nutrients.

Urgency 4: Enterobacteriaceae

The basic information the CDC provides:

  • Primary examples are multi-drug resistant Escherichia coli and Klebsiella pneumoniae.
  • Mainly affects those requiring invasive catheters, undergoing surgery, or taking long courses of antibiotics.
  • Infected 13,100 patients, of which 1,100 died, in the US in 2017.
  • Occasionally resistant to all available antibiotics, resorting to more toxic or ineffective treatments.
  • 30% of clinical isolates have mobile genetic elements that enable the efficient transfer of antimicrobial-resistant genes.

Escherichia coli and Klebsiella pneumoniae are the major threats of the Enterobacteriaceae family. They cause infections of the central nervous system, bloodstream, lungs, and soft tissues (e.g., muscles, ligaments, nerves). Its mortality rate is as high as 50%, but a more recent 2019 cohort study reported 63.8%. And they spread by direct contact with contaminated skin or stool.

Carbapenem was the first treatment choice, but the CDC now said it is a carbapenem-resistant Enterobacteriaceae. Owing to the extensive travel and efficient bacterial genes transfer, carbapenem-resistant genes have spread to E. coli and K. pneumoniae all over the world at an exponential rate. “Enterobacteriaceae are categorized as one of the most successful pandemics in the history of Gram-negative bacteria, particularly due to K. pneumoniae,” said a 2019 review in Antibiotics.

The efficient gene transfer makes K. pneumoniae and E. coli evolve resistance at an exponential rate — earning their name as “one of the most successful pandemics in the history of Gram-negative bacteria.”

Like Acinetobacter baumannii, the science’s last-resort antibiotic, colistin has to be used again. But other antibiotics are needed as an adjunct because colistin-resistant Enterobacteriaceae are also emerging at an alarming rate.

Urgency 5: Neisseria gonorrhoeae

The basic information the CDC provides:

  • A sexually transmitted bacterium that is symptomless.
  • Missed diagnosis may later result in lethal ectopic pregnancy, permanent infertility, and infections of the heart and nervous system.
  • It can also increase the risk of contracting and transmitting HIV.
  • Infected 1.14 million people, of which 550,000 are drug-resistant, per year.
  • Since the 1980s, this bacterium is slowly gaining resistance to antibiotics one by one. Only combined antibiotics remain as sole treatment now.

Neisseria gonorrhoeae is the second most common sexually transmitted bacterium, falling behind Chlamydia trachomatis. Its course of antimicrobial resistance evolution over the decades is somewhat predictable — slowly but surely. Combined antibiotics still work, but there have been recent reports of reduced efficacy. Resistance is catching up.

While it is often symptomless, some early signs are similar to other sexually transmitted diseases such as unusual pain, itch, and discharge of the reproductive organs. Still, a symptomless infection is itself an issue because diagnoses are missed, and N. gonorrhoeae always causes lifelong health complications as listed above.

Neisseria gonorrhoeae infection is often silent. The unintentional transmission would then later causes lethal and permanent health problems.

Moreover, tracking symptomless infection is complicated. “Questions persist about how to either implement or enhance surveillance, especially in low- and middle-income countries,” stated a 2019 review in Sexually Transmitted Disease. Many countries are not tracking the spread of N. gonorrhoeae effectively. This bacterium is presently spreading silently with foreseeable detrimental health consequences.

What the Future Holds

These five superbugs the CDC classified as urgent threats are nearly resistant to all available antimicrobials. Prudent use of antibiotics must still be practiced to prevent more superbugs like these. Research and production of novel antimicrobials also need to be quickened. It won’t be long before these five superbugs are incurable; some already are.

Not to mention the current limited antimicrobials availability is also a problem. Less availability means more use of a given antibiotic and, thus, faster evolution of antimicrobial resistance. We are already behind and it would take a hefty workload to catch up. Otherwise, the 2050 statistics might be a reality — that antimicrobial resistance would be a bigger killer than cancer.

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The good news is that the pipeline for new antimicrobials has increased owing to the collective international effort. New antimicrobials for these superbugs are likely available in the next decade, a 2019 statistical forecasting research found. But “this result may not hold for all countries, especially mid-income countries like Brazil, India, and China which have recently seen the largest increases in antibiotic consumption,” the paper also warned.

We are already behind, but we are catching up. If not, antimicrobial resistance would soon be a bigger killer than cancer.

If antibiotics overuse remains, be it on agriculture or humans, new ones that cost enormous resources to develop would just suffer the same fate. Science will eventually have new antimicrobials. Currently, there are 60 novel antimicrobials in clinical development, and about 250 in the preclinical stage, the WHO reported in 2019. But how long the future antimicrobials will remain useful is a question mark.

This article was originally published here.

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