Superbugs: Challenging Our Notions of Medical Supremacy

From the discovery of penicillin prior to World War I through the 1990s, the history of medicine was one of victory after victory. Polio, smallpox, tuberculosis, measles — formerly deadly and debilitating diseases — went from newspaper headlines to history books as medical science continued its seemingly unstoppable march to a better future. But even as these miracle drugs were first being mass produced and used in physicians’ offices and hospitals around the world, doctors and researchers began noticing that some strains of bacteria were increasingly resistant to antibiotics.

As more powerful antibiotics were produced in research laboratories, and as common infections waned as serious health concerns, the incipient danger posed by these drug-resistant bacteria was known mostly to only specialists and researchers. It wasn’t until the early 2000s that stories began to show up in newspapers and on TV about infections that doctors could no longer treat and about bacteria that could not be killed by even the most powerful antibiotics. Soon after, these drug-resistant bacteria had a nickname in popular culture: “superbugs.”

Today, the Centers for Disease Control and Prevention (CDC) warns we may be heading back to a day when we do not have drugs available to treat infection: “Can you imagine a day when antibiotics don’t work anymore? It’s concerning to think that the antibiotics that we depend upon for everything from skin and ear infections to life-threatening bloodstream infections could no longer work. Unfortunately, the threat of untreatable infections is very real.”¹

What Are Superbugs?

It turns out that superbugs are likely an unavoidable part of using antibiotics to treat bacterial infections, which is endemic to the world we live in. Consider the combination of these factors: 1) the sheer number of disease-causing bacteria in the world; 2) random chance mutations to DNA that exist in all life on Earth; and 3) bacteria’s reproductive cycle, which is measured in hours, if not minutes. These add up to create a range of genetic diversity even among the same species of bacteria that is mind-bogglingly broad.

The fact is that no antibiotic yet approved is capable of killing all organisms in any bacterial infection, thus unavoidably leaving behind surviving organisms that have the ability to live even when swimming in the antibiotic. And, these survivors’ succeeding generations share their parents’ resistance to the drug, with far fewer nonresistant competitors with which they have to share resources.

Even as the lifesaving properties of penicillin were burnishing its reputation as a miracle of modern science in civilian hospitals in the years after World War II, almost immediately physicians began to notice that some bacterial infections that had previously responded well to penicillin treatment no longer did.² Fortunately, most of these infections could still be successfully treated with newer drugs such as vancomycin (discovered in 1953) and methicillin (discovered in 1959). But already by 1961, bacterial infections that could not be stopped by either of these drugs had been found in Great Britain.³ The term “methicillin-resistant Staphylococcus aureus,” or MRSA, was coined to describe these bacteria.

Adding to the difficulty in devising drugs that can successfully treat infection is the fact that bacteria can share genetic material laterally (even across species) through the swapping of plasmids,⁴ allowing a resistant population of bacteria to replace a nonresistant one in days, if not sooner.

Today, in addition to MRSA, CDC lists a host of other resistant bacteria that pose a public health threat:¹

• vancomycin-resistant enterococcus
• extended-spectrum cephalosporin-resistant Klebsiella pneumoniae
• multidrug resistant Escherichia coli and Enterobacter
• carbapenem-resistant Pseudomonas aeruginosa
• carbapenem-resistant Klebsiella pneumoniae (and Klebsiella oxytoca)

And, this is only a partial list.

The Threat

CDC now lists superbugs as one of its top public health threats. A 2013 agency report states that some two million people a year are infected by resistant bacteria in the United States alone, and “at least 23,000 people die each year as a direct result of these antibiotic-resistant infections. Many more die from other conditions that were complicated by an antibiotic-resistant infection.… In addition, almost 250,000 people each year require hospital care for Clostridium difficile (C. difficile) infections. In most of these infections, the use of antibiotics was a major contributing factor leading to the illness. At least 14,000 people die each year in the United States from C. difficile infections.”⁵

In addition to tracking the types of bacteria that have growing populations of resistant members, CDC also now classifies resistant bacteria by the location where the infection was contracted: healthcare facilities, food supply or the community.

The agency has also prioritized the public health threat posed by different strains of resistant bacteria into three categories: urgent, serious and concerning.⁵ Those classified as urgent are considered a priority health threat requiring aggressive coordinated action to contain immediately. The three drug-resistant bacteria classified as urgent are:

• C. difficile
• carbapenem-resistant Enterobacteriaceae
• drug-resistant Neisseria gonorrhoeae

C. difficile causes severe and often fatal diarrhea, and the overall population of this bacteria is increasingly resistant to fluoroquinolone antibiotics, in addition to earlier drugs. Carbapenem-resistant Enterobacteriaceae causes dangerous bloodstream infections in hospitalized patients and has a 50 percent mortality rate. This species is resistant to all drugs currently in use. Both C. difficile and carbapenem-resistant Enterobacteriaceae are primarily contracted in healthcare settings.Neisseria gonorrhoeae is a sexually transmitted disease, with roughly 30 percent of all cases now showing signs of resistance to antibiotics.

The 12 pathogens classified by CDC as serious are not considered as critical a threat to public health as the above three, but they warrant serious attention by the medical profession to prevent them from becoming more prevalent:

• multidrug-resistant Acinetobacter
• drug-resistant Campylobacter
• fluconazole-resistant Candida (a fungus)
• extended spectrum ß-lactamase producing Enterobacteriaceae
• vancomycin-resistant enterococcus
• multidrug-resistant Pseudomonas aeruginosa
• drug-resistant non-typhoidal Salmonella
• drug-resistant Salmonella typhi
• drug-resistant Shigella
• MRSA
• drug-resistant Streptococcus pneumoniae
• drug-resistant tuberculosis

Drug-resistant bacteria that are classified as concerning are being monitored in case they become more widespread. These include:

• vancomycin-resistant Staphylococcus aureus
• erythromycin-resistant group A Streptococcus
• clindamycin-resistant group B Streptococcus5

Viruses, Parasites and Other Infectious Agents

Just as bacterial populations can become resistant to antibiotics due to the inevitable survival of resistant organisms, so can other microscopic life forms that cause disease in humans. The 2013 CDC report on drug resistance specifically excluded viruses and protozoa parasites, even while acknowledging that HIV and influenza virus populations are exhibiting signs of drug resistance, as are the protozoa that cause malaria.⁵ While the CDC report acknowledged the growing risk these resistant populations pose, it explained that they were beyond the scope of the report. (The one exception to this is fluconazole-resistant Candida, which CDC included because it is the leading source of bloodstream infections in healthcare settings.)⁶

Symptoms, Diagnosis and Treatment

The initial symptoms of resistant bacteria are no different from symptoms the same bacteria caused a century ago before the introduction of antibiotics, whether it’s a skin infection, pneumonia, tuberculosis, etc. The diagnoses for these infections are also unchanged (although additional diagnostic tests to determine whether an infection is resistant are increasingly the norm when any of the above listed agents are suspected as the cause of the infection). What has changed dramatically is the ability, or rather inability, of physicians to effectively treat the infection by killing the bacteria causing it. In many cases of resistant infection, if the infection does not respond to ever-more-aggressive antibiotic treatment, palliative care while the patient’s own immune system battles the infection may be the only remaining option. Treatment regimens may also include additional procedures to ensure the resistant strain is contained and not spread to other patients.

Among the greatest challenges facing government health officials and healthcare professionals is that so many of these superbugs are firmly ensconced in hospitals and other healthcare facilities, where the most vulnerable patients are the most likely to contract them. As such, CDC’s National Action Plan to Prevent Health Care-Associated Infections: Road Map to Elimination provides clear guidelines on containing resistant infections in healthcare facilities. Mainly, the plan outlines the need for providing staff training and oversight with the goal of consistent usage of best practices so that a resistant strain does not spread.⁷ When resistant infections do spread, it is almost always due to a breach in standard operating procedures.

While hospitals and other medical facilities may remain the main battlefront in the war against resistant bacteria, a more recent front is the spread of resistant infections to the general population and the food supply. Of particular worry in the general population are resistant tuberculosis, resistant Streptococcus pneumoniae, skin infections caused by MRSA, and sexually transmitted gonorrhea.⁵ A notable example of this was the news in October last year that New York Giants’ tight end Daniel Fells was diagnosed with a MRSA skin infection on his foot. After enduring seven surgeries to quell the infection that even spread to his lungs, he lost part of his foot and, of course, his football career.⁸

CDC lists four core approaches in its plan to combat resistant infections:

• Preventing infections and preventing the spread of resistance.
• Tracking resistant bacteria.
• Improving the use of today’s antibiotics.
• Promoting the development of new antibiotics, and developing new diagnostic tests for resistant bacteria.

In addition to tracking incidences of resistant infections, CDC is working to improve the use of current generation antibiotics to maximize their efficiency. In particular, it is promoting its Get Smart program to encourage physicians to not overprescribe antibiotics in a variety of ways, from resisting patient demands for a prescription (as in the case of a cold, when an antibiotic will not help) to ordering lab tests to ensure a bacteria really is the cause.9 It is thought that overprescribing of antibiotics is a contributing factor in the rise of resistant populations.

The food supply is another worry for federal public health officials because antibiotics remain the single best tool for fighting dangerous intestinal tract infections. Historically, intestinal tract infections have been one of the leading causes of premature death — a trend only altered in the last century with the advent of antibiotics, refrigeration and safe food-handling procedures. Overuse of antibiotics in the agricultural sector could lead to resistant strains of salmonellosis and campylobacteriosis in the food supply, a trend CDC is working with the U.S. Food and Drug Administration (FDA) to counter.⁵

Prevention and Research

By tracking the source and severity of resistant bacterial populations, CDC hopes to slow their spread while promising that new research that may yet give physicians the upper hand in the battle against infectious bacteria has time to come to fruition.

Research into new antibiotics is showing promise as scientists learn more about how bacteria’s internal processes operate at a molecular level. While penicillin was discovered to be an effective antibiotic decades before researchers understood the specifics of how it killed harmful bacteria while leaving other cells unharmed, today’s researchers look for key moments in a bacterium’s life cycle and then try to find methods of interfering with that critical function (much like research into treating cancers looks for weaknesses in a cancer cell’s defenses at the molecular level).

While that basic research continues, pharmaceutical researchers also continue to look for antibiotics in the same place they found penicillin: nature. Many microbes such as bacteria, mold and protozoa defend themselves by emitting poisons. Labs around the world are busy growing samples of uncultured microbes harvested from nature.

In 2015, researchers announced the discovery of a new drug called teixobactin, which is produced by one of the many bacteria researchers were cultivating. Teixobactin contains a molecule that interferes with the ability of some bacteria to maintain their cellular membrane. Initial tests show it to be 100 percent effective against some strains — meaning no resistance has yet been found.¹⁰

While tests continue on teixobactin (it is not yet approved for use), CDC notes that, overall, the number of new antibiotics introduced has been steadily declining over the past three decades. The last new antibiotic approved by FDA for use was ceftaroline in 2010. Before that was telavancin in 2008. Only six others have been approved since 2000.5

Teixobactin has only been shown to be effective against gram-positive bacteria, which means, if approved, it could be used to treat C. difficile, tuberculosis, MRSA and other dangerous diseases, but not many others caused by gram-negative bacteria. (Gram-negative or -positive refers to the results of a test using a specific stain to determine the type of membrane a cell has.)

Another drug in testing, brilacidin, has shown similar results in early testing and, if approved, would be used to treat skin infections.¹¹

Even if these two drugs are approved and prove effective against previously resistant strains, researchers warn that all it will take is one bacteria that is able to survive to start the cycle all over again. As such, it may turn out that resistance to antibacterial drugs is simply going to be part of the future medical landscape.