[ed note: This is the latest in a series of articles from medical writer “Doc Gumshoe” (who, yes, is not actually a doctor) — it’s on the hot topic if antibiotic resistance, and we’ll likely continue to see companies touted and teased that aim to either fight resistant bacteria or clean up hospitals to slow the spread of these bacteria… hopefully this will be helpful in explaining the issues involved if you’re every planning on investing in the companies working on this.]
On September 16th this year, the Centers for Disease Control and Prevention announced that at least two million persons in the US become ill every year as a result of infection with a microbe that was resistant to an antibiotic, and that 23,000 people died from these infections. The figure for deaths from antibiotic-resistant infections was much lower than previous estimates, because the CDC eliminated all deaths that could be attributed to other causes. For example, if the patient had an antibiotic-resistant lower-respiratory infection that led to pneumonia, but the immediate cause of death was heart failure, that patient’s death was not counted in the total – even if there was a strong likelihood that the patient would not have succumbed to heart failure if it were not that he/she had become infected with the resistant pathogen in the first place. It’s a bit like the mobster entering a “not guilty” plea on the grounds that the guy he shot in the hold-up died of a stroke.
To my mind, there’s no question that this is a cause for considerable concern, even among entirely healthy people. The increasing prevalence of these resistant microbes has led to a reversal of thinking about infectious diseases in general. For most of the second part of the 20th century, the prevailing view was that we wouldn’t have to worry much about common infections, because we had a wealth of highly effective antibiotics that could deal with these former killers. In developed parts of the world, the big bugaboos of former times were no longer thought to be a threat. And the not-so-serious infections – the ones that might have kept kids out of school for a week or so – were now being knocked out fairly quickly.
And that, in fact, is one of the root causes of the spread of antimicrobial resistance! We’re attacking pathogens with agents that we have developed, often based on the natural enemies of these pathogens, and the bad bugs are fighting back.
But before we get into particulars, let’s explore how resistance develops in microbes.
Why do microbes develop resistance to antibiotics?
The short answer is, to survive! Micro-organisms, like all organisms, evolve in nature, which as we have heard, is “red in tooth and claw.” Every organism is constantly under threat from other organisms, and every species of organism constantly undergoes mutations, some of which are beneficial, and some of which turn out to be entirely the opposite of beneficial.
In the context of discussing disease, we tend to think of mutations as being dangerous, e.g., the notorious BRCA1 gene that increases the likelihood that a woman will develop breast cancer. But there are great numbers of beneficial mutations – mutations that lead to a real survival benefit. For example, it’s normal in much of the world’s population to lose the enzyme that permits us to metabolize lactose, once we have passed the breast-feeding age. But a mutation that generates that enzyme is hugely beneficial in parts of the world where milk is an essential part of the diet Individuals in those parts of the world who have that mutation are more likely to survive and reproduce than individuals who lack the mutation. It would have been hard for Laplanders, who formerly depended on reindeer milk, to survive without that mutation. So a beneficial mutation tends to spread, while a mutation that increases risk tends to die out.
The same thing is true for micro-organisms, which exist in a highly competitive environment. Microbes have evolved fighting antibiotics, probably for billions of years.
“But how could this be?” you say – antibiotics have only been in existence since about the middle of the 20th century.
Technically, that’s true, if we think of antibiotics as drugs developed by scientists with the express purpose of combating infection. But antibiotics exist in nature, and many of the antibiotics used clinically are derived from natural, living organisms, which for their own survival, prey on micro-organisms in their environment. Some of the microbes that survived these hostile organisms did so because they possessed mutations that incapacitated their enemies, those organisms that we might think of as “natural” antibiotics. The ones that had the mutations survived and reproduced, while the ones without the mutations failed to reproduce.
How does resistance to antibiotics spread among micro-organisms?
It’s really kindergarten Darwin. A population of organisms is threatened by a deadly agent, which we call an antibiotic. Some, but not all, of the organisms perish. Some survive because they happened to dodge the antibiotic, but others survive because they possess a characteristic that makes the antibiotic less effective against them – perhaps not total immunity, but something that permits them to fight against the antibiotic. (Later on, we’ll look at some specific mechanisms through which microbes resist antibiotics.)
Let’s say that prior to being exposed to the antibiotic, a fairly small proportion of the micro-organisms had this protective mutation – maybe 5%. Exposure to the antibiotic kills off half of the entire microbe population right away. But the surviving half includes most of the ones possessing the protective mutation – i.e., antibiotic resistance – so those now constitute about 10% of the remaining microbe population. So in the next generation of microbes about 10% will have inherited resistance. Continuous exposure to the antibiotic kills off the unprotected microbes, sparing the resistant microbes, until most of the microbial population is resistant to that antibiotic.
It’s not as simple as that, of course. In most cases, antibiotic resistance is far from total. It confers a survival advantage, which is transmitted to succeeding generations. But it’s not a bullet-proof vest. Many antibiotics, at sufficient concentrations, will kill – or at least stop the proliferation of – resistant pathogens. So this brings us to one of the truly vexatious aspects of treating infections, which is that resistance to antimicrobials is often the result of stopping treatment too soon or treating at insufficient doses. An objective of treating infections, beyond getting rid of the infection itself, is eliminating the infection-causing pathogens, so that the patient is not left with a population of resistant pathogens that may come back and cause a really difficult-to-treat infection. As infectious disease docs say, “Dead bugs don’t multiply.”
A typical scenario that leads to antibiotic resistance
Clarence is nine years old. He seems to catch cold every month or so, to the extreme vexation of his dear mother, Minerva. These don’t seem to be bad colds – he just sniffles and gets a runny nose, so Minerva doesn’t keep him home from school, because it would be a major inconvenience, since she has to go to work. But the third cold of the school year is a bit worse, so Clarence stays home from school, and after a couple of days, Minerva decides to take him to the doctor. The doctor tells her that what Clarence has is almost certainly a common virus, and Clarence will be fine in a couple of days, but if he’s not, bring him back, because we want to be sure he doesn’t develop a more serious infection. But Minerva, having taken Clarence to the doctor, wants to walk out of the office with something – a prescription for some medicine of some kind. So the doctor, against his better judgment, writes a prescription for a common antibiotic. He figures that there’s always a possibility that Clarence might develop a bacterial infection that could lead to something nasty, like an ear infection.
The instructions on the package say that the pills should be taken daily for ten days. But after two days, Clarence feels just fine. His cold has gone away! He doesn’t want to take his daily pill, and his mother doesn’t want to engage in a battle of the wills to make him do it, and besides she doesn’t think he needs it.
But about a month later, Clarence develops another cold. This time, Minerva knows just what to do. She still has several of those antibiotic pills left in the medicine cabinet, and she gives Clarence a pill right away, and gives him another one the next day. And, guess what, the pills work great! Clarence is cured of his cold in two or three days.
What his mother doesn’t know is that the pills did nothing to cure Clarence’s cold, since it was indeed caused by a common virus, which was totally unaffected by the antibiotic. Like most colds, it went away on its own. What the pills did, however, was to create an environment in Clarence’s upper respiratory system that fostered the growth of pathogens resistant to that class of antibiotics. All of us are colonized by micro-organisms that have the potential to cause troublesome infections. Mostly they are kept in check by competition from other microbes. But it doesn’t take much to upset the balance. Many antibiotics are indiscriminate in their effects. They don’t know which are the good guys and which are the bad guys – they attack them all. The ones that are most likely to survive are the ones that possess those protective mutations that fight back against the antibiotics, and those resistant survivors are the ones that reproduce and become the dominant microbial species.
So now Clarence’s pharynx is populated by a resistant strain of a particular pathogen called Staphylococcus aureus. Clarence is basically a healthy lad, and the Staph aureus in his mucous membranes don’t do him much harm. But now there’s a visit from his grandmother, Eunice, who adores him. Eunice is getting on and has had her share of health problems over the years. The next time Clarence comes home from school with a cold, Eunice catches cold. But Eunice’s cold gets worse. She becomes very congested. She develops bronchitis, which progresses to a lower respiratory infection. She is, quite legitim