[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 legitimately, prescribed an antibiotic. But, guess what, the antibiotic doesn’t work! That’s because Clarence not only passed his rhinovirus to his grandmother, he also transmitted his resistant strain of Staph aureus to the old lady, who is a bit frail to start with.

Not to turn this into a tragedy, we’re going to say that Eunice was admitted to the hospital, her sputum was cultured, a methicillin-resistant Staph aureus (MRSA) was identified, she was treated with one of several antibiotics that deal effectively with the little buggers, and she recovered. But it doesn’t always turn out that way. Eunice might easily have been one of the 23,000 people in the US that died as a result of an antibiotic-resistant infection.

What this little story tells us is that there are at least a couple of different ways a resistant pathogen can infect us. We can foster and harbor resistant pathogens in our own bodies, and we can also be infected by resistant pathogens out there in the community.

Overuse of antibiotics as a cause of antibiotic resistance

In the case of Clarence, there were at least a couple of errors. Clarence’s doctor should not have given in to Clarence’s mother and prescribed an antibiotic. Clarence had a cold, caused by a virus, which would not be in the least affected by an antibiotic such as the one the doctor prescribed. If Clarence developed a bacterial infection, that would be when to start treatment with an antibiotic, not before. And, having prescribed the antibiotic, the doctor should have been emphatic with Minerva that Clarence had to complete the entire course of antibiotics – take all the pills. Finally, Minerva should not have kept the unused antibiotics in the medicine cabinet.

But this kind of thing happens all the time. Antibiotics are over-prescribed, and then the treatment course is not completed, so that a population of predominantly resistant pathogens remains to cause future infections. The CDC report, by the way, estimated that at least half of antibiotic use in humans is inappropriate.

Where are we most likely to encounter resistant pathogens?

Unfortunately, the red zones in terms of danger from resistant pathogens tend to be hospitals and health-care facilities. Hospital-acquired infections are not only common, but frequently exceedingly difficult to treat. They often affect patients who are frail and perhaps have compromised immune systems, sometimes as a result of treatment that they are undergoing.

A typical scenario might feature an elderly patient, perhaps like Clarence’s grandmother Eunice, who is admitted to the hospital with pneumonia. Because she spends most of her time in bed, she is less able to clear her lungs of fluid and mucous. Her breathing becomes labored. Her doctors decide that she needs breathing assistance, so they intubate her. In spite of precautions by the nursing staff, at some point the breathing tube introduces a particularly nasty pathogen into Eunice’s airways – let’s say, just to make the case really scary, Pseudomonas aeruginosa.

This microbe is fairly common, and can cause mild skin rashes and other non-life-threatening infections. But in the hospital setting, it easily acquires antibiotic resistance, and in frail and susceptible patients, it can rapidly cause serious and even fatal respiratory infections. Treatment for a patient infected with Pseudomonas can be effective, but requires rapid culturing of the sputum and treatment with a drug that is known to kill that particular Pseudomonas strain.

Fortunately, there are such drugs, but it’s a constant race to stay ahead of the many pathogens that are constantly changing to do battle with antibiotics.

Antibiotic resistance: a vexing challenge for pharmaceutical companies

Business leaders are always telling us that every problem is really a challenge and an opportunity, and we would all like to think that they are right. But let’s take a look at the particular challenges to drug development posed by the spread of resistance to antibiotics.

Here’s a scenario: a pharma outfit identifies a particular fungus in a tropical forest that seems to do a really good job in inhibiting the formation of cell walls in surrounding soil bacteria, which kills the bacteria. After some crafty lab work, they are able to manufacture the active molecule, and they test it in Petri dishes, and then in animals, and finally in humans, and run it through a series of clinical trials, and finally get it approved by the FDA, and bring it to the market as a new, highly effective antibiotic, that treats a number of common infections, including infections with many common resistant pathogens.

One would think that would be a perfect example of the problem – resistant pathogens, confronted and turned into an opportunity.

Let’s suppose that this new antibiotic was effective against lower respiratory infections, including Pseudomonas aeruginosa, the pathogen that was infecting Eunice. So, why wasn’t it used in Eunice in the first place?

The answer might well be that even though the clinicians at the hospital knew about this drug, and were aware that a patient like Eunice might develop a resistant infection, they preferred to use a more common antibiotic, and to hold back the new drug until they were pretty sure they really needed to use it. Why? Because drugs that are highly effective against certain resistant microbes are rare, and some clinicians and hospitals don’t want to expose a lot of pathogens to these new drugs, lest the pathogens also become resistant to the new drugs. They want to reserve the new drugs as the ultimate weapons – the drugs of last resort.

This, of course, is precisely contrary to what the pharmaceutical company wants. They would like their new antibiotic to be widely used, so as to recoup the enormous investment they made in research and development. They’ll accept the risk that if their new drug is widely used, resistant pathogens are likely to emerge. They probably figure that they’ll keep on developing new antibiotics, so when their new antibiotic loses some of its effectiveness due to pathogenic resistance, they’ll have something else.

So there’s some inherent conflict between the infectious disease treatment community and the pharmaceutical industry. ID folks are quite clear that it’s not usually appropriate to treat a whole range of common viral infections with antibiotics, and that the relatively small number of drugs that are highly effective against certain resistant pathogens should be reserved until it has been determined that indeed it’s a specific resistant pathogen that’s causing the infection.

That means that a pharmaceutical company could, conceivably, invest billions on bringing a terrific new antibiotic to market, and then discover that the medical establishment is using it so sparingly that the pharma outfit is not recovering its investment.

In fact, reluctance on the part of clinicians to use – “overuse,” they might call it – the most effective antibiotics may be a disincentive to pharma outfits to invest the necessary dollars to develop such antibiotics. They might figure that their R & D dollars might be better spent on some other treatment areas.

When is empiric treatment advisable?

The ideal procedure in treating an infection is something like this: first, precisely identify the pathogen; then, hit the pathogen with an agent that precisely eradicates the entire population of that particular pathogen, quickly, and without affecting any of the other micro-organisms in the patient’s system, and, of course, without causing the patient any adverse effects. Ideally, there are data showing that the pathogenic population has been wiped out in a certain time period, so after that time period, treatment with the antibiotic can stop. This is called definitive treatment.

Needless to say, it seldom happens that way. Antibiotics generally are active against a group of pathogens, not just one single pathogen. And they almost always kill off not only the pathogens that are causing the infection, but a lot of harmless and even beneficial micro-organisms.

However, equally important is the element of time. It is not always possible to identify the source of an infection quickly. Microbiologists can narrow the search, using a variety of techniques, but it takes time. Some microbes grow fairly quickly in a culture, but others may take a week or even longer, and some may not grow at all. In the meantime, the patient is getting sicker.

That’s when empiric treatment comes in. The physician basically makes an educated guess, based on symptoms, and also of knowledge of what pathogens are prevalent in the community at that time. Or, if the infection has taken place in a hospital setting, the hospital will have kept extremely careful track of which microbes are the current likely culprits.

Based on whatever information is available at the time when it becomes clear that the patient requires treatment, the physician will chose an antibiotic. Empiric treatment frequently means that the choice will be a broad-spectrum antibiotic, i.e., one that is effective against a wide range of pathogens. But, of course, it is precisely those antibiotics that most lead to increasing resistance in the microbial population.

So, the bottom line is that empiric treatment is frequently inevitable, because there isn’t enough information to develop an effective narrowly-targeted treatment plan quickly enough. But empiric treatment also – and inevitably – leads to resistance.

So, how do these microbes demonstrate their resistance?

There are several broad classes of antibiotics which attack bacteria and other microbes in different ways. By far the most common are the cell-wall antibiotics, which, as the name implies, attack the bacterial wall. These include all of the penicillin-related antibiotics, known as beta-lactams, including amoxicillin, ampicillin, and methicillin, but also the cephalosporins, which are the largest class of antibiotics, as well as vancomycin and daptomycin.

Bacteria mount resistance to the beta-lactams by attacking the beta-lactam ring, which is the entity within the antibiotic molecule that attacks the bacterial cell wall. This form of resistance could be characterized as a direct, all-out counterattack against the antimicrobial threat. Some bacteria are able to secrete an enzyme called beta-lactamase that deactivates the antibiotic. By the way, “methicillin-resistant,” as in those notorious MRSA pathogens, means resistance to the entire family of penicillin-derived antibiotics.

Other classes of antibiotics include drugs that target other bacterial functions. These include the sulfonamides – the “sulfa” drugs – and the fluoroquinilones, such as ciprofloxacin. The sulfonamides target bacterial synthesis of folic acid, which the bacteria require to survive – except that some bacteria develop a form of resistance which entails not needing to synthesize their own folic acid, but scavenging it from other sources. The fluoroquinolones attack DNA gyrase, which twists the single DNA strands into the familiar double helix. However, some bacteria develop mutations in their DNA gyrase, rendering them resistant to fluoroquinolones. Another mechanism of resistance is termed “efflux pumping,” meaning that the clever little creatures have developed means of pumping out the antibiotic.

Antibiotics that target protein synthesis include the tetracyclines and the macrolides – erythromycin and its relatives. Resistance to these drugs is also by means of efflux pumping.

We can’t emphasize too many times that these mechanisms of resistance didn’t just develop when we started using antibiotics to treat infections. They almost certainly developed in the natural world, as the micro-organisms competed with, and fought against, other micro-organisms in their environment. What we have done, perhaps by overuse of antibiotics, is to amplify and reinforce these mechanisms, by creating an environment where expressing resistance is simply an evolutionary advantage.

… and if that weren’t the only thing …

Another bit of bad news is that microbes can acquire the genes that confer resistance from other microbes. They don’t actually have to be exposed to the antibiotic, or be descended from bugs that were exposed to the antibiotic. They can swap genes with other bugs, so they can become resistant to several antibiotics. Some pathogens are designated as multi-drug-resistant (MDR) or extensively-drug-resistant (EDR) and even totally-drug resistant (TDR). TDR strains of the bacterium that causes tuberculosis, Mycobacterium tuberculosis, have been identified in several countries, although, fortunately, not yet in the United States. These pathogens are resistant to drugs that have previously been used to treat tough-to-treat TB infections, such as in populations with HIV, drug abusers, and others.

A particularly nasty and dangerous group of bacteria may be found in the intestinal tract of some unfortunate patients. These are resistant to a drug called carbapenem, which has been used as the ultimate weapon for some infections. These CRE (carbapenem resistant Enterobacter) are relatively rare so far, but they have been found in health-care facilities in the US in 44 states.

What about the use of antibiotics in animal feed?

There’s a good deal of controversy about this. The infectious disease community is strongly opposed; the agricultural folks say they need to do it; the government gets tugged back and forth. A middle view is that it’s perhaps okay to use antibiotics to prevent animal diseases, but not okay to put antibiotics in the feed to make the cows and chickens grow faster. However you look at it, antibiotic use in animal feed accounts for about 70% of the total antibiotic use in the United States.

Where do we go from here?

Is it remotely conceivable that the human race is going to scale back on antibiotic use? It was just about 87 years ago that Alexander Fleming discovered, by accident, that a little bit of the penicillin mold that fell into a Petri dish killed the Staphylococcus aureus that it come into contact with, essentially kicking off the development of antibiotics. Before that, there was very little that medicine could do to treat an infection that was inside a human being. Antibiotics absolutely were, and continue to be, miracle drugs. People with infections will continue to demand antibiotics, and the demand is increasing, as more and more people in the developing world get access to decent medical care. Therefore, antibiotic use will grow, not shrink. And so will antibiotic resistance. My hope, and my expectation, is that antibiotics will be used more appropriately and intelligently, and that the development of new antibiotics will continue to be pursued, so that we humans can stay ahead of the microbes that cause infection.

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You will have noticed that there are lots of things I didn’t discuss in this piece – resistant viruses, the benefits of vaccination, other potential ways of curbing infectious diseases, and on and on. I welcome suggestions about where else I should poke my nose. And I welcome comments regarding where I might have gone astray. After all, I clearly remember my 11th grade math teacher, Miss Charlotte Truesdale, who would look over my shoulder as I was taking my weekly quiz, and tell me, “Michael, you made a mistake in line three. Fix it.” Many thanks, Michael Jorrin, aka Doc Gumshoe.