Microbes That Just Say No To Drugs

by Alison Grinthal
Cancer-causing chemicals were found in at least four of the six schools in the pilot project.

In 1969, as war raged in Vietnam and riots tore through cities across the United States, one person triumphantly proclaimed peace. According to surgeon general W. H. Stewart, the long nightmare of bacterial plagues was officially over.

Unfortunately, the bacteria had other ideas. Not ones to be outdone by a species millions of years their juniors, they had been learning how to outsmart antibiotics since long before humans and their drugs came on the scene. While many of them did succumb to the unmitigated pharmaceutical artillery we poured on them, the survivors emerged not only unscathed but poised to spread their resistance tactics to their more naive counterparts.

Now, after years of complacency, doctors and public health officials are again wringing their hands. Diseases that had been retired to history books are reemerging as life-threatening epidemics, formerly trivial infections are spawning strains resistant to most or all antibiotics, and drug-resistant bacteria are spreading throughout hospitals and communities across the world. Dr. Mitchell Cohen, Director of Bacterial Resistance at the Centers for Disease Control, reflects the fears of patients, doctors, and scientists in his warning that "...the post-microbial era may be rapidly approaching in which infectious disease wards housing untreatable conditions may again be seen."

Bad trip for bacteria

Sixty years ago the bacterial infection scene was ugly. At best an infected person was in for quarantine, surgical drainage, maybe a visit to the sanitorium, and, at worst, unalleviated suffering and death. This all changed when Alexander Fleming discovered that he could make a hole in a layer of bacteria by dropping mold on it. With his subsequent revelation that he could reproduce the hole with just a single mold component, penicillin, humans acquired the secret to which mold, fungi, and bacteria had long been privy: bacteria could be induced to drop dead in the face of drugs. As penicillin rose to savior status in the 1940's, death by bacteria was no longer necessary.

Penicillin in its streamlined drug form had reached a grand old age of three years when a bacterial strain first outsmarted it. Strains of Staphylococcus aureus, a common cause of surgical wound, skin, and respiratory infections, were isolated in 1944 with the capacity to synthesize an enzyme that destroyed penicillin, and the resistance spread throughout the world during the 1950's until by the 1990's more than ninety-five percent of S. aureus was immune to penicillin. Staphylococcus pneumoniae, notorious for causing pneumonia as well as ear infections, sinusitis, and meningitis, followed suit with its first penicillin-resistant strain in 1967 and with a more highly resistant version in 1977.

Now, in contrast to 1941 when four days of ten thousand units of penicillin could cure pneumonia, twenty-four million units a day may not save an infected personÕs life. Growing penicillin resistance in Neisseria gonorrhea likewise brought the need for progressively higher drug doses during the 1950's and 1960's until some strains of the bacteria became entirely resistant in the early 1970's. Shigella, the bacterial culprit in the diarrheal disease shigellosis, made its resistant debut in the 1960's, and by 1986 nearly a third of a United States Shigella sample was resistant to ampicillin, a relative of penicillin . Enterococci, a set of bacteria responsible for most cases of endocarditis and urinary tract, wound, abdominal, and pelvic infections, remained susceptible to penicillin until 1983 but since then has rapidly caught up in its resistance.

I need a new drug

Yet, in the midst of all this, the surgeon general somehow managed to come up with the statement that it was "time to close the book on infectious diseases" in 1969. Furthermore, the pharmaceutical industries in the United States and Japan decided in the 1980's that bacterial diseases were under control and no longer worth working on, despite the outbreaks of drug-resistant dysentery, cholera, and pneumonia taking place as they rewrote their budgets. Were these people out of their minds?

Only a little bit. As resistant strains were appearing, the drug industry had been doing a fine job of turning out new antibiotics to combat them, and after several decades, a smorgasbord of over one hundred fifty antibiotics lined the shelves ready to undermine every imaginable facet of bacterial metabolism . For the original resistant S. aureus, which has turned into a classic example of the progression of drug resistance, methicillin took over the inhibition of cell wall synthesis where penicillin failed. When methicillin started to fail, a new family of drugs called fluoroquinolones came to the rescue with their capacity to interrupt DNA coiling. Mupirocin then arrived to inhibit protein biosynthesis, but resistant strains were not far behind. Vancomycin, another inhibitor of cell wall formation albeit a far more expensive and unpleasant one than penicillin, remains a useful agent against these resistant S. aureus strains as well as against pneumonia and other penicillin-resistant bacteria.

Add all these drugs to those developed against other resistant bacteria and the framework for complacency grows clearer. After decades of turning out new and stronger antibiotics, drug companies as well as physicians figured we were well-stocked. Resistant strains could indeed emerge, but our arsenal was big enough that another drug was always available. With far more options than a given person could ever try in a lifetime, it was hard not to have faith that any infection would always be curable by at least one of them. Meanwhile, solutions to heart disease, cancer, viral disease, and chronic illnesses grew urgent, not to mention more profitable to pursue.

Rebound. It is said that "the greatest trick the devil ever played was convincing the world he didn't exist."No sooner had the pharmaceutical and medical communities turned their backs on bacteria and the issue faded into the woodwork than the problem grew larger than anything the world had seen since before antibiotics were discovered. Drug resistance had appeared steadily since the advent of antibiotics, but between the mid 1980's and the mid 1990's the numbers of resistant species, precentages of each species with resistance to one or more drugs, and, perhaps most frightening, the number of drugs each organism could resist grew to unprecedented proportions. Right in the heart of our faith in antibiotics we had entered what NIH scientist Richard Krause has deemed Òan epidemic of microbial resistance."

By the mid 1990's nearly every common pathogenic bacterium had some degree of resistance, and over two dozen strains were life-threatening due to their resistance to nearly all available antibiotics . More than half of all hospital-acquired infections were resistant, and according to the (now defunct) Office of Technological Assessment about nineteen thousand people per year were dying from such infections in the United States alone . Furthermore, diseases that were supposed to have been conquered are reemerging. One of the most notable and alarming among these is tuberculosis. Formerly on the decline and considered highly curable, TB has acquired resistance to so many drugs that as of 1992 it was the number one cause of death among infectious diseases . Its toll has risen by nearly a third since the 1980's ; outbreaks of resistant strains have befallen at least thirty-six states ; and the chance of dying if a drug-resistant form of this formerly curable disease is contracted has climbed to about fifty percent, or eighty percent for anyone who happens to be otherwise immunocompromised, such as by HIV . If these numbers sound staggering, it's because they are, particularly for a disease for which the main risk behavior is breathing.

As if that weren't enough, diphtheria has resurged to strike nearly one and a half times as many people in 1996 as in the beginning of the decade . Cholera is on the rise, and the forgotten bubonic plague now registers the highest totals since global data began in 1954. Kermit the Frog needed a new voice recently because streptococcus A, a bacterial strain that was history until the late 1980's, reemerged and took the life of Jim Henson in 1990.

With vancomycin on reserve as the last resort against strains that currently resist everything else, our last bastion of confidence in the dominance of antibiotics was struck with a sobering thud when a vancomycin-resistant strain of enterococcus emerged in 1989. While enterococcus itself was not yet resistant to everything else, it signalled the potential downfall of vancomycin and held the threat that its vancomycin resistance gene would spread to other strains for which no other antibiotics were left. By 1994 vancomycin-resistant enterococci had spread all over the world, had been found in every hospital in New York City, and accounted for fourteen percent of all enterococci, an occurrence twenty times higher than not so long ago in 1987. With this rate of spread, Barry Eisenstein of Eli Research Labs as well as most of the medical community fears that "it's just a matter of time" until vancomycin resistance renders S. aureus and other pathogens resistant to every antibiotic we have . Scientists have already alarmed themselves by combining vancomycin-resistant enterococci with methicillin-resistant S. aureus in the lab to create omniresistant bacteria.

HELP! Where did this crisis come from, why now, and what are we supposed to do about it?

Human flesh failure

With all due respect, the bacteria could not have been psychic enough to know we were scaling down our research efforts against them; pharmaceutical rebudgetting was not singlehandedly responsible for precipitating a crisis. On the contrary, we may have become, as writer R. F. Service suggests, the "victims of [our] own success" by going overboard with antibiotics in recent years. Indeed, several studies have revealed unmistakable correlations between recent trends in antibiotic use and an unprecedented rise in the emergence of resistant strains. In a study involving several hospitals, E. coli jumped from zero resistance in 1983-1990 to twenty-eight percent resistant in 1991-1993, in conjunction with the use of fluoroquinolones in 1.4 percent of patients between 1983 and 1985 and in forty-five percent of patients between 1991 and 1993 (13). Granted a correlation is ambiguous in terms of cause and effect, but another study of E. coli showed that resistance to the folic acid metabolism inhibitor trimethoprim rapidly rose by a million-fold after administration of the drug (13). To some degree the generation of resistance is inevitable and, as we've seen, the norm throughout the rest of history, but a recent rise in indiscriminate use of antibiotics for minor infections, for illnesses such as viral infections that may not even involve bacteria, and for preventive measures may well have pushed the resistance rate into crisis territory. On top of that, unwitting use of antibiotics against strains that are already resistant has often ended up helping them grow by selecting them over other bacteria. As a result, not only have otherwise minor illnesses turned into serious diseases in some patients, but the chance of spreading resistance has multipled. Pampering food animals the same way in the name of keeping them healthy and pathogen-free has added both to the quantity of anitbiotics people ingest and to their exposure to antibiotic-resistant bacteria.

The social and environmental scene in which bacteria travel has also been growing more conducive to their proliferation. According to a report by the Institute of Medicine at the end of 1995, commercial global travel and urbanization have served as red carpets for the spread of resistant bacteria; if antibiotics lead to the generation of resistant TB strains in Colorado, it is now almost a given that the strain will appear in New York . Furthermore, day care centers have become a common exchange site for resistant bacteria . Although the theory is difficult to test, both the Institute of Medicine and subscribers to the global climate change school of thought point to environmental disruptions as a major aggravating factor in the bacterial crisis. In particular, a warming trend may be widening the geographic range and biting rate of disease-carrying vectors while shortening the time of pathogen incubation. In the case of malaria, the vectors themselves are developing drug resistance .

Finally, the subpopulation of ideal human vectors is reportedly growing . An immunocompromised body is paradise for a bacterium, and, fortunate as we are to be walking around rather than buried, many of us are much better pathogen havens than we'd like to be thanks to immune deficiencies linked to chronic fatigue, AIDS, environmental toxins, stress, and yes, taking too many antibiotics that wipe out useful bacteria that help to keep pathogenic invaders in check. Disease-causing strains, including those with drug resistance, therefore have a better chance not only of wreaking havoc in whatever body they land in but also of finding a safe base from which to proliferate and spread whether or not they cause their host trouble.

Creation of a monster

Okay. So in recent years overuse and abuse of antibiotics have invited the population of drug-resistant strains to attain its current unwieldy status, and a combination of social and environmental changes has paved the way for their spread. But is this enough to jet propel us from complacecy to crisis in less than a decade? Urban civilization wasn't born yesterday, and airplanes have been around since long before the late 1980's. And even with the abuse of antibiotics and selection of resistant strains, drug stores are still chock full of antibiotics the average sick person has never even heard of. Why are so many of these drugs failing with people and diseases for which they've never been used, and why has the pace of the problem recently grown so out of proportion to the growth of the trends that appear to cause it?

The answer lies partly in the fact that bacteria have turned drug resistance into an art. If they had stuck to resisting individual drugs, the problem would have been troubling enough, but their complex mechanisms of accomplishing, sharing, and accumulating resistance have not only thrived on recent human practices but have synergized with these practices to create the current monster.

While the first bacteria to resist penicillin did so by synthesizing an enzyme that destroyed the drug, subsequent strains have branched out into the more subtle yet broadly applicable practice of altering the molecule against which the drug is targetted. In the case of penicillin, the bacterial DNA codes for a new version of the cell wall component that was formerly bound by penicillin, thus allowing cell wall formation to proceed uninhibited. Since a whole set of antibiotics was designed to bind to this cell wall compoberculosis likewise developed resistance to the drug rifampin by altering the targetted subunit of its transcription machinery, thus enabling RNA chains to continue forming in spite of the drug. Meanwhile, cholera and several other pathogens have developed efflux mechanisms to rid themselves of tetracycline and all its relatives. Others have reduced their permeability to drugs.

While such mechanisms singlehandedly outwit multiple drugs, the genetic process by which they accumulate and spread raises their resistance power to another dimension. The genetic material inside a bacterial cell consists of a single chromosome as well as an assortment of DNA plasmids, and while resistance genes can occur on both types of DNA as well as be incorporated from one form to the other, plasmid genes have the unique advantage that they can be transferred among bacterial species through little more than cell-cell contact. Thus, if a person with staphylococcus containing a tetracycline-resistant plasmid contracts cholera, the cholera can gain resistance to tetracycline if it comes in contact with the staphylococcus. On top of this, resistance plasmids tend to accumulate resistance genes, so when a bacterium acquires one type of resistance an entire collection of resistance genes gets thrown in gratuitously . As a result, a single antibiotic can select for a strain that resists nearly everything.

In addition to the collection version of multiple drug resistance, a family of single genes each conferring even more comprehensive multiple drug resistance has been on the rise. The genes code for pumps that extrude just about any drug that happens to find its way into the bacterium, whether the drug has been used for years or was patented yesterday. In many cases the pump is encoded on a resistance plasmid that enables it to cross species barriers.

As if the bacteria needed another trick, a set of recent outbreaks of E. coli and salmonella has alerted FDA researchers to the unnerving capacity of some strains to mutate at an unusually high frequency. In addition to frequent mutation, these bacteria also readily take up other bacteria's DNA, creating what D. Grady calls a double whammy that speeds their evolution up by one hundred- to one thousand-fold. The mutators, which now account for as many as six percent of some strains, took the world off guard since ordinarily any organism with their traits would die. According to Philip Hanawalt, a scientist who studies DNA repair at Stanford, their infiltration of the microbial ranks "has very far-reaching implications and is even a bit ominous."

War on drug resistors

Bernard Dixon put a sobering touch on the situation with his 1994 prophesy that "Such is the adaptability and versatility of microorganisms as compared with humans and other so-called 'higher' organisms, that they will doubtless continue to colonize and alter the face of the Earth long after we and the rest of our cohabitants have left the stage forever. Microbes, not macrobes, rule the world."

So do humans and their humble limbic systems have a prayer of averting a disastrous surrender to resistant bacteria? At the very least, we can postpone the day of reckoning. For the first line of action, public health and medical officials are working to generate large scale day-to-day surveillance measures to insure weÕre at least clued in to the nature of the problem as it evolves. Based on the assumption that resistance genes can spread more readily than they can reemerge, the World Health Organization (WHO) recently established a Division of Emerging, Viral, and Bacterial Diseases Surveillance and Control charged with keeping on top of and placing teams at outbreak sites within twenty-four hours in order to contain the pathogens . The Centers for Disease Control, as well as other groups, have stepped up their efforts and techniques for tracking the spread of resistant strains , and the WHO has started handing out contracts to keep track of all mobile DNA and plasmids. In addition, doctors are being urged to identify and report all instances of resistance immediately, as well as to quarantine infected patients and to limit prescription of antibiotics.

But anyone who ends up on the wrong side of the quarantine door is unlikely to see surveillance and containment as an entirely satisfactory solution. Is there any hope for curing the people already infected with multiple-drug resistant pathogens? The plethora of drug ideas presented at the 1995 meeting of the Interscience Conference on Anti-Microbial Agents and Chemotherapy suggests that after the the last several years of silence the pharmaceutical industry is hard at work again. One compound, an oxazolidinone for those keeping track of names, has shown promise against resistant strains in animals, without undue toxicity. Its mechanism of action is not entirely understood but may involve an early stage of protein synthesis. Another drug in the works attacks a previously untargetted part of the bacterial cell wall, thus making the bacteria more susceptible to the activity of the human immune system. In addition, researchers are working on revamping old drugs as well as developing compounds that clear the way for existing drugs by nullifying resistance mechanisms. On the latter front, a drug that clogs the pump used by bacteria to pump out tetracycline has enabled tetracycline to kill resistant strains, while a drug that inhibits the bacterial enzyme that destroys penicillin has shown promise in the treatment of drug resistant tuberculosis.

Yet a troubling question remains: how are new drugs going to fare any better than the old ones? Are we embroiled in an addiction to antibiotics such that the more we create and use them the faster we need new ones, and the stronger the new ones have to be? One hope is that in the context of surveillance, containment, public health improvements, and more frugal use of antibiotics the problem won't flare up quite as rapidly as in the past few years. Nevertheless a conflict of interest between public health officials and drug companies threatens to undermine both of their efforts; while the former recommends focusing on narrowly targetted drugs in order to minimize the selection of broadly resistant microbes, the laborious process of developing a drug and the need for companies to pay their employees favor developing a few broad spectrum drugs that appeal to everyone rather than a large collection of compounds each targetted to a small population. Thus, while development of new antibiotics certainly beats doing nothing and holds the promise of saving lives, the long term benefits in the war against bacteria remain questionable.

Can't we all just get along?

Perhaps, just as antibiotics changed our concept of bacterial diseases in the 1940's, a new framework for approaching the war on bacteria would be useful right about now. The fact that a human body, even a healthy one, harbors more microbes than human tissue cells suggests the assumption that bacteria keep each other in check under normal conditions. In the long run these approaches may not work. They may turn out to encourage resistance just as readily as antibiotics. And they will most likely require major research in order to extricate the fuzzy concept of balance from the New Age fad. But, against a backdrop of continuing public health improvements and discriminating use of antibiotics, they may also turn out to be crucial to the long-term coexistence of humans and microbes.