Soon, because of drug use policies in both the wealthy and the poor countries, antibiotic-resistant pneumococcal strains turned up all over the world, some able to withstand exposure to six different classes of antibiotics simultaneously.34 By the 1990s S. pneumoniae strains had outwitted all aminoglycoside-type antibiotics, chloramphenicol, erythromycin, and all penicillin-type drugs, leaving physicians with few options, and epidemiologists worrying about when vancomycin resistance would also turn up in that bacterial species.
Genetic analysis of the various new mutant S. pneumoniae strains offered some clues as to the origins of these emergences. One multiply resistant strain (dubbed 23F) first appeared in Spain in 1978 in a hospital setting, bearing all its resistance capabilities save invulnerability to erythromycin. That trait was acquired when the organism, carried by an infected human, made its way to Ohio. Subsequent improvements in the bacterium’s ability to withstand hostile drug-laden human ecologies came as the organism’s descendants made their way to South Africa, Hungary, the U.K., back to Spain, and then again to the American Midwest. By 1992 it was possible to trace every known type of 23F S. pneumoniae back to a single mutant clone that arose in the 1970s in Spain.35
The nightmare example was S. pneumoniae type 19A, which emerged in Durban, South Africa, in May 1977. Five small children came down with the new strain while hospitalized for other reasons at King Edward III Hospital; three died. When the 19A strain was tested in the laboratory it was discovered that it was resistant to a huge list of drugs: penicillin, ampicillin, cephalothin, carbenicillin, streptomycin, methicillin, cloxacillin, erythromycin, clindamycin, gentamicin, fusidic acid, chloramphenicol, and tetracycline.36 Recognizing the futility of standard antibiotic therapy, the Durban physicians switched to rifampin plus fusidic acid for treatment. Though the organism was somewhat resistant to fusidic acid, it was vulnerable to rifampin.
But the new mutant strain could not be contained. A month after the first baby fell ill in Durban, a three-year-old boy was hospitalized in Johannesburg for heart disease. There, he developed pneumonia due to strep 19A infection, and only recovered after over six weeks of treatments with a variety of antibiotics. Soon it was apparent that the super-strep bug had infected dozens of pediatric patients and hospital personnel, and the entire measles ward was overrun by the mutant microbe. Three of the measles patients died of 19A pneumonia.
Vigorous control measures were taken, including treating all infected hospital personnel with high doses of rifampin and scrubbing down the Johannesburg and Durban pediatric wards. Nevertheless, 19A was never eliminated, and the mutant bacterium resurfaced periodically over the years. In a 1978 survey of Johannesburg’s six leading hospitals, over half of all pneumonia patients were found to carry the 19A strain. Fifteen percent of all pneumonia cases in Durban that year also involved strep 19A.37
Bacteriologist Alexander Tomasz at Rockefeller University in New York later did genetic analysis of the 19A strain, making what he termed “an astonishing discovery.†The Durban strain matched one that surfaced ten years earlier in a little boy living in a remote rural village in Papua New Guinea. By means Tomasz was never able to determine, the bizarre bacterium made its way to South Africa a decade later, and from there to Spain, Hungary, England, the United States, and eventually all over the world.
“But the point is,†Tomasz said, “all these bacteria can be traced to a single clone. And it all started with one transformed bacterium.â€38
In response to antibiotic pressure, the microbes altered far more than their ability to withstand the drugs. Tomasz discovered that the strep pneumococci weren’t very efficient at absorbing plasmids, as were most other bacteria. But they compensated for that failing by being voracious DNA scavengers. Tomasz actually caught them in the act with his camera and microscope, gobbling up long strings of random DNA. As a result, they changed the biochemical composition of their cell walls so radically, he said, “that we must actually say that these are new species.â€
Inside their DNA, Tomasz found massive numbers of genes that were just plain wrong—they weren’t pneumococci genes at all.
Such emergences of drug resistance usually took place in communities of social and economic deprivation.39 Poor people all over the world were more likely to self-medicate, purchasing antibiotics on the black market, over the counter in many countries, or borrowing leftovers from relatives. Without consulting often costly physicians, and certainly in the absence of expensive tests that could determine the drug sensitivities of the bacterial strains with which they were infected, the world’s poor were compelled to guess what drug might cure the disease that was ravaging their children or themselves.
This state of affairs guaranteed that a sizable percentage of the human population were walking petri dishes, providing ideal conditions for accelerated bacterial mutation, natural selection, and evolution.
Whether one looked in Spain,40 South Africa, the United States, Romania, Pakistan, Brazil, or anywhere else, the basic principle held true: overuse or misuse of antibiotics, particularly in small children and hospitalized patients, prompted emergence of resistant mutant organisms. 41
The basic problem with the antibiotic approach to control of pathogenic bacteria was evolution. Long before Homo sapiens discovered the chemicals, yeasts, fungi, and rival bacteria had been making antibiotics and spewing the compounds around newly claimed turf to ensure that rival species couldn’t invade their niches.
The rivals, of course, had long since evolved ways to rapidly mutate to withstand such chemical attacks. So rivals would make different chemicals, their foes would mutate again, and the cycle repeated itself countless times over the millennia. Humans simply accelerated the natural process by exposing billions of microbes at a time to drugs derived from the natural chemicals, and doing so with less lethal efficiency than had the microbial competitors in their ancient microscopic turf fight.
Often the genetic changes the microbes underwent in order to overcome the antibiotics offered unexpected additional advantages, enhancing the bacteria’s ability to withstand wider temperature variations, outwit more elements of the host immune system, or kill host cells with greater certainty.
So the patterns seen with Staphylococcus and Streptococcus were mimicked with other dangerous microbes.42 Leprosy, which was caused by Mycobacterium leprae, was easily treated prior to 1977 with the antibiotic dapsone. But that year a dapsone-resistant strain of the bacterium surfaced in Ethiopia.43 Though dapsone remained the drug of choice for treatment of leprosy, resistance increasingly rendered use of the antibiotic problematic. Within ten years the situation had become severe, with high percentages of the M. leprae strains from all over the world appearing invulnerable to the drug: 37 percent in Chingleput, India; 39 percent in Dakar, Senegal, and Paris, France; over 30 percent of strains in Guadeloupe, Martinique, and New Caledonia; a quarter of those in Fujian, China; and over half of all M. leprae in Shanghai and Jiangsu, China.44 Subsequently, resistance emerged all over the world to the alternative drug, rifampin, and in Ethiopia a patient was found to have essentially untreatable leprosy, suffering from a strain that was invulnerable.45
Gonorrhea was also increasingly difficult to treat, having acquired widespread penicillin resistance during the 1970s and spectinomycin insensitivity by the mid-1980s.46 The next drugs in line, then, were cefoxitin and tetracycline, and treatment was sufficiently complicated to require special guidelines from the CDC and WHO.47 In addition to the penicillin-resistance plasmid N. gonorrhoeae strains had acquired during the late 1970s, gonorrhea also took on a plasmid around 1985 that gave it the ability to withstand tetracycline.48
So the New York Academy of Medicine in 1989 recommended that physicians inject the antibiotic ceftriaxone into their gonorrhea patients and give them oral doxycycline.49 In addition to being considerably more expensive and available only in injectable form, ceftriaxone was a sulfur drug to which many
people (up to 20 percent in the United States) were allergic.
By 1990 physicians all over the world were using ciprofloxacin, ceftriaxone, or another member of the quinolone group of antibiotics to treat gonorrhea, finding the drugs highly effective. But in 1992, Australian physicians reported that the drugs were becoming less effective in treating patients who had recently traveled in Southeast Asia. By mutating changes in its cell wall, making itself less permeable to all the quinolone drugs, N. gonorrhoeae was, once again, outmaneuvering another line of human defense. A few resistant cases turned up in England as well—again, among recent travelers to Southeast Asia.50 Presumably the widespread black-market availability of antibiotics in much of Southeast Asia contributed to selective emergence of quinolone-resistant gonorrhea.
The most dangerous emergences of resistance to antibiotics for people living in poor countries were those in bacteria that caused intestinal disease and diarrhea. In 1991, 80 percent of the people living in the world’s poorest countries had no sanitary facilities for the disposal of human wastes. Even in the moderately developed countries—nations with middle-class populations and some industrial capacity—about half the people lacked sanitary toilet/sewage facilities.51 Under such circumstances it was easy for a water- or food-borne microbe to enter the water supply, be ingested by a human, grow and thrive in the human’s gastrointestinal tract, and then be expelled via human feces back into the community water supply.
Not surprisingly, diarrheal diseases were a major cause of death among young children in poor countries. In 1991 the World Health Organization estimated that 3.2 million children annually died before reaching their fifth birthday, victims of diarrheal diseases.
Whether new antibiotic-resistant intestinal pathogens emerged first in the industrialized world or in poor countries made little difference on the net outcome: the microbes’ greatest toll was taken among the world’s poorest, weakest children. And as resistant strains pushed up the costs of treatment, forcing the use of more expensive antibiotics, doctors in poor countries had little choice but to ration the drugs, triaging access.
During the early 1960s, Shigella dysenteriae became the first diarrheal bacterium to emerge with resistance to penicillins. In the absence of antibiotic treatment S. dysenteriae killed up to 20 percent of the children in whom it caused disease, and fatality rates as high as 15 percent had been seen in adults. Even the less severe types of Shigella (S. flexneri, S. sonnei, and S. boydii) could be lethal diseases in up to 10 percent of those people who fell ill. And natural immunity to the organisms was weak—nearly half the Shigella survivors suffered recurring disease.
In September 1983 a middle-aged Hopi woman living on her tribe’s national lands in Arizona was hospitalized with Shigella dysentery. Doctors soon realized that she suffered from an altogether new mutant strain of the microbe that was resistant to ampicillin, carbenicillin, streptomycin, trimethoprim, sulfamethoxazole, sulfisoxazole, and tetracycline. It turned out the woman had a long history of urinary tract infections, for which she had taken trimethoprim and sulfamethoxazole off and on for at least three years.
Her intestines had become a breeding colony for resistant bacteria. Subjected repeatedly to antibiotic assaults, the microbes shared resistance plasmids. Colonies of Escherichia coli were apparently already in possession of a plasmid bearing genes that conferred resistance to trimethoprim and sulfamethoxazole, and they shared that plasmid with Shigella in the Hopi woman’s gastrointestinal tract.52 Though health authorities did what they could to limit the spread of the super-bug, by 1987 up to 21 percent of all Shigella infections among the Hopi and nearby Navajo were caused by the mutant strain. Nationwide, 7 percent of all Shigella infections in 1986 involved the super-bug, and a third of all cases were also ampicillin-resistant.
In Ontario, Canada, even higher levels of Shigella resistance were apparent by 1990: eight out of every ten human illnesses with the organism involved resistant strains. And half of all Shigella infections were caused by bacteria that were resistant to four or more antibiotics. 53
Again, the most devastating impact of such multiply resistant Shigella was felt in the world’s poorest nations. When a new multiply resistant strain reached the African country of Burundi, for example, the nation’s Ministry of Health was unable to come up with enough foreign exchange to purchase alternative drugs from wealthy-nation pharmaceutical companies. So untold numbers of people died of dysentery.54
Similarly, between 1960 and 1993 several other enteric bacteria—species that infected the human gastrointestinal tract—acquired profound genetic abilities to resist Homo sapiens weaponry. These included E. coli, Klebsiella, Proteus, Salmonella, Serratia marcescens, Pseudomonas, Enterococcus faecium, Enterobacteriaceae, and cholera. The situation by 1990 was quite grave, particularly in poor countries that lacked sufficient resources or capital to eliminate the unsanitary conditions responsible for the transmission of the microbes from humans to the water supply and from food to humans.55
Salmonella, the leading cause of food poisoning, was appearing in the Caesar salads served up in restaurants on Manhattan’s posh Upper East Side, or in taco stands along the border caminos of Juarez, Mexico.56 By 1993 it was an essentially untreatable diarrheal disease, as no known antibiotic seemed capable of reducing the three to four days of agony a typical Salmonella infection produced in Homo sapiens.57 Fortunately, the microbe rarely caused anything more dangerous in its human hosts than headaches, acute stomach pain, diarrhea, nausea, and dehydration.
One of the most disturbing prospects for physicians worldwide was the emergence around 1988 of vancomycin-resistant Enterococcus faecium and faecalis. With vancomycin the only remaining reliable treatment for staph and strep infections, there was great concern that resistant enterococcal bacteria could share their resistance genes with the other, otherwise untreatable microbes.
“It hasn’t happened yet, but everybody thinks it will,†CDC bacteriologist Bill Jarvis said.
Such a bacterial strain, if it did emerge, would be virtually incurable and extremely dangerous, for it would possess not only special drug-resistant genes but also those for heightened virulence.
Physicians and scientists working outside the field of bacteriology in the 1990s generally assumed that, as had been the case before, another class of antibiotics would be developed and the problem would go away.
But they were wrong.
“There’s nothing on the shelf. Nothing in the pipeline. If we lose vancomycin we’re going to be back to the 1930s with staph,†Jarvis said. The same could be true for Streptococcus.
“That would be the real nightmare,†predicted the CDC’s Bill Jarvis.
The nightmare began unfolding in 1988 with first reports of vancomycin-resistant E. faecium strains surfacing all over the world, usually appearing first inside hospitals.58
For example, a handful of hospitalized patients in New York City hospitals fell ill with vancomycin-resistant strains during 1988: their cases were isolated, and there was no evidence of bacterial spread to other patients or into the community. Between September 1989 and March 1991, however, vancomycin-resistant strains of enterococci emerged in twenty different New York City hospitals. A survey of the first hundred of those New York cases revealed that ninety-eight people became infected while in the hospital; two acquired their infections in the community.
Forty-two of the hundred patients died; incurable enterococci was the direct cause of death for nineteen of them, a contributor in the remaining terminal cases. Most of the dead were elderly individuals.
When laboratory molecular studies were done on bacterial samples from twenty-one of the patients, New York City Health Department researchers found that nineteen were resistant to all available drugs. And individuals who were infected with the super-resistant strains also progressed to full-blown blood disease (septicemia) more quickly.59
; By 1994 all of the Greater New York City large hospitals had cases of vancomycin-resistant enterococci, and infection control had become a major crisis for facilities throughout eastern New Jersey, New York City, and neighboring suburban counties.60 Similarly grim outbreaks of vancomycin-resistant super-bugs were seen in London,61 Sheffield, England,62 and Ancona, Italy.63
A CDC survey of key U.S. hospitals found that by 1994 some 7.9 percent of all reported Enterococcus infections involved vancomycin-resistant strains. On the nation’s intensive-care units, where the risk of infection was highest, vancomycin-resistant strains accounted for just 0.4 percent of all enterococcal infections in 1989, and 13.6 percent by 1993. The highest incidence of the problem was in New York City hospitals, where 8.9 percent of all enterococcal infections were of vancomycin-resistant strains.64
Inside American hospitals the emergence of super-enterococci was facilitated by practices that allowed the organism to instantly spread from one susceptible human to another: electronic thermometers,65 catheters and surgical instruments,66 intravenous lines, mechanical ventilation, and overuse of cephalosporin-type antibiotics.67 The latter increased the risk of hospital-acquired enterococcal infection because the cephalosporin-type antibiotics had no effect on enterococcal bacteria but did devastate colonies of rival microbes, rendering the treated human especially vulnerable.
By the end of 1993, with vancomycin-resistant enterococci reports coming in from all over the world, CDC and WHO scientists waited anxiously for the seemingly inevitable—exchange of the vanA or other resistance plasmids from the E. faecalis or E. faecium to Staphylococcus or Streptococcus . It had been done experimentally. European scientists had proven the microbial species capable of such a feat.68 It only remained for nature to take its course.69
The human gastrointestinal tract was an ideal ecology for such microbial events as plasmid exchanges because it was densely populated with dozens of species of both pathogenic and helpful—commensal—organisms. More bacteria lived on a single square inch of the human intestine than there were humans on the entire planet. There were more microbes colonizing a given human’s body than there were human tissue cells.
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