The Coming Plague (74 page)
Authors: Laurie Garrett
Initially bacterial resistances were incomplete, meaning that some of the organisms would die off with penicillin treatment, the child's ears would clear up, and both parents and physician would believe the illness had passed. But not all the
Pneumococcus
colony inside the child's ear had, indeed, been killed. With time, the surviving microbes would multiply, and after a few weeks the child's ears would again be in pain. If the parents pulled leftover penicillins out of their medicine cabinets and treated the child again, they would possibly see another apparent recovery in the child. But this time the
S. pneumoniae
colony was more resistant, fewer of the bacteria were killed by the drugs, and otitis media returned quickly with a vengeance.
Pneumococcus
colony inside the child's ear had, indeed, been killed. With time, the surviving microbes would multiply, and after a few weeks the child's ears would again be in pain. If the parents pulled leftover penicillins out of their medicine cabinets and treated the child again, they would possibly see another apparent recovery in the child. But this time the
S. pneumoniae
colony was more resistant, fewer of the bacteria were killed by the drugs, and otitis media returned quickly with a vengeance.
The old
S. pneumoniae
scourge of rheumatic fever, in which the bacteria colonized human connective tissue, had virtually disappeared from the Western industrialized world by 1970. A dangerous ailment, rheumatic fever usually struck children aged five to fifteen years, causing arthritislike pain in the joints and potentially lethal infections of the heart. In the preantibiotic era rheumatic fever survivors often suffered lifelong heart and arthritic problems due to damage wrought by the bacteria.
22
S. pneumoniae
scourge of rheumatic fever, in which the bacteria colonized human connective tissue, had virtually disappeared from the Western industrialized world by 1970. A dangerous ailment, rheumatic fever usually struck children aged five to fifteen years, causing arthritislike pain in the joints and potentially lethal infections of the heart. In the preantibiotic era rheumatic fever survivors often suffered lifelong heart and arthritic problems due to damage wrought by the bacteria.
22
In 1985 rheumatic fever broke out among white middle-class residents of the Salt Lake City region of Utah. In just three years' time the incidence of the disease skyrocketed eightyfold (between 1982 and 1985), and nearly a quarter of the patients suffered recurrences of the disease despite aggressive antibiotic therapy.
23
The Salt Lake City rheumatic fever outbreak was followed by increasing numbers of cases of the disease occurring all over the United States, and the upward trend would continue into 1994.
24
23
The Salt Lake City rheumatic fever outbreak was followed by increasing numbers of cases of the disease occurring all over the United States, and the upward trend would continue into 1994.
24
At about the same time Salt Lake City physicians were trying to comprehend their sudden surge in rheumatic fever cases, doctors in Oklahoma noted a striking increase in cases of multiply resistant pneumococcal infection. Hardest hit in the Oklahoma outbreak were the state's poor black urban residentsâthe overall rate of strep pneumonia in blacks was 60 percent higher than that seen in whites. The disease struck with the greatest severity among the state's poorest residents and elderly citizens living in nursing homes. More than 15 percent of those who developed the pneumonia died.
25
25
Of course, such ailments as rheumatic fever, strep pneumonia, and general respiratory infections with
Streptococcus
in young children had never disappearedâor even significantly diminishedâIn the poor countries of the world. Strep infections of the upper respiratory tract and lungs of small children remained, by 1990, major causes of sickness and death in poor countries. The World Health Organization estimated in 1992 that about 2 billion children per year suffered acute respiratory tract infections, 4.3 million of whom died as a direct result. About 800,000 of the deaths each year were due to neonatal bacterial infections, primarily of
S. pneumoniae
or
Haemophilus influenzae
.
26
And overall, 80 percent of the deaths were due to bacterial infection of the children's lungs,
27
the remainder being the result of viral infections (measles, respiratory syncytial virus, influenza, and whooping cough).
Streptococcus
in young children had never disappearedâor even significantly diminishedâIn the poor countries of the world. Strep infections of the upper respiratory tract and lungs of small children remained, by 1990, major causes of sickness and death in poor countries. The World Health Organization estimated in 1992 that about 2 billion children per year suffered acute respiratory tract infections, 4.3 million of whom died as a direct result. About 800,000 of the deaths each year were due to neonatal bacterial infections, primarily of
S. pneumoniae
or
Haemophilus influenzae
.
26
And overall, 80 percent of the deaths were due to bacterial infection of the children's lungs,
27
the remainder being the result of viral infections (measles, respiratory syncytial virus, influenza, and whooping cough).
In poor countries the prevention and management of pediatric respiratory diseases had to be handled with scarce resources, available antibiotic supplies, and little or no laboratory support to identify the organisms infecting children's lungs. So health professionals defined the disease process not in terms of the organisms involved but according to the parts of the body infected and the severity of those infections. In general, infections of the upper respiratory tractâwhich were usually viralâwere milder, while deep lung involvement signaled potentially lethal bacterial disease.
28
28
In 1990 the World Health Organization concluded that the best policy in developing countries was to assume that all pediatric pneumonias were due to bacterial infections, and treat children with penicillins in the absence of laboratory proof of strep or
H
.
influenzae
infection.
29
Studies done in India, Nepal, and Papua New Guinea showed that presumptive antibiotic treatment of acute respiratory infections reduced the number of child deaths in the test areas by more than a third.
30
Even more striking, there was a 36 percent reduction in child deaths
due to all other causes
: preventing or curing respiratory infections in children stopped not only those lung infections but a host of other secondary pediatric diseases.
31
H
.
influenzae
infection.
29
Studies done in India, Nepal, and Papua New Guinea showed that presumptive antibiotic treatment of acute respiratory infections reduced the number of child deaths in the test areas by more than a third.
30
Even more striking, there was a 36 percent reduction in child deaths
due to all other causes
: preventing or curing respiratory infections in children stopped not only those lung infections but a host of other secondary pediatric diseases.
31
That was the good news.
The bad news was that penicillins and other antibiotics offered no more benefit to children with mild, usually viral, respiratory infection than did basic nondrug home care.
32
Antibiotics have no effect on viruses.
32
Antibiotics have no effect on viruses.
“Our results show that there is no justification for use of ampicillin to treat mild ARI [acute respiratory infection] among Indonesian children,” wrote a University of Indonesia team. “This practice is both expensive and potentially harmful and is not in the interests of the medical community, the Ministry of Health, or the Indonesian people.”
33
33
The key danger, of course, was that village paramedics, lacking the training and laboratory support to correctly distinguish viral versus bacterial, and mild versus acute disease, would overuse antibiotics. And that, in turn, would promote the emergence of, among other things, antibiotic resistant
S. pneumoniae
.
S. pneumoniae
.
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.
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
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.
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
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.”
38
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.”
Inside their DNA, Tomasz found massive numbers of genes that were just plain wrongâthey 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.
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
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.
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
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
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