Authors: Laurie Garrett
The Coming Plague (73 page)
In order to prove Koch's Postulate, however, Schlievert needed to show that injections of TSST-1 could produce Kawasaki syndrome in animalsâa feat that, by 1994, he had yet to accomplish.
In collaboration with researchers from the National Jewish Center for Immunology and Respiratory Medicine in Denver and Boston's New England Medical Center, Schlievert demonstrated in 1993 that Kawasaki syndrome in at least some children was related to the TSST-1 toxin. Sixteen children with Kawasaki were compared with fifteen youngsters who were suffering fevers and rashes due to other causes. Bacteria that secreted TSST-1 were found in the blood or mucus swabs of thirteen of sixteen Kawasaki patients, compared with only one of the controls. And the toxin produced proliferation of a specific population of T cells in the kids with Kawasaki (VB2 + T cells); there was no such cellular population expansion seen in the controls.
47
47
The 1993 Kawasaki study had provided further evidence for another Schlievert observation: namely, that the strain of S. aureus that produced TSST-1 was genetically unique, and had not played a significant role in human disease prior to 1975.
A survey of dozens of samples of TSS-producing bacteria from diverse geographic locales showed that they were all descendants of a single clone of
Staphylococcus
.
48
In addition to producing the killer toxin, the apparently new strain of staph was dependent on its hosts for supplies of the amino acid tryptophan. (Normal
Staphylococcus
make their own tryptophan.) In laboratory cell cultures the new strain actually looked different to the naked eye: normal staph colonies thrived on red blood cells and appeared golden in color, but the new strain seemed unable to digest beef or human blood cells and colonies were white or blanched.
Staphylococcus
.
48
In addition to producing the killer toxin, the apparently new strain of staph was dependent on its hosts for supplies of the amino acid tryptophan. (Normal
Staphylococcus
make their own tryptophan.) In laboratory cell cultures the new strain actually looked different to the naked eye: normal staph colonies thrived on red blood cells and appeared golden in color, but the new strain seemed unable to digest beef or human blood cells and colonies were white or blanched.
The new strain grew up to 10,000 times faster than normal staphylococcal colonies, churning out massive quantities of the TSST-1 poison, as well as enzymes that rendered it immune to penicillin, ampicillin, and other members of the penicillin-class of antibiotics.
In laboratory tests, TSST-1 and five other toxins extracted from various staph strains proved to be the most potent T-cell stimulators ever found.
49
In the short run, the immune chaos it produced could lead to huge expansions in the CD4 T-cell population (the same population that is destroyed by the AIDS virus). That, in turn, caused secretions of CD4-related chemicals that produced the symptoms of high fevers, shock, and rashes. If lab animals or people were continually reexposed to the toxin, as was the case for many menstruating women who suffered increasingly severe monthly bouts with the bacteria, this CD4 T-cell overstimulation could lead to a wasting syndrome, anorexia, and chronic overproduction of key immune system chemicals.
50
49
In the short run, the immune chaos it produced could lead to huge expansions in the CD4 T-cell population (the same population that is destroyed by the AIDS virus). That, in turn, caused secretions of CD4-related chemicals that produced the symptoms of high fevers, shock, and rashes. If lab animals or people were continually reexposed to the toxin, as was the case for many menstruating women who suffered increasingly severe monthly bouts with the bacteria, this CD4 T-cell overstimulation could lead to a wasting syndrome, anorexia, and chronic overproduction of key immune system chemicals.
50
This dramatic immunological effect resulted in TSST-1's designation as a “superantigen”âan extraordinarily potent immune system stimulator capable of inducing a cascade of activities within the system.
Using sophisticated molecular biology techniques developed in the late 1980s, various scientists were able to show that the unique genetic characteristics for the virulence of the toxic shock staph strain, as well as those responsible for its inability to consume red blood cells and produce septicemia, all clustered together as a continuous segment of bacterial DNA. Furthermore, that segment of DNA was mobileâit could move around along the bacterial chromosome.
51
In most cases, it took up residence alongside either the gene for production of tryptophan or, less frequently, that responsible for making another key amino acid that was occasionally deficient in TSST-1 strains, tyrosine.
52
51
In most cases, it took up residence alongside either the gene for production of tryptophan or, less frequently, that responsible for making another key amino acid that was occasionally deficient in TSST-1 strains, tyrosine.
52
The strain's ability to withstand penicillin was due to another transposable DNA segment that caused production of an enzyme, beta-lactamase, which rendered penicillin harmless to the bacteria. This penicillin-resistant genetic segment was first observed in staphylococci shortly after the introduction of penicillin into clinical medicine in North America and Europe, and was known to move about in the microbial world as a plasmid.
53
53
The two transposons (TSST-1 and beta-lactamase) appeared to be linked in the new staph strain; TSST-1 was never present in a
Staphylococcus
bacterium without beta-lactamase, and their expression seemed to be simultaneous.
Staphylococcus
bacterium without beta-lactamase, and their expression seemed to be simultaneous.
So a tempting conclusion was revealed: perhaps the Toxic Shock Syndrome outbreak followed a unique genetic event in which a plasmid that carried both gene sets was absorbed into an S.
aureus
bacterium sometime in the 1970s under ecologic circumstances that were ideal for that organism's growth and rapid multiplication.
aureus
bacterium sometime in the 1970s under ecologic circumstances that were ideal for that organism's growth and rapid multiplication.
It was tempting to conclude that misuse of penicillin antibiotics was responsible for the event. Because the poison genes and those for antibiotic resistance appeared to be carried together on a plasmid, selection pressure imposed by penicillin use could have caused the mutation event. That was, of course, pure speculation. Proving such an event took placeâmuch less where and when it happenedâwas impossible.
However the new strain originally emerged, its debut elicited a strong human response. A multimillion-dollar industry was shaken, menstruating women were terrified, scientists feuded, and the credibility of two U.S. federal agenciesâthe FDA and the CDCâwas challenged.
As was the case with HIV and so many other microbes, the new poisonous microbe was victorious. Despite the frenetic (though ineffective) efforts of
Homo sapiens
, the microbe succeeded in carving out a biological niche in the human world and taking permanent hold.
Homo sapiens
, the microbe succeeded in carving out a biological niche in the human world and taking permanent hold.
By 1994 Toxic Shock Syndrome was an enduring addition to the list of human pathogens, and though it no longer attracted lawsuits and front-page news, the novel
S
.
aureus
strain was causing nearly as many infections, ailments, and deaths in the 1990s as it had in 1983. Though Rely had been off the market for over a decade, and tampon boxes were covered with a variety of warnings, menstruating women continued to come down with TSS, particularly those who used superabsorbent products.
S
.
aureus
strain was causing nearly as many infections, ailments, and deaths in the 1990s as it had in 1983. Though Rely had been off the market for over a decade, and tampon boxes were covered with a variety of warnings, menstruating women continued to come down with TSS, particularly those who used superabsorbent products.
One could only take comfort in the fact that the disease, if quickly diagnosed and treated, was curable. Though the TSST-1 bacterium was resistant to penicillin antibiotics, it was vulnerable to other classes of the drugs.
At least, so far.
The Revenge of the Germs, or Just Keep Inventing New Drugs
DRUG-RESISTANT BACTERIA, VIRUSES, AND PARASITES
Â
Consider the difference in size between some of the very tiniest and the very largest creatures on Earth. A small bacterium weights as little as 0.00000000001 gram. A blue whale weighs about 100,000,000 grams. Yet a bacterium can kill a whale ⦠. Such is the adaptability and versatility of microorganisms as compared with humans and other so-called “higher” organisms, that they will doubtless continue to colonise 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.
âBernard Dixon, 1994
As Toxic Shock Syndrome demonstrated, the bacterial world was in a state of constant evolution and change. The mutability of bacteria, coupled with their ability to pass around and share genetic trumps in a microscopic game of cards, seemed to increasingly leave
Homo sapiens
holding losing hands.
Homo sapiens
holding losing hands.
Staphylococcus
had plenty of tricks that extended well beyond Toxic Shock Syndrome. Despite the Age of Antibiotics, staph infections remained potentially lethal. By 1982 fewer than 10 percent of all clinical staph cases could be cured with penicillinâa dramatic shift from the almost 100 percent penicillin susceptibility of
Staphylococcus
in 1952. Most strains of the bacterium accomplished the feat of penicillin resistance in the same manner as had the TSST-1 strain: by absorbing the beta-lactamase plasmid into their DNA. Once the plasmid was fully incorporated into the bacterial genome, and passed from one microbial generation to the next, physicians witnessed their patients failing to improve with therapy.
1
had plenty of tricks that extended well beyond Toxic Shock Syndrome. Despite the Age of Antibiotics, staph infections remained potentially lethal. By 1982 fewer than 10 percent of all clinical staph cases could be cured with penicillinâa dramatic shift from the almost 100 percent penicillin susceptibility of
Staphylococcus
in 1952. Most strains of the bacterium accomplished the feat of penicillin resistance in the same manner as had the TSST-1 strain: by absorbing the beta-lactamase plasmid into their DNA. Once the plasmid was fully incorporated into the bacterial genome, and passed from one microbial generation to the next, physicians witnessed their patients failing to improve with therapy.
1
Fortunately, alternative drugs existed that did not use the beta-lactam mechanism to neutralize staph, so physicians weren't alarmed. They switched en masse from penicillin to methicillin during the late 1960s, and though a smattering of hospitals in Paris, London, and throughout the United States reported apparent methicillin resistance cases, the overall outcome was positive. Once again, humanity had
Staphylococcus
on the run.
Staphylococcus
on the run.
But in the early 1980s, clinically significant strains of
Staphylococcus
emerged that were resistant not only to methicillin but to its antibiotic cousins, such as naficillin. For example, in May 1982 a newborn baby died on the neonatal ward of the University of California at San Francisco's Moffitt Hospital of a strain that was resistant to the penicillins, cephalosporins, and naficillin. The mutant strain had drifted about the hospital and the local community for three years, infected a nurse on the neonatal ward, and then found its way to three babies. The only way the hospital could prevent further cases was to aggressively treat the ward staff and babies with antibiotics to which the bacteria remained susceptible, close the ward off to new patients, retrofit all organic material on which dormant staph might lie (rubber fittings on equipment, curtains, sheets, etc.), and scrub the entire facility with disinfectants.
Staphylococcus
emerged that were resistant not only to methicillin but to its antibiotic cousins, such as naficillin. For example, in May 1982 a newborn baby died on the neonatal ward of the University of California at San Francisco's Moffitt Hospital of a strain that was resistant to the penicillins, cephalosporins, and naficillin. The mutant strain had drifted about the hospital and the local community for three years, infected a nurse on the neonatal ward, and then found its way to three babies. The only way the hospital could prevent further cases was to aggressively treat the ward staff and babies with antibiotics to which the bacteria remained susceptible, close the ward off to new patients, retrofit all organic material on which dormant staph might lie (rubber fittings on equipment, curtains, sheets, etc.), and scrub the entire facility with disinfectants.
This was, unfortunately, not an isolated event. Outbreaks of resistant bacteria inside hospitals were commonplace by the early 1980s, particularly on wards that housed the most immune-compromised patients: people who had suffered major burns, prematurely born babies, individuals with endstage cancer, people who had undergone major surgery, intensive-care patients.
Methicillin-resistant
Staphylococcus aureus
(MRSA) outbreaks increased in size and frequency worldwide throughout the 1980s.
2
By 1990, MRSA would represent a clear economic and health crisis for hospitals all over the globe. The incidence of MRSA infections and deaths would soar steadily, spreading from massive urban medical centers outward, eventually reaching to suburban clinics and rural treatment centers.
3
Staphylococcus aureus
(MRSA) outbreaks increased in size and frequency worldwide throughout the 1980s.
2
By 1990, MRSA would represent a clear economic and health crisis for hospitals all over the globe. The incidence of MRSA infections and deaths would soar steadily, spreading from massive urban medical centers outward, eventually reaching to suburban clinics and rural treatment centers.
3
In 1992 roughly 15 percent of all
Staphylococcus
strains in the United States were methicillin-resistant; nearly 40 percent of those strains isolated from patients in large American hospitals were MRSA. Significant MRSA problems were soon showing up in far-Hung locations, from rural Ethiopia
4
to Perth, Australia.
5
By 1993 only one surefire
Staphylococcus
killer would remain: vancomycin.
6
And even the reliability of vancomycin was in jeopardy, as some physicians reported the existence of MRSA strains that could not readily be cured with the last of the available anti-staph drugs.
7
Staphylococcus
strains in the United States were methicillin-resistant; nearly 40 percent of those strains isolated from patients in large American hospitals were MRSA. Significant MRSA problems were soon showing up in far-Hung locations, from rural Ethiopia
4
to Perth, Australia.
5
By 1993 only one surefire
Staphylococcus
killer would remain: vancomycin.
6
And even the reliability of vancomycin was in jeopardy, as some physicians reported the existence of MRSA strains that could not readily be cured with the last of the available anti-staph drugs.
7
Switching from inexpensive penicillins to methicillin increased drug treatment costs for a typical patient approximately tenfold; changing to vancomycin meant turning to one of the most expensive antibiotics on the market. It was a burden in the wealthy countries, but not prohibitive. The
increased cost was beyond the reach of poorer nations, however, rendering some staphylococcal infections, practically speaking, untreatable.
increased cost was beyond the reach of poorer nations, however, rendering some staphylococcal infections, practically speaking, untreatable.
Staphylococcus
was everywhere: all
Homo sapiens
, as well as some mammalian pets, had staphylococci in their bodies. Most of the time the staph one person passed to another through a handshake, or that a weekend gardener absorbed while turning up soil for a bed of tulips, was rendered harmless by the human immune system. But if the bacteria happened upon a cut, wound, burned skin area, or immune-stressed human, the infection might be extremely advantageous to the organism.
was everywhere: all
Homo sapiens
, as well as some mammalian pets, had staphylococci in their bodies. Most of the time the staph one person passed to another through a handshake, or that a weekend gardener absorbed while turning up soil for a bed of tulips, was rendered harmless by the human immune system. But if the bacteria happened upon a cut, wound, burned skin area, or immune-stressed human, the infection might be extremely advantageous to the organism.
This explained why hospitals and child care centers seemed to be particularly fertile ground for the microbes. Every employeeânurse, doctor, orderly, teacherâcould serve as a mobile unit that carried the microbes from one potential human host to another. The vast majority of hospitalized humans had surgical wounds or were suffering ailments that occupied the full attention of their immune systems; similarly, small children in day care centers could be relied upon to have plenty of scrapes, cuts, runny noses, unwashed hands, and dirty faces.
Recognizing the problem, humans living in wealthier nations adopted standardized antibiotic practices, giving the drugs, for example, to all preoperative patients to prevent postsurgical infections. And small children got antibiotics almost as a matter of routine for all manner of infections.
Yet the microbes persevered, resisting the prophylactic and treatment uses of antibiotics. In the United States in 1992 some 23 million Americans underwent surgery, nearly every one of them receiving preoperative antibiotics. Up to 920,000 of them developed postsurgical bacterial infections, the majority of which were due to
Staphylococcus,
particularly MRSA.
8
Staphylococcus,
particularly MRSA.
8
Outside day care centers and medical facilities, most dangerous
Staphylococcus
infection was acquired either at random by an ailing individual (one battling cancer, AIDS, heart disease, etc.) or an injecting drug user. In a 1986â89 Danish survey about 7 percent of community-acquired major MRSA infections were the results of sharing contaminated needles: that rate exceeded 10 percent in many inner-city areas of the United States.
9
Staphylococcus
infection was acquired either at random by an ailing individual (one battling cancer, AIDS, heart disease, etc.) or an injecting drug user. In a 1986â89 Danish survey about 7 percent of community-acquired major MRSA infections were the results of sharing contaminated needles: that rate exceeded 10 percent in many inner-city areas of the United States.
9
Super-strains of staph that were resistant to huge numbers of potential drugs existed naturally by 1990. For example, an Australian research team treated a patient infected with a strain that was resistant to cadmium, penicillin, kanamycin, neomycin, streptomycin, tetracycline, and trimethoprim. Since each of these drugs operated by specific biochemical mechanisms that were used by a host of related drugs, the Australian staph could resist, to varying degrees, some thirty-one different drugs.
10
10
In a series of test-tube studies the Australians showed that these various resistance capabilities were carried on different plasmids that could be separately passed from one bacterium to another. The most common mode of passage was conjugation: one bacterium simply stretched out its cytoplasm and passed plasmids to its partner.
Using PCR genetic fingerprinting techniques to trace back in time over 470 MRSA strains, a team of researchers from the New York City Health Department discovered that all of the MRSA bacteria descended from a strain that first emerged in Cairo, Egypt, in 1961. By the end of that decade the strain's descendants could be found in New York, New Jersey, Dublin, Geneva, Copenhagen, London, Kampala, Nairobi, Ontario, Halifax, Winnipeg, and Saskatoon. A decade later they were seen planet-wide.
11
11
Fortunately, staph wasn't resistant to vancomycin.
Not yet, anyway.
Staphylococcus
wasn't the only bacterial organism that was successfully using plasmids, jumping genes, mobile DNA, mutations, and conjugative sharing of resistance factors to overcome whatever drugs Homo sapiens threw at them.
12
In fact, by 1993 nearly every common pathogenic bacterial species had developed some degree of clinically significant drug resistance. And over two dozen of these emergent strains posed life-threatening crises to humanity, having outwitted most commonly available antibiotic treatments.
13
wasn't the only bacterial organism that was successfully using plasmids, jumping genes, mobile DNA, mutations, and conjugative sharing of resistance factors to overcome whatever drugs Homo sapiens threw at them.
12
In fact, by 1993 nearly every common pathogenic bacterial species had developed some degree of clinically significant drug resistance. And over two dozen of these emergent strains posed life-threatening crises to humanity, having outwitted most commonly available antibiotic treatments.
13
“The increasing frequency of resistance indicates the need for a stronger partnership between clinical medicine and public health,” wrote the CDC's director of bacterial research, Dr. Mitchell Cohen, in 1992.
14
“Unless currently effective antimicrobial agents can be successfully preserved and the transmission of drug-resistant organisms curtailed, the post-antimicrobial era may be rapidly approaching in which infectious disease wards housing untreatable conditions will again be seen.”
14
“Unless currently effective antimicrobial agents can be successfully preserved and the transmission of drug-resistant organisms curtailed, the post-antimicrobial era may be rapidly approaching in which infectious disease wards housing untreatable conditions will again be seen.”
NIH senior scientist Richard Krause labeled the bacterial situation “an epidemic of microbial resistance.” It seemed that new strains of bacteria were emerging everywhere in the world by the late 1980s, and their rates of emergence accelerated every year. In the United States alone, such emergences were adding an estimated $200 million a year to medical bills because of the need to use ever more exoticâand expensiveâantibiotics, and longer patient hospitalizations for everything from strep throat to life-threatening bacterial pneumonia. When the costs of extended hospital care were added, the estimated increase due to antibiotic resistant organisms topped $30 billion annually.
15
Though these trends started in huge inner-city hospital complexes, striking elderly and extremely ill patients, they had by the 1990s reached the level of universal, across-the-board threats to
Homo sapiens
of all ages, social classes, and geographic locales.
15
Though these trends started in huge inner-city hospital complexes, striking elderly and extremely ill patients, they had by the 1990s reached the level of universal, across-the-board threats to
Homo sapiens
of all ages, social classes, and geographic locales.
Jim Hensonâfamed puppeteer-inventor of the Muppetsâdied in the spring of 1990 of another common, allegedly curable, bacterial infection. An apparently new mutant strain of
Streptococcus
struck that was resistant to penicillins and possessed genes for a killer toxin very similar to that which Patrick Schlievert had discovered in the Toxic Shock Syndrome strain of S.
aureus
.
Streptococcus
struck that was resistant to penicillins and possessed genes for a killer toxin very similar to that which Patrick Schlievert had discovered in the Toxic Shock Syndrome strain of S.
aureus
.
Indeed, it was Schlievert who first spotted the new organism in 1989,
16
and dubbed the disease strep A-produced TSLS (Toxic Shock-Like Syndrome).
By the time Henson succumbedâjust a year after its discovery âlethal human cases of TSLS had been reported from Canada, England, Scandinavia, Germany, several places in the United States, and New Zealand.
17
In addition, streptococcal strains of all types were showing increasing levels of antibiotic resistance. In the early 1970s these antibiotics, particularly erythromycin and penicillin, were almost universally effective against
Streptococcus
, and the appearance of strep-related complications, such as rheumatic fever and impetigo, were marks of inadequate medical care, not antibiotic failure.
18
16
and dubbed the disease strep A-produced TSLS (Toxic Shock-Like Syndrome).
By the time Henson succumbedâjust a year after its discovery âlethal human cases of TSLS had been reported from Canada, England, Scandinavia, Germany, several places in the United States, and New Zealand.
17
In addition, streptococcal strains of all types were showing increasing levels of antibiotic resistance. In the early 1970s these antibiotics, particularly erythromycin and penicillin, were almost universally effective against
Streptococcus
, and the appearance of strep-related complications, such as rheumatic fever and impetigo, were marks of inadequate medical care, not antibiotic failure.
18
According to Columbia University antibiotics expert Dr. Harold Neu, a dose of 10,000 units of penicillin a day for four days was more than enough to cure strep respiratory infections in 1941. Then, most streptococcal infections in the United States involved bacteria of the strep A type, and the number one life-threatening complication of strep infection was scarlet fever.
That strep A strain appeared to be particularly vulnerable to penicillins and other common antibiotics, and it disappeared entirely from the clinical scene. American and European medical students of the 1960s had only picture books to refer to in order to learn what this once-common disease known as scarlet fever was.
With its ecological competitor out of the way, tough strep B strains quickly emerged, primarily among newborn babies. By the late 1970s strep B was the most serious life-threatening disease in neonatal units all over the industrialized world, and 75 percent of all infections in babies under two months of age were fatal, despite aggressive antibiotic treatment.
19
19
In the late 1980s strep A returned, with the emergence of the hearty new strain that killed Jim Henson. While strep B continued to dominate the world's baby wards, strep A struck people of all ages, and did so without any clear pattern of host vulnerability. But by 1992 the same ailment required 24 million units of penicillin a day, and might, despite such radical treatment, still be lethal.
20
20
Even more serious was the emergence of virulent, highly antibiotic-resistant strains of
Streptococcus pneumoniae,
or
Pneumococcus
. The bacteria normally inhabited human lungs, and usually did so without causing undue harm to their
Homo sapiens
hosts. If, however, a person inhaled a strain of
S
.
pneumoniae
that differed enough from those to which he or she had previously been exposed, the individual's immune system might not be able to keep the organisms in check. And any condition that weakened a host's immune system could, similarly, allow the pneumococcal population to explode.
Streptococcus pneumoniae,
or
Pneumococcus
. The bacteria normally inhabited human lungs, and usually did so without causing undue harm to their
Homo sapiens
hosts. If, however, a person inhaled a strain of
S
.
pneumoniae
that differed enough from those to which he or she had previously been exposed, the individual's immune system might not be able to keep the organisms in check. And any condition that weakened a host's immune system could, similarly, allow the pneumococcal population to explode.
Over the years subsequent to the introduction of penicillin, strains emerged that could resist common antibiotics. For example, parents and pediatricians noticed during the 1980s that their young children seemed to suffer increasingly from ear infections, and otitis media-caused hearing loss became an urgent problem. By 1990 about a third of all ear infections
in young children were due to
Pneumococcus
and nearly half those cases involved strains that were resistant to penicillins.
21
in young children were due to
Pneumococcus
and nearly half those cases involved strains that were resistant to penicillins.
21
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