—Bernard Dixon, 1994
I
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.
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 penicillin—a 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.
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.
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
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 Ethiopia4 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.
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.
This explained why hospitals and child care centers seemed to be particularly fertile ground for the microbes. Every employee—nurse, doctor, orderly, teacher—could 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
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 1986–89 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
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
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
“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.â€
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 exotic—and expensive—antibiotics, 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.
Jim Henson—famed puppeteer-inventor of the Muppets—died 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.
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 succumbed—just a year after its discovery —lethal 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
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
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.
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
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.
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
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
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 residents—the 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
Of course, such ailments as rheumatic fever, strep pneumonia, and general respiratory infections with Streptococcus in young children had never disappeared—or even significantly diminished—In 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 tract—which were usually viral—were milder, while deep lung involvement signaled potentially lethal bacterial disease.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
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.
“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.â€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.
The Coming Plague Page 64