Missing Microbes: How the Overuse of Antibiotics Is Fueling Our Modern Plagues (33 page)

only as long as the person was consuming the special diet
: L. A. David et al., “Diet rapidly and reproducibly alters the human gut microbiome,”
Nature
(2013): DOI 10.1038/nature12820.

millions of unique genes:
Just as the human microbiome has been the focus of “big science” in the United States, another large group coalesced in Europe, the MetaHit consortium. They have done important work that is both unique and complementary to the findings of the HMP. J. Qin et al. (“A human gut microbial gene catalogue established by metagenomic sequencing,”
Nature
464 [2010]: 59–65) showed the huge range in composition from person to person. M. Arumugan et al. (“Enterotypes of the human gut microbiome,”
Nature
473 [2011]: 174–80) postulated that humans could be divided into three major types based on the composition of their gut microbiome, perhaps analogous to human blood types. Whether the typing scheme will stand up over time and whether the types are relatively stable in an individual host remain to be determined.

bacterial genes in subjects’ guts varied dramatically:
In a recent paper by the MetaHit group (E. Le Chatelier et al., “Richness of human gut microbiome correlates with metabolic markers,”
Nature
[2013]: 500, 541–46), 292 subjects were studied in terms of their gut microbial gene counts and their metabolic status. The results clearly show the gene count for the two groups: high for about three-quarters of the subjects and low for the remaining quarter. On average the people in these two groups differ significantly in their metabolic status. Those in the low-gene-count group were much more likely to have the metabolic syndrome, a constellation of findings associated with obesity, diabetes, hardening of the arteries, and high blood pressure. One question that could not be resolved by the study is which came first, low gut microbial gene count or the metabolic syndrome. But a companion paper showed that dietary interventions that improve metabolic status raise the gene count (A. Cotillard et al., “Dietary intervention impact on gut microbial gene richness,”
Nature
500 [2013]: 585–88).

staggering ten million–fold:
Qin et al., “A human gut microbial gene,” showed this.

never before encountered:
See I. Cho and M. J. Blaser, “The human microbiome: at the interface of health and disease,”
Nature Reviews Genetics
13 (2012): 260–70, where we more fully discuss the concept of contingency organisms.

cows and their rumen bacteria:
The rumen is the specialized, first stomach in ruminants like cows and sheep. It is a specialized compartment in which the microbes that are present ferment the ingested feed, allowing its energy to be digested by the host. The rumen is also a prime example of symbiosis, and the resident microbes include bacteria, fungi, protozoa, and viruses.

if you played fair and square:
See M. J. Blaser and D. Kirschner, “The equilibria that allow bacterial persistence in human hosts,”
Nature
449 (2007): 843–49, for a fuller exposition of these ideas about equilibrium relationships between our microbes and us.

4. THE RISE OF PATHOGENS

causing a form of encephalitis:
Encephalitis means inflammation of the brain. It is usually an acute infection caused by a virus or a bacterium, but may be due to other organisms, or may be noninfectious.

eat their prey from within:
D. Quammen,
Spillover: Animal Infections and the Next Human Pandemic
(New York: W. W. Norton & Company, 2012).

and killed fifty:
The outbreak came out of nowhere, and uncounted thousands were exposed to the contaminated sprouts. A medical description of the outbreak was published in U. Buchholz et al., “German outbreak of
Escherichia coli
O104:H4 associated with sprouts,”
New England Journal of Medicine
365 (2011): 1763–70; and a description of the characteristics of the strain in C. Frank et al., “Epidemic profile of Shiga-toxin-producing
Escherichia coli
O104:H4 outbreak in Germany,”
New England Journal of Medicine
365 (2011): 1771–80; and how it all happened in M. J. Blaser, “Deconstructing a lethal foodborne epidemic,”
New England Journal of Medicine
365 (2011): 1835–36.

epidemic diseases began to take off:
W. McNeill,
Plagues and Peoples
(New York: Anchor, 1977).

might infect from one-third to one-half of those exposed for the first time:
A nineteenth-century accounting of what happened when measles came to an isolated island was by Peter Panum in his classic “Observations Made During the Epidemic of Measles on the Faroe Islands in the Year 1846” (
Bibliothek for Laeger
, Copenhagen, 3R., 1 [1847]: 270–344). There also have been more recent observations, e.g., when a boat landed in Greenland in the 1940s with a crew member who had measles.

18 deaths every hour:
World Health Organization data on measles and deaths,
http://www.who.int/mediacentre/factsheets/fs286/en/
. Measles, the relatively mild and nearly universal childhood disease in the developed world until an effective vaccine was introduced in the 1990s, shows a very different face in developing countries. There, in the setting of malnourishment, immunodeficiency, and concurrent infections, measles is a killer. Each year, more than one hundred thousand children die as a result of measles. It is a calamity and one that vaccine can prevent. But the problems in deploying the vaccine to all in need have been political, logistic, and economic.

human population of 500,000 people:
Decades before it entered the mainstream, Francis Black was one of the first to think about island biogeography in terms of the spread of infectious diseases in humans. (See F. L. Black, “Measles endemicity in insular populations: critical community size and its evolutionary implication,”
Journal of Theoretical Biology
11 [1966]: 207–11.)

the measles virus quickly spread from person to person:
Panum, “Observations Made During the Epidemic of Measles.”

grain bins and trash heaps:
M. J. Blaser, “Passover and plague,”
Perspectives in Biology and Medicine
41 (1998): 243–56.

broke out in Kinshasa, Zaire:
Not only in the fourteenth century but also in this one, plague still visits cities when the conditions are ripe for it. In Africa and India there has been urban plague in recent years. See, for example, G. Butler et al., “Urban plague in Zaire,”
Lancet
343 (1994): 536; and details of a continued endemic focus: P. Boisier et al., “Epidemiologic features of four successive annual outbreaks of bubonic plague in Mahajanga, Madagascar,”
Emerging Infectious Diseases
8 (2002): 311–16.

Twenty percent of children did not survive:
Several different techniques were used to measure mortality. Extensive work was done by Samuel H. Preston and Michael R. Haines on estimating childhood mortality. See the chapter “New Estimates of Child Mortality During the Late-Nineteenth Century” in their book
Fatal Years: Child Mortality in Late-Nineteenth Century America
(Princeton: Princeton University Press, 1991), 49–87.

5. THE WONDER DRUGS

difficult-to-treat malignancy:
In several studies, working with colleagues in Hawaii, at the Mayo Clinic, and in Japan, we had shown that people carrying that bacterium in their stomachs were more likely to have or to later develop stomach cancer (A. Nomura et al., “
Helicobacter pylori
infection and gastric carcinoma among Japanese Americans in Hawaii,”
New England Journal of Medicine
325 [1991]: 1132–36; N. Talley et al., “Gastric adenocarcinoma and
Helicobacter pylori
infection,”
Journal of the National Cancer Institute
83 [1991]: 1734–39; M. J. Blaser et al., “
Helicobacter pylori
infection in Japanese patients with adenocarcinoma of the stomach,”
International Journal of Cancer
55 [1993]: 799–802). Other studies, conducted in England by David Forman and in California by Julie Parsonnet, showed very similar results. In a couple of years, we changed what people knew about the cause of stomach cancer, then and now the number-two cause of cancer death in the world (after lung cancer). We now know that more than 80 percent of all stomach cancer cases can be attributed to
H. pylori
(see chapter 9).

from white blood cells and from saliva:
Fleming discovered lysozyme, a constituent of innate immunity, in saliva. It is an enzyme that by breaking the chemical bonds that hold the cell walls of bacteria together effectively dissolves (lyses) bacterial cells. It was a major discovery (in retrospect) of one of the arms of our innate (inborn) immunity. We have evolved a variety of molecules, like lysozyme, that have antagonistic activity against whole classes of bacteria. They reduce contamination on our mucosal surfaces, our coastlines, and also help clear tissues of invading bacteria. But most important, Fleming’s discovery of lysozyme prepared him to recognize the lytic activities possessed by the accidental mold that landed on his plates a few years later. (A. Fleming, “On a remarkable bacteriolytic element found in tissues and secretions,”
Proceedings of the Royal Society, Series B
93 [1922]: 306–17.)

They had been inoculated with staph:
“Staph” is a nickname used by health professionals to refer to
Staphylococcus
. Usually this is in reference to
Staph aureus,
a major pathogen, rather than “
Staph epi
” (
S. epidermidis
), an important colonizer of the skin, with low virulence.u
sed molds to treat infected wounds:
Gloria’s grandmother, who lived in rural Spain in the early twentieth century, would use moldy bread to help infections heal; it was common knowledge among the peasants, but never explored for how it worked.

After publishing his results:
A. Fleming, “On the antibacterial action of cultures of a penicillium, with special reference to their use in isolation of B. influenzae,”
British Journal of Experimental Pathology
10 (1929): 226–36.

the first sulfonamide:
Sulfonamidochrysoidine, the red dye called Prontosil, was shown by Domagk in 1932 to protect mice from
Strep
. It had actually been discovered more than twenty years earlier, but its medical use was not tested then. In 1935, a French group found that Prontosil was a pro-drug, metabolized to sulfanilamide, the active agent.

but not good enough:
Co-trimoxazole, the drug that was successfully used to treat my case of paratyphoid fever, was actually a derivative of those original sulfa drugs. But they worked much better in combination than did the early forms of the drugs in the 1930s and ’40s.

a way of growing the penicillium molds:
When I later visited the Pfizer plant and research center in Groton, Connecticut, in the mid-1990s, the air was redolent with the odor of molasses. Why that sweet characteristic smell? Oceangoing ships from the West Indies would come up the Thames River, and each would dock with its hold filled with molasses, which was used as the main source of food for giant vats of the
Penicillium
mold that itself manufactured the life-saving penicillin.

made by one living form to fight against another:
Penicillin, the first antibiotic, was produced by a mold as an antibacterial substance. The sulfa drugs were made by chemical synthesis in a factory. They are not technically antibiotics, because they are synthetic, but we use the term antibiotics generically to include both true antibiotics and chemically synthesized agents (same for fluoroquinolones, like cipro).

6. THE OVERUSE OF ANTIBIOTICS

5.5 million stoves:
The statistics about our prosperity and pent-up demand in 1945–1949 come from the Public Broadcasting System’s show
The American Experience
and the episode “The Rise of American Consumerism.”

derives from these ultracontagious human viruses:
See T. M. Wassenaar and M. J. Blaser, “Contagion on the Internet,”
Emerging Infectious Diseases
8 (2002): 335–36, for a discussion of the parallels between infectious diseases and so-called computer viruses, the malware that is transmissible from person to person (or rather from computer to computer).

after a couple of weeks:
For a natural history of cough in URIs, see: S. F. Dowell et al., “Appropriate use of antibiotics for URIs in children, Part II: Cough, pharyngitis and the common cold,”
American Family Physician
58 (1998): 1335–42.

to ward off rheumatic fever:
The purpose of antibiotics for treatment of children with strep throat or what appears to be strep throat is complex. In S. T. Shulman et al., (“Clinical practice guideline for the diagnosis and management of Group A streptococcal pharyngitis: 2012. Update by the Infectious Diseases Society of America,”
Clinical Infectious Diseases
55 [2012]: e86–102), the IDSA guidelines committee makes important recommendations that I paraphrase: they note that testing for Group A strep (GAS) usually is not recommended for children or adults who have an acute sore throat with clinical features that strongly suggest a viral cause (e.g., cough, runny nose, hoarseness, and mouth ulcers). Diagnostic studies for GAS are usually not indicated for children under three years old because acute rheumatic fever is rare in children under three, and the incidence of strep throat is uncommon in this age group. Laboratory confirmation is essential in making a precise diagnosis because physicians often greatly overestimate the probability that GAS is the cause of sore throat. A test that is negative for GAS provides reassurance that the patient’s sore throat likely has a viral cause. While treatment early in the course leads to a more rapid clinical cure in patients with acute GAS pharyngitis and decreases transmission of GAS to other children, the predominant rationale for treatment of this self-limited illness is the prevention of acute rheumatic fever and other complications. The committee states that efforts to identify GAS carriers are not ordinarily justified, nor do carriers generally require antimicrobial treatment because they are unlikely to spread strep throat to their close contacts and are at little or no risk for developing acute rheumatic fever.