Missing Microbes: How the Overuse of Antibiotics Is Fueling Our Modern Plagues (35 page)

to one in three births in 2011:
In 1981, of one hundred women coming to the hospital to give birth, the rates in nineteen industrialized countries ranged from 5 percent in Czechoslovakia to 18 percent in the United States. (See F. C. Notzon et al., “Comparisons of national Cesarean-section rates,”
New England Journal of Medicine
316 [1987]: 386–89.) More recently, the rates in the United States climbed to 30.5 percent between 2002 and 2008. (See J. Zhang et al., “Contemporary Cesarean delivery practice in the United States,”
American Journal of Obstetrics and Gynecology
203 [2010]: 326.e1–10.) For births in 2011, the CDC reported a national rate of 32.8 percent, a more than 80 percent increase in thirty years from our already high rate.

13 percent in the Netherlands:
According to the World Health Organization (2008), the highest rates in the world are in countries like Brazil (46 percent), Iran (42 percent), and the Dominican Republic (42 percent). The lowest country is the Netherlands (about 13 percent), and Scandinavia, in general, has rates much lower than that of the rest of the world. Is the medical care in Brazil, Iran, and the Dominican Republic more advanced than it is in northern Europe, or are other factors at play?

and all will get intravenous penicillin:
Unless the mother is allergic to penicillin, in which case another antibiotic will be substituted.

acquired from his or her mother:
“Prevention of Perinatal Group B Streptococcal Disease,” Revised Guidelines from CDC, 2010, MMWR,
Recommendations and Reports
59(RR10): (Nov. 19, 2010): 1–32.

For our review of the subject of current antibiotic use in pregnancy, see W. J. Ledger and M. J. Blaser, “Are we using too many antibiotics during pregnancy?”
British Journal of Obstetrics and Gynecology
120 (2013): 1450–52; I. A. Stafford et al., “Efficacy of maternal and neonatal chemoprophylaxis for early-onset group B streptococcal disease,”
Obstetrics and Gynecology
120 (2012): 123–29. Although overall national rates of early-onset sepsis have diminished substantially, rates of early-onset GBS sepsis were unchanged after thirteen years of prophylaxis at one major medical center, reflecting a host of accumulated problems.

get the procedure:
Episiotomy rates vary widely from country to country (see I. D. Graham et al., “Episiotomy rates around the world: an update,”
Birth
32 [2005]: 219–23). For an older, very comprehensive review, see G. Carroli and J. Belizan, “Episiotomy for vaginal birth,”
Cochrane Database of Systematic Reviews
3, no. CD000081 (2007): DOI: 10.1002/14651858.CD000081. Also see F. Althabe et al., “Episiotomy rates in primiparous women in Latin America: hospital-based descriptive study,”
British Medical Journal
324 (2002): 945–46.

first silver nitrate:
Dr. Albert Barnes developed a dilute solution of silver nitrate around the turn of the twentieth century. It was called Argyrol and was used to treat gonorrheal eye infections that lead to blindness. He sold his company in 1929 for millions on the eve of the stock market crash. The proceeds from Argyrol formed the foundation for the renowned Barnes Foundation art collection in Philadelphia.

among the millions of births a year:
We now screen pregnant women for HIV so that with proper prevention we can almost eliminate the risk of its transmission to the baby.

9. A FORGOTTEN WORLD

depending on context:
Theodor Rosebury, a student and researcher of the oral microbiota beginning in the 1930s, had great insight into the biological relationships that we have with our residential organisms. His seminal works include:
Microorganisms Indigenous to Man
(New York: McGraw Hill, 1962) and
Life on Man
(London: Seeker and Warburg, 1969). In 1962 he coined the neologism
amphibiosis.
Today’s scientists like the concept so much that they use it with a more modern name. They call the microbes pathobionts rather than the amphibionts originally described by Rosebury. But since it is the same idea, I give Rosebury credit and use his terms throughout.

in the continent’s jungles and highlands:
From Venezuelan patients who underwent upper gastrointestinal endoscopy, María Gloria Domínguez Bello (later my wife) and her colleagues in Venezuela obtained gastric biopsies from those living in urban areas near the coast and from deep in the interior in Puerto Ayacucho, the capital of Amazonas State. The
H. pylori
strains (that were isolated in pure culture by Chandra Ghose, a graduate student in my lab) from the biopsies of some of the Amerindian patients in Puerto Ayacucho had genetic signatures that were closely related to strains from present-day people in China and Japan. In contrast, the strains isolated from the coastal patients had the signatures of present-day Europeans and Africans. The most parsimonious explanation for these findings is that the ancestors of the Amerindians had East Asian strains of
H. pylori
in their stomachs when they crossed the Bering Strait and that the descendants of those people and their
H. pylori
strains flourished until Columbus and the European conquest. With the decimation of the Amerindians and the introduction of
H. pylori
strains arriving in the stomachs of Europeans and their African slaves, there were few remaining Amerindian strains in coastal areas. But deep in the interior, these strains persisted, and the secret of their ancestry could be revealed by DNA sequencing. (See C. Ghose et al., “East Asian genotypes of
Helicobacter pylori
strains in Amerindians provide evidence for its ancient human carriage,”
Proceedings of the National Academy of Sciences
99 [2002]: 15107–11.) Subsequently, we worked with an international team that made sense of a worldwide collection of
H. pylori
isolates to understand how the organisms spread around the world in the past 58,000 years. (See D. Falush et al., “Traces of human migration in
Helicobacter pylori
populations,”
Science
299 [2003]: 1582–85.) In later studies, Gloria and her colleagues deciphered the whole genome sequence of one of the strains from Puerto Ayacucho, showing its uniqueness in the
H. pylori
universe. (See S. P. Mane et al., “Host-interactive genes in Amerindian
Helicobacter pylori
diverge from their old world homologs and mediate inflammatory responses,”
Journal of Bacteriology
192 [2010]: 3078–92.)

organisms from fecal specimens:
The methods used for isolation of
Campylobacter
were developed by Martin Skirrow, a clinical microbiologist in Worcester, England. It was his paper (M. Skirrow, “Campylobacter enteritis: a new disease,”
British Medical Journal
2 [1977]: 9–11), which I read in July 1977 shortly after I had been caring for the patient with
C. fetus
infection (see chapter 1), that brought me into the field of medical research. Later we modified Skirrow’s medium (M. J. Blaser et al., “Campylobacter enteritis: clinical and epidemiologic features,”
Annals of Internal Medicine
91 [1979]: 179–85) to improve isolation of these fastidious organisms.

never bothered again by
H. pylori
:
B. J. Marshall et al., “Attempt to fulfil Koch’s postulates for pyloric campylobacter,”
Medical Journal of Australia
142 (1985): 436–39.

the same relationships in their own studies:
B. J. Marshall et al., “Prospective double-blind trial of duodenal ulcer relapse after eradication of
Campylobacter pylori
,”
Lancet
2 (1988): 1437–42. An Irish group (J. G. Coghlan et al., “Campylobacter pylori and recurrence of duodenal ulcers—a 12-month follow-up study,”
Lancet
2 [1987]: 1109–11) published similar findings more than a year earlier but, despite more than five hundred citations, their paper was mostly forgotten, and Marshall et al. received most of the scientific credit. Later studies in the United States (D. Y. Graham et al., “Effect of treatment of
Helicobacter pylori
infection on the long-term recurrence of gastric or duodenal ulcer: a randomized, controlled study,”
Annals of Internal Medicine
116 [1992]: 705–8) and in Austria (E. Hentschel et al., “Effect of ranitidine and amoxicillin plus metronidazole on the eradication of
Helicobacter pylori
and the recurrence of duodenal ulcer,”
New England Journal of Medicine
328 [1993]: 308–12) cemented the finding that antibiotic treatments that eradicated
H. pylori
markedly improved the natural history of peptic ulcer disease, often leading to a cure.

based on their having antibodies to the organism:
Guillermo received his doctoral degree based on studies we did together exploring the nature of the antigens of
C. jejuni
and
C. fetus
strains. By 1985 I was convinced that this new “campylobacter” could be medically important, so we began to apply the same biochemical and immunological approaches to it. (See G. I. Pérez-Pérez and M. J. Blaser, “Conservation and diversity of
Campylobacter pyloridis
major antigens,”
Infection and Immunity
55 [1987]: 1256–63; G. I. Pérez-Pérez et al., “
Campylobacter pylori
antibodies in humans,”
Annals of Internal Medicine
109 [1988]: 11–17.)

a very good lead:
We were particularly interested in comparing people with ulcers with those who had gastritis only. Among the seventy-four patients who had gastritis (meaning inflammation of the stomach), about 60 percent had antibodies to the CagA protein. But each of the thirty-one patients who had duodenal ulcers had these antibodies. (See T. L. Cover et al., “Characterization of and human serologic response to proteins in
Helicobacter pylori
broth culture supernatants with vacuolizing cytotoxin activity,”
Infection and Immunity
58 [1990]: 603–10.) For the first time, we had a blood test that could highlight people who were at high risk for getting ulcers. About a year and a half later, a group in England led by Jean Crabtree (“Mucosal IgA recognition of
Helicobacter pylori
120 kDa protein, peptic ulceration, and gastric pathology,”
Lancet
338 [1991]: 332–35) identified the same protein with the same proportions of people having antibodies when they had gastritis (~60 percent) and ulcers (100 percent) as we did. At that point, I was certain we had identified a critical
H. pylori
protein—two independent groups, across the ocean, with nearly identical observations—not a chance event. The confirmation makes a discovery a real discovery.

for cytotoxin-associated gene:
As often happens in science, a second group, from the Biocene Company in Siena, Italy, was following a similar strategy. Even though we recognized the association with ulcers earlier and cloned the gene earlier, once they got started, they more rapidly uncovered many of the same associations. By chance we learned that they had identified the same gene and that they had given it a different name. Guided by a shared spirit of scientific collaboration, we eventually agreed on a common name, CagA, because those strains produced unusually high levels of the cytotoxin that injures human cells (cytotoxin-associated gene A). This collaboration saved the field from the uncertainty and divisiveness that occur when there are two names for the same thing. (See M. Tummuru et al., “Cloning and expression of a high-molecular-mass major antigen of
Helicobacter pylori:
evidence of linkage to cytotoxin production,”
Infection and Immunity
61 [1993]: 1799–809; A. Covacci et al., “Molecular characterization of the 128-kDa immunodominant antigen of
Helicobacter pylori
associated with cytotoxicity and duodenal ulcer,”
Proceedings of the National Academy of Sciences
90 [1993]: 5791–95.)

we discovered and named VacA:
T. L. Cover et al., “Divergence of genetic sequences for the vacuolating cytotoxin among
Helicobacter pylori
strains,”
Journal of Biological Chemistry
269 (1994): 10566–73; and T. L. Cover and M. J. Blaser, “Purification and characterization of the vacuolating toxin from
Helicobacter pylori
,”
Journal of Biological Chemistry
267 (1992): 10570–75, described the discovery of the protein, which we called VacA, and then we called the gene
vacA.
VacA was discovered as a toxin, but I now think of it as a signaling molecule, a way in which
H. pylori
tells the host what it wants the host to do. One effect of VacA is to tone down the immune response of T-cells, as a way of ensuring its own survival. (See B. Gebert et al., “
Helicobacter pylori
vacuolating cytotoxin inhibits T lymphocyte activation,”
Science
301 [2003]: 1099–1102.) If it is too toned down, there might not be enough inflammation for
H. pylori
, and thus not enough nutrients. So it has to strike a balance. Many years ago, Tim and I had the notion that CagA is the accelerator and VacA is the brake. It stills looks like a good idea.

But two years later:
In 1989 we published an article in the
New England Journal of Medicine
on the relationship of
H. pylori
to gastritis (C. P. Dooley et al., “Prevalence of
Helicobacter pylori
infection and histologic gastritis in asymptomatic persons,”
New England Journal of Medicine
321 [1989]: 1562–66), again confirming the utility of our blood test. After he read that article, Dr. Nomura wrote to me. We communicated mostly by mail and sometimes by telephone. Although we worked closely on a number of studies that were very important to both of us, and worked very well together, we did not actually meet in person for about ten years!