Missing Microbes: How the Overuse of Antibiotics Is Fueling Our Modern Plagues (34 page)

follow the safer course:
Recommendations by the American Academy of Pediatrics (AAP) regarding antibiotic use have been in place for a long time. (See S. F. Dowell et al., “Principles of judicious use of antimicrobial agents for pediatric upper respiratory tract infections,”
Pediatrics
101, suppl. 1 [1998]: 163–65.) An important update was issued last year: A. S. Lieberthal et al., “The diagnosis and management of acute otitis media,”
Pediatrics
131 (2013): e964–99.

patients with pneumonia:
W. S. Tillett et al., “The treatment of lobar pneumonia with penicillin,”
Journal of Clinical Investigation
4 (1945): 589–94.

antibiotics to people in the United States:
L. Hicks et al., “US outpatient antibiotic prescribing, 2010,”
New England Journal of Medicine
368 (2013): 1461–62.

in the United States and other developed countries:
For antibiotic use in other developed countries, for example, see M. Sharland, “The use of antibacterials in children,”
Journal of Antimicrobial Chemotherapy
60, suppl. 1 (2007): i15–i26.

MRSA stands for methicillin-resistant
Staphylococcus aureus
:
MRSA infections were noted in the 1960s, almost immediately after antibiotics like methicillin were used to treat people with
Staph aureus
infections. But such drugs were mostly used in hospitalized patients, and MRSA strains were largely confined to the hospital. But in recent years, MRSA has been spreading in the community. These days, among serious staph infections in people coming to emergency rooms for treatment, about 80 percent are due to MRSA. (G. J. Moran et al., “Methicillin-resistant
S. aureus
infections among patients in the emergency department,”
New England Journal of Medicine
355 [2006]: 666–74.) This is a dramatic change from the past. Resistance in
Staph
is spreading so greatly that the natural divisions between hospital and community have been blurred. But in fact the dominant MRSA strains are different. There are two largely separate populations of MRSAs, each adapted to its own ecological niche but each driven and selected by the enormous antibiotic pressures in both hospital and community.

“a tiny little thing that I can not see”:
Brandon Noble, IDSA website:
http://www.idsociety.org/Brandon_Noble/
.

NCAA Division III championships:
Ricky Lannetti, MRSA awareness website:
http://www.mrsaawareness.com/mrsaawareness/Home.html
.

7. THE MODERN FARMER

an endless game of chemical warfare:
See extended discussion of the arms races in chapter 2.

which have similar core structures:
See V. D’Costa et al., “Antibiotic resistance is ancient,”
Nature
477 (2011): 457–61; and K. Bhullar et al., “Antibiotic resistance is prevalent in an isolated cave microbiome,”
PLOS ONE
7 (2012): e34953.

resistance from our activities:
By studying large fish, which feed on smaller fish and are living on top of the food chain, scientists can most easily assess antibiotic contamination in the ocean. A recent survey found resistance in all six sites sampled and in all eight fish species studied. (See J. K. Blackburn et al., “Evidence of antibiotic resistance in free-swimming, top-level marine predatory fishes,”
Journal of Zoo and Wildlife Medicine
41 [2010]: 7–15.)

animals fed a drug-free diet:
The idea that antibiotics could be useful as growth promoters was first developed in the 1940s, shortly after their first deployment to treat infections in both humans and animals: P. R. Moore and colleagues (“Use of sulfasuxidine, streptothricin, and streptomycin in nutritional studies with the chick,”
Journal of Biological Chemistry
165 [1946]: 437–41) are generally credited for this observation. W. J. Visek (“The mode of growth promotion by antibiotics,”
Journal of Animal Sciences
46 [1978]: 1447–69) wrote an outstanding review of the accumulated knowledge about thirty-five years ago; in the light of today’s knowledge, the observations seem very accurate. Also see P. Butaye et al., “Antimicrobial growth promoters used in animal feed: effects of less well-known antibiotics on gram-positive bacteria,”
Clinical Microbiology Reviews
16 (2003): 175–88; E. Ozawa, “Studies on growth promotion by antibiotics,”
Journal of Antibiotics
8 (1955): 205–14.

a particularly interesting study from 1963:
M. E. Coates et al., “A comparison of the growth of chicks in the Gustafsson germ-free apparatus and in a conventional environment, with and without dietary supplements of penicillin,”
British Journal of Nutrition
17 (1963): 141–50.

which animals and why:
The Pew Charitable Trust has focused on antibiotic use in food animals. In February 2013 it reported on record-high sales of antibiotics for meat and poultry production. It found that in 2011 nearly 80 percent (30 million) of the nearly 38 million pounds of antibiotics consumed each year in the United States was for animals sold for meat and poultry production. See
http://www.pewhealth.org/other-resource/record-high-antibiotic-sales-for-meat-and-poultry-production-85899449119
. See also a commentary by former FDA commissioner David Kessler, “Antibiotics and the meat we eat,”
New York Times
op-ed page (March 27, 2013).

121 of 132
Yersinia
samples:
Consumer’s Union tested 198 pork chops and ground-pork products purchased at retail in six U.S. cities. Of these, 69 percent were positive for
Yersinia enterocolitica
, an important food-borne pathogen that causes diarrheal and systemic illnesses, most of whose isolates were antibiotic resistant, and of those 39 percent were multiply resistant (
Consumers Reports
, January 2013).

bacteria resistant to antibiotics:
2011 Retail Meat Report from the National Antimicrobial Resistance Monitoring System. See it at:
http://www.fda.gov/downloads/AnimalVeterinary/SafetyHealth/AntimicrobialResistance/NationalAntimicrobialResistanceMonitoringSystem/UCM334834.pdf
.

an indication of fecal contamination:
The issues from the 2011 NARMS report are highlighted by the Environmental Working Group in its own report and analysis of the findings: D. Undurraga, “Superbugs invade American supermarkets,”
http://static.ewg.org/reports/2013/meateaters/ewg_meat_and_antibiotics_report2013.pdf
.

forbade the practice in 1999:
M. Casewell et al., “The European ban on growth-promoting antibiotics and emerging consequences for human and animal health,”
Journal of Antimicrobial Chemotherapy
52 (2003): 159–61. The final ban on all growth-promoting antibiotics in the EU went into effect in 2006. But in some countries, farmers circumvented the ban with higher rates of treatments for “infections,” which is allowed. Vigilance by regulators is needed.

patterns of antibiotic resistance:
In fall of 2013 a large outbreak of
Salmonella heidelberg
from chickens was one of the latest episodes. The outbreak involved hundreds of people in more than twenty states. Many of the victims were hospitalized because of bloodstream infections caused by these multiply antibiotic-resistant organisms. See CDC, “Multistate outbreak of multidrug-resistant
Salmonella
heidelberg infections linked to Foster Farms brand chicken,”
http://www.cdc.gov/salmonella/heidelberg-10-13/index.html
.

from contact with their animals:
E. M. Harrison et al., “Whole genome sequencing identifies zoonotic transmission of MRSA isolates with the novel
mecA
homologue
mecC
,”
EMBO Molecular Medicine
5 (2013): 509–15.

especially sulfa drugs and tetracycline:
In a November 1990 report to Congress, the General Accounting Office (GAO) indicated that twenty antibiotics were approved for use in dairy cows. It reported results of FDA testing of milk on retail store shelves in several surveys from 1988 to 1990. In all of them, antibiotics, particularly sulfa drugs (including sulfamethazine, which is not approved for use in cattle), were found. Reported rates ranged from 5 to 86 percent, and the GAO questioned whether the FDA tests were sufficiently sensitive. See GAO RCED 91-26,
http://www.gao.gov/products/RCED-91-26
and
http://www.gao.gov/assets/220/213321.pdf
. In China, sulfas and quinolone antibiotics were detected in 40 percent and 100 percent, respectively, of milk sampled in 2011. Levels were reported as low but still widely present (R.-W. Han et al., “Survey of tetracyclines, sulfonamides, sulfamethazine, and quinolones in UHT milk in China market,”
Journal of Integrative Agriculture
12 [2013]: 1300–305).

from treatment plants, and tap water:
C. Xi et al., “Prevalence of antibiotic resistance in drinking water treatment and distribution systems,”
Applied and Environmental Microbiology
75 (2009): 5714–18.

8. MOTHER AND CHILD

the toll of misery mounted relentlessly:
Some doctors prescribed thalidomide to men for its sedative effects. It was safe because men absolutely could not get pregnant. One of these doctors was Jacob Sheskin, my grandmother’s first cousin, a dermatologist who cared for patients with leprosy. When he gave thalidomide to several men with advanced leprosy to help them sleep, he observed that one type of their terrible skin lesions improved. He conducted careful clinical trials and proved to a skeptical world that this was true (J. Sheskin, “Thalidomide in the treatment of lepra reactions,”
Clinical Pharmacology and Therapeutics
6 [1965]: 303–6; and J. Sheskin, “The treatment of lepra reaction in lepromatous leprosy. Fifteen years’ experience with thalidomide,”
International Journal of Dermatology
6 [1980]: 318–22). Sheskin was a clinician and did not understand the basis for thalidomide’s action, but later others did, and they went on to extend its uses. Today thalidomide and a family of related drugs are used in cancer therapy as a mainstay for certain conditions, including multiple myeloma and other tumors. If someone predicted this fifty years ago, everyone would have assumed it to be a very sick form of joke.

Did not improve pregnancy outcomes in the least:
From the early 1940s through the 1960s, diethylstilbestrol (DES) was prescribed for pregnant women to reduce the risk of pregnancy complications and losses. However, beginning in the early 1950s, studies began to appear in the obstetrics literature indicating that DES was not effective in promoting better pregnancy outcomes. For example, a widely cited clinical trial that was performed in Chicago showed no improvement in adverse pregnancy outcomes in women who were randomly assigned to receive DES or to serve as controls. (W. J. Dieckmann et al., “Does the administration of diethylstilbestrol during pregnancy have therapeutic value?”
American Journal of Obstetrics and Gynecology
66 [1953]: 1062–81.) By the time that DES usage stopped in the late 1960s, millions of pregnant women (and thus their babies) had received the drug. See also R. J. Apfel and S. M. Fisher,
To Do No Harm: DES and the Dilemmas of Modern Medicine
(New Haven: Yale University Press, 1986).

clear-cell adenocarcinoma of the vagina:
A. L. Herbst et al., “Adenocarcinoma of the vagina: association of maternal stilbestrol therapy with tumor appearance in young women,”
New England Journal of Medicine
284 (1971): 878–81.

(33.3 percent vs. 15.5 percent):
R. Hoover et al., “Adverse health outcomes in women exposed in utero to diethylstilbestrol,”
New England Journal of Medicine
365 (2011): 1304–14. As indicated on its website, “the DES Follow-Up Study investigates the long-term health consequences associated with exposure to diethylstilbestrol (DES). Since 1992, the National Cancer Institute in collaboration with research centers throughout the United States has been conducting the DES Follow-Up Study of more than 21,000 mothers, daughters, and sons.”

is coming under question:
As discussed in the chapter 3 notes, recently investigators have pointed out that in many animal species, the transfer of microbes from mother to child begins before birth, while their baby is still in the womb (Funkhauser and Bordenstein, “Mom knows best”). There isn’t much information yet about humans, but studies should address this in the next few years. If this occurs, then the importance of antibiotic use during pregnancy may rise.

women who have been studied:
O. Koren et al., “Host remodeling of the gut microbiome and the metabolic changes during pregnancy,”
Cell
150 (2012): 470–80. This is the first part of the study in Ruth Ley’s lab that is discussed below.

rapidly colonizes the mother’s skin:
M. G. Domínguez-Bello et al., “Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns,”
Proceedings of the National Academy of Sciences
107 (2010): 11971–75.

foundation of microbes:
In a study of the gut microbiota of healthy people in three places—the United States, Malawi, and Venezuela (Amerindians)—Yatsunenko and her colleagues, including my wife, Gloria, catalogued which microbes were present across people of all ages (see chapter 1). Initially I was surprised, but the more I thought about it, the more sense it made. This was consistent with my hypotheses about the importance of the early-life microbiota.

the rate is about 4 percent:
In Järna, a Swedish community near Stockholm, families try to sustain as natural a lifestyle as possible. They minimize antibiotic use, and virtually all of their babies are breast fed. They try to have C-sections only when absolutely required: their rate, at 4 percent, is lower than the rest of Sweden (about 17 percent), and a lot lower than that of the United States (32 percent). See J. S. Alm et al., “An anthroposophic lifestyle and intestinal microflora in infancy,”
Pediatric Allergy and Immunology
13 (2002): 402–11.