Missing Microbes: How the Overuse of Antibiotics Is Fueling Our Modern Plagues (39 page)

overall picture of drug-resistant bacteria in the United States:
“CDC Threat Report 2013: Antibiotic resistance threats in the United States, 2013,” at
http://www.cdc.gov/drugresistance/threat-report-2013/
.

fending off disease-causing bacteria:
In their initial experiments, Marjorie Bohnhoff and her colleagues showed that the dose of
Salmonella
required to infect half of the exposed mice went from about 100,000 bacterial cells to 3, following a one-day exposure to the antibiotic streptomycin. (M. Bohnhoff et al., “Effect of streptomycin on susceptibility of intestinal tract to experimental
Salmonella
infection,”
Proceedings
of the Society for Experimental Biology and Medicine
86 [1954]: 132–37.) In later studies, the team extended the work, showing that penicillin was just as effective as streptomycin, that they could enhance susceptibility of mice to a
Staphylococcus
species that was incapable of colonizing by itself, and that injecting the antibiotic into tissues had no effect, thus implicating the normal gut bacteria in the protective effect and their depletion by antibiotics in promoting infections. (M. Bohnhoff and C. P. Miller, “Enhanced susceptibility to
Salmonella
infection in streptomycin-treated mice,”
Journal of Infectious Diseases
111 [1962]: 117–27.) These and further observations are more than fifty years old, but they have been largely forgotten.

160,000 people became ill and several died:
C. Ryan et al., “Massive outbreak of antimicrobial-resistant salmonellosis traced to pasteurized milk,”
Journal of the American Medical Association
258 (1987): 3269–74.

found in the human gut and on human skin:
M. Sjölund et al., “Long-term persistence of resistant
Enterococcus
species after antibiotics to eradicate
Helicobacter pylori
,”
Annals of Internal Medicine
139 (2003): 483–87; and M. Sjölund et al., “Persistence of resistant
Staphylococcus epidermidis
after a single course of clarithromycin,”
Emerging Infectious Diseases
11 (2005): 1389–93.
Staphylococcus epidermidis
is a very common type of
Staphylococcus
that colonizes the human skin, and it has much less potential to be a pathogen than
S. aureus
. Change in its abundance is a good indicator of perturbations of the skin environment.

a large number of much less common ones:
Fundamental studies have been done in the last few years describing the outlines of the populations of residential bacteria in our bodies, as well as the genes they carry. For an introduction into this area, see C. Huttenhower et al., “Structure, function and diversity of the healthy human microbiome,”
Nature
486 (2012): 207–14; and J. Qin et al., “A human gut microbial gene catalogue established by metagenomic sequencing,”
Nature
464 (2010): 59–64.

microbial diversity and the genes that accompany it:
T. Yatsunenko et al. found that adults in the United States carried 15–25 percent fewer bacterial species in their intestines than did people who were from Malawi, or were Amerindians in Venezuela, respectively (T. Yatsunenko et al., “Human gut microbiome viewed across age and geography,”
Nature
486 [2012]: 222–27). Le Chattlier and colleagues found that a large proportion of Europeans had about 40 percent fewer bacterial genes than Europeans with a full complement of genes. Those with low gene numbers were much more likely to be obese (E. Le Chatelier et al., “Richness of human gut microbiome correlates with metabolic markers,”
Nature
500 [2013]: 541–46). Although these data are consistent with our idea that depletion of our resident microbes predisposes to obesity (M. J. Blaser and S. Falkow, “What are the consequences of the disappearing human microbiota?”
Nature Reviews Microbiology
7 [2009]: 887–94), the data do not yet permit ascertaining the direction of causality.

16. SOLUTIONS

I recommended that she start antibiotics immediately:
Lyme disease is caused by
Borrelia burgdorferi
, a bacterium that lives mostly in rodents but can be transmitted by ticks to larger mammals like deer and us.

it kills bacteria on contact:
Triclosan, an antimicrobial and antifungal agent, has been used since the late 1960s to prevent hospital-acquired infections. It was put into underarm deodorants in the 1970s to reduce microbial populations that contribute to human body smells. Today triclosan is in thousands of products: soaps, toothpaste, pizza cutters, mouthwash, clothing, cleaning supplies, mattresses, and some flooring—anywhere you might want to reduce bacterial or fungal counts. You also see little dispensers of hand sanitizers not only in hospitals but also in grocery stores, offices, classrooms, conference centers, hotels, gyms, in fact, everywhere. As advertisers vilify germs, the public slathers on the triclosan and many products with similar antibacterial effects. Evidence that triclosan is affecting the bacterial communities that live on us is growing. See S. Skovgaard et al., “
Staphylococcus epidermidis
isolated in 1965 are more susceptible to triclosan than current isolates,”
PLOS ONE
16 (2013): e62197; D. J. Stickler and G. L. Jones, “Reduced susceptibility of
Proteus mirabilis
to triclosan,”
Antimicrobial Agents and Chemotherapy
52 (2008): 991–94; and A. E. Aiello et al., “Relationship between triclosan and susceptibilities of bacteria isolated from hands in the community,”
Antimicrobial Agents and Chemotherapy
48 (2004): 2973–79.

are being prescribed annually to U.S. children:
G. Chai et al., “Trends of outpatient prescription drug utilization in U.S. children, 2002–2010,”
Pediatrics
130 (2012): 23–31. Of the top eight drugs given to U.S. children in 2010, five were antibiotics, accounting for more than 41 million individual courses. In steady state, just these five antibiotics would account for about ten courses per child during the first eighteen years of life, and the evidence suggests that we have improved in recent years, so the rate was probably higher in the past. Four of the five are beta-lactam antibiotics, the descendants in a sense of pencillin, and the other was azithromycin, the “Z-pak.” Interestingly, the other three drugs in the top-eight list, accounting for 13 million courses, are mostly used for asthma (see chapter 11).

people living in western states:
L. Hicks et al., “US outpatient antibiotic prescribing, 2010,”
New England Journal of Medicine
368 (2013): 1461–62.

the highest rate of antibiotic use:
O. Cars et al., “Variation in antibiotic use in the European Union,”
Lancet
357 (2001): 1851–53. France had more than fourfold higher use than nearby Netherlands.

“only when necessary”:
V. Blanc et al., “‘Antibiotics only when necessary’ campaign in the Alpes-Maritimes District: no negative impact on invasive infections in children in the community 1998–2003,”
Presse Med
37 (2008): 1739–45. Use has fallen by about half (B. Dunais et al., “Antibiotic prescriptions in French day-care centres: 1999–2008,”
Archives of Disease in Childhood
96 [2011]: 1033–37).

204
And in Sweden:
In response to the U.S. study, Swedish investigators summarized their country’s antibiotic use in 2012. The differences are striking. Not only is the aggregate usage less than half (47 percent) of ours, but in the first three years of life, the most crucial period, on average Swedish children are receiving less than one and a half courses of antibiotics versus about four in U.S. children. We are not seeing higher death rates in Swedish children (in fact they are lower), nor more hearing deficits. The regional variation is also less, the difference between the extremes of urban Stockholm (408/1000) and the rural north (315/1000) about 30 percent. See A. Ternhag and J. Hellman, “More on U.S. outpatient antibiotic prescribing, 2010,”
New England Journal of Medicine
369 (2013): 1175–76. These numbers tell us that major reductions in prescribing can be readily accomplished.

for patients with cancer:
My dad had a low-grade lymphoma diagnosed in his late eighties. He did well on no treatment until about five years later, when he developed a severe form of anemia. Now treatment was needed. After receiving an antibody for a protein on the surface of his malignant cells, he responded immediately and well. In total, he received four weekly injections while sitting in a chair watching TV for a few hours each time. The treatment was fantastic, but the cost, $110,000, was huge. He needed three more of these courses over the next couple of years, and now, nearly five years later, he is fine. He paid his insurance premiums all of those years and made his contributions to Social Security as well. Treatment with this designer drug definitely extended both the quality and quantity of his life. Pharmaceutical companies and hospitals can make large returns this way as long as insurance plans still pay. He has a relatively uncommon condition. But to treat millions of infections in young children with designer drugs of the kind I outlined would break the bank; a different economic is needed.

by identifying specific agents:
X. Hu et al., “Gene expression profiles in febrile children with defined viral and bacterial infection,”
Proceedings of the National Academy of Science
s 110 (2013): 12792–97.

which organism is causing the trouble:
A. Zaas et al., “A host-based RT-PCR gene expression signature to identify acute respiratory viral infection,”
Science Translational Medicine
5 (2013): 203ra126.

even higher than it is in the United States:
L. Dong, “Antibiotic prescribing patterns in village health clinics across 10 provinces of Western China,”
Journal of Antimicrobial Chemotherapy
62 (2008): 410–15. Hospitals can mark up the price of antibiotics sold to patients, providing financial incentives for their overuse. One estimate is that Chinese patients have more than double the antibiotic use of U.S. patients, and on pig farms, it is four times more. In a survey of large pig farms Y.-G. Zhu et al. found 149 different antibiotic-resistance genes, often at extremely high concentrations (Y.-G. Zhu et al., “Diverse and abundant antibiotic resistance genes in Chinese swine farms,”
Proceedings of the National Academy of Sciences
110 [2013]: 3435–40).

no one really knows what causes it:
Diverticulitis is a complication of diverticulosis, a condition with finger-size or smaller out-pouching in the colon. Usually, diverticulosis has no symptoms, and is mostly associated with aging, but occasionally it leads to diverticulitis. As in the patient described, it can be a painful illness with fever, due to inflammation of the wall of the out-pouch.

a much stronger scientific base for their efficacy:
A few probiotics have been successful in treating or preventing infectious diseases. We have limited evidence that probiotics can help prevent
C. diff
infection, and possibly protect against serious infections due to the particularly virulent
E. coli
(O157:H7) strains (K. Eaton et al., “A cocktail of non-pathogenic bacteria naturally occurring in the digestive tract of healthy humans can protect against a potentially lethal
E. coli
infection [EHEC 0157:H7],” abstract presented at the 113th Annual Meeting of the American Society of Microbiology, Denver, CO, May 2013). Eaton and her colleagues gave EHEC to mice colonized by six normal human commensals of the gut or not colonized at all and found that there was no toxin production in the former group but high levels in the latter. These findings suggest possible probiotic candidates for the prevention or treatment of serious EHEC infections.

pivotal and attention-getting study:
Solid evidence that fecal transplantation works to cure patients with recurrent
C. diff
infections (E. van Nood et al., “Duodenal infusion of donor feces for recurrent
Clostridium difficile,
”
New England Journal of Medicine
368 [2013]: 407–15).

not far-fetched to think:
R. A. Koeth et al., “Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis,”
Nature Medicine
19 (2013): 576–85; W. H. W. Tang et al., “Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk,”
New England Journal of Medicine
368 (2013): 1575–84.

ruling was quite reasonable:
A group of physicians and scientists (including myself) was asked by the American Gastroenterological Association to comment on the ruling. Our consensus was that it was appropriate, and we discussed the reasoning and implications. See G. Hecht et al., “What is the value of an FDA IND for fecal microbiota transplantation to treat
Clostridium difficile
infection?”
Clinical Gastroenterology and Hepatology
(2014), in press.

can teach us the key principles?:
I. Pantoja-Feliciano, “Biphasic assembly of the murine intestinal microbiota during early development,”
ISME Journal
7 (2013): 1112–15. Ida, who studied for her PhD with Gloria, examined the relationship of the microbiota in mice in relation to their mother’s vagina and intestine. In earliest life, the gut organisms of the pups looked like those of their mother’s vagina. While they were nursing, they had a very restricted microbiota dominated by a few major bacteria, like lactobacillus, and then after they were weaned, the profile changed again and resembled that of their mother’s intestine. In a few short weeks, Gloria’s group had recapitulated the early-life development of the intestinal residents of human children.

Rob Knight and José Clemente:
Rob Knight, a very tall, thin biochemist originally from New Zealand who heads a large research group in Colorado, has been brilliant in the creation of software programs to analyze the complexity of the microbiome and to deconvolute it. José Clemente, originally from Spain, came to work with Rob via Japan and now has his own lab in New York. Rob had come in on a conference and was staying with us. José took the subway down. I was getting ready to take the train up to Brown to speak about my own work. Still I couldn’t resist listening in on them, and witnessing the discoveries for myself.