Francesca Tomasi received her B.A. from the University of Chicago and is now a microbiologist.
In 1928, Alexander Fleming stumbled upon the mold that changed the world: penicillin, the first antibiotic, would forever change the course of medicine. Infections that once killed millions of people and kept the average human life expectancy near 50 were cured almost overnight. In 1967, William H. Stewart, the US Surgeon General, told the White House “It’s time to close the books on infectious diseases, declare the war against pestilence won, and shift natural resources to such chronic problems as cancer and heart disease.” It was a medical fairy tale. But now there’s a sequel.
We are on the brink of a post-antibiotic era. You’ve heard it before, and you’ll hear it again. The over-prescription and misuse of antimicrobial drugs over the last nine decades created the perfect environment for bacteria to become resistant to most first-line, many second-line and even some third-line antibiotics. In fact, some diseases now can only be treated using the latter category of drugs. These are the more powerful, more toxic drugs that were only supposed to be around as a last resort. Alexander Fleming warned us about it in his Nobel Prize acceptance speech: "The time may come when penicillin can be bought by anyone in the shops. Then there is the danger that the ignorant man may easily underdose himself and by exposing his microbes to non-lethal quantities of the drug make them resistant."
So how do bacteria become drug resistant as in Fleming’s hypothetical illustration? Bacteria reproduce asexually. That is, a single microbe splits into two identical microbes, which turn into two more each, and so on. This happens quickly, and it happens imperfectly: factors both intrinsic and extrinsic to bacteria result in little mistakes taking place here and there when the organism makes new copies. For this reason, bacteria occasionally split into two different bacteria. If an environmental stressor such as an antibiotic is introduced, and one of the microbes happens to have a mutation that makes it resistant to the antibiotic, this microbe will successfully grow exponentially, leaving the drug-susceptible bugs in the dust.
Other times, however, bacteria have the ability to give each other genes they can use to survive an antibiotic attack. This is broadly known as horizontal gene transfer, or HGT. Horizontal gene transfer occurs both within and among species, making it potentially more powerful than a single species relying on mutations to live forever. HGT is driven by three mechanisms: transformation, transduction, and conjugation. Transformation refers to the introduction, uptake, and expression of foreign genetic material. Transduction instead is mediated by viruses, which transfer DNA from one bacterium to another. Third, conjugation is the transfer of DNA via a plasmid from a donor to a recipient cell upon cell-to-cell contact. A plasmid is a structure that can replicate independently of the bacterial chromosome, typically in the form of a small circular DNA strand. In fact, plasmids are so mobile that scientists use them all the time to manipulate organisms in research projects.
Given the immense prevalence of bacteria on Earth on the order of 1028 (1) and the even higher prevalence of viruses on the order of 1031 (2), it is safe to assume that horizontal gene transfer is an incredibly powerful mechanism without which any ecological system would be dramatically different, for better or for worse. What better way to underscore this point than with a story? New Delhi Metallo-ß-lactamase-1, or NDM-1, is a bacterial gene that confers broad-spectrum beta-lactam resistance, the type of antibiotic that penicillin is. Carbapenems are another type of beta-lactam drug, and these are supposed to be reserved for only hard-to-treat infections. As a result, the rise and spread of NDM-1 present a serious clinical challenge.
NDM-1 was first isolated in 2009 from a Swedish patient of Indian origin who was infected with antibiotic-resistant Klebsiella pneumoniae (3). Whether this was the first case of NDM-1 in the world or simply the first identified one is uncertain, but epidemiologists have concluded that NDM-1 did in fact first develop in India. In May of 2010, a case of E. coli expressing NDM-1 was identified in the United Kingdom in a patient who had visited India 18 months prior in order to undergo dialysis (3). In June 2010, three cases of Enterobacteriaceae isolates were identified in the United States in patients who, according to the Center for Disease Control, had all received recent medical care in India (3). In July of the same year, a cluster of cases arose in Chennai, India, with NDM-1-expressing Acinetobacter baumannii (3). In August 2010, The Lancet Infectious Diseases compiled a report on the gene, naming 37 cases in the UK, 44 in Chennai, 26 in Haryana, and 73 in other sites across Pakistan and India (4). Further study found that most of these strains carried NDM-1 on plasmids, implicating horizontal gene transfer through conjugation – rather than independent point mutations – as the source of the geographical explosion of NDM-1 (3). Within that same month, Canada reported its first case of an NDM-1 superbug in Brampton, Ontario, followed by a few other confirmed cases in British Columbia and Alberta (3). In September, Japan detected its first case of an NDM-1 strain in a patient who had previously been hospitalized on a trip to India (3). Epidemiological and environmental analyses have detected 20 different bacterial strains with NDM-1 just in drinking water across New Delhi, providing a clear pool for natural horizontal gene transfer (5).
These accounts show that both international travel and individuals’ use of multiple countries' healthcare systems served as a catalyst for the rapid spread of NDM-1. In today's highly interconnected world, horizontal gene transfer may occur more readily than ever before, facilitated by more frequent contact between organisms. Furthermore, natural reservoirs such as lakes or streams from which many people obtain drinking water are interactive environments for bacteria, too, to obtain survival genes. Rapid identification and isolation of patients harboring bacteria with NDM-1 have so far prevented serious outbreaks as the gene jumps across strains and geographic regions, but surveillance mechanisms need to be maintained for consistent prevention (3).
By 2014, most bacteria isolated worldwide with NDM-1 had originated from people colonized or infected in India who then traveled elsewhere (3). The emergence of NDM-1 in the Indian subcontinent is largely due to the fact that broad-spectrum antibiotics there do not require a prescription, given underlying economic incentives (3). As a result, strong selective pressure acted on bacteria to evolve and spread NDM-1 quickly and efficiently. Given the volume of modern international travel and the stubbornness of superbugs to antibiotic treatment, it is likely that NDM-1-bearing bacteria will continue to spread worldwide, making even more species hops.
The ability for physically diverse bacteria to successfully inhabit a new niche, such as a human body introduced with beta-lactam drugs or a body of water with runoff that contains excreted or disposed-of antibiotics, is largely driven by horizontal gene transfer, which is more rapid and geographically influential than useful mutations occurring from scratch in individual species. The emergence of multidrug resistance in every corner of the world within decades of the introduction of antibiotics is just more evidence of the potency and ubiquity of horizontal gene transfer when it confers adaptive traits.
The quantitative potential of horizontal gene transfer events is puzzling when compared to the size of bacterial genomes, which rarely exceed a few thousand genes. There are two possible explanations for this: either the actual rate of gene transfer is low, or the rate of maintenance of transferred sequences is low. Bacterial genomes are too small to contain arbitrary genetic elements that serve no purpose. As a result, despite the possibility that most transfer events go unnoticed due to their inability to become permanent, the beneficial events have become established across many species and have a huge effect on bacterial evolution. The most obvious effect, of course, is the transfer of antibiotic resistance. Ecological communities are defined by the positive and negative interactions between a variety of species, and mobile elements are highly favorable when it comes to facing a transient selective pressure like that imposed by antibiotics.
Horizontal gene transfer accounts for much more than the acquisition of antibiotic resistance. Plenty of microbes both in natural ecosystems and within organisms are constantly adapting to changing environments, and take advantage of genes from their own neighbors. As such, horizontal gene transfer provides the ultimate venue for bacterial diversification by the re-assortment of existing capabilities, but also for homogenization against negative pressures. Interspecific consistency in relative genome sizes, however, indicates that microbes are programmed to delete non-essential DNA: bacterial genomes can only maintain a finite amount of information, and the ability to sample foreign DNA provides a spectacular means to add, remove, and rearrange genes in a manner contingent upon their usefulness and essentialness.
So remember this the next time you go to the doctor, and make sure you do in fact have a bacterial infection before taking antibiotics. If you do take them, take the whole course even if you feel better before you’ve taken all the pills. Antibiotics were a miracle almost a hundred years ago and a given today, but we’re traveling backward in our ability to treat common infectious diseases. And this time, the solution won’t be something as simple as penicillin: all the easy drugs have been taken.
Schloss PD, Handelsman J. Status of the microbial census. Microbiol Mol Biol Rev. 2004;68(4):686-91.
Nature Reviews Microbiology 9, 628 (September 2011) doi:10.1038/nrmicro2644
Fomda BA, Khan A, Zahoor D. NDM-1 (New Delhi metallo beta lactamase-1) producing Gram-negative bacilli: emergence & clinical implications. Indian J Med Res. 2014;140(5):672-8.
Struelens MJ, Monnet DL, Magiorakos AP, Santos O'Connor F, Giesecke J. New Delhi metallo-beta-lactamase 1-producing Enterobacteriaceae: emergence and response in Europe. Euro Surveill. 2010;15(46)
Berrazeg M, Diene S, Medjahed L, et al. New Delhi Metallo-beta-lactamase around the world: an eReview using Google Maps. Euro Surveill. 2014;19(20)
Sekizuka T, Matsui M, Yamane K, et al. Complete sequencing of the bla(NDM-1)-positive IncA/C plasmid from Escherichia coli ST38 isolate suggests a possible origin from plant pathogens. PLoS ONE. 2011;6(9):e25334.
Kumarasamy KK, Toleman MA, Walsh TR, et al. Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a molecular, biological, and epidemiological study. Lancet Infect Dis. 2010;10(9):597-602.
Ochman H, Lawrence JG, Groisman EA. Lateral gene transfer and the nature of bacterial innovation. Nature. 2000;405(6784):299-304.
Nevo O, Zusman T, Rasis M, Lifshitz Z, Segal G. Identification of Legionella pneumophila effectors regulated by the LetAS-RsmYZ-CsrA regulatory cascade, many of which modulate vesicular trafficking. J Bacteriol. 2014;196(3):681-92.
Mary Melati is a sophomore at Cornell University studying biological sciences.
The relationship between Gram-positive bacterium Streptococcus pyogenes (Group A Streptococcus; GAS) and the human host is the leading cause of human acute bacterial pharyngitis, more commonly known as strep throat.
GAS follows a general bacterial disease cycle, which includes transmission, attachment, infection, colonization, and reproduction. GAS transmission can happen directly between hosts. Humans are the largest maintenance population of GAS. In fact, one quarter of all people who experience sore throat (1/3 of them school-aged children) have GAS pharyngitis (Danchin et al., 2007). The advent of child care, which concentrates many children in one place, also leads to higher rates of GAS transmission in young children (Danchin et al., 2007). Moreover, individuals are twice more likely to have a secondary case of GAS pharyngitis from a family member than from a primary case in the community (Danchin et al., 2007). In other words, GAS bacteria can spread widely from normal human interaction. Unhygienic habits such as coughing or sneezing without covering the mouth or using a disposable tissue can also lead to greater spread of the pathogen indirectly through the environment. Because GAS can grow to a high density in saliva, its chances of transmission to new hosts are high, especially since host mouth-and-hand and hand-and-surrounding interactions occur so frequently each day (Tart et al., 2007). Bar-Dayan et al. (1997) found that food-borne transmissions can also happen. Once it enters the host, GAS targets host immune defense mechanisms and attach to the host pharynx, or throat. Having survived entry into the human host, GAS then proceeds to invade the host cells to maximize its fitness and adapt to the host environment. GAS proliferates in the host pharynx, where saliva contains a rich medium that supports bacterial growth. In this way, GAS has a long-lasting and persistent infection and successful colonization in human hosts.
The host body actively retaliates the GAS infection with a slew of internal changes aimed at disrupting the pathogen’s environment. However, GAS overcomes these changes through rapid and extensive remodeling of its transcriptome, or all the RNA molecules expressed from its genome. Graham et al. (2005) found that within 30 minutes after being placed in human blood ex vivo, GAS had upregulated 716 and downregulated 425 gene transcripts. This finding highlights the aptitude of GAS to adjust and proliferate in different host environments. GAS can even regulate their levels of virulence, or ability to cause disease, to balance with its host. GAS virulence factors are all directed towards overcoming innate host defenses and cause severe cellular damage. However, it may be detrimental for the bacteria to cause so much damage that the host dies before the pathogen can transmit to another host. Hence, in a vital evolutionary tradeoff, GAS must regulate the transcription of its virulence factors in order to maximize its life and persist long enough in the host to disperse to other hosts.
GAS does not only change its virulence factors to modulate its ability to make the human host sick, but also its serotypes, or characteristic bacterial features that induce a host immune response. Virtaneva et al. (2003) showed that in one patient infected with two strains of serotypes, differences are present even in the transcript level, making it difficult to predict and treat against specific strains of GAS. There is also a continuous pouring in of new serotypes from the environment, which ultimately leads to random genetic drift that also makes it difficult for host immune responses to detect GAS.
Studies on GAS antibiotic resistance reveal a bleak answer to why GAS is difficult to treat. Internalization of GAS within host cells enables the pathogen to evade host defenses and offers protection against antibiotics such as penicillin, which does not enter cells (Tart et al., 2007). Moreover, antibiotics could fail because GAS bacteria can survive intracellularly for days before the host cell dies, which means GAS can persist in the host for longer than the prescribed dosage of antibiotics (Courtney et al., 2002). A Wake Forest School of Medicine study also suggested high asymptomatic streptococcal carriage in pediatric patients, which highlights the difficulty of knowing when to isolate a patient carrying the pathogen since it is difficult to detect the presence of GAS in the first place (Roberts et al., 2012). It is clear that GAS bacteria is opportunistic and can easily evade human immune responses.
This situation calls for an effective management plan in the future. First, there must be effective detection of the pathogen. Then a doctor may prescribe an antibiotic schedule. But to deal with antibiotic resistance and antigenic variation trends, this disease management plan will also look at other strategies, such as immune and non-immune mediated killing of pathogen and management outside the body.
Detection. A quicker detection of GAS in infected individuals can lead to an earlier administration of medical treatment, which will consequently lead to less chance of spread to other individuals. This strategy is important on a temporal scale because it shortens the period during which an infected individual can spread the pathogen to another person and can decrease the unnecessary prescription of antibiotics. In other words, this management strategy will target the earlier stages of the GAS disease cycle in an attempt to treat it quickly and effectively before GAS colonizes the host.
Current detection techniques include using rapid strep tests and throat cultures (McIsaac et al., 2004). Rapid strep tests entail the patient’s throat being swabbed for a sample of mucus. Then, the sample is applied to a nitrocellulose film on which GAS antigens would bind with antibodies and induce a visible color change, signaling a positive result for GAS (Cohen et al., 2013). On the other hand, throat cultures also entail the patient’s throat being swabbed, but the sample is then cultured in lab for two days to see the presence and growth of GAS bacteria. While the throat culture method is generally more accurate and sensitive, the rapid testing without confirmatory cultures is more cost effective (McIsaac et al., 2004).
Antibiotics. Antibiotics are originally derived from soil bacteria and have been molded for human benefit to kill off other competing bacteria in human systems. Though antibiotics can be highly effective against GAS pathogens, they must still be avoided because of ever increasing drug-resistant GAS strains.
Using antibiotics to eradicate GAS pathogen is efficient and relative low cost. It can also be crucial in a spatial scale, since the more GAS bacteria get degraded in a host system by the antibiotics, the smaller chance it has of proliferating. Shulman et al. (2012) noted that patients with GAS-induced diseases should be treated with appropriate antibiotics at an appropriate dose for a duration of about 10 days to eradicate the pathogen from the pharynx. The recommended drugs against GAS bacteria are penicillin, amoxicillin, or cephalosporin. Unlike with many other bacteria, a pencillin-resistant GAS has never been documented (Shulman et al., 2012). On the other hand, tetracyclines (antimicrobials) should not be used because of high prevalence of resistant strains (Shulman et al., 2012). If patients are allergic to penicillin, macrolides are often prescribed. However, frequent use of macrolides leads to GAS resistance, so in the past years, use of macrolides prescription in pediatric population has decreased (Gagliotti et al., 2015).
Because of the generally increasing number of resistant strains of bacteria, it is important to use less and less antibiotics and look at alternative strategies to manage the GAS pathogen-induced diseases. Interestingly, better rapid strep tests can allow family doctors to persuade patients that negative rapid test results (hence, perhaps a viral infection) means antibiotics are not required (Worrall et al., 2007). Contrary to popular belief, symptoms caused by bacterial sore throat do not go away faster with antibiotics than if they were untreated. This issue raises questions about whether doctors should be prescribing antibiotics for strep throat at all. Doctors are not necessarily the only antagonists in this situation, since patients also pressure doctors to give them unnecessary antibiotic prescriptions because that is what they expect. A solution to this problem could be to better educate the public about antibiotics so that antibiotics usage keeps decreasing, an effort the CDC and other public health organizations are currently working very hard to address.
Vaccines and the Body. One alternative solution to prevent the prescription of antibiotics is the vaccine. Vaccines work by exposing the individual to some part of the pathogen so that the host immune system can create antibodies to detect that pathogen in the future and thus effectively and quickly protect the body from the pathogen. Effective vaccination can avoid the need of medicine for GAS-induced diseases altogether, because the individual host will be well-prepared to combat the pathogen. Some obstacles to this strategy could be its acceptance and its availability to all members of the population. Recently, there is a focus for an M-protein based vaccine because M-protein is a variable, multi-functional adhesive GAS protein with the ability to bind to many host plasma proteins (Batzloff et al., 2004). Increasing host antibodies which can detect GAS virulence factors like M-protein will lead to quicker eradication of GAS and less disease. Ji et al. (1997) also found that intranasal immunization produced significant mucosal and systematic antibody responses that could detect and eliminate the foreign substance faster and faster each time it is administered. Perhaps nasal or oral vaccines are more effective than injections so that the mild virulence factors travel directly to the typical site of infection for a faster host response. Batzloff et al. (2004) argue that a greater library of antigens and protective mechanisms should be mandatory and pursued for long-lasting efficacious GAS vaccine strategy. Moreover, Brandt et al. (2000) found that vaccines should be administered early in childhood to lead to greater adulthood immunity and enhanced detection of the pathogens.
Bacteriophages. An alternative method of controlling GAS is using commensal bacteria already in the body to compete with GAS. A strength of this method is that it is more natural and avoids the use of antibiotics. Batzloff et al. (2004) found that some commensal bacteria secrete inhibitory substances that work against GAS colonization. Perhaps infusion of large numbers of other commensal bacteria to the body can also work to control GAS by commensal bacteria outcompeting GAS bacteria in the throat so that GAS cannot proliferate. However, a possible problem with this method is that introducing new bacteria to the body may cause an imbalance in the microbiome and cause other diseases. A way to avoid this is to infuse more of the commensal bacteria already inside the body in equal ratio to the normal conditions. Furthermore, bacteriophages, viruses that parasitizes bacteria by infecting it and reproducing inside it, can be used to manage GAS. There seems to be little research done on bacteriophages in the last decade, but in the past Fischetti and Zabriskie (1968) found that GAS bacteriophages absorb into GAS cell walls effectively and irreversibly. In other words, bacteriophages could work commensally with the body to degrade GAS in the pharynx very quickly.
Surgery. Another idea is to physically remove infected tissue. Pus can be drained from the infection or use surgical procedures to remove all infected cells so that GAS cannot spread (Steer et al., 2012). However, this method receives a lot of criticism because it is neither time nor cost efficient and seems unnecessary especially with the effective drugs currently available.
Outside the Body. So far the focus has been on the biological aspects of management inside the body. However, the host environment is also important to consider in managing the disease because it can lead to prevention of GAS infection. First, all cases of suspected infection should be identified and notified to local health protection specialists (Steer et al., 2012). This is important so that infected individuals can be treated sooner and avoid spreading the pathogen to others, especially since every day places are very interactive. Along the same lines, when there is a breakout of strep throat, there should be additional throat screening of individuals (Ridgway & Allen, 1993). This is to ensure that the pathogen spread is cut short and those infected can be let known as soon as possible so that they know to avoid other individuals until they have recovered. In addition, patients with GAS should be placed in isolation for a minimum of 24 hours until the throat cultures show negative or their rapid strep tests no longer detect the presence of GAS (Steer et al., 2012). Environmental contamination of everyday objects may also provide a source of infection of patients (Ridgway & Allen, 1993). Thus, environmental cleaning and hand washing should be more regulated to prevent spread by touching every-day objects (Steer et al., 2012; Ridgway & Allen, 1993). This is one of the most useful preventive measures with any infectious disease.
There are many aspects of GAS infection biology that need to be considered for a disease management plan against strep throat. The bacteria can be managed before it even begins its disease cycle by properly controlling the host environment, which includes hand-washing and isolating infected humans to prevent transmission. Though the human body is well equipped and prepared to combat infection, GAS bacteria can easily adapt its gene expression to better cope with the unfavorable host environment. The use of antibiotics should be discouraged because it could lead to GAS antibiotic resistance. This is what led to the idea that competition from other bacteria could manage GAS pathogen in the throat led researches to explore bacteria phages as a way of management. Though it is still an under-written topic, investment in research regarding this could lead to rewarding results for an alternative form of disease management. Other current strategies of managing GAS disease includes strengthening immune mediated killing of the pathogen, such as by using vaccines. New vaccines can be effective, though it may be very expensive to develop and difficult to keep updated with increasing GAS antigenic variation.
This management plan can also be used for similar bacterial infections, such as Bordetella pertussis, which causes whooping cough. With existing opportunities to use various developing methods to manage GAS, GAS-induced diseases can one day be controlled effectively.
Orly Farber received her B.A. from the University of Chicago and now does allergy research.
In The Republic of Therapy, medical anthropologist and physician Dr. Vinh-Kim Nguyen traces the local and international responses to the HIV epidemic in French-speaking West Africa. Nguyen’s work spans the years between 1994 and 2000, a pivotal period in the global AIDS epidemic. This period begins with the discovery of effective treatments for HIV and ends with the reversal of the international consensus that those treatments should not be used in Africa. Until 2000, international organizations deemed antiretroviral drugs too expensive and too difficult to formally administer in Africa, but not in North America. Consequently, millions of individuals selectively lived and died with HIV/AIDS. As Nguyen writes, his work aims to “explore and expose the obscene inequality and insidious logic that values lives differently” (4). He asks: who lived, who died, and why?
Nguyen points to a paradox, which he terms “triage.” With the advent of life-saving drugs, international and local organizations tasked with responding to the epidemic in West Africa unwittingly triaged, sorting those who should receive treatment and live from those who would go without treatment and, likely, die. In its original conception, triage was a military tactic employed to preserve manpower. It was a calculation used to allocate scarce resources and medical care to those who were combat-ready rather than to those who needed care most. In civilian use, triage serves an alternate purpose, providing care first to those who need it urgently in order to maximize the number of lives saved. Therefore, in medicine, there exists a precedent for deploying triage to different ends--whether that end be to return the healthiest soldiers to the battlefield or to save high-risk civilians. Those ends, Nguyen argues, are based on criteria that value life differently under different circumstances.
The Republic of Therapy elucidates how triage evolved during the HIV epidemic in the West African countries Burkina Faso and Côte d'Ivoire, where Nguyen worked as an HIV physician, community organizer, and activist. Using ethnographic and historical accounts, Nguyen walks his readers through his argument: the HIV epidemic and its struggle over access to treatment ushered in a new form of political power, a power he terms “therapeutic sovereignty.” The informal and formal processes deployed to negotiate who should receive treatment during the AIDS epidemic constitute an exercise of sovereignty; they reveal how and by whom power over life was exercised.
The Republic of Therapy chronicles the efforts to organize communities with HIV and focuses on the emergence of testimonials as a tool for triage. Although political and economic circumstances barred a much-needed influx of HIV treatment, drugs did trickle into West Africa and, the more visible one made his or her illness, the more likely he or she was to acquire drugs. Having a good story about living with HIV could grant access to treatment. Furthermore, as Nguyen writes, “[P]roducing ‘real’ people with HIV came to be seen as evidence that ‘something is being done’” (23). As such, across the continent, Africans were urged to give testimonials, to produce narratives of their illnesses--often, for financial compensation. The bulk of The Republic of Therapy explores how privileging those testimonials for triage--even, Nguyen suggests, rendering them valuable capital--disrupted local HIV communities and altered the course of treatment in West Africa.
Nguyen’s argument culminates with the assertion that, “[T]riage is not just political, it is politics. More fundamentally, triage is about sovereignty” (176). Triage embodies a battle over resources and power that, ultimately, dictates life or death. Through his ethnographic narratives and the history of the African AIDS epidemic, Nguyen constructs a framework that transcends its own historical moment. He reminds his readers to examine all global efforts to “heal” and interventions to “rescue” with a critical, political eye. He reminds us to contend with the powers at work when decisions of life and death are being made. In global health politics, we must pause and ask: who lives, who dies, and why?