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Antibiotic Resistance in Aquatic Environments of Rio de Janeiro, BrazilFelipe Hernandes Coutinho1, Leonardo Henriques Pinto1, Ricardo Pilz Vieira1, Orlando Bonifacio Martins1, Gigliola Rhayd Boechat Salloto2, Deborah de Oliveira Santoro2, Maysa Mandetta Clementino2 and Alexander Machado Cardoso3[1] Federal University of Rio de Janeiro - UFRJ, Rio de Janeiro, Brazil[2] Oswaldo Cruz Foundation - FIOCRUZ, Rio de Janeiro, Brazil[3] East Region Universitary Center -UEZO, Rio de Janeiro, Brazil1.
Scanning electron micrograph of methicillin-resistant Staphylococcus aureus and a dead human neutrophil, June 2006. On a sunny June day in 2014, I returned home from a walk in my neighborhood with what I thought were mosquito bites on my leg. MRSA outbreaks have become distressingly common among athletes, both amateur and professional. I got a prescription for an antibiotic that MRSA is not supposed to be resistant to, but it didn’t help, and my infection continued to spread. MRSA first showed up in the United Kingdom in 1961, shortly after methicillin was introduced, and it soon spread around the world.
I often get asked where I picked up MRSA and whether I had been to a hospital in the days before my infection. But the truth is that MRSA has become so widespread that anyone can now become infected, even an otherwise healthy adult like myself.
An even bigger problem is in agriculture, where about 80 percent of antibiotics administered in the United States are used. I recovered from my bout with MRSA with a small scar to remind me of the experience, an apartment laced with the bacteria, and a 50 percent chance of getting infected again.
Note: If you need help accessing information in different file formats, see Instructions for Downloading Viewers and Players. Slideshare uses cookies to improve functionality and performance, and to provide you with relevant advertising. Bacterial antibiotic resistance is a topic that is causing increasing concern in the health community. Their discovery was one of the leading causes for the dramatic rise of average life expectancy in the 20th century and their significance to public health would be impossible to overstate. Schematic representation of the interactions between pollution, resistant bacteria and aquatic environments.5. Antibiotic-susceptibility profiles of 23 isolates obtained from Jacarepagua lagoon system determined by disc diffusion method. H Carlson, Antibiotic Resistance Genes as Emerging Contaminants: Studies in Northern Colorado. L Martinez, Natural antibiotic resistance and contamination by antibiotic resistance determinants: the two ages in the evolution of resistance to antimicrobials.
Staph is a widespread and usually harmless bacterium; about a third of people carry staph in their nose, a major reservoir for the bacteria. The drugs have been a literal lifesaver for millions of people, contributing to a dramatic increase in lifespan in the past century. The solution: cut the infection out, a procedure that took only a few minutes and left me with a hole in my skin just below my right knee. Infections at that time centered around hospitals, where the bacteria flourished among a vulnerable patient population. New York Giants tight end Daniel Fells has been battling a MRSA infection on his ankle this fall, and his doctors were worried they might have to amputate his foot. The National Institutes of Health has sponsored an initiative to design and conduct clinical studies that reduce the threat of antibiotic resistance, and developing new antibiotics is one of the goals. Antibiotics are a necessary drug to help protect and heal us from pathogenic infections that our immune system is unable to successfully combat on its own. Antibiotics are defined as any compound which either kills or severely impedes the growth of bacteria. Case study 1 - Samples represented by circles: Mangrove system (MS), Paranaioca River (PR) and Parnaioca Beach (PB), Barra da Tijuca (BT), Guanabara Bay (GB) and Cunha Channel (CC). Red squares indicate resistance; blue squares indicate susceptibility and unavailable data is represented in white. Unfortunately, these sites are subjected to high levels of anthropogenic impact worldwide [1]. R Vaezzadeh, S Herzig, et alDaptomycin resistance mechanisms in clinically derived Staphylococcus aureus strains assessed by a combined transcriptomics and proteomics approach. E Hancock, Involvment of outer membrane of Pseudomonas cepacia in aminoglycoside and polymyxin resistance. A WHO survey had found that in some countries, antibiotics no longer worked for half of the people infected with common diseases like bacterial pneumonia. By the 1990s, MRSA was endemic in large university hospitals and intensive care units in the United States. MRSA outbreaks have become distressingly common among athletes, both amateur and professional, and especially in sports where skin-to-skin contact occurs.
And certain populations may be more vulnerable, including children, native Hawaiians and Alaskans, and anyone in a household where someone has had MRSA.
Scientists have found MRSA lingering on the seatbacks of airplanes, in meat from the supermarket, in coastal waters, and possibly even in the wind.
But we are not doomed to an antibiotic-free future, Robert Daum, head of the MRSA Research Center at the University of Chicago Medicine, told me. And the CDC is working with pediatricians and other doctors to reduce antibiotic use to slow the development of new resistant strains of bacteria.
And while the Food and Drug Administration recently released voluntary guidelines to reduce antibiotic use in livestock, there are gaps that may allow for overuse. Alexander Fleming, in accepting his Nobel Prize in Physiology or Medicine in 1945 for discovering penicillin, warned that it was likely to occur. However, bacteria are very adept at utilizing evolutionary processes to develop antibiotic resistance in order to promote their own survival, reproduction and persistence. Upon the introduction of penicillin into general clinical practice in 1944, formerly deadly illnesses such as Strep throat and tuberculosis became instantly curable. Case Study 2 - Samples represented by stars: Engenho Novo (JM), Jacarepagua lagoon (JC), Camorim lagoon (CAM), Tijuca lagoon (TJ), Marapendi lagoon (MR) and Joa channel (JOA). Numbers in the right end of the table indicate how many isolates where resistant to the antibiotic of each line. After days of denial, I dragged myself into the doctor’s office, where I was told it was probably a MRSA infection and sent home with a prescription for antibiotics and with a lot of fear. But that becomes more difficult with MRSA strains of staph, which can’t be killed by penicillin, methicillin, or related antibiotics. The Centers for Disease Control and Prevention estimates that 2 million people in the United States contract antibiotic-resistant diseases every year, and some 23,000 die from these infections. Staying ahead of evolution requires a three-pronged approach: developing new vaccines against bacteria like S. Every time someone takes an antibiotic for a viral infection, not only will the drug be completely useless and possibly have harmful side effects, but it may also help induce resistance in previously harmless bacteria.
So while it’s great that the problem is getting attention, that WHO declared a World Antibiotic Awareness Week this month and the White House released a national plan for combating antibiotic resistance, overuse of antibiotics is still rampant. Fertilizers, sludge, organic compounds, heavy metals and all sources of wastewater are released into water bodies often without appropriate treatment. Scientists have traced a strain of MRSA carried by livestock to patients in British hospitals. In 1998, in the United States, it was estimated that there were 80 million prescriptions of antibiotics for human use, the equivalent of about 12,500 tons in one year.
A few possible outcomes from these contaminations are: eutrophication, hypoxia, toxicity, bioaccumulation, and dissemination of pathogens [2].
M Albano, et alRelationships between bacterial diversity and environmental variables in a tropical marine environment, Rio de Janeiro. We must slow bacterial evolution enough to save these miracle drugs so they keep saving lives for generations to come. With techniques for genomic sequencing now readily available, understanding of genetic mechanisms of resistance and evolution as a whole has been advancing rapidly.
When animal and agricultural uses of antibiotics are added to human use, it is estimated that in the past 50 years, more than 1 million tons have been produced and disseminated.Almost as soon as antibiotics were introduced into clinical circulation, cases where their ability to effectively stop infection were observed. Researchers have found that bacteria are very adept at gene mutation and horizontal gene transfer. As the use of antibiotics became more widespread, the prevalence of antibiotic resistant bacteria increased.


Thus, sparsely populated areas where human activities are less intense are also affected by those disturbances [1].Environmental contamination affects microbial communities in a myriad of ways. New insights regarding pleiotrophy and epistasis have been provided through these techniques. In a recent study in Atlanta, 25% of bacterial pneumonia cases were shown to be resistant to penicillin, while a further 25% of cases were resistant to more than one antibiotic. Source and amount of pollutants together with ecosystem dynamics modulate the responses of microorganisms to anthropogenic impacts [3]. Resistance development has resulted in perpetual research and development in the search of new antibiotics in order to maintain a pool of effective drugs at all times. Microbe communities react with drastic changes in ecosystem functioning, species composition and abundance [2,4]. However, as the research is demonstrating, even if we develop new antibiotics, bacteria will develop resistance to them. While the development of resistant strains is inevitable, the speed and scale of development has been exacerbated by the practices through which we use and disseminate antibiotics.The discovery and development of antibioticsIn 1928, Alexander Fleming was searching for potential antibacterial compounds. Thus, important considerations to be taken from the research include finding ways to slow the development of resistance as we will most likely never be able to stop it entirely. He noticed that a patch of the mould Penicillium notatum had grown on a plate containing the bacteria Staphylococcus and that around the mould there was a zone where no Staphylococcus could grow. The connection between these impacts and potentially pathogenic bacteria is of particular relevance for human welfare [2].High amounts of organic matter deposited in water bodies leads to nutrient enrichment.
After more research, he was able to show that culture broth of the mold prevented growth of the Staphylococcus even when diluted up to 800 times. This promotes growth of heterotrophic bacteria, which include various opportunistic pathogens such as Shigella sp., Salmonella enterica and Vibrio cholerae. These are the etiological agents of waterborne diseases, like cholera and diarrhea, which affect millions of people worldwide.
Several years later, in 1939, Ernst Chain and Howard Florey developed a way to isolate penicillin and used it to treat bacterial infections during the Second World War. Those illnesses are most frequent in developing countries, where access to treated water and sanitation is limited [5]. The new drug came into clinical circulation in 1944 and made a huge impact on public health. Also, pathogenic bacteria originated from human feces are released directly into the environment through wastewater discharges, compromising water quality [2].Since the discovery of inhibitory properties of antibiotics they have been widely used for treating bacterial infections.
For these discoveries Fleming, Chain and Florey were awarded the Nobel Prize for Medicine in 1945.
Is antimicrobial resistance caused entirely by overuse or inappropriate use of prescription antibiotics, both in humans and animals? Their discovery and development revolutionized modern medicine and paved the way for the development of many more natural antibiotics.While Fleming was working on penicillin, Gerhard Domagk, a German doctor, announced the discovery of a synthetic molecule with antibacterial properties.
These drugs are natural or synthetic substances capable of killing bacteria or retarding their growth. Cox: Any use of antibiotics, even appropriate therapeutic use, can promote the development of resistant bacteria.
The drug was named Prontosil and was the first of a long series of synthetic antibiotics called sulfonamides or sulfa drugs. However, the effectiveness of treatments based on antibiotic therapy has been reduced over time, as a result of the spread of antibiotic resistant bacteria [7].The selective pressure imposed by the use of antibiotics (ABs) results in death of susceptible bacteria while favors resistant strains. Prontosil was introduced to clinical use in the 1930s and was used to combat urinary tract infections, pneumonia and other conditions. Bacteria may be inherently tolerant to these drugs or incorporate resistance genes by assimilating exogenous DNA. That's why it's important to only use antibiotics when your doctor prescribes them for the treatment of a bacterial infection. While sulfa drugs in many cases are not as effective as natural antibiotics, they are now in widespread use for the treatment of many conditions.
Extensive genetic exchange occurs in the environment, where opportunistic pathogens (commonly found in free-living communities) may become resistant upon acquiring resistance mechanisms.The increasing spread of antibiotic resistance (AR) among environmental bacteria has led some authors to consider antibiotic resistant bacteria (ARB) and antibiotic resistance genes (ARG) as emerging pollutants [6,8,9]. Taking an antibiotic when you don't have a bacterial infection doesn't treat your illness and can set off a chain of events that can lead to the development of resistant bacteria. Gerhard Domagk was awarded the Noble prize in 1939 for his discovery of prontosil.Several strategies are currently used to find new antibacterial compounds. These entities have a special property when compared to other contaminants: their ability to amplify and spread, persisting in the environment [9]. So it's vital that we use these drugs appropriately to help slow the rate at which bacteria develop resistance to antibiotics. Potential candidates for natural antibiotics are discovered by screening bacterial and fungal species for antimicrobial activity. Since human populations are dependent on aquatic environments, the propagation of ARB and ARG within these sites represents a serious threat to public health [10].However, antibiotic resistance is not just a medical issue but also an ecological matter. White: Some antimicrobial resistance occurs naturally and is known as intrinsic resistance, an inherent characteristic of some specific types of bacteria.
To understand the process by which resistance propagates, it is necessary to consider not only hospital settings, but also the ecology and evolution of resistant microorganisms [11].
These intrinsic resistances should generally be known by health care professionals to avoid the use of inappropriate or ineffective treatments. Synthetic drugs are serendipitously discovered or designed intelligently to bind to bacteria in a specific way.Antibiotics generally work in one of five ways. In this chapter, we discuss how ARG and ARB arise and disseminate in aquatic environments, with special attention to how pollution affects this phenomenon. We describe the origins of antibiotic resistance genes and their interactions with environmental and pathogenic bacteria. In addition, we present 3 case studies regarding resistance in pristine and impacted aquatic environments from Rio de Janeiro. When bacteria become resistant to the antibiotics typically used to treat an infection, doctors could be forced to resort to treatments not proven to be as effective, or that have more side effects. Finally, we describe prospects for reversing, or at least to mitigate the dissemination of antibiotic resistance among environmental bacteria. White: The fundamental concern over the agricultural use of antibiotics arises from the potential that resistant bacterial strains can be transferred to humans via direct contact, or ingestion of food derived from treated animals. Through the text, the terms ‘microbial communities’, ‘microbes’ and ‘microorganisms’ are used to refer exclusively to members of the Bacteria domain.2. This is a legitimate concern as epidemiological and microbiological data show that resistant bacteria from food animals can reach humans via the food supply. Antibiotics and resistant bacteriaIn the mid-1900s several new drugs originated from environmental microbes were discovered.
Penicillin; Vancomycin)For example, penicillin works by blocking the formation of peptide bonds in the bacterial cell wall and thereby weakens it, leaving the bacterium susceptible to osmotic lysis. Although there appears to be wide assortment of antibiotics and mechanisms of action, there are a very limited number of targets through which bacteria are susceptible to antibacterial activity. This was started by the discovery of substances originated from free-living organisms that were able to inhibit microbial growth, such as penicillin [12]. Researchers must constantly look for new ways to combat bacteria.Development and acquisition of resistanceMany infectious diseases have been brought under control around the world yet this remains the leading cause of death in the world. Antibiotics belong to several classes of molecules that act impairing key microbiological processes like metabolic pathways and protein synthesis [13,14] (Table 1).
Furthermore, previously controlled infections are becoming increasingly common in patients with diseases like AIDS where the immune system is compromised. As a result, high enough levels of these drugs lead to death or inhibition of growth.Antibiotics are mainly used for treating human infections.
Antibiotics are also used to improve feed efficiency and weight gain in healthy animals, a practice the FDA has been working to change. The ability for the pathogens to grow despite the presence of antibiotics, through the development of antibiotic resistance, has rendered victims as vulnerable as patients from the pre-antibiotic era. These substances are extensively applied in animal husbandry for veterinary objectives and also as growth promoters.
We think that this voluntary approach will move us forward in the quickest way possible, and it doesn't rule out future regulation. The development of resistance is inevitable following the introduction of a new antibiotic.


ABs are also used in agriculture and aquaculture [23] for both prophylaxis and to fight bacterial contaminations [6]. Cox: A lot of CDER's efforts are focused on facilitating the development of new antibiotic drugs for treating bacterial infections in patients. However modern uses of antibiotics have caused a huge increase in the number of resistance bacteria. This is a result of the spreading of ARB; organisms capable of continuously growing in toxic concentrations of these drugs.
We've been revising our recommendations on approaches to developing new antibiotics so that development programs are both scientifically sound and practical, given the challenges of developing a new antibiotic and the urgent need for new therapies. In fact within eight to twelve years, after wide spread use, strains resistant to multiple drugs become widespread.How do bacteria become resistant to antibiotics and what are the biochemical mechanisms that they use?
Millions of individuals have their health compromised by infections caused by resistant microorganisms, making resistance a global concern [13]. It is important that we have ongoing development of new antibiotics as we try to stay ahead of the development of resistance in bacteria. Several mechanisms have been developed by bacteria in order to deal with antibiotics but all require either the modification of existing genetic material or the acquisition of new genetic material.Originally it was believed that all resistance was acquired through spontaneous mutation. Errors in DNA synthesis during replication and occasional failures in the DNA repair systems result in a spontaneous mutation frequency for an individual base pair of about 10-7-10-8.
This means that for every 107-108 bacteria, we would expect one single base pair to be changed.
However, the spontaneous mutation rate to acquire a mutation that causes resistance is often even lower since multiple mutations must take place before primary antibiotic resistance can be acquired. Participating laboratories from FoodNet states isolate the bacteria of interest and forward the isolates to FDA for further analysis.
Department of Agriculture are all conducting research on resistant strains, including studying their genetic makeup to determine how resistance arises and transfers among microorganisms.
While this is an extremely rare event, the very fast growth rate of bacteria means that it doesn’t take long before resistance is developed in a population.
Once the resistance genes are acquired, the genes can be transferred directly to all the bacteria’s progeny. Cox: Patients should take antibiotics exactly as directed by their health care professional.
This is known as vertical gene transfer.The widespread development of multi-drug resistance in many species of bacteria simultaneously led scientists to believe that another mechanism beyond spontaneous mutation was responsible for the acquisition of antibiotic resistance.
They should not demand antibiotics to treat viral infections, such as coughs, colds and the flu. Lateral or horizontal gene transfer (HGT) is a process whereby genetic material contained in small packets of DNA can be transferred between individual bacteria. Taking an antibiotic drug when it won't treat your illness is still associated with the risk of side effects from that drug, and can contribute to the development of antibiotic resistance.
Transduction occurs when bacteria-specific viruses or bacteriophages transfer DNA between two closely related bacteria. Consumers must carefully clean any kitchen surfaces used to prepare or store meat or poultry before using them to prepare raw ingredients that will not be cooked.
Transformation is a process where parts of DNA are taken up by the bacteria from the external environment. This DNA is normally present in the external environment due to the death of another bacterium. Conjugation occurs when there is direct cell-cell contact between two bacteria (which need not be closely related) and transfer of small pieces of DNA called plasmids takes place.
But we're very mindful of the patients whose illnesses have become difficult to treat because of antibiotic resistance, and who urgently need new antibiotic treatment options.
However, we need to stay vigilant in monitoring emerging antibiotic resistance trends in all disease-causing bacteria of significance to animal and human health. Horizontal Gene Transfer.Mechanisms of antibiotic resistanceSeveral mechanisms have evolved in bacteria which confer them with antibiotic resistance. This article appears on FDA's Consumer Updates page, which features the latest on all FDA-regulated products. These mechanisms can either chemically modify the antibiotic or alternatively render it inactive through physical removal from the cell, or through modification of its target site. An existing enzyme is modified to process the antibiotic and modifies it so that it no longer affects the microorganism.
An alternative strategy utilized by bacteria is the alteration of the antibiotic target site. Mechanisms of Antibiotic Resistance.The scope of the problemTo combat the occurrence of resistant bacteria, pharmaceutical companies must constantly research, develop and test new antimicrobials in order to maintain a pool of effective drugs on the market. Five years ago, there were approximately 150 antibiotics available to the public with new drugs appearing every 8-10 years. Since the drug development process is very costly, pharmaceutical companies often concentrate on finding antimicrobials similar to the ones already found to reduce the risk of producing an unmarketable drug.
This means that it is easy for microorganism to develop resistance to a similar drug to which it already has resistance.
Past and current strategies to combat resistance are not effective.The rate of resistance acquisition is accelerated by the widespread misuse of antibiotics.
Antibiotics in animal feed, unnecessary and unfinished antibiotic prescriptions have been identified as causes for an enhanced rate of resistance development. Delivering antibiotics to livestock in animal feed is similar to giving people antibiotics all their life even when they are healthy. They can acquire resistant genes, infect humans, cause food poisoning from consumption of beef or chicken and can horizontally transfer those resistance genes to other bacteria. Unnecessary prescriptions of antibiotics are made when antibiotics are prescribed for viral infections (antibiotics have no effect on viruses). This gives the opportunity for benign bacteria to acquire resistance that can be later passed on to pathogens. Unfinished antibiotic prescriptions leave some bacteria alive and exposes them to sub-inhibitory concentrations of antibiotics for a prolonged period of time.
Mycobacterium tuberculosis is a slow growing bacteria which infects the lung and causes tuberculosis. Unfortunately due to the slow growing nature of the infection, treatment programs last for months or even years. The rate has been reduced by 23 % from 1995-2000 in children less than 3 yrs old with similar trends being mimicked in older children. Large scale public health education efforts are now underway to stress the importance of finishing prescriptions. Indeed in many places, failure to finish tuberculosis prescriptions can result in jail time.
In addition, several countries such as the UK have regulations concerning the use of antibiotics in animal feed.Reversal of resistance by removal of antibiotics from use was an idea that was put forth.
Generally mutation in a bacterial gene to confer resistance often results in a loss of fitness leading to slower growth. Therefore it was believed that removal of antibiotics would cause selection against these bacteria when competing with non-resistant, fit bacteria. Bacteria often acquire compensatory mutations that allow them to grow as fast as or even faster than wild type, non-resistant bacteria.
Consequently, the selective advantage of the non-resistant bacteria and the selection against the resistance mutation is eliminated.The discovery of antibiotics was a leap in modern medicine. The work on penicillin by Fleming, Chain and Florey was followed by many scientists and pharmaceutical companies in search of new antibiotics with different modes of actions.
However, the bacteria in particular have proven to be much more innovative and adaptive than scientists had imagined. We could soon return to a state of medical health that was as dire as that which occurred prior to antibiotic use. However, with more research, education of the public, and well thought out government regulations, we will be well on our way to slowing down the resistance phenomenon.References1. The evolutionary history of chromosomal super-integrons provides an ancestry for multiresistant integrons.



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