Antibiotic Resistance: Past, present and future

Antibiotic Resistance: Past, present and future.In order to appreciate the current situation of antibiotic resistance it is important to first have an understanding of the origin of antimicrobial therapy and the dawn of modern resistance mechanisms. By examining this history before evaluating the current predicament being faced by the scientific and medical communities the importance of solving the problem can be appreciated. Once the scale of the issue is understood then it is important to gain an insight into the possible solutions that scientists can work towards to ensure that the golden age of antibiotic therapy doesnt come to an end.The term antibiotic was first used in the early 1940s by Selman Waksman who coined the word to define small molecules produced by a micro-organism that have a negative effect on the growth of other micro-organisms, (Sengupta and Chattopadhyay, 2012; Clardy et.al, 2009). Modern antimicrobial therapy also originates from around the same time with the discovery of penicillin and its subsequent introduction during the Second World War. However, within only four years of its introduction organisms showing resistance began to be reported (Sengupta and Chattopadhyay, 2012).This isnt the first example of antibiotic resistance though as shown in the work of DCosta et.al published in Nature magazine in 2011. Their study showed that samples taken from 30,000 year old permafrost had genetic material ecoded with resistance to antibiotics based on glycopeptides, tetracycline and -lactams. This research clearly demonstrated that antibiotic resistance isnt something that has been brought about my modern clinical use of antibiotics but by a totally natural phenomenon. Two of the authors on this paper suggested that the reason behind this is that in the nearly four million years that bacteria have existed on the planet they must have had exposure, either indirect or direct, to antibiotics most of which are created from naturally occurring fungi and plants (Wright and Poinar, 2012).This doesnt mean that the modern era of antimicrobials hasnt had a hand in the current explosion of different resistance mechanisms found in medically significant bacteria. A review by Gillings and Stokes (2012) suggests that it is the dissemination of resistant cells into the human waste stream that is causing an increase in the evolutionary rate of bacteria through a process known as lateral gene transfer (LGT), this is the way that bacteria transfer genetic material other than by direct vertical descent. Their review states that it is in selected hotspots such as sewage treatment plants where effluents and waste water carry bacteria from the environment, both pathogenic and commensal organisms, and it is in places like these where transfer of DNA between species is likely to occur due to the formation of biofilms.An interesting review on modern antibiotics resistance has been written by David Livermore (2012a), the former Director of the Antibiotic Resistance Monitoring and Reference Laboratory who are part of the Health Protection Agency. It covers the fourteen years he spent in the role and the trends of resistant organisms over the period. Discussion on methicillin resistant Staphylococcus aureus (MRSA) shows the rise and fall of cases in the United Kingdom and raises the question of whether it was the introduction of better infection control methods in hospitals such as the use of alcohol based hand rubs or more natural methods like bacteriophage attack or burn out that brought about the steady decline of reported cases. MRSA is but one of the organisms mention in the article along with Neisseria gonorrhoeae and Streptococcus pneumoniae but it is the Gram-negative bacteria that fall into the category of extended spectrum -lactamases (ESBLs) that are seen as the biggest threat to current antimicrobial treatment.Extended spectrum -lactamase is an enzyme that breaks down a wide selection of -lactam antibiotics such as penicillin and cephalosporins and is found in certain Gram-negative organisms (Ford, 2010). Given how important these antibiotics are in treatment it is easy to see just how vital work in this area is.Another review by David Livermore (2012b), viewed as an expert in the field of antibiotic resistance mechanisms, covers the epidemiology and increasing resistance of these pathogenic Gram-negative organisms but firstly gives a brief history on anti-Gram-negative antibiotics. Sulfonamides were the first of these antibiotics and appeared in the 1930s; the 1940s saw tetracyclines with chloramphenicol appearing in the 1950s. The 1960s gave the world first generation cephalosporins and the 1980s brought about the third and fourth generations of cephalosporin as well as other drug families that remain to this day to be the standard treatment for infections brought about by Gram-negative pathogens. The lack of any current development in antibiotics to treat these pathogens has brought about the present situation where resistance to treatment is reducing the number of possibilities available to medical staff to counter infection by Gram-negative organisms. This isnt to say that research isnt being undertaken, just that none of the anti-Gram-negative agents currently in development cover all Gram-negative pathogens and therefore lack the potential to have as big an impact as the antibiotics discovered in the latter part of the 20th century.The dissemination of antibiotic resistant cells back into the food / water cycle isnt the only potential cause of the prevalence of these organisms and David Livermore states that one of the reasons is the growth of global markets in countries such as China and India (2012a). These countries have huge populations which when combined account for nearly one third of the planets population. China uses a great many antibiotics in its agriculture and this causes organisms resistant to many antibiotics to gain access to the food chain. The other problem he relates to the sewage network in India being incapable of treating water properly and allowing tap water to be contaminated with faecal matter. This is a huge issue as India is seen as a country with excellent medical facilities and people travel there for treatment, at the same time being exposed to contaminated water sources. The scale of the problem in these two countries has seen the rate of ESBLs in Gram-negative organisms rise from between 13-35% of Escherichia coli tested in China during the late 1990s and an estimated figure of 60% for India. Data from the late 2000s suggests that the levels of ESBLs in both E.coli and Klebsiella pneumoniae have increased to between 50-80%. These organisms arent just restricted to the Eastern continents though and half of the first patients affected by New Delhi metallo -lactamase 1(NDM-1) had been in hospital in either Pakistan or India.A study was undertaken in Bangladesh (Islam et.al, 2012), the neighbour of India and Pakistan, to ascertain whether the levels of NDM-1 that were seen in countries on its borders were that same in Bangladesh itself as it was seen that the spread of NDM-1 was a matter of concern for the international community as well as being a large and new problem in the study of pathogenic organisms. The study itself tested 1,816 consecutive specimens from patients at the International Centre for Diarrhoeal Disease Research and although 403 Gram-negative organisms were isolated only 14 were positive for NDM-1, a total percentage of 3.5% of the specimens tested. These levels were certainly not comparable to other countries and the authors of the study state that this figure may be low due to the screening method that they used which was based around an imipenem screening disk and may not have detected all organisms that produced NDM-1. They go on to point out that the study also only contained specimens taken from patients who were already ill and attending the clinic and as such there was no data from healthy individuals. The possibility of the positive cases being caused via hospital acquired infection was also raised as all of the positive cases has been hospitalised at one time in the three month period preceding the trial and had also undergone antibiotic therapy.Nosocomial, or health care related, infection is still an important area to study especially if trying to determine the pathogenicity and prevalence of an organism such as E.coli that could be an ESBL producing bacteria. A study by Gndodu et.al (2012) in Queensland, Australia, was undertaken because E.coli above all other Gram-negative organisms is the primary cause of urinary tract infection and septicaemia in patients admitted to hospital. Women, children and elderly patients are highly susceptible to urinary tract infections (UTIs) and it is the most common heath care related infection. UTIs also have the potential to cause urosepsis which is the cause of between 20-30% of sepsis cases. This normally occurs where E.coli has managed to make its way into the urinary tract and, once there, made its way first to the kidneys causing a bacterial infection known as pyelonephritis before travelling directly into the blood stream, once there causing septicaemia. This study collected 296 strains of E.coli from inpatients with acute symptomatic urinary tract infections from four hospitals in the Queensland area. In total eight of the samples were found to contain a recognised ESBL, this equates to approximately 3% of the total, a figure not too dissimilar to the Bangladesh study.Escherichia coli was the organism of choice for the study undertaken by Kraker et.al (2011). The first reason was because they saw it as the most common cause of blood stream infections in hospitals throughout Europe. The second reason was because E.coli shows a larger increase in antibiotic resistance than any other pathogen, both in Europe and the rest of the world. The third reason was the shortage of research meaning new antibiotics to counter the problem are not on the immediate horizon and finally, there is little conclusion as to how large an impact is caused in a clinical environment by infections caused by antibiotic resistant strains of E.coli. The study was actually undertaken in thirteen health care centres throughout Europe and in order to have a control there were two groups of patients, one with patients infected with an E.coli that was resistant to third generation cephalosporins and a second group whose E.coli was sensitive to the same antibiotics. The result of the study showed that in over three quarters of a million admissions to the participating centres there were 1.328 episodes of blood stream infection by E.coli reported of which 10% were resistant to third generation cephalosporins. This figure of 10% hides alarming figure from some of the participating countries though and makes others look worse than they are in actuality, in some cases more than doubling the national percentage. Belgium, Croatia and Slovenia all had a national resistant E.coli percentage of 4% whereas Malta and Romania had 21% and 24% respectively.Another piece of disturbing data from this study was the difference in mortality rates between patients with a resistant E.coli compared to those with a susceptible one. The mortality rate at thirty days showed that a patient with a blood stream infection caused by a resistant E.coli was 2.5 times more likely to die from their infection than those with a susceptible organism with this figure rising to 2.9 times more likely when applied to the entire hospital mortality figure. The team behind this study took certain measures to ensure a balanced result by using a control group and only one organism and this gives the study a greater appearance of accuracy than a number of others.So if Escherichia coli, along with other members of the Enterobacteriaceae family, are proving increasingly resistant to third and fourth generation cephalosporins and there is no wonder drug on the horizon what current treatment can be used. At present the antibiotic group of choice are the carbapenems but a study from Sweden (Adler et.al, 2012) sheds interesting light on the effect of extended spectrum -lactamase causing spontaneous evolution of E.coli to become carbapenems resistant.This study shows that there are three mechanisms that can provide Enterobacteriaceae with carbapenems resistance; the acquisition of carbapenemases, an alteration of penicillin binding proteins through mutation or the over expression of AmpC or another ESBL enzyme combining with a loss of porins which would cause a reduced permeability of the outer membrane of a Gram-negative organism. Other bacteria from the Enterobacteriaceae family already show clinical resistance through the methods above, K.pneumoniae and Enterobacter spp. for example, but given the clinical importance of E.coli as a human pathogen it was deemed important to see the effects of the possible alteration mechanisms upon the organism. Thankfully although it was possible to infer carbapenems resistance to strains of E.coli the loss of porin expression reduced the growth rate of the organism which, the researchers believed, is what has meant that wild strains of carbapenems resistant E.coli havent been found.Given the historical background of antimicrobial therapy showing penicillin resistant organisms within four years of its general use and the current situation of organisms becoming resistant to not just one but many antibiotics what sort of developments are on the horizon to help humankind keep their heads above water in what seems like a war it in inevitable as a species they will lose.A review by Jenny Fernebro (2011) lists numerous possible treatment options for the future in the struggle against bacterial infections. The first of these is through the use of antimicrobial peptides. These function by having both hydrophobic and hydrophilic areas which cause disruption to the bacterial cell wall and effectively eradicate the organism. This form of treatment isnt just restricted to bacteria and could also have medical use against a number of viruses and fungi also. Such a broad spectrum would be a useful tool clinically as it would allow a cover-all treatment while investigation was underway to determine the actual cause of infection. The downside to treatment of this nature is that some peptides exhibit high levels of toxicity raising the question of them doing more harm than good.Next on the list are anti-virulence strategies. Virulence is the ability of a pathogen to spread disease and it is believed that by removing the virulence of an organism it will render it ineffective. This would be a very specific treatment method, singling out a particular organism whilst leaving the patients normal flora untouched but such a high level of specificity has a few drawbacks as well. The first is that investigation methods would need to improve to allow a more rapid diagnosis as most culture methods take around 48 hours to grow. The second issue would be the cost of researching and producing a treatment that would only work on one organism.Bacteriophages suffer from similar drawbacks to the anti-virulence techniques in that they are highly specific. This method involves the introduction of viruses that use bacteria as a host to reproduce which causes the organism to lyse and die. One other negative to this method of treatment is that the bacterial cell could develop resistance to the virus very quickly in the same manner as antibiotic resistance has been evolved.The fourth area of research with antimicrobial potential is through the use of therapeutic antibodies, a technique which is already used clinically to treat cancer patients. This technique introduces antibodies that bind to the virulent parts of pathogenic organisms allowing the hosts natural defences time to combat the infection. Again though this method is highly specific and the problems with diagnosis time and cost previously mentioned also apply here.Another treatment option already in use is vaccination. Tuberculosis, commonly caused in humans by Mycobacterium tuberculosis, M.bovis or M.africanum (Ford, 2010), is already part of an immunization programme. This is already a huge area of research and is seen as the most cost effective method of controlling pathogenic organisms.Potentiators, reagents that enhance the abilities of existing antibiotics, are also already in use to reverse resistance mechanisms in certain organisms. By enhancing a -lactam antibiotic with a -lactamase inhibitor it would be possible to negate the -lactamase being produced by the organism and allow the drug to work. This method seems sound in practice but strains of bacteria with resistance to this method have already been found.The final area of research suggested by Fernebro is in preventing infection caused by biomaterials, catheters and artificial valves as an example. The risk to patients with major artificial devices as well as those with non-invasive devices such as urinary catheters, a primary cause of urinary tract infection, would be greatly reduced if the devices were made from, or coated in, an antimicrobial material.As mentioned earlier one of the reasons that NDM-1 is spreading is the medical tourism industry in India but the other problem facing that particular country is that antibiotics are available for purchase from pharmacies. This allows people to buy just enough of an antibiotic to make themselves feel an improvement but without destroying the organism completely thereby allowing any survivors to build up resistance. Indias government are trying to develop a plan to counter this but they have refused an outright ban on self-prescription which was put forward as the best recommendation by a government formed task force (Westley, 2012).If governments arent prepared to initiate such changes it seems like any new developments will eventually be overcome. After all, it was only seven decades ago that a wonder drug started to be defeated by bacteria within four years of its introduction. Bacteria have four billion years of evolution behind them and humans need to change their thinking if they are to stand a chance of surviving this war.Word Count: 2,905ReferencesAdler, M., Anjum, M., Anderson, D.I., and Sandegren, L. (2013). Influence of aquired -lactamases on the evolution of spontaneous carbapenem resistance in Escherichia coli. Journal of Antimicrobial Chemotherapy. 68, 51-59Clardy, J., Fischbach, M. and Currie, C., (2009). The natural history of antibiotics. Current Biology. 19(11), 437-441.DCosta, V.M., King, C.E., Kalan, L., Morar, M., Sung, W.W.L., Schwarz, C., Froese, D., Zazula, G., Calmels, F., Debruyne, R., Golding, G.B., Poinar, H.N., and Wright, G.D., (2011). Antibiotic resistance is ancient. Nature. 477, 457-461.de Kraker, M.E.A., Wolkewitz, M., Davey, P.G., Koller, W., Berger, J., Nagler, J., Icket, C., Kalenic, S., Horvatic, J., Seifert, H., Kaasch, A., Paniara, O., Argyropoulou, A., Bompola, M., Smyth, E., Skally, M., Raglia, A., Dumpis, U., Melbarde Kelmere, A., Borg, M., Xuereb, D., Ghita, M. C., Noble, M., Kolman, J., Grablijevec, S., Turner, D., Lansbury, L. and Grundmann, H. (2011). Burden of antimicrobial resistance in European hospitals: excess mortality and length of hospital stay associated with bloodstream infections due to Escherichia coli resistant to third-generation cephalosporins. Journal of Antimicrobial Chemotherapy. 66, 398-407Fernebro, J., (2011). Fighting bacterial infections - Future treatment options. Drug Resistance Updates. 14, 125-139Ford, M., (ed.) (2010). Medical Microbiology. Oxford: Oxford University Press.Gillings, M.R. and Stokes, H.W., (2012). Are humans increasing bacterial evolvability? Trends in Ecology and Evolution. 27(6), 346-352.Gndodu, A., Long, Y.B., and Katouli, M. (2012). Prevalence and pathogenesis of extended-spectrum-beta-lactamase producing Escherichia coli causing urinary tract infection in hospitalized patients. European Journal of Clinincal Microbiology and Infectious Disease. 31, 3107-3116Islam, M.A., Talukdat, P.K., Hoque, A., Huq, M., Nabi, A., Ahmed, D., Talukder, K.A., Pietroni, M.A.C., Hays, J.P., Cravioto, A. and Endtz, H.P. (2012). Emergence of multidrug-resistant NDM-1-producing Gram-negative bacteria in Bangladesh. European Journal of Clinincal Microbiology and Infectious Disease. 31, 2593-2600.Livermore, D.M., (2012a). Fourteen years in resistance. International Journal of Antimicrobial Agents. 39, 283-294.Livermore, D.M., (2012b). Current Epidemiology and Growing Resistance of Gram-Negative Pathogens. Korean Journal of Internal Medicine. 27(2), 128-142.Sengupta, S. and Chattopadhyay, M.K., (2012). Antibiotic Resistance of Bacteria: A Global Challenge. Resonance. February, 177-191.Westly, E., (2012). India moves to tackle antibiotic resistance. Nature. 489, 192Wright, G.D. and Poinar, H., (2012). Antibiotic resistance is ancient: implications for drug discovery. Trends in Microbiology. 20(4), 157-159.Paul Quinn W1263597 Page | 1