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Microbial resistance as global as well as national problem
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  • 1. Microbial resistance: causes and remedy Ranjit Pandey, chhabi lal chaudhary CiST College, 7th sem, B. Pham ranjitpandey17@gmail.com KTM Nepal.contact-+977-9849464685 Introduction Antibiotics are those chemical compounds produced by actinomycetes, fungi, or bacteria that is used to kill or alter the bacterial process without altering or harm to the eukaryotic host having the infection[1].The emergence of antimicrobial resistance is a complex problem driven by many interconnected factors, in particular the use and misuse of antimicrobials. Antibiotic resistance has drastically increased in recent years in developed and developing countries and prevalence of resistance is varies within countries between the pathogen and become the great public concern [2]. Bacteria that are not inhibited by normal dose schedule in minimal inhibitory concentration range usually by achievable systemic concentration of antibiotics is called antibiotic resistance[3].Antibiotic resistance occurs when bacteria evolve under selection pressure from antibiotic use and become resistant to the medication. Because a generation for a bacterium is extremely short (no more than one day, and often less than an hour), such evolution can occur very quickly. The result is that existing antibiotics lose their effectiveness over time (FDA).There are multiple mechanisms of antibiotic resistance including chromosomal mutation, regulation of resistance gene, transfer of resistance gene etc.[4]. Managing this problem is main concern for the world today, find alternative medicine, decrease resistance, development of new drugs may the long term solution to this issue[2]. Rationale Our research focuses current issue of antibiotics resistance, the global as well as national problem. The resistance is increasing drastically while discovery and development of new sensitive compound is quits low as compare to resistance rate. The chance of getting resistance is high but difficult to discover and develop new molecules, also the great challenge for developing country like Nepal. However minimization of resistance is better way to overcome these problems in the world. There are several factors like ineffective regulatory affairs; irrational drug use, absence or passive role of pharmacist in health care system may responsible for this resistance. We hope our research will help to health policy maker, for rationale drug use and medical practicener to beneficial public health concern by awarding the need and responsibility with the active participation of the pharmacist.
  • 2. Objectives  To describe the microbial resistance as a global as well as national problem.  To describe the mechanism of antimicrobial resistance.  To describe the potential causes of increased microbial resistance in Nepal.  To suggest the possible measures to overcome microbial resistance in Nepal Methodology Article review Firstly, the articles were searched from Google Scholar. After obtaining initial information the original article and full length research article were retrieve from WHO hinari and other online journal sites. Resistance as a global as well as national problem Resistance to antibiotics represents a worldwide health-care problem that affects therapy of infectious diseases caused by a large variety of organisms including Gram-negative, Gram positive bacteria or mycobacteria[5]. The global emergence of multi-drug resistant bacterial strains is increasing limit the effectiveness of current drugs and causing significant failure of treatment of infections. Examples include methicillin-resistant staphylococci, pneumococci ncomycin-rresistant topenicillin and macrolides, vaesistan enterococci as well as multidrugresistant gram-negative organisms. The past recordof rapid, widespread and emergence of resistance tonewly introduced antimicrobial agents indicates that even new families of antimicrobial agents will have a short life expectancy[6]. Antibiotics were discovered in the middle of the nineteenth century and brought down the threat of infectious diseases which had saved the human race. However, soon after the discovery of penicillin in 1940, a number of treatment failures and occurrence of some bacteria such as staphylococci which were no longer sensitive to penicillin started being noticed. Scientific antibiotic discovery started in the early 1900s by Alexander Fleming, who observed inhibition of growth on his agar plate on which he was growing Staphylococcus spp. It was later found that a microorganism that was later to be called Penicilliumnotatum was the cause of the inhibition of the Staphylococcus around it as a result of excreting some chemical into the media. That marked the beginning of the discovery of penicillin which together with several other different antimicrobial agents was later to save millions of humans and animals from infectious disease-
  • 3. causing organisms.Drug-resistant strains initially appeared in hospitals, where mostantibiotics were being used. Sulfonamide-resistant Streptoccoccuspyogenesemerged in military hospitals in the 1930s. PenicillinresistantStaphylococcus aureusconfronted London civilian hospitalsvery soon after the introduction of penicillin in the 1940s.Similarly,Mycobacterium tuberculosis with resistance to streptomycin emergedin the community soon after the discovery of this antibiotic.Resistance to multiple drugs was first detected among enteric bacteria—namely, Escherichia coli,Shigellaand Salmonella—in the late1950s to early 1960s. Such strains posed severe clinical problemsand cost lives, particularly in developing countries[7]. There is an alarming increase of antibiotic resistance of bacteria thatcause either community infections or hospital - acquired infections. Resistance to methycillin and vancomycin is most commonly developed in nosocomialinfections and non-hospital units. Penicillin-resistant Streptococcus pneumoniae is frequentlydetected in pediatric units. Hospital infections with methycillin- resistant Staphylococcusaureus occur most frequently in patients with invasive medical handling or immunesuppressed patients with prolonged treatment in health care centers or dialysis[8]. In Nepal, antimicrobial resistance is a common and major problem, contributing to increased treatment costs, hospital stay, morbidity and mortality. The resistance is more common among Gram-negative than Gram-positive organisms. Resistance to commonly available and affordable antimicrobials poses a major concern in the management of bacterial infection. Irrational practices in the use of antimicrobial agents in human medicine and for prophylaxis in animal husbandry may contribute significantly to the emergence of multidrug-resistant (MDR) strains. Study showed that E. coli is highly resistant to ampicillin and cotrimoxazole and their sensitivity is poor with cefotaxime as well. The other gram-ve bacilli K. pneumoniaeis mostly resistant to cephalexin and nalidixic acid. Similarly, S. aureusis mostly resistant to ampicillin and cephalexin in urine samples. Common pathogens of blood sample S. typhiand S. paratyphi were sensitive to the tested antimicrobials. E. coli and S. aureusare the commonestpathogens in pus. E. coli is highly resistant to ampicillin and is mostly resistant to cotrimoxazole. Similarly, S. aureus is also highly resistant to ampicillin[9]. As the success to develop new classes of antibiotics with novel mode of action hasbeen compromised in the last decades, pharmaceutical companies abandoned or drasticallydecreased investments in the antibiotic research because of resistant strains occurs sorapid for some bacteria that clinical usefulness of theantibiotics is lost within a 5 year period[6].It seems that partnerships of bigpharmaceutical companies with biotechnology organizations might be a way to move forwardin this field. In the absence of major new classes of antibiotics, otherstrategies have to be considered in order to minimize the development of resistance, such asthe restrictive and educational antibiotic stewardship programmes[8].
  • 4. Mechanism of antimicrobial resistance The prevalence of drug resistance limits the therapeutic options for treatment of infections, which some of the most effective tools treatment for the physician including antibiotics, anti- tuberculosis and anti-malarial drugs lose their effectiveness [10]. Antibiotic resistance occurs when bacteria overcome the selection pressure from antibiotic use and become resistantto the medication. Because a generationfor a bacterium is extremely short (nomore than one day, and often less thanan hour), such evolution can occur very quickly. The result is that existing antibiotics lose their effectivenessover time[11]. How do antibacterial agents work? Most antimicrobial agents used for the treatment of bacterial infections may be categorized according to their principal mechanism of action. There are 4 major modes of action: (1) interference with cell wall synthesis, (2) inhibition of protein synthesis, (3) interference with nucleic acid synthesis, and (4) inhibition of a metabolic pathway [12-14]. Table 1 Mechanisms of action of antibacterial agents Mechanism Examples Interference with cell wall synthesis  β-Lactums: penicillins, cephalosporins, carbapenems, monobactams  Glycopeptides: vancomycin, teicoplanin Protein synthesis inhibition  Bind to 50S ribosomal subunit: macrolides, chloramphenicol, clindamycin, quinupristin-dalfopristin, linezolid  Bind to 30S ribosomal subunit: aminoglycosides, tetracyclines  Bind to bacterial isoleucyl-tRNAsynthetase: mupirocin
  • 5. Interference with nucleic acid synthesis  Inhibit DNA synthesis: fluoroquinolones  Inhibit RNA synthesis: rifampin Inhibition of metabolic pathway  sulfonamides, folic acid analogues Disruption of bacterial membrane structure  polymyxins, daptomycin All antibiotics may undergo microbial resistance due to the use and misuse of antimicrobials, over-the-counter availability of antimicrobials without professional controls, the use of drugs of low potency and indications or contraindications. Among these above mentioned metabolic pathway inhibitors antibiotics are highly susceptible to resistance, if any of the drug of same class get resistant then there will be chances of getting resistant to all of that class [15, 16]. Resistance can be described in two ways: 1) intrinsic or natural whereby microorganisms naturally do not possess target sites for the drugs and therefore the drug does not affect them or they naturally have low permeability to those agents because of the differences in the chemical nature of the drug and the microbial membrane structures especially for those that require entry into the microbial cell in order to effect their action or 2) Resistance whereby a naturally susceptible microorganism acquires ways of not being affected by the drug. Acquired resistance to antimicrobials is as a result of three main strategies namely enzymatic inactivation of the drug, modification of target sites and extrusion by efflux. While chemical modifications could be significant in antibiotic resistance, exclusion from the cell of unaltered antibiotic represents the primary strategy in denying the antibiotic, access to its targets and this is believed to enhance resistance even in cases where modification is the main mechanism[6].
  • 6. Figure1. Main mechanisms of bacterial resistance to antimicrobial drugs[8]. a) Alteration of target site Chemical modifications in the antibiotic target may result in reduced affinity of the antibiotic to its binding site. This is a mechanism employed by a number of pathogenic bacteria in evading the effect of antibiotics. Modifications are usually mediated by constitutive and inducible enzymes. Resistance to macrolides, lincosamide and streptogramin B antibiotics (MLSB resistance) in pathogenic Streptococcus species is a result of methylation of the N6 amino group of an adenine residue in 23S rRNA. This is presumed to cause conformational changes in the ribosome leading to reduced binding affinity of these antibiotics to their binding sites in the 50S ribosomal subunit. Beta-lactams antibiotics function by binding to and inhibiting the biosynthetic activity of Penicillin Binding Proteins (PBPs), thereby blocking cellwall synthesis. In S. aureus and S. pneumoniae, resistance to β-lactams can be a result of mutations leading to the production of PBP2a and PBP2b respectively. The two proteins have a reduced affinity for β-lactams and yet they take over the functions of normal PBPs in the presence of inhibitory levels of β-lactams. This mechanism of resistance is also responsible for β-lactam resistance in non- β- lactamase producing Haemophillus influenza [17, 18].
  • 7. b) Enzymatic inactivation The production of hydrolytic enzymes and group transferases is a strategy employed by a number of pathogens in evading the effect of antibiotics. Genes that code for antibiotic degrading enzymes are often carried on plasmids and other mobile genetic elements. The resistance to β- lactam antibiotics by both gram negative and gram positive bacteria has long been attributed to β-lactamases. These enzymes confer significant antibiotic resistance to their bacterial hosts by hydrolysis of the amide bond of the fourmembered β-lactam ring. Resistance to aminoglycosides in gram-negative bacteria is most often mediated by a variety of enzymes that modify the antibiotic molecule by acetylation, adenylation or phosphorylation[19, 20]. b) Antibiotic efflux It is now widely recognized that constitutive expression of efflux pump proteins encoded by house-keeping genes that are widespread in bacterial genomes are largely responsible for the phenomenon of intrinsic antibiotic resistance. Several studies have shown that active efflux can be a mechanism of resistance for almost all antibiotics. The majority of the efflux systems in bacteria are non-drug-specific proteins that can recognize and pump out a broad range of chemically and structurally unrelated compounds from bacteria in an energy-dependent manner, without drug alteration or degradation. The consequence of this drug extrusion is that, it leads to a reduced intracellular concentration of the antimicrobial such that the bacterium can survive under conditions of elevated antimicrobial concentration[21]. The MIC of the drug against such organisms will be higher than predicted. Multi-drug resistance efflux pumps are ubiquitous proteins present in both gram-positive and gram-negative bacteria as either chromosomally encoded or plasmid encoded. Although, such proteins are present constitutively in bacteria, the continued presence of the substrate induces over-expression. This increased transcription is responsible for the acquired resistance. In gramnegatives bacteria, the effect of the efflux pumps in combination with the reduced drug uptake due to the double membrane barrier is responsible for the high inherent and acquired antibiotic resistance often associated with this group of organisms. Efflux transporters constitute about 6 to 18% of all transporters found in any given bacterial cell [22]. Currently, much attention is being paid towards understanding the operating mechanisms of these pumps. This has potential applications in the design of transport inhibitors that could be used in combination with antibiotics in development of clinically useful drugs. The MDR pumps of pathogenic bacteria known so far, belong to five families of transporters namely; the major facilitator super-family (MFS), the adenosine triphosphate (ATP)-binding cassette (ABC) super-family, the small multi-drug resistance (SMR) family and the resistancenodulation-
  • 8. cell division (RND) super-family and the multidrug and toxic compound extrusion (MATE) family [21, 22]. Acquired resistance mechanisms can occur through various ways as described by Fluit et al. (2001) summarized in Box 2.1 and illustrated in Fig. 2.1. Alteration of target site  a mutation in the antimicrobial agent’ starget, which reduces the binding of the antimicrobial agent  post-transcriptional or post-translational modification of the antimicrobial agent’s target, which reduces binding of the antimicrobial agent  reduced uptake of the antimicrobial agent Enzymatic inactivation  the presence of an enzyme that inactivates the antimicrobial agent  the presence of an alternative enzyme for the enzyme that is inhibited by the antimicrobial agent Antibiotic efflux  active efflux of the antimicrobial agent Potential causes of increased microbial resistance Increasing prevalence of resistance has been reported in many pathogens over the years in different regions of the world including developing countries[23]. This has been attributed to changing microbial characteristics, selective pressures of antimicrobial use, and societal and technological changes that enhance the development and transmission of drug-resistant organisms. Although antimicrobial resistance is a natural biological phenomenon, it often enhanced as a consequence of infectious agents’ adaptation to exposure to antimicrobials used in humans or agriculture and the widespread use of disinfectants at the farm and the household levels[24]. It is now accepted that antimicrobial use is the single most important factor responsible for increased antimicrobial resistance [23, 25]. In general, the reasons for increasing resistance levels include the following:  suboptimal use of antimicrobials for prophylaxis and treatment of infection,  noncompliance with infection-control practices,  prolonged hospitalization, increased number and duration of intensive care- unit stays,  multiple comorbidities in hospitalized patients,  increased use of invasive devices and catheters,  ineffective infection-control practices, transfer of colonized patients from hospital to hospital,  grouping of colonized patients in long-term-care facilities,  antibiotic use in agriculture and household chores, and  Increasing national and international travel.
  • 9. The level of antibiotic resistance is dependent on the population of organisms that spontaneously acquire resistance mechanisms as a result of selective pressure either from antibiotic use or otherwise, the rate of introduction from the community of those resistant organisms into health care settings, and the proportion that is spread from person to person. Antibiotic can also be increased by misuse of the drugs, refer to antibiotics given in the wrong context (e.g., for diseases that are not caused by bacteria, or bacterial infections that would get better on their own), or at the wrong dose or for the wrong duration, is called irrational use of the antibiotics. Exposing infectious agents to sub-inhibitory or sub-lethal concentrations of a drug particularly favors the development of AMR[26]. While the contribution of each factor is difficult to quantify, the overall link between the consumption of antibiotics and the prevalence of resistance across developing country and the world is undisputed [27]. Factors contributing to the non-rational use of antimicrobials at different levels Patients •Self-medication (unnecessary use, inadequate dose, substandard drug quality) • Poor adherence to regimens (medication oversight, treatment interruption) • High need (poor underlying health, poor living conditions) • Misperception (over-reliance on antimicrobials, inappropriate belief, ‘expensive is better’ myth) •Poverty-associated under-treatment (inability to afford full course of treatment) •Response to direct-to-consumer advertising by pharmaceutical manufacturers and retailers Prescribers and dispenser •Lack of knowledge (inappropriate prescribing: indication, dose, route, duration) • Inadequate diagnosis tools (lack of accurate tests at point-of-care) • Prescriptions in response to patient pressure • Exaggerated fear of bad clinical outcomes (including fear of litigation) • Economic incentives Governments and Health System •Absence or lack of implementation of national policies to contain AMR (surveillance of AMR) •Ineffective regulatory mechanisms for drug licensing and selling (substandard drug, counterfeit) •Control of drug supply (distribution and sales not regulated, informal sector sales) •Lack of hospital therapeutics committee (uncontrolled use of antimicrobials
  • 10. Hospitals by clinicians) •Lack of antimicrobial policies not updated with surveillance data and/or poor information flow •Lack of infection control committees, procedures or guidelines (inadequate hygiene practices, e.g., hand hygiene) •Lack of sterile supplies (transmission of micro-organisms via non-sterile procedures) Non-medical use of antimicrobials •Use of growth promoters in food animals •Use of antimicrobials for treatment and disease prevention (prophylaxis, metaphylaxis) in food animals, agriculture and aquaculture Private industry •Industry/wholesaler/retailer pressure to sell and/or over- promotion/misleading promotion Possible measures to overcome microbial resistance The amount of antibiotics used and the speed with which resistance develops and spreads, along with the difficulty of developing new antimicrobials, the only reasonable solution is to limit the use of antibiotics to the necessary minimum. Although this necessary minimum is difficult to define, many experts consider that global antimicrobial use can be greatly reduced and optimized. The World Health Organization (WHO) defines the appropriate use of antimicrobials as “the cost-effective use of antimicrobials which maximizes clinical therapeutic effect while minimizing both drug-related toxicity and the development of antimicrobial resistance[26]. Possible solutions  Rationalize the use of available antimicrobial agents with support of Antimicrobial Susceptibility Testing (AST) for the prevention and containment of AMR  Regional participation in AMR as pathogens are common in the region (SAARC)  Public awareness on empirical use of antibiotics  Frequent monitoring of the laboratories involved in diagnosis  Frequent monitoring of the pathogens from hospitals and treatment centers for AMR  Multi-sectorial collaboration at human animal interface regular monitoring of the distribution of antibiotics in the country
  • 11. Managing the Drug Resistance Problem 1. Limiting the Spread of Drug Resistant Bacteria Several measures could be used to prevent the spread of drug resistant bacteria. First, we could use better treatment strategies; better immunization programs; improved hygiene and nutrition; and initiatives targeting the poor populations. Second, it might be useful to establish antibiotic resistance surveillance programs. Third, better education of health care professionals is required to prevent the prescription of unnecessary antibiotics. It is noteworthy that significant investment of time, effort, and money is necessary in order to control antibiotic resistant bacteria. Of course, as long as antibiotics are used, antibiotics resistance is bound to occur. However, we might be able to reduce the drug resistance problem. One strategy is to ensure that antibiotics are used only when necessary. A second strategy is to ensure that they are used for the appropriate amount of time; that is, that the treatment is not stopped before it is completed. Patient compliance is a key problem in that respect. A third strategy for limiting drug resistance is to use antibiotics combinations. Unfortunately, while all these strategies seem sound in theory, in reality, the problem persists[5]. 2. Development of New Antibiotics Another possibility is to develop new antibiotics. However, that is not an easy task. The sad irony is that many pharmaceutical companies have decided to abandon their antibiotic development programmes when new antibiotics are needed most, since 99% of the drug candidates fail, and antibiotics are not as profitable as other, more commonly used, drugs. he traditional approach of screening microbes for antibiotics is not efficient. A second approach, which utilises target-based screening, became popular when genomics tools became available. However, although the idea is appealing, in reality, it is extremely difficult. Many companies have tried this approach, and so far they have all failed. The whole organism-based approach is more feasible but the conditions of screen need careful consideration [27, 28]. 3. Phage Therapy Phage therapy can also be used to deal with antibiotics resistance. This approach had already been used by the Russians during the Second World War, and has been gaining popularity again in recent years. Phage can be applied on the wounds of a patient to kill the bacteria, and has proven to be quite effective. Of course, it cannot be used for internal infections, and the bacteria might also develop phage resistance[29]. 4. Mobilisation of Host Defence Mechanisms Yet another approach is to mobilise host defence mechanisms. This can be achieved through the mobilisation of innate immunity such as defensins, or through the development of vaccines,
  • 12. which make antibiotics less necessary. The idea is to boast the immune response capability to control the bacterial infection. Of course, that approach is not always successful[30]. Discussion and Conclusion It is clear that bacteria will continue to develop resistance to currently available antibacterial drugs by either new mutations or the exchange of genetic information, that is, putting old resistance genes into new hosts. The development of antibiotics is among the greatest achievements of medicine in human. History, built is clear that infection disease are still of major medical and scientific concern. The ability of bacterial pathogen to gain resistance to new antibiotics has been proved. Since them early Introduction of sulfonamides and penicillin’s into clinical use. It is of great importance to rethink strategies for preventing and extending the useful life of antibiotics such as rotating the use of antibiotics and combination antibiotics therapy. Infectious and antimicrobial resistance is a major problem in Nepal, contributing to increased treatment costs, hospital stay, morbidity and mortality. The resistance is more common among Gram-negative than Gram-positive organisms, the precise extent of the problem is not known since the majority of the published reports derive from individual units or hospitals. Resistance to commonly available and affordable antimicrobials poses a major concern in the management of bacterial infection. Irrational practices in the use of antimicrobial agents in human medicine and for prophylaxis in animal may play significantly role to the emergence of multidrug-resistant (MDR) strains. Transmission of highly resistant bacteria from patient to patient within the hospital environment (nosocomial transmission) amplifies the problem of antimicrobial resistance and may result in the infection of patients who are not receiving antimicrobials. However, to minimize and control of the antibiotics resistance, several strategies should be considered when prescribing, dispensing and use of the antimicrobial therapy for the treatment, prevention and prophylaxis of infection and risk factors in human and animals. A. Give the optimal antibiotic 1. Is it necessary? 2. Is the pathogen sensitive? 3. Will the drug get to the site of infection? 4. Are therapeutic concentrations achieved at the site of infection? 5. Is toxicity acceptable (risk vs. benefit?) 6. Is the therapy cost effective? B. Administer high antibiotic loading doses for antibiotics that display concentration dependent killing. e.g. a one-time dose for STDs or single dose daily therapy for aminoglycosides.
  • 13. C. Stress good patient compliance - directly observed therapy for STDs & tuberculosis D. Simultaneous therapy with unrelated antibiotics - Synergy & decreased chance of resistance. E. Use antibiotics only when necessary -strict formulary review & use criteria F. Place absolute limits on use of certain antibiotics e.g. quinolones, amikacin, linezolid G. Reduce antibiotic exposure - animal feeds, self-limiting infections H. Randomly rotate use of different antibiotics - limits continual exposure in institution I. Use inhibitors of inactivating enzymes In sum, many institutional, environmental, behavioral, and financial factors shape the global antimicrobial resistance problem. Health economists and other social scientists studying health policy should play an important role in understanding the behaviors that underlie antimicrobial resistance and how to design incentives to coordinate a global response References 1. Yoneyama H. and katsumata R., Antibacterial resistence in bacteria and its future for novel antibitic development. Bioci. Biotechnol. Biochem., 2006. 70(5): p. 1060-1075. 2. Vila J. and Pal T., Update on Antibacterial Resistance in Low-Income Countries: Factors Favoring the Emergence of Resistance. The Open infectious Journal, 2010. 4: p. 38-54. 3. Bista R., et al., Antibiotic Resistance –A Global Issue of Concern. Asian Journal of Pharmaceutical and Clinical Research, 2009. 2(2): p. 34-39. 4. Tenover C. F., Mechanisms of Antimicrobial Resistance in Bacteria. The American Journal of Medicine, 2006. 119(6A): p. 3-10. 5. Martins A., Hunyadi A., and Amaral L., Mechanisms of Resistance in Bacteria: An Evolutionary Approach. The Open Microbiology Journal, 2013. 7: p. 53-58. 6. SibandaT. and Okoh A. I., The challenges of overcoming antibiotic resistance: Plant extracts as potential sources of antimicrobial and resistance modifying agents. African Journal of Biotechnology, 2007. 6(25): p. 2886-2896. 7. Levy S. B. and Marshall B., Antibacterial resistance worldwide: causes, challenges and responses. Nature Medicine Suppliment, 2004. 10(12): p. 122-129. 8. Oancea S. and Stoia M., Antibiotic resistance of bacterial pathogens: the magnitude of the problem from two perspectives - Romanian and worldwide. Romanian Biotechnological Letters, 2010. 15(5): p. 5591-5529. 9. Kafle K. K. and Pokhrel BM., Antimicrobial resistance at different levels of health-care services in Nepal, in Regional Health Forum. 2011. p. 9- 17. 10. Eggleston K., Zhang R., and Zeckhauser R. J., The Global Challenge of Antimicrobial Resistance: Insights from Economic Analysis. International Journal of Environmental Research and Public Health, 2010. 7: p. 3141-3149. 11. Rubin P. H., The FDA’s Antibiotic Resistance, E. University, Editor. 2004-2005. p. 34-37. 12. Karahalios, P., et al., On the mechanism of action of 9-O-arylalkyloxime derivatives of 6-O-mycaminosyltylonolide, a new class of 16-membered macrolide antibiotics. Mol Pharmacol, 2006. 70(4): p. 1271-80. 13. Rake J. B., et al., Glycopeptide antibiotics: a mechanism-based screen employing a bacterial cell wall receptor mimetic. J Antibiot (Tokyo), 1986. 39(1): p. 58-67. 14. Schmid B. and K.F. H., Resistance to beta-lactam antibiotics and aminoglycosides in gram negative bacteria. 2. Mechanism of resistance. Zentralbl Bakteriol Orig A, 1976. 234(3): p. 384-92. 15. Grape, M., L. Sundstrom, and G. Kronvall, Sulphonamide resistance gene sul3 found in Escherichia coli isolates from human sources. J Antimicrob Chemother, 2003. 52(6): p. 1022-4. 16. Trobos M., et al., Prevalence of sulphonamide resistance and class 1 integron genes in Escherichia coli isolates obtained from broilers, broiler meat, healthy humans and urinary infections in Denmark. Int J Antimicrob Agents, 2008. 32(4): p. 367-369. 17. Golemi. K. D, et al., Resistance to beta-lactam antibiotics and its mediation by the sensor domain of the transmembrane BlaR signaling pathway in Staphylococcus aureus. The Journal Biological Chemistry., 2003. 278(20): p. 19-25. 18. Senka D. and Jagoda B., Antibiotic Resistance Mechanisms in Bacteria: Biochemical and Genetic Aspects. Food Technol. Biotechnol., 2008. 46(1): p. 11-21. 19. Over U., et al., The changing nature of aminoglycoside resistance mechanisms and prevalence of newly recognized resistance mechanisms in Turkey. Clinical Microbiology and Infectious Diseases, 2001. 7(9): p. 0-8. 20. Wang F., Cassidy C., and James C., Crystal Structure and Activity Studies of the Mycobacterium tuberculosis β-Lactamase Reveal Its Critical Role in Resistance to β-Lactam Antibiotics. Antimicrob Agents Chemotherapy, 2006. 50(8): p. 2762-2771. 21. Kumar, A. and H.P. Schweizer, Bacterial resistance to antibiotics: active efflux and reduced uptake. Advance Drug Delivery Reviews 2005. 57(10): p. 486-513.
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