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Antimicrobial resistance has developed as a serious threat due to overuse and misuse of antibiotics. Key bacterial infections like pneumonia, meningitis and tuberculosis are showing resistance to first-line drugs. This results in prolonged illness, higher mortality and increased healthcare costs to use second and third-line drugs. Resistance develops through genetic mutations and transfer of genes between bacteria. Improving antibiotic use can help control the emergence and spread of resistance.
Prerna presentation
- 1. DEVELOPMENT OF ANTIMICROBIAL RESISTANCE AND ITS PREVENTION Soumya Ranjan Parida Basic B.Sc. Nursing 4th year Sum Nursing College
- 2. INTRODUCTION Since discovery during the 20th century, antimicrobial agents have substantially reduced the threat posed by infectious diseases. The use of these "wonder drugs", combined with improvements in sanitation, housing, and nutrition, and the advent of widespread immunization programmes, has led to a dramatic drop in deaths from diseases that were previously widespread, untreatable, and frequently fatal. Over the years, antimicrobials have saved the lives and eased the suffering of millions of people. By helping to bring many serious infectious diseases under control, these drugs have also contributed to the major gains in life expectancy experienced during the latter part of the last century.
- 3. These gains are now seriously jeopardized by another recent development: the emergence and spread of microbes that are resistant to cheap and effective first choice, or "firstline" drugs. The bacterial infections which contribute most to human disease are also those in which emerging and microbial resistance is most evident: diarrhoeal diseases, respiratory tract infections, meningitis, sexually transmitted infections, and hospitalacquired infections Some important examples include penicillinresistant Streptococcus pneumoniae, vancomycinresistant enterococci, methicillinresistant Staphylococcus aureus, multiresistant salmonellae, and multiresistant Mycobacterium tuberculosis. The development of resistance to drugs commonly used to treat malaria is of particular concern, as is the emerging resistance to antiHIV drugs.
- 4. Consequences The consequences are severe. Infections caused by resistant microbes fail to respond to treatment, resulting in prolonged illness and greater risk of death. Treatment failures also lead to longer periods of infectivity, which increase the numbers of infected people moving in the community and thus expose the general population to the risk of contracting a resistant strain of infection.
- 5. When infections become resistant to firstline antimicrobials, treatment has to be switched to second or thirdline drugs, which are nearly always much more expensive and sometimes more toxic as well, e.g. the drugs needed to treat multidrugresistant forms of tuberculosis are over 100 times more expensive than the firstline drugs used to treat nonresistant forms. In many countries, the high cost of such replacement drugs is prohibitive, with the result that some diseases can no longer be treated in areas where resistance to first line drugs is widespread. Most alarming of all are diseases where resistance is developing for virtually all currently available drugs, thus raising the spectre of a postantibiotic era. Even if the pharmaceutical industry were to step up efforts to develop new replacement drugs immediately, current trends suggest that some diseases will have no effective therapies within the next ten years.
- 6. Causes Microbes cause infectious diseases, and antimicrobial agents, such as penicillin, streptomycin, and more than 150 others, have been developed to combat the spread and severity of many of these diseases. Resistance to antimicrobials is a natural biological phe nomenon that can be amplified or accelerated by a variety of factors, including human practices. The use of an antimicrobial for any infection, real or feared, in any dose and over any time period, forces microbes to either adapt or die in a phenomenon known as "selective pressure". The microbes which adapt and survive carry genes for resistance, which can be passed on.
- 7. Bacteria are particularly efficient at enhancing the effects of resistance, not only because of their ability to multiply very rapidly but also because they can transfer their resistance genes, which are passed on when the bacteria replicate. In the medical setting, such resistant microbes will not be killed by an antimicrobial agent during a standard course of treatment. Resistant bacteria can also pass on their resistance genes to other related bacteria through "conjugation", whereby plasmids carrying the genes jump from one organism to another. Resistance to a single drug can thus spread rapidly through a bacterial population. When antimicrobials are used incorrectly for too short a time, at too low a dose, at inadequate potency; or for the wrong disease the likelihood that bacteria and other microbes will adapt and replicate rather than be killed is greatly enhanced.
- 8. Much evidence supports the view that the total consumption of antimicrobials is the critical factor in selecting resistance. Paradoxically, underuse through lack of access, inadequate dosing, poor adherence, and substandard antimicrobials may play as important a role as overuse. For these reasons, improving use is a priority if the emergence and spread of resistance are to be controlled.
- 9. MECHANISM OF ANTIMICROBIAL RESISTANCE INACTIVATING ENZYMES These enzymes degrade antibiotics such as aminoglycodies inactivating enzymes, beta lactames, chloramphenicol acetyl transferase. Aminoglycosides such as gentamicin, amikacin, netilmicin and tobramycin are broad spectrum antimicrobials used to treat infections caused by aerobic gram negative bacilli. The most common mechanism of resistance to aminoglycosides is through producing aminoglycoside modifying enzymes that inactivate the drugs.
- 10. ALTERATION OF THE TARGET SITE Structural modification result in a lower affinity of the target site for the antibiotics so that the antibiotic binding to the target is decreased or totally eliminated. For penicillin resistance in streptococcus pneumoniae the mechanism involves alteration in one or more of the penicillin binding protien. MRSA which codes for an altered penicillin binding protein renders all beta lactames ineffective.
- 11. ALTERATION OF BACTERIAL CELL MEMBRANE There is a structural difference between the cell walls of gram positive and gram negative organism. Gram positive have a single cell membrane with external layer of peptidoglycan. Gram negative bacteria posess an inner plasma membrane and outer cell membrane includes lipopolysaccharides which tightly bound hydrocarbon molecule, which impede hydrophobic substances like erythromycin and nafcillin. Porin proteins- are arrange to form water filled diffusion channel through which antibiotics traverse.
- 12. Negatively charged molecules move slowly across the membrane than the more positively charged molecules. Beta lactams with buly side chains such as piperacillin and cefaperazone cross the membrane poorly. Resistance to imipenem is by decreased permeability through this porin channel.
- 13. ANTIBIOTIC EFFLUX In some bacteria an important mechanism of resistance is active removal of antibiotics from the bacterial cell so that intracellular concentration of antibiotics never reach a sufficiently high level to exert antimicrobial activity. This efflux mechanism is energy depandant this is a prime defense for bacteria against tetraclines, macrolids and meropenum.
- 14. Key factors in emergence of resistance The emergence and spread of multiply resistant organisms represent variety of factors that include mutations in common resistance genes that extend their spectrum of activity; the exchange of genetic information among microorganisms in which resistance genes are transmitted to new hosts; the development of environmental conditions in hospitals and communities (selective pressures) that facilitate the development and spread of resistant organisms; the proliferation and spread, in some cases globally, of multiply resistant clones of bacteria; and the inability of some laboratory testing methods to detect emerging resistance phenotypes
- 15. Genetic exchange. The ability of bacteria to exchange genetic information by a variety of mechanisms has been recognized for >40 years. The most commonly recognized modes of exchange are transformation and transduction (among gram-positive organisms), and conjugation (among gram-negative organisms). Among gram-negative organisms, plasmid transfer among a variety of enteric bacilli led to prolonged outbreaks of multiresistant organisms in hospitals. More recently, the acquisition of multidrug resistance plasmids by strains of Vibrio cholerae and Shigella dysenteriae has made control of diarrheal disease and dysentery difficult in many African countries
- 16. The ability of gram-positive organisms to exchange DNA via conjugation is often overlooked by microbiologists; however, it is a very effective means for transmitting antimicrobial agent resistance genes among organisms. The sharing of aminoglycoside resistance genes among several species of staphylococci and enterococci is one example of an active pathway. Genetic exchange pathways also exist between gram- positive and gram-negative organisms in which the transfer of kanamycin resistance genes has been observed.
- 17. Enterococci provide an excellent example of how organisms can accumulate resistance genes by genetic exchange and develop into multidrug- resistant pathogens. The first vancomycin-resistant enterococci (VRE) were reported in the United States in 1989; most were recovered from patients in intensive care units. In 1996, the percentage of VRE isolates in intensive care units approached 14%, and many of these were also resistant to ampicillin, gentamicin, and streptomycin, leaving few therapeutic options. .
- 18. Most of the resistance determinants in these multiresistant strains were borne on mobile plasmids and transposons. The genetics of enterococcal resistance to glycopeptides is complex and involves a number of unique determinants. In addition to the vanA (high-level), vanB (moderate- level), and vanC (low-level, intrinsic resistance) determinants in enterococci, 2 novel determinants were recently described. The vanD determinant was first recognized in New York City in 1990 and has subsequently been recognized in a Boston medical center
- 19. Initially, VRE appeared primarily in animals in Europe, but in the United States it appeared almost exclusively in hospitalized patients. Infections with VRE in humans are emerging throughout the world. VRE now appear to be present in all 50 states in the United States and in Europe, South America, South Africa, Australia, and Taiwan . Just as the organisms have disseminated, so have the resistance genes also migrated to other species and genera. The vanA determinant has been detected in Oerskovia turbata, Arcanobacterium haemolyticum, and Bacillus circulans, and the vanB gene has been detected in Streptococcus bovis. The transfer of the vanA gene from E. faecalis to S. aureus has been accomplished in the laboratory, but naturally occurring isolates of S. aureus with high-level vancomycin resistance have yet to be recovered from humans or animals.
- 20. Selective pressures in health care and community settings Selective pressure refers to the environmental conditions that enhance the ability of bacteria to develop resistance to antimicrobial agents and to proliferate. This ability to survive may be the result of acquisition of new DNA (as is often the case with VRE) or it may be due to spontaneous mutation, as is often the case for rifampin-resistant organisms. Expanded use of antimicrobial agents in hospitals and in sites outside the hospital increases the selective pressure for resistant organisms to emerge in these settings. The intensity of use of antimicrobial agents appears to be proportional to the resistance levels in organisms in hospital settings. Recent studies have shown that, among staphylococci, enterococci, and pseudomonads, levels of resistance are highest in organisms from patients in intensive care units (where use of antimicrobial agents is highest) but are lower in patients from other wards in the hospital and are even lower in outpatient settings
- 21. Selection of resistance in bacteria can occur in a variety of ways. In a study reported by Rasheed et al., one strain of E. coli that was isolated, on multiple occasions, from the blood samples of a young girl with aplastic anemia was originally noted to carry a TEM-1 β-lactamase. During therapy with extended-spectrum cephalosporins, the organism acquired an SHV-1–type β-lactamase that, because of hyperproduction, began to manifest resistance to ceftazidime and other extended-spectrum cephalosporins. A spontaneous mutation in the SHV-1 β-lactamase led to the development of a novel SHV-8 variant with enhanced ceftazidimase activity, increasing the ceftazidime MICs from 16 μg/mL to >64 μg/mL. This was the result of a single amino acid change from aspartate to asparagine at position 179. Simultaneously, the organism lost 1 of its porins (outer-membrane channels), thus becoming resistant to cephamycins (i.e., cefoxitin and cefotetan). All these changes occurred within 3 months while the child was undergoing multiple courses of anti-infective chemotherapy.
- 22. Detection of Resistance to Antimicrobial Agents in the Clinical Laboratory Decreased susceptibility to vancomycin in S. aureus can be difficult to detect in the laboratory. Disk diffusion does not differentiate vancomycin-susceptible strains from those with increasing resistance; however, use of vancomycin agar screening plates made with either Brain Heart Infusion agar or Mueller-Hinton agar works well. This is one of several examples of novel resistance phenotypes that are difficult to detect using traditional antimicrobial agent susceptibility testing methods. During the past several years, various proficiency testing studies, including those conducted by the Centers for Disease Control and Prevention (CDC) and the College of American Pathologist, have highlighted the difficulties that laboratories experience in detecting several of the newer bacterial resistance mechanisms with current laboratory methods
- 23. Data from proficiency testing studies conducted by the CDC suggest that laboratories not only have difficulty detecting ESBL-producing strains, but often do not follow National Committee for Clinical Laboratory Standards (NCCLS) guidelines regarding the appropriate antimicrobial agents to test and report. For example, 6 of 38 laboratories did not test an extended-spectrum cephalosporin or aztreonam against gram-negative bacilli reported to be isolates from blood cultures. Perhaps the most difficult phenotypes to detect are decreased susceptibility to β-lactams in pneumococci and decreased susceptibility to vancomycin in staphylococci
- 24. Clinical laboratories must be constantly aware of changes that occur in the susceptibility patterns of pathogenic microorganisms. However, growing restraints on the personnel and supply budgets in hospital-based microbiology laboratories may hinder the widespread implementation of the newer tests that improve detection of these novel phenotypes. In fact, newer MIC testing systems often use only 1–3 dilutions of a drug to determine resistance. Often the highest dilution tested on commercially prepared test panels is only in the intermediate range. These breakpoint panels eliminate important quantitative information, such as the actual MICs of antimicrobial agents, and result in a report that lists only the interpretive categories of susceptible, intermediate, and resistant. Thus, the ability to monitor the gradual increase in MICs of a particularly species over time is lost.
- 25. Circulation of Multiply Resistant Bacterial Clones The final issue of importance is the development and global spread of multiply resistant bacterial pathogens. In the past, multidrug resistance was often equated with decreased virulence; however, loss of virulence clearly has not occurred with several globally disseminated strains of pneumococci and S. aureus. The serotype 23F Spanish clone of S. pneumoniae, which is resistant to penicillin, chloramphenicol, tetracycline, and trimethoprim-sulfamethoxazole, and the serotype 6B isolate, which originated in Spain and spread throughout Iceland in the early 1990s, are 2 examples of multiresistant organisms that maintained their virulence. In the United States, the Spanish 23F clone was noted as a cause of infections among children who attended a day care center. Some isolates of this clone have been reported to have acquired resistance to cefotaxime and erythromycin in addition to its already established multidrug resistance profile
- 26. Another example of a highly virulent, multidrug resistant clone was the trans-Canadian spread of a single clone of methicillin-resistant S. aureus that was introduced into a small hospital in Canada via a patient who arrived from India with dermatitis. Although the patient spent only 4 h in the hospital, 4 cases of nosocomial methicillin-resistant S. aureus were linked to the patient in that institution. An additional 21 cases were observed in a Vancouver hospital to which the patient was transferred, and 26 cases were observed in a Manitoba hospital where the patient also was admitted
- 27. Factors that encourage the spread of resistance The emergence and spread of antimicrobial resistance are complex problems driven by numerous interconnected fac-tors, many of which are linked to the misuse of antimicrobi-als and thus amenable to change. In turn, antimicrobial use is influenced by an interplay of the knowledge, expectations, and interactions of prescribers and patients, economic in-centives, characteristics of a country's health system, and the regulatory environment.
- 28. Patient-related factors are major drivers of inappropriate antimicrobial use. For example, many patients believe that new and expensive medications are more efficacious than older agents. In addition to causing unnecessary health care expenditure, this perception encourages the selection of re-sistance to these newer agents as well as to older agents in their class
- 29. Self-medication with antimicrobials is another major factor contributing to resistance. Self- medicated antimicrobials may be unnecessary, are often inadequately dosed, or may not contain adequate amounts of active drug, especially if they are counterfeit drugs. In many developing countries, antimi-crobials are purchased in single doses and taken only until the patient feels better, which may occur before the patho-gen has been eliminated. Inappropriate demand can also be stimulated by marketing practices. Direct-to-consumer advertising allows pharmaceu-tical manufacturers to market medicines directly to the public via television, radio, print media, and the Internet. In par-ticular, advertising on the Internet is gaining market pen-etration, yet it is difficult to control with legislation due to poor enforceability.
- 30. Prescribers' perceptions regarding patient expectations and demands substantially influence prescribing practice. Physi- cians can be pressured by patient expectations to prescribe antimicrobials even in the absence of appropriate indications. In some cultural settings, antimicrobials given by injection are considered more efficacious than oral formulations. Such perceptions tend to be associated with the over- prescribing of broad-spectrum injectable agents when a narrow-spec-trum oral agent would be more appropriate. Prescribing “just to be on the safe side" increases when there is diagnostic uncertainty, lack of prescriber knowledge re-garding optimal diagnostic approaches, lack of opportunity for patient follow-up, or fear of possible litigation. In many countries, antimicrobials can be easily obtained in pharmacies and markets without a prescription
- 31. Hospitals are a critical component of the antimicrobial re- sistance problem worldwide. The combination of highly sus-ceptible patients, intensive and prolonged antimicrobial use, and cross-infection has resulted in nosocomial infections with highly resistant bacterial pathogens. Resistant hospital-acquired infections are expensive to control and extremely dif-ficult to eradicate. Failure to implement simple infection control practices, such as handwashing and changing gloves before and after contact with patients, is a common cause of infection spread in hospitals throughout the world. Hospi-tals are also the eventual site of treatment for many patients with severe infections due to resistant pathogens acquired in the community. In the wake of the AIDS epidemic, the preva-lence of such infections can be expected to increase.
- 32. Veterinary prescription of antimicrobials also contributes to the problem of resistance. In North America and Europe, an estimated 50% in tonnage of all antimicrobial production is used in food-producing animals and poultry. The largest quantities are used as regular supplements for prophylaxis or growth promotion, thus exposing a large number of animals, irrespective of their health status, to frequently subtherapeutic concentrations of antimicrobials. Such wide-spread use of antimicrobials for disease control and growth promotion in animals has been paralleled by an increase in resistance in those bacteria (such as Salmonella and Campylobacter) that can spread from animals, often through food, to cause infections in humans.
- 33. STRATEGIES TO COMBACT ANTIMICROBIAL RESISTANCE Physicians education and awarness to prevent misuse of antibiotics. Rigorous adherence to infection control guidelines. Reducing the use of antibiotics with high potential for resistance and rotating them with low potential resistance drugs. Good antibiotics stewardship with antibiotic policies that work.
- 34. Eliminating inappropriate therapy for ‘look alike’ non infectious clinical syndromes that mimic sepsis. De-escalation of broad spectrum antibiotic therapy once sensetives are in. Optimising adequate antibiotic dosing. Discouraging antibiotic weaning.
- 35. THANK YOU.