|Year : 2015 | Volume
| Issue : 1 | Page : 1-5
Preventing bacterial resistance: Need of the hour
Gajanan S Gaude
Department of Pulmonary Medicine, KLE University's J. N. Medical College, Belagavi, Karnataka, India
|Date of Web Publication||5-Jun-2015|
Dr. Gajanan S Gaude
Department of Pulmonary Medicine, KLE's University J. N. Medical College, Belagavi, Karnataka
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Gaude GS. Preventing bacterial resistance: Need of the hour. Indian J Health Sci Biomed Res 2015;8:1-5
The introduction of antibiotics in the early 1940s has been recognized as a major milestone in the history of medicine. The synthesis of arsphenamine, in the fight against syphilis, by Paul Ehrlich marked the dawn of the antimicrobial era. The middle of the 20 th century was the period when true antibiotics effective against bacteria were developed. Antituberculous and antifungal agents then followed. Antivirals were introduced to complete the arsenal against pathogens. Resistant strains of Staphylococcus aureus emerged shortly after the introduction of penicillin, and within 10 years, 59% of S. aureus organisms were penicillin resistant. The remarkable ability of almost all species of bacteria, fungi, and viruses to adapt and prevail over hostile mechanisms used by antibiotics has presented clinicians with the prospect of a postantibiotic era. Antimicrobial resistance, a global problem, is particularly pressing in developing countries where the infectious disease burden is high, and cost constraints the replacement of older antibiotics with newer, more expensive ones. Management of common and lethal bacterial infections has been critically compromised by the appearance and rapid spread of antibiotic-resistant bacteria. The bacterial disease burden in India is among the highest in the world;  consequently, antibiotics will play a critical role in limiting morbidity and mortality in the country. As a marker of disease burden, pneumonia causes an estimated 410,000 deaths in India each year,  and it is the number-one killer of children.  Many of these deaths occur because patients do not have access to life-saving antibiotics when and where these are needed. At the other extreme, antibiotics are used in situations where these cannot be expected to improve the patient's condition, particularly as a treatment for the common cold and uncomplicated cases of diarrhea.
"Drug selection pressure" is the single most important factor in the evolution of drug resistance in bacteria. The reasons for drug pressure are multi-factorial and involve both human and animal use. Although drug resistance is primarily a medical problem, the factors that influence the spread of resistance are ecological, epidemiological, cultural, social, and economic. Patients, physicians, veterinarians, and healthcare facilities and retailers-from large pharmacies to local drug sellers-have little motivation (economic or otherwise) to acknowledge the consequences of their use of antibiotics on others, especially on future generations. Every time an antibiotic is used-whether appropriately or not, the probability of the development and spread of antibiotic-resistant bacteria is increased. , Antibiotic effectiveness is a globally shared resource and a shared responsibility. That responsibility is to maintain antibiotic effectiveness as long as possible while allowing the maximum possible health benefits to accrue to the world's population. The actions needed to achieve this goal cannot be decided globally. Each nation must adopt strategies tailored to its own conditions.
Most bacteria have multiple routes to resistance to any drug and once resistant, can rapidly give rise to vast numbers of resistant progeny. Natural selection favors mechanisms that confer resistance with the least fitness cost and those strains that are least burdened by their resistance. Selection may also favor determinants that prevent their own counter selection and resistant strains with enhanced survival ability or virulence. To this genetic and biochemical potential must be added the wide variety of bacteria that cause opportunistic infections in vulnerable human patients and the fact that the numbers of vulnerable patients grow steadily with advances in other fields of medicine. In short, the emergence of resistance is profoundly unsurprising; what is remarkable is how long it has taken for the problem to become a source of public, as well as scientific, concern. Resistance can result from modification of an antibacterial's target or from functional bypassing of that target, or it can be contingent on impermeability, efflux, or enzymatic inactivation.  All members of a species may be resistant. Alternatively, resistance may arise in hitherto susceptible organisms via mutation or DNA transfer. The aim of this article is not to catalog individual mechanisms or their prevalence - that has been done elsewhere - but to emphasize the continuing dynamism of resistance, its impact on therapy, and the difficulty - but also the potential for combating the problem.
| Mechanisms of Bacterial Resistance|| |
Antibacterial use disrupts the microbial ecology of the patient, unit, or population. Entire species may be selected. The increasing role of enterococci as opportunist pathogens in the past 20 years partly reflects increasing use of fluoroquinolones and cephalosporins, to which these organisms are inherently resistant.  As DNA is replicated, uncorrected base substitutions occur randomly, at a frequency of 9-10 per gene.  In addition, copying errors may lead to the partial or complete deletion of individual genes. As a result, the targets of antibacterials may be altered, drug-inactivation or efflux systems may be up- or down-regulated, and uptake pathways (porins and active transporters) may be lost or activated. Resistance genes or their repressors also can be activated or inactivated by the migration of insertion sequences. Approximately, 3% of Bacteroides fragilis ates have the carbapenemase gene ccrA (cfiA), but its enzyme product is expressed only if an insertion sequence has migrated upstream of this structural gene.  Classical experiments showed that antibacterials cause the selection of preexisting variants, not the emergence of new mutants. This observation entirely agrees with the precepts of Darwinian evolution, but a twist is given by the observations that bacteria can become hypermutable through inactivation of the proofreading and DNA mismatch - repair systems that normally correct DNA copying errors.  Hypermutators have up to 200-fold higher mutation rates than normal cells and so are more likely to become resistant to a first antibacterial by mutation. Once selected by this first drug, they are then "primed" to develop resistance to further agents. To this extent, antibacterials may cause the emergence of variants with an increased propensity to develop further resistance. Other mechanism for bacterial resistance is by DNA transfer.  Transfer of DNA is most often via plasmids. These existed long before humans used antibacterials but did not then carry resistance determinants, or rarely did so. Since the advent of the antibacterial era, plasmids have, however, proved to be the ideal vehicles for recruitment and dissemination of resistance genes. Within plasmids, resistance genes are often carried by transposons, which can shuttle determinants between more and less promiscuous plasmids, or into and out of the chromosome. Some transposons are directly transmissible between bacteria, particularly (but not exclusively) among Gram-positive species. Resistance genes also may be transferred by lysogenic bacteriophage. This latter mechanism seems likely with the mecA determinant staphylococci, which has never been located on mobile DNA but which has spread among a few S. aureus lineages, and among different coagulase-negative species. 
Beta-lactamases are enzymes capable of hydrolyzing the beta-lactam ring of penicillins, cephalosporins, and other related antibiotics, thereby making them ineffective. Cephalosporins were continuously modified to the extent that extended-spectrum members of this class (such as ceftazidime, ceftriaxone, and cefotaxime), possessing better stability against beta-lactamases, became available. Enteric Gram-negative bacilli with transferable resistance to the extended-spectrum cephalosporins were first reported in Europe in the mid-1980s. These strains were reported in the United States shortly thereafter. The term extended-spectrum beta-lactamases refers to plasmid-mediated beta-lactamases that hydrolyze penicillins, cephalosporins, and aztreonam, but are inhibited by the beta-lactamase inhibitors, such as sulbactam, clavulanate, and tazobactam. Genes encoding the ESBLs are carried on plasmids, which are circular and supercoiled segments of DNA, physically separate from the bacterial chromosome, and replicate independently of the chromosome. Because these genes are carried on transposable elements, they can be disseminated widely among Gram-negative bacilli. Genes targeted by mutations include TEM-3 to -28, and SHV-2 to -6, TEM and SHV being the representative beta-lactamases.  Studies have demonstrated that the ESBLs arose as a result of selective pressure created by the use of extended-spectrum cephalosporins. Many ESBL-producing organisms do not appear to be resistant to the newer cephalosporins and aztreonam upon "routine" susceptibility testing. Therefore, laboratories must have methods to specifically look for ESBLs. In our laboratory, once our automated system detects an ESBL, a special double-disk test is performed to confirm the ESBL characteristic.
Impact of resistance
The consequences of resistance are harder to define than microbiologists, health care managers, and politicians might wish. Some patients recover despite inadequate treatment, exactly as some recovered before antibacterials were available. The infection of others failed to respond despite appropriate therapy. In compromised patients, it often remains debatable whether infection or an underlying disease was ultimately fatal. Perhaps the clearest link between in vitro resistance and in vivo responses is between penicillin and gonorrhea. It has been observed that that the incidence of complications, including reoperation, abscess formation, and wound infection, increased 2-fold if empirical therapy for intra-abdominal sepsis failed to cover all the pathogens subsequently isolated and that the length of hospital stay was likewise extended.  The incidence of complications rose further if inadequate empirical regimen was not modified when resistant pathogens were isolated. There had been 2-fold higher mortality among intensive care unit (ICU) patients and those with ventilator-associated pneumonia (VAP) when the pathogens proved resistant to the antibacterials used empirically. Many of the failures in these series reflected infection by Pseudomonas aeruginosa or methicillin-resistant S. aureus, which were not well-covered by the empirical regimens routinely used. Risk factors for isolation of these pathogens and so for poor outcomes included the previous use of antibacterials and previous hospitalization. Such factors, as well as the likely pathogens and their likely local resistance patterns, should always be taken into account when designing empirical regimens for hospital units. Other effects are more insidious. Physicians and surgeons are forced to use previously reserved agents as first-line therapy. These may be inherently less potent or more toxic that classical regimens: Vancomycin is increasingly used as a first-line antistaphylococcal (and for prophylaxis) but is less convenient to administer safely and less bactericidal than the semisynthetic antistaphylococcal penicillins, which themselves are 100-fold less active than benzylpenicillin against fully susceptible staphylococci. Previously reserved agents - now used earlier - may be undermined by resistance. Finally, resistance adds cost: Treatment failures extend the length of hospital stay or demand repeated physician visits; hospital beds are blocked to new patients, and productive time is lost. If new or hitherto reserved antibacterials are needed as therapy, these are usually more expensive than previous regimens. These costs seem unlikely to decline in the future, especially with the growing demand of regulators and the new costs of genomics-based drug discovery.
| Drug Resistance Prevention and Control|| |
Antibiotic resistance and antibiotic use: Two complementary types of surveillance are recommended: Surveillance for antibiotic resistance and surveillance for antibiotic use. This supports a recommendation made in the national policy document. By itself, surveillance of any type will not change the antibiotic use or the spread of resistant organisms, but knowing resistance levels and tracking them over time is a powerful tool to support real changes. Once the link between resistance and antibiotic use is accepted, tracking antibiotic use can be used as a surrogate for changes in resistance patterns. To some extent, these patterns can produce evidence for whether interventions are working, and can help identify problem areas, as is the case for antibiotic resistance surveillance.  Surveillance results/data can also be fed into standard treatment guidelines and essential drug lists.
Distributing standard treatment guidelines
Standard treatment guidelines have been developed at various levels, from the hospital (e.g., for diarrhea and pneumonia) to national-level programs (e.g., for tuberculosis and HIV/AIDS).  These guidelines should be tailored to local situations and specific to levels of care. However, employees at all levels in the healthcare system often have little knowledge of the content of these STGs. One means of distributing STGs is through drug-bug "pocket cards:" These cards would provide summaries of locally recommended treatments for common conditions, and prescribers would be encouraged to carry and refer to these.
Infection control interventions
Hospitals create their own ecology in the bacterial-human interface. The use of antibiotics is much more intense in hospitals than in the community, and highly resistant bacteria may be found and spread there. In response, infection control interventions have been developed to contain bacterial infections in hospitals, including increased hand-washing, isolation rooms, reminders to limit catheter use, and use of gloves and gowns. The Ministry of Health and Family Welfare task force recommends that all hospitals create an infection control plan, committee, and team. It further recommends that clinical microbiologists conduct audits, such as by spot-checking prescribing sheets in wards. 
Continuing education of doctors, nurses, dentists, pharmacists, and veterinarians is a perpetually attractive opportunity for instructing these professionals about antibiotic use and resistance. In India, continuing education is beginning to be required for certain professionals. A new Medical Council of India rule that doctors must attend 30 h of continuing medical education every 5 years to maintain their licenses will help encourage such courses.  Workshops on antibiotics could be offered as part of this, and similarly for other professions. Furthermore, the establishment of clinical microbiology and infectious diseases post graduate courses should be encouraged.
The draft guideline from the Center for Disease Control (CDC)  for control of drug resistance in the health-care setting recommends the following seven measures: Administrative support and intervention measures, education, judicious use of antimicrobial agents, surveillance, standard and contact precautions, environmental measures, and decolonization. In a review by Kollef et al.  focusing on antibiotic resistance in the ICU, the antimicrobial strategies deemed effective at limiting the emergence of resistance included the establishment of protocols and guidelines to avoid unnecessary use of antibiotics, hospital formulary restrictions, use of narrower-spectrum antibiotics, use of quantitative bacterial cultures in instances such as VAP, combination antibiotic therapy, routine input by infectious disease specialists, antibiotic cycling, area-specific modification of antibiotic use, and prudent use of newer antimicrobial agents. However, the authors advocate the use of selective digestive decontamination only in high-risk patients in an outbreak situation in conjunction with infection-control practices.
In the same review, the authors advocate the following nonantimicrobial strategies for the prevention of resistance: Reducing the duration of mechanical ventilation; minimizing use of central venous catheters with strict hygiene precautions during insertion; vaccination against Haemophilus influenzae, Streptococcus pneumoniae, and influenza virus (to name just a few); hand washing; reducing nursing and house-staff workloads in the ICU; and use of gloves and gowns. Even though transmission of microorganisms occurs mainly from the hands of health-care workers, and hand washing remains the most important preventive measure, a large observational study demonstrated the following: Nurses were more likely to wash hands than physicians; hand washing was more likely to occur during weekends; pediatric care units had the highest rate of hand washing compliance; ICUs had the poorest rates of compliance; the higher the workload, the lower was the compliance; and the overall compliance rate was about 50%. The CDC,  in a campaign to prevent antimicrobial resistance in health-care settings, has elucidated the following 12 steps: Vaccinate, get the catheters out, target the pathogen, access the experts, practice antimicrobial control, use local data, treat infection, not contamination, know when to say no to vancomycin, stop antimicrobial treatment, isolate the pathogen, and break the chain of contagion.
Antimicrobial resistance is here to stay. In a telling commentary by Livermore,  the author reports that it may be naive to anticipate reaching a grand control over resistance. The hope perhaps lies in slowing down the development of newer resistance while continuing to develop new agents at a rate sufficient to keep ahead of bacteria.
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