Indian Journal of Medical Sciences Medknow Publications on behalf of Indian Journal of Medical Sciences Trust ISSN: 0019-5359 EISSN: 1998-3654 Vol. 59, Num. 3, 2005, pp. 120-129

Indian Journal of Medical Sciences, Vol. 59, No. 3, March, 2005, pp. 120-129

Practitioners section

Antibacterial resistance: Current problems and possible solutions

Sharma Rashmi, Sharma ChamanLal, Kapoor Bhuvneshwar

Postgraduate Deptt. of Pharmacology and Therapeutics, Govt. Medical College, Jammu
Correspondence Address:216-A, Last Morh Gandhi Nagar Jammu, Tawi - 180 004, J&K
E-mail: rashmichams@yahoo.com

Code Number: ms05020

ABSTRACT

KEYWORDS: Rational drug use, Multidrug resistance, Newer antibiotics

Drug Resistance can be described as a state of insensitivity or of decreased sensitivity to drugs that ordinarily cause growth inhibition or cell death. This phenomenon has been recognized since the latter part of the 19^th century in the micro-organisms and more recently in mammalian cells in vitro and in cancer cells in vivo. The discovery of antimicrobial agents by Paul Ehrlich was one of the most remarkable discoveries, that changed the face of medical practice.[1] However, the increased global flow of antimicrobials brought with it the threat of antimicrobial resistance. Concern about the resistance increased in the late 1990′s since then, many governmental and agency reports have been published regarding the agricultural use of antibacterials, advising less use of antibacterials, appropriate choice of antibacterials and regimens, prevention of cross-infection and development of new antibacterials. As antimicrobials are frequently misused and overused in many developing countries, thus resistance to antimicrobials, has led to an increase in morbidity, mortality and cost of health care. To maintain the useful life of antimicrobial drugs in developing countries there is need to improve access to diagnostic laboratories, improved surveillance of the emergence of resistance, better regulation of the use of antibiotics, and better education of the public, doctors, and veterinarians in the appropriate use of the drugs.

MECHANISMS OF DRUG RESISTANCE

POSSIBLE SOLUTIONS

The emergence of multidrug resistant strains of Gram-negative bacteria (Pseudomonas, Klebsiella, Enterobacter, Acinetobacter, Salmonella species) and Gram-positve organisms (Staphylococcus, Enterococcus, Streptococcus species) is the more worrisome in the present therapeutic scenario. Methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci and multiresistant Gram-negative bacteria are spread primarily by direct or indirect person-to-person contact. The spread of penicillin-resistant pneumococci (PRP) and MDRTb is due to airborne transmission. Risk factors for the spread of PRP include overcrowding, tracheostomies and excessive use of penicillins for viral respiratory infections; where as for MDRTb they include poor compliance, convergence of immuno-suppressed patients, delayed diagnosis, delayed treatment, inadequate ventilation and isolation facilities. Nosocomial infection is an important factor in the spread of resistant bacteria. However, the possible solutions to fight against existing antimicrobial resistance threat are as follows:-

Rational use of Antimicrobials: Ideal antimicrobial use involves use of correct drug by the best route in right dose at optimum intervals for the appropriate period and after an accurate diagnosis.[23] The high prevalence of resistant bacteria seems to be related to irrational antimicrobial usage: 1) easy availability without prescription at drug stores, 2) injudicious use in hospitals, and 3) uncontrolled use in agriculture, animal husbandry, and fisheries. Many traditional practitioners are using allopathic drugs irrationally.[23] Moreover, it has been reported that dispensing medical practitioners (who earn by sale of medicines) prescribe more drugs than non-dispensing practitioners, thus further adding to irrational drug use.[23] In many developing countries the use of antimicrobial drugs for treating people and animals is unregulated; antibiotics can be purchased in pharmacies, general stores, and even market stalls. In the Rajbari district of Bangladesh, a survey of rural medical practitioners showed that each practitioner saw on an average 380 patients per month and prescribed antibiotics to 60% of these patients on the basis of symptoms alone.[13] Moreover, in some countries like India local production of many different antimicrobial drugs with poor quality and potency control, coupled with poor compliance of patients to costly antimicrobials further adds to the threat of antimicrobial resistance.[13] In a study from five districts of Tamilnadu state, India,: 285 general practitioners and specialists believed that antibiotics are overprescribed, especially broad-spectrum antibiotic and purulent discharge (65%), antibiotic-resistance concerns (48%), fever (40%), and patient satisfaction (29%) were proposed as the strong reasons to prescribe an antibiotic.[24] Factors like patient and time pressures, diagnostic and treatment uncertainties, poor patient compliance due to high cost and fear of antibiotic resistance are the key forces behind irrational prescription of antimicrobial combinations. Moreover, antimicrobials have been increasingly used to treat diseases in animals and plants. Antibiotics like glycopeptides and streptogramins are increasingly used as growth enhancers in subtherapeutic dose in animals further adding to the threat of antibacterial resistance.[25] The widespread use of antimicrobials in farming is also leading to emergence of resistant bacteria (Salmonella, Campylobacter) in animals, which in turn gets transmitted to humans from food of animal origin or through direct contact with farm animals.[25] It is urgently required to ban the sale of antibiotics without prescription, to use antibiotics more judiciously in hospitals by intensive teaching of the principles of the use of antibiotics, and to establish better control measures for nosocomial infections.[26] Regulation of antimicrobials for other than human use is also required. These issues require the collective action of governments, the pharmaceutical industry, health care providers and consumers.

Regulation of OTC(over the counter) drugs:- In developing countries like India, easy availability of a wide range of drugs coupled with inadequate health services result in increased proportions of drugs used as self medication compared to prescribed drugs thus resulting into impending health problems like irrational use of antimicrobials resulting into antimicrobial resistance, increased load of mortality and morbidity and economic loss.[27] The need for promoting appropriate use of drugs in health care system is not only because of the financial reasons with which policy makers and manager are usually most concerned, but also for health and medical care of patients and the community. There is need for authorities to make the existing laws regarding OTC drugs strong to ensure their rational sale and use of antimicrobials.

Preserve existing agents: In the prevailing situation of antimicrobial resistance, it is advisable to preserve the existing antimicrobials for future use and the new molecules should only be used if the old ones are ineffective. The emergence of reduced susceptibility to ciprofloxacin among Salmonella enterica serotype Typhi and serotype Paratyphi A leading to clinical failure of treatment poses a great therapeutic challenge.[28] However, Salmonella species, sensitive to chloramphenicol are increasingly emerging. It has been reported that a formulary switch to amikacin from gentamicin resulted into decline in resistance to the latter. Whereas, a shift from ceftazidime and imipenem from older cephalosporins resulted in the emergence of imipenem resistant Acinetobacter and Pseudomonas aeruginosa. [29] Recently data from Sir Ganga Ram Hospital, New Delhi also reported a correlation between Escherichia coli resistance to third-generation cephalosporins and increased cephalosporin use, as well as resistance to co-amoxyclav and its use.[30]

Development of new drugs: New groups and newer compounds from the old groups of antimicrobial drugs are being developed to meet the challenge of antimicrobial resistance [Table - 1].[2],[31],[32],[33],[34],[35],[36],[37] However, rapid development of resistance to some of these newer agents has already been reported and this trend magnifies the importance of further need for effective antimicrobial agents. Several investigational agents, such as dalbavancin, oritavancin and tigecycline, are in advanced stages of development and are likely to proceed to licensing in the next few years. With their long half-lives, these agents have an advantage of less frequent dose administration with more rapid bactericidal activity and less likelihood for development of resistance. However, because of their proven activity against highly resistant organisms, these antibacterial agents should be reserved only for life-threatening situations and/or when resistant pathogens are suspected. Recent developments in the genomic mapping of many bacteria and advances in combinatorial chemistry promise to usher in a new era of antibiotic development.

Development of inhibitors of drug destroying molecules: Beta-lactamase inhibitors (clavulanic acid, sulbactam, tazobactam) resemble beta-lactam molecules, but have very weak antimicrobial activity. They are more active against Ambler class A beta-lactamases.[38] An effective countermeasure is to employ a combination product, consisting of both a beta-lactam antibiotic and a beta-lactamase inhibitor. Unfortunately, currently available inhibitors narrowly target only class A beta-lactamases.[39]

Future approaches under development: Various alternative strategies under development are plasmid containing engineered DNA to destroy genes of pathogens, antimicrobial peptides like protegrins, defensins, squalamines, histaninv, magainins etc, immunotherapy with cytokines [interleukin(IL)-2, IL-12, TNF(tumor necrosis factor), IFN(interferon)-r], recombinant colony stimulating factors etc, vaccine induced immunity, agents attacking quorum (Gram negative and Gram positive bacteria use quorum sensing communication circuits to regulate a diverse array of physiological activities like symbiosis, virulence, competence, conjugation, antibiotic production, motility, sporulation and biofilm formation) sensing in bacteria, bacteriophages, non-antibiotics (compounds having potential to modify cell wall permeability with broad spectrum antimicrobial activity) like. phenothiazines, anaesthetic agents, antihistamines, antihypertensives and diuretics and phototherapy by using differential phototoxicity of photosensitizers in bacterial and human cells and specific antibody linked photosensitizers.[2],[40],[41],[42],[43]

Antimicrobial resistance has snowballed to a serious public health concern with economic, social and political implications. The problem of changing resistance patterns will remain an ongoing threat for both developed and developing countries. Resistance to some agents can be overcome by modifying the dosage regimens (e.g., using high-dose therapy) or inhibiting the resistance mechanism (e.g., beta-lactamase inhibitors), whereas other mechanisms of resistance can only be overcome by using an agent from a different class. Understanding of the mechanisms of action of various agents can help clinicians to identify the agents that will increase the likelihood of achieving optimal outcomes. However, large number of commercial preparations, unethical drug promotions by pharmaceutical houses and irrational prescribing habits of clinicians are the important reasons for irrational prescription of drugs in clinical practice. Physician-industry interactions appears to affect prescribing and professional behavior which may result into negative outcomes like inability to identify wrong claims about medication, positive attitude toward pharmaceutical representatives, increasing prescription rate, prescribing fewer generic but more expensive, newer medications at no demonstrated advantage, antibiotic prescribing for viral conditions, prescribing of irrational antimicrobial combinations, antimicrobial prescribing for inadequate period etc. Thus, it is highly recommended that practicing physicians should become aware of the magnitude of existing problem of antimicrobial resistance and help in fighting this deadly threat by rational prescribing.

References

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