|Year : 2012 | Volume
| Issue : 4 | Page : 384-390
Emergence and dissemination of antibiotic resistance: A global problem
R Choudhury, S Panda, DV Singh
Infectious Disease Biology, Institute of Life Sciences, Nalco Square, Bhubaneswar-751 023, Odisha, India
|Date of Submission||10-Apr-2012|
|Date of Acceptance||30-May-2012|
|Date of Web Publication||24-Nov-2012|
D V Singh
Infectious Disease Biology, Institute of Life Sciences, Nalco Square, Bhubaneswar-751 023, Odisha
Source of Support: Department of Science and Technology, New Delhi, grant no: SR/SO/HS-117/2007 to DVS, DST-WOS-A grant no: SR/WOS-A/208/2009 to RC, and fund contributed by Department of Biotechnology, New Delhi to Institute of Life Sciences, Bhubaneswar., Conflict of Interest: None
Antibiotic resistance is a major problem in clinical health settings. Interestingly the origin of many of antibiotic resistance mechanisms can be traced back to non-pathogenic environmental organisms. Important factors leading to the emergence and spread of antibiotic resistance include absence of regulation in the use of antibiotics, improper waste disposal and associated transmission of antibiotic resistance genes in the community through commensals. In this review, we discussed the impact of globalisation on the transmission of antibiotic resistance genes in bacteria through immigration and export/import of foodstuff. The significance of surveillance to define appropriate use of antibiotics in the clinic has been included as an important preventive measure.
Keywords: Antibiotics, globalisation, immigration, MRSA, surveillance
|How to cite this article:|
Choudhury R, Panda S, Singh D V. Emergence and dissemination of antibiotic resistance: A global problem. Indian J Med Microbiol 2012;30:384-90
|How to cite this URL:|
Choudhury R, Panda S, Singh D V. Emergence and dissemination of antibiotic resistance: A global problem. Indian J Med Microbiol [serial online] 2012 [cited 2020 Jan 21];30:384-90. Available from: http://www.ijmm.org/text.asp?2012/30/4/384/103756
| ~ Introduction|| |
With the advent of antibiotics, the optimism of conquest over infectious diseases came. This optimism was soon eroded with the development of antibiotic resistance in bacteria which is particularly pressing in developing countries where the infectious burden is very high and cost constrains the replacement of older antibiotics. The bacterial disease burden in India is among the highest in the world, therefore, antibiotics has a role to play in limiting morbidity and mortality.  Infections caused by multidrug-resistant (MDR) bacteria are often associated with prolonged and expensive treatment. The most important factor in the evolution of drug resistance in bacteria is the drug selection pressure, which involves use of drugs in both human and animals. In some cases, these infections may lead to higher morbidity and mortality. MDR organisms have been an epidemiological concern as they may spread locally, regionally or globally through individual contacts, poor sanitation, travel or food chain. 
The discovery of penicillin changed the world of therapeutics and opened the gate to explore the possibility of alternative roles of antibiotics in nature. Various groups showed their involvement in signalling pathways, weapons for carrying out competition in microbial-communities and as signalling molecules mediating chemical communication, like auto-inducers in quorum sensing inducing biofilm formation. 
Antimicrobial resistance has not been a priority area in most developing and in many developed countries. Although resistance against antibiotics is at very high levels in many places in India, the problem remain largely unknown because there are not much studies published and relatively there is lack of a surveillance system. The issue of antibiotic resistance came into light only when New Delhi metallo-β-lactamase-1 (NDM1), first reported in 2009. NDM1 is an enzyme produced by the gene bla NDM-1, carried on plasmids, could be transferred to many bacterial species, for example Klebsiella pneumoniae and Escherichia More Details coli, conferring resistance to multiple antibiotics, including carbapenems. 
Resistance determinants attenuating the efficacy of the antibiotics in clinical settings have shown functions that ensure self resistance. Apart from intervening resistance, all organisms requires it for detoxification of intracellular metabolites, virulence, cell homeostasis and intercellular signal trafficking. Some of these resistance determinants are transferred to the pathogen, by horizontal gene transfer, making them resistant against antibiotics that may help them to gain foothold in clinical settings. 
Causes and prevention
[Figure 1] shows the ability of bacteria to transfer genes from one bacterium to another by lateral gene transfer (LGT), which has played an integral role in evolution and diversification of antibiotic resistance in bacteria. , Primarily, drug resistance has been recognised a medical problem. However, the factors which really influence the spread of antibiotic resistance are multifaceted such as ecological, epidemiological, cultural, social and economic. When antibiotic is used either in human or animal, there is possibility of the development and spread of antibiotic resistance in bacteria. The responsibility lies to maintain antibiotic effectiveness as long as possible while allowing health benefits to accrue to the world population. Therefore, there is need of each nation to adopt strategies fitted to its own condition rather formulating strategies at the global level. 
|Figure 1: Spread of antibiotic resistance: There exists a gene pool in nature for resistance to antibiotics for self defence, homeostasis, detoxification, cell signalling, etc. In natural settings, antibiotics act as weapon, signal, cue and manipulator. Anthropogenic activities facilitate the spread and maintenance of antibiotic resistant genes (ARGs). ARGs find their way into the pathogenic organisms thereby rendering them resilient to most of the antibiotics|
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Transmission of antibiotic resistant genes
NDM-1, a newly described metallo-beta-lactamase (MBL), belong to the family of carbapenemases, was first identified in single isolates of K. pneumoniae and E. coli, both recovered from a patient repatriated to Sweden after treatment in a hospital in New Delhi, India.  Subsequent studies reported NDM-1 from the tertiary centre in Mumbai, following isolation of MDR Enterobacteriacae in hospitals in Chennai and Haryana and from drinking water and seepage water in New Delhi. Although NDM-1 may be the most widely known form of antibiotic resistance in India, resistance to a wide range of antibiotics has been reported among hospital-acquired Gram-negative organisms, for example Acinetobactor, Pseudomonas, Klebsiella, E. coli, Salmonella More Details and Neisseria More Details gonorrhoeae.  The prevalence of extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae is increasing globally, and community-onset infections with ESBL-producing E. coli are a major clinical concern in many countries including India. 
The most common bacteria causing traveller's diarrhoea are enteroaggregative E. coli (EAEC), enterotoxigenic E. coli (ETEC), Shigella, Salmonella, Campylobacter, Vibrio and Aeromonas. Few viruses and protozoa have also been reported to cause this disease. Resistance to tetracycline, nalidixic acid, co-trimoxazole and streptomycin has been reported among Vibrio cholerae strains.  MDR E. coli has been isolated from an outbreak in Ahmedabad, India.  In Spain, high incidence of quinolone-resistance in EAEC and ETEC isolated from travellers who visited India and North Africa was found. 
The first epidemic caused by a chloramphenicol-resistant Salmonella typhi was reported in 1972 in Mexico.  Subsequent outbreak was reported in Kerala, India by chloramphenicol-resistant S. typhi with high mortality. Since 1989, MDR S. typhi strains showing resistant to chloramphenicol, ampicillin and trimethoprim causing outbreaks have been reported in the Indian subcontinent, Southeast Asia and Africa.  MDR S. typhi showing resistance to first line antibiotics; ampicillin, chloramphenicol and trimethoprim-sulfamethoxazole including nalidixic acid have also been reported. Study conducted on children in New Delhi showed 67% of S. typhi had resistance to multidrug including ampicillin, co-trimoxazole, chloramphenicol and amoxicillin.  Nath and Maurya  showed MDR including ciprofloxacin and cefriaxone in S. typhi isolated over a period of two decades in Varanasi, India. Isolation of MDR strains of S. typhi (22.4%) have also been reported among travellers in South Asia. 
Emergence of MDR N. gonorrhoeae in Southeast Asia has become a public health concern. Sethi et al. reported isolation of ciprofloxacin resistant, in addition to tetracycline and penicillin resistant, N. gonorrhoeae in north India of which 22% were β-lactamase producers. Subsequently, quinolone-resistant gonorrhoea appeared in the United States and simultaneously spread to other parts of the world. Community acquired acute bacterial meningitis has been reported from a 10-year study conducted in a tertiary neurocare centre in south India. Subsequently, group-A beta haemolytic Streptococcus resistant to macrolide, tetracycline and cotrimoxazole was found in children suffering with acute pharyngotonsilitis in north and south India. 
The first methicillin-resistant S. aureus (MRSA) was detected in 1961 in a British hospital within a year of the introduction of the methicillin and in 1963, in Danish hospitals, which subsequently spread to the other parts of the world. However, MDR or MRSA was first reported in the United States in 1968. In India, the most common causes of hospital acquired infection are S. aureus and Pseudomonas aeruginosa i>. MRSA was reported from different parts of the country especially from tertiary care hospitals and special wards.  MRSA and methicillin-sensitive S. aureus (MSSA) strains showing resistance to quinolones has also been isolated from the eye hospital in Bhubaneswar, India.  Genetic diversity among MRSA and MSSA strains isolated from a community in the Caribbean's, a popular tourist destination, have been demonstrated. 
About 440,000 new cases of multidrug-resistant tuberculosis (MDR-TB) reported annually in 64 countries till date, and causing at least 150,000 deaths.  Recently, Udwadia et al . reported isolation of extensively drug-resistant tuberculosis (XDR-TB) from patients in Mumbai, which showed resistance to first line drugs (isoniazid, rifampicin, ethambutol, pyrazinamide and strepyomycin) and second line drugs (ofloxacin, moxifloxacin, kanamycin, amikacin, capreomycin, para-aminosalicyclic acid and ethionamide). Their observation was that the majority of prescription were inappropriate, and could only serve to further amplify resistance to, converting MDR-TB to XDR-TB and TDR-TB.
Traditionally medicine and public health have focused on individual pathogens. It was suggested to have a closer look on globally mobile populations, travellers' behaviours, demographics or geographic origins so that high-risk populations of travellers can be identified and appropriate preventive measures can be taken. Prevention strategies should include social mobilisation, public health education, behavioural change and communication strategies. Travel and migration medicine have important roles to play in curbing risks associated with international travel.
Immigration-related transmission of antibiotic resistant genes
There is an increased risk of transmission of antibiotic resistant genes (ARGs) with population mobility. The emergence of high-level penicillin resistance by Streptococcus pneumoniae was first described in South Africa in 1977. The relationship between original MDR South African isolates of S. pneumoniae and other resistant clones indicated the spread of pneumococcal clones was in part parallel to human migration from and to South Africa and UK. Bhat et al . reported isolation of closely related MSSA strain ST398 in samples collected from humans in northern Manhattan, New York, USA, and in the Dominican Republic and correlated his finding in relation to the travel between the two regions as northern Manhattan has large population of first-generation immigrants from the Dominican Republic. Another viewpoint was that the live poultry markets of northern Manhattan could serve as the reservoir of ST398, which is an animal-associated strain.
Due to the rapid increase of international air travel during the past several decades, emergence of drug-resistant pathogens in a specific location should not be considered as an isolated event but seen in larger global context exemplified by the spread of NDM-1 and MRSA. Future research should aim at better methods of data accumulation by incorporating drug resistance patterns across countries, movement of ARGs across national boundaries and assessment of how those ARGs are progressing.
Spread of antibiotic resistant genes through foodstuff
Modern food production facilitates the emergence and spread of antibiotic resistance through intensive use of antimicrobial agents and international trade of both animals and food products. Walsh and Fanning  reported that sublethal dose exposure to biocides may select bacteria having enhanced multidrug efflux pump activity, which provide both resistance to biocides and cross-resistance to multiple antibiotics. Whereas antibiotics are used to treat human illness, these antibiotics have also been used in livestock and poultry, although in low doses in animal feed, to promote growth and improve production of animal products. In India, there is no regulation of the use of antibiotics in food, animals and dairy. Precisely there is no indicator to see the effect of agricultural antibiotics use on resistance level in the general population, but World Food and Agricultural Organisation, and World Organisation of Animal Health found clear evidence of adverse effect on human health due to resistant organism resulting from non-human usage of antimicrobials. 
The preliminary route of transmission among food, animals and humans is via food products. Studies conducted in India on animal products, for example honey showed that continuous long-term exposure to low level of antibiotics lead to antibiotic resistance in pathogenic organisms.  Overuse of antibiotics in modern farming practices and food-producing animals accentuates the transmissibility of mobile-genetic elements. The spread of these mobile genetic elements carrying antibiotic resistance determinants, possibly by globalisation of food trade led to the universal dispersal of ARGs.
The impressive growth in aquaculture industry in developed and developing countries has led to increase in the use of antibiotics in aquatic environments.  The presence of class I integron, in Salmonella weltevedren, carrying dehydrofolate reductase (dhfrA7) and dihydropteroate synthetase genes was reported in fish and shellfish obtained from Mangalore, India . Different serovars of Salmonella were also reported from sprouts and varieties of freshwater and marine fish from India. About 82% of the strains carrying class I integron were resistant to more than one antibiotic and Salmonella oslo showed resistance to 13 antibiotics . MDR strain of Salmonella typhimurium DT104 emerged after the approval of fluoroquinolones use in food-producing animals in the 1990s. Highly resistant strain of Salmonella serotype Newport, Newport-MDRAmpC, resistant or less-susceptible to at least nine antimicrobials including cephalosporins made the task difficult to treat children with serious cases of Salmonellosis More Details.
To see the presence of putative virulence factors and antibiotic resistance in S. aureus strains from intra-mammary infections of river buffalos, which are important source of milk in South-Asian countries were undertaken. Authors found high incidence of MDR S. aureus strains among the clinical isolates. High level of resistance to tetracycline, gentamycin, streptomycin, penicillin and ampicillin were observed and correlated with the use of these antibiotics in the veterinary hospital . MRSA strains ST398 showing resistance to trimethoprim, tetracycline and phenicol / lincosamide / oxazolidinone / pleuromutilin / streptograminA have been isolated from professionals in contact with pigs in several European countries, for example Belgium, Germany, Italy, Spain and Denmark, as well as in Canada and Singapore. 
In food safety, tracing and surveillance systems play a key role in detecting food borne ARGs and outbreaks. To do so World Health Organisation has established Global Foodborne Infections Network (GFN)  and INFOSAN another network which is joint initiative between WHO and Food and Agriculture Organisation (FAO). These organisations enable trans-border collaboration and assistance among food safety officials. It is evident that forces of globalisation may modify and amplify development of infections and thereby transmission of ARGs. There is a necessity of integrated approach for its management, based on the principles of international law regulating provision of medical services, human rights, environmental protection, trade and other human activities.
| ~ Use, Overuse and Misuse of Antibiotics|| |
Irrational use of antibiotics has driven the problem of antibiotic resistance in bacteria.  Data on Staphylococcal ocular infections show a positive co-relation between the use of fluoroquinolones in the clinic and fluoroquinolone resistance in the isolates.  In India, there is enormous and growing problem of antibiotic use and abuse in neonatal care. It was rightly warned that 'unless neonatologists stop using broad spectrum antibiotics for prolonged periods, resistance to antibiotics will rise. . A study conducted in the crowded area of Dharavi, Mumbai by Udwadia et al . revealed that only 5 of 106 private practitioners could prescribe a correct prescription for MDR tuberculosis. Use of antibiotics is not limited to therapeutics that accounts only less than half of antibiotics produced commercially, but also as growth promoters in animal farms, aquaculture and as anti-coccidial agent in poultry besides their use in research, industry, biocides in hand care and household cleaning products. 
Lack of rapid and easy diagnostics is another factor contributing to injudicious use of antibiotics.  Easy and rapid diagnosis of causative organism and their antibiotic susceptibility pattern will help physician to choose targeted therapies.  An important interventional measure is the dose/duration of treatment. Careful selection of dosing regimens based on pharmacodynamic and pharmacokinetic properties of drugs will prevent emergence of resistance and selection of mutants (mutant prevention concentration).  Antimicrobial Stewardship Programmes (ASPs) promotes the appropriate use of antimicrobials by selecting the appropriate dose, duration and route of administration. Implementation of an ASP requires a multidisciplinary approach which involves education, empirical use of broad-spectrum antibiotic, post-prescription review, de-escalation of therapy, intravenous-to-oral (IV-to-PO) switch therapy and dose optimisation. 
Socioeconomic factors-lack of regulations
Emergence of resistance to new drugs has been noted in the developed world. This could be because of production and use of new drugs in treatment of the disease. However, the ARGs are rapidly spreading in the developing world because of rapid urbanisation where sanitation and hygiene is poor and contributing in the emergence and dissemination of antibiotic resistant bacteria. Sahoo et al .  reported prevalence of drug-resistant E. coli in stool, cow-dung and drinking water in coastal and non-coastal areas of Odisha, India. The study clearly pointed out the positive impact of proper healthcare facilities available to healthcare practitioners, sanitation and public awareness on the transmission of ARGs. India has the largest number of private sector physicians in the world. Often, these practitioners have dubious qualifications and unregulated prescribing practices.  The causes of injudicious prescription of antibiotics are highly varied, and depend on relationship between the doctor and the patient. An unstable doctor/patient relationship, due to lack of continuity of care, patient pressure in a stress-loaded society, the doctor's personal characteristics are perceived as the reasons behind prescribing the non-pharmacological antibiotics. 
Local surveillance and availability of data on the local antibiotic resistance pattern, awareness among the physicians and general public, rapid diagnosis and resistance pattern of the pathogen are important to use antibiotics judiciously.  Proper implementation and enforcement of legislation at the level of manufacture, delivery and disposal of antibiotics are necessary steps which should be taken for the prevention of pharmaceutical contamination of the environment. 
Hospital settings, especially, intensive care units (ICUs) are the hot-spots of ARG transmission. Diwan et al . quantified antibiotic residues in waters associated with a hospital in India and assessed their association with quantities of antibiotics prescribed in the hospital and the susceptibility of E. coli found in the hospital effluent. A positive correlation was observed between the isolates from two sources highlighting the need of further research in this area. It is recommended that hospital waste must be treated before its release into the environment. 
It has been shown that the rates of hospital-acquired bacterial infection and frequency of antibiotic resistance can be reduced by decreasing the rate of turnover of patients, applying the transmission control measures and the use of second-line drugs for which there is no resistance.  Recent study by Kouyos et al . has shown the impact of hospital size on the transmission of ARGs. Small hospitals typically lead to considerably lower resistance levels than large hospitals. However, the beneficial effect of small hospital size may be reduced if bacteria are transmitted indirectly through the environment. Therefore, reducing environmental transmission might be particularly important in small hospitals.
| ~ Pollution and Waste Disposal|| |
Pollution is broadly defined as harmful inputs of chemical, biological and physical waste products into the environment from various sources like hospitals, homes, urban and agricultural industries.  Environmental pollution caused by pharmaceutical waste, heavy metals and other waste releases influence the transmission of ARGs.  For the efficient transmission of ARGs by LGT, three steps are required, namely, (i) delivery of the donor DNA into the recipient cell, (ii) incorporation of the alien genes into the genome of the recipient cell and (iii) expression of the acquired genes in a manner that befits the recipient organism. The first two steps are largely indiscriminate and can take place by three mechanisms: (i) transformation, (ii) transduction and (iii) conjugation.  Dubey and Ben-Yehuda  demonstrated that non-conjugative plasmids can be transferred from one cell to another through nanotubes resulting in transmission of hereditary features of recipient cells.
Both freshwater and marine systems act as a reservoir for bacteria that carry ARGs and play active role in the transmission of ARGs among bacteria. The main routes by which these bacteria enter into aquatic systems are through treated and untreated sewage, hospital waste and agricultural run-off.  It has been argued that phages survive better in the aquatic systems than in their bacterial hosts, therefore, could be suitable intermediaries for the transfer of ARGs among bacteria.  Biofilm formation and the presence of sediment matrix in aquatic systems facilitate the process of transfer of antibiotic resistant determinants among bacteria.
Wastewater treatment and monitoring for ARGs are important for the containment of the antibiotic resistance. Improved wastewater treatment plants that could remove all kinds of antibiotics are required. It was observed that adsorption is an important mechanism of removal for both ciprofloxacin and tetracycline, but not for sulfamethoxazole and trimethoprim. Rahube and Yost  have underscored the need for greater assessment of antibiotic resistant plasmid diversity and persistence in the environment following their introduction by anthropogenic activities such as release of wastewater effluent, and application of activated sludge as fertiliser. There can be various checkpoints where we can keep an eye on antibiotic production and its consumption [Figure 2].
|Figure 2: Various checkpoints to address antibiotic production and consumption|
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Continuous interaction between the commensal bacteria and the host macroorganism, mandated extensive study on role of commensals in the spread of ARGs.  There are three major bacterial ecosystems in humans: (i) the intestine; (ii) skin and (iii) the upper respiratory tract.  Commensals inhabiting the workers associated with farms and hospitals and hospitalised patients may have been the source of bacteria harbouring ARGs. The resistance, once developed, can be transmitted to the pathogens invading the host. Alternatively, under certain conditions/changes in the microbial niches, the non-pathogenic commensal bacteria may gain the status of pathogens. Acquisition of ARGs from the neighbouring community by these pathogenic commensals may create therapeutic problems.
Various researchers have suggested antibiotic cycling (or rotation), the scheduled alternation of use of varying classes of antibiotics, as a valid option to decrease antibiotic resistance.  However, the reservoir of resistant genes present in the environment may reduce the effect of antibiotic cycling; therefore, extensive research in this area is warranted.
Surveillance: An Important Preventive Measure
The risk of transmission of antibiotic resistant (AR) bacteria either within the country or from one country to another country grows as the 'global village' shrinks. Early detection of resistant bacteria is crucial to prevent further transmission of the newly developed ARGs. For understanding the emergence and spread of antibiotic resistance, it is important to undertake both forms of surveillance-antimicrobial resistance and antimicrobial use. Documentation of antibiotic use will provide information for developing dosing strategies to reduce emergence of resistance. A positive correlation was found between the quantity of antibiotics prescribed in the hospital and antibiotic residue levels in the hospital wastewater. Based on the suggestions by American Academy of Microbiology, an ideal resistance surveillance system should include the following:
- A rigorous, co-ordinated surveillance network to provide quantitative data that can be used to assess the current and future impacts of drug resistance.
- Surveillance should begin at local level and collected and compared at national level.
- Careful sampling strategies.
- A system of easy-to-access global surveillance and molecular epidemiological data could help track critical organisms and phenotypes.
- Surveillance programs should be designed as Alert Systems.
- Data should be available both electronically and in real time.
- An electronic surveillance system should feed into a reference laboratory that can collect the unusual resistant isolates and integrate information from multiple sources to identify trends and outbreaks.
- Surveillance should also include monitoring for commensal organisms.
| ~ Conclusions|| |
The consequences of antimicrobial resistance are  longer duration of illness,  higher mortality,  treatment with expensive drugs,  increased burden on the health system,  negation of technological advances in the medical sector, complex surgeries, transplantations and other interventions,  development of patient as a reservoir of resistant organisms for the community and health-care workers  and huge impact on the economy. 
Thus, antibiotic resistance is a public health problem. It has to be addressed with a multifaceted, coordinated approach. A well integrated effort comprising of wide range of stake holders, including health care professionals, veterinarians, agriculturists, pharmaceutical manufacturers, government, media representatives, consumers and other interested parties can bring about the required change. Research on role of commensals and environmental pollution on the spread of ARGs should be encouraged. Developing alternative/synergistic therapies to antibiotics is the need of present day therapeutics when mankind is threatened with the return of pre-antibiotic era.
| ~ Acknowledgments|| |
This study, in part, was supported by Department of Science and Technology, New Delhi, grant no: SR/SO/HS-117/2007 to DVS, DST-WOS-A grant no: SR/WOS-A/208/2009 to RC, and fund contributed by Department of Biotechnology, New Delhi to Institute of Life Sciences, Bhubaneswar.
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[Figure 1], [Figure 2]
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