Received: 02.06.2021 Revision: 09.06.2021 Accepted: 18.06.2021 Published: 30.06.2021
Zareen Unnisa1, Mohammed Fareedullah*2 and Sheema Jabeen1
1Pharm.D Intern, Department of Pharmacy Practice, Deccan School of Pharmacy
2Associate Professor & Head, Department of Pharmacy Practice, Deccan School of Pharmacy
Abstract: AMR is defined as the ability of microorganism to survive the exposure of antibiotics at a dose that would kill or hinder their growth. Large population of India is usually a blame for easy dissemination of resistant strains. Poor public health indicators, growing incomes, and the availability of cheap antibiotics over the counter without a prescription are merged to generate the optimal conditions for a large scale selection and spread of resistant genes in India. In the previous years the use of antibiotics has been increasing steadily. The data from Medline, Google search and others were collected and later evaluated by authors for discrepancies and recent advancements was presented in the form of description tables and figures. This review discusses about the development of multidrug resistant bacteria that increased at an alarming rate over the past decades and caused serious problems. There is a vital need to promote new antibiotic therapies due to substantial increase of resistant strains of bacteria. Hence it requires the combined efforts of all members of society including patients, prescribers, pharmacist, individual to international regulators and policy makers to combat against this global burden of AMR.
Antibiotics are described as chemical agents originated from a microorganism that kill or hinder the growth of another microorganism (Byrne, M. K. et al., 2019). In contrast to other class of drugs used in clinical settings antibiotics acts on microorganism rather than host (Sabtu, N. et al., 2015) and are the fundamental drugs for prevention and control of various infectious diseases and loss of its antibacterial activity is causing a threat to public health (Farooqui, H. H. et al., 2018).
Sir Alexander Fleming highlighted antimicrobial resistance (AMR) as a potential problem soon after the introduction of the first effective antimicrobial penicillin (Singhai, A. 2018). AMR is defined as the ability of microorganism to survive the exposure of antibiotics at a dose that would kill or hinder their growth. AMR is a threat to the adequate hindrance and cure of an constantly rising spectrum of infections caused by bacteria, parasites, viruses and fungi (Sabtu, N. et al., 2015).
Irrational method of prescribing antibiotics in the hospital has been increasing globally which has lead to the development of multipledrug resistant bacteria (Alemkere, G. et al., 2019). There is a strong association between empirical use of antibiotics and development of AMR (Farooqui, H. H. et al., 2018).
The factors contributing to the development of AMR are
Over use and misuse of antibiotics.
Low quality of antibiotics.
Self medication or taking antibiotics without prescription.
Poor infection control practices.
Lack of appropriate diagnostic testing systems.
High burden of diseases.
Patients non compliance to the treatment given.
Following unprofessional suggestions in treating various illness (Ha, T. V. et al., 2019).
Hence, it is becoming a major threat to developing countries like India where the rate of infectious diseases and development of antimicrobial resistance is high (Singh, S. K. et al., 2019).
Many studies have documented that in India rates of antimicrobial resistance are high and India is posing a threat because of high cost of treatment of resistant infections and less number of antibiotics available. In addition other studies reported that availability of essential medicines in general and the availability of antibiotics in particular is finite in India (Farooqui, H. H. et al., 2018).
Numerous approaches like education programmes, guidelines and interventions have been developed to spread the awareness about correct usage of these precious drugs and to save these antibiotics from the development of bacterial resistance (Alemkere, G. et al., 2019; Ha, T. V. et al., 2019; & Singh, S. K. et al., 2019). AMR can be decreased by using antibiotics wisely based on the guidelines of Antimicrobial Stewardship Programs (ASPs), diagnostic testing, culture and sensitivitytesting (CST), pharmacokinetic and pharmacodynamic properties of antibiotics, therapeutic response, effects on various microorganism, together with development of new antibiotics. This global problem can be decreased only by the combined efforts of representatives of society for assuring the continued efficacy of antibiotics (Lee, C. R. et al., 2013).
Materials and Methods:
This review was conducted during august 2019 to November 2019. Data was collected from Medline, Google search and others. The keywords used for the search included: antibiotic usage, antimicrobial resistance, India, strategies, novel drugs, role of pharmacist. Primarily the literature search was carried out for the appropriate information on Indian perspective since the year 2003 till date which yielded 40 references out of which 25 were included for analyzing. These articles were evaluated for discrepancies and information on recent advancements was presented in the form of description, tables and figures.
Antibiotic Usage in India:
Since the burden of infectious diseases in India is high, it is the one of the largest consumers of antibiotics in the world (Dixit, A. et al., 2019) and the per capita was increased by 66% from 2000 to 2010 (Gopalkrishnan, R. et al., 2019) and there is a rapid increase in the sale of antibiotics. Even though there is decrease in the rate of communicable diseases the sale of antibiotics rapidly increases (Dixit, A. et al., 2019). Large population of India is usually a blame for easy dissemination of resistant strains (Laxminarayan, R., & Chaudhury, R. R. 2016). Poor public health indicators, growing incomes, and the availability of cheap antibiotics over the counter without a prescription are merged to generate the optimal conditions for a large scale selection and spread of resistant genes in India (Laxminarayan, R., & Chaudhury, R. R. 2016).
In the previous years the use of antibiotics has been increasing steadily. The following chart shows the consumption of antibiotics in India from the years 2005 to 2015 (figure 1). The use of cephalosporin’s increased rapidly from 2005 to 2015 when compared to other antibiotics and there was also a marked increase in the use of broad spectrum antibiotics whereas the increase in the use of other antibiotics like amino glycosides and tetracycline’s was very slow.
Figure Image is available at PDF file
Figure 1: Antibiotic Use in India from 2005 to 2015
On the other hand antibiotics like flouroquinoles, macrolides and trimethoprim there was a slight decrease in their usage from 2005 to 2015.
This data not only shows the increased use of antibiotics but also proves that most often the antibiotics are used in inappropriate ways.
Systemic antibiotics use in India from 2008 to 2012:
The figure (figure 2) below revealed that there was a significant variation in the consumption of systemic antibiotics across different antibiotic classes from the year 2008 to 2012. For example, there was an increase in the consumption of cephalosporins from 12.7% to 16.3%, likely there was also an increase in the use macrolide antibiotics during this time period. However, there was a significant decline in the use of quinolones from 30.7% to 23.4%. whereas there was a declining trend in the consumption of sulfonamides, tetracyclins and aminoglycosides from 2008 to 2011 (Farooqui, H. H. et al., 2018).
Figure Image is available at PDF file
Figure 2: Systemic Antibiotic Use in India from 2008 - 2009
Development of Resistance:
Antimicrobial resistance is the capability of microbes to overcome the effects of antibiotics (Gandra, S. et al., 2017). Development of antimicrobial resistance is an alarming problem throughout the world and has obscured the activity of antibiotics in reducing mortality rate caused due to infectious diseases. It is approximated that Asia will have 4.7 million deaths directly caused by AMR by the year 2050 (Gopalkrishnan, R. et al., 2019).
According to recent studies AMR in India is widespread (Gopalkrishnan, R. et al., 2019) and has highest resistance among bacteria that usually causes infections to public (Gandra, S. et al., 2017) with up to 12-59% of Escherichia colibeing extended spectrum beta lactamase producers (ESBL) and 30% being carbapenemase producers (CP). Klebsiella pneumoniae has appeared to be a highly resistant microbe accounting for 50% resistance to carbapenems and expediting increase resistance to polymyxins. The outbreak of MRSA contributed to 30% nationwide (Gopalkrishnan, R. et al., 2019).
Based on the reports of ICMR 2017 and the study based on national scale laboratory by Gandraet.al. 2016 the data obtained on resistance of gram negative bacteria is illustrated in the following tables 1 and gram positive in table 2 (The Center for Disease Dynamics Economics & Policy. 2018; & Gandra, S. et al., 2016).
Among the three gram negative bacteria mentioned in the table resistance developed by cephalosporin and flouroquinolones was high when compared to other drugs but the table also indicates that the resistance developed by cephalosporin, flouroquinolones and piperacillintazobactam decreased in 2017 when compared to 2014 whereas the resistance developed by carbapenems increased in 2017 (Gandra, S. et al., 2017; & The Center for Disease Dynamics Economics & Policy. 2018) (figure 3).
Figure Image is available at PDF file
Figure 3: Resistance Pattern of Cephalosprins 3rd Generation
Among the gram positive bacteria the percentage of MRSA was 46.5% in Gandra et al., 2014 study whereas in ICMR 2017 the percentage was 39% which indicates that there was decrease in percentage of MRSA in 2017 when compared to 2014. table2
On the other hand the percentage of resistance developed by enterococcus faecium was 10.5% in 2014 as reported by Gandraet.al whereas there was an increase in resistance in 2017 as reported by ICMR (27%) figure 4
Figure Image is available at PDF file
Figure 4: Resistance Pattern of Vancomycin
Strategies to Overcome the Process of Resistance:
Antibiotic resistance is the universal problem but it can be solved at national or regional level. Rational use of antibiotics can be increased by limiting the overuse & misuse of antibiotics and to through better public health. National strategies should be implemented to change the norms antibiotics use that should target both public and health care providers (The Center for Disease Dynamics Economics & Policy. 2018).
The desire to get rid of this global threat is declining due to decrease discovery of novel antibiotics and the evolution of resistance among the microbes to this novel drugs as the adjust rapidly to the prevailing antibiotics. Therefore effective strategies are required to curtail this major problem (Lee, C. R. et al., 2013).
Finding strategies in contrast to the growth of AMR is an extensive universal challenge for the healthcare sectors and for the public health. Recent decades has witnessed a significant increase in the growth of resistant strains to one or multiple antibiotics globally (Frieri, M. et al., 2017).
The development of multidrug resistant bacteria has increased at an alarming rate over the past decades and cause serious problems. Hence there is a paramount need to find solutions to fight AMR (Frieri, M. et al., 2017).
The combined efforts are required at different levels. Different measures for fighting AMR can be conducted at international, national, community, hospital, individual and patient level (Uchil, R. R. et al., 2014). figure 5
Figure Image is available at PDF file
Figure 5: measures to minimize AMR
The Development of Novel Antibiotics:
Antibiotics are the special class of drugs that directly affect the growth of causative microorganisms rather than targeting human biochemical process. The best way to fight AMR is to continue to develop novel antibiotics. Although, nearly all the classes of antibiotics being used today were originated during the period 1930-1960 (Gopalkrishnan, R. et al., 2019) Figure 6
Figure Image is available at PDF file
Figure 6: antibiotic resistance pipeline. On the left, antibiotics introduced and on the right antibiotic resistance identified
Source: bioMerieux (https://amr.biomerieux.com)
Antibiotics discovery had confronted a discovery gap over the last 30 yrs and no new classes of antibiotics were introduced in the market until 2000, when linezolid was approved. As for now, novel drugs have been originated to reinstate the older, progressively the ineffective ones. There is a prevailing lack of new antibiotics with less pharmaceutical companies employed in the process of drug development since 1990s (Annunziato, G. 2019).
The situation is so frightful that the WHO cautioned that we may enter a post antibiotic era within this century. Undoubtedly, it has been approximated that if no new antibiotics are discovered by 2050, 10 million people will die globally as a direct cause of AMR. Therefore, there is a vital need to promote new antibiotic therapies due to substantial increase of resistant strains of bacteria hitched with the lack of novel drugs effective in killing these microorganisms (Martín-Rodríguez, A. J. et al., 2016).
Pharmaceutical industries are the primary source for the development of novel drugs. In this view government has devised approaches to drive the pharmaceutical industry to do research and development of novel drugs. The government had developed a National Action Plan for Combating Antibiotic-Resistant Bacteria (NAPCAB) which works under the collaboration of NIH and pharmaceutical industries for conducting clinical trials of molecules showing promising antimicrobial activity. Additionally, the Congress government has passed Generating Antibiotics Incentives Now (GAIN) Act which was signed into law by president of USA Obama in 2012. FDA approved two drugs Avycaz and Cresemba under this Act in 2015. Hence, these approaches taken by the government to increase development of antibiotics is producing some positive results (Singhai, A. 2018).
Indeed, only after a few years of golden age of antimicrobials, alarming signals of AMR were observed. It is universally accepted that the use of antibiotics agents effectively controlled and even eradicated the infectious disease, but their overuse/or misuse has caused development of resistant strains (Annunziato, G. 2019).
In order to circumvent the problems of AMR and need of novel drugs, radical new ways are being developed.
There are as follows
Host immune biomarkers (https://amr.biomerieux.com)
Role of Pharmacist:
AMR has become a universal health assert as a result of irrational use of antimicrobials posing great threat to human health (Balamurugan, K. et al., 2018). The preceding rates of AMR are occupying silently the highest cause of mortality. The relationship between the overuse/ misuse of antibiotics and the emergence of AMR is atomizing antibiotic use across the healthcare units and this remains a vital component for international and national efforts to save antibiotics for future use and to curtail the problem of rising of resistance among microorganism (Broom, A. et al., 2015).
One of the major cause particularly in developing countries are people who use antimicrobials as on their own, without realization of actual therapy which not only effect the individual but also the entire society (Balamurugan, K. et al., 2018). To curb the problem of development and spread of AMR requires combined efforts of all healthcare professionals (Sakeena, M. H. F. et al., 2018). Consequently, one of the vital dispute facing countries is to make sure the fine use of these antibiotics. In this relation the role of pharmacist is important as the pharmacist is the main trader and controller of antibiotics (International Pharmaceutical Federation (FIP). 2015) are the vital members of healthcare team who plays an important in medication usage and outlines the instructions in regard to relevant usage of medicines (Sakeena, M. H. F. et al., 2018).
Almost 40% of all prescriptions involving antibiotics are disproportionate. Therefore pharmacist in conjunction with prescriber can best reform the situation by making proper use of antibiotics in their countries (Balamurugan, K. et al., 2018). Clinical Pharmacist have a fixed role in hospitals to promote the practice of evidence based medicine and cost effective prescribing (Wickens, H. J. et al., 2013).
Researchers have recently recommended that pharmacist are best placed to engage in decision making and to improve the atomization of antibiotic use (Broom, A. et al., 2015). As most of the doctors has less time for research and development in drug utilization because of their busy schedule (Balamurugan, K. et al., 2018).
Common errors in antibiotic prescribing are:
Inappropriate choice of antibiotic spectrum
Prescribing antibiotics with little evidence of bacterial infection,
Excess use of intravenous agents,
Unessential lengthy courses of antibiotics.
These results in rise of escapable side effects for the patients, increase economic burden and increase AMR for the community as a whole (Weller, T. M. A., & Jamieson, C. E. 2004). Hence education and training of pharmacist are important for changing the pattern and use of antibiotics as a part of multidimensional strategy that might influence the behavior of healthcare team members and consumers (Sakeena, M. H. F. et al., 2018). Moreover, education of consumers is also a vital part to combat AMR and pharmacist can counsel the consumers in the best way regarding safe and appropriate antibiotics practices. Therefore developing countries should consider the efforts of well qualified and trained pharmacist (Sakeena, M. H. F. et al., 2018).
India being a highly populated nation, it is hard to control the irrational use of antibiotics and moreover WHO reported India as one of the countries with immense rates of drug resistance and high injudicious use of antimicrobials.
In this view India has started implementing antimicrobial guidelines, stewardship programs in the past years led by pharmacists and also India has introduced a Pharm D program in 2008 which has strengthened the department of Pharmacy Practice through the out coming students with good knowledge of rational use of drugs (Balamurugan, K. et al., 2018). Hence there is a need to address the roles and responsibilities of a pharmacist to fight against AMR.
AMR is one of the most significant threats not only to the public health but to the community as a whole. Moreover there is an emergence in the spread and development multidrug resistant (MDR) patterns in gram positive and gram negative species and is posing a great challenge to clinician to treat them with conventional antibiotics. Hence requires development of novel treatment option. Preventing the spread of infectious diseases and AMR is the best stool by implementing proper strategies at international and national level. Since the rates of AMR are high in India, addressing the problems of injudicious use of antibiotics are vital. These can be achieved by promoting rational use of antibiotics, development of novel drugs, diagnostic testing, antimicrobial susceptibility testing. Hence it requires the combined efforts of all members of society including patients, prescribers, pharmacist, individual to international regulators and policy makers to combat against this global burden of AMR.
Zareen Unnisa & Sheema Jabeen : data acquisition and data analysis, literature search, manuscript preparation, manuscript editing, Mohammed Fareedullah: conceptualization, design, manuscript review & supervision, final approval , validation.
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