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Year : 2019  |  Volume : 51  |  Issue : 5  |  Page : 291--295

Emerging antimicrobial resistance and newer tools to address the resistance

Pardeep Kumar Goyal, Ankita Semwal, Ajay Prakash, Bikash Medhi 
 Department of Pharmacology, PGIMER, Chandigarh, India

Correspondence Address:
Prof. Bikash Medhi
Department of Pharmacology, PGIMER, Chandigarh - 160 012
India




How to cite this article:
Goyal PK, Semwal A, Prakash A, Medhi B. Emerging antimicrobial resistance and newer tools to address the resistance.Indian J Pharmacol 2019;51:291-295


How to cite this URL:
Goyal PK, Semwal A, Prakash A, Medhi B. Emerging antimicrobial resistance and newer tools to address the resistance. Indian J Pharmacol [serial online] 2019 [cited 2019 Dec 16 ];51:291-295
Available from: http://www.ijp-online.com/text.asp?2019/51/5/291/271640


Full Text



Antimicrobial resistance (AMR) is globally a serious threat in public health causing unfavorable effects which could be clinical (death or treatment failure) or economic (care cost and stay period).[1] The current data on antibiotic resistance are signaling to a difficult situation as this could land any country into drastic health as well as economic crisis. There is a global increase of 65% in antibiotic consumption in the year 2015 as compared to 2000.[2] It is estimated that by 2050, there would be a decrease in gross domestic product rate by 23.5% as a consequence of AMR.[1]

A political declaration has been adopted by global leaders including India at UN general assembly in 2006 which calls for global collaborative response to threat of AMR.[3] National action plan for AMR has been released by India which outlined various strategies to tackle AMR which includes awareness of AMR through effective training, optimizing the use of antibiotics in healthcare settings, promoting the investments for AMR research, reducing the risk of infection, and strengthening of Indian leadership on AMR. The national policy also mentioned proposal for color-coding antibiotic strips and newer molecules (carbapenems and tigecycline) to stop the use of these antibiotics outside the tertiary care hospitals. Red line campaign was launched in New Delhi in 2016 as central government has made it mandatory to display a 5 mm-thick red vertical line on packaging of prescription-only antibiotic drugs.[3]

Despite these efforts, AMR continues to increase and there is still a need to adopt more strategic plans in this regard. Various tools have been developed and adopted by many countries after recognizing the need for antimicrobial stewardship and rational drug use for antibiotics. These include tools which can diagnose infection or antibiotic resistance (diagnostic tools), tools to measure antibiotic consumption (surveillance tools), or tools to guide physician in selecting appropriate antibiotics (e.g., access, watch, reserve (AWaRe) tool, be antibiotic AWaRe tool).

 Surveillance Tools



Surveillance means 'The continuing systematic collection, assay and data interpretation in relation to health that would be essential for the purpose of planning, utilization and evaluation of the data in public health.'[4] Any variation in antibiotic resistance over the time can also be monitored with these tools. These tools aid in compiling data for antibiotic consumption which reflects the current situation of antibiotic use. Periodic measurement of consumption can increase the awareness among prescribers and policy-makers about antibiotic use and aids in defining the levels of optimal antibiotic use. These tools can also assess the impact of interventions. Data related to antimicrobial consumption can be measured with WHO-recommended defined daily dose (DDD) criteria or AWaRe tool.

Defined daily dose

WHO has recommended anatomical therapeutic classification (ATC) and DDD for the monitoring of drug utilization and the research for the improvement in antibiotic prescription and use.[5] In ATC, the active substances for drugs are classified in different five levels of hierarchy. DDD is the average maintenance dose/day for a particular drug, required for its main indication in adults. The DDD is based on reviews and available information of pattern of doses used in different countries. Prescribed daily dose may vary from DDD, and by applying DDD metrics, it is possible to examine changes in drug utilization of antimicrobials over time, make international comparisons, and evaluate regulatory effects.[5]

One DDD is designated as per ATC code and its route for administration. The DDDs for antibiotics are assigned on the basis of the average daily dose of ongoing treatment. Antibiotics for systemic use are classified under J01 category which are further subdivided for instance J01A (tetracyclines), J01B (amphenicols), J01C (beta lactam, penicillins), J01D (other beta lactams), J01E (sulfonamides and trimethoprim), J01F (macrolides), (lincosamides and streptogramins), J01G (aminoglycosides), J01M (quinolones), J01R (combination of antibiotics), and J01X (other antibiotics).[6]

Access, watch, reserve tool (AWaRe tool)

“AWaRe Tool” was launched with aim to use narrow-spectrum access antibiotics while reserving broad-spectrum antibiotics for “hardest to treat infections.” AWaRe tool provides the recommendation about antibiotics for 21 most common infections. The WHO advised the adoption of AWaRe approach which classifies antibiotics into three groups.[7]

Access category

This includes narrow spectrum antibiotics of choice for the most common infections. In this group, maximum number of antibiotics belongs to β–lactam (52.63%), followed by aminoglycosides (15.78%), macrolides (5.26%), and tetracyclines (5.26%).

Watch category

These antibiotics are only indicated for specific limited number of infections and are more prone to the target of antibiotic resistance. These drugs are preferred over access antibiotics in serious infections. Beta lactams (54.54%) constitute maximum share of watch group antibiotics followed by macrolides (18.18%), aminoglycosides (9.09%), and carbapenems (9.09%).

Reserve category

These include antibiotics that must be used sparingly or preserved and used only as a last resort, when other options for antimicrobials get failed. The reserve group is majorly constituted of polymyxin (28.57%) followed by β-lactams (14.28%) and aminoglycosides (14.28%).

Surveillance of antibiotic consumption can be done by evaluating percentage of antibiotics prescribed from each above category. Other indexes which can be used to measure antibiotic consumption include amoxicillin index, access to watch ratio, watch percentage, and access percentage.[8]

 Access, Watch, Reserve Versus Defined Daily Dose as Metrics for Antibiotic Consumption



Complexity of DDD metrics requires specialist knowledge of pharmacological as well as therapeutic systems. Denominator data are not always available for the most commonly used metrics such as “Defined daily dose/1000 inhabitants/day” and it also demonstrates only limited information about quality of antibiotic use.[9] This metrics could not be useful to measure antibiotic consumption in pediatric population as there is a wide variation in weights in hospitalized children. On another hand, AWaRe tool can be simple easy to understand tool for physicians as well as policy makers. Application of this tool helps in accessing information about absolute and relative consumption of antibiotics which indicates overall antibiotic use in a country. This tool can be useful in measuring antibiotic consumption in pediatric populations by using various metrics.

Global antimicrobial resistance surveillance system

This surveillance system supports the global action plan for reduction in AMR. The aim of the tool is to support the global surveillance and analyze the data for strengthening the evidence to deal with AMR. Countries can participate in global AMR surveillance system (GLASS) by establishing AMR surveillance systems. GLASS focuses on eight most priority bacteria (Escherichia coli, Klebsiella pneumoniae, Acinetobacter spp., Staphylococcus aureus, Streptococcus pneumoniae, Salmonella spp., Shigella spp., and Neisseria gonorrhoeae) and 4 types of specimens (blood, urine, stool, and genital swabs) taken from patients. There are three core components of a national AMR surveillance system: a national coordinating center, national reference laboratory, and one or more surveillance sites. The data gathered at the surveillance sites flow through the national coordinating center to GLASS.[10]

Diagnostic tools

Rapid diagnostic tests (RDTs) for infectious diseases have become an integral tool for antimicrobial stewardship program. These diagnostic tools have shown to decrease mortality, shorten hospital stay, and decrease healthcare costs. Study by Cals et al. in Netherlands demonstrated that diagnostic tests are cost-effective with cost saving of €22 per patient, and moreover, patients enrolled in intervention group required less antibiotics and less physician visits.[11]

Some of the RDTs are described as follows:

Resistance Plus GC

The Food and Drug Administration (FDA) has granted breakthrough status to this test which guide treatment decisions in treating gonorrhea with ciprofloxacin instead of ceftriaxone (broad spectrum and more prone to resistance). This tool detects both N. gonorrhea and sequences in the gyrA gene of the bacteria associated with susceptibility or resistance to ciprofloxacin.[12]

Accelerate pheno test blood culture kit

This diagnostic test can detect systemic infections and aid in the identification of suitable antibiotic within 6 h. This kit identifies different 14 species of bacteria and 2 different species of yeast that causes systemic infections, and also, it provides antibiotic sensitivity data for a subset of the identified organisms.[13]

Vidas brahms assay

US FDA has extended the use of the Vidas Brahms procalcitonin (PCT) assay to aid the physicians in decision to put a patient on antibiotic treatment or not in case of community-acquired pneumonia (CAP). This test uses PCT as a biomarker. It helps in antibiotic management decisions in patients with CAP. Low levels of PCT suggest a viral infection or other noninfectious cause of diseases whereas high titers of PCT suggest bacterial infection as a cause of disease.[14] Application of PCT kinetics as a decision maker tool resulted in less duration of treatment with antibiotics.[15]

Antimicrobial susceptibility test

FDA launched a tool that will give physicians direct and timely access to current updates about antibiotics. A new website by FDA will provide information about the antimicrobial susceptibility. This tool aids physicians in selecting an appropriate antibacterial drug to treat a patient's infection. The tests are based on criteria of “breakpoints” that help determine susceptibility of bacteria to various antibiotics. Any update about the breakpoints is usually shared by FDA through a website.[16]

Point of care diagnostics

This diagnostic test is performed directly on the patient at the time of consultation and aids physicians to prescribe antibiotic as per empirical therapy. For instance, the use of these rapid tests helps to diagnose the three major causes of death due to the bacteria (CAP [S. pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis], antenatal syphilis [Treponema pallidum] and tuberculosis [Mycobacterium tuberculosis]). This will help in preventing millions of deaths that are recorded annually in many developing countries.[17],[18]

Other RDTs include MALDITOF-Mass spectrometry, Xpert MRSA/SA blood culture (BC), FilmArray BC identification panel, verigene, prove-it sepsis, and the Unyvero BCU application.[19]

 Tools to Optimize Antibiotic Use



Be antibiotic aware tool

An effort was made by Centres for Disease Control and Prevention (CDC) against emerging antibiotic resistance and helps in improving the prescribing patterns and safe use of antibiotics. This tool disseminates information about rational antibiotic use in different settings as follows.[20]

Antibiotic prescription and usage in hospitals and long-term cares: CDC tool guides physicians in prescribing the right choice drug for a patient with right dose and timing. Appropriate use of antibiotics for long term can reduce rates of clostridium difficile infection and antibiotic resistanceAntibiotic prescription and use on the farm: Antibiotic use on farms and administration of antibiotics to animals will lead to the production of antibiotic-resistant germs. Exposure of resistant bacteria is easily possible when people eat animal products contaminated with resistant bacteria and their products or by coming into contact with animal fecal matter. In US, every year, as many as 410,000 estimated food borne infections are due to antibiotic-resistant Salmonella and CampylobacterCore elements of antibiotic stewardship: The unified approach cannot be implemented to optimize antibiotic use for all settings. This tool offers physicians a key set of principles to make efforts in the improving the use of antibiotics in different settings such as nursing homes, small critical access hospitals, and resource-limited settings. Important core elements included in antibiotic stewardship includes the leadership commitment, accountability, drug expertise, action, tracking, reporting, and education.[20]

Access, watch, reserve tool (AWaRe tool)

Apart from its use as diagnostic tool, AWaRe can also aid physicians in prescribing appropriate antibiotic for particular indication. WHO has started the global campaign called “AdoptAWaRe, Handle antibiotics with care” to optimize the use of antibiotics. In G20 meeting on December 1, 2018, health ministers of 20 different countries had supported for implication and progress of AWaRe tool. Focus of this aware tool is to guide prescribers to prescribe more narrow spectrum antibiotics as compared to other two AWaRe categories to prevent resistance. By the end of 2023, WHO aims to support countries in improving antibiotic prescribing practices so that 60% of prescribed antibiotics should be from access category.[21]

 Antimicrobial Stewardship Metrics in India



Data of surveillance tools depict alarming situation in India. As per a surveillance report by WHO on antibiotic consumption in South East region of Asia, cephalosporins and quinolones were found to be most consumable with very high levels in some countries. As per report, there is a high-level consumption of third-generation cephalosporins.[22]

Recent two studies assessed the overall antibiotic use by using AWaRe categorization. Analysis of one day point prevalence survey antibiotic prescription data of 23,572 patients included from 56 countries was done by Hsia et al. The analysis data showed high diversity in the patterns of AWaRe antibiotic use among these 56 studied countries. In many regions of South-East Asia, the data for the use of antibiotics of access group were very high, as reported for the treatment of neonatal sepsis (74.2%) in Thailand, whereas the use of this group of antibiotics was comparatively lower in India (30.7%). More number of antibiotics were prescribed from watch group as compared to access group in Indian children with neonatal sepsis or lower respiratory tract infection.[8]

In a study by Hsia et al., access-to-watch index was evaluated to assess the oral antibiotic consumption of appropriate formulations among the children from different 70 countries. The results showed that access-to-watch index in India was <1 with lower access percentage (35%), higher watch percentage (47.3%), and considerable use of unclassified antibiotics (17.4%).[23]

Study conducted by McGettigan to analyze antibiotic sales between 2007 and 2012 showed worrisome results. Antibiotic sales increased by 26% in 2011–2012 as compared to sales in 2007. The study revealed the data in 2011–2012 for the sale of fixed dose combinations of antibiotics as: 499 million Units of antibiotics of access group, 367 million Units of antibiotics of watch group, and 3 million units of reserve group. Sales of antibiotic from AWaRe group had risen by 20%, 73%, and 174%, respectively, in 2011–2012.[24]

Study by Klein et al. to analyze the trends of antibiotic consumption revealed that among high-income countries, maximum consumers were US, France, and Italy while top consumers among low-/middle-income countries were from India, Pakistan, and China. The consumption of antibiotic is increased in India by 103% in 2000, from 3.2 billion to 6.5 billion in the year 2015. In India, the rate of antibiotic consumption has been increased from 8.2 to 13.6 DDDs/1000 inhabitants/day (63%).[2]

 Future Perspectives



Pharmacovigilance programme of India (PvPi) is being conducted with the support of Ministry of Health and Family Welfare to keep records of adverse drug reactions (ADRs) for monitoring the safety of drugs.[25] Data can be collected from PvPi database to analyze frequency of Type F ADRs (unexpected therapeutic failures), and its relation with AMR can be evaluated.

Reintroduction of old antibiotics can be another alternative to fight drug resistance. As per the current situation of increasing multiple drug resistance to antibiotics and difficulty in the development of newer antibiotics, focus can be to reintroduce the 'abandoned old' antibiotics. For instance, the recent reports suggest that S. typhi is now more sensitive to older antibiotics as amoxicillin, trimethoprim/sulfamethoxazole, and chloramphenicol that belongs to access group of antibiotics.[26] Some old antibiotics as fosfomycin, chloramphenicol, rifamicin, fusidic acid, and many others can also be focused to reintroduce in clinical practices. Fosfomycin is found to be useful to treat vancomycin-resistant enterococci infections in intensive care, and fusidic acid is found to be effective against many strains of Staphylococcus. Chloramphenicols can be used as empirical therapy for patients with uncomplicated fever, and colistin/rifampicin combination can act synergistically against Acinetobacter baumannii and Pseudomonas aeruginosa infections.[27]

Recent study conducted in Delhi to evaluate availability of antibiotics showed unavailability of benzathine penicillin at primary, secondary, and tertiary healthcare facilities of public sector, and ampicillin suspension was available in only one-fourth of primary care centers.[28] Steps should be taken to ensure availability of good-quality antibiotics at all healthcare settings. This study also showed that median price ratio is more than 1 for amoxicillin, doxycycline, and erythromycin.[28] Hence, there is also a need to focus on easy affordability of antibiotics in developing country such as India.

There is also a need to promote manufacturing of new antibiotics by implementing various strategies such as providing incentives to pharmaceutical companies.

 Conclusion



Antimicrobial stewardship metrics in terms of DDDs as well as access to watch ratio of antibiotic use is reflecting a serious situation in India. Appropriate policy decision can be implemented to adopt above tools in systematic pattern to combat AMR. Although surveillance tools can only aid in evaluating current resistance pattern, other tools including diagnostic tools, AWaRe tool, and Be antibiotic aware toolkit can aid physician for rational use of antibiotics which further leads to decrease in incidence of AMR.

Best strategic approach and proper utilization of available tools can help in fighting the evil of the AMR. Collaborative approach is needed for proper implementation of available tools in the best effective way.

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