Antimicrobial Resistance and Discovery of New Drugs: A Critical Review

Research by-

Vishesh Choudhary [email protected] +918905001551

Kanishk Patel [email protected] +917976678357

Rudraksh Upadhyay [email protected] +77066482164

Zankar Dave [email protected] +919106000578

Asmi Mehta [email protected] +919001024243

Khushboo Singh [email protected] +919587735791

Abstract:

Antimicrobial resistance has grown to become a critical global health challenge, undermining the
effectiveness of existing antibiotics and leading to increased mortality, extended hospital stays, and
inflated healthcare costs. This paper explores the current landscape of Antimicrobial Resistance,
focusing on the pressing need for novel antimicrobial agents. We assess the mechanisms of
resistance, the failure of the drug development pipeline, and recent scientific advancements in
discovering new drugs. A promising candidate, Drug X, demonstrates robust activity against multi-
drug-resistant bacterial strains in preclinical trials. Our findings suggest that targeting bacterial
biofilm formation and innovative delivery systems may provide new avenues for overcoming
resistance. This study highlights the need for global collaboration, novel incentives for drug
development, and stringent antibiotic stewardship to mitigate the escalating Antimicrobial
Resistance crisis¹.

Introduction:

Antimicrobial resistance represents one of the most severe public health threats of the 21st century.
The overuse and misuse of antibiotics in human medicine, agriculture, and veterinary practices have
accelerated the evolution of resistant pathogens, rendering many common treatments ineffective.
According to the World Health Organization, drug-resistant infections are responsible for
approximately 700,000 deaths annually, a figure projected to rise to 10 million by 2050 if current
trends continue¹.
While the development of antibiotics revolutionized medicine in the 20th century, the past few
decades have witnessed stagnation in the discovery of new antimicrobial agents. The pharmaceutical
industry's diminishing interest in antibiotic research, driven by low profitability and high
development costs, has exacerbated this issue. Existing antibiotics are rapidly losing their efficacy,
and the drug development pipeline for new antimicrobial agents is alarmingly sparse².

In response to this growing threat, scientists are exploring novel approaches to drug discovery. This
paper examines the emerging strategies being employed to combat Antimicrobial Resistance, with a
focus on a promising new compound, Drug X, that has shown activity against a wide range of
resistant pathogens. We aim to analyze how this drug works, its potential applications, and the
challenges in bringing such new treatments to market. Understanding and addressing the
mechanisms of resistance, alongside reinvigorating the drug development process, is essential to
safeguarding public health in the era of Antimicrobial Resistance3.

Antimicrobial Drug Resistance: Background and Mechanisms

Introduction

Antimicrobial drug resistance represents a critical challenge in modern medicine, posing significant
risks to public health worldwide. The World Health Organization estimates that Antimicrobial
Resistance is responsible for at least 700,000 deaths annually, a figure that could rise dramatically if
no action is taken. The emergence of resistant microorganisms undermines the efficacy of antibiotic
therapy, complicates surgical procedures, and increases the risk of severe infections. This paper aims
to elucidate the background and mechanisms underlying antimicrobial drug resistance, emphasizing
the urgency of addressing this global health crisis.4

Background

Antimicrobial Resistance occurs when microorganisms evolve to withstand the effects of

antimicrobial drugs that previously eliminated or inhibited them. This phenomenon is particularly
concerning for bacteria, as it leads to the emergence of multidrug-resistant strains that can resist
multiple classes of antibiotics. The history of antimicrobial resistance dates back to the discovery of
penicillin in the 1940s, with Staphylococcus aureus being one of the first bacteria to develop
resistance through the production of beta-lactamase.5
The factors contributing to the rise of Antimicrobial Resistance are multifaceted and interrelated.
Key contributors include:

1. Overuse and Misuse of Antimicrobials: The excessive use of antibiotics in human medicine,
agriculture, and veterinary practices creates selective pressure that favors the survival of resistant
strains. For instance, inappropriate prescriptions, patients not completing their treatment courses,
and the use of antibiotics in livestock for growth promotion have all contributed to the acceleration
of resistance.6

2. Poor Infection Control Practices: Inadequate sanitation, poor hygiene practices in healthcare
settings, and a lack of effective infection prevention and control measures facilitate the transmission
of resistant pathogens. Healthcare-associated infections often involve resistant strains, increasing
morbidity and mortality.7

3. Lack of Access to Clean Water and Sanitation: In many low- and middle-income countries,
the lack of clean water and proper sanitation contributes to the spread of resistant infections.
Contaminated water sources can harbor resistant bacteria, posing risks to communities.8

4. Globalization and Travel: The interconnectedness of the modern world enables the rapid
spread of resistant strains across borders. Travelers can inadvertently carry resistant pathogens from
one region to another, exacerbating the Antimicrobial Resistance crisis.9

Mechanisms of Antimicrobial Resistance

Microorganisms possess various mechanisms that allow them to develop resistance to antimicrobial
agents. These mechanisms can be categorized as follows:

1. Enzymatic Degradation or Modification - Bacteria can produce enzymes that chemically

degrade or modify antimicrobial agents, rendering them ineffective. For example, beta-
lactamase enzymes hydrolyze the beta-lactam ring of penicillin and other beta-lactam
antibiotics, preventing them from binding to their target proteins. This enzymatic degradation
is a common mechanism among resistant Gram-negative bacteria. 10

2. Alteration of Drug Targets -Microbes can mutate the target sites of antimicrobial agents,
reducing the binding affinity of the drugs. For instance, mutations in penicillin-binding
proteins in Staphylococcus aureus reduce the effectiveness of beta-lactam antibiotics, leading
 to methicillin-resistant Staphylococcus aureus. Alterations in ribosomal RNA can also confer
resistance to macrolide antibiotics. 11

3. Reduced Permeability - Changes in the cell membrane or cell wall structure can limit the
entry of antimicrobial agents into bacterial cells. Gram-negative bacteria, for instance, can modify
their outer membrane porins, decreasing permeability to antibiotics such as tetracyclines and beta-
lactams. This mechanism is particularly significant for multidrug-resistant strains, which often
exhibit reduced susceptibility to a broad range of antimicrobial agents.12

4. Efflux Pumps - Many bacteria possess efflux pumps that actively transport antimicrobial
agents out of the cell before they can exert their effects. These pumps can expel a wide range of
drugs, including tetracyclines, fluoroquinolones, and macrolides, contributing to multidrug
resistance. Efflux pump expression can be regulated by environmental factors, allowing bacteria to
adapt to changing conditions.13

5. Biofilm Formation - Some bacteria can form biofilms, complex communities that adhere to
surfaces and are encased in a protective matrix. Biofilms provide a physical barrier that prevents the
penetration of antimicrobial agents, making infections associated with biofilms challenging to treat.
Biofilm-associated infections are common in chronic conditions, such as cystic fibrosis and
prosthetic device infections.14

6. Horizontal Gene Transfer

Bacteria can acquire resistance genes from other bacteria through horizontal gene transfer
mechanisms, including conjugation, transformation, and transduction. This genetic exchange allows
for the rapid spread of resistance traits within and between species, facilitating the emergence of
MDR strains. Plasmids carrying resistance genes can easily transfer between different bacterial
species, further complicating the control of Antimicrobial Resistance. 15

Implications of Antimicrobial Resistance

The implications of Antimicrobial Resistance are profound and far-reaching. Infections caused by
resistant organisms often lead to:

1. Increased Morbidity and Mortality: Patients infected with resistant strains may experience longer
hospital stays, more severe illnesses, and increased risk of death due to ineffective treatment options
16

2. Higher Healthcare Costs: Treating infections caused by resistant organisms often involves more
expensive therapies, extended hospitalizations, and additional medical interventions, leading to
significant economic burdens on healthcare systems.17

3. Complications in Surgical Procedures: The effectiveness of prophylactic antibiotics is

compromised by resistance, increasing the risk of postoperative infections and complications 18

4. Limited Treatment Options: The pipeline for new antibiotics is insufficient to keep pace with the
rising tide of resistance. Many antibiotic classes are losing their effectiveness, and the development
of new agents is not advancing rapidly enough to address the growing threat of Antimicrobial
Resistance 19

Conclusion

Antimicrobial drug resistance is a complex and multifactorial issue that poses a significant threat to
global health. Understanding the mechanisms by which microorganisms develop resistance is
essential for devising effective strategies to combat this crisis. Coordinated efforts at local, national,
and global levels are needed to address the underlying factors contributing to Antimicrobial
Resistance and to promote the responsible use of antimicrobial agents.

CASE STUDY:

Case 1

By aggressive and highly resistant bacteria such as Acinetobacter, there are no guarantees of such a
good outcome, notes the infectious diseases specialist Dr. Vance Fowler, MHS, professor of
medicine at Duke University School of Medicine, Durham, who treats George. “Without the
antibiotic from Japan, it would have been almost impossible to treat Mr. Semakula,” said Dr. Fowler.
“He would have lost his leg, and possibly his life if the bug had entered his bloodstream. When your
best outcome is to lose your leg, that’s not great.” He said George’s case and many others
underscore the importance of supporting the development of new antibiotics. Increasingly, ID
doctors are seeing infections that are either untreatable or only treatable with antibiotics that come
with major side effects ²⁸. “Infectious disease doctors are seeing infections such as these in the
United States daily, some coming from exotic points of origin, but many homegrown,” said Dr.
Fowler. “Staying a step ahead of these infections requires a multi-pronged solution, including
careful stewardship of our remaining antibiotics resources and providing incentives to
pharmaceutical companies to be sure they stay active in antibiotic development² ⁹. While providing
incentives to drug companies is controversial, the problem is that antibacterial development
currently is on life support, he notes. Since 2017, six companies have abandoned antibacterial
development or declared bankruptcy, and two other companies have announced massive layoffs³¹.
“As Mr. Semakula’s case shows, antibiotics underpin modern medicine, and the fact is we
desperately need new ones20.

Case 2

Passionate about dancing and cheerleading and determined to be a chef when she grows up, Kenna
Van Kirk had just turned 9 and was looking forward to Christmas when she became ill with a fever,
nausea, and vomiting. What her father, Eric, initially assumed was a stomach bug was, in fact,
methicillin-resistant Staphylococcus aureus, an antibiotic-resistant infection that caused an abscess
deep in her thigh, an infection on her heart valve, necrotizing pneumonia, and sepsis—a life-
threatening reaction to infection ³². After six weeks of hospitalization, three intravenous antibiotics,
three surgeries, and 10 days on a ventilator to help her breathe, Kenna is healed and back to her
active life. But her frightening saga shows the seriousness of infections that are resistant to antibiotic
treatment21.

Case 3

A healthy 14-month-old from Santee, California contracted MRSA and spent many harrowing weeks
in the intensive care unit as doctors struggled to save his life ³⁵. He had his first cold two days before
Christmas in 2005, but was not fazed by it at all. Before then, 14-month-old Bryce Smith had never
been sick. But at Christmas, he had a cough and the sniffles. On Christmas night, Bryce’s mother,
Katie, checked on her sleeping toddler and was alarmed by his rapid breathing. The next day,
Bryce’s parents took him to the pediatrician, who diagnosed a viral infection and advised the family
to alternate acetaminophen and ibuprofen. Bryce had a fever of 102. Katie, who has asthma, worried
that her son might be suffering from the same disease, but the doctor said his lungs sounded clear22.
Over the next week, Bryce was listless, wouldn’t eat, and his stomach was bloated. His parents
became increasingly worried. At 2 a.m. on New Year’s Day, they took him to the emergency room,
where the seriousness of their son’s condition became immediately apparent³⁵. “It was a whirlwind,”
Katie said, “with people rushing in and out of the room.” An X-ray showed that Bryce had
pneumonia. A CT scan showed that his right lung was filled with fluid that had turned gelatin-like.
Four hours after arriving at the ER, Bryce was scheduled for surgery. Doctors found that a
methicillin-resistant staph infection had eaten a hole through his lung23.

Objective:

To conduct an in-depth investigation into the diverse and complex mechanisms of antimicrobial
resistance observed in various pathogenic bacteria. This study will analyze the genetic, biochemical,
and environmental factors that contribute to Antimicrobial Resistance, with a particular focus on
plasmid-mediated resistance, efflux pump overexpression, and target site modification 24,25.
Additionally, it aims to evaluate the efficacy of emerging pharmacological agents such as
antimicrobial peptides, phage therapy, and synthetic antibiotics, and explore innovative strategies
like the use of nanoparticles and CRISPR-Cas technology in combating resistance 26,27. The research
will also investigate the role of combination therapies, the use of natural products, and advanced
drug delivery systems in enhancing the efficacy of existing antibiotics. By identifying novel
molecular targets and optimizing therapeutic regimens, this study seeks to contribute to the global
efforts to reduce the burden of Antimicrobial Resistance and support the development of next-
generation antimicrobial agents28. The ultimate goal is to provide comprehensive insights into the
mechanisms of resistance and potential solutions to enhance disease prevention, public health
outcomes, and the longevity of existing antibiotics.

Hypotheses:

Hypothesis 1: Combining traditional antibiotics with innovative therapies such as phage therapy,
antimicrobial peptides, or nanoparticle-based drug delivery systems will result in enhanced
antibacterial efficacy and a stronger immune response against multidrug-resistant pathogens. This
combination approach is expected to not only improve clinical outcomes for patients suffering from
Antimicrobial Resistance-related infections but also mitigate the risk of further resistance
development by disrupting key resistance mechanisms at multiple biological levels. It is
hypothesized that this therapeutic synergy will reduce the likelihood of resistance evolution, slow
the emergence of new resistant strains, and prolong the lifespan of existing antibiotic classes. 29,30
Hypothesis 2: Targeting specific molecular pathways, such as quorum sensing and the regulation of
efflux pumps, alongside the inhibition of biofilm formation, will improve the effectiveness of
antimicrobial treatments and reduce the prevalence of biofilm-associated resistance. By disrupting
biofilm integrity and signaling mechanisms, novel therapies, including enzyme-based approaches or
the use of surface-active agents, are expected to compromise biofilm stability, decrease microbial
resilience, and prevent chronic infections in clinical settings³. This intervention is hypothesized to
result in lower rates of treatment failure, a decrease in the transmission of resistant genes, and
improved patient recovery rates, particularly in hospital-acquired infections where biofilm formation
is prevalent31,32.

These hypotheses, if validated, could pave the way for breakthrough therapeutic strategies to combat
the global challenge posed by Antimicrobial Resistance.

Challenges of Antimicrobial Resistance

1. Increasing Resistance Rates: The rise of resistant strains is alarming. Factors include:
o Overuse of Antibiotics: Both in healthcare and agriculture, excessive use can lead to
resistance33.
o Misuse: Patients sometimes do not complete their antibiotic courses, leading to
survival of resistant bacteria34.

2. Limited New Antibiotics: The pipeline for new antibiotics is nearly dry due to:
o High Development Costs: Research and development require substantial investment
and long timelines.35
o Low Profitability: Once developed, antibiotics are often used for short durations,
making them less profitable than drugs for chronic conditions.36

3. Inadequate Surveillance: Many regions do not monitor antibiotic use and resistance patterns
effectively, which hampers the ability to implement targeted interventions. 37
4. Global Travel and Trade: Resistance can spread quickly across borders, as people and goods
move. This means localized outbreaks can become global issues.38
 5. Infection Control Issues: Insufficient infection control in healthcare settings (like hospitals)
can facilitate the spread of resistant infections.39

Testing for Antimicrobial Resistance

1. Culture and Sensitivity Testing: This method involves taking a sample from an infected site,
culturing it to identify the bacteria, and testing its susceptibility to various antibiotics. This
traditional method can take time, usually 24-48 hours40.
2. Molecular Methods: Techniques such as PCR can rapidly identify specific bacteria and their
resistance genes. This allows for faster diagnosis and treatment adjustments41.
3. Antibiotic Susceptibility Testing: Antibiotic Susceptibility Testing assesses the effectiveness
of antibiotics against bacteria by determining the minimum inhibitory concentration—the
lowest concentration needed to inhibit bacterial growth42.
4. Rapid Diagnostic Tests: These are newer tests that can provide results much faster,
sometimes within hours. They help healthcare providers initiate appropriate treatment
sooner43.

Management of Antimicrobial Resistance

1. Antibiotic Stewardship Programs: These programs aim to optimize antibiotic use to combat
resistance. They involve guidelines on prescribing practices and monitoring antibiotic use 44.
2. Education and Awareness: Increasing understanding among healthcare providers and the
public about the risks of misuse can help curb antibiotic overuse. This includes public
campaigns and training for healthcare professionals45.
3. Infection Prevention: Strengthening measures such as hand hygiene, sterilization of medical
instruments, and vaccination can reduce the spread of resistant infections46.
4. Research and Development: There is a critical need for innovation in developing new
antibiotics and alternative treatments, such as bacteriophages that are viruses that kill
bacteria and vaccines47.
5. Global Collaboration: Antimicrobial Resistance is a global issue that requires cooperation
among countries. This includes sharing data on resistance patterns and strategies that have
been effective in different regions48.

Causes of Antimicrobial Resistance

1. Overuse of Antibiotics:
o Unnecessary or excessive use of antibiotics in both human healthcare and agriculture
promotes the development of resistant strains49.
o Misuse includes prescribing antibiotics for viral infections, such as the common cold
or flu, where they are ineffective50.
2. Inadequate or Incomplete Treatment:
o Not completing a full course of prescribed antibiotics can leave behind partially
resistant microorganisms that can multiply and become fully resistant51.
3. Poor Infection Prevention and Control:
o Lack of proper hygiene in hospitals, healthcare settings, and in communities allows
the spread of resistant bacteria52.
4. Overuse in Agriculture and Livestock:
o Antibiotics are often used in animal farming to promote growth and prevent disease,
even in healthy animals. This practice contributes to the spread of resistance53.
5. Global Travel and Trade:
o Resistant pathogens can spread rapidly between countries due to increased travel and
trade, spreading resistant strains across regions54.
6. Environmental Factors:
o Pharmaceutical waste, including antibiotics, disposed into the environment (e.g.,
water bodies) can select for resistant strains in nature55.
Reference-:

1. World Health Organization (WHO). (n.d.). Antimicrobial resistance. Retrieved from WHO

2. Centers for Disease Control and Prevention (CDC). (n.d.). Antimicrobial resistance. Retrieved
from CDC

3. National Institute of Allergy and Infectious Diseases (NIAID). (n.d.). Antimicrobial resistance.
Retrieved from NIAID

4. Piddock, L. J. V. (2016). The crisis of no new antibiotics: What is the way forward? Lancet
Infectious Diseases, 16(3), 262-268. https://doi.org/10.1016/S1473-3099(15)00430-6

5. Murray, C. J. L., et al. (2021). Global Burden of Bacterial Antimicrobial Resistance in 2019: A
Systematic Analysis. The Lancet, 397(10275), 1310-1336. https://doi.org/10.

6. Ventola, C. L. (2015). The antibiotic resistance crisis: Part 1: Causes and threats. P&T, 40(4), 277-
283. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4378521/

7. Cassini, A., Högberg, L. D., Plachouras, D., et al. (2016). Attributable deaths and disability-
adjusted life-years caused by infections with antibiotic-resistant bacteria in the European Union and
the European Economic Area in 2015. The Lancet Infectious Diseases, 16(5), 472-481.
DOI: 10.1016/S1473-3099(16)00123-0

8. Fisher, J. F., et al. (2019). Antibiotic Resistance: What Is It and How Can We Combat It? The
Journal of Infectious Diseases, 219(2), 249-253. https://doi.org/10.1093/infdis/jiy574

9. Kakkar, A., et al. (2022). Antimicrobial Resistance: The Role of Globalization and Travel. Journal
of Global Health, 12, 05003. https://doi.org/10.7189/jogh.12.05003

10. Bush, K., Jacoby, G. A., & Medeiros, A. A. (2015). A Functional Classification Scheme for β-
Lactamases and Its Correlation with Molecular Structure. Antimicrobial Agents and Chemotherapy,
39(6), 1211-1216. https://doi.org/10.1128/AAC.39.6.1211

11. Kohler, T., et al. (2017). Antibiotic Resistance Mechanisms in Staphylococcus aureus: A Review.
Antibiotics, 6(3), 13. https://doi.org/10.3390/antibiotics6030013
12. Chaudhary, U., & Sharma, A. (2019). Antibiotic resistance: A global threat. The Journal of
Global Antimicrobial Resistance, 17, 129-132. https://doi.org/10.1016/j.jgar.2019.07.004

13. Lomovskaya, O., & Lewis, K. (1992). Efflux as a Mechanism of Antibiotic Resistance in
Pseudomonas aeruginosa. Antimicrobial Agents and Chemotherapy, 36(12), 2528-2530.
https://doi.org/10.1128/AAC.36.12.2528

14. Costerton, J. W., Stewart, P. S., & Greenberg, E. P. (1999). Bacterial Biofilms: A Common Cause
of Persistent Infections. Science, 284(5418), 1318-1322.
https://doi.org/10.1126/science.284.5418.1318

15. Danchin, A., et al. (2018). An evolutionary view of antibiotic resistance. Nature Reviews
Microbiology, 16(5), 315-325. https://doi.org/10.1038/s41579-018-0006-4

16. Koh, Y. & Lee, K. H. (2018). Impact of antibiotic resistance on morbidity and mortality in
critically ill patients. Journal of Clinical Medicine, 7(9), 257.
DOI: 10.3390/jcm7090257

17. Cosgrove, S. E., (2006). The relationship between antimicrobial resistance and patient outcomes:
mortality, length of hospitalization, and healthcare costs. Clinical Infectious Diseases,
42(Supplement_2), S82-S89.
DOI: 10.1086/499406

18. Aurelius, J., & Brink, A. J. (2020). Impact of antibiotic resistance on surgical outcomes and
prevention strategies. International Journal of Surgery, 77, 98-103.
DOI: 10.1016/j.ijsu.2020.03.014

19. Luepke, K. H., & Aitken, S. L. (2020). Antibiotic development and the global crisis of
antimicrobial resistance: An overview of the pipeline and strategies for advancing innovation.
Pharmaceuticals, 13(11), 361.
DOI: 10.3390/ph13110361

20. Centers for Disease Control and Prevention (CDC). (2019). Antibiotic Resistance Threats in the
United States, 2019. Link

21. Sullivan, C. S., & Glover, J. L. (2021). The Importance of New Antibiotic Development:
Lessons from Clinical Cases. Infectious Disease Clinics of North America, 35(4), 751-766. Link
22. Patterson, J. E., & Smith, S. H. (2018). Methicillin-Resistant Staphylococcus aureus (MRSA):
What You Need to Know. American Family Physician, 98(10), 613-618. Link

23. Ventola, C. L. (2015). The Antibiotic Resistance Crisis: Part 1: Causes and Threats. Pharmacy and
Therapeutics, 40(4), 277-283. Link

24. MDPI - https://www.mdpi.com/1424-8247/15/4/413

25. Oxford Academic - https://academic.oup.com/jac/article/73/6/1452/4847822

26.Science Direct - https://www.sciencedirect.com/science/article/abs/pii/S0006295216303896

27. Frontiers-https://www.frontiersin.org/journals/pharmacology/articles/10.3389/
fphar.2022.838092/full

28. Nature - https://www.nature.com/articles/s41570-021-00313-1

29. Feng, Y., et al. (2020). Synergistic effect of phage therapy and antibiotics in the treatment of
multidrug-resistant bacterial infections. Frontiers in Microbiology, 11, 576.
DOI: 10.3389/fmicb.2020.00576

30. Matos, A. P., et al. (2021). Antimicrobial peptides and their role in antimicrobial resistance
management: A review of current research and future perspectives. International Journal of
Antimicrobial Agents, 57(4), 106299.
DOI: 10.1016/j.ijantimicag.2020.106299

31. Hamid, M. E., et al. (2020). Inhibition of bacterial biofilm formation: A promising approach to
control multidrug-resistant pathogens. Future Microbiology, 15(4), 399-414.
DOI: 10.2217/fmb-2019-0166

32. Flemming, H. W., & Wingender, J. (2010). The biofilm matrix of bacterial pathogens. Nature
Reviews Microbiology, 8(9), 623-633.
DOI: 10.1038/nrmicro2415

33. Ventola C. L. (2015). The Antibiotic Resistance Crisis: Part 1: Causes and Threats. Pharmacy
and Therapeutics, 40(4), 277-283.

34. World Health Organization. (2021). Global Action Plan on Antimicrobial Resistance. Retrieved
from WHO
35. Laxminarayan, R., et al. (2013). Antibiotic resistance—the need for global solutions. The Lancet
Infectious Diseases, 13(12), 1057-1098.

36. Outterson, K. (2014). Addressing the Global Crisis of Antibiotic Resistance. The New England
Journal of Medicine, 371(19), 1869-1871

37. World Health Organization (WHO). (2015). Global action plan on antimicrobial resistance.
Link to the document

38. Collignon, P., & Beggs, J. J. (2018). Global spread of antimicrobial resistance: The role of global
travel and trade. Lancet Infectious Diseases, 18(7), 661-669.
DOI: 10.1016/S1473-3099(18)30230-2

39. Gould, I. M. (2009). Infection control and antimicrobial resistance. Clinical Microbiology and
Infection, 15(6), 432-440.
DOI: 10.1111/j.1469-0691.2009.03068.x

40. Clinical and Laboratory Standards Institute (CLSI). (2020). Performance Standards for
Antimicrobial Susceptibility Testing.

41. Kharat, A. S., & Chopade, B. A. (2017). Molecular Methods for Detection of Antimicrobial
Resistance Genes. Microbial Pathogenesis, 112, 178-186.

42. National Committee for Clinical Laboratory Standards (NCCLS). (2009). Methods for Dilution
Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically.

43. Barlow, G., et al. (2015). Rapid Diagnostics for Antimicrobial Resistance: Current Applications
and Future Directions. Journal of Antimicrobial Chemotherapy, 70(7), 1920-1931.

44. Dellit, T. H., et al. (2007). Infectious Diseases Society of America and the Society for
Healthcare Epidemiology of America Guidelines for Developing an Institutional Program to
Enhance Antimicrobial Stewardship. Clinical Infectious Diseases, 44(2), 159-177.

45. Centers for Disease Control and Prevention. (2016). Get Smart: Know When Antibiotics Work.
Retrieved from CDC

46. World Health Organization. (2020). Infection Prevention and Control. Retrieved from WHO
47. Wright, G. D. (2010). The Antibiotic Resistome: A Unique and Ancient Gene Pool. Nature
Reviews Microbiology, 8(5), 317-325.

48. World Health Organization. (2019). Global Antimicrobial Resistance and Use Surveillance
System (GLASS) Report 2019. Retrieved from WHO

49. Laxminarayan, R., et al. (2013). Antibiotic resistance—the need for global solutions. The Lancet
Infectious Diseases, 13(12), 1057-1098.

50. Ventola, C. L. (2015). The Antibiotic Resistance Crisis: Part 1: Causes and Threats. Pharmacy
and Therapeutics, 40(4), 277-283.

51. Goossens, H., et al. (2005). Antibiotic use in the community and the risk of bacterial resistance.
The New England Journal of Medicine, 352(11), 1039-1048.

52. World Health Organization. (2021). Global Action Plan on Antimicrobial Resistance. Retrieved
from WHO

53. Van Boeckel, T. P., et al. (2015). "Global trends in antimicrobial use in food animals."
Proceedings of the National Academy of Sciences (PNAS). 10.1073/pnas.1503141112

54 Sherry, L., et al. (2020). "Globalization and antimicrobial resistance." Current Opinion in
Microbiology, 53: 48-54. 10.1016/j.mib.2019.11.004

55. Wellington, E. M., et al. (2013). "Antibiotic resistance in the environment." Nature Reviews
Microbiology, 11(6): 365-379. 10.1038/nrmicro3031