Antimicrobial resistance: The silent Pandemic Challenging Modern Medicine

Microorganisms are small microscopic organisms which can’t be seen with the naked eye. Microorganisms also known as microbes. Microbes are found all over the world and even in extreme harsh conditions. Also the human body contains trillions of microbes. Some microbes are essential for biological processes and some cause disease in the living beings.

Antimicrobials are the agents which are used in prevention and treatment of various antimicrobial infections. Antimicrobials are able to kill or stop the growth of other microorganisms. Antimicrobials include Antiseptic, Antibiotics, Antifungal, Antiparasitic. 

Antibiotics are generally prescribed by the medical practitioner. Doctors may prescribe a broad-spectrum antibiotic or a narrow-spectrum antibiotic. A broad-spectrum antibiotic can treat a wide range of infections, while a narrow-spectrum antibiotic is only effective against a few types of bacteria.

Taking antibiotics when they’re not needed will not help, and their side effects can still cause harmful effects on the patient.

Taking antibiotics regularly or very often can lead to various problems such as toxicity, hypersensitive reactions, super infection, and one of the major problem across the globe that is antimicrobial resistance

Antimicrobial resistance is a condition in which microbes become resistant to the particular drug and the drug becomes ineffective against the microbes.

Antimicrobial Resistance can be natural or acquired.

Natural Resistance: When microbes are naturally resistant to the particular drug because they don’t have a target site for that particular drug. Generally natural resistance is not a major clinical problem.

Tetracycline is ineffective against Mycobacterium Tuberculosis because it has a high level of intrinsic resistance due to presence of tetracycline destructases enzyme.

Acquired Resistance: When microbes develop resistance over the period of time due to overuse and misuse of antimicrobial agents. This resistance depends upon the microbes as well as on the drug. Acquired resistance is a global clinical concern nowadays. 

Acquired resistance occurs when microbes change its way to protect itself from drugs and are able to survive. Acquired resistance develops by 2 processes.

1) Mutation: Also called Vertical Transfer Of Gene. Mutation means change in DNA sequence. When high concentration of a particular drug is given, microbes are able to change the specific site of DNA and develop defense mechanisms and are able to survive antimicrobial treatment. When microbes develop resistance, they will be able to increase their number by the process of natural selection. 

2) Gene Transfer: Also called Horizontal Transfer of Gene. Gene Transfer means transfer of resistance genes from one organism to another. Resistance genes can be transferred from cell to cell by conjugation, transformation or transduction. This resistance causes major problems in the treatment of infections.

Resistant Microorganisms are divided into 2 groups :

1. Drug Tolerant: When microorganisms get used to antimicrobial drugs and no longer respond to the drug. In this condition either more concentration of drug is needed or different drugs will be used for treating the infection. 

Example: Resistant E. coli develops a RNA polymerase that does not bind to Rifampin.

2. Drug Destroying: When resistant microorganisms develop an enzyme which is capable of destroying the drug and making it ineffective for treatment. 

Example : Some bacterial species produce Beta Lactamases which destroy the beta lactam ring of penicillin antibiotics and make them inactive. 

Cross Resistance: Resistance to one Antimicrobial Agent causes resistance to other antimicrobial agents which are never used against specific microbes. 

Example: Overuse of ciprofloxacin causes resistance to nalidixic acid because both belong to quinolones antibiotic and both drugs inhibit topoisomerase enzyme which is important for DNA replication. 

Self-Medication: Self Medication means taking any medication or drug without the prescription of a qualified doctor. Self-Medication drugs are mostly over the counter drugs which can be obtained easily. 

SM, as defined by the World Health Organization (WHO), is the use of medicinal products to treat self-diagnosed disorders or symptoms, or the intermittent or continued use of a medication prescribed for chronic or recurring diseases or symptoms (Morris and Stevens, 2006. 

Clinical Importance

The critical importance of a One Health approach to antimicrobial resistance (AMR) stems from the interconnectedness of human, animal, and environmental health. This approach recognizes that the health of people is closely connected to the health of animals and the environment. 

1. Inter connectedness: AMR is a complex issue that affects humans, animals, and the environment. Antibiotics used in humans and animals can lead to the development of resistance in bacteria, which can then spread to other environments through water, soil, and food.

2. Shared Environment: Humans, animals, and the environment share the same microbial ecosystems. Antibiotics and resistant bacteria can be transmitted between them, leading to the development and spread of AMR.

3. Collaboration: A One Health approach involves collaboration between human health, animal health, and environmental health sectors. This collaboration is essential for developing strategies to prevent and control AMR.

4. Surveillance: Surveillance of AMR in humans, animals, and the environment is crucial for understanding the spread of resistance and guiding intervention strategies.

5. Prevention: Preventing the spread of AMR requires a multifaceted approach that includes reducing the unnecessary use of antibiotics in humans and animals, improving hygiene and infection control practices, and promoting responsible antibiotic use in agriculture.

6. Policy Development:  Policy development is essential for implementing One Health strategies to address AMR. Policies should aim to reduce antibiotic use, promote research and development of new antibiotics, and improve surveillance and monitoring of AMR.

7. Global Action:  Addressing AMR requires global action, as resistant bacteria can spread across borders. International collaboration is essential for developing and implementing effective strategies to combat AMR.

The One Health approach is crucial for addressing AMR’s complex nature and ensuring antibiotics remain effective for future generations.

Lack of New Antibiotic Development 

1. Market Challenges: Developing antibiotics is costly and time-consuming. Compared to other drugs, antibiotics are used for short periods, which makes recouping investment challenging for pharmaceutical companies.

2. Regulatory Hurdles: The regulatory process for approving new antibiotics is stringent due to the need to ensure their safety and efficacy. This adds time and cost to the development process.

3. Resistance Development: As new antibiotics are introduced, bacteria can develop resistance to them over time through various mechanisms, such as mutation or acquiring resistance genes from other bacteria.

4. Low Return on Investment: Because of the challenges mentioned, many pharmaceutical companies have shifted their focus to developing drugs for chronic conditions, which offer a more stable and profitable market compared to antibiotics. 

5. Decline in Antibiotic Discovery: The number of new antibiotics approved by the FDA has declined since the 1980s. In the 1980s, there were about 16 new antibiotics approved, but in recent decades, there have been only a few new classes of antibiotics discovered.

6. Economic Factors : The cost of developing a new antibiotic is estimated to be around $1 billion. However, the potential revenue from antibiotics is lower compared to drugs for chronic conditions because antibiotics are often used for short durations.

7. Market Failure : Many pharmaceutical companies have exited the antibiotic market in recent years due to low profitability. This has led to a lack of competition and innovation in the field of antibiotic development.

8. Rise in Antibiotic Resistance : The overuse and misuse of antibiotics have contributed to the rise in antibiotic resistance. For example, the CDC estimates that at least 30% of antibiotics prescribed in the United States are unnecessary.

Antimicrobial resistance surveillance

According to WHO’s annual analyses, the number of new antibiotics in clinical development against priority pathogens decreased from 31 in 2017 to 27 in 2021. In the preclinical stage, the number of products has remained relatively stable over the past three years.

In a broader context, the report indicates that out of the 77 antibacterial agents in clinical development, 45 are traditional direct-acting small molecules and 32 are non-traditional agents, such as monoclonal antibodies and bacteriophages. It currently takes approximately 10–15 years to progress an antibiotic candidate from the preclinical to the clinical stages, with only a small percentage reaching patients.

Measuring Antimicrobial Consumption

● The European Commission outlined an action plan in 2011 to combat bacterial resistance to last-line antibiotics, including measures to raise awareness about appropriate antimicrobial use and strengthen surveillance systems.

● Evolution of human consumption of antimicrobial agents shows that while most antimicrobials are prescribed in the community, hospital infections tend to be caused by more resistant microorganisms due to higher antimicrobial use in hospitals.

● Data on resistance to antimicrobial agents is typically obtained from Clinical Microbiology services, using laboratory information systems or specialized software like WHONET.

Antibiotic Pressure and Resistance Development

● Antibiotic exposure does not directly cause resistance but exerts selective pressure, allowing resistant organisms to proliferate.

● Antibiotics act as selective agents in a natural process of survival of the fittest, where mutants with resistance traits may appear spontaneously.

Antibiotic Restriction and Bacterial Activity

● Studies have shown that restricting antibiotic use can reduce resistance profiles in bacteria. For example, a study in Israel observed a significant reduction in quinolone consumption, leading to decreased isolation of E. coli.

Impact of New Antibiotics on Resistance

● The evolution of antimicrobial resistance and the lack of new antibiotics raise concerns about untreatable multi-drug resistant infections. 

● Cases of extreme drug-resistant bacteria, or “superbugs,” are becoming more common, highlighting the urgent need for new antimicrobial strategies.

Complexity of Antibiotic Resistance

Antibiotic resistance is a complex issue influenced by various factors, including the natural selection of resistant bacteria due to antibiotic use and other environmental pressures

Evolution of Antibiotics: From Penicillin to Antimicrobial Peptides

Since the discovery of penicillin, antibiotics have played a crucial role in improving public health by curing previously incurable infections. The development of streptomycin, the first effective agent against tuberculosis, stands out as a significant milestone in medical history. However, the overuse of antibiotics has led to the emergence of multidrug-resistant microorganisms, making it increasingly difficult to treat infections caused by pathogens such as Mycobacterium tuberculosis, Pseudomonas aeruginosa, Staphylococcus aureus, and Acinetobacter baumannii. To address this challenge, novel antibiotics like linezolid have been developed, but even these face resistance issues. This has led to growing interest in antimicrobial peptides (AMPs) as a new class of antibiotics. AMPs have diverse mechanisms of action and strong antimicrobial activity against a broad spectrum of microorganisms, including drug-resistant strains. Despite their potential, AMPs have limitations such as hemolytic activity, rapid turnover in the body, and high production costs. Overcoming these challenges will be crucial for their clinical application.

Mechanism of Action of Cationic Antimicrobial Peptides (AMPs)

Cationic AMPs are peptides with hydrophobic amino acid residues and an overall positive charge. A prime example is lactoferricin, derived from lactoferrin. Lactoferricin is rich in arginine, valine, and tryptophan, and shows potent antimicrobial activity against drug-resistant pathogens like S. aureus, A. baumannii, and Candida albicans. These peptides disrupt bacterial cell membranes by adopting different structures in different environments, such as aqueous or membrane-mimetic solutions. In the membrane-mimetic environment, they form an amphipathic helix that interacts with the bacterial membrane, leading to pore formation and leakage of cellular contents.

Diverse Mechanisms of Action of AMPs

While membrane disruption is a key mechanism, AMPs also target key cellular processes like DNA and protein synthesis, protein folding, cell wall synthesis, and metabolic turnover. For example, buforin II from the Asian toad Bufo gargarizans inhibits DNA and RNA function, while peptides like drosocin, pyrrhocoricin, and apidaecin act on heat shock proteins and suppress cellular stress responses. Some AMPs also show other beneficial effects like neutralizing endotoxins, promoting wound healing, and modulating the immune response. 

Resistance and Future Directions

AMPs are less likely to induce resistance compared to conventional antibiotics due to their direct disruption of microbial components. However, some bacteria can develop resistance mechanisms, such as modifying cell surface teichoic acid to reduce negative charges or producing proteases to degrade AMPs. Understanding these mechanisms is crucial for developing effective strategies against resistant pathogens. AMPs hold great promise as future antibiotics, but overcoming limitations like hemolytic activity and high production costs is essential for their clinical application