Unseen Threat: The Growing Problem of Antimicrobial Resistance

Prerna Tiwari¹*, Pratibha Tiwari, Pratixa Patel

¹ROFEL Shri G.M. Bilakhia College of Pharmacy, Vapi, Gujarat, 396191, India.

²ROFEL Shri G.M. Bilakhia College of Pharmacy, Vapi, Gujarat, 396191, India.

³Department of Pharmacology, ROFEL Shri G.M. Bilakhia College of Pharmacy,

Vapi, Gujarat, 396191, India.

*Corresponding Author E-mail: prerna15122002@gmail.com

ABSTRACT:

Antimicrobial resistance (AMR) is emerging as one of the most significant threats to global public health, with the potential to reverse the medical advances achieved over the past century. Since Alexander Fleming's discovery of penicillin in 1928, antibiotics have been indispensable in treating bacterial infections, enabling safe surgical procedures, and extending life expectancy. However, the efficacy of these life-saving drugs is rapidly diminishing due to the widespread misuse and overuse of antibiotics in both human medicine and agriculture. AMR occurs when bacteria evolve mechanisms to withstand the effects of antibiotics, rendering standard treatments ineffective. The primary mechanisms of resistance include the reduction of drug uptake, modification of drug targets, enzymatic inactivation of drugs, and the active efflux of antibiotics out of bacterial cells. These resistant strains can spread through human contact, environmental reservoirs, and the food chain, exacerbated by the use of antibiotics in animal husbandry. The consequences of AMR are dire. Infections that were once easily treatable are becoming increasingly difficult and expensive to manage, leading to higher rates of morbidity and mortality. The financial burden on healthcare systems is substantial, with prolonged hospital stays, the need for more expensive drugs, and the requirement for more intensive care. To address this growing crisis, a multifaceted approach is essential. Stricter regulations on the use of antibiotics, both in healthcare settings and in agriculture, are critical to curbing the spread of resistance. Enhancing access to vaccines and promoting appropriate use of existing antibiotics can help prevent infections and reduce the need for antibiotic use. Additionally, international cooperation is crucial for monitoring and responding to AMR on a global scale. Investing in research and development of new antibiotics and alternative therapies is also imperative. Public awareness campaigns aimed at educating both healthcare professionals and the general public about the dangers of antibiotic misuse are essential for changing behaviour. Without these immediate and coordinated efforts, AMR could lead to a future where routine surgeries, chemotherapy, and even minor infections become life-threatening, effectively turning back the clock on modern medicine.

KEYWORDS: Antimicrobial Resistance (AMR), Antibiotics, Mechanisms of Resistance, Drivers of Resistance, Measures to Combat Resistance.

INTRODUCTION:

Alexander Fleming’s 1928 discovery of penicillin revolutionized medicine, enabling safer procedures like childbirth and transplants. However, antimicrobial resistance (AMR) from misuse and agricultural practices now poses a global crisis, increasing mortality and costs, as seen in XDR-TB. Addressing AMR requires strict regulations, surveillance, and global cooperation.¹

Fig.1: Timeline of the Evolution of Antibiotic Resistance²

Background and History:

Fleming’s discovery transformed bacterial treatment, but resistance emerged by the 1960s, notably in gram-negative bacteria. Cases like Neisseria gonorrhoeae’s Ampicillin resistance and Haemophilus’ multidrug resistance highlight AMR’s spread. Genome sequencing has identified ~20,000 resistance genes, yet knowledge gaps persist. Bioinformatics offers potential solutions (Fig 1).²

Antibiotic resistance in humans and animals is driven by poor hygiene, hospital-acquired infections, excessive livestock use, improper disposal, and global travel, increasing environmental resistance (Fig 2,4). Diseases like sepsis, gonorrhea, pneumonia, TB, and foodborne infections are harder to treat, raising costs, prolonging treatments, and increasing mortality. Urgent solutions include new drugs and alternative therapies.³

Monitoring and Epidemiology:

The widespread misuse of antibiotics drives antibiotic resistance (AMR), a global health threat.⁴ Non-traditional treatments like phage therapy and passive immunization are being explored. Governments must enforce antibiotic stewardship via national plans, surveillance, and databanks.⁵ Key efforts include education, animal vaccinations, proper antibiotic use, and hygiene. Research on resistance patterns, disease transmission, and treatment options, especially post-COVID-19, is essential.

Antibiotic Resistance Control Approach:

Controlling AMR requires proper antibiotic use, resistance profiling, and strict infection control. Medical waste disposal and regulations are crucial, while computational biology and nanotechnology offer solutions. Public awareness, reduced livestock misuse, and behavioral changes are key. Hygiene, surveillance, and targeted treatments can mitigate AMR and costs.

Interventions for Therapy:

Global initiatives like GARDP, CARB-X, and the AMR Action Fund drive antimicrobial development. Alternative therapies, including bacteriophages, antibodies, mRNA vaccines, and plant metabolites, are gaining traction. Molecular diagnostics enable precise, cost-effective resistance profiling. Combating AMR requires identifying resistance genes, analyzing transmission, and enhancing preventive strategies. Effective stewardship and resistance data are key to life-saving interventions.

Sources and Routes of Transmission of Amr:

AMR spreads through human contact and environmental reservoirs, including animals, water, and soil. Resistance genes circulate among humans, animals, and the environment. Hotspots like wastewater, sludge, and natural fertilizers contribute to resistance spread. Animal AMR from antibiotic-treated feed reaches humans via consumption, direct contact, or contaminated food and water.

Fig.2 Resistance development, sources and routes of transmission⁵

Mechanism of Drug Resistance:

Fig.3 Anti-Microbial Drug acting on Bacterial cell whose alteration results into AMR⁵

Bacteria and antibiotics coexist in the same environment, leading bacteria to develop defenses. Antibiotics target four key bacterial cell areas: the cell wall, membrane, protein synthesis, and nucleic acid production. Resistance mechanisms include reduced drug uptake, target modification, drug inactivation, and increased drug efflux. Acquired resistance often involves target modification, drug inactivation, and efflux, while intrinsic resistance primarily arises from uptake restriction, drug inactivation, and efflux. Structural differences between gram-positive and gram-negative bacteria influence resistance strategies. Gram-positive bacteria have limited efflux mechanisms and lack an LPS outer membrane, whereas gram-negative bacteria utilize all four primary resistance mechanisms as shown in Fig 3,4.⁵

Reducing Drug Consumption:

The outer membrane of gram-negative bacteria, primarily composed of lipopolysaccharides, acts as a barrier, reducing antibiotic permeability and contributing to resistance. Changes in outer membrane proteins, such as porins, can lead to acquired resistance, particularly for hydrophilic antibiotics like chloramphenicol, tetracyclines, fluoroquinolones, and beta-lactams. Mutations affecting porin expression or function, combined with mechanisms like efflux pumps or enzymatic degradation, further enhance resistance. Biofilm formation, seen in bacteria like E. coli and Pseudomonas aeruginosa, protects against antibiotics by limiting penetration and reducing bactericidal concentrations as shown in Fig 3,4.⁶

Alteration of Drug Targets:

Bacteria can mutate genes encoding drug target proteins, preventing effective drug binding. For instance, mutations in the quinolone⁸¹-resistance-determining region (QRDR) cause fluoroquinolone resistance in topoisomerases.⁴³ Methylation, as seen in Staphylococcus species and others, is another effective resistance strategy. Additionally, Staphylococcus species express altered penicillin-binding proteins, encoded by mecA and mecC genes, which reduce beta-lactam antibiotic affinity.⁷

Fig.4 Stages of AMR development⁷

Drug Inactivation:

Bacteria inactivate antibiotics by enzymatic degradation or chemical modification. Beta-lactamases, produced by gram-positive and gram-negative bacteria, hydrolyze the beta-lactam ring, rendering beta-lactam antibiotics ineffective.⁷ Other enzymes, like those encoded by the TetX gene, hydrolyze tetracyclines. Common inactivation mechanisms include acetylation (aminoglycosides), phosphorylation, and adenylation (fluoroquinolones and chloramphenicol).⁸

Drug Efflux:

Efflux pumps in bacterial membranes expel antibiotics, metabolites, and signaling molecules, reducing drug accumulation.⁴ The first plasmid-encoded efflux pump, identified in E. coli, expelled tetracycline.⁹ Efflux systems, particularly the Resistance-Nodulation-Division (RND) superfamily in gram-negative bacteria, play a significant role in multidrug resistance.⁹ Gram-positive bacteria primarily utilize the ATP-Binding Cassette (ABC) and Major Facilitator Superfamily (MFS) efflux pumps. Efflux pumps can be encoded on chromosomal or mobile genetic elements, contributing to resistance in various bacterial species.¹⁰

The Factors That Lead to Resistance to Antibiotics:

Antibiotic resistance, a natural process enabling germs to survive, has been accelerated by factors such as excessive and incorrect prescribing, overuse, use as animal growth promoters, and a lack of novel antibiotics. Recent studies highlight the adverse effects of promoting antibiotic use and emphasize the need to educate the medical community, including undergraduates, on tackling this critical public health issue. Resistance develops when microbes adapt to neutralize the drug's effects, such as altering the bacterial envelope, producing degrading enzymes, reducing drug intake, or enhancing efflux, as summarized in Table 2.¹¹

Fig.5 Variation or Mutation that leads to AMR¹²

The misuse of broad-spectrum antibiotics and current prescribing practices exacerbate the AMR epidemic, as shown in Fig.5. AMR complicates disease management, weakens immunity, and increases risks during procedures like cancer treatments, dialysis, and knee replacements. Patients with coexisting illnesses face higher chances of severe consequences, prolonged hospital stays, and increased treatment costs due to "last-resort" antibiotics. Developing effective clinical management methods, improving public health education on immunization and infection prevention, and emphasizing appropriate antibiotic use based on accurate diagnoses are critical to combating AMR.

Emerging nations face challenges such as limited diagnostic resources, inadequate regulations, and widespread self-medication with over-the-counter antibiotics, worsening AMR. Reducing financial incentives for antibiotic overprescription by pharmaceutical companies is essential. Additionally, modern travel accelerates the global spread of AMR. For instance, Indian travelers to Europe have carried Carbapenemase-producing Enterobacteriaceae (CPE) without prior contact with the Indian healthcare system, highlighting the global nature of AMR spread, as seen during the COVID-19 pandemic.

POLYPHARMACY AND EXCESSIVE ANTIBIOTIC USE:

Polypharmacy is the use of multiple drugs at once, while irrational use of antibiotics is the use of antibiotics in an inappropriate way. Both can have negative effects on patient health as given in Table 1.¹³

Polypharmacy is more common in the elderly population. The prevalence of polypharmacy in the geriatric population increased from 24% to 39% between 2000 and 2012.¹⁴

Table.1, Difference between Polypharmacy and Irrational use of Antibiotics¹³

	Polypharmacy	Irrational use of Antibiotics
Definition	Taking multiple drugs at the same time, including prescription and over-the-counter medications	Using antibiotics in an inappropriate way, such as for non-bacterial infections, with inadequate dosage, or outside clinical guidelines
Effects	Increased risk of side effects, adverse drug events, falls, drug-drug interactions, and noncompliance	Can lead to antimicrobial resistance
Factors	Comorbid conditions, such as multiple illnesses in a patient's medical records	Lack of proper knowledge from both patients and providers

Table.2, Anti-Microbial Drugs and reason for AMR development¹⁴

Antimicrobial Drugs	Common resistance bacteria	Reason of AMR
Penicillin Penicillin G, Penicillin V, Amoxicillin, Ampicillin	Staphylococcus Aureus, Escherichia Coli, Klebsiella Pneumoniae	Production of Beta-lactamase enzymes that hydrolyse the Beta-lactam ring, rendering the antibiotic ineffective.
Cephalosporins Cefalexin, Cefuroxime	E. Coli, K.Pneumoniae, Pseudomonas Aeruginosa	Extended spectrum Beta-lactamases (ESBLs) that degrade cephalosporins.
Carbapenems Imipenem, Meropenem, Ertapenem	K.Pneumoniae, P.Aeruginosa,Acinetobacter Baumannii, Enterobacter Cloacae	Carbapenemase enzymes such as KPC (klebsiella pneumoniae Carbapenemase) and NDM (New Delhi Metallo-beta-lactamase) that hydrolyse Carbapenems.
Fluoroquinolones Ciprofloxacin, Levofloxacin, Moxifloxacin	E. Coli, K. Pneumoniae, P. Aeruginosa, Staphylococcus Aureus	Mutations in DNA gyrase and topoisomerase IV, efflux pumps, and decreased permeability of the bacterial cell wall.
Aminoglycosides Gentamicin, Tobramycin, Amikacin	E. Coli,K. Pneumoniae, P. Aeruginosa, Acinetobacter Baumannii	Enzymatic modification (acetylation, phosphorylation), efflux pumps, and mutations in ribosomal proteins.
Monobactams Aztreonam	E. Coli, K.Pneumoniae, P.Aeruginosa	Beta-lactamase enzyme production, altered penicillin binding proteins.
Lincosamides Clindamycin, Lincomycin	Staphylococcus Aureus (Including MRSA) Streptococcus Pneumoniae Enterococcus Spp. Bacteroides Fragilis	Bacteria can resist antibiotics by modifying ribosomal RNA with enzymes, using efflux pumps to remove the antibiotic, and producing enzymes that inactive the antibiotic.
Polypeptides Bacitracin, Polymyxin B, Colistin (Polymyxin E), Tyrothricin, Gramicidin	Pseudomonas Aeruginosa Acinetobacter Banumannii Klebsiella Pneumoniae Enterobacter Spp.	Modification of lipid A in the bacterial cell membrane, efflux pimps, and production of enzymes that degrade colistin.
Nitroimidazoles Metronidazole, Tinidazole	Helicobacter Pylori Bacteroides Fragilis Clostridium Difficile Trichomonas Vaginalis	Reduce uptake by decreasing cell wall permeability, using efflux pumps to remove the drug, producing Nitro reductases to inactivate the drug, and mutations affecting the enzymes involved in the drug’s activation.
Streptogramins Quinupristin/ Dalfopristin (Combines as Synercid)	Enterococcus Faecium (Especially Vancomycin Resistant Strains, VRE) Staphylococcus Aureus (Including MRSA) Streptococcus Pneumoniae	Bacteria can resist antibiotics by modifying ribosomal RNA through methylation, using efflux pumps to remove the antibiotic, and producing enzymes that inactivate the antibiotic.
Ansamycins Rifampicin, Rifabutin	Mycobacterium Tuberculosis (resistant strains, MDR-TB and XDR-TB) Staphylococcus aureus (including MRSA) Neisseria meningitidis	Bacteria can resist antibiotics through mutations in the RNA polymerase enzyme and by using efflux pumps to actively remove the antibiotic from the cell

Various Means to Increase Public Awareness Regarding Antibiotic Utilisation:

Targeting Key Groups:

Informal healthcare providers, nurses, and small-scale farmers, often overlooked in AMR campaigns, should be prioritized, especially in LMICs. Schools and colleges must include topics like the microbiome, responsible drug use, and AMR in their curricula. Civil society organizations can enhance government efforts through advocacy, while consumer associations should promote "antibiotic-smart" food and antibiotic-free farming.

Effective Communication and Leadership:

Health ministries should lead AMR campaigns, funded by governments with foreign aid as a secondary source. Larger nations can establish interministerial bodies, while smaller ones can collaborate regionally. Transparent decision-making and civil society involvement are essential. UNESCO, UNICEF, WHO, FAO, and OIE must deliver consistent global messaging through a Global Health Partnership.¹⁵

Strategic Messaging:

Awareness campaigns should use existing government channels to highlight antibiotic residues in fast food and advocate for better meat sourcing standards, driving policy changes and consumer demand for "antibiotic-smart" food. Lessons from HIV campaigns can guide strategies, with safeguards against pharmaceutical influence.

Engaging Industry and Professionals:

National action plans must focus on professionals who use or recommend antibiotics, involving trade unions, professional associations, and civil society. International organizations should support monitoring antibiotic use and fostering industry codes of conduct. Short training programs and specialized modules should be implemented, overseen by interministerial groups and local health authorities.

Fig.6 Communication strategies to increase public awareness about antibiotic utilization

Parties Involved in the Messaging Strategy:

Addressing AMR requires a multisectoral approach to align messaging and target audiences. While large campaigns raise awareness, they may not always yield proportional results. A bottom-up approach is essential to address barriers at individual, community, and health system levels. Family doctors and local officials are crucial for integrating healthcare messaging into primary care. Machine-driven sectors using antibacterial products should also contribute grassroots support as given in Fig6.

Understanding and Changing Behavior:

Behavioral change is critical for reducing antibiotic overuse and building a sustainable healthcare system. Raising awareness alone is insufficient; change requires four pillars: awareness, strong regulations, financial incentives, and a supportive social environment.⁸³ Efforts should strengthen regulations, incentivize healthcare providers and farmers, and promote societal disapproval of antibiotic overuse to ensure lasting behavioral change.¹⁶

Changing Microbial Communities To Combat Infections That Resist:

The human microbiota, comprising bacteria, viruses, and fungi, plays a crucial role in maintaining health and preventing infections. Altering the microbiota through fecal microbiota transplants (FMTs) has shown success in treating C. difficile colitis, and research is ongoing to use FMTs for decolonizing multidrug-resistant pathogens. Efforts to develop live biotherapeutic agents—pharmaceuticals made from specific live organisms—are progressing. While the gut microbiome remains the primary focus, strategies may also address infections in areas like the skin and respiratory tract. Novel approaches, such as gram-negative pathogen-parasitic bacteria like Bdellovibrio and Micavibrio, are also under investigation.

Bacteriophages, viruses that specifically target bacteria, are a promising tool against AMR. Despite early 20th-century efforts to treat infections like cholera and plague with phages, their popularity declined in the West with the rise of antibiotics. However, renewed interest has emerged due to their pathogen specificity and effectiveness against drug-resistant infections. Recent randomized trials in the UK showed clinical benefits of phage therapy for chronic antibiotic-resistant P. aeruginosa infections, and ongoing European trials are assessing its efficacy for burns and wounds.

Innovative applications of phages include lysins, lytic enzymes that target biofilms and gram-positive bacteria like S. aureus. Phase 1 trials are ongoing for the first lysin-based pharmaceutical. Researchers are also developing engineered phage products to alter bacterial virulence factors and antibiotic resistance mechanisms. ¹⁷

CRISPR-Cas systems, natural bacterial defense mechanisms, are being explored to target resistant bacteria. Loss of CRISPR systems in enterococci is linked to multidrug resistance, suggesting their potential to combat resistance genes via horizontal gene transfer. Using phages to deliver CRISPR systems could allow precise targeting of resistant strains.

Tigecycline, a glycylcycline antibiotic developed by Wyeth and marketed as Tygacil, was approved by the FDA to combat antibiotic-resistant pathogens like Staphylococcus aureus.

Current and Recent Microbes Which Have Achieved Resistance:

The 2024 WHO Bacterial Priority Pathogens List (BPPL) identifies critical and high-priority antibiotic-resistant pathogens, posing global health threats. Key concerns include carbapenem-resistant Acinetobacter baumannii, third-generation cephalosporin-resistant Enterobacterales, fluoroquinolone-resistant Salmonella Typhi, and multidrug-resistant Neisseria gonorrhoeae. High-priority pathogens include methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus faecium, and antibiotic-resistant Pseudomonas aeruginosa. These rising resistances highlight the urgent need for research, surveillance, and novel treatment development.¹⁸

Novel Antibiotics for Bacterial Strains Resistant to Multiple Drugs:

Cefiderocol:

A siderophore cephalosporin that can overcome most resistance mechanisms, including metallo-beta-lactamases.

Ceftazidime-avibactam:

Active against most Enterobacterales and P. aeruginosa, but not XDR A. baumannii.

Omadacycline:

A semisynthetic drug that is active against Gram-positives, including MRSA, and some Gram-negatives.¹⁹

Cefepime:

A fourth-generation cephalosporin that is active against many multidrug-resistant gram negatives.

Eravacycline:

A newly approved antibiotic that is effective against a variety of multidrug-resistant pathogens.

A study published in Science in February 2024 examined lincosamides, an older class of antibiotic, as a potential new treatment for drug resistance. Lincosamide antibiotics are semi-synthetic drugs based on molecules found in nature.²⁰

Future Directions:

Investing in the development of new antibiotics and alternative therapies such as bacteriophages and antimicrobial peptides is crucial. Advancing diagnostic tools like rapid tests and next-generation sequencing (NGS) will enable precise identification of infections and resistance patterns. Strengthening antibiotic stewardship through comprehensive training for healthcare providers, stricter prescription regulations, and robust monitoring systems is essential. Enhancing public health measures, including vaccination promotion, infection control protocols, and public awareness campaigns about antibiotic misuse, will help reduce resistance spread. Encouraging global collaboration to share resources and strategies, supporting global action plans like the WHO's Global Action Plan on AMR, and creating economic incentives for pharmaceutical companies to develop new antibiotics are vital steps to address this growing threat.

CONCLUSION:

The discovery of antibiotics has transformed healthcare, but the rising threat of antimicrobial resistance (AMR) jeopardizes these advancements. As resistant pathogens render existing antibiotics ineffective, AMR poses a complex global challenge. Addressing it requires systemic changes, including improved stewardship, strengthened surveillance, innovative research for new antibiotics, and reduced agricultural antibiotic use. Public health education is crucial to raise awareness about misuse and adherence to prescribed treatments. Technology, like AI and advanced diagnostics, can optimize antibiotic use and reduce unnecessary prescriptions. International collaborations and funding for new antimicrobial agents are vital to combat drug-resistant strains. Without decisive action, minor infections could become fatal, underscoring the need for coordinated global efforts to prevent AMR from becoming a crisis.

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Received on 31.08.2024      Revised on 27.12.2024

Accepted on 04.03.2025   Published on 23.04.2025

Available online from April 26, 2025

Asian J. Pharm. Tech. 2025; 15(2):181-188.

DOI: 10.52711/2231-5713.2025.00029

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