Sage Journals: Discover world-class research

Abstract

Antimicrobial resistance (AMR) poses a significant global health threat by diminishing the effectiveness of once-powerful antimicrobial agents, leading to higher rates of illness and death, along with escalating healthcare costs. While bacterial resistance is a primary concern, resistance is also increasing against antifungal, antiparasitic, and antiviral drugs. Many of the last-resort drugs are becoming less effective due to AMR. Projections indicate that by 2050, AMR could cause up to 10 million deaths annually, making it the leading cause of death worldwide, a situation that could result in a post-antibiotic era with substantially increased morbidity and mortality. This review aims to raise awareness about the dangers of AMR and its potential to become a silent global pandemic. It begins by examining antimicrobial drugs, followed by a discussion on AMR, focusing on resistance to antibacterial, antifungal, antimalarial, and antiviral drugs, along with its effects on health, and the economy, and prioritized global pathogens. Finally, it explores preventive measures and innovative strategies to combat AMR.

Keywords

antibacterial resistance antifungal resistance antimalarial resistance antimicrobial stewardship global priority pathogens One Health

Overview of antimicrobials and antimicrobial resistance as a global threat

Introduction

An antibiotic is a compound produced by, or extracted from, a microorganism that can either kill or prevent the growth of another microorganism. An antimicrobial is a substance derived from any source (microorganisms, plants, animals, synthetic, or semi-synthetic) that acts against any type of microorganism, such as bacteria, fungi, parasites, and viruses. Every antibiotic falls under the category of antimicrobials, but not all antimicrobials are antibiotics.¹ Antimicrobials, by inhibiting cell wall, protein, and nucleic acid synthesis of germs,² are used in controlling infections affecting humans and animals.³ Since the early 20th century, antimicrobials have saved millions of lives³ and have made hospital procedures like general surgery, organ transplants, renal dialysis, and cancer chemotherapy possible, as their ability to manage associated infections is vital for the success of these treatments.^4,5 Hence, without effective antimicrobials, carrying out hospital procedures may lead to severe infections such as sepsis, leading to increased morbidity and mortality.

Antimicrobial resistance (AMR) emerges when microorganisms such as bacteria, fungi, viruses, and parasites adapt after being exposed to antimicrobial agents such as antibacterials, antifungals, antivirals, antimalarials, and anthelmintics, ultimately reducing or eliminating the effectiveness of these medications.⁶ Simply put, AMR is when a microorganism can withstand the growth-inhibiting or killing effects of an antimicrobial, going beyond the normal sensitivity of that particular germ.^7,8 This review explores various aspects related to antimicrobial agents, including the discovery of antimicrobials, AMR, and an overview of resistance to antibacterial, antifungal, antimalarial, and antiviral drugs. It also covers the prevalence and economic impact of AMR and identifies global priority pathogens (superbugs). Finally, it explains control strategies to contain AMR. Hence, this review aims to awaken the community, healthcare providers, and regulatory bodies to the silent pandemic nature of AMR and its control strategies.

The discovery and use of antimicrobial agents

The modern antimicrobial era began with the discovery of Salvarsan in 1910 by Paul Ehrlich and penicillin in 1928 by Alexander Fleming. Although Salvarsan had a complicated injection process and could cause side effects, it was highly successful when marketed by Hoechst, eventually becoming the most widely prescribed drug. This popularity persisted until penicillin replaced it in the 1940s.⁹ Surprisingly, the exact mechanism by which Salvarsan works is still unclear, and the debate regarding its chemical structure was resolved lately.¹⁰ Moreover, Salvarsan has also been shown to extend life expectancy by more than 20 years.¹¹ Consequently, Salvarsan is considered the first modern antimicrobial that was effectively used to treat bacterial infections during that era.

Paul Ehrlich’s systematic screening approach laid the foundation for drug discovery methods, leading to the identification and development of thousands of drugs used in clinical practice. In the early days of antibiotic research, this method was instrumental in the discovery of sulfa drugs, specifically sulfonamidochrysoidine (KI-730, Prontosil).¹² It turned out to be a prodrug, with its active component, sulfanilamide.¹³ In the early 20th century, scientists were driven by a strong desire to discover and identify new therapeutic compounds. Their focused efforts and achievements laid the groundwork for innovating new groups of antimicrobial medications that are still in use today, particularly during the 1940s to the 1970s.

Alexander Fleming serendipitously discovered penicillin on September 3, 1928.¹⁴ Twelve years after penicillin discovery, Howard Florey and Ernest Chain found a method on how to purify penicillin to produce sufficient penicillin to be used clinically.¹⁵ Their method ultimately paved the way for the large-scale production of penicillin, employing deep-tank fermentation pioneered by Pfizer. This process allowed for extensive use of penicillin by the Allied Forces during World War II to treat traumatic and postoperative infections.^16,17 Following the war, penicillin became available for widespread prescription to the general public, earning the nickname “wonder drug” due to its remarkable effectiveness.¹⁸ The timeframe from the 1950s to the 1970s is often called the “golden era” of antimicrobial discovery. During this period, many of the antimicrobial classes that we use today were discovered or synthesized.¹⁹

Moreover, following the discovery of penicillin, antimicrobials have transformed medicine and saved many lives,²⁰ and it was seen as signaling the end of infectious diseases.²¹ The use of antimicrobials has significantly lowered mortality rates from infectious diseases, that previously accounted for the highest human mortality.²² The discovery and use of antimicrobials was significant healthcare breakthrough of the last century.¹¹ Due to the use of antimicrobials, Sir Frank MacFarlane Burnet, a Nobel Prize laureate in Medicine in 1960, wrote about the reduction in infectious diseases in 1962.²³

Overview of antimicrobial resistance by microorganisms of medical importance

The introduction of sulfonamides to the market was soon followed by the emergence of sulfa drug resistance.¹³ Even before penicillin was widely used, there were indications that bacteria could break it down through enzymatic degradation.²¹ When Alexander Fleming received the Nobel Prize in 1945 for discovering penicillin, he used his Nobel lecture to caution that bacteria could become “easily resistant to penicillin”²⁴ Penicillin resistance emerged in the 1940s, shortly after it began to be used widely.²⁵ Resistant strains to different antimicrobials, such as methicillin and vancomycin, were reported just a few years after their introduction. The emergence of penicillin-resistant bacteria by 1960 raised serious concerns. In response, new β-lactam antibiotics were developed and incorporated into medical practices to tackle the issue.²⁶ The rapid emergence of resistance shortly after the use of existing antimicrobials causes people to despair, casting doubt on the possibility of a future free from infections.

But during this time, bacteria began to become resistant to the new antibiotics by secreting β-lactamases capable of inactivating such drugs. Methicillin-resistant Staphylococcus aureus (MRSA) was discovered in the UK in 1961, which was a pivotal point for the occurrence of AMR.²⁷ Since then, MRSA has spread extensively around the world.²⁸ Moreover, due to their overuse globally, resistance to antimicrobials has become a significant issue, with some strains developing resistance within a year of an antimicrobial’s introduction, and many others developing resistance within 5 years.² Timeline of selected antimicrobials’ first use and resistance reported has been shown in Table 1.

Table 1.

Timeline of antimicrobial drug resistance for selected antimicrobials.

Type of antimicrobial	Name of the antimicrobial	Year of first use	Year of first report of resistance
Antibacterials^8,29,30	Penicillin	1941	1942
	Sulphonamides	1930	1933
	Tetracycline	1950	1956
	Erythromycin	1953	1955
	Methicillin	1960	1960
	Gentamycin	1967	1979
	Vancomycin	1958	1988
	Ceftazidime	1985	1987
	Cefotaxime	1980	1983
	Azithromycin	1980	1980
	Imipenem	1985	1998
	Ciprofloxacin	1987	1987
	Levofloxacin	1996	1996
	Linezolid	2000	2001
	Daptomycin	2003	2004
	Ceftaroline	2010	2011
	Ceftazidime-avibactam	2015	2015
Antifungals⁸	Amphotericin B	1959	2016
	Fluconazole	1988	1988
	Caspofungin	2001	2004
Antimalarials³¹	Quinine	1632	1910
	Primaquine	1940	1944
	Chloroquine	1945	1957
	Proguanil	1948	1949
	Artemisinin	1967	2008
	Sulphadoxine-pyrimethamine	1967	1967
	Mefloquine	1977	1982
	Atovaquone	1996	1996
Antivirals^32–36	Acyclovir	1982	1982
	Zidovudine	1987	1989
	Lamivudine	1995	1996
	Atazanavir	2003	2004

Each time a new class of antimicrobials is introduced, resistance to it and other classes soon follow. Even the latest antimicrobial classes, despite their broad-spectrum activity, are already showing signs of reduced susceptibility.³⁷ Without timely intervention, the prospect of reverting to the pre-antibiotic era is increasingly likely in numerous regions around the world.³⁸ AMR has been linked to higher rates of illness and death, longer hospital stays, and rising healthcare costs.^39,40 Drug-resistant fungal strains, such as Candida auris, gram-positive bacteria like Staphylococcus aureus, and anaerobic species including Clostridium difficile, all pose significant health risks to the population.⁴¹ Almost all microorganisms of medical importance, such as bacteria, fungi, parasites, and viruses, have developed resistance to most of the available antimicrobial agents.

Antibacterial drug resistance

Currently, AMR has been found in microorganisms of medical importance, including viruses, parasites, fungi, and bacteria.⁴² When compared to the other germs resistance, antibacterial drug resistance is the main factor behind disease burden due to their nature of rapid development of resistance to different new antibacterials across all WHO regions, posing significant challenges.^39,42 It’s important to highlight those treating diseases caused by resistant bacteria is generally more challenging than those caused by non-resistant strains.⁴ The challenge becomes even more severe as the number of new antibacterials in the drug development pipeline continues to decline.⁴³

Various studies have thoroughly described the mechanisms by which bacteria resist antimicrobial drugs.^44,45 Bacteria can acquire resistance to antibacterial agents through four main mechanisms.⁴⁶ These mechanisms include enzymatic degradation of antibacterials, the activation of efflux pumps to maintain subinhibitory intracellular drug levels, alterations in the target site of the antibacterial, and modifications in cell membrane permeability.⁴⁷ An additional bacterial characteristic, aside from the selection of antibacterial resistance genes, that contributes to AMR is biofilm formation.⁴⁸ A biofilm is a stable, three-dimensional structure created by microorganisms that cluster on a surface to establish a colony.⁴⁹

Resistance traits may be passed down genetically from one generation to another. In addition, bacteria can acquire AMR genes through horizontal gene transfer (HGT), which occurs via processes like conjugation, transformation, or transduction.⁸ Among the mechanisms of HGT, conjugation is particularly important. This process necessitates direct physical contact between the cells of the bacteria, facilitating the transfer of genetic material. A sex pilus forms during conjugation, allowing a plasmid to be transferred to the recipient bacterium. Through a single conjugation event, multiple antibiotic resistance genes encoded on the plasmid can be transmitted, potentially resulting in the emergence of multidrug-resistant strains.⁵⁰ Transformation is a DNA recombination process in which a microorganism absorbs external DNA segments, also known as naked DNA, from the environment, incorporating them into its genetic structure, and making them inheritable traits.⁵¹ Transduction is a bacteriophage-mediated process in which genetic material is transferred between a virus (bacteriophage) and a bacterial cell it infects.⁴⁴

Multidrug-resistant (MDR) bacteria, defined as bacterial strains having resistance to one or more antimicrobial agents from three or more different classes of antibiotics, pose a major public health threat in developing countries. These bacteria lead to higher morbidity and mortality rates and make treatment more difficult.⁵² The growing frequency of bacterial strains that are resistant and multi-resistant has turned into a major challenge for healthcare systems worldwide.⁵³ The majority of pathogens are becoming MDR, posing a heightened risk of treatment failure with conventional therapies. This leads to an elevated burden of disease, longer hospitalizations, and increased healthcare expenses.^54,55

Antifungal drug resistance

The rise of antifungal drug resistance has alarmed the scientific community, signaling the occurrence of a new health concern alongside antibacterial and antiviral resistance.⁵⁶ Moreover, the prevalence of diseases due to invasive fungal pathogens is on the rise globally.⁵⁷ Recent epidemiological data indicate a global surge in serious mycoses, with over 150 million cases recorded annually and more than 1.7 million resulting in death each year.^58,59 In total, such projections suggest that over 6.55 million people are afflicted annually by a life-threatening fungal disease, causing more than 3.75 million deaths, with about 2.55 million of these deaths directly attributable to the fungal disease itself.⁶⁰ The WHO released the first-ever list of fungi that pose a risk to public health to guide research and development efforts. The purpose of this list is to improve the worldwide response to mycoses and antifungal resistance (Table 2).⁶¹

Table 2.

WHO priority fungal pathogens.⁶¹

Name of the fungal pathogen	Classification
Cryptococcus neoformans	Yeast
Candida auris	Yeast
Aspergillus fumigatus	Mold
Candida albicans	Yeast
Nakaseomyces glabrata (Candida glabrata)	Yeast
Histoplasma spp.	Mold
Eumycetoma causative agents	Various fungal pathogens
Mucorales	Mucorales (molds)
Fusarium spp.	Molds
Candida tropicalis	Yeast
Candida parapsilosis	Yeast
Scedosporium spp.	Molds
Lomentospora prolificans	Mold
Coccidioides spp.	Dimorphic fungi
Pichia kudriavzeveii (Candida krusei)	Yeast
Cryptococcus gattii	Yeast
Talaromyces marneffei	Dimorphic fungus
Pneumocystis jirovecii	Yeast
Paracoccidioides spp.	Dimorphic fungi

Numerous adaptive mechanisms of resistance to antifungal drugs have been recognized, including the alteration or excessive expression of drug targets, the upregulation of multidrug efflux pumps, and the activation of cellular stress pathways.⁶² Substitutions of amino acids within cytochrome P450 14 α-demethylase, encoded by the ERG11 (CYP51) gene, have been identified as a resistance mechanism to azole antifungals due to changes in its affinity for azoles.^63,64 Azole resistance may be driven by energy-dependent efflux pumps, like those known as ATP-binding cassette (ABC) multidrug transporters.⁶⁵ Amino acid substitutions in the target site of the 1,3-β-d-glucan synthase (GS) Fks1p subunit are enough to cause reduced susceptibility to echinocandins.⁶⁶ Polyene resistance is typically associated with a reduction in the target ergosterol, which is caused by mutations leading to the loss of function in ergosterol synthesis genes.⁶⁴

Growing azole resistance in isolates of non-Candida albicans, azole resistance in Aspergillus fumigatus, and echinocandin resistance in Candida glabrata are examples of acquired antifungal resistance.^67,68 In addition, new species are appearing to resist multiple classes of currently available antifungal agents, such as Candida auris.⁶⁹ Currently, the majority of antifungal drugs become ineffective due to antifungal resistance. This scenario is severe, especially in immunocompromised patients such as cancer patients (leukemia or lymphoma), autoimmune diseases (such as lupus or rheumatoid arthritis), patients with Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome (HIV/AIDS), and patients taking other immune-suppressing treatments.

Antimalarial drug resistance

Worldwide in 2023, there were approximately 263 million cases of malaria, leading to 597,000 deaths.⁷⁰ Malaria elimination efforts face challenges due to antimalarial drug resistance, such as artemisinins and their partner drugs in Artemisinin Combination Therapy (ACT).^71,72 Currently, this problem has been noted in Plasmodium falciparum, Plasmodium vivax, and Plasmodium malariae.⁷¹

Resistance mechanisms in malaria parasites include drug efflux, changes to the drug target, and enzymatic degradation or modification of the drug. In addition, there are fewer common mechanisms linked to the parasite’s lifecycle and metabolism.⁷³ For example, mutations in pfk13 contribute to artemisinin resistance by prolonging the parasite’s stay in the earlier, less drug-sensitive ring stage. This also enhances the unfolded protein response, which halts development as artemisinin is rapidly cleared and the damaged peptides are removed.⁷² Hence P. falciparum artemisinin resistance, which emerged in the Mekong Subregion in 2008, resulting from mutations in the pfkelch13 gene.⁷⁴

The K76T mutation in the chloroquine resistance transporter gene (pfcrt) is strongly related to chloroquine resistance in P. falciparum.⁷⁵ Mechanistic studies show that mutations in PfCRT enable the transporter to pump chloroquine out of the digestive vacuole membrane into the cytosol, preventing it from reaching its target, heme/hemozoin.^76,77 Although PfCRT is the primary driver of chloroquine resistance, sequence variants of PfMDR1, an ABC transporter located on the digestive vacuole membrane, can influence the extent of resistance.⁷⁸ Moreover, chloroquine resistance in P. vivax appears to be driven by an unidentified mechanism, involving transcriptional alterations in the orthologous pvcrt-o gene. This points to interspecies variations in the native function of the transporter, which is still not fully understood.⁷⁹

Early reports suggesting quinine resistance surfaced as far back as 1910.⁸⁰ During the WHO Global Malaria Eradication Program (1955–1969), the first instances of chloroquine resistance in P. falciparum were reported independently in South America and Southeast Asia.^81,82 A comprehensive review of antimalarial drugs resistance was conducted by Matthew M. Ippolito et al.⁸³ and Didier Menard et al.⁸⁴ Resistance to artemisinin and its derivatives in P. falciparum is a growing concern in Southeast Asia, leading to high failure rates with ACT in several countries within the Greater Mekong subregion. This resistance threatens the region’s malaria elimination goals. If these hard-to-treat parasite strains reach sub-Saharan Africa, it could significantly increase malaria-related morbidity and mortality, indicating a need for intensive surveillance.⁸⁴ Every antimalarial drug has reports of resistance. This includes artemisinin, its derivatives, and ACT, which are the last resort for managing infections caused by P. falciparum.

Antiviral drug resistance

Antiviral drug resistance is becoming a growing concern, particularly among immunocompromised patients.⁸⁵ Acyclovir-resistant herpes simplex virus is recognized to cause conditions such as meningitis, esophagitis, and pneumonia in immunocompromised patients.^86,87 When HIV replicates while the infected person is on antiretroviral (ARV) drugs, it can lead to the selection of drug-resistant strains. This HIV drug resistance can undermine the effectiveness of ARV drugs for both HIV prevention and treatment, potentially increasing HIV incidence, morbidity, and mortality⁸⁸ Zidovudine resistance was initially detected in clinical isolates in 1989.³⁴ The consequences of resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) are generally more apparent than those of zidovudine resistance. As observed in in vitro studies, NNRTI-resistant strains can rapidly develop in real-life settings.⁸⁹ Nevertheless, resistance to HIV medications can undermine the effectiveness of antiretroviral (ARV) drugs in lowering HIV incidence as well as reducing HIV-associated morbidity and mortality.⁹⁰ Thus, WHO recommends consistent and periodic surveillance of HIV drug resistance to guide public health recommendations at local, national, and global levels.⁹¹ Although various viruses can develop resistance, ARV drug resistance is particularly prominent and could potentially undermine the progress achieved in ARV treatment.

As the use of antiviral agents becomes more widespread in-patient care, antiviral resistance has transitioned from being primarily a laboratory concern to a clinical issue. Currently, resistant viruses are most commonly found in immunocompromised individuals who have been taking antiviral drugs for extended periods. Therefore, the development of antiviral resistance is likely to become more frequent and significant in the long term.⁹² Developing antiviral drugs is very challenging due to the significant genetic diversity of viruses showing rapid mutation rates, which is aggravated by the development of resistance to antiviral drugs.

Acyclovir resistance in herpes simplex virus (HSV) is associated with mutations in the viral thymidine kinase (TK) or DNA polymerase.⁹³ Mutations in TK can result in either a total loss of TK activity (TK deleted or deficient virus) or, less commonly, a change in the substrate specificity of TK (TK altered virus).⁹⁴ In clinical practice, suspected or confirmed acyclovir-resistant HSV is typically treated with foscarnet, or less commonly, cidofovir. Treatment is often initiated empirically based on the prevalence of TK mutations, but cross-resistance can occur due to DNA polymerase mutations. There have also been reports of resistance to both foscarnet and cidofovir developing during therapy.^95,96 Similar to HSV, varicella zoster virus (VZV) also produces a TK, and most cases of VZV drug resistance are due to mutations in the TK,⁹⁷ which often leads to a premature stop codon, rendering the virus TK-deficient, and they tend to cluster at specific loci within the VZV TK gene.⁹⁸ Foscarnet resistance has emerged in a small number of patients undergoing treatment with the drug for acyclovir-resistant VZV,⁹⁹ and linked to a mutation in the viral DNA polymerase.⁹⁹ In hepatitis B virus (HBV), high-level lamivudine resistance is mainly driven by M204I/V mutations, which occur in the YMDD (tyrosine-methionine-aspartate-aspartate) motif within the C domain of the polymerase gene,¹⁰⁰ and, less commonly, by A181V/T mutations.¹⁰¹

There are two biochemical mechanisms by which resistance to nucleoside reverse transcriptase inhibitors (NRTIs) occurs. The first mechanism involves base changes that enable the reverse transcriptase (RT) enzyme to selectively exclude NRTIs during synthesis, inhibiting their incorporation into the DNA chain.¹⁰² The second mechanism involves mutations that increase the rate of phosphorolytic removal of the chain-terminating NRTI residue from the 3’ end of the elongating viral DNA, allowing DNA synthesis to continue.^102,103 The K70R mutation at codon 70 was initially identified in patients undergoing AZT monotherapy.¹⁰⁴ The mutations associated with NNRTI resistance are found near the hydrophobic pocket of the RT.¹⁰⁵ K103N is the most common resistance mutation that develops during the failure of an NNRTI-based regimen^106,107 Resistance to protease inhibitors is linked to mutations in the protease gene, where amino acid changes decrease the ability of the inhibitor to bind to the protease.¹⁰⁸

AMR as a global threat

The United Nations General Assembly Resolutions in December 2015¹⁰⁹ and September 2016¹¹⁰ acknowledged AMR as a global threat¹¹¹ and declared it to be among the top 10 global health threats.¹¹² AMR endangers our capacity to effectively treat infectious diseases.^34,113 The lack of new antimicrobials in the development pipeline and infections caused by MDR pathogens becoming resistant make AMR to be a global threat.^42,114 AMR is often called the “Silent Pandemic,” emphasizing the urgent need for immediate and more effective action to address the problem.¹¹⁵

Antimicrobials that are effective against common bacterial infections such as sepsis, urinary tract infections, and diarrhea are becoming increasingly rare worldwide.¹¹⁶ Consider the implications if all existing antimicrobials were to become ineffective in preventing and treating common infections. Such a scenario would be dire, signaling the arrival of the dreaded “post-antibiotic era.” Although we hope to avoid this grim future, there are already signs indicating that it could become a reality.

Prior research suggests that underdeveloped nations are probably the ones most negatively impacted by antibiotic resistance, despite the paucity of comprehensive data. This susceptibility results from ongoing developmental obstacles, such as specific problems with their healthcare systems.^117,118 In developing countries, the risk that AMR could lead to higher rates of morbidity and mortality is elevated. This is due to a greater burden of bacterial illnesses, limited access to diagnostic tools, particularly microbiology, and fewer second-line antibiotics.¹¹⁹ To put it another way, the lack of community awareness about AMR, limited access to high-quality and effective antimicrobials, inadequate antimicrobial stewardship programs, and weak drug regulatory activities in these countries all contribute to the rise of AMR.

The growing resistance rates among community-acquired infections, such as upper and lower respiratory tract infections, bacterial diarrhea, and typhoid fever, are not being met with the development of newer antibiotics.¹²⁰ This reduced effectiveness has led to greater difficulties in treating various illnesses, such as gonorrhea, tuberculosis, septicemia, and pneumonia.^121,122 AMR can be transmitted and spread across large geographical areas through the environment.¹²³ Wastewater contamination, which frequently results from hospital or intensive farming operations, is a typical mechanism for antibiotics and antibiotic-resistant microorganisms to enter the environment.¹²⁴ The ongoing selective pressure has driven the evolution and spread of resistant strains, making many antimicrobials decrease their effectiveness.³ When AMR is combined with inadequate infection control practices, resistant bacteria can readily transmit to other patients and into the environment.¹²⁵ Resistant bacteria can spread between individuals via direct contact, airborne particles, contaminated surfaces, food, and water.¹²⁶

Prevalence of AMR

Global estimates indicated that the number of deaths directly associated to AMR was 1.27 million in 2019.^39,127 In addition, the Institute for Health Metrics and the University of Washington estimated that AMR might have contributed to nearly 5 million deaths worldwide in 2019.³⁹ If no decisive measures are implemented to address AMR, the projected number of deaths from infections caused by multidrug-resistant pathogens could rise to 10 million per year by 2050.¹²⁸ Approximately 50,000 lives are estimated to be lost annually in the USA and Europe due to infections related to AMR.¹²⁹ Notably, AMR-related mortality has risen to become the third leading cause of death globally.³⁹ Estimated number of deaths by 2014, 2019, and 2050 is shown in Figure 1.

Figure 1.

Estimated number of global deaths by 2014, 2019, and 2050 per year.^39,127,128

The African continent experiences a significant level of resistance to widely used antimicrobials.¹³⁰ A study titled “Antimicrobial resistance in human and animal pathogens in Zambia, Democratic Republic of Congo, Mozambique and Tanzania” highlighted a rising trend in resistance to commonly used antimicrobials such as third-generation cephalosporins.¹³¹ The occurrence of penicillin-resistant pneumococci, initially noted in the 1960s, has increased significantly over the past decade.^132,133 A research carried out in 1997 indicated that approximately 33% of pneumococci exhibited resistance to penicillin.¹³³ A study conducted in Nigeria showed that 82% of Klebsiella isolates from blood showed resistance to ceftriaxone.¹³⁴ A different study from Nigeria conducted in 1996 found that 82% of Klebsiella isolates were resistant to ceftazidime and 71% were resistant to ceftriaxone.¹³⁵ AMR to various antimicrobials used in human medicine has been observed in bacteria isolated from food animals. Approximately 54% of Klebsiella and Escherichia coli species demonstrate strong resistance to third-generation cephalosporins.¹³⁶ Nowadays, there is no safe zone around the world free of AMR.

Economic impact of AMR

AMR could potentially reduce the global gross domestic product (GDP) by up to 3% by 2030, leading to an additional US$ 700 billion in global healthcare costs that year, with low-income countries bearing the brunt of this impact.^128,137,138 The World Bank has estimated that up to 3.8% of the global gross domestic product could be lost due to AMR by 2050.¹³⁷ Another study reported that the Global GDP decline by 2050 has been estimated to be 2−3.5%, incurring a global cost of US$ 100 trillion by 2050.¹²⁸

The European Center for Disease Prevention and Control (ECDC) reported that approximately €1.5 billion is spent on additional patient care expenses due to infections related to AMR.¹³⁹ Worries about the financial impact of using antimicrobials to treat infections that are resistant to several drugs are growing. Furthermore, various studies highlight the significant additional costs these infections impose on the healthcare system.¹⁴⁰ The management of drug-resistant infections through longer hospital stays, the use of costly additional medications, heightened morbidity, and reduced workforce productivity results in greater expenses. This escalation in costs can lead to increased poverty and pose obstacles to achieving the Sustainable Development Goals.

Global priority pathogens/superbugs

Microorganisms that possess resistance mechanisms to at least one agent in a minimum of three different classes of antibiotics are commonly classified as MDR organisms.^52,141 Superbugs are microbes that are resistant to the antimicrobial drugs. In many cases, infections caused by superbugs have limited treatment options.¹⁴² Infections caused by superbugs lead to increased morbidity and mortality rates because treatment options for these resistant bacteria are significantly compromised. In addition, they incur hefty treatment expenses and frequently necessitate lengthy hospital stays.¹⁴³ Superbugs include hospital-acquired infections due to gram-positive bacteria like Staphylococcus epidermidis, Clostridioides difficile, and Streptococcus pneumoniae and gram-negative bacteria like Burkholderia cepacia, Stenotrophomonas maltophilia, Campylobacter jejuni, Citrobacter freundii, Enterobacter spp., Haemophilus influenzae, Proteus mirabilis, Salmonella spp., and Serratia species.¹⁴⁴ Without proper intervention to combat AMR, superbugs could turn into biological threats that claim millions of lives annually.

WHO, in 2017, identified ESKAPE pathogens Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species as critical-priority bacteria, which play a significant role in the development of deadly AMR.^43,145 Mycobacterium tuberculosis, the bacteria responsible for tuberculosis, should also be included in this list. Moreover, a global priority pathogen of a list of drug-resistant bacteria has been published (Table 3).¹⁴⁶ Bacterial pathogens are ranked as critical, high, or medium based on various factors like mortality rates, resistance prevalence, treatability, or the current development pipeline.¹⁴⁷ The high and medium categories encompass bacteria with growing drug resistance, which necessitates enhanced monitoring and prevention efforts.¹⁴⁸ Drug research and development, along with antimicrobial stewardship programs, should prioritize efforts to combat superbugs and the ESKAPE pathogens.

Table 3.

Priority pathogens for R&D of new antibiotics.¹⁴⁶

Priority level	Pathogen	Notes on resistance
Global priority	Mycobacterium tuberculosis	Multidrug-resistance tuberculosis (MDR-TB) (resistance to rifampicin and isoniazid)Extensively drug-resistant TB (XDR-TB) – (XDR-TB defined as MDR plus resistance to fluoroquinolones and injectables (kanamycin, amikacin, capreomycin))
Critical priority	Acinetobacter baumannii	Carbapenem-resistant
	Pseudomonas aeruginosa	Carbapenem-resistant
	Enterobacteriaceae	Carbapenem-resistant, 3rd gen. Cephalosporin-resistant
High priority	Staphylococcus aureus	Vancomycin-resistant methicillin-resistant
	Campylobacter species	Fluoroquinolone-resistant
	Neisseria gonorrhoeae	3rd gen. Cephalosporin-resistant, fluoroquinolone-resistant
	Enterococcus faecium	Vancomycin-resistant
	Helicobacter pylori	Clarithromycin-resistant
	Salmonella species	Fluoroquinolone-resistant
Medium priority	Streptococcus pneumoniae	Penicillin-non-susceptible
	Haemophilus influenzae	Ampicillin-resistant
	Shigella species	Fluoroquinolone-resistant

The primary causes of nosocomial infections worldwide include Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter spp., and Escherichia coli, collectively known as the ESKAPE-E pathogens.¹⁴⁹ Noteworthy innate resistance and a broad capacity to develop resistance to several drugs are features of the ESKAPE-E infections. These pathogens have been identified by the WHO as a global health threat that urgently requires intervention.⁴³

In other words, critical-priority bacteria comprise Acinetobacter baumannii and Pseudomonas aeruginosa, which are resistant to carbapenem, and Enterobacteriaceae, which are resistant to both carbapenem and third-generation cephalosporins.⁴³ Whereas, high-priority bacteria include Enterococcus faecium, resistant to vancomycin; Helicobacter pylori, resistant to clarithromycin; and Staphylococcus aureus, resistant to methicillin. Other high-priority bacteria are Shigella spp., resistant to fluoroquinolones; Campylobacter spp., also resistant to fluoroquinolones; Haemophilus influenzae, resistant to ampicillin; and Streptococcus pneumoniae, resistant to penicillin.¹⁵⁰ In addition, the CDC grouped disease-causing germs into categories of urgent, serious, and concerning, threats and a watch list, depending on their AMR threat level⁸ (Table 4). In addition, prioritizing disease-causing microorganisms allows stakeholders to take focused and effective action to control AMR.

Table 4.

Threat level of germs in causing AMR.⁸

Threat level	Resistant microorganism
Urgent threats	Carbapenem-resistant AcinetobacterCandida auris (C. auris)Clostridioides difficile (C. difficile)Carbapenem-resistant Enterobacteriaceae (CRE)Drug-resistant Neisseria gonorrhoeae (N. gonorrhoeae)
Serious threats	Drug-resistant Campylobacter Drug-resistant Candida Extended-spectrum beta-lactamase (ESBL)-producing EnterobacteriaceaeVancomycin-resistant Enterococci (VRE)Multidrug-resistant Pseudomonas aeruginosa (P. aeruginosa)Drug-resistant nontyphoidal Salmonella Drug-resistant Salmonella serotype Typhi Drug-resistant ShigellaMethicillin-resistant Staphylococcus aureus (MRSA) Drug-resistant Streptococcus pneumoniae (S. pneumoniae)Drug-resistant Tuberculosis (TB)
Concerning threats	Erythromycin-resistant group A Streptococcus Clindamycin-resistant group B Streptococcus
Watch list	Azole-resistant Aspergillus fumigatus (A. fumigatus)Drug-resistant Mycoplasma genitalium (M. genitalium)Drug-resistant Bordetella pertussis (B. pertussis)

The growing trend of AMR has rendered even last-resort drugs less effective. For instance, vancomycin, a drug for MRSA, is facing diminished efficacy due to increasing resistance.^151,152 Isolates of vancomycin-intermediate Staphylococcus aureus (VISA), linked to hospital stays, persistent infections, and the extension or failure of vancomycin therapy, have been found in various regions around the world.¹⁵³ The first vancomycin-resistant Staphylococcus aureus (VRSA) strain, with a minimum inhibitory concentration (MIC) for vancomycin of 16 μg/mL or less, was documented in the United States in 2002. This came decades after reports of similar European isolates that exhibited reduced susceptibility to teicoplanin, a glycopeptide antibiotic from the same class as vancomycin.^154,155 Currently, treatment options for infections due to resistant germs are very limited.

Prevention and control strategies for antimicrobial drug resistance

Global actions/measures taken to tackle AMR

The World Health Organization and its global action plan on AMR and global antimicrobial resistance and use surveillance system

In May 2015, the 68th session of the World Health Assembly approved a global action plan, emphasizing the urgent need to enhance the knowledge and evidence base on AMR through surveillance and research to address the growing AMR threat.¹⁵⁶ World Health Organization (WHO) and its Global Action Plan summarize five pivotal strategic goals to address AMR: (1) Improve knowledge and awareness of AMR; (2) enhance knowledge via surveillance and research to strengthen infection control practices; (3) Enforce proper sanitation, hygiene, and infection prevention measures; (4) optimize the use of antimicrobials in human and animal healthcare; and (5) Encourage long-term investment in the development of new drugs, diagnostic tools, and vaccines.¹⁵⁶

During the same year, the WHO launched the Global Antimicrobial Resistance and Use Surveillance System (GLASS). Since then, substantial investment has been made to enhance AMR surveillance, aiming to generate high-quality evidence regarding its scale, distribution, and diversity worldwide.¹⁵⁷ Notably, GLASS is the first system to facilitate the harmonized global reporting of official national data on AMR and antimicrobial consumption (AMC).¹⁵⁷

One Health

The One Health approach, developed in 2003, is a collaborative effort between various sectors and is now supported by the joint quadripartite consortium, which includes the Food and Agriculture Organization of the United Nations (FAO), WHO, the World Organization for Animal Health (WOAH, formerly OIE), and the United Nations Environment Program (UNEP).¹⁵⁸ According to the One Health Institute at the University of California, Davis, One Health is a strategy aimed at ensuring the health and welfare of humans, animals, and the environment through collaborative problem-solving at local, national, and international levels.¹⁵⁹ AMR is a One Health issue, highlighting the connection between the health of humans, animals, and the environment.⁸

It addresses a wide range of sustainable development goals to design, execute, and oversee programs, policies, and research on AMR surveillance. The goal is to enhance evidence and promote robust intersectoral collaboration among humans, animals, plants, and their common environment.¹⁶⁰ The One Health approach is built on three core principles: (1) communication, (2) coordination, and (3) collaboration, bringing together professionals from human, animal, and environmental sectors to share their expertise and work together.¹⁶¹ A global evaluation of the One Health approach would promote AMR prevention through awareness initiatives, education on proper antibiotic usage, advocacy for political support, and antimicrobial stewardship. Moreover, cutting-edge computational and sequencing technologies, such as whole-genome sequencing (WGS) and next-generation sequencing (NGS), are valuable tools for investigating AMR across different sectors of the One Health framework.¹⁶²

Antimicrobial Stewardship Program

An Antimicrobial Stewardship Program (ASP) is an organized effort designed to ensure the proper use of antimicrobials. Its main objectives are to enhance to improve patient outcomes, reduce AMR, and limit the transmission of infections caused by MDR pathogens.¹⁶³ Originally, ASP was established to coordinate interventions that optimize antimicrobial use by selecting the most appropriate agent, determining the correct dose, route of administration, and duration of treatment, with a primary focus on ensuring the best possible outcomes for patients.¹⁶⁴

Reduced AMR can be achieved through the careful and responsible use of antimicrobials, following the principles outlined in the ASP.¹⁶⁵ Strategies to manage resistance involve educating both the general public and healthcare professionals about antimicrobial resistance, promoting the rational use of antimicrobials, and employing preventive measures to minimize infections and prevent resistance from spreading, such as vaccination and effective infection control protocols.¹⁶⁶

A key document in the area of AMR is the O’Neill report, which addresses all measures aimed at curbing its likely future implications. This includes fostering awareness and better hygiene practices to reduce the risk of the spread of infections, reducing unnecessary antimicrobial use, enhancing surveillance of AMR, and promoting the development of novel diagnostic tools.¹²⁸ One of the most effective measures proposed for ASP is to raise public awareness about AMR its preventive strategies, which necessitates efficient engagement with all relevant stakeholders.¹⁶⁷ The figure below depicts the global actions and measures implemented to combat AMR (Figure 2).

Figure 2.

Global actions/measures taken to control AMR.

Novel strategies to control AMR

To control the emergence of AMR, alongside efforts such as the GAP-AMR, GLASS, One Health initiative, and AMS programs, it is essential to utilize novel antimicrobials or strategies with proven effectiveness. These include antimicrobial peptides, efflux pump inhibitors, antimicrobial combinations, phage therapy, and optimizing drug delivery systems, which are discussed below.

Antimicrobial peptides have gained significant interest as a new category of antibiotics. These peptide-based antimicrobials possess an amphipathic structure, which arises owing to their positive charges and hydrophobic amino acid components.¹⁶⁸ These peptides typically consist of fewer than 100 amino acids and often feature residues with a positive charge, including lysine, arginine, and histidine, along with a significant fraction of hydrophobic residues (exceeding 50%).¹⁶⁹ Antimicrobial peptides mainly exert their effect by interacting directly with the bacterial cell membrane.¹⁷⁰ In addition to compromising membrane integrity, antimicrobial peptides disrupt the production of proteins and DNA and suppress essential cellular processes such as folding of proteins, synthesis of the cell wall, and metabolic turnover.^171,172 Owing to their multiple modes of action, AMPs exhibit potent antimicrobial effects on a broad spectrum of microorganisms, such as Gram-positive and Gram-negative bacteria, fungi, and viruses.^173,174 Furthermore, these peptides show efficacy against disease-causing organisms that exhibit resistance to commonly used medications.¹⁷⁵

As traditional antimicrobial agents, antimicrobial peptides have their own pros and cons. One notable advantage of antimicrobial peptides is their ability to target biological sites different from those of traditional antibiotics.¹⁷⁶ Moreover, a key characteristic of many antimicrobial peptides is their capacity to utilize various mechanisms of action, which boosts their overall antimicrobial efficacy. For example, human cathelicidin LL-37 demonstrates direct antimicrobial effects, immune modulation, and antibiofilm activity.¹⁷⁷ While LL-37 is predominantly recognized for its action on the bacterial cell membrane, it also modulates both pro-inflammatory and anti-inflammatory immune responses.¹⁷⁸ Moreover, LL-37 demonstrates antibiofilm activity at concentrations that are physiologically relevant, which are significantly lower than its in vitro MIC.^179,180 In contrast, some antimicrobial peptides have demonstrated notable nephrotoxicity, primarily as a result of the high doses required for effective treatment.¹⁸¹ Even antibiotics that are clinically in use, like colistin, are reserved as a last resort due to their nephrotoxic effects.¹⁸² Novel drug delivery systems can help minimize the systemic adverse effects associated with antimicrobial peptide therapy. Some commercially available peptide-based antibacterials include dalbavancin, daptomycin, colistin, oritavancin, polymyxin B, teicoplanin, vancomycin, and telavancin.¹⁸³

Another strategy to control AMR is the use of efflux pump inhibitors (EPIs). EPIs are compounds that obstruct the function of efflux pumps, which are key targets in drug resistance. By integrating these inhibitors into combination therapies, the effectiveness of antimicrobials can be significantly improved.^184,185 EPIs are typically simple, stable, and affordable compounds that are generally safe for humans.¹⁸⁶ Certain EPIs also have the capability to prevent bacterial biofilm formation. Compounds such as thioridazine, Phe-Arg β-naphthylamide (PAβN), and arylpiperazine NMP are categorized as EPIs. When introduced, these compounds have been demonstrated to considerably decrease biofilm formation in different bacteria, including E. coli, K. pneumoniae, S. aureus, and Pseudomonas putida.¹⁸⁷

Restoring bacterial susceptibility has been successfully achieved by the use of combination antimicrobials. A synergistic effect can improve treatment efficacy when two or more medicines are combined according to the pathogenic microorganisms’ susceptibility patterns. This strategy inhibits the same target through different mechanisms (e.g., streptogramins), targets in different pathways (e.g., antibiotics used in antituberculosis therapy), or targets at different points within the same pathway (e.g., trimethoprim and sulfamethoxazole).^188,189 Combination antibiotic therapy is often chosen to increase treatment efficacy for a number of infectious disorders, including HIV/AIDS, malaria, and tuberculosis.¹⁸⁸

Phage therapy targets and eradicates harmful bacteria by using bacterial viruses, or bacteriophages. Often referred to as “bacteria eaters,” phages have a number of benefits over conventional antibiotics, including ease of availability, diversity, natural replication, low toxicity, host-specificity, lack of antibiotic cross-resistance, and minimum environmental impact. Phage therapy has demonstrated efficacy in treating topical infections where antibiotics have failed, although it is unlikely to completely replace antibiotics.¹⁹⁰ Combining phages with antibiotics has demonstrated a synergistic effect, especially in addressing multidrug-resistant biofilms.¹⁹¹

Another promising strategy to combat AMR is the use of novel drug delivery systems. These systems have been developed to overcome the limited cell permeability of antibiotics, enhancing the drug’s ability to penetrate cells.¹⁹² Among the drug delivery systems, nanoparticles (NPs) can operate as both active antibacterial agents and drug delivery systems (DDS); their application is showing promise in the fight against AMR. Hence, by preventing biological degradation of the loaded antibiotics and blocking efflux pumps, NPs can operate as drug nanocarriers and aid in the fight against bacterial resistance.¹⁹³ In addition, NPs allow for controlled and sustained drug release, ensuring that therapeutic agents remain active for extended periods. This minimizes adverse effects on healthy cells and tissues by requiring lower dosages of the antibacterial agent to produce a therapeutic effect.¹⁹⁴ In addition, reactive nitric oxide (NO) and reactive oxygen species (ROS) produced by metallic NPs harm bacterial cell components.¹⁹⁵ Furthermore, liposome-encapsulated antimicrobials have demonstrated the capacity to circumvent a number of microorganism resistance mechanisms, such as enzymatic degradation, efflux mechanisms, and impermeable outer membranes.¹⁹⁶ Consequently, the effectiveness of antimicrobials in the fight against AMR can be increased by employing innovative DDS that enable targeted delivery, sustained release, and prevention of enzymatic degradation of antimicrobials.

Conclusion

AMR is an increasingly serious global health issue that endangers the effectiveness of antibacterials, antifungals, antiparasites, and antivirals. As bacteria, viruses, fungi, and parasites develop ways to resist these medications, the impact on human health and agriculture is significant. AMR results in prolonged illnesses, greater mortality rates, and higher medical expenses as a result of the requirement for more complex and intensive treatments. AMR is declared to be a global threat and is estimated to claim about ten million lives per year by 2050. More notably, the ESKAPE pathogens are responsible for a higher number of nosocomial infections and pose a serious threat to public health. Therefore, to control AMR, in addition to collaborative efforts through the One Health initiative and antimicrobial stewardship programs, the development and use of next-generation antimicrobials like antimicrobial peptides, bacteriophages, EPIs, and the use of novel antimicrobial delivery systems are crucial.

Footnotes

Acknowledgements

None.

Declarations

ORCID iDs

Wubetu Yihunie Belay

Samuel Agegnew Wondm

Abebe Fenta

References

AGISAR

Critically Important Antimicrobials for Human Medicine, 5th rev. Geneva: World Health Organization Press, 2017.

Bush

Antibacterial drug discovery in the 21st century. Clin Microbiol Infect 2004; 10: 10–17.

Davies

Origins and evolution of antibiotic resistance. Microbiol Mol Biol 2010; 74: 417–433.

Laxminarayan

Duse

Wattal , et al. Antibiotic resistance—the need for global solutions. Lancet Infect Dis 2013;13:1057–1098.

Hibbitts

O’Leary

Emerging nanomedicine therapies to counter the rise of methicillin-resistant Staphylococcus aureus. Materials 2018; 11: 321.

Antimicrobial resistance. Fact sheet . Geneva: World Health Organization, https://www.who.int/en/news-room/fact-sheets/detail/antimicrobial-resistance (2018, accessed 27 December 2024).

Acar

Röstel

Antimicrobial resistance: an overview. Rev Sci Tech OIE 2001; 20: 797–810.

CDC. Antibiotic resistance threats in the United States, 2019. Atlanta, GA: U.S. Department of Health and Human Services, CDC, 2019.

Mahoney

Arnold

Harris

Penicillin treatment of early syphilis. A preliminary report. Verer Dis Inform 1943; 24: 355–357.

10.

Lloyd

Morgan

Nicholson

, et al. The composition of Ehrlich’s Salvarsan: resolution of a century-old debate. Angew Chem Int Ed 2005; 44: 941–944.

11.

Hutchings

Truman

Wilkinson

Antibiotics: past, present and future. Curr Opin Microbiol 2019; 51(1): 72–80.

12.

Domagk

Ein Beitrag zur Chemotherapie der bakteriellen Infektionen. Dtsch Med Wochenschr 1935; 61: 250.

13.

Enne

Bennett

Livermore

, et al. Enhancement of host fitness by the sul2-coding plasmid p9123 in the absence of selective pressure. J Antimicrob Chemother 2004; 53: 958–963.

14.

Fleming

On antibacterial action of culture of Penicillium, with special reference to their use in isolation of B. influenzae. Br J Exp Pathol 1929; 10: 226–236.

15.

Chain

Florey

Gardner

, et al. The classic: penicillin as a chemotherapeutic agent. 1940. Clin Orthop Relat Res 2005; 439: 23–26.

16.

Fleming

Classics in infectious diseases: on the antibacterial action of cultures of a penicillium, with special reference to their use in the isolation of B. influenzae by Alexander Fleming, Reprinted from the British Journal of Experimental Pathology. Rev Infect Dis 1980; 2: 129–139.

17.

Aminov

RI.

A brief history of the antibiotic era: lessons learned and challenges for the future. Front Microbiol 2010; 1: 134.

18.

Hamblin

Abrahamse

Can light-based approaches overcome antimicrobial resistance?

Drug Dev Res 2018; 1–20.

19.

Chopra

Hesse

O’Neill

Discovery and development of new anti-bacterial drugs. Pharmacochem Libr 2002; 32213–-225.

20.

Charani

McKee

Ahmad

, et al. Optimising antimicrobial use in humans-review of current evidence and an interdisciplinary consensus on key priorities for research. Lancet Reg Health Eur 2021; 7: 100161.

21.

Abraham

Chain

An enzyme from bacteria able to destroy penicillin. Nature 1940; 146: 837.

22.

Aminov

RI.

A brief history of the antibiotic era: lessons learned and challenges for the future. Front Microbiol 2010; 1(134): 134.

23.

Burnet

FM.

Natural history of infectious disease. Cambridge: University Press, 1962.

24.

Fleming

Penicillin. Nobel lecture.1945.

25.

Wiesch

Kouyos

Engelstädter

, et al. Population biological principles of drug-resistance evolution in infectious diseases. Lancet Infect Dis 2011; 11: 236–247.

26.

Salam

Al-Amin

Salam

, et al. Antimicrobial resistance: a growing serious threat for global public health. Healthc (Basel). 2023;11:1946.

27.

Ohlsen

Ziebuhr

Koller

, et al. Effects of subinhibitory concentrations of antibiotics on alpha-toxin (hla) gene expression of methicillin-sensitive and methicillin-resistant Staphylococcus aureus isolates. Antimicrob Agents Chemother. 1998 Nov 1;42(11):2817-23.

28.

Sun

, et al. Combating antimicrobial resistance: the silent war. Front Pharmacol. 2024; 15: 1347750.

29.

U.S. Department of Health and Human Services. CDC. Antibiotic resistance threats in the United States, 2013. Atlanta, GA, 2013.

30.

Dam

Post-transcriptional regulation of porin expression in Escherichia coli and its impact on antibiotic resistance. Bacteriology. Aix-Marseile Université, HAL open science, France, 2018.

31.

Moss

Mańko

Krishna

, et al. How has mass drug administration with dihydroartemisinin-piperaquine impacted molecular markers of drug resistance? A systematic review. Malaria J 2022; 21(1): 186.

32.

De Clercq

. Approved antiviral drugs over the past 50 years. Clin Microbiol Rev 2016; 29(3): 695–747.

33.

Crumpacker

Schnipper

Marlowe

, et al. Resistance to antiviral drugs of herpes simplex virus isolated from a patient treated with acyclovir. N Engl J Med 1982; 306(6): 343–346.

34.

Larder

Darby

Richman

DD.

HIV with reduced sensitivity to zidovudine (AZT) isolated during prolonged therapy. Science 1989; 243(4899): 1731–1734.

35.

Wainberg

Hsu

, et al. Effectiveness of 3TC in HIV clinical trials may be due in part to the M184V substitution in 3TC-resistant HIV-1 reverse transcriptase. Aids 1996; 10: S3–S10.

36.

Colonno

Rose

McLaren

, et al. Identification of I50L as the signature atazanavir (ATV)-resistance mutation in treatment-naive HIV-1-infected patients receiving ATV-containing regimens. J Infect Dis 2004; 189(10): 1802–1810.

37.

Kouyos

Abel

Zur

Wiesch

Bonhoeffer

On being the right size: the impact of population size and stochastic effects on the evolution of drug resistance in hospitals and the community. PLoS Pathog 2011; 7(4): e1001334.

38.

Souli

Galani

Giamarellou

Emergence of extensively drug-resistant and pandrug-resistant Gram-negative bacilli in Europe. Euro Surveill 2008; 13(47): 1–11.

39.

Antimicrobial Resistance Collaborators. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet 2022; 399: 629–655.

40.

Shrestha

Cooper

Coast

, et al. Enumerating the economic cost of antimicrobial resistance per antibiotic consumed to inform the evaluation of interventions affecting their use. Antimicrob Resist Infect Control 2018; 7: 98.

41.

Nguyen

Garcia

Gruenberg

, et al. Multidrug-resistant pseudomonas infections: Hard to treat, but hope on the horizon? Curr Infect Dis Rep 2018; 20: 23.

42.

Prestinaci

Pezzotti

Pantosti

Antimicrobial resistance: a global multifaceted phenomenon. Pathog Glob Health 2015; 109(7): 309–318.

43.

Tacconelli

Carrara

Savoldi

, et al. Discovery, research, and development of new antibiotics: the WHO priority list of antibiotic-resistant bacteria and tuberculosis. Lancet Infect Dis 2018; 18(3): 318–327.

44.

Reygaert

WC.

An overview of the antimicrobial resistance mechanisms of bacteria. AIMS Microbiol 2018; 4: 482–501.

45.

Belay

Getachew

Tegegne

, et al. Mechanism of antibacterial resistance, strategies and next-generation antimicrobials to contain antimicrobial resistance: a review. Frontiers in Pharmacology 2024; 15: 1444781.

46.

Walsh

Molecular mechanisms that confer antibacterial drug resistance. Nature 2000; 406(6797): 775–7781.

47.

Crofts

Gasparrini

Dantas

Next-generation approaches to understand and combat the antibiotic resistome. Nat Rev Microbiol 2017; 15(7): 422–434.

48.

Røder

Sørensen

Burmølle

Studying bacterial multispecies biofilms: where to start?

Trends Microbiol 2016; 24(6): 503–513.

49.

Sharma

Misba

Khan

AU.

Antibiotics versus biofilm: an emerging battleground in microbial communities. Antimicrob Resist Infect Control 2019; 8: 76.

50.

Graf

Palm

Warringer

, et al. Inhibiting conjugation as a tool in the fight against antibiotic resistance. Drug Dev Res 2019; 80(1): 19–23.

51.

Winter

Buckling

Harms

, et al. Antimicrobial resistance acquisition via natural transformation: context is everything. Curr Opin Microbiol 2021; 64: 133–138.

52.

Hussein

AL-Kubaisy

Al-Ouqaili

MTS

. The influence of efflux pump, outer membrane permeability and β-lactamase production on the resistance profile of multi, extensively and pandrug resistant Klebsiella pneumoniae. J Infect Public Health 2024; 17(11): 102544.

53.

Strathdee

Davies

Marcelin

JR.

Confronting antimicrobial resistance beyond the COVID-19 pandemic and the 2020 US election. Lancet 2020; 396: 1050–1053.

54.

Woolhouse

Waugh

Perry

, et al. Global disease burden due to antibiotic 402 resistance – state of the evidence. J Glob Health 2016; 6: 010306.

55.

Bengtsson-Palme

Kristiansson

, et al. Environmental factors influencing the development and spread of antibiotic resistance. FEMS Microbiol Rev 2018; 42: fux053.

56.

Ahmad Khan

Alshehrei

Al-Ghamdi

, et al. Virulence and biofilms as promising targets in developing antipathogenic drugs against candidiasis. Future Sci OA 2020; 6: FSO440.

57.

Fisher

Denning

DW.

The WHO fungal priority pathogens list as a game-changer. Nat Rev Microbiol 2023; 21: 211–212.

58.

Kainz

Bauer

Carmona-Gutierrez

Fungal infections in humans: the silent crisis. Microb Cell 2020; 7: 143–145.

59.

Stop neglecting fungi. Nat Microbiol 2017; 2(8): 17120.

60.

Denning

DW.

Global incidence and mortality of severe fungal disease. Lancet Infect Dis 2024; 24(7): e428–e438.

61.

World Health Organization. WHO Fungal Priority Pathogens List to guide Research, Development and Public Health Action. Geneva, Switzerland: World Health Organization, 2022

62.

Shapiro

Robbins

Cowen

LE.

Regulatory circuitry governing fungal development, drug resistance, and disease. Microbiol Mol Biol Rev 2011; 75: 213–267.

63.

Marichal

Koymans

Willemsens

, et al. Contribution of mutations in the cytochrome P450 14α-demethylase (Erg11p, Cyp51p) to azole resistance in Candida albicans. Microbiology 1999; 145: 2701–2713.

64.

Cowen

Sanglard

Howard

, et al. Mechanisms of antifungal drug resistance. Cold Spring Harb Perspect Med 2015; 5: a019752.

65.

Sanglard

Ischer

Monod

, et al. Cloning of Candida albicans genes conferring resistance to azole antifungal agents: characterization of CDR2, a new multidrug ABC transporter gene. Microbiology 1997; 143: 405–416.

66.

Park

Kelly

Kahn

, et al. Specific substitutions in the echinocandin target Fks1p account for reduced susceptibility of rare laboratory and clinical Candida sp. isolates. Antimicrob Agents Chemother 2005; 49: 3264–3273.

67.

Vallabhaneni

Cleveland

Farley

, et al. Epidemiology and risk factors for echinocandin nonsusceptible Candida glabrata bloodstream infections: data from a large multisite population-based candidemia surveillance program, 2008–2014. Open Forum Infect Dis 2015; 2(4): ofv163.

68.

Verweij

Chowdhary

Melchers

, et al. Azole resistance in Aspergillus fumigatus: can we retain the clinical use of mold-active antifungal azoles? Clin Infect Dis 2016; 62(3): 362–368.

69.

Lockhart

Etienne

Vallabhaneni

, et al. Simultaneous emergence of multidrug-resistant Candida auris on 3 continents confirmed by whole-genome sequencing and epidemiological analyzes. Clin Infect Dis 2017; 64(2): 134–140.

70.

World Health Organization. World malaria report 2024. Geneva: World Health Organization, 2024.

71.

Rosenthal

PJ.

The interplay between drug resistance and fitness in malaria parasites. Mol Microbiol 2013; 89:1025-1038.

72.

Mok

Ashley

Ferreira

, et al. Drug resistance. Population transcriptomics of human malaria parasites reveals the mechanism of artemisinin resistance. Science 2015; 347(6220): 431–435.

73.

Mbengue

Bhattacharjee

Pandharkar

, et al. A molecular mechanism of artemisinin resistance in Plasmodium falciparum malaria. Nature 2015; 520(7549): 683–687.

74.

Ménard

Khim

Beghain

, et al; KARMA Consortium. A worldwide map of plasmodium falciparum K13-propeller polymorphisms. N Engl J Med 2016; 374(25): 2453–2464.

75.

Fidock

Nomura

Talley

, et al. Mutations in the P. falciparum digestive vacuole transmembrane protein PfCRT and evidence for their role in chloroquine resistance. Mol Cell 2000; 6(4): 861–871.

76.

Roepe

PD.

PfCRT-mediated drug transport in malarial parasites. Biochemistry 2011; 50(2): 163–171.

77.

Summers

Nash

Martin

RE.

Know your enemy: understanding the role of PfCRT in drug resistance could lead to new antimalarial tactics. Cell Mol Life Sci 2012; 69(12): 1967–1995.

78.

Veiga

Dhingra

Henrich

, et al. Globally prevalent PfMDR1 mutations modulate Plasmodium falciparum susceptibility to artemisinin-based combination therapies. Nat Commun 2016; 7: 11553.

79.

Fernández-Becerra

Pinazo

González

, et al. Increased expression levels of the pvcrt-o and pvmdr1 genes in a patient with severe Plasmodium vivax malaria. Malar J 2009; 8: 55.

80.

Nocht

Werner

Observations on relative quinine resistance in malaria from Brazil. German Medical Weekly 1910; 36: 1557–1660.

81.

Moore

Lanier

JE.

Observations on two Plasmodium falciparum infections with an abnormal response to chloroquine. Am J Trop Med Hyg 1961; 10: 5–9.

82.

Harinasuta

Migasen

Bunnag

Chloroquine resistance in Plasmodium falciparum in Thailand. UNESCO 1st Regional Symposium on Scientific Knowledge of Tropical Parasites. Singapore: University of Singapore. 1962.

83.

Ippolito

Moser

Kabuya

, et al. Antimalarial drug resistance and implications for the WHO Global Technical Strategy. Curr Epidemiol Reports 2021; 8: 46–62.

84.

Menard

Dondorp

Antimalarial drug resistance: a threat to malaria elimination. Cold Spring Harb Perspect Med 2017; 7(7): a025619.

85.

Lynne

Strasfeld

Sunwen

Chou

. Antiviral drug resistance: mechanisms and clinical implications. Infect Dis Clin North Am 2010; 24(2): 413–437.

86.

Sacks

Wanklin

Reece

, et al. Progressive esophagitis from acyclovir-resistant herpes simplex. Clinical roles for DNA polymerase mutants and viral heterogeneity? Ann Internal Med 1989; 111: 893–899.

87.

Ljungman

Ellis

Hackman

, et al. Acyclovir-resistant herpes simplex vims causing pneumonia after marrow transplantation. J Infect Dis 1990; 162; 244–248.

88.

Phillips

Stover

Cambiano

, et al. Impact of HIV drug resistance on HIV/AIDS-associated mortality, new infections, and antiretroviral therapy program costs in sub-Saharan Africa. J Infect Dis 2017; 215: 1362–1365.

89.

Saag

Emini

Laskin

, et al. A short-term clinical evaluation of L-697,661: a non-nucleoside inhibitor of HIV-1 reverse transcriptase. N Engl J Med 1993; 329: 1065–1072.

90.

World Health Organization. HIV drug resistance report 2021. Geneva: World Health Organization, 2021.

91.

World Health Organization. HIV drug resistance strategy, 2021 update. Geneva: World Health Organization, 2021.

92.

Kimberlin

Whitley

RJ.

Antiviral resistance: mechanisms, clinical significance, and future implications. J Antimicrob Chemother 1996; 37: 403–421.

93.

Coen

Schaffer

PA.

Two distinct loci confer resistance to acycloguanosine in herpes simplex virus type 1. Proc Natl Acad Sci USA 1980; 77(4): 2265–2269.

94.

Morfin

Thouvenot

Herpes simplex virus resistance to antiviral drugs. J Clin Virol 2003; 26(1): 29–37.

95.

Chen

Scieux

Garrait

, et al. Resistant herpes simplex virus type 1 infection: an emerging concern after allogeneic stem cell transplantation. Clin Infect Dis 2000; 31(4): 927–935.

96.

Wyles

Patel

Madinger

, et al. Development of herpes simplex virus disease in patients who are receiving cidofovir. Clin Infect Dis 2005; 41(5): 676680.

97.

Morfin

Thouvenot

De Turenne-Tessier

, et al. Phenotypic and genetic characterization of thymidine kinase from clinical strains of varicella-zoster virus resistant to acyclovir. Antimicrob Agents Chemother 1999; 43(10): 2412–2416.

98.

Gilbert

Bestman-Smith

Boivin

Resistance of herpesviruses to antiviral drugs: clinical impacts and molecular mechanisms. Drug Resist Updat 2002; 5(2): 88–114.

99.

Visse

Dumont

Huraux

, et al. Single amino acid change in DNA polymerase is associated with foscarnet resistance in a varicella-zoster virus strain recovered from a patient with AIDS. J Infect Dis 1998; 178(Suppl. 1): S55–S57.

100.

Allen

Deslauriers

Andrews

, et al. Identification and characterization of mutations in hepatitis B virus resistant to lamivudine. Lamivudine Clinical Investigation Group. Hepatology 1998; 27(6): 1670–1677.

101.

Villet

Pichoud

Billioud

, et al. Impact of hepatitis B virus rtA181V/T mutants on hepatitis B treatment failure. J Hepatol 2008; 48(5): 747–755.

102.

Menéndez-Arias

Mechanisms of resistance to nucleoside analogue inhibitors of HIV-1 reverse transcriptase. Virus Res 2008; 134(1–2): 124–146.

103.

Meyer

Matsuura

Mian

, et al. A mechanism of AZT resistance: an increase in nucleotide-dependent primer unblocking by mutant HIV-1 reverse transcriptase. Mol Cell 1999; 4(1): 35–43.

104.

Sarafianos

Marchand

Das

, et al. Structure and function of HIV-1 reverse transcriptase: molecular mechanisms of polymerization and inhibition. J Mol Biol 2009; 385(3): 693–713.

105.

Bauman

Das

, et al. Crystal engineering of HIV-1 reverse transcriptase for structure-based drug design. Nucleic Acids Res 2008; 36(15): 5083–5092.

106.

Deeks

SG.

International perspectives on antiretroviral resistance. Nonnucleoside reverse transcriptase inhibitor resistance. J Acquir Immune Defic Syndr 2001; 26(Suppl. 1): S25–S33.

107.

Bacheler

Jeffrey

Hanna

, et al. Genotypic correlates of phenotypic resistance to efavirenz in virus isolates from patients failing nonnucleoside reverse transcriptase inhibitor therapy. J Virol 2001; 75(11): 4999–5008.

108.

Erickson

Gulnik

Markowitz

Protease inhibitors: resistance, cross-resistance, fitness and the choice of initial and salvage therapies. AIDS 1999; 13(Suppl. A): S189–S204.

109.

UNGA, https://www.un.org/en/ga/70/meetings/index.shtml (205, accessed 24 December 2024).

110.

UN. GENERAL ASSEMBLY. Seventy-First Session Agenda Item 127 Global Health and Foreign Policy Draft Resolution Submitted by the President of the General Assembly Political Declaration of the High-Level Meeting of the General Assembly on Antimicrobial Resistance, New York, 2016.

111.

Pinto Ferreira

Battaglia

Dorado García

, et al. Achieving Antimicrobial Stewardship on the Global Scale: Challenges and Opportunities. Microorganisms 2022; 10: 1599.

112.

World Health Organization. Ten threats to global health in 2019. Geneva: World Health Organization, 2019.

113.

World Health Organization (WHO). Antimicrobial Resistance: Global Report on Surveillance. Geneva, Switzerland: WHO, 2014.

114.

Goossens

Expert-proposed European strategies to monitor and control infection, antibiotic use, and resistance in health-care facilities. Lancet Infect Dis 2011; 11(5): 338–340.

115.

Founou

Blocker

Noubom

, et al. The COVID-19 pandemic: a threat to antimicrobial resistance containment. Future Sci 2021; 7(8): FSO736.

116.

Ranjbar

Alam

; Antimicrobial Resistance Collaborators (2022). Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Evid Based Nurs 2023; 27: 1.

117.

Laxminarayan

Matsoso

Pant

, et al. Access to effective antimicrobials: a worldwide challenge. Lancet 2016; 387(10014): 168–175.

118.

Allegranzi

Bagheri Nejad

Combescure

, et al. Burden of endemic health-care-associated infection in developing countries: systematic review and metaanalysis. Lancet 2011; 377(9761): 228–241

119.

WHO. Global Action Plan on Antimicrobial Resistance; WHO Report; WHO: Geneva, Switzerland, 2015.

120.

Bhagwati

Guidelines for antibiotic usage in common situations. JAPI (Suppl.). 2010; 58: 49–50.

121.

Jia

Zhao

The antibacterial activity of fluoroquinolone derivatives: an update (2018–2021). Eur J Med Chem 2021; 224: 113741.

122.

Burki

Superbugs: an arms race against bacteria. Lancet Respir Med 2018; 6: 668.

123.

Singer

Ward

Maldonado

Can landscape ecology untangle the complexity of antibiotic resistance?

Nat Rev Microbiol 2006; 4: 943–952.

124.

Baquero

Martínez

J-L

Cantón

Antibiotics and antibiotic resistance in water environments. Curr Opin Biotechnol 2008; 19: 260–265.

125.

Akova

Epidemiology of antimicrobial resistance in bloodstream infections. Virulence 2016; 7(3): 252–266.

126.

Handal

Olsen

Antimicrobial resistance with focus on oral beta-lactamases. Eur J Oral Sci 2000; 108(3): 163–174.

127.

O’Neill

Review on antimicrobial resistance: tackling drug-resistant infections globally: final report and recommendations. Wellcome Trust, London, 2016.

128.

O’neill

. Antimicrobial resistance: tackling a crisis for the health and wealth of nations. Rev Antimicrob Resist 2014.

129.

Simlai

Mukherjee

Mandal

, et al. Partial purification and characterization of an antimicrobial activity from the wood extract of mangrove plant Ceriops decandra. EXCLI J 2016; 15: 103.

130.

Tadesse

Ashley

Ongarello

, et al. Antimicrobial resistance in Africa: a systematic review. BMC Infect Dis 2017; 17: 1–7.

131.

Mshana

Matee

Rweyemamu

Antimicrobial resistance in human and animal pathogens in Zambia, Democratic Republic of Congo, Mozambique and Tanzania: an urgent need of a sustainable surveillance system. Ann Clin Microbiol Antimicrobials 2013; 12: 1–0.

132.

Doern

Pfaller

Kugler

, et al. Prevalence of antimicrobial resistance among respiratory tract isolates of Streptococcus pneumoniae in North America: 1997 results from the SENTRY antimicrobial surveillance program. Clin Infect Dis 1998; 27(4): 764–770.

133.

Jones

Low

Pfaller

Epidemiologic trends in nosocomial and community-acquired infections due to antibiotic-resistant gram-positive bacteria: the role of streptogramins and other newer compounds. Diagn Microbiol Infect Dis 1999; 33(2): 101–12.

134.

West

Peterside

Sensitivity pattern among bacterial isolates in neonatal septicaemia in port Harcourt. Ann Clin Microbiol Antimicrob 2012; 11: 1–6.

135.

Egri-Okwaji

Iroha

Kesah

, et al. Bacterial pathogens causing Neonatal sepsis in an out-born Neonatal unit in Lagos, Nigeria. Niger Quarterly J Hospital Med 1996; 6(3): 149–152.

136.

Hou

Long

Wang

, et al. Global trend of antimicrobial resistance in common bacterial pathogens in response to antibiotic consumption. J Hazardous Mater 2023; 15; 442: 130042.

137.

World Bank. Drug-resistant infections: a threat to our economic future. World Bank, Washington, DC, 2017.

138.

OECD. Stemming the superbug tide: just a few dollars more. Paris: Organisation for Economic Co-operation and Development, 2018.

139.

ECDC

The bacterial challenge: time to react. Stockholm: European Center for Disease Prevention and Control, 2009.

140.

Wilke

MH.

Multiresistant bacteria and current therapy – the economical side of the story. Eur J Med Res 2010; 15: 571–576.

141.

Magiorakos

Srinivasan

Carey

, et al. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect 2012; 18(3): 268–281.

142.

Morris

Kellner

Low

DE.

The superbugs: evolution, dissemination and fitness. Curr Opin. Microbiol 1998; 1: 524–529.

143.

Parmanik

Das

Kar

, et al. Current treatment strategies against multidrug-resistant bacteria: a review. Curr Microbiol 2022; 79: 388.

144.

Kaur

Prasad

Varma

Prevalence and antibiotic susceptibility pattern of methicillin resistant staphylococcus aureus in tertiary care hospitals. Biotechnol J Int 2014, 4: 228–235.

145.

Karaman

Jubeh

Breijyeh

Resistance of gram-positive bacteria to current antibacterial agents and overcoming approaches. Molecules 2020; 25: 2888.

146.

World Health Organization. Prioritization of pathogens to guide discovery, research and development of new antibiotics for drug-resistant bacterial infections, including tuberculosis. Geneva: World Health Organization, 2017.

147.

Papp-Wallace

Endimiani

Taracila

, et al. Carbapenems: past, present, and future. Antimicrob Agents Chemother 2011; 55: 4943–4960.

148.

Brown

Wright

GD.

Antibacterial drug discovery in the resistance era. Nature 2016; 529: 336–343.

149.

Tabah

Koulenti

Laupland

, et al. Characteristics and determinants of outcome of hospital-acquired bloodstream infections in intensive care units: the EUROBACT International cohort study. Intensive Care Med 2012; 38(12): 1930–1945.

150.

Khan

Siddiqui

Park

Current and emerging methods of antibiotic susceptibility testing. Diagnostics 2019; 9(2): 49.

151.

Ruef

Epidemiology and clinical impact of glycopeptide resistance in Staphylococcus aureus. Infection 2004; 32(6): 315–327.

152.

Tong

SYC

Lye

Yahav

, et al. Effect of vancomycin or daptomycin with vs without an antistaphylococcal b-lactam on mortality, bacteremia, relapse, or treatment failure in patients with MRSA bacteremia: a randomized clinical trial. JAMA 2020; 323: 527–537.

153.

McGuinness

Malachowa

DeLeo

FR.

Vancomycin resistance in Staphylococcus aureus. Yale J Biol Med 2017; 90(2): 269–281.

154.

Gottleib

CDC reports first case of vancomycin resistant Staphylococcus aureus. BMJ 2003; 326: 783.

155.

W, Seo

Dorman

Lerner

. Emergence of teicoplanin resistance during therapy of Staphylococcus aureus endocarditis. J Infect Dis 1990; 162: 103–108.

156.

World Health Organization. Global action plan on antimicrobial resistance. Geneva: World Health Organization, 2015:1.

157.

World Health Organization. Global Antimicrobial Resistance and Use Surveillance System (GLASS). Geneva: World Health Organization, https://www.who.int/initiatives/glass (2015, accessed 2 February 2025).

158.

Sudatip

Chasiri

Kritiyakan

, et al. A one health approach to assessing occupational exposure to antimicrobial resistance in Thailand: The FarmResist project. PLoS One 2021; 16(1): e0245250.

159.

Mackenzie

Jeggo

The one health approach-why is it so important?

Trop Med Infect Dis 2019; 4(2): 88.

160.

WHO. One Health Initiative, https://www.who.int/teams/one-health-initiative (accessed 21 January 2025).

161.

CDC. One Health Basics, https://www.cdc.gov/onehealth/basics/index.html (accessed 15 January 2025).

162.

Van Camp

Haslam

Porollo

Prediction of antimicrobial resistance in gram-negative bacteria from whole-genome sequencing data. Front Microbiol 2020; 11: 1013.

163.

Doron

Davidson

LE.

Antimicrobial stewardship. Mayo Clin Proc 2011; 86: 1113–1123.

164.

Majumder

MAA

Rahman

Cohall

, et al. Antimicrobial stewardship: fighting antimicrobial resistance and protecting global public health. Infect Drug Resist 2020; 13: 4713–4738.

165.

Kościuczuk

Lisowski

Jarczak

, et al. Cathelicidins: family of antimicrobial peptides. A review. Mol Biol Reports 2012; 39: 10957–10970.

166.

Pushpanathan

Gunasekaran

Rajendhran

Antimicrobial peptides: versatile biological properties. Int J Peptides 2013; 2013(1): 675391.

167.

Brogden

KA.

Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria?. Nat Rev Microbiol 2005; 3(3): 238–250.

168.

Park

Hahm

KS.

The role of antimicrobial peptides in preventing multidrug-resistant bacterial infections and biofilm formation. Int J Mol Sci 2011;12(9): 5971–592.

169.

Yamauchi

Tomita

Giehl

, et al. Antibacterial activity of lactoferrin and a pepsin-derived lactoferrin peptide fragment. Infect Immun 1993; 61(2): 719–728.

170.

Mygind

Fischer

Schnorr

, et al. Plectasin is a peptide antibiotic with therapeutic potential from a saprophytic fungus. Nature 2005; 437(7061): 975–980.

171.

Zasloff

Antimicrobial peptides of multicellular organisms. Nature 2002; 415(6870): 389–395.

172.

Bucki

Leszczyńska

Namiot

, et al. Cathelicidin LL-37: a multitask antimicrobial peptide. Archivum immunologiae et therapiae experimentalis. Arch Immunol Ther Exp (Warsz) 2010; 58(1): 15–25.

173.

Agier

Efenberger

Brzezińska-Błaszczyk

Cathelicidin impact on inflammatory cells. Central Eur J Immunol 2015; 40(2): 225–235.

174.

Overhage

Campisano

Bains

, et al. Human host defense peptide LL-37 prevents bacterial biofilm formation. Infect Immun 2008; 76(9): 4176–4182.

175.

Dean

Bishop

Van Hoek

ML.

Susceptibility of Pseudomonas aeruginosa biofilm to alpha-helical peptides: D-enantiomer of LL-37. Front Microbiol 2011; 2: 128.

176.

Mahlapuu

Håkansson

Ringstad

, et al. Antimicrobial peptides: an emerging category of therapeutic agents. Front Cell Infect Microbiol 2016; 6: 194.

177.

Gai

Samodelov

Kullak-Ublick

, et al. Molecular mechanisms of colistin-induced nephrotoxicity. Molecules 2019; 24: 653.

178.

Browne

Chakraborty

Chen

, et al. A new era of antibiotics: the clinical potential of antimicrobial peptides. Int J Mol Sci 2020; 21(19): 7047.

179.

González-Bello

Antibiotic adjuvants – A strategy to unlock bacterial resistance to antibiotics. Bioorg Med Chem Lett 2017; 27(18): 4221–4228.

180.

Melander

The challenge of overcoming antibiotic resistance: An adjuvant approach?

ACS Infect Dis 2017; 3(8): 559–563.

181.

Laws

Shaaban

Rahman

KM.

Antibiotic resistance breakers: current approaches and future directions. FEMS Microbiol Rev 2019; 43(5): 490–516.

182.

Worthington

Melander

Combination approaches to combat multidrug-resistant bacteria. Trends Biotechnol 2013; 31(3): 177–184.

183.

Pulingam

Parumasivam

Gazzali

, et al. Antimicrobial resistance: prevalence, economic burden, mechanisms of resistance and strategies to overcome. Eur J Pharm Sci 2022; 170: 106103.

184.

Lomovskaya

Watkins

WJ.

Efflux pumps: their role in antibacterial drug discovery. Curr Med Chem 2001; 8(14): 1699–711.

185.

Mahamoud

Chevalier

Alibert-Franco

, et al. Antibiotic efflux pumps in Gram-negative bacteria: the inhibitor response strategy. J Antimicrob Chemother 2007; 59(6): 1223–1229.

186.

Marquez

Bacterial efflux systems and efflux pumps inhibitors. Biochimie 2005; 87(12): 1137–1147.

187.

Kvist

Hancock

Klemm

Inactivation of efflux pumps abolishes bacterial biofilm formation. Appl Environ Microbiol 2008; 74(23): 7376–7382.

188.

Bebell

Muiru

AN.

Antibiotic use and emerging resistance: how can resource-limited countries turn the tide?

Glob Heart 2014; 9(3): 347–358.

189.

Fischbach

MA.

Combination therapies for combating antimicrobial resistance. Curr Opin Microbiol 2011; 14(5): 519–23.

190.

Brives

Pourraz

Phage therapy as a potential solution in the fight against AMR: obstacles and possible futures. Palgrave Commun 2020; 6(1): 1–1.

191.

Akturk

Oliveira

Santos

, et al. Synergistic action of phage and antibiotics: parameters to enhance the killing efficacy against mono and dual-species biofilms. Antibiotics (Basel) 2019; 8(3): 103.

192.

Gou

Liao

, et al. Recent advances in nano-targeting drug delivery systems for rheumatoid arthritis treatment. Acta Materia Medica 2023; 2(1): 23–41.

193.

Dey

Kamatchi

Vickram

, et al. Role of nanomaterials in deactivating multiple drug resistance efflux pumps – a review. Environ Res 2022; 204(Pt A): 111968.

194.

Chamundeeswari

Jeslin

Verma

ML.

Nanocarriers for drug delivery applications. Environ Chem Lett 2019; 17: 849–865.

195.

Alabdali

Kzar

Chinnappan

, et al. Application of nanoantibiotics approach against anti-bacterial resistance. Int J Appl Pharm 2022; 14: 34–39.

196.

Ferreira

Ogren

Dias

JNR

, et al. Liposomes as antibiotic delivery systems: a promising nanotechnological strategy against antimicrobial resistance. Molecules 2021; 26(7): 2047.

Antimicrobial resistance with a focus on antibacterial,antifungal,antimalarial,and antiviral drugs resistance,its threat,global priority pathogens,prevention,and control strategies: a review

Abstract

Keywords

Overview of antimicrobials and antimicrobial resistance as a global threat

Introduction

The discovery and use of antimicrobial agents

Overview of antimicrobial resistance by microorganisms of medical importance

Antibacterial drug resistance

Antifungal drug resistance

Antimalarial drug resistance

Antiviral drug resistance

AMR as a global threat

Prevalence of AMR

Economic impact of AMR

Global priority pathogens/superbugs

Prevention and control strategies for antimicrobial drug resistance

Global actions/measures taken to tackle AMR

The World Health Organization and its global action plan on AMR and global antimicrobial resistance and use surveillance system

One Health

Antimicrobial Stewardship Program

Novel strategies to control AMR

Conclusion

Footnotes

Acknowledgements

Declarations

ORCID iDs

References