Polymyxin Antibiotic Resistance: Unraveling the Escalating Crisis in Last-Line Infection Defense. Discover How This Growing Threat Challenges Global Health and What the Future Holds. (2025)

Introduction: The Critical Role of Polymyxins in Modern Medicine
Mechanisms of Polymyxin Resistance: Genetic and Biochemical Insights
Global Epidemiology: Tracking the Spread of Resistance
Clinical Impact: Consequences for Patient Outcomes and Healthcare Systems
Detection and Surveillance: Current Methods and Emerging Technologies
Drivers of Resistance: Agricultural, Clinical, and Environmental Factors
Therapeutic Alternatives and Combination Strategies
Regulatory and Stewardship Initiatives: Policies from WHO and CDC
Market and Public Interest Forecast: Projected 40% Increase in Research and Awareness by 2030
Future Outlook: Innovations, Challenges, and the Path Forward
Sources & References

Introduction: The Critical Role of Polymyxins in Modern Medicine

Polymyxins, particularly polymyxin B and colistin (polymyxin E), have re-emerged as essential antibiotics in the global fight against multidrug-resistant (MDR) Gram-negative bacterial infections. Originally discovered in the 1940s, their clinical use was limited for decades due to nephrotoxicity and neurotoxicity concerns. However, the alarming rise of carbapenem-resistant Enterobacteriaceae (CRE) and other MDR pathogens has necessitated their renewed application as last-resort therapies in both hospital and critical care settings. In 2025, polymyxins remain among the few effective options for treating life-threatening infections caused by organisms such as Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa.

The World Health Organization (WHO) has classified these pathogens as “critical priority” due to their resistance to most available antibiotics, underscoring the indispensable role of polymyxins in modern medicine. The World Health Organization and the Centers for Disease Control and Prevention (CDC) have both highlighted the urgent need to preserve the efficacy of polymyxins, as resistance to these agents would severely limit treatment options and increase mortality rates from otherwise manageable infections.

Recent surveillance data indicate that polymyxin resistance is rising globally, with the spread of mobile resistance genes such as mcr-1 posing a significant threat. The European Centre for Disease Prevention and Control (ECDC) and national public health agencies have reported increasing detection of polymyxin-resistant isolates in both clinical and agricultural settings. This trend is particularly concerning in regions with high antibiotic usage and limited stewardship programs, where resistance can rapidly disseminate across healthcare and community environments.

The critical role of polymyxins is further emphasized by their inclusion in the WHO’s Model List of Essential Medicines, reflecting their status as a cornerstone of contemporary antimicrobial therapy. As the world faces a post-antibiotic era, the preservation of polymyxin efficacy is a top priority for global health authorities. Ongoing research, coordinated surveillance, and international collaboration are essential to monitor resistance trends, develop novel therapeutics, and implement effective stewardship strategies. The outlook for the next few years will depend on the collective efforts of governments, healthcare providers, and organizations such as the World Health Organization and European Medicines Agency (EMA) to safeguard these vital antibiotics for future generations.

Mechanisms of Polymyxin Resistance: Genetic and Biochemical Insights

Polymyxins, including colistin and polymyxin B, are last-resort antibiotics used to treat infections caused by multidrug-resistant Gram-negative bacteria. However, the emergence and global spread of polymyxin resistance, particularly since the discovery of plasmid-mediated mcr genes in 2015, have raised significant concerns for public health. As of 2025, research continues to elucidate the genetic and biochemical mechanisms underlying this resistance, with a focus on both chromosomal mutations and horizontally acquired genes.

The most prominent mechanism of polymyxin resistance involves modifications to the lipid A component of lipopolysaccharide (LPS) in the bacterial outer membrane. These modifications, such as the addition of phosphoethanolamine or 4-amino-4-deoxy-L-arabinose, reduce the negative charge of LPS, thereby decreasing polymyxin binding affinity. Chromosomal mutations in regulatory systems, notably the pmrAB and phoPQ two-component systems, can upregulate these modifications. Recent genomic surveillance has identified novel mutations in these pathways, particularly in Klebsiella pneumoniae and Acinetobacter baumannii, that confer high-level resistance and are increasingly reported in clinical isolates worldwide.

A major breakthrough in the past decade has been the identification and tracking of mobile colistin resistance (mcr) genes, which encode phosphoethanolamine transferases. These genes, now numbering at least ten variants (mcr-1 to mcr-10), are often located on plasmids, facilitating rapid horizontal transfer between bacterial species. The mcr-1 gene remains the most widespread, but recent surveillance in 2024–2025 has highlighted the emergence of mcr-8 and mcr-9 in both clinical and agricultural settings. The World Health Organization and Centers for Disease Control and Prevention have both issued alerts regarding the increasing detection of these genes in Enterobacteriaceae, emphasizing the need for coordinated global monitoring.

Biochemically, the action of MCR enzymes results in the direct modification of lipid A, mirroring chromosomal resistance mechanisms but with the added threat of rapid dissemination. Structural studies published in 2024 have provided detailed insights into the active sites of MCR proteins, opening avenues for the development of targeted inhibitors. However, as of 2025, no clinically approved MCR inhibitors are available, and resistance continues to outpace drug development.

Looking ahead, the outlook for controlling polymyxin resistance hinges on enhanced genomic surveillance, stewardship of polymyxin use in both human and veterinary medicine, and the development of novel therapeutics. International collaborations, such as those coordinated by the European Centre for Disease Prevention and Control, are expected to play a critical role in tracking resistance trends and informing policy in the coming years.

Global Epidemiology: Tracking the Spread of Resistance

Polymyxin antibiotics, particularly colistin and polymyxin B, have become critical last-resort treatments for multidrug-resistant Gram-negative bacterial infections. However, the global epidemiology of polymyxin resistance has shifted dramatically in recent years, with 2025 marking a period of heightened surveillance and concern. The spread of resistance is now recognized as a major threat to public health, prompting coordinated international monitoring and response efforts.

The emergence of plasmid-mediated colistin resistance, primarily via the mcr gene family, has been a pivotal event in the global dissemination of resistance. Since the first identification of mcr-1 in China in 2015, subsequent years have seen the gene detected in clinical, veterinary, and environmental isolates across all continents. By 2025, the mcr genes (including mcr-1 through mcr-10) have been reported in over 60 countries, with particularly high prevalence in parts of Asia, the Middle East, and South America. Surveillance data from the World Health Organization (WHO) and regional public health agencies indicate that the prevalence of colistin-resistant Enterobacterales in clinical settings now exceeds 10% in some high-burden regions.

The European Centre for Disease Prevention and Control (ECDC) and the Centers for Disease Control and Prevention (CDC) in the United States have both classified carbapenem-resistant and colistin-resistant Enterobacterales as urgent threats. In Europe, ECDC’s 2024 surveillance report highlighted a continued increase in colistin resistance among Klebsiella pneumoniae and Escherichia coli isolates, particularly in southern and eastern countries. The CDC’s Antibiotic Resistance Threats report similarly notes sporadic but concerning outbreaks of colistin-resistant infections in U.S. healthcare facilities, often linked to international travel or medical tourism.

The global spread is further complicated by the use of colistin in agriculture, especially as a growth promoter in livestock. Although regulatory bans and restrictions have been implemented in the European Union, China, and other regions, enforcement and compliance remain variable, contributing to ongoing environmental reservoirs of resistance genes. The Food and Agriculture Organization of the United Nations (FAO) continues to monitor and advise on antimicrobial use in food production, emphasizing the need for a One Health approach.

Looking ahead, the outlook for controlling polymyxin resistance depends on sustained global surveillance, rapid diagnostics, and coordinated stewardship efforts. The WHO’s Global Antimicrobial Resistance Surveillance System (GLASS) is expanding its coverage and data integration, aiming to provide real-time tracking and early warning of resistance trends. However, the continued evolution and spread of mcr genes, coupled with limited therapeutic alternatives, underscore the urgency of international collaboration and innovation in both human and animal health sectors.

Clinical Impact: Consequences for Patient Outcomes and Healthcare Systems

Polymyxin antibiotics, particularly colistin and polymyxin B, have re-emerged as critical last-line therapies against multidrug-resistant (MDR) Gram-negative bacterial infections. However, the global rise in polymyxin resistance is now exerting a profound clinical impact, with significant consequences for patient outcomes and healthcare systems in 2025 and the foreseeable future.

Recent surveillance data indicate that resistance rates to polymyxins are increasing, especially among Enterobacterales and Acinetobacter baumannii isolates. The World Health Organization (World Health Organization) has repeatedly highlighted the threat posed by carbapenem-resistant and polymyxin-resistant bacteria, which are associated with high morbidity and mortality due to limited therapeutic options. Infections caused by these resistant pathogens are linked to prolonged hospital stays, increased need for intensive care, and higher healthcare costs.

Clinically, patients infected with polymyxin-resistant organisms face a higher risk of treatment failure. A 2024 multicenter study across several tertiary hospitals in Europe and Asia reported mortality rates exceeding 50% in bloodstream infections caused by colistin-resistant Klebsiella pneumoniae. The lack of effective alternatives often necessitates the use of unproven or more toxic combination regimens, further complicating patient management and increasing the risk of adverse drug reactions.

Healthcare systems are under mounting pressure as outbreaks of polymyxin-resistant bacteria require enhanced infection prevention and control measures. The European Centre for Disease Prevention and Control and the Centers for Disease Control and Prevention in the United States have both issued updated guidance in 2025, urging hospitals to strengthen antimicrobial stewardship and surveillance programs. These measures, while essential, add to operational costs and resource demands, particularly in settings already strained by high rates of antimicrobial resistance.

The outlook for the next few years remains challenging. Although novel antibiotics and adjunctive therapies are in development, their clinical availability is limited, and resistance mechanisms—such as plasmid-mediated mcr genes—continue to spread globally. The World Health Organization and national health authorities are prioritizing research, rapid diagnostics, and stewardship initiatives, but the gap between resistance emergence and new drug approval persists.

In summary, polymyxin antibiotic resistance in 2025 is directly undermining patient outcomes and straining healthcare systems worldwide. Without accelerated innovation and coordinated global action, the clinical and economic burden of these infections is expected to intensify in the coming years.

Detection and Surveillance: Current Methods and Emerging Technologies

The detection and surveillance of polymyxin antibiotic resistance have become critical priorities in 2025, as resistance to last-resort agents like colistin and polymyxin B continues to threaten global health. Current methods for detecting polymyxin resistance in clinical and environmental isolates primarily rely on phenotypic assays, such as broth microdilution (BMD), which remains the gold standard for minimum inhibitory concentration (MIC) determination. However, BMD is labor-intensive and time-consuming, prompting the development and adoption of rapid diagnostic tools.

Automated systems, including VITEK 2 and BD Phoenix, are widely used in clinical microbiology laboratories for routine susceptibility testing. Yet, these platforms have shown variable accuracy for polymyxin resistance, particularly in detecting heteroresistant populations. To address these limitations, the Centers for Disease Control and Prevention and the World Health Organization have issued updated guidelines emphasizing the need for confirmatory BMD testing and the use of reference strains for quality control.

Molecular methods are increasingly supplementing phenotypic assays. Polymerase chain reaction (PCR) and whole-genome sequencing (WGS) are now routinely employed to detect plasmid-mediated mcr genes (e.g., mcr-1 to mcr-10), which confer transferable resistance to polymyxins. The European Centre for Disease Prevention and Control has supported the integration of WGS into national surveillance programs, enabling real-time tracking of resistance gene dissemination across borders.

Emerging technologies are poised to transform resistance detection in the coming years. CRISPR-based diagnostics and nanopore sequencing platforms offer the promise of rapid, point-of-care identification of resistance determinants, with turnaround times measured in hours rather than days. Several academic and public health laboratories are piloting these technologies in 2025, aiming to bridge the gap between detection and actionable infection control measures.

Surveillance efforts are also expanding beyond clinical settings. Environmental monitoring, particularly in wastewater and agricultural sites, is being scaled up to detect the spread of mcr genes in non-human reservoirs. The U.S. Food and Drug Administration and international partners are collaborating on One Health surveillance initiatives, recognizing the interconnectedness of human, animal, and environmental health in the fight against antimicrobial resistance.

Looking ahead, the integration of advanced molecular diagnostics, real-time data sharing, and global surveillance networks is expected to enhance early detection and containment of polymyxin resistance. Continued investment in laboratory infrastructure and workforce training will be essential to keep pace with the evolving threat landscape through 2025 and beyond.

Drivers of Resistance: Agricultural, Clinical, and Environmental Factors

Polymyxin antibiotics, particularly colistin and polymyxin B, have become critical last-resort treatments for multidrug-resistant Gram-negative bacterial infections. However, the emergence and spread of polymyxin resistance is a growing global health concern, driven by interconnected agricultural, clinical, and environmental factors. As of 2025, these drivers are shaping the trajectory of resistance and influencing policy and research priorities worldwide.

In agriculture, the use of colistin as a growth promoter and prophylactic agent in livestock has been a major contributor to resistance. The discovery of the plasmid-mediated mcr-1 gene in 2015, which confers transferable resistance to colistin, highlighted the risk of resistance genes moving from animals to humans via the food chain. Despite regulatory actions in several countries—including bans or restrictions on colistin use in food animals—surveillance data indicate that mcr genes remain prevalent in agricultural settings, particularly in regions with less stringent oversight. The World Organisation for Animal Health (WOAH, formerly OIE) continues to monitor and report on antimicrobial use in animals, emphasizing the need for global harmonization of stewardship practices.

Clinically, the increased reliance on polymyxins to treat carbapenem-resistant Enterobacteriaceae (CRE) and other multidrug-resistant infections has intensified selective pressure in hospitals. Reports from the Centers for Disease Control and Prevention and the World Health Organization (WHO) highlight rising rates of polymyxin-resistant infections, particularly in intensive care units and among immunocompromised patients. The spread of mcr genes and chromosomal mutations conferring resistance complicates treatment options and increases morbidity and mortality. In response, infection control measures and antimicrobial stewardship programs are being strengthened, but challenges remain in resource-limited settings.

Environmental factors also play a significant role. Wastewater from hospitals, pharmaceutical manufacturing, and agricultural runoff can contain both polymyxins and resistant bacteria, facilitating the dissemination of resistance genes in natural ecosystems. The United Nations Environment Programme (UNEP) has identified antimicrobial resistance as an environmental threat, calling for integrated approaches to reduce contamination and monitor resistance in water, soil, and wildlife.

Looking ahead, the drivers of polymyxin resistance are expected to persist, with ongoing risks of gene transfer across sectors and borders. International organizations are advocating for a One Health approach, integrating human, animal, and environmental health strategies. Enhanced surveillance, regulatory harmonization, and investment in alternative therapies are likely to shape the global response in the coming years.

Therapeutic Alternatives and Combination Strategies

The rise of polymyxin antibiotic resistance, particularly to colistin and polymyxin B, has become a critical concern in the management of multidrug-resistant (MDR) Gram-negative infections. As resistance rates continue to increase globally in 2025, clinicians and researchers are urgently exploring therapeutic alternatives and combination strategies to preserve treatment efficacy and patient outcomes.

Recent surveillance data indicate that resistance to polymyxins, often mediated by plasmid-borne mcr genes, is now reported in clinical isolates from all continents. The World Health Organization (WHO) has classified carbapenem-resistant and polymyxin-resistant Enterobacteriaceae as critical priority pathogens, underscoring the need for new therapeutic approaches. In response, several international consortia and national health agencies are coordinating research and stewardship efforts to address this threat.

Therapeutic alternatives to polymyxins are limited, but some progress has been made. Novel β-lactam/β-lactamase inhibitor combinations, such as ceftazidime-avibactam and meropenem-vaborbactam, have shown activity against certain MDR organisms, though their efficacy against polymyxin-resistant strains is variable. The European Medicines Agency (EMA) and U.S. Food and Drug Administration (FDA) have approved several of these agents for complicated infections, but resistance is already emerging, necessitating careful stewardship.

Combination therapy remains a cornerstone strategy in 2025. In vitro and clinical studies suggest that combining polymyxins with other antibiotics—such as tigecycline, fosfomycin, or carbapenems—may enhance bactericidal activity and suppress resistance development. However, the optimal combinations and dosing regimens are still under investigation. The Centers for Disease Control and Prevention (CDC) and WHO recommend individualized therapy based on susceptibility testing and local epidemiology.

Looking ahead, several new agents are in late-stage clinical development, including siderophore cephalosporins and next-generation aminoglycosides, which may offer additional options for treating polymyxin-resistant infections. The global research community, supported by organizations such as the National Institutes of Health (NIH), is also investing in non-traditional approaches, including bacteriophage therapy and antimicrobial peptides.

In summary, while polymyxin resistance poses a formidable challenge in 2025, ongoing innovation in therapeutic alternatives and combination strategies—guided by robust surveillance and stewardship—offers hope for maintaining effective treatment of MDR Gram-negative infections in the coming years.

Regulatory and Stewardship Initiatives: Policies from WHO and CDC

Polymyxin antibiotics, particularly colistin and polymyxin B, have become critical last-resort treatments for multidrug-resistant Gram-negative infections. However, the global rise in polymyxin resistance—driven by both clinical misuse and agricultural practices—has prompted urgent regulatory and stewardship responses from leading health authorities. In 2025, the World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC) continue to spearhead international and national efforts to curb the spread of resistance.

The WHO, as the United Nations’ specialized agency for public health, has maintained polymyxins on its “Reserve” list within the AWaRe (Access, Watch, Reserve) classification, emphasizing their use only for confirmed or suspected infections by multidrug-resistant organisms. In 2025, the WHO is reinforcing its Global Action Plan on Antimicrobial Resistance by urging member states to implement stricter controls on the prescription and distribution of polymyxins, especially in regions with high resistance rates. The organization is also supporting the development of national surveillance systems to monitor resistance trends and antibiotic consumption, with a focus on integrating data from both human health and animal agriculture sectors.

The CDC, as the United States’ national public health institute, has updated its Antibiotic Resistance Threats framework to highlight the growing threat of polymyxin-resistant Enterobacterales and Pseudomonas aeruginosa. In 2025, the CDC is expanding its Antibiotic Resistance Laboratory Network to enhance detection of mobile colistin resistance genes (such as mcr-1) and to provide technical support for rapid outbreak response. The CDC’s Core Elements of Hospital Antibiotic Stewardship Programs now include specific guidance on restricting polymyxin use, promoting diagnostic stewardship, and ensuring that these agents are reserved for cases with no effective alternatives.

Both the WHO and CDC are collaborating with international partners to phase out the use of colistin as a growth promoter in food-producing animals, a practice linked to the emergence of transferable resistance genes.
New regulatory requirements in 2025 mandate reporting of all clinical isolates with confirmed polymyxin resistance to national surveillance systems, aiming to improve data granularity and inform public health interventions.
Ongoing educational campaigns target prescribers and pharmacists, emphasizing the critical role of stewardship in preserving the efficacy of last-resort antibiotics.

Looking ahead, both organizations are expected to intensify their efforts over the next few years, with a focus on global harmonization of stewardship standards, expanded surveillance, and support for research into alternative therapies. The coordinated regulatory and stewardship initiatives from the WHO and CDC are central to mitigating the threat of polymyxin resistance and safeguarding public health.

Market and Public Interest Forecast: Projected 40% Increase in Research and Awareness by 2030

The global concern over polymyxin antibiotic resistance is expected to intensify significantly through 2025 and into the next several years, with projections indicating a 40% increase in research activity and public awareness by 2030. Polymyxins, including colistin and polymyxin B, are considered last-resort antibiotics for multidrug-resistant Gram-negative infections. However, the emergence and rapid dissemination of resistance mechanisms—most notably the plasmid-mediated mcr genes—have prompted urgent calls for action from health authorities and research organizations worldwide.

In 2025, the World Health Organization (WHO) continues to list polymyxin-resistant bacteria among its highest priority pathogens, emphasizing the critical need for new diagnostics, surveillance, and stewardship programs. The Centers for Disease Control and Prevention (CDC) in the United States and the European Centre for Disease Prevention and Control (ECDC) in Europe have both reported rising rates of colistin resistance in clinical isolates, particularly among carbapenem-resistant Enterobacteriaceae (CRE). These agencies are expanding their surveillance networks and investing in public health campaigns to raise awareness among clinicians and the general public.

Market analysis for 2025 suggests a robust increase in funding for research and development targeting polymyxin resistance. Major pharmaceutical companies and academic institutions are accelerating efforts to discover novel antibiotics, alternative therapies, and rapid diagnostic tools. The National Institutes of Health (NIH) and the European Medicines Agency (EMA) are prioritizing grants and regulatory pathways for innovations addressing antimicrobial resistance, with a particular focus on last-line agents like polymyxins.

Public interest is also expected to grow, driven by high-profile outbreaks and increased media coverage of antibiotic resistance crises. Educational initiatives led by organizations such as the World Health Organization and national health ministries are projected to expand, aiming to inform both healthcare professionals and the public about the prudent use of polymyxins and the dangers of resistance. The anticipated 40% increase in research output and awareness campaigns by 2030 reflects a coordinated global response, with cross-sector collaborations between governments, academia, and industry.

Looking ahead, the outlook for combating polymyxin resistance hinges on sustained investment, international cooperation, and the successful translation of research into clinical practice. The next few years will be critical in determining whether these efforts can outpace the evolving threat of resistance and preserve the efficacy of these vital antibiotics.

Future Outlook: Innovations, Challenges, and the Path Forward

The future outlook for combating polymyxin antibiotic resistance is shaped by a complex interplay of scientific innovation, global health policy, and the persistent evolution of bacterial pathogens. As of 2025, polymyxins—primarily colistin and polymyxin B—remain critical last-resort antibiotics for multidrug-resistant Gram-negative infections. However, the rapid emergence and global dissemination of resistance mechanisms, particularly plasmid-mediated mcr genes, have raised urgent concerns among health authorities and researchers.

Recent surveillance data indicate that mcr-mediated resistance is now detected in clinical and agricultural settings across all continents, with especially high prevalence in parts of Asia and Europe. The World Health Organization (WHO) continues to list carbapenem-resistant and polymyxin-resistant Enterobacteriaceae as critical priority pathogens, underscoring the need for accelerated research and stewardship efforts. The Centers for Disease Control and Prevention (CDC) in the United States has also highlighted the increasing detection of colistin-resistant isolates in its annual threat reports, prompting enhanced surveillance and infection control measures.

Looking ahead, several innovative strategies are under development to address polymyxin resistance. These include:

Novel Polymyxin Derivatives: Pharmaceutical research is focused on next-generation polymyxin analogs with improved safety profiles and reduced nephrotoxicity. Early-stage clinical trials are underway, with some candidates demonstrating promising activity against mcr-positive strains.
Combination Therapies: Combining polymyxins with other antibiotics or adjuvants is being explored to restore efficacy and suppress resistance. Preclinical studies and pilot clinical trials are evaluating synergistic effects, particularly with β-lactams and non-traditional agents.
Rapid Diagnostics: The development and deployment of rapid molecular diagnostics for mcr genes are expected to improve detection and guide targeted therapy, reducing inappropriate polymyxin use.
Global Stewardship Initiatives: International organizations such as the World Health Organization and national agencies are intensifying antimicrobial stewardship programs, with a focus on restricting polymyxin use in agriculture and human medicine.

Despite these advances, significant challenges remain. The adaptability of Gram-negative bacteria, limited pipeline of new antibiotics, and the widespread use of polymyxins in food animal production continue to drive resistance. The next few years will require coordinated global action, investment in research, and robust surveillance to preserve the efficacy of polymyxins. The path forward hinges on integrating scientific breakthroughs with policy reforms and public health strategies, as emphasized by leading authorities such as the World Health Organization and Centers for Disease Control and Prevention.

Sources & References

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