Climate change and antimicrobial resistance: The silent pandemic

Climate change and antimicrobial resistance: The silent pandemic

Climate change Disaster

Dr. Amira A. Moawad:

Global climate change is the worst anthropogenic crisis the entire world is currently facing. Global cooperation is required to reverse the impending catastrophe of climate change. Human usage of fossil fuels and the resulting greenhouse gas and carbon footprint are the main causes of climate change. Climate change is a disaster threatens the survival of human and all other living species on Earth. Human, animal and environment are strongly connected in an approach called One Health, which is an integrated and unified approach that aims at the health of humans, animals and balanced ecosystems in a sustainable way. A healthy planet keeps us alive and vice versa!!

Climate change It is not only a matter of human health, but also of social justice. Marginalized populations are contributing in a very small amount of the global gas emission. Nevertheless, they are the most affected by the adverse impacts. Where the wealthiest 20% of the population are responsible for 80% of all carbon emissions [1].

Heat-related morbidity and mortality, food and water insecurity, rising sea levels, wildfires-caused mortalities, novel mechanisms of infectious disease transmission, cardiovascular morbidity, and the other health effects resulting from extreme weather events like droughts and floods are few examples of how climate change affects the world´s One Health [2].

The impacts of climate change on human, animal and environment health are numerous and are getting worse very rapidly. Microbial-caused infections and accompanied Antimicrobial Resistance (AMR), are an area where One Health and climate change interact in a largely undisclosed manner. This viewpoint review discusses the direct and indirect impact of climate change on the development and spread of AMR.

Antimicrobials and Antimicrobial Resistance

The existence of potent antibiotics for bacterial illnesses is one of the basic stanchions supporting the efficiency of our modern healthcare system. With the absence of effective antimicrobials, Surgeries such as caesarean sections or hip replacements, cancer chemotherapy, and organ transplantation, would be fatal. Even the low risk procedures that are taken for granted from tooth extraction to small skin scratches, would be deadly.

According to the World Health Organization (WHO), AMR is one of the most dangerous threats to One Health in the twentieth century, AMR is rising to dangerously high levels in all parts of the world as novel resistance mechanisms develop and spread across the globe each day, AMR is increasing to dangerously high levels in every region of the planet. Treatment of patients with even common infectious diseases like pneumonia has becoming harder, and in some cases impossible, as drug efficacy declines. Increasing microbial resistance has resulted in what’s called “superbugs” that are multi- and pan-resistant bacteria and are not treatable with existing antimicrobial medicines. As all antimicrobial drugs are affecting pathogens through limited mechanisms, it is not possible to develop other drugs with new mechanisms. Additionally, prolonged research period (that can reach 20 years) and huge budgets are always needed to develop more antimicrobial drugs. It worth mentioning that bacterial pathogens are always faster than us and has the ability to develop resistance more than we can imagine.

The cost of providing patient care is rising as more expensive medications take the place of primary therapy antibiotics. The financial burden on patients and society is increased by longer illness and treatment durations as well as frequent hospitalizations [3]. In 2019, the global deaths due to AMR either directly or indirectly have reached 1.2 Million cases more than deaths caused by HIV/AIDS and Malaria [4]. AMR has a substantial financial impact on national economies and health systems as it reduces patient and their caretakers` productivity by necessitating longer hospital stays and more intensive treatment.

In addition to intrinsic resistance that exists naturally in some pathogens, AMR develops throughout time, typically as a result of genetic alterations either due to mutations or horizontal gene transfer from the same genus members or even other genera [5]. AMR-producing pathogens are present in environment (water, soil and air), humans, animals, food and plants. They can be transmitted from one person to another or between humans and animals, especially through food of animal origin.

The misuse and overuse of antimicrobials are the main causes of AMR existence. Additionally, the lack of sanitary conditions for both people and animals, inadequate disease prevention and control in hospitals and farms, the lack of access to high-quality, reasonably priced medications, vaccines, and diagnostics, the lack of awareness and education, and the lack of legal enforcement are the main causes of spread of AMR.

Bacteria have developed resistance to every antimicrobial discovered so far, sometimes even before the drug reached the markets. Some of these drugs are critical and considered as the last resort treatment options for serious infections in humans and animals (eg; Linezolid, ceftaroline and levofloxacin) [6].

The global impact of climate change on AMR-existence and spread

The world is changing through increasing populations and expansion into untouched areas of the planet. Increasing travel of humans, animals and products throughout the whole world, in addition to the global climate changes have been contributing the spread of AMR crisis worldwide.

Human, animal and environment health are strongly interconnected in a One Health term. Changes in the environment and their health effects (including AMR) should not be ignored.

Infectious diseases exacerbated by climate change risks

Increasing the earth temperature and the global warming has resulted in exacerbation of many infections in humans and animals;

Viruses; Covid-19, common cold, aseptic meningitis and Arboviral diseases

Bacteria; Escherichia coli, Vibriosis, Botulism, MRSA and Q-Fever

Fungi: Cryptococcosis, ROCM, Chromoblastomycosis and fungal allergic diseases

Protozoans: Amoebiasis, Blastocystosis, Cyclosporiasis and Acanthamebiasis.

Global warming and infection rates

Increased temperature is closely linked with increased bacterial infections. Bacterial growth rates usually increase in high temperature. Moreover, horizontal gene transfer, a major mechanism for the acquisition of AMR, is increased by increasing temperatures [7].

There’s a critical prove that bacterial disease rates are related with increments in temperature. A worldwide survey of 22 cities found that near distance from the equator and low socioeconomic factors were both related with greater chances of Gram-negative bacteremia [8]. Another study found that elevated humidity and temperature were all related with higher rates of Gram-negative circulatory system contaminations in hospitalized patients [9]. Less antibiotic-susceptible Acinetobacter infections exist amid winter months [10]. Salmonella, the most important diarrheal pathogens, are always related to heat and humidity. In addition, poultry intestinal colonization with Salmonella is increased by heat stress. With millions of global cases and increased colonization rates in humans and animals, climate change has the potential to increase significantly the burden and morbidity from salmonellosis worldwide [11]. There was a dose–response relationship between urinary tract infections and temperature. Similarly, the relationship between temperature and infection rate holds genuine also for surgical site infections after hip and knee arthroplasty, and other types of surgical site infections [12].

Global warming and bacterial resistance

In addition to bacterial dissemination and infection rates, AMR is also increased with higher temperatures. Increasing local temperature and population density both lead to increased rates of AMR. The relationship between temperature and population density was genuine for the global pathogens Escherichia coli, Klebsiella pneumoniae, and Staphylococcus aureus [13]. It was found that the increases in AMR were associated with the temperature, which has been on the rise due to climate change. As climate change worsens in progress, the combination of expanded numbers of infections and progressively AMR-producing pathogens will unavoidably lead to more resistant pathogens.

Another indirect effect of higher temperatures is the passive heat stress that affects human behavior, causing irritability and reduced critical thinking. These symptoms are common in many different diseases that lead to misdiagnosis and increased unnecessary antibiotic prescriptions [14].

Disasters and dissemination of infections and AMR

Flooding

As the climate warms, the atmosphere holds more humidity and water, leading to more extreme storms associated with more precipitation. More precipitation leads to flooding. Flooding leads to spread of water contamination and waterborne infections since the flooding of sullied water is contaminated with sewage lines or animal excreta. Flooding usually carries the polluted water and its huge content of resistant bacteria to new places, where the same infection was not usual. Additionally, flood refugees are considered as reservoirs to transmit the infection related pathogens and accompanied resistance genes to new environments [9]. A clear form of AMR related to climate-refugees and resulted crowding, is tuberculosis. As increased population density is strongly associated to spread of AMR-tuberculosis. The co-occurrence of poverty, AMR tuberculosis, and lack of medical care, result in a huge outbreak of treatment-resistant tuberculosis [15].

Nitrogen fertilized soil increases spread of AMR, as most fertilizers are originated from animal excreta. Eutrophication due to floodwater caused by climate change will lead to dissemination of resistant pathogens and AMR genes [16].

As a result of increased dissemination of AMR, progressive use of broad-spectrum antibiotics will be required, resulting in a lethal cycle of AMR and its spread.

Pollution

Increased water precipitation will lead to increased water overflow and inevitably higher levels of pollution in water. Pollutants, including heavy metals from manufacturing and industrial practices, can spread into the environment with flooding caused by climate warming. As metals in soil are known to increase bacterial resistance throughout what is called “selective pressure”, that leaves only the very resistant pathogens alive. These pathogens are termed as “superbugs” that are resistant to most of lethal factors that can kill bacteria. This process will result in the dissemination of AMR. Pollutants are also known to induce expression of AMR genes and bacterial mutagenesis. Increased agricultural runoff (i.e. eutrophication from fertilizers) will increase bacterial blooms in water systems and associated AMR genes [17]. Climate change, with its associated extreme weather events and pollution, has also proved to contribute to cardiopulmonary morbidity and prolonged treatment.

Drought

In addition to flooding, extreme weather events will also lead to drought in some regions. Water scarcity during droughts leads to shortage in sanitation and increased number of people sharing the same water source. With crowding and shared water, waterborne-outbreaks are increased. Water and food scarcity could result in worsen nutrition with increased diarrheal diseases. Children’s risk of acquiring AMR enteric pathogens is affected by malnutrition. Lowered immunity converts commensal bacteria that are normally inhabitants in the body, into pathogenic bacteria. Higher morbidity and mortality rates, particularly with higher rates of AMR preventing the administration of effective therapy [18].

 Wildfire

In addition to loss of biodiversity from massive wildfires, long-lasting respiratory issues will occur in survivors from humans and animals. Increased cardiovascular morbidity and mortality in both short and long term were found to be associated with wildfires. In addition, direct exposure to fire can result in bronchiectasis and permanent lung-scarring. Patients with bronchiectasis are known to require intensive treatment and to harbor AMR- bacteria and to have multiple infections [19, 20].

Indirect effects of climate change on AMR

As the climate changes, bacterial and viral infections are increased and vector habitats expand, leading to increased numbers of vector-borne infections. Higher temperatures also increase insect vector activity. Mosquito for example, as a malaria-vector will multiply in the residual pools of stagnant water. As a result of increased exposure of populations, there will be increases in the number of hospital admissions from vector-borne diseases. The result of increased hospitalizations, with more hospital-acquired infections, that are often antimicrobial resistant. The population at risk for vector-borne diseases as a result of climate change is expected to elevate, that will reach about 500 million more people at risk by 2050 [21].

Greater than average rainfall due to climate change will increase opportunities for mosquito proliferation due to increased standing water. With the help of mosquitos, the infection is spread to places that were previously not endemic [2].

Climate change increasingly brings humans and animals into contact and will continue to result in outbreaks of zoonotic and vector-borne diseases with pandemic potential [22, 23]. Since climate change is a social justice issue, people in low- and middle-income nations will be disproportionately affected by it in terms of their health and well-being. We currently need to act on all fronts to reverse the flow of an oncoming climate catastrophe. Being resistant to antimicrobials has no negative effects on a bacterium’s fitness, so it is better to prevent it now rather than try to address it later. All responsible authorities allover the world must address both antimicrobial resistance and climate change.

Global Action Plan on Antimicrobial Resistance (GAP)

During the 2015 World Health Assembly, nations made global commitments to the framework outlined in the Global Action Plan1 (GAP) 2015 on AMR as well as to the creation and execution of multisectoral national action plans. The World Organization for Animal Health (OIE) and the Food and Agriculture Organization of the United Nations (FAO), in addition to the World Health Organization (WHO) have set up strategies, in which countries must assure costing and the execution of national action plans across all sectors to guarantee sustainable progress. The WHO Global Strategy for Containment of AMR, which was created in 2001 and provides a framework of actions to limit the emergence and reduce the spread of AMR, was one of the global initiatives to control it prior to the endorsement of the GAP in 2015.

Potential alternative treatment options to Combat Antibiotic-Resistant Pathogens

Although antimicrobial treatment remains as the main strategy in most of infectious diseases, its effectiveness is becoming limited, and it has been resulted in the evolution of many AMR-producing strains of pathogen, which in turn has become a critical challenge to human health. The problem of AMR emergence is provoked further due to slow-pace inventions in the development of novel antibiotics. Therefore, seeking efficient alternative approaches for the eradication of drug-resistant bacterial agents seems to be an unmet requirement and not a luxury anymore. Especially those derived from natural organic materials like plants and animals-byproducts.

The continuously developed non-antibiotic strategies are safer to humans and livestock and effective against infectious pathogens [24]. Use of antimicrobial peptides (AMPs) or bacteriocins [24, 25] antimicrobial adjuvants, vaccines, fecal microbiota transplant (FMT), bacteriophage [26], genetically modified probiotics and postbiotics, and nanoparticles are the prospective alternative strategies.

Stem Cell-Derived Antimicrobial Peptides

Mesenchymal stem cells (MSCs) are being used since years as safe and promising therapeutic products against a broad range of chronic diseases through promoting immunomodulation and tissue healing. Human MSCs synthesize factors are recently used as antimicrobial peptides (AMPs) that eradicate the bacteria through multiple mechanisms including inhibition of bacterial cell wall synthesis. Therefore, AMPs represent a promising treatment against various infections [27-29].

CRISPR-Cas Against AMR- Pathogens

Clustered regularly interspaced short palindromic repeats (CRISPR)-cas is a characteristic adaptive immune feature in archaea and bacteria that provides protection against invading bacteriophages. Short sequences from bacteriophages or plasmids called as spacers are inserted into the bacterial genome as CRISPR array; the guide RNAs from the spacers will be utilized by the Cas protein machinery for specific targeting of the invading nucleic acid carrying the same sequence [30]. Several groups have shown the use of CRISPR-Cas9 in selective removal of AMR genes from bacterial populations resulting in increased sensitivity of the bacteria to antibiotics [31]. However, narrow host range of CRISPR-Cas vectors and resistance due to anti-CRISPR genes are considered as limitations for use of CRISP-Cas [30].

Development of Vaccines

Vaccines are still the potential solution for many bacterial and viral infections through boosting the immune system of host. Maintaining appropriate neutrophil count in the blood is the main mechanism that helps the immune system to combat infections. Vaccines have reduced primary and secondary bacterial infections through time, and subsequently, reducing the use of various antibiotics. Vaccines continue to be one of the most significant ways to prevent infections. However, not all pathogens have an effective vaccine until the moment, for example, Coxiella burnetii. Developing more vaccines is still targeted by many pharma companies [32].

Phage Therapy

Phage therapy is considered as an alternative therapy to combat bacterial infections and AMR. These genetically engineered phages were firstly introduced in the 1920s in Georgia, having the advantage of being ubiquitous, host-specific and harmless. They can be administered orally with food, topically on open wounds or intravenously in case of systemic infections [33]. Recombinant phages are developed to deliver antimicrobial proteins in target bacteria. Bacteriophage lysins, are the extremely specific peptidoglycan hydrolases, named “enzybiotics”. Lysins can be engineered to kill several pathogens including Gram-negative bacteria. These enzymes have attractive features that they do not activate an adverse immune response, and no resistance is developed. Lysins are considered as a new model of effective therapy to fight AMR producing pathogens [34].

Probiotics, Postbiotics and Synbiotics

The animal-derived probiotics, the non-viable microbial postbiotics, and the probiotic metabolites that have biological activities in host are all recently used as alternative therapeutic combinations [35].

Probiotics, the live microorganisms have two classes of lactic acid-producing microorganisms: the Bifidobacteria and lactic acid bacteria (LAB) including species such as; Enterococcus, Lactobacillus, Lactococcus and Streptococcus spp. Probiotics are safe and most of them are found in GI tract, mammary gland and feminine genitourinary tract [36]. Bioengineered probiotics or pharmabiotics, are becoming a bio-therapeutic strategy against bacterial infection through competition for nutrition. They have the advantage of high site specificity than common drug administration regimes. Vaccinations using recombinant probiotics against many bacterial species have been developed and have generated desirable immune responses in murine models. This makes them recommended for human use.

Nanoparticles

Nanoparticles (NPs) are minute particles having a size range of 1 to 100 nm. The use of NPs as antimicrobial agents is gaining more attention due to their reduced cost and the exceptional physicochemical properties. NPs have shown antimicrobial effects, particularly those synthesized using green methods [37]. The antibacterial effects NPs include diminishing of metabolism or bacterial integrity, replication and transcription disruption, protein denaturation, tRNA, ATPases, membrane-bound enzymes, biofilm inhibition and reactive oxygen species (ROS) production. Various NPs such as gold (Au), silver (Ag), and lower-cost NPs such as zinc oxide (ZnO), silica (SiO2), nickel (Ni), titanium-oxide, (TiO), and bismuth (Bi) NPs have deciphered efficient bactericidal effects. Various methods of NP delivery to cells for antibacterial activity include carbon NPs, liposomes, polymeric NPs, and metal or metal-oxide NPs. Nanoparticles have been used as inexpensive prognostic and therapeutic agents in a variety of biomedical science applications. The use of green synthesis and inexpensive components like albumin and chitosan improves the effectiveness of NPs for therapeutic applications [38].

The endlessly increasing AMR in pathogenic bacteria necessitates the development of unconventional non-antibiotic therapies to tackle the emergence of infectious pathogenic microorganisms and associated multidrug resistance. The efficacy of antibiotics is declining since they became a part of modern medicine. Decreasing the dependence on chemical therapeutics is a must in the present scenario. Additionally, unnecessary prescription and over prescription of antibiotics and non-therapeutic prophylactic uses must be avoided. Good hygiene and appropriate infection control measures are eagerly needed to decrease the need to therapeutic interventions.

 

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