Antimicrobial resistance genes (ARGs) from wastewater can end up in natural biofilms in rivers, but they may not stick around very long. In a new research in mSphere, researchers report that after ARGs are introduced to a river they invade and initially join natural biofilms.

As river temperature rises, the prevalence of these introduced ARGs diminishes notably, indicating that the existing microbial community outcompetes the resistant newcomers. At 30°C (86°F), ARG levels reverted to baseline within just 2 weeks.

This discovery implies that rivers could serve as a natural barrier against disseminating ARGs from wastewater, contrary to the researchers' initial assumptions. Typically originating from human feces, most ARGs flourish at body temperature, which is higher than that of waterways. Microbiologists anticipated warm rivers to be conducive environments for ARG proliferation.

 

A coherent cluster of bacterial cells embedded in a matrix that are more tolerant to most microbial and host defenses than planktonic bacterial cells are called biofilms.

The best example to understand the structure of biofilms is a mushroom-like tree. At the top, there will be more oxygen, resulting in more growth, while on the inner surface, there will be less oxygen and slower growth. So, in conclusion, the outer part is more tolerable and the main support for biofilm compared to the inner part. If any Abx succeeds in entering inside the biofilm, there is no chance for an encounter.

Bacteria first multiply to form a matrix (have DNA, proteins, and LPS) and then form biofilms. Hosts respond to biofilms in three ways:

• non-inflammatory response
• immune response
• inflammatory response

The non-inflammatory defense involves permanent mechanisms that maintain the self-cleaning capacity of the organism, such as the skin and the respiratory tract. This defense system is continuous by default, which means that it is constitutively active and can be modulated by infectious microorganisms. The immune response is the body’s response to antigens. Antigens include pathogen-associated molecular patterns such as extra-cellular DNA, various toxins, LPS, and other microbial components. 

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A gram-negative, flagellated, facultatively anaerobic bacillus called S. typhi has three main antigens: the flagellar antigen (H), the somatic antigen (O), and the vi antigen. The organism often transitions from one phase to another. H antigen can be present in either or both of the two phases. O antigens are found on the exterior of the membrane. Overlying the O antigen, the Vi antigen is a surface antigen. Salmonellae are distinguished from S.typhi by the Vi antigen.

S. typhi is a pathogen that is effective due to a variety of traits. This species possesses a Gram-negative organism-specific endotoxin in addition to the Vi antigen, which is expected to boost virulence.

History of AMR in S.typhi: 

Chloramphenicol was the most efficient and widely used treatment for typhoid fever when it was first discovered. Due to its widespread and indiscriminate use, chloramphenicol-resistant S. typhi isolates were discovered in England within two years. These strains were also resistant to ampicillin. co-trimoxazole was a successful alternative medication until co-trimoxazole-resistant strains were discovered in France. Despite the paucity of safety evidence, pediatricians worldwide were forced to employ ciprofloxacin in the late 1980s due to the epidemic of antibiotic resistance.

Fluoroquinolones consequently became the preferred medication for treating MDRTF all over the world. However, soon after, there were reports of S. typhi isolates that were resistant to fluoroquinolones. With the development of quinolone (nalidixic acid) resistance, third-generation cephalosporins were used for treatment, and reports of resistance to them also followed.

Mechanisms of AMR in S.typhi:

Following are some methods that S.typhi resists the effects of antibiotics.

• Antimicrobial agent inactivation
• Transport or efflux of the antibiotic
• Antimicrobial target site modification
• Decrease in the antibacterial agent's permeability

Antimicrobial agent inactivation:

This is a typical reason why antimicrobial agents are destroyed or become activated. The bacterial pathogens prevent attacks by chemically altering medications to keep them inactive. The initial strains of antibiotic-resistant  S.typhi carried chloramphenicol acetyltransferase type I, which encodes an enzyme that inactivates chloramphenicol via acetylation.

Transport or efflux of the antibiotic:

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Development of resistance in M .tuberculosis is a depiction of Darwin’s theory of evolution “survival of the fittest”. Due to selective pressure caused by antibiotics, M. tuberculosis comes up with survival mutants. Combination therapies have created the evolution of strains, eventually, causing resistance to all available drugs. Also, the exposure to bactericidal antibiotics is resulting in an induced mutation which ends up promoting mutant MDR phenotypes. Drugs like isoniazid and ethionamide are prodrugs that work cytotoxically after activation by redox enzymes in the bacterial cytoplasm. This process produces reactive oxygen and radicals that kill the bacterial cell, if they fail to kill, they eventually turn into bad promoting mutagenesis that ends up producing multidrug resistance.

There are some specialized mechanisms that help in detoxifying drug molecules that become able to penetrate the cytoplasm of bacteria. They can be enlisted as:

•       Target alteration
•       Target mimicry
•       Drug modification
•       Drug degradation
•       Drug efflux

Target alteration:

Since the 1960s, the widespread use of antibiotics has chosen resistant bacteria, raising the incidence of infectious illnesses that are lethal and placing financial pressure on society. Despite the fact that this issue is commonly acknowledged as a global one, its scope is not fully understood in many parts of the world. There has not yet been a systematic examination of antimicrobial resistance (AMR) in Pakistan.

Urinary Tract Infection (UTI) is the most often reported clinical diagnosis in Pakistan (16.1%), according to studies published in the previous ten years. E. coli was found in 28 (30.11%) investigations, all of which had significant first-line antibiotic resistance. In 49% of all instances of Staphylococcus aureus that were reported, MRSA was discovered. Disk Diffusion Method (DDM) (82.8%) has been used most frequently to examine phenotypic resistance patterns, with Clinical Laboratory Standards Institute (CLSI) breakpoint reference guidelines being used in 79.6% of investigations. Only 28 (30.11%) research has successfully identified the resistance gene using molecular methods.

The most common known resistance genes are blaTEM (78.94% in Shigella spp.) and blaNDM-1 (32.75% in Klebsiella spp.), followed by VanA (45.53% in Enterococcus spp.), mcr-1 (1.61% in Acinetobacter spp.), and blaKPC-2 (31.67% in E. coli). Sindh (40.86%) and Punjab (35.48%) were the two provinces with the most studies, whereas Baluchistan's AMR data wasn't accessible.

Conclusion:

1. Pakistan has a very high frequency of AMR to routinely give antibiotics. 
2. Significant surveillance holes are discovered In other words, no research on antibiotic resistance was recorded for the region of Baluchistan. Additionally, there weren't enough investigations done on some bacteria to determine their resistance patterns.
3. Numerous research includes methodological data gaps that raise questions about the validity of the investigations and make analysis challenging.
4. There are very few molecular investigations available that are necessary for the appropriate and efficient administration of medicinal drugs.

Therefore, it is essential to regularise monitoring procedures and to conduct ongoing regional and national surveillance, molecular investigations, and targeted efforts to reduce the risk brought on by the rise in AMR.

But do you really think that would be enough?

Antimicrobial resistance has emerged as a major cause of disease and mortality around the world. Antibiotics were assumed to have won the war against microbes when they were initially introduced in the early 1900s. Most pathogenic bacteria appear to be capable of developing antimicrobial resistance to at least some antimicrobial agents. Because so many bacteria have developed resistance to many antimicrobial drugs, the battle appears to be shifting in favor of bacteria. Infectious diseases are a major cause of morbidity and mortality around the world today. Lower respiratory infection, diarrheal diseases, HIV/AIDS, and malaria are among the top 10 causes of morbidity and mortality, according to a World Health Organization (WHO) assessment of these diseases.

         
MACHANISM OF ANTIBIOTIC RESISTANCE:

      Antimicrobial resistance mechanisms can all be classified into four categories:

•   Drug uptake limitation

•   Drug target modification

•   Drug inactivation

•   Active drug efflux

      Intrinsic resistance may make use of limiting uptake, drug inactivation, and drug efflux; Drug target alteration, drug inactivation, and drug efflux are examples of acquired antibiotic resistance mechanisms. The sorts of mechanisms utilised by gramme negative bacteria and gramme positive bacteria differ due to changes in structure and other factors. Gram negative bacteria employ all four primary mechanisms, whereas gramme positive bacteria use limiting drug uptake less frequently (because they lack an LPS outer membrane) and lack the capacity for some types of drug efflux mechanisms.

 

WHAT IS AN ANTIBIOTIC?

        Antibiotics are medicines that are used to treat bacterial infections. In 1936, antibiotics were used for the first time to treat bacterial infections. Antibiotics have made it possible to treat late infections.

Antibiotics are still effective life-saving treatments for those suffering from serious infections today. They can also keep infections that aren't as serious from becoming more serious.

CLASSES OF ANTIBIOTICS:

          There are many classes of antibiotics. Certain types of antibiotics work against specific type of bacterial infections. Antibiotics come in many forms:

·         Tablets

·         Capsules

·         Liquids

·         Creams

·         Ointments

          Most antibiotics are only available with your doctor prescription. Some are available over the counter.

TYPES OF ANTIBIOTICS:

           Mainly there are two types of antibiotics that are bactericidal and bacteriostatic.

•        BACTERICIDAL: 

          Antibiotics that are bactericidal kill germs directly. The antibiotic damages the bacteria's plasma membrane, causing their contents to flow out. Because of osmosis, bacteria and other cells must maintain a precise balance of ions on both sides of the plasma membrane in normal circumstances. These medicines upset the bacterial balance, allowing other essential components like DNA and RNA to leak out, resulting in the bacterium's death.

•           BACTERIOSTATIC:  

              Antibiotics that inhibit bacterial growth are known as bacteriostatic antibiotics. Bacteria in our bodies generally divide quite quickly, and their numbers can swiftly spiral out of control. The host's immune system will be able to get rid of the bacteria if an antibiotic stops them from multiplying and dividing.

          Other types of antibiotics are narrow spectrum and broad spectrum antibiotics:

•        NARROW SPECTRUM ANTIBIOTICS:

                 Antibiotics with a narrow spectrum of activity are only effective against a few number of microorganisms. It frequently has to do with an antibiotic's ability to penetrate the bacterial membrane. Gram positive bacteria have a relatively loose outer wall that can be diffused by any antibody, whereas gram negative bacteria have a relatively hard membrane that can only be penetrated by specific antibiotics.

•          BROAD SPECTRUM ANTIBIOTICS:

                   Broad-spectrum antibiotics are effective against a wide range of bacteria.

HOW DO ANTIBIOTICS WORK?

          Antibiotics treat bacterial illnesses in a variety of ways, many of which entail interfering with bacteria's ability to survive and proliferate in the human body.

Bacteria have cell walls that protect them from the harsh conditions within your body. The delicate core of the cell, which houses the DNA and crucial proteins that bacteria utilise to reproduce asexually, is protected by these cell walls. Antibiotics are usually effective in one of three ways:

1. Antibiotics kill bacteria by rupturing or preventing the bacteria's protective cell walls from developing in the first place.
3. Antibiotics prevent bacteria from copying their DNA, which is required for reproduction.
4. Antibiotics disrupt the metabolism of bacteria, making it difficult for them to reproduce and spread throughout the body.

WHAT DO ANTIBIOTICS TREAT?

            Doctors prescribe antibiotics for all types of bacterial infections from minor strep throat or urinary tract infections to severe, life-threatening conditions such as bacterial pneumonia or sepsis.

       "The properties of some antibiotics make them amenable to other medical conditions, as well,” says Anthony Kaveh, MD, physician

            Antibiotics can also have anti-inflammatory properties, which can help with viral infection-related inflammation. For example, researchers are looking into how the antibiotic azithromycin can aid COVID-19 patients by reducing inflammation.

           Kaveh, on the other hand, reminds out that "This effect of antibiotics is still being studied. One of these antibiotics is azithromycin. It's probable that some of azithromycin's observed success stems from its anti-inflammatory properties."

HOW LONG ANTIBODY TAKE TO DO WORK?

            Antibiotics start working as soon as you start taking them. However, it's possible that you won't feel better for another two to three days. Antibiotics should be administered for 7 to 14 days in most cases. Shorter treatments can sometimes be just as effective. Your doctor will choose the appropriate antibiotic type and duration of treatment for you. Even if you feel better after a few days of therapy, it's crucial to finish the antibiotic programme to get rid of your infection completely. This may also assist in the prevention of antibiotic resistance.

LEARN MORE ABOUT ANTIBIOTIC RESISTANCE  

                      

 

 

 

ANTIBIOTIC RESISTANCE:

        Antibiotics are medicine that are used to prevent and treat infections caused by bacteria. Antibiotic resistance occurs when bacteria's response to antibiotics changes. Antibiotic-resistant bacteria cause diseases in both people and animals. These diseases are more difficult to treat than those caused by bacteria that aren't resistant to antibiotics. Antibiotic resistance raises medical expenses, lengthens hospital stays, and raises fatality rates.

     The world urgently needs to modify how antibiotics are prescribed and used. Antibiotic resistance will always be a danger, even if new medications are developed. Vaccination, hand washing, safer sex, and excellent food hygiene are all examples of behavior modifications that can help prevent the transmission of illnesses.

SCOPE:

       In the world, antibiotic resistance is increasing to a worrisome degree. New resistant mechanisms are arising and spreading around the world, posing a danger to our ability to treat common illnesses. Because medicines are becoming less effective, illnesses such as pneumonia, tuberculosis, and gonorrhoea are getting more difficult to cure. Antibiotic resistance is a major worry since some bacteria have developed resistance to practically all of the commonly used antibiotics. These bacteria have the potential to cause significant illness, making them a major public health concern..

TRANSMITION OF RESISTANT BACTERIA:

        Most commonly bacteria transmit through contaminated utensils like in hospitals through

ü  Contact with contaminated surface, syringes, stethoscope, and mainly by hands of hospital staff.

Standard precautions in hospitals are work practices that provide a basic level of infection control for the care of all people, regardless of their diagnosis or presumed infection status.

WAYS TO PREVENT ANTIBIOTIC RESISTANCE:

       Antibiotic resistance must be controlled urgently to ensure the safety of people's lives; else, the world would soon descend into chaos. Antibiotic resistance is increased, according to the WHO, by antibiotic abuse and overuse, as well as poor infection prevention and control. To lessen the impact and spread of resistance, actions can be taken at all levels of society.

Individuals can help to prevent and limit the spread of antibiotic resistance by:

• Antibiotics should only be used if a doctor has recommended them.
• If your doctor says you don't need antibiotics, don't take them.
• When taking antibiotics, always listen to your doctor's advise.
• Never share or utilise antibiotics that have been left over.

Policymakers can increase policies, programmes, and the implementation of infection prevention and control measures to prevent and control the spread of antibiotic resistance.

The health business can invest in research and development of new medicines, vaccines, diagnostics, and other instruments to prevent and control the spread of antibiotic resistance.

Antibiotic resistance can be prevented and controlled in the agriculture industry by:

• Antibiotics should only be given to animals under veterinary supervision.
• Antibiotics should not be used to promote growth or prevent disease in healthy animals.
• Animals should be vaccinated to limit the need for antibiotics and alternative treatments should be used.