What’s in the web for family physicians - a review on antibiotic resistance

Sio-pan Chan 陳少斌，Wilbert WB Wong 王維斌，Alfred KY Tang 鄧權恩

The World Health Organization (WHO) has identified antimicrobial resistance (AMR), which encompasses resistance among bacteria, fungi, viruses, and parasites, as a contributing factor to nearly 5 million deaths annually. The organization has also expressed concern over the inadequate investment in research and development for new antimicrobials. As a result, AMR has been recognised as one of the top 10 global public health threats. Without proactive measures, WHO estimates that AMR-related deaths could soar to 10 million per year by 2050. The issue of antibiotic resistance was first brought to light by Alexander Fleming, the discoverer of penicillin, in his 1945 Nobel Prize acceptance speech. Despite his cautionary words, the subsequent development of new antibiotics led to a false sense of security in the battle against bacterial infections.

The common misconception is that antibiotic resistance stems solely from doctors overprescribing antibiotics. However, the reality is that the problem is multifaceted. This article aims to dissect the complex issue of AMR from multiple perspectives.

Antibiotics are extensively used outside of human medicine; an estimate of up to 70-80% of all antibiotics are used in the industrial farming of animals and fish. To promote hygiene and accelerate growth in densely populated livestock conditions, antibiotics and hormones are frequently added to animal feed. This practice of administering low-dose antibiotics is a recipe for breeding resistant bacteria. Although primarily penicillin and tetracycline are used in agriculture, evidence suggests that such use can lead to cross resistance to cephalosporins. Superbugs originating from animal farms are a proven risk, with the potential to contaminate surrounding soil, water sources, and sewage systems. The contamination is so severe that health authorities have advised against washing raw chicken meat in the kitchen before cooking due to safety concerns.

Antibiotic resistance poses a grave threat to public health by undermining the efficacy of antibiotics in treating infections. As a result of AMR, infections are more challenging to manage, leading to extended illnesses, increased morbidity and mortality, and limited treatment options. The financial burden of treatment escalates, along with the necessity for longer hospital stays. Patients may be forced to resort to more toxic antibiotics with severe side effects, or in some cases, face a complete absence of viable treatments. Furthermore, AMR endangers patients undergoing modern medical procedures such as joint replacements, heart valve surgeries, and bone marrow transplants, which become exceedingly risky in the presence of resistant pathogens.

For reference, the following is a chronicle of the presently available groups of antibiotics:

1. Penicillins: - Penicillin G (1928) - Ampicillin (1961) - Amoxicillin (1972)
2. Aminoglycosides : - S t rep tomycin (1943) - Gentamicin (1963) - Amikacin (1976)
3. Tetracyclines : - Chlortetracycline (1948) - Doxycycline (1967) - Minocycline (1972)
4. Macrolides: - Erythromycin (1952) - Clarithromycin (1991) - Azithromycin (1980s)
5. Cephalosporins: - Cephalothin (1964) - Ceftriaxone (1984) - Ceftazidime (1985)
6. Fluoroquinolones: - Ciprofloxacin (1983) - Levofloxacin (1996) - Moxifloxacin (1999)
7. Sulfonamides : - Sulfanilamide (1935) - Sulfamethoxazole (1961) - Trimethoprim - sulfamethoxazole (1968)
8. Carbapenems: - Imipenem (1985) - Meropenem (1996) - Doripenem (2005)
9. Glycopeptides: - Vancomycin (1956) - Teicoplanin (1984) - Dalbavancin (2014)
10. Oxazolidinones: - Linezolid (2000) - Tedizolid (2014)

* At the time of writing of this article, it was just published a new class of antibiotic called Clovibactin which is still under clinical trials, which is claimed to be very effective against many bacterial resistance.

What are the AMR and “Superbugs” of concern?

There are many types of AMR microbes, clinically the more important ones include:

1. Methicillin-resistant Staphylococcus aureus (MRSA)
2. Vancomycin-resistant Enterococcus (VRE)
3. Carbapenem-resistant Enterobacteriaceae (CRE)
4. Extended-spectrum beta-lactamase (ESBL) producing bacteria
5. Clostridium difficile (C. difficile)
6. Multi-drug resistant tuberculosis (MDR-TB)
7. Acinetobacter baumannii
8. Pseudomonas aeruginosa
9. Klebsiella pneumoniae
10. Neisseria gonorrhoeae (drug-resistant strain)
11. Candida auris (as listed by the Centre for Health Protection)

Plasmid transfer as a mechanism of AMR

doi/10.1038/sj.bjp.0707607

A plasmid is a small DNA molecule present in bacteria and some microbes. Plasmids play a significant role in antibiotic resistance because they can carry and transfer genetic material that confers resistance to antibiotics. Bacteria can acquire plasmids containing antibiotic resistance genes through horizontal gene transfer. The transfer of plasmids carrying antibiotic resistance can occur between different species of bacteria, allowing for the sharing of genetic material. This can contribute to the spread of antibiotic resistance in a diverse bacterial population.

Other mechanisms of developing AMR

DOI: 10.3109/03009734.2014.901444
DOI: 10.1038/35021219

1. Stop the antibiotic from reaching its target:
   Pump the antibiotic out from the bacterial cell. Bacteria can produce pumps that sit in their membrane or cell wall. These efflux pumps are very common and can transport a variety of compounds, including antibiotics, out of the bacterium, thereby lowering the antibiotic concentration inside the bacterial cell.
   Decrease permeability of the membrane that surrounds the bacterial cell. Certain changes in the bacterial membrane make it more difficult for the antibiotic to pass through, resulting in less of the antibiotic getting into the bacteria.
   Destroy the antibiotic. Bacterial enzymes, such as β-lactamase, can inactivate antibiotics. For example, β-lactamase destroys the active component (the β-lactam ring) of penicillins, which are extremely important antibiotics for treating human infections. In recent years, bacteria that produce extended spectrum β-lactamases, known as ESBL-producing bacteria, have become a major problem.


2. Modify or bypass the target of the antibiotic:
   Camouflage the target. Changes in the composition or structure of the target in the bacterial cell, resulting from mutations in the bacterial DNA, can prevent the antibiotic from interacting with the target. Alternatively, bacteria can add different chemical groups to the target structure, shielding it from the antibiotic.
   Express alternative proteins. Some bacteria are able to produce alternative proteins that can be used instead of the ones inhibited by antibiotics. For example, the bacterium Staphylococcus aureus can acquire the resistance gene mecA and produce a new penicillin-binding protein. These proteins are necessary for the synthesis of the bacterial cell wall and are the targets of β-lactam antibiotics. The new penicillin-binding protein has low affinity to β-lactam antibiotics, making the bacteria resistant to the drugs and allowing them to survive treatment. This type of resistance is the basis of MRSA (methicillin-resistant Staphylococcus aureus).
   Reprogram the target. Sometimes bacteria can produce a different variant of a structure it needs. For example, Vancomycin-resistant bacteria make a different cell wall compared to susceptible bacteria. The antibiotic is not able to interact as effectively with this type of cell wall.

The WHO stewardship to combat antibiotic resistance

The objective is to utilise antibiotics both effectively and judiciously, thereby reducing the emergence of antibiotic resistance, maintaining the efficacy of current antibiotics, and improving patient health outcomes. The WHO's Antibiotic Stewardship Programme encompasses a range of interventions and policies, such as:

1. Awareness and Education: to educate healthcare providers on the proper use of antibiotics and the dangers of antibiotic resistance.
2. Guidelines and Protocols: to formulate evidence based guidelines for healthcare providers that facilitate well-informed decisions regarding antibiotic prescriptions and treatments.
3. Surveillance and Monitoring: to track patterns of antibiotic resistance and usage, and help identify trends and areas requiring targeted interventions.
4. Access to Diagnostics: to provide precise and cost effective diagnostic tests, allowing healthcare professionals to discern between bacterial and viral infections, thus reducing unwarranted antibiotic use.
5. Research and Development: to encourage further research and the development of novel antibiotics, as well as alternative approaches and technologies to tackle antibiotic resistance.
6. Collaboration and Coordination: to formulate international strategies to combat antibiotic resistance, facilitating cross-sectoral collaboration among different stakeholders in the healthcare system.

Bacteriophage therapy

Bacteriophages have several attributes that make them promising candidates for therapeutic applications. They possess exceptional specificity and efficacy in targeting and destroying pathogenic bacteria, and their safety has been demonstrated through extensive clinical use in certain regions, along with their historical availability in the United States dating back to the 1940s. Bacteriophages also have the ability to swiftly adapt to address emerging bacterial challenges. Furthermore, a substantial volume of research, some of which was examined in this mini review, suggests that phages could be effective therapeutic agents in certain clinical scenarios.

In this mini review, the history of bacteriophage discovery was succinctly recounted, along with an overview of early clinical studies involving phages. Recent studies conducted in Poland and the former Soviet Union were reviewed. The discussion also explored why the clinical application of bacteriophages had not been established in Western medicine and offered insights into potential future directions of phage therapy research.

Antibiotic adjuvants: a versatile approach to combat antibiotic resistance

The mechanisms employed by bacteria to resist antibiotics were discussed. The major focus of this review was how to target these resistance mechanisms by the use of antibiotic adjuvants. The author concluded by providing insights on the existing challenges preventing clinical translation of different classes of adjuvants and proposed a framework about the possible directions that can be pursued to fill this gap. Antibiotic-adjuvant combination therapy has immense potential to be used as an upcoming orthogonal strategy to conventional antibiotic discovery.

The field of antibiotic adjuvants has gained significant attention in recent years, with exploration of mechanisms beyond β-lactamase inhibition. Various types of direct-acting and indirect resistance breakers were discussed, including enzyme inhibitors, efflux pump inhibitors, inhibitors of teichoic acid synthesis, and other cellular processes.

In addition to these well-explored strategies, recent research has identified other targets for developing adjuvants to combat antimicrobial resistance. The article also highlighted important advances in this area, including adjuvants that inhibit teichoic acid synthesis or nonessential steps in bacterial metabolic processes, as well as host-modulating adjuvants.