# RKS: BUGS LOVE THEIR LIFE (II) - Bugs Also Need To Defend Themselves! (For Heaven's Sake)

 

# RKS: BUGS LOVE THEIR LIFE (II)

BUGS ALSO NEED TO DEFEND THEMSELVES! 

(FOR HEAVEN'S SAKE)

RKS / 2024-2025 / Ser 6 / Blog 4

1st January 2025

BUGS vs DRs. IS A GAME OF CHESS

UNDERSTANDING THE DEFENCE MECHANISMS OF BUGS

Dear Reader,

Self-preservation is a behavior or set of behaviors that ensures the survival of an organism. It is thought to be the universal norm among all living organisms including bugs. In fact, an organism's fitness is measured by its ability to pass on its genes. Another survival phenomenon has also been noticed in animals and humans (tribes, society, etc.) and that is cooperative survival. This is also the current trait amongst bugs resulting in emergence of the era of 'superbugs'.

It is indeed interesting to decipher the mechanisms of how bugs become resistant to antibiotics and how the same is relevant, or even critical, from human health perspective.

BACTERIAL RESISTANCE

Bacterial resistance means the ability of bugs to withstand the effect of antimicrobials that are intended to kill or control them.

RESISTANCE MECHANISMS

There are 3 mechanisms of producing resistance to antimicrobials that have been developed by bacteria.  

1. Enzymes are produced by bacteria which can destroy the antimicrobial.
2. Proteins present on bacterial wall are altered such that they cannot be recognized thereafter as targets to be attacked by the antimicrobial.
3. The cell wall of bug alters it's permeability so that the attacking antimicrobial cannot enter.

Fig: Resistance mechanisms. 

Another mechanism developed by bacteria is to pump out back (efflux) the antimicrobial that has entered within its cell before it has a chance to kill the organism.

RESISTANCE TRANSFER

The resistance to antimicrobials is transferred either:

• By chromosomes from one bacterial species to its offspring.
• By plasmids, which are detachable pieces of DNA (deoxyribonucleic acid) that carry genes, from an already resistant bug to other species or even different genus of co-existing pathogens.

Fig: Plasmid.

Resistance via plasmids can therefore spread not only as intraspecies but even interspecies when the infections is polymicrobial and this type of transfer is the most dangerous and detrimental to health since treatment by antibiotics is highly challenged.

FAVORITE RESISTANCE MECHANISM

The very first antibiotic discovered in the world was in 1928 by Alexander Fleming and it was named as penicillin.

Fig: Sir Alexander Fleming.

Also, it was in 1940 that the very first resistance mechanism by bacterial pathogen was discovered - destroying the beta-lactam ring within the penicillin with an enzyme that became labeled as beta-lactamase.

Fig: Beta-lactam ring in beta-lactams.

It is very evident that the beta-lactamases enzymes split wide open the beta-lactam ring present to render the beta-lactam class of antibiotics ineffective.

Just to recapitulate from the previous blog, beta-lactam antibiotics can be classified into 4 groups:

1. Penicillins
2. Cephalosporins
3. Carbapenems
4. Monobactams

All these are advocated for Gram-positive as well as Gram-negative bacterial infections, including mixed types.

WHICH PATHOGEN IS MORE PREVALENT & A CULPRIT?

Overall, the incidence of infections with Gram-positive bacteria is 47% the rest is by Gram-negative species. However, infections are of two types:

1. Community-acquired - day-to-day infections wherein one consults doctors and consumes the prescribed antimicrobial in the course of daily living.
2. Nosocomial - infections in hospitalized patients is the most concerning since these are more serious and could lead to mortality.

The thumb rule has been to prefer antimicrobial pills for community-acquired infections but to initiate injectable antibiotics for nosocomial pathogens.

GRAM-POSITIVE vs GRAM-NEGATIVE PATHOGENS

According to World Health Organization (WHO) when the density of suspended bacteria in the air is less than 180 cfu/m3 the possibility of causing infection is very small, but when the density of suspended bacteria in the air reaches 700-1800 cfu/m3 there is a risk of transmission of infection. Gram-negative bacteria are the main pathogens in all the four seasons, followed by Gram-positive cocci, and even less likelier are the fungal infections. The reason why infections with Gram-negative bacteria is also more prevalent comparatively is because they acquire greater virulence because of increased temperature.

PREFERRED ANTIMICROBIAL FOR GRAM-NEGATIVE PATHOGENS

There are primarily 3 antimicrobials which, have injectable options and, cater to treating hospital infections due to Gram-negative bacteria:

1. Beta-lactams
2. Quinolones
3. Aminoglycosides

Of these beta-lactams have been the most favored and preferred on account of their predictable efficacious outcomes. [Cornaglia G. Clinical Microbiology and Infection 2000; 6(Suppl 3): 41-45]

WHY GRAM-NEGATIVE PATHOGENS ARE MORE RESISTANT?

In addition to their greater prevalence, it more difficult to destroy Gram-negative pathogens by beta-lactam antibiotics since these act by destroying peptidoglycans and this layer is embedded more deeply in this sub-type of bacteria. 

Fig: Cell wall of Gram-positive and Gram-negative bacteria.

Peptidoglycans are a protein moiety which many of the antimicrobials attack to decimate the bacteria. It is very apparent that the peptidoglycan in Gram-negative, being drowned much inside the cell wall, are not easily accessible to beta-lactams to attack.

To fortify the defences further, the Gram-negative bacterium produces beta-lactamases and holds it back within the space beneath the outer wall so as to protect the peptidoglycans, just like the guards inside the palace. This is in contrast to Gram-positive bacteria which manufacture and release the protective enzyme so as to surround it - akin to guards outside the walls of the fort.

As a result, the antimicrobial resistance (AMR) becomes a bigger challenge for treating infections with Gram-negative pathogens and it is this bacteria that is responsible for the nosocomial infections.

BETA-LACTAMASES vs BETA-LACTAMS

There has been an ongoing battle between the beta-lactamase and the beta-lactam and the chess players have been the bug and the scientific researching medical professionals.

BETA-LACTAMASES

Beta-lactamases have been differentiated as per the Ambler's classifications into:

1. Class A
• PENICILLNASES: Resist penicillins
• EXTENDED SPECTRUM BETA-LACTAMASES (ESBLs): Resist 1st & 2nd generation cephalosporins
• CARBAPENEMASES: Resist penicillins, cephalosporins, carbapenems like meropenem as well as monobactams
2. Class B
• METALLO-BETA-LACTAMASES (MBLs): Resist carbapenems BUT NOT monobactams
3. Class C
• AmpC BETA-LACTAMASES (ABLs): Resist even 3rd & 4th generation cephalosporins
4. Class D
• OXACILLINASE (OXA) BETA-LACTAMASES: Resist even ureidopenicillins like piperacillin
• CARBAPENEMASES: Resist penicillins, cephalosporins, carbapenems like meropenem as well as monobactams

Carbapenemases are deadliest beta-lactamase enzymes that need to be overcome successfully in present times if lives are to be saved in hospitalized patients. 

BETA-LACTAMASES PRODUCING GRAM-NEGATIVE PATHOGENS

Before we begin to understand the moves in the game of chess, it is critical to appreciate the types of Gram-negative bacteria that cause infections in hospitalized patients.

1. Enterobacteriaceae spp. (fermenters)
• Citrobacter spp.
• Edwardsiella spp.
• Escherichia (E.) coli
• Klebsiella (K.) pneumoniae
• Morganella spp.
• Proteus spp.
• Providencia spp.
• Salmonella spp.
• Serratia spp.
• Shigella spp.
• Yersinia spp.
2. Non-fermenters Gram-negative bacteria (NFGNB)
• Acinetobacter (A.) baumannii
• Moraxella spp.
• Pseudomonas (P.) aeruginosa

Gram-negative bacteria can be categorized as fermenters and non-fermenters on the basis of their ability to catabolize carbohydrates. 56% of the infecting Gram-negative pathogens are Enterobacteriaceae spp. whilst 44% are NFGNB. 

BETA-LACTAM INHIBITORS

Attempts to identify inhibitors of common β-lactamases began in the mid-1970s and clavulanic acid was the first agent to become available. Thereafter, sulbactam and tazobactam were added to the armamentarium. All these inhibitors of beta-lactamases enzymes are NOT antibiotics. They merely degrade the enzyme. Hence, when either clavulanic acid or sulbactam or tazobactam is combined with a penicillin, cephalosporin or carbapenem the corresponding antibiotic gets access to bind with the peptidoglycan of the pathogenic bacteria since the beta-lactam inhibitor, which with it has been combined, has already destroyed the defending enzyme.

Clavulanic acid is combined with capsules and tablets forms of beta-lactams whilst sulbactam and tazobactam are commonly available as fixed dose combination (FDC) with higher generations of cephalosporins, injectable penicillins and carbapenems.

TREATING NOSOCOMIAL INFECTIONS 

THE GAME OF CHESS

Carbapenemases have posed the greatest challenge and are divisible into 3 subtypes: 

[Daha P. Carbapenemases- Definition, Types, Significance, Bacteria. Arya S (Ed) 2023; https://microbenotes.com/carbapenemases/]

• Fermenters as well as NFGNB elaborate Class A and Class B carbapenemases; whilst
• Class D enzymes are produced primarily by P. aeruginosa and K. pneumoniae. 

Further, Class A carbapenemase is susceptible to beta-lactam inhibitors whilst Class D carbapenemases cannot be overcome by clavulanic acid, sulbactam / tazobactam. 

The last resort antibiotics (carbapenem + beta-lactam inhibitor / aztreonam + beta-lactam inhibitor), also categorized as 'reserve' drugs as per 2019 WHO list of AWaRe (Access, Watch, Reserve) classification, are being given by medical professionals to overcome carbapenemases. However, if these enzymes are of Class D the outcome with beta-lactams, including combinations with beta-lactamase inhibitors, has disappointing outcomes and other options have to be resorted to. In the case of MBL producers, the only current hope is additional EDTA (ethylenediaminetetraacetic acid) to injectable cephalosporins + beta-lactam inhibitor as of now.

CONCLUSIONS 

There are 6 pathogens which are responsible for most infections in the world and these have been grouped as 'ESKAPE' as a distinct category:

1. E - Enterococcus faecium
2. S - Staphylococcus aureus
3. K - K. pneumoniae
4. A - A. baumannii
5. P - P. aeruginosa
6. E - Enterobacter spp. 

In addition to the above, there are some 'relatives' of the ESKAPE cluster which also enjoy the safety cover if any corresponding from the 6 pathogens have developed antimicrobial resistance mechanism. [Simpson A. 2019 JCCC Science and Mathematics Poster Symposium. https://scholarspace.jccc.edu/science-math-symposium/2019/friday/13/#:~:text=The%20first%20pathogen%20of%20the,the%20safe%20relative%20Escherichia%20coli.]

• Enterococcus fecelis - safe relative is Enterococcus fecium.
• Staphylococcus aureus - safe relative is Staphylococcus epidermidis.
• K. pneumoniae - safe relative is E. coli.

There is a hide-n-seek game being played in hospital setting between the bug and the treating doctor. It is indeed interesting to follow how the game of chess between the bug and the doctor has been evolving. 

ESKAPE pathogens are responsible for 15.5% of infections globally and most of these have acquired resistance via plasmids to various antimicrobials. [ESKAPE). https://en.wikipedia.org/wiki/ESKAPE)] What has added fuel to the fire is the resistance fireball set rolling by NDM (New Delhi Metallo-beta-lactamase) variant of MBL enzyme. 

Following its first isolation from an Indian patient in a hospital in Sweden in 2009, NDM now appears to have become endemic to the Indian subcontinent, Balkan countries, Northern Africa, and the Arabian Peninsula, besides Europe. The Indian clinician has been given a 'check' call by the bug but from the equation table it seems the treatment antibiotic armamentarium is yet to be checkmated!

The upcoming last part of the superbug series in February 2025 will dwell into the why such a scary scenario of perceptibly unsurmountable AMR has emerged and how the same could have been prevented and also the future courses of actions required to be taken by regulators, medical professionals and patients alike.

DR R K SANGHAVI

Prophesied Enabler

Experience & Expertise: Clinician & Healthcare Industry Adviser

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