# RKS: BUGS & ANTI-BUGS (I) - Basics On Infecting Bacteria & Killer Drugs

    

# RKS: BUGS & ANTI-BUGS (I)

BASICS ON INFECTING BACTERIA & KILLER DRUGS


RKS / 2024-2025 / Ser 6 / Blog 3


1st December 2024

MICROORGANISMS INFECTING HUMANS

UNDERSTANDING ANTIMICROBIALS & THEIR CAPABILITIES


Dear Reader,

A bug is microorganism and could be a virus, bacterium, fungus or a parasite. There are:

  • 10 nonillion (1 followed by 30 zeroes in US and 54 zeroes in Great Britain) viruses on earth.
  • 5 nonillion bacteria present on the earth.
  • 2.5 million (mn) fungi species on earth.
  • 1-3 lakh parasite species on earth. 

Infection-related deaths reported globally are 13.7 mn in 2019 of which bacterial-related mortality accounted for 7.7 mn. Out of every 8 patients dying, 1 is on account of bacterial infection! Hence, bacteria are the most dangerous bugs for mankind. 

One gram of soil holds 40 million (mn) bacterial cells whilst 1 mL of fresh water has 1 mn of these squirming in the liquid. Humans also harbor bacteria under normal circumstances and these are called commensals or friendly bacteria whose synergistic presence provides many advantages. The human body has a total of 10(x13) cells but the commensals number 10(x14) bacteria and are present in mouth, intestines (gut), skin and vagina. 

More than 1,500 species of bacteria are known to infect humans and these are called pathogens. To counter such infecting pathogens, antimicrobials are routinely prescribed and taken by patients. Superbugs are those microbes which are resistant to the eliminating action of multiple drugs. 

Superbugs are now a leading global health risk, according to a major United Nations (UN) report published. It is thus imperative to understand how one does not empower bugs to become superbugs and turn into invincible enemies towards one's own health and well-being.


BACTERIA

BACTERIAL CLASSIFICATION

The bacteria can be classified as 2 characteristics from the point of view of choosing an antibacterial to eliminate the related infection.

  1. APPEARANCE (MORPHOLOGY) ON MICROSCOPY
    • Gram-positive: When the bacteria appear BLUE when stained they are called Gram-positive. 
    • Gram-negative: When the bacteria cannot retain the BLUE dye and appear RED under the microscope, they are referred to as Gram-negative.
  2. REQUIREMENT OF OXYGEN
    • Aerobes: Bacteria require the presence of oxygen for their survival.
    • Anerobes: Bacteria survive in spite of absence of oxygen.

In addition to the above, there are some pathogens which are neither classified as Gram-positive nor Gram-negative and these are referred to as atypical bacteria.


GRAM-POSITIVE & GRAM-NEGATIVE PATHOGENS

Some of the important species of Gram-positive bacteria that infect humans are:

  • Staphylococcus aureus (S. aureus)
  • Streptococcus pyogenes (Strep. pyogenes)
  • Streptococcus pneumoniae (Strep. pneumoniae)
  • Clostridium tetani (cause tetanus)

Some of the important species of Gram-negative pathogens include:

  • Escherichia coli (E. coli)
  • Hemophilus influenzae (H. influenzae)
  • Salmonella typhi (cause typhoid)
  • Shigella dysenteriae (cause dysentery)
  • Pseudomonas aeruginosa (P. aeruginosa)
  • Klebsiella pneumoniae (K. pneumoniae)
  • Acinetobacter baumannii (A. baumannii)
  • Helicobacter pylori (H. pylori) (only known bacteria to infect the otherwise acid-containing stomach)

ATYPICAL PATHOGENS

There are 3 common atypical bacteria that infect humans:
  1. Legionella pneumophila (L. pneumophila)
  2. Mycoplasma pneumoniae (M. pneumoniae)
  3. Chlamydia trachomatis (C. trachomatis)


ANEROBES & AEROBES

Most pathogens are aerobes. However, the significant anerobic species include:

  • Peptococcus spp.
  • Peptostreptococcus spp.
  • Clostridium spp.
  • Bacteroides spp.
  • Fusobacterium spp.


COMMON INFECTING BACTERIAL SPECIES

Globally, the 6 common bacterial pathogens which are responsible for over 54% of deaths are: 

[Christopher MJL et al. Lancet 2019; 399(10325): 629-655]

    1. S. aureus
    2. E. coli
    3. Strep. pneumoniae
    4. K. pneumoniae
    5. A. baumannii
    6. P. aeruginosa

    In India, the same top 5 bacterial species are the commonest pathogens.


    COMMON INFECTIONS

    75% of the 7.7 million bacterial deaths occur because of three syndromes: (https://www-thehindu-com.cdn.ampproject.org/c/s/www.thehindu.com/sci-tech/health/five-bacteria-types-claimed-68-lakh-lives-in-india-in-2019/article66168419.ece/amp/)

    1. Lower respiratory infections (LRI)
    2. Bloodstream infections (BSI)
    3. Peritoneal and intra-abdominal infections (IAA) 

    Gram-positive bacteria are by and large the exclusive pathogens for skin and bone infections as well as sore throat. LRI and for all other infections, in which there is pus, the Gram-positive bacteria are to be suspected as culprit pathogens.

    Besides participating as important pathogens for LRI, the Gram-negative bacteria are the predominant invaders in BSI, IAA, brain infection (meningitis) and urinary tract infections (UTI).


    ANTIMICROBIALS PRESCRIBED

    Antimicrobials are classified as:

    • Chemotherapeutic agents: Synthetic antimicrobials
      • Antibacterials: Sulfamethoxazole + Trimethoprim (co-trimoxazole), quinolones (ciprofloxacin, ofloxacin)
      • Antifungals: Fluconazole, terbinafine
      • Antivirals: Acyclovir
      • Antiprotozoals: Metronidazole, tinidazole, ornidazole (for dysentery-causing amebiasis) and lumefantrine (for malaria) 
    • Antibiotics: Naturally produced antimicrobials from living organisms
      • Aminoglycosides: Amikacin, gentamicin, tobramycin
      • Beta-lactams: Penicillins {amoxicillin, co-amoxiclav [amoxicillin-clavulanic acid (CA)], piperacillin-tazobactam}, cephalosporins [first generation: cephalexin; second generation: cefuroxime; third generation: cefixime, cefpodoxime, cefotaxime, ceftriaxone, cefoperazone; fourth generation: cefepime; fifth generation: ceftobiprole, ceftaroline], carbapenems (imipenem, meropenem)
      • Cyclic Lipopeptides: Daptomycin
      • Glycopeptides: Vancomycin
      • Glycylcyclines: Tigecycline
      • Lincosamides: Clindamycin, lincomycin
      • Macrolides: Azithromycin
      • Oxazolidinones: Linezolid
      • Tetracyclines: Doxycycline

    CA, sulbactam and tazobactam are not antibiotics but are available in combination with many beta-lactam agents inorder to strengthen their action against microbes which have developed resistance.


    ANTIBACTERIALS & SUSCEPTIBLE PATHOGENS

    • AMINOGLYCOSIDES: Gram-negative pathogens
    • CARBAPENEMS: Gram-negative pathogens including resistant bacteria
    • FIRST GENERATION CEPHALOSPORINS: Gram-positive pathogens
    • SECOND GENERATION CEPHALOSPORINS: Gram-negative pathogens predominantly
    • THIRD GENERATION CEPHALOSPORINS: Gram-negative resistant bacteria
    • FOURTH GENERATION CEPHALOSPORINS: Gram-negative and Gram-positive pathogens as well as anerobes
    • FIFTH GENERATION CEPAHALOSPORINS: Gram-positive resistant bacteria predominantly
    • GLYCOPEPTIDES, LINCOSAMIDES, MACROLIDES, OXALINEDINONES: Gram-positive and atypical pathogens
    • PENICILLINS: Gram-positive pathogens
    • QUINOLONES: Gram-negative pathogens predominantly and atypical pathogens
    • TETRACYCLINES: Besides bacteria, doxycycline can also eliminate chlamydia, rickettsia, viruses and / or protozoa.

    Rickettsia are a type of bacteria but which are smaller in size.

    Based on the above susceptibility pattern, antimicrobials are also classified as:

    • Narrow-spectrum: Can eliminate usually only Gram-positive pathogens.
    • Extended-spectrum: Can eliminate both Gram-positive and Gram-negative pathogens.
    • Broad-spectrum: Can eliminate both Gram-positive and Gram-negative pathogens plus other microbes such as chlamydia, rickettsia, viruses and / or protozoa.

    BACTERIAL RESISTANCE

    The Gram-negative bacteria have a 3-layered outer cell wall covering it.

    1. Outer membrane (OM): It comprises of phospholipids as well as porins (gaps).
    2. Middle layer: This is a rigid covering of peptidoglycans and also is responsible for the shape of the bacterium.
    3. Inner membrane (IM): In addition to OM, the phospholipids also constitute the IM. 

    Fig: The cell wall of Gram-negative bacteria.


    When antibacterials are given to destroy the bacteria, they have to first enter the cell via the OM in the Gram-negative pathogens. If the antimicrobial is hydrophobic (repelled by water) it diffuses inside via the phospholipid barrier and, if hydrophilic (attracted by water), the antibacterial will pass through the porins. In resistant bacteria, the OM properties of hydrophobicity or the nature of porins are altered so as to prevent the entry of antibacterials. Surprisingly, the OM is absent in the Gram-positive pathogens and hence the risk of resistance by these bacteria to antimicrobials is lesser. [Breiyeh Z et al. Molecules 2020; 25(6): 1340] 


    CONCLUSION

    Globally the DALYs (Daily Adjusted Life-Years) per year have been documented for infections as follows:

    (https://ourworldindata.org/burden-of-disease)

    • 1990: ~808 mn DALYs
    • 2000: ~718 mn DALYs
    • 2010: ~565 mn DALYs
    • 2020: ~511 mn DALYs

    DALYs are used to measure total burden of disease - both from years of life lost and years lived with a disability. One DALY equals one lost year of healthy life. The US FDA has approved 21 new antibiotics in the decade of 1990 to 2000 but only 6 in the subsequent 10 years (2000-2010); 18 new antibiotics have been approved since 2010 till 2020 in US. The ~10-20% decline in incidence of infections globally has been thanks to the continual availability of newer and more effective antimicrobials year after year.

    Out of the total ailing population in India, more than one-third has an infection-related disease. In India, 78 single-dose antibiotics have been sold and 112 fixed dose combinations (FDCs) of antimicrobials were marketed in 2020. (Koya SF et al. Lancet 2019; 4: 100025)

    Although the widespread consumption of antibiotics has been blamed for the antimicrobial resistance (AMR) in India it is notable that there has been a 36% decline in DALYs on account of infection between 1990 to 2016 (https://www.healthdata.org/research-analysis/health-by-location/disease-burden-initiative-india) which is a paradox to the current line of thinking of regulators and doctors alike! 

    The subsequent blogs will attempt to dissect this topic of AMR and assess whether prescribing antimicrobials more freely in India is a curse or has been a boon for the Indian patient and population at large. 


    DR R K SANGHAVI

    Prophesied Enabler

    Experience & Expertise: Clinician & Healthcare Industry Adviser




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