Antibiotics and Antimicrobials

• Antimicrobials are substances to kill or inhibit microbe growth
• Antimicrobials categorized as antibacterial, antiviral, antifungal and antiparasitic

Antibiotics

• Antibiotics are drugs from microorganisms and used to treat bacterial infections
• Alexander Fleming accidentally discovered Penicillin in 1928
• Penicillin is produced by the fungus Penicillium notatum and destroys Staphylococci
• The discovery of Penicillin started the antibiotic era
• Since the accidental discovery, multiple classes of antibiotics have been identified

Classifications of Antibiotics

Based on source:

• Natural antibiotics are obtained from microorganisms
• Semi-synthetic antibiotics are modified derivatives of a natural antibiotic
• Synthetic antibiotics are made completely in a laboratory

Based on chemical structure:

• Different classes are β-lactams, macrolides, tetracyclines, aminoglycosides, sulfonamides, and quinolones

Based on type of action:

• Bactericidal antibiotics kill microorganisms
• Bacteriostatic antibiotics inhibit growth of microorganisms

Based on spectrum of action:

• Broad-spectrum antibiotics are active against a wider range of bacteria
• Narrow-spectrum antibiotics are effective against one or a very limited range of bacteria

Mechanisms of Action of Antibiotics

• Inhibition of cell wall synthesis
• Alteration of cell membrane permeability
• Inhibition of protein synthesis
• Inhibition of nucleic acid synthesis
• Inhibition of essential metabolites

Complications of Antibiotics

• Toxic effects may occur e.g. Streptomycin is toxic to the 8th cranial nerve which can lead to deafness. Aminoglycosides are nephrotoxic, and Chloramphenicol may cause bone marrow depression
• Allergic reactions/hypersensitivity
• Elimination of normal flora may cause superinfection by pathogenic microbes that are resistant to the antibiotic given e.g. Candida, Clostridium difficile/antibiotic-associated diarrhea
• Indiscriminate use before diagnosis may mask symptoms and interfere with appropriate diagnosis
• Development of antimicrobial resistance

Causes of Antibiotic Failure

• Clinical conditions are not susceptible to antimicrobials, e.g. viral infection
• Mixed infection
• Wrong choice of antibiotics or use of antagonistic antibiotic combination
• Inadequate doses, duration, or route of administration
• Bacteria may be walled off within an abscess cavity so the drug cannot penetrate effectively, so surgical drainage becomes a necessary adjunct to chemotherapy
• Development of antimicrobial resistance

Antimicrobial Resistance (AMR)

• Unresponsiveness of organisms to administered drug
• It is one of the top global public health threats
• In 2019, bacterial AMR was directly responsible for 1.27 million global deaths

Origin of Antimicrobial Resistance

• Non-genetic origin: Organism in an inactive stage becomes physiologically resistant to the drug e.g. T.B. bacilli
• Genetic origin:
  • Natural (intrinsic) resistance: Some species are naturally insensitive due to species' impermeability to an agent or by its lack of a target site e.g. Mycoplasmas without a cell wall are intrinsically resistant to antimicrobials targeting the cell wall
  • Acquired resistance via mutation or gene transfer, such as R plasmid/plasmid, which carries genes for antibiotic resistance

Mechanisms of Antimicrobial Resistance

• Microorganisms produce enzymes such as β-lactamase that destroy the drug, which destroys the β-lactam ring of penicillins & cephalosporins
• Microorganisms alter their target structure for the drug e.g. alteration of penicillin receptors/penicillin-binding-proteins (PBPs)
• Microorganisms change their permeability to the drug e.g. resistance to polymyxins
• Bacteria actively pump the drug out using an efflux pump
• Alteration of the metabolic pathway inhibited by drug e.g. some bacteria bypass the PABA pathway and utilize performed folic acid, resisting sulphonamides

Different Patterns of Resistance

• Multidrug-resistant (MDR): resistance to at least one agent in 3 different antimicrobial classes
• Extensively drug-resistant (XDR): resistance to at least one agent in all except two different antimicrobial classes
• Pandrug-resistant (PDR): resistance to all agents in all antimicrobial classes
• Important examples of strains: Methicillin-resistant Staphylococcus aureus (MRSA), Vancomycin-Resistant Enterococci (VRE), Extended-spectrum β-lactamase (ESBLs) producing Gram-negative bacteria/E.coli, PDR Pseudomonas aeruginosa, PDR Acinetobacter spp

Effect of Overuse & Misuse of Antibiotics

• Prescribing multiple antibiotics when one would be sufficient, using antibiotics in self-limited infections, unnecessary prescribing of antibiotics for prophylaxis and overuse of broad-spectrum antibiotics
• Extensive use of precious antimicrobials in hospitals creates a fertile environment for the spread of antimicrobial-resistant germs
• In many countries, antibiotics are sold over the counter to the general public, encouraging inappropriate and indiscriminate use of the drugs
• Use of antibiotics in agriculture & animal feed to prevent infections and promote growth selects for resistant organisms in the animals and contributes to the pool of resistant organisms in humans

Antibiotic Combinations

• Combinations of more than one antibiotic within the same patient
• Advantages of drug combination include synergistic combination which increases treatment efficacy, which treats serious infection and prevents or delays drug resistance
• Mechanisms of drug synergism: one drug may affect the cell membrane and facilitate the entry of the second drug e.g. Penicillin & Aminoglycosides; one drug may inhibit the bacterial enzyme that destroys the second drug e.g. Ampicillin & Clavulinic acid

Antimicrobial Susceptibility Tests

• Disk-diffusion method (Kirby-Bauer) is the most widely used method, giving results that are qualitatively interpreted as resistant, intermediate, or susceptible
• Dilution methods provide quantitative determination of minimal inhibitory concentration (MIC), which is the lowest concentration/highest dilution of antibiotic that inhibits the growth of the organism/showing NO visible turbidity, and minimal bactericidal concentration (MBC) is the lowest concentration of antibiotic/highest dilution required to kill 99.9% of the bacteria, where MBC > MIC
• E test (Epsilometer test): Simple test to quantitatively determine MIC on agar medium
• Automated methods e.g. Vitek 2