Antibacterials I 2024 Lecture Notes PDF

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University of KwaZulu-Natal - Westville

2024

Ms H Parkar

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bacteriology antibiotics microbiology medical science

Summary

These lecture notes cover the basics of antibacterial agents, including discussions on antibiotics, antimicrobials, bacterial growth, resistance, and various associated factors. The focus is on the biological context and applications rather than mathematical calculations.

Full Transcript

ANTIBACTERIALS I Ms H Parkar ([email protected]) What is an Antibiotic? An agent which destroys or inhibits microbial growth Originally referred to any agent with biological activity against living micro- organisms including bacteria, fungi, protozoa...

ANTIBACTERIALS I Ms H Parkar ([email protected]) What is an Antibiotic? An agent which destroys or inhibits microbial growth Originally referred to any agent with biological activity against living micro- organisms including bacteria, fungi, protozoa %% Antimicrobials versus Antibiotics Antibiotic: low molecular substance produced by a microorganism that at a low concentration inhibit or kill other microorganisms Antimicrobial: any substance of natural, semisynthetic or synthetic origin that kills or inhibits the growth of microorganisms but causes little or no damage to the host Antimicrobials versus Antibiotics Antibiotics do not include antimicrobials which are: Synthetic (sulfonamides) Semisynthetic (amoxicillin) Plant (alkaloids) or animal derivatives (lysozyme) All antibiotics are antimicrobials but not all antimicrobials are antibiotics Antimicrobials versus Antibiotics Antimicrobials: all agents acting against all microorganisms Bacteria, viruses, fungi and protozoa Classification of antimicrobials based on Chemical structure Mechanism of action Site of action Activity against microorganisms Antibacterials Largest and most widely known class of antimicrobials What is Resistance? Bacteria are considered resistant to an antibiotic if the maximal level of that antibiotic that can be tolerated by the host does not halt their growth Some organisms are inherently resistant to an antibiotic Microbial species that are normally responsive to a particular drug may develop more virulent or resistant strains %% Some strains become resistant to more than one antibiotic Resistance %% Resistance “The world is heading towards a post-antibiotic era, in which common infections and minor injuries, which have been treatable for decades, can once again kill” - WHO Drug resistant tuberculosis now affects 630,000 people %% Ten countries have reported cases of gonorrhea that don't respond to any antibiotic Drug effectiveness is declining for serious diseases like malaria, HIV and the flu Bacteria Prokaryotes (single-celled or non-cellular organisms) Reproduce by fission (splitting into two or more parts) Lack a membrane-bound nucleus, mitochondria and other membrane-bound organelles Phyla: %% 1. Gram (+): no outer membrane with thick peptidoglycan layer 2. Gram (-): outer membrane 3. Unknown/ungrouped Gram-positive Bacteria Simple structure, 15-50 nm thick 50% peptidoglycan 40-45% acidic polymer (highly polar, negatively charged) 5-10% proteins and polysaccharides %% Gram-negative Bacteria Complex structure Periplasmic space Peptidoglycan layer (2 nm thick) Outer membrane: lipid bilayer Proteins lipoproteins linked to peptidoglycan and porins %% Complex polysaccharides Gram staining Differentiates bacterial species into gram-positive and gram-negative Detection of peptidoglycan in cell walls present in large amounts in the cell wall of Gram-positive bacteria Gram-negative cells also contain peptidoglycan, but a very small layer of it that is dissolved when the alcohol is added and therefore loses its colour % Gram-positive bacteria retain crystal violet dye (stained violet) Gram-negative bacteria do not, counterstain is added (safranin or fuchsine) which stains Gram-negative bacteria a pink colour Gram staining Procedure https://youtu.be/2gTaZUSvn58 Primary stain (crystal violet) applied to a heat-fixed smear of a bacterial culture Heat fixation kills some bacteria but is mostly used to affix the bacteria to the %% slide so that they don't rinse out during the staining procedure Iodide is the added which binds to crystal violet and traps it in the cell Rapid decolorization with ethanol or acetone Counterstaining with safranin or Carbol fuchsin (anaerobic bacteria) Bacterial morphology %% Bacterial Growth Curve %% Bacterial Growth Curve 1. Lag phase: Bacterial cells adapt to environment and LITTLE GROWTH OCCURS 2. Exponential growth phase also known as log phase: %% Bacterial cells flourish and multiply- EXPONENTIAL GROWTH 3. Stationary phase: Nutrient sources become scarce and toxic metabolites can accumulate- CELL GROWTH = CELL DEATH 4. Death phase: Growth decreases as cell death and hibernation increases- DECLINE IN CELL NUMBERS Factors Affecting Bacterial Growth 1. Solute and water activity Changes in osmotic concentration of the surroundings can affect growth 2. pH Each species has a definite pH growth range 3. Temperature Temperature affects sensitivity of enzyme-catalyzed reactions 4. Oxygen level Aerobe- grow in the presence of atmospheric O2 Anaerobe- grow in absence of atmospheric O2 5. Pressure Bacteria found in deep sea are subjected to high pressure 6. Radiation Many forms of electromagnetic radiation are very harmful to microorganisms Medically Important Microorganisms 1. Gram (+) and (-) cocci Spherical, ovoid shaped 2. Gram (+) and (-) bacilli Rod-shaped %% 3. Spirochaetes Double membraned long, helically coiled 4. Mycoplasma Lack a cell wall around cell membrane 5. Anaerobic organisms Obligate, aerotolerant, facultative Medically Important Microorganisms Micro-organism Main illness or disease state Gram-positive cocci Septic infections (bacteraemia, toxic shock), endocarditis, pneumonia Gram-negative cocci Sinusitis, gonorrhoea, meningitis Gram-positive bacilli Tetanus, gangrene, diphtheria Gram-negative bacilli Urinary tract infections, dysentery, typhoid, cholera, pneumonia, peptic ulcer associated helicobacter, influenza infections of the ear, sinus and respiratory tract, meningitis, syphilis, Lyme disease, tick-bite fever Spirochaetes (gram-negative) Lyme disease, relapsing fever, syphilis, yaws Clinically important microorganisms in decreasing frequency are: 1. Gram-negative bacilli 2. Gram-positive cocci 3. Gram-positive spore-forming and non-spore-forming bacilli 4. Gram-negative cocci Diagnosing Microbial Diseases 1. Direct or indirect identification Microscopy in combination with biochemical staining 2. Microbial culture Streak plate method 3. Biochemical tests Metabolic and enzymatic products 4. Molecular diagnostics PCR allows for identification and testing for specific nucleic acids Terminology Minimal Inhibitory Concentration (MIC) Minimum concentration needed to inhibit growth of organism Lower MIC, more effective Good indicator of potency Minimal Bacteriocidal Concentration (MBC) Minimum concentration needed to kill the organism Lower MBC, more effective Tolerance Reduced MIC and increased MBC Defined as an MBC/MIC ratio Terminology Selective toxicity Ability to inhibit growth or kill pathogen without harming host cell Takes advantage of biochemical differences Cidal Antimicrobials that kill Static Antimicrobials that inhibit growth and replication Selection of Antimicrobial Agents 1. Identification of infecting organism 2. Empirical therapy prior to identification 3. Antimicrobial susceptibility testing Narrow, broad or extended spectrum Mono- or combination therapy 4. Severity of infection 5. Drug-related factors 6. Site and type of infection 7. Patient factors 8. Cost of therapy Selection of Antimicrobial Agents Site of infection Lipid solubility of drug Molecular weight of drug Protein binding of drug Patient factors Pregnancy and lactation Immune system Renal / hepatic dysfunction Poor perfusion Age Selection of Antimicrobial Agents Types of infection Localized or extensive Mild or severe Superficial or deep Acute, sub-acute or chronic Extracellular or intracellular Severity of infection Infection with multiple organisms Sensitivity of organism Source of infection: community versus hospital acquired Chemotherapeutic spectra Narrow-spectrum antibacterial Activity against single or limited group of microorganisms Isoniazid Broad-spectrum antibacterial Activity against gram (+) and some gram (-) microorganisms Tetracycline and chloramphenicol Can drastically alter normal bacterial flora Extended-spectrum antibacterial Chemical modifications enhance activity Carbenicillin Types of Antibacterial Therapy Definitive or directed therapy Confirmed bacterial infections Narrow spectrum, lower toxicity, cheap and easy-to-administer Empirical therapy Restricted to critical cases and influenced by site of infection Time is inadequate for identification and isolation Septicaemia, immunocompromised, severe systemic infection, neutrophilic leukocytosis, raised ESR Drug that covers most probable infective agent Types of Antibacterial Therapy Prophylaxis Medical: tuberculosis, rheumatism, endocarditis Surgical: invasive medical procedures No single prophylaxis for all possible bacterial infections Narrow spectrum, highly specific drugs Rational dosing Concentration-dependent killing High peak plasma levels: rapid killing of pathogen Aminoglycosides, fluroquinolones, carbapenems Time-dependent killing Beta-lactams, glycopeptides, macrolides Post-antibiotic effect (PAE) Persistent suppression of microbial growth once antibiotic levels fall below MIC Time defined as time taken to achieve log-phase growth Long PAE: one dose per day PK/PD Approaches Pharmacokinetics Time course of antimicrobial concentrations Pharmacodynamics Relationship between concentration and antimicrobial effect MIC: indicator of potency but not time-course of activity PK/PD Approaches Key pharmacokinetic parameters Quantify serum level time course but not killing activity Peak serum level: Cmax Trough level: Cmin Area under serum concentration curve (AUC) PK/PD Approaches PK/PD parameters quantifying antimicrobial activity: Peak/MIC ratio T>MIC (time above MIC) 24 hours-AUC/MIC ratio Antibacterial Patterns 1. Type I 2. Type II 3. Type III %% Type I Antibacterials Concentration-dependent killing Prolonged persistent effects Ideal dosing regimen Maximize concentration Higher concentration: more extensive and faster the killing Predictors of antibiotic response 24h-AUC/MIC ratio Peak/MIC ratio efficacy Aminoglycosides, fluoroquinolones Type II Antibacterials Time-dependent killing and minimal persistent effects Demonstrate opposite properties to type I antibiotics Ideal dosing regimen Maximizes the duration of exposure Predictors of antibiotic response T>MIC (time above MIC) Beta-lactams, erythromycin Maximum killing T>MIC is at least 70% of dosing interval Type III Antibacterials Time-dependent killing Moderate to prolonged persistent effects Mixed properties Ideal dosing regimen Maximizes the amount of drug Predictors of antibiotic response 24h-AUC/MIC ratio Azithromycin, vancomycin Check your discussion board for this week’s activity %%

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