Untitled Quiz

Antimicrobial Chemotherapy

• Antimicrobial chemotherapy is a significant contribution to therapeutics, especially crucial in developing countries.
• Drugs in this category are designed to target and eliminate the infecting organism while minimizing harm to the patient.
• These drugs are called chemotherapeutic agents.

Principles of Chemotherapy

• Chemotherapy is the treatment of systemic infections with drugs selectively killing the infecting microbe without harming the host.
• Neoplastic disease treatment with drugs is also categorized as chemotherapy.
• Similar treatment approaches are used for both systemic infections and neoplastic diseases.
• Chemotherapeutic agents target specific differences between pathogens (or cancerous cells) and normal host cells.
• The goal of treatment is complete inhibition of growth for both microbes and cancer cells.

Introduction

• Chemotherapy is the treatment of systemic infections with drugs that selectively kill the infecting microorganism without significantly affecting the host.
• Treatment of neoplastic diseases also falls under the umbrella of chemotherapy.
• The common ground between treating systemic infections and neoplastic diseases lies in the use of chemotherapeutic agents.

Similarities

• Selective targeting of differences between the microbe or cancer cells and normal host cells is a shared goal in both treatments.
• Both aim for complete inhibition of the growth of the microorganism or cancer cell.
• Combination therapy is necessary due to the potential for microbes and cancer cells to develop resistance to single-drug therapies.

Antimicrobials

• Antimicrobials are a cornerstone in disease management, particularly in countries with limited resources.
• Derived from the Greek words "anti" (against), "mikros" (little), and "bios" (life), the term reflects the concept of inhibiting microbial life.
• Encompasses natural, semisynthetic, and synthetic drugs.
• The term “antibiotic” was introduced by Selman Waksman.

Antibiotic

• Antibiotic: A substance produced by microorganisms that selectively suppresses the growth of or kills other microorganisms at very low concentrations.
• This definition excludes other natural substances that inhibit microbes (like antibodies) or those produced by microbes needing high concentrations (like ethanol, lactic acid, and hydrogen peroxide).

Antimicrobials: Types

• Antimicrobials are classified as selective or nonselective.
• Non-selective antimicrobials include disinfectants, antiseptics, and preservatives.
• Selective antimicrobials are categorized by offending agent type (viral, bacterial, protozoan, fungal, and helminthic), effect (bacteriocidal or bacteriostatic), specific targets (cell wall synthesis, membrane, protein synthesis, or nucleic acid metabolism), chemical structure, and spectrum of activity.

Selective antimicrobials: Classification

• Anti-microbials are categorized based on these properties:
  • The type of offending agent they target.
  • How they affect the offending agent (e.g., Bacteriocidal or Bacteriostatic).
  • Their specific targets within the offending agent.
  • The chemical structure of the drug.
  • The spectrum of their activity.

Antimicrobials: Types (Specific Examples)

• Antivirals
• Antibacterials
• Antiprotozoals
• Antifungals
• Antihelminths (Anthelmintics)
• Bacteriocidal or Bacteriostatic based on effect

Bacteriostatic Antimicrobial Agents

• Bacteriostatic agents only inhibit the growth or multiplication of the microbe.
• The host's immune system is then involved in clearing the bacteria.
• The effectiveness of bacteriostatic agents is dependent on the host's immune system.

Bacteriocidal Antimicrobial Agents

• Bacteriocidal agents directly kill the microbe.
• The host's immune system might or might not be involved in the killing process.
• Examples include inhibitors of bacterial cell wall synthesis, cytoplasmic membrane, protein synthesis, or nucleic acid metabolism.

Chemical Structure

• Specific examples of antimicrobial chemical structures:
  • Sulfonamides (e.g., dapsone, para-aminosalicylic acid (PAS))
  • Diaminopyrimidines (e.g., trimethoprim, pyrimethamine)
  • Quinolones (e.g., nalidixic acid, norfloxacin, ciprofloxacin, levofloxacin)
  • Beta-lactam antibiotics (e.g., penicillins, cephalosporins, monobactams, carbapenems)
  • Tetracyclines (e.g., oxytetracycline, doxycycline).
  • Aminoglycosides (e.g., streptomycin, gentamicin, amikacin, neomycin)
  • Macrolide antibiotics (e.g., erythromycin, clarithromycin, azithromycin)
  • Polypeptide antibiotics (e.g., polymyxin-B, colistin, bacitracin)
  • Polyene antibiotics (e.g., nystatin, amphotericin B)
  • Azole derivatives (e.g., miconazole, clotrimazole, ketoconazole, fluconazole)

Spectrum of Activity

• Broad-spectrum antibiotics: e.g., tetracycline, chloramphenicol.
• Narrow-spectrum antibiotics: e.g., penicillin G, streptomycin, erythromycin.
• Extended-spectrum antibiotics: e.g., carbenicillin, mezlocillin, piperacillin, ticarcillin.

Historical Perspective

• Pre-antibiotic era: Infections considered trivial could quickly become deadly, resulting in high mortality rates from pneumonia and pyelonephritis. Treatment relied on infection control and herbs.
• 1910: Paul Ehrlich developed arsphenamine (Salvarsan), the first drug to reliably treat a human disease (syphilis). He coined the term "chemotherapy".
• 1928: Alexander Fleming discovered penicillin by observing the inhibition of bacterial growth around a mold.
• 1940s: Selman Waksman and his team systematically searched soil microbes to discover additional antibiotics (e.g., streptomycin). Following this, there was a boom in tetracycline- and macrolide-type antibiotics development.

Selective Toxicity

• Selective toxicity is a primary goal in chemotherapy.
• It describes the ability of an agent to cause more harm to the infecting microbe than to the host cell.
• This is achieved by exploiting differences between the invading organism and the host. This approach prioritizes targets unique to the microbe, such as prokaryotic ribosomes versus eukaryotic ribosomes (in protein synthesis inhibitors).
• The goal is to affect the pathogen in a way that minimizes damage to the host. Common pathways are not ideal targets, as they are shared between host and pathogen cells.
• Selectivity is also quantified by the chemotherapeutic index.

Selective Targeting

• Selective targeting of the bacterial peptidoglycan cell wall involves targeting enzymes involved in crucial stages of synthesis, such as cross-linking steps.
• Penicillin and related $\beta$-lactam antibiotics specifically target bacterial transpeptidase enzymes, minimizing harm to the host’s transpeptidases.
• Fungal cell wall components (like $\beta$-(1,3)-D-glucan) are also potential unique targets for anti-fungal agents (like echinocandins).

Mechanisms of Selective Targeting

• Selective targeting exploits differences in pathways or metabolic processes between the microbe and the host.

• Similar targets may be used, but subtle differences in target structure permit the drug to preferentially damage the target of the pathogenic organism.

• This strategy is exhibited in examples of inhibitors of bacterial protein synthesis.

• Examples of processes included here include:

  • Transcription (DNA to mRNA)
  • Translation (mRNA to protein)

Antibacterial Spectrum

• Broad-spectrum: Effective against many pathogens; often used when a pathogen has not yet been identified.
  • Examples: tetracyclines, some cephalosporins, fluoroquinolones, and carbapenems.
• Narrow-spectrum: Effective against a limited range of pathogens; chosen when a pathogen has been identified.
  • Examples: natural penicillins, penicillinase-resistant penicillins, monobactams.
• Extended-spectrum: Intermediate range of activity.
  • Examples: aminopenicillins, antipseudomonal penicillins, and some cephalosporins.

Mechanisms and Sites of Action

• Agents affecting cell walls, cell membranes, protein synthesis, and DNA are classified into primary groups.
• Drugs affecting cell wall synthesis (e.g., $\beta$-lactams, vancomycin, bacitracin, fosfomycin, cycloserine)
• Drugs targeting cell membranes (e.g., polymyxins, daptomycin)
• Inhibitors of protein synthesis (e.g., aminoglycosides, tetracyclines, macrolides, chloramphenicol, clindamycin).
• Drugs affecting DNA structure (e.g., sulfonamides, trimethoprim, quinolones, nitrofurantoin, nitroimidazoles).

Effect of Bacteria on the Drug

• Classifications include bacteriocidal (kill bacteria) and bacteriostatic (inhibit bacterial growth).
• Bacteriostatic drugs are sufficient for uncomplicated infections; bacteriocidal drugs are essential when bacterial growth becomes a significant threat to the patient (e.g., infections in areas that have limited immune response access, like the cerebrospinal fluid or endocardial vegetations).
• The concentration of the drug and bacterial factors have significant impacts on effectiveness.

Microorganisms Susceptibility

• Susceptibility testing is a secondary tool in confirming a correct diagnosis.
• Used as a secondary approach to initial treatment decisions.
• Disk diffusion methods (or the E-test)
• Broth dilution methods.

Antimicrobial Resistance

• Antimicrobial resistance (AMR) occurs when a microorganism is no longer responsive to a chemotherapeutic agent.
• Several mechanisms can lead to resistant bacterial strains:
  • Mutational resistance
  • Transmissible resistance.

Mechanisms of Genetic Resistance

• The transfer of genetic material responsible for drug resistance among bacterial cells occurs through three main processes:
  • Transduction
  • Transformation
  • Conjugation

Types of Resistant Organisms

• Drug-tolerant organisms: Exhibit reduced affinity of the drug target.
• Drug-destruction organisms: Produce enzymes that inactivate the drug.
• Drug-impermeable organisms: Have reduced drug entry or increased efflux mechanisms.

Promoters of Drug Resistance

• Prescribing antibiotics for viral infections
• Using broad-spectrum antibiotics inappropriately or with improper doses
• Self-treating with antibiotics
• Adding antibiotics to livestock feed.

Consequences of Antibiotic Resistance

• Therapeutic failure or treatment relapse
• Increased incidence of untreatable infections
• Pressure on medical professionals to use newer and potentially more costly/toxic treatments
• Competitive advantage for resistant microbes within a patient.

Antimicrobial Combination Therapy

• Combining drugs from different classes may enhance effectiveness, prevent resistance or increase therapeutic window.
• Different combinations of antimicrobial agents can affect bacterial infections in different ways:
  • Synergism (combined effect greater than either agent alone)
  • Additivity (combined effect equal to the sum of the individual effects)
  • Indifference (combined effect similar to the most effective agent alone)
  • Antagonism (combined effect less than the effect of the most effective agent alone).

Types of Anti-microbial Therapies

• Definitive therapy requires information on the causative agent and drug susceptibility.
• Empiric therapy is appropriate when information about the infectious agent is not yet available. Treatments are selected based on the probable cause and the need to consider the possibility of antimicrobial drug resistance.
• Prophylactic therapy aims to prevent infection by administering agents before (or immediately after) exposure that could lead to infections.

Failure of Anti-microbial Therapy

• Treatment failure is a complex issue. Causes can include:
  • Improper drug selection
  • Incorrect dosage
  • Incorrect administration route
  • Inappropriate treatment duration
  • Treatment starting too late
  • Patient non-compliance.
  • Insufficient additional treatment measures.