Antimicrobial Drugs

Introduction

Antimicrobial drugs are essential tools in the treatment and prevention of infectious diseases. This chapter explores the history, mechanisms, and clinical applications of antibiotics and other antimicrobial agents, focusing on their selective toxicity and the challenges posed by resistance.

The History of Chemotherapy

Key Concepts and Contributors

• Selective toxicity: The ability of a drug to target pathogens without harming the host.

• Chemotherapy: The use of chemicals to treat disease, especially infections.

• Antibiotic: A substance produced by a microbe that inhibits the growth of other microbes in small amounts.

• Antimicrobial drugs: Synthetic substances that interfere with microbial growth.

• Paul Ehrlich: Pioneered the concept of selective toxicity and developed the first chemotherapeutic agent (Salvarsan for syphilis).

• Alexander Fleming: Discovered penicillin in 1928, produced by Penicillium.

• 1932: Prontosil red dye used for streptococcal infections.

• 1940: First clinical trials of penicillin.

• Antibiotic resistance is a growing global problem.

Representative Sources of Antibiotics

Spectrum of Antimicrobial Activity

Definitions and Clinical Relevance

• Narrow spectrum of microbial activity: Drugs that affect a limited range of microbial types.

• Broad-spectrum antibiotics: Drugs that affect a wide range of gram-positive and gram-negative bacteria.

• Superinfection: Overgrowth of normal microbiota resistant to antibiotics, often occurring after broad-spectrum antibiotic use.

Table: Spectrum of Activity of Antibiotics and Other Antimicrobial Drugs

The Action of Antimicrobial Drugs

Modes of Action

• Bactericidal: Drugs that kill microbes directly.

• Bacteriostatic: Drugs that prevent microbes from growing.

Five Major Modes of Action

1. Inhibition of cell wall synthesis (e.g., penicillins, cephalosporins, bacitracin, vancomycin)

2. Inhibition of protein synthesis (e.g., chloramphenicol, erythromycin, streptomycin, tetracyclines)

3. Inhibition of nucleic acid replication and transcription (e.g., quinolones, rifampin)

4. Injury to plasma membrane (e.g., polymyxin B)

5. Inhibition of synthesis of essential metabolites (e.g., sulfanilamide, trimethoprim)

Common Antimicrobial Drugs

Inhibitors of Cell Wall Synthesis

• Penicillins: Contain a β-lactam ring; prevent cross-linking of peptidoglycans, especially in gram-positive bacteria.

• Natural penicillins: Extracted from Penicillium cultures; Penicillin G (injected), Penicillin V (oral); narrow spectrum; susceptible to β-lactamases.

• Semisynthetic penicillins: Chemically modified to resist β-lactamases (e.g., oxacillin, ampicillin).

• Cephalosporins: Broader spectrum; resistant to some β-lactamases.

• Polypeptide antibiotics: Bacitracin (topical), Vancomycin (last resort for resistant gram-positives).

Inhibitors of Protein Synthesis

• Chloramphenicol: Inhibits peptide bond formation by binding to the 50S subunit; broad spectrum; can suppress bone marrow.

• Aminoglycosides: Change the shape of the 30S subunit; can cause auditory damage (e.g., streptomycin, neomycin, gentamicin).

• Tetracyclines: Produced by Streptomyces spp.; interfere with tRNA attachment; broad spectrum; penetrate tissues; can suppress normal intestinal microbiota.

• Macrolides: Contain a macrocyclic lactone ring; narrow spectrum against gram-positives (e.g., erythromycin).

Injury to the Plasma Membrane

• Lipopeptides: Daptomycin (skin infections; attacks cell membrane).

• Polymyxin B: Topical; bactericidal; effective against gram-negatives; often combined with bacitracin and neomycin.

Inhibitors of Nucleic Acid Synthesis

• Rifamycin: Inhibits mRNA synthesis; penetrates tissues; used for tuberculosis.

• Quinolones and fluoroquinolones: Inhibit DNA gyrase (e.g., nalidixic acid, norfloxacin, ciprofloxacin); broad spectrum; relatively nontoxic.

Inhibitors of Synthesis of Essential Metabolites

• Sulfonamides: Antimetabolites that compete with para-aminobenzoic acid (PABA), inhibiting folic acid synthesis needed for nucleic acid and protein synthesis.

• Drug synergism: Combination of trimethoprim and sulfamethoxazole (TMP-SMZ) enhances effectiveness.

Effects of Drug Combinations

• Synergism: The effect of two drugs together is greater than the effect of either alone.

• Antagonism: The effect of two drugs together is less than the effect of either alone.

Antifungal Drugs

Agents Affecting Fungal Sterols

• Polyenes: Amphotericin B (produced by Streptomyces); toxic to kidneys.

• Azoles: Imidazoles (topical; treat cutaneous mycoses), Triazoles (systemic infections).

• Allylamines: Used for azole-resistant infections.

Agents Affecting Fungal Cell Walls

• Echinocandins: Inhibit synthesis of β-glucan.

Agents Inhibiting Nucleic Acids

• Flucytosine: Cytosine analog interferes with RNA synthesis; converted to 5-fluorouracil by cytosine deaminase.

Antiviral Drugs

Mechanisms of Action

• Entry and fusion inhibitors: Block receptors on host cells and prevent fusion of virus and cell.

• Uncoating, genome integration, and nucleic acid synthesis inhibitors: Prevent viral uncoating, inhibit viral DNA integration, and inhibit RNA/DNA synthesis (e.g., acyclovir).

Antiprotozoan and Antihelminthic Drugs

Antiprotozoan Drugs

• Quinine and chloroquine: Treat malaria by preventing detoxification of heme.

• Artemisinin: Kills Plasmodium (malaria); interferes with multiple parasite life cycle stages.

• Metronidazole (Flagyl): Treats anaerobic bacteria and protozoan infections (e.g., Trichomonas vaginalis, Giardia lamblia, Entamoeba histolytica).

Antihelminthic Drugs

• Niclosamide: Prevents ATP production; treats tapeworms.

• Praziquantel: Alters membrane permeability; treats tapeworms and flukes.

• Mebendazole and albendazole: Interfere with nutrient absorption; treat intestinal helminths.

• Ivermectin: Causes paralysis of helminths; treats roundworms, hookworms, mites.

Tests to Guide Chemotherapy

Methods for Determining Microbial Susceptibility

• Disk-diffusion method (Kirby-Bauer test): Paper disks with drugs placed on agar; zone of inhibition indicates sensitivity.

• E test (epsilometer test): Determines minimal inhibitory concentration (MIC).

• Broth dilution tests: Determine MIC and minimal bactericidal concentration (MBC).

• Antibiograms: Profiles of organism susceptibility/resistance to antibiotics; useful for tracking resistance patterns and guiding therapy.

Resistance to Antimicrobial Drugs

Mechanisms and Clinical Impact

• Persister cells: Microbes with genetic traits allowing survival during antibiotic exposure.

• Superbugs: Bacteria resistant to multiple antibiotics.

• Resistance genes: Often spread horizontally via plasmids or transposons (conjugation, transduction).

• Mechanisms of resistance: Enzymatic destruction/inactivation, prevention of penetration, alteration of drug target, rapid efflux.

Antibiotic Misuse and Safety

• Misuse includes outdated drugs, inappropriate use (e.g., for viral infections), use in animal feed, incomplete regimens, and sharing prescriptions.

• Therapeutic index: Ratio of risk to benefit; important for drug safety.

• Drug interactions (e.g., rifampin reduces effectiveness of contraceptives), organ toxicity, and risks to the fetus must be considered.

Summary Table: Major Classes of Antimicrobial Drugs

Key Equations and Chemical Structures

• β-lactam ring (penicillin core):

• Penicillinase reaction:

• Sulfonamide inhibition of folic acid synthesis:

Additional info:

• Antibiograms are increasingly used in clinical settings to guide empiric therapy and monitor resistance trends.

• Drug resistance mechanisms may involve multiple genetic and biochemical pathways, including efflux pumps and target modification.