chapter 12

Section 12.1: Principles of Antimicrobial Therapy

Learning Outcomes

1. Main Goal of Antimicrobial Treatment: To administer a drug to an infected person which destroys the infective agent without harming the host’s cells.
2. Sources of Common Antimicrobial Drugs: Identification of the most frequently used antimicrobial agents.
3. Methods for Testing Antimicrobial Susceptibility: Summarization of at least two methods for assessing antimicrobial susceptibility in microorganisms.
4. Therapeutic Index: Definition of the therapeutic index and clarification on whether a high or low index is preferable in drug therapy.
5. Selective Toxicity: Explanation of the concept of selective toxicity in antimicrobial therapy.
6. Major Targets of Antimicrobial Agents: Identification of the five major targets of contemporary antimicrobial agents, along with listing major drugs associated with each target.
7. Selective Toxicity Categories: Identification of drug categories most selectively toxic towards pathogens and explanation of the reasoning.
8. Drug Toxicity vs. Allergic Reactions: Distinction between drug toxicity and potential allergic reactions to these drugs.
9. Superinfection: A clear definition of superinfection and a summary of how it can develop in patients.

Goal of Antimicrobial Chemotherapy

• The ultimate objective is to give a medication that effectively eradicates the causative agent of an infection while safeguarding the host's cells. It is important to note that the ideal drug, which would perfectly achieve this goal without any adverse effects, does not exist.

Characteristics of the Ideal Antimicrobial Drug

1. Toxicity: It must be toxic to the infecting microbe but non-toxic to the host organism.
2. Microbicidal vs. Microbiostatic: The drug should be microbicidal (capable of killing microbes) rather than microbiostatic (merely inhibiting growth).
3. Solubility: It should be soluble in body fluids to ensure effective delivery.
4. Potency: The drug must remain potent long enough to allow effective action within the body, without being degraded or excreted too quickly.
5. Resistance: There should be a slow or non-existent development of resistance to the drug by pathogens.
6. Assistance: The drug should complement or enhance the activity of the host’s immune defenses.
7. Site Delivery: It should efficiently reach the site of infection.
8. Health Impact: The drug should not adversely affect the host’s health by causing allergies or creating susceptibility to other infections.

Terminology of Antimicrobials

1. Prophylaxis: The preventive use of a drug to avert infection in a person at high risk.
2. Antimicrobial Chemotherapy: The application of drug therapies to manage infections in patients.
3. Antimicrobials: A broad term for all drugs that target microorganisms, covering various types of microbial agents.
4. Antibiotics: Naturally occurring or laboratory-derived substances that inhibit or destroy microbes, primarily targeting bacteria.
5. Semisynthetic Drugs: Antibiotics that have been chemically altered in the lab after extraction from natural sources.
6. Synthetic Drugs: Compounds entirely produced through chemical reactions in laboratories.
7. Narrow-Spectrum Antimicrobials: Effective against limited groups of microorganisms, e.g., targeting primarily gram-positive bacteria.
8. Broad-Spectrum Antimicrobials: Active against a wide range of organisms, including both gram-positive and gram-negative microbes.

Origins of Antimicrobial Drugs

• Antibiotics originate as metabolic products of bacteria (e.g., Streptomyces) and fungi. These substances, by inhibiting the growth of other microorganisms, reduce competition for nutrients and space in their environment, thus offering a selective advantage that promotes their survival through evolutionary processes.

Starting Treatment for Infections

Before commencing antimicrobial therapy, it is crucial to establish the following:

1. Identity of the Microorganism: Identification of the specific pathogen causing the infection should be undertaken before any drug administration.
2. Susceptibility: Assessing the microorganism's susceptibility (sensitivity) to different antimicrobial agents is necessary.
3. Patient Health Status: Understanding the overall medical condition of the patient is essential to tailor the treatment effectively.

Testing for Drug Susceptibility

Kirby–Bauer Technique

• This method involves spreading the surface of a plate containing special growth medium with the test bacterium. Subsequently, small discs impregnated with premeasured quantities of antibiotics are placed onto the bacterial lawn. Following incubation, a zone of inhibition may appear, which is measured from its edges, providing information on the bacterium's susceptibility.
• Antibiogram: A systematic profile indicating patterns of antimicrobial sensitivity in a particular bacterium based on its response to various drugs.

Results Interpretation in Kirby-Bauer Test

• Sample results display different zones of inhibition based on specific drugs:
  • Erythromycin: >18 mm = S, <13 mm = R; Example result = 15 mm (Intermediate)
  • Penicillin G: >29 mm = S, <20 mm = R; Example result = 10 mm (Resistant)
  • Streptomycin: >15 mm = S, <11 mm = R; Example result = 11 mm (Resistant)
  • Vancomycin: >12 mm = S, <9 mm = R; Example result = 15 mm (Sensitive)

Tube Dilution Tests

• Minimum Inhibitory Concentration (MIC): This term defines the smallest concentration of drug (highest dilution) that visibly inhibits the growth of a microorganism; essential for determining effective dosages and useful for comparative indices against other antimicrobials. Automated machinery in clinical laboratories typically performs these tests.

The Therapeutic Index (TI)

• The Therapeutic Index (TI) is defined as the ratio of the toxic dose of a drug to its effective dose:
  • $ext{TI} = \frac{ ext{Toxic dose}}{ ext{Effective dose}}$
• A smaller TI indicates a greater risk for adverse effects or toxicity, making a TI of 1.1 riskier than a TI of 10.
• Therapeutic Window: Refers to the range in blood levels within which the drug exerts its desired effect while remaining non-toxic.

Patient History Considerations

• Factors that imperative to consider include:
  • Preexisting conditions that may influence drug activity or patient response.
  • Previous allergic reactions to certain drug classes.
  • Underlying renal or hepatic diseases affecting metabolism.
  • Special precautions for infants, elderly, and pregnant patients due to altered pharmacokinetics.

Selection of Antimicrobial Drugs

Choosing a drug is an art that incorporates the following aspects:

1. Understanding synergistic and antagonistic effects of various drugs.
2. Recognizing the impact of antimicrobials on the human microbiome.

Selective Toxicity

• Definition: A pivotal principle in antimicrobial treatment that asserts antimicrobial drugs should effectively target microbial cells while sparing host tissues. The ideal antimicrobial agents inhibit or destroy microbial functions without damaging vertebrate cells.
• Examples of Selective Toxicity: Penicillins inhibit the synthesis of bacterial cell walls, a structure unique to bacteria and absent in human cells.

Mechanisms of Drug Action on Microbes

1. Cell Wall Synthesis: Inhibition of cell wall synthesis (e.g., penicillins and cephalosporins).
2. Nucleic Acid Function: Interference with nucleic acid structure and function.
3. Protein Synthesis: Disruption of protein synthesis, especially at ribosomal sites.
4. Cell Membrane Function: Inhibition of cell membrane integrity and function.
5. Folic Acid Synthesis: Suppression of folic acid synthesis critical for microbial metabolism.

Effects of Antimicrobials on Humans

• Adverse reactions to antimicrobial drugs occur in at least 5% of patients, including:
  • Direct tissue damage via toxicity.
  • Allergic responses.
  • Imbalance of normal microbial flora leading to complications.

Major Adverse Toxic Reactions

• Examples of toxic reactions from common antimicrobial agents:
  • Penicillin G: Skin abnormalities.
  • Cephalosporins: Can inhibit platelet function and cause nephritis.
  • Sulfonamides: Risk of crystal formation in kidneys, blockage of urine flow, and hemolysis.
  • Polymyxins: Damage kidneys and weaken muscle responses.
  • Quinolones (ciprofloxacin): Can cause headaches, dizziness, and gastrointestinal distress.

Antibiotic-Induced Microbiota Disruption

• Antimicrobial treatments can disrupt the balance of beneficial microbiota, which may allow for opportunistic pathogens to overgrow. This phenomenon leads to a superinfection, examples include:
  • Vaginal Candida Infections: Following antibiotic use.
  • Antibiotic-Associated Colitis: Due to overgrowth of Clostridioides difficile post-antibiotic therapy.

Concept Check - Section 12.1

1. List and describe four characteristics of an ideal antimicrobial drug.
2. Identify the test that utilizes large agar plates, a bacterial lawn, and antibiotic-infused disks to show antimicrobial susceptibility.
3. True/False: An antibiotic with a therapeutic index of 4 is less toxic than one with a therapeutic index of 40.
4. True/False: An antibiotic acting on the bacterial cell wall will have no effect on human cells.

Section 12.2: Survey of Major Antimicrobial Drug Groups

Learning Outcomes

1. Distinction: Understand the difference between broad-spectrum and narrow-spectrum antimicrobials and the significance of this distinction.
2. Development of β-Lactam Drugs: Trace and identify which microbes are affected.
3. β-Lactamases and Resistance: Describe what β-lactamases are and their importance in drug resistance.
4. Examples of Other β-Lactams: Know additional examples of β-lactam antibiotics.
5. Cell Wall Antibiotics: Describe common non-β-lactam antibiotics targeting cell walls.
6. Targets for Protein Synthesis Inhibitors: Identify targets for several antibiotics impacting protein synthesis.
7. Cellular Target of Quinolones: Specify targets and give two examples of quinolone drugs.
8. Drugs Targeting Cellular Membrane: Name two drugs that affect cellular membrane integrity.
9. Biofilm Treatment: Describe unique strategies for treating biofilm infections.
10. Categories of Antifungal Agents: Name four main categories of antifungal agents and provide examples.
11. Antiprotozoal and Antihelminthic: List drugs used for these conditions.
12. Modes of Action of Antiviral Drugs: Describe major strategies of antiviral drugs.

Major Antimicrobial Drug Groups

Broad-Spectrum vs. Narrow-Spectrum Drugs

• Broad-Spectrum Drugs: Effective against multiple bacterial groups, e.g., tetracyclines.
• Narrow-Spectrum Drugs: Target specific groups only, e.g., polymyxin and penicillin.

Spectrum of Activity for Antibiotics

• Mycobacteria: Tuberculosis.
• Gram-Negative Bacteria: Salmonellosis, plague, gonorrhea.
• Gram-Positive Bacteria: Strep throat, staph infections.
• Chlamydias and Rickettsias: Chlamydia, trachoma, rocky mountain spotted fever.

Antibacterial Drugs Targeting the Cell Wall: The Penicillin Group of β-Lactams

• β-Lactams: A diverse class of antibiotics, consisting of penicillin and its derivatives.
• Subgroups of Penicillins:
  1. Penicillins G and V: Natural forms, treatment of gram-positive cocci and some gram-negative bacteria.
  2. Ampicillin, Carbenicillin, Amoxicillin: Broad-spectrum semisynthetics effective against gram-negative rods.
  3. Methicillin, Nafcillin: Used for penicillinase-producing bacteria.
  4. Clavulanic Acid: Added to penicillins to combat β-lactamase-producing bacteria.

Cephalosporins and Others

• Isolated from Cephalosporium acremonium in the 1940s.
• Have a β-lactam ring and similar action to penicillins;
• Carbapenems: Reserved for special conditions when other drugs fail; they are powerful but potentially toxic.
• Examples of Other drugs targeting the cell wall include Bacitracin, Isoniazid, and Vancomycin.

Concept Check - Section 12.2

1. Name one antibiotic for each group: • Drugs targeting the cell wall • Drugs that inhibit protein synthesis • Drugs affecting folic acid synthesis • Drugs targeting DNA or RNA • Drugs impacting the cell membrane.
2. True/False: Antifungal and antihelminthic drugs can also harm human cells.
3. True/False: There are as many antiviral drugs as antibiotics available.

Section 12.3: Antimicrobial Resistance

Learning Outcomes

1. Microbial Resistance Acquisition: Describe two methods microbes use to develop resistance, intrinsic vs. acquired.
2. Mechanisms Used: List five cellular or structural mechanisms utilized by microbes to resist antimicrobials.
3. Novel Strategies: Discuss at least three new strategies under investigation for combating microbial resistance.

Acquisition of Drug Resistance

• Drug Resistance: This refers to the adaptive response by which microorganisms start to tolerate levels of drugs that would usually inhibit their growth. It arises from genetic diversity within microbial populations, leading to either intrinsic or acquired resistance.
  • Intrinsic Resistance: Occurs naturally in bacteria that produce the antibiotics.
  • Acquired Resistance: Happens in bacteria pre-sensitized to a drug, resulting from mutations or genetic transfer mechanisms.

Mechanisms of Drug Resistance

1. Enzyme Synthesis: Bacteria synthesize new enzymes that deactivate the drugs, e.g., penicillinase.
2. Decreased Drug Permeability: Mutations can lead to changes that decrease drug entry into bacterial cells.
3. Immediate Drug Elimination: Newly acquired genes allow bacteria to expel drugs promptly.
4. Reduced Binding Affinity: Mutations could lead to fewer or reduced affinity binding sites for the drugs.
5. Pathway Alteration: Some bacteria can shut down metabolic pathways affected by drugs or use alternative pathways.

Natural Selection and Drug Resistance

• Natural selection plays a significant role in the evolution of drug resistance. Under drug pressure, sensitive bacteria are eliminated, which enables resistant strains to proliferate. Over time, resistant traits become dominant within microbial populations.

Human Role in Antimicrobial Resistance

• Vast quantities of antimicrobial prescriptions, particularly for viral infections, contribute significantly to developing resistance.
• Antibiotic overuse in agriculture, along with exposure in hospital settings, exacerbates the situation.

Concept Check - Section 12.3

1. True/False: It is possible for bacteria to be resistant to antibiotics without previous exposure to these drugs.
2. Enumerate and describe five mechanisms by which antibiotic resistance may occur.
3. True/False: The bulk of antibiotics prescribed for humans target viral infections.
4. Nearly 80% of antibiotics in the U.S. are given to _______.
5. _______ have been effectively used in Eastern Europe to treat bacterial infections.

Conclusion

This detailed account encompasses fundamental principles of antimicrobial treatment, mechanisms of actions, resistance profiles, and the implications of drug therapy, providing comprehensive learning resources for microbiology.