ANTI-INFECTIVE AGENTS

Development of Anti-infective Therapy

• 1920s Paul Ehrlich worked on developing a synthetic chemical effective against infection-causing cells only.
Scientists discovered penicillin in a mold sample
• 1935 The sulfonamides were introduced

Mechanisms of Action
1. Interfere with biosynthesis of the bacterial cell wall
2. Prevent the cells of the invading organism from using substances essential to their growth and development
3. Interfere with steps involved in protein synthesis
4. Interfere with DNA synthesis
5. Alter the permeability of the cell membrane to allow essential cellular components to leak out

Mechanism of Anti-infective Agents

Anti-infective Activity
🞄 Anti-infectives vary in their effectiveness against invading organisms
🞄 Some are selective: they are effective only for a small number of organisms
🞄 Bactericidal: kill the cell
🞄 Bacteriostatic: prevent reproduction of the cell

Narrow Spectrum vs Broad Spectrum

1. Narrow spectrum of activity - Effective against only a few microorganisms with a very specific metabolic pathway or
enzyme
2. Broad spectrum of activity - Useful in treating a wide variety of infections

Human Immune Response

1. Goal of anti-infective therapy is reduction of the population of the invading organism
2. Drugs that eliminate all traces of any invading pathogen might be toxic to the host as well
3. Immune response is a complex process involving chemical mediators, leukocytes, lymphocytes, antibodies, and
locally released enzymes and chemicals

Problems with Treating Infections in Immunosuppressed Patients

• Anti-infective drugs cannot totally eliminate the pathogen without causing severe toxicity in the host
• These patients do not have the immune response in place to deal with even a few invading organisms

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Resistance
• Anti-infectives act on a specific enzyme system or biological process; many microorganisms that do not act on a
specific system are not affected by the particular drug
• This is considered natural or intrinsic resistance to that drug

Acquired Resistance
• Microorganisms that were once sensitive to the particular drug have begun to develop acquired resistance
• This results in serious clinical problems

Ways Resistance Develops

1. Producing an enzyme that deactivates the antimicrobial drug
2. Changing cellular permeability to prevent the drug from entering the cell
3. Altering transport systems to exclude the drug from active transport into the cell
4. Altering binding sites on the membranes or ribosomes, which then no longer accept the drug
5. Producing a chemical that acts as an antagonist to the drug

Preventing Resistance
1. Limit the use of antimicrobial agents to the treatment of specific pathogens sensitive to the drug being used
2. Make sure doses are high enough, and the duration of drug therapy long enough
3. Be cautious about the indiscriminate use of anti-infectives

Identification of the Pathogen

1. Identification of the infecting pathogen is done by culture
2. A culture of a tissue sample from the infected area is done
o A swab of infected tissue is allowed to grow on an agar plate
o Staining techniques and microscopic examination identify the bacterium
3. Stool can be examined for ova and parasites

Sensitivity of Pathogen
1. Shows which drugs are capable of controlling the particular microorganism
2. Important to be done for microorganisms that have known resistant strains
3. Along with a culture, identifies the pathogen and appropriate drug for treatment

Factors Affecting Prescribing Anti-infective Agents

1. Identification of the correct pathogen
2. Selection of the right drug
–One that causes the least complications for that particular patient
–One that is most effective against the pathogen involved
Combination Therapy
1. Use of a smaller dosage of each drug
2. Some drugs are synergistic
3. In infections caused by more than one organism, each pathogen may react to a different anti-infective agent
4. Sometimes, the combined effects of the different drugs delay the emergence of resistant strains

Adverse Reactions to Anti-infective Therapy

1. Kidney damage
2. Gastrointestinal (GI) tract toxicity
3. Neurotoxicity
4. Hypersensitivity reactions
5. Superinfections

Prophylaxis of Anti-infective Agents

• People traveling to areas where malaria is endemic
• Patients who are undergoing gastrointestinal or genitourinary surgery
• Patients with known cardiac valve disease, valve replacements, and other conditions requiring invasive procedures

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 ANTIBIOTICS

• Antibiotics are defined as: Chemicals that inhibit specific bacteria

Types of Antibiotics
1. Bacteriostatic - Substances that prevent the growth of bacteria
2. Bactericidal - Substances that kill bacteria directly

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 Signs of Infection
1. Fever
2. Lethargy
3. Slow-wave sleep induction
4. Classic signs of inflammation (redness, swelling, heat, and pain)

Goal of Antibiotic Therapy

Decrease the population of the invading bacteria to a point where the human immune system can effectively deal with the
invaders

Selecting Treatment
• Identification of the causative organism
• Based on the culture report, an antibiotic is chosen that is known to be effective at treating the invading organism

Bacteria Classification
1. Gram-positive - The cell wall retains a stain or resists decolorization with alcohol
2. Gram-negative - The cell wall loses a stain or is decolorized by alcohol
3. Aerobic - Depend on oxygen for survival
4. Anaerobic - Do not use oxygen

I. Aminoglycosides - A group of powerful antibiotics used to treat serious infections caused by gram-negative aerobic
bacilli
• Common medications:
– Amikacin (Amikin)
– Gentamicin (Garamycin)
– Kanamycin (Kantrex)
– Neomycin (Mycifradin)
– Streptomycin
– Tobramycin (Nebcin, Tobrex)

• Bactericidal
• Indications: treatment of serious infections caused by susceptible bacteria
• Action: inhibit protein synthesis in susceptible strains of gram-negative bacteria causing cell death
• Pharmacokinetics
– Poorly absorbed from the GI tract but rapidly absorbed after IM injection, reaching peak levels within 1 hour
– Widely distributed throughout the body, crossing the placenta and entering breast milk
– Excreted unchanged in the urine and have an average half-life of 2 to 3 hours
– Depend on the kidney for excretion and are toxic to the kidney
• Contraindications: Known allergies, renal or hepatic disease, and hearing loss
• Adverse effects: Ototoxicity and nephrotoxicity are the most significant
• Drug-to-drug interactions: Diuretics and neuromuscular blockers

II. Cephalosporins
• Similar to penicillin in structure and activity
• Action - Interfere with the cell-wall–building ability of bacteria when they divide
• Indication - Treatment of infection caused by susceptible bacteria
• Pharmacokinetics
– Well absorbed from the GI tract
– Metabolized in the liver, excreted in the urine
• Contraindications: Allergies to cephalosporins or penicillin
• Adverse effect: GI tract
• Drug-to-drug interactions: Aminoglycosides, oral anticoagulants, and ETOH

III. Fluoroquinolones
• Relatively new class of antibiotics with a broad spectrum of activity
• Indications: treat infections caused by susceptible strains of gram-negative bacteria, including urinary tract, respiratory
tract, and skin infections
• Actions: interferes with DNA replication in susceptible gram-negative bacteria, preventing cell reproduction
• Pharmacokinetics
– Absorbed in the GI tract

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 – Metabolized in the liver
– Excreted in the urine and feces
• Contraindications: Known allergy, pregnancy, and lactation
• Adverse effects: Headache, dizziness, and GI upset
• Drug-to-drug interactions: Antacids, quinidine, and theophylline

IV. Macrolides
• Antibiotics that interfere with protein synthesis in susceptible bacteria
• Indications: treatment of respiratory, dermatologic, urinary tract, and GI infections caused by susceptible strains of
bacteria
• Actions: bind to cell membranes causing a change in protein function and cell death; can be bacteriostatic or
bactericidal
• Pharmacokinetics
– Absorbed from the GI tract
– Metabolized in the liver, excreted in the bile to feces
• Contraindications: Allergy and hepatic dysfunction
• Adverse effects: GI symptoms
• Drug-to-drug interactions: Digoxin, oral anticoagulants, theophylline, and corticosteroids

V. Lincosamides
• Similar to macrolides but more toxic
• Action: Similar to macrolides
• Indications: Severe infections
• Pharmacokinetics: Well absorbed from the GI tract or IM
– Metabolized in the liver and excreted in the urine and feces
• Contraindications: Hepatic or renal impairment
• Adverse effects: GI reactions

VI. Monobactams
• Unique structure with little cross-resistance
• Action: Disrupts bacteria cell wall synthesis, which promotes the leakage of cellular content and cell death
• Indications: Treatment of infections caused by susceptible bacteria; UTI, skin, intra-abdominal, and gynecologic
infections
• Pharmacokinetics: Well absorbed from the IM injection; Excreted unchanged in the urine
• Contraindications: Allergy
• Adverse effects: GI and hepatic enzyme elevation

VII. Penicillins
• First antibiotics introduced for clinical use
• Action: Inhibit synthesis of the cell wall in susceptible bacteria, causing cell death
• Indications: Treatment of infections caused by streptococcal, pneumococcal, staphylococcal, and other susceptible
bacteria
• Pharmacokinetics: Well absorbed from the GI tract; Excreted unchanged in the urine
• Contraindications: Allergy; Caution in patients with renal disease
• Adverse effects: GI effects
• Drug-to-drug interactions: Tetracyclines and aminoglycosides

VIII. Sulfonamides
• Drugs that inhibit folic acid synthesis
• Action: Interfere with the cell-wall–building ability of dividing bacteria
• Indications: Treatment of infections caused by gram-negative and gram positive-bacteria
• Pharmacokinetics: Well absorbed from the GI tract; Metabolized in the liver and excreted in the urine
• Contraindications: Allergy and pregnancy
• Adverse effects: GI symptoms and renal effects related to the filtration of the drug
• Drug-to-drug interactions: Cross sensitivity with thiazide diuretics; Sulfonylureas

IX. Tetracyclines
• Developed as semisynthetic antibiotics based on the structure of a common soil mold
• Action: Inhibit protein synthesis in susceptible bacteria, preventing cell replication

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 • Indications: Treatment of various infections caused by susceptible strains of bacteria and acne, and when penicillin is
contraindicated for eradication of susceptible organisms
• Pharmacokinetics: Adequately absorbed from the GI tract; Concentrated in the liver and excreted unchanged in the
urine
• Contraindications: Allergy, pregnancy, and lactation
• Adverse effects: GI, skeletal: damage to bones and teeth
• Drug-to-drug interactions: Penicillin G, oral contraceptive therapy, methoxyflurane, and digoxin

X. Antimycobacterials
• Contain pathogens causing tuberculosis and leprosy
• Action: Act on the DNA of the bacteria, leading to lack of growth and eventual bacterial death
• Indication: Treatment of acid-fast bacteria
• Pharmacokinetics: Well absorbed from the GI tract; Metabolized in the liver and excreted in the urine
• Contraindications: Allergy and renal or hepatic failure
• Adverse effects: CNS effects and GI irritation
• • Drug-to-drug interactions: Rifampin and INH can cause liver toxicity

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