9. Antimicrobial Therapy

Define and describe chemotherapy.

Treatment of systemic/topical infection with drugs that have selective toxicity for an invading pathogen without harming the host cells

Define and describe antibiotics.

Produced by microorganisms; selectively suppress the growth of/kill other microorganisms at very low concentrations

Define and describe antimicrobial agents (AMA).

• AMA = antibacterial agents + antibiotics

• Broad term

• Includes drugs synthesized (antibacterial agents) as well as those obtained from fermentation of microorganisms (antibiotics)

List the classifications of AMAs.

1. Chemical structure: sulfonamide, quinolones

2. Type of action

3. Mechanism of action

4. Antimicrobial activity

5. Spectrum of activity

6. Source (antibiotic obtained from): fungi, bacteria, etc

List the classifications of AMAs based on their type of action.

1. Bacteriostatic

2. Bactericidal

Define and describe bacteriostatic.

• Arrest the growth and replication of bacteria, thus limit spread of infection

• Adequate in uncomplicated infections (host cells themselves help in eradicating microorganism)

Define and describe bactericidal.

• Kill/irreversibly damage the multiplying bacteria so that total number of viable bacteria decreases

• Fungistatic and fungicidal also exist

• Some primarily static drugs may become cidal at higher concs. (sulfonamides and erythromycin)

List the classifications of AMAs based on their mechanisms of action.

1. Inhibit cell wall synthesis

2. Cause alteration of cell membrane integrity

3. Inhibit ribosomal protein synthesis

4. Suppression of DNA synthesis:

   • By inhibiting the synthesis of folate

   • By inhibiting either DNA/RNA polymerase

   • By inhibiting DNA gyrase

Mechanism of Action

List drugs that inhibit cell wall synthesis.

β-lactams

1. Penicillins

2. Cephalosporins

Mechanism of Action

List drugs that cause alteration of cell membranes integrity.

1. Polymyxins

2. Antifungals

Mechanism of Action

List drugs that inhibit ribosomal protein synthesis.

1. Tetracyclines and Aminoglycosides (bind to 30S ribosomal unit)

2. Chloramphenicol (inhibits 50S ribosomal unit)

Mechanism of Action

List drugs that suppress DNA synthesis by inhibiting the synthesis of folates.

Sulfonamides

Mechanism of Action

List drugs that suppress DNA synthesis by inhibiting either DNA/RNA polymerase.

1. Acyclovir

2. Anticancer drugs

3. Antiretroviral drugs

Mechanism of Action

List drugs that suppress DNA synthesis by inhibiting DNA gyrase.

Ciprofloxacin

List the classifications of AMAs by antimicrobial activity.

1. Anti-bacterials

2. Anti-fungal AMAs

3. Antiviral

4. Antiprotozoal

5. Antihelmintic

Antimicrobial Activity

List antibacterial drugs.

1. Penicillins

2. Cephalosporins

3. Fluoroqinolones

Antimicrobial Activity

List antifungal AMAs.

1. Fluconazole

2. Griseofulvin

Antimicrobial Activity

List antiviral drugs.

1. Acyclovir

2. Zidovudine

Antimicrobial Activity

List antiprotozoal drugs.

1. Chloroquine

2. Metronidazole

Antimicrobial Activity

List antihelmintic drugs

Mebendazole

How are AMAs classified by their spectrum of activity?

List the concentration and time-dependent effects of AMAs.

1. Toxicity

2. Hypersensitivity reactions

3. Nutritional deficiencies

4. Drug resistance

5. Super-infections

Describe the local and systemic toxicity of AMAs.

• Local irritancy: at site of administration

• Systemic toxicity: almost all produce dose-related and predictable organ toxicities

What does high therapeutic index mean? Which AMAs have a high therapeutic index?

• Many-fold increase in dose without apparent damage to host cells

• Penicillins

• Cephalosporins

What does low therapeutic index mean? Which drugs have low therapeutic index?

• Does have to be individualized and toxicity watched for

• Aminoglycosides: 8th cranial nerve damage and kidney toxicity

What is very low therapeutic index? Which drugs have very low therapeutic index?

• Use is highly restricted to conditions where no suitable alternative available

• Polymyxin B: neurological and renal toxicity

Describe hypersensitivity reactions in relation to AMAs. Which AMAs can cause hypersensitivity reactions?

• All AMAs capable of causing hypersensitivity reactions

• Unpredictable and unrelated to dose

• Rashes to anaphylactic reactions

• Penicillin, cephalosporins, fluoroquinolones

Describe nutritional deficiencies in relation to AMAs. Which AMAs can cause them?

• Vitamin B complex and Vitamin K synthesized by intestinal flora

• Prolonged use of AMAs can alter flora; may produce vitamin deficiencies

• E.g. neomycin

Define drug resistance and list the 2 mechanisms of drug resistance.

• Unresponsiveness of microorganism to an AMA

• Phenomenon of tolerance seen in higher organisms

• Mechanisms:

1. Natural

2. Acquired

Describe the natural mechanism of drug tolerance.

• Some microbes always resistant

• Lack metabolic process/target site

• E.g. Gram negative bacilli are normally unaffected by penicillins

Describe the acquired mechanism of drug resistance.

• Development of resistance by an organism that was previously sensitive

• Due to use of AMA over a period of time

• Depends on drug and microorganism

• E.g. Gonococci quickly developed resistance to sulfonamides, slowly-gradually to penicillins)

Describe superinfections.

• Appearance of new infection as a result of AM therapy

• Microbial flora of body get affected; contributes to host defense by inhibiting pathogenic organisms

• Non-pathogenic component of flora, which is not inhibited by drug, may predominate and invade

• More difficult to treat; manifested as antibiotic-induced diarrhea and colitis

Which antibiotics are commonly associated with superinfections?

Broad/extended spectrum antibiotics:

1. Tetracyclines

2. Ampicillin

3. Chloramphenicol

Superinfections due to ___________ ________ or _______ are more serious, leading to pseudomembranous colitis.

Clostridium difficile

Candida

Define and describe chemoprophylaxis.

• Use of AMAs for preventing the setting of an infection/suppressing contracted infection before it becomes clinically manifest

• Often done against all organisms capable of causing infections

List the 3 conditions under which chemoprophylaxis is done.

1. Prophylaxis against specific organisms

2. Prevention of infections in high-risk situations

3. Prevention of infection in general

Chemoprophylaxis

Describe prophylaxis against specific organisms.

• Highly satisfactory

• Choice of drug is clear-cut

• E.g. tuberculosis (children, HIV positive cases: isoniazid alone or with rifampicin is recommended)

• HIV infection (health care workers: zidovudine + lamivudine)

Chemoprophylaxis

Describe prevention of infections in high risk situations.

• May be valid, satisfactory in certain situation, but controversial in others

• E.g. dental extraction, tonsillectomy, endoscopies

• Appropriate prophylaxis with amoxicillin/clindamycin may be given few hours before and after

Chemoprophylaxis

Describe prevention of infections in general.

• Highly unsatisfactory in most cases

• E.g. in neonates after prolonged after prolonged delivery, mothers after normal delivery to prevent post partum infections, viral URTI to prevent secondary bacterial invasion etc

• AM prophylaxis may be hazardous (infection by resistant organisms, chances of suprainfections)

Define antimicrobial combination and when they are done.

• More than one AMAs used

• Frequently used

• Should be done with specific purpose, not blindly

List advantages of antimicrobial combination.

1. To achieve synergism (supra-additive effect) e.g. Sulfonamide + trimethoprim, β-lactamase inhibitor + amoxicillin

2. To reduce severity or incidence of adverse effects: if combination is synergistic, then dose is reduced, required with AMAs with low safety margin

3. To prevent emergence of resistance: valid primarily for chronic infections needing prolonged therapy

4. To broaden the spectrum of antimicrobial action: in mixed infections, initial treatment of severe infections, etc

List the disadvantages of AMA combination.

1. Increased incidence and variety of adverse effects; toxicity of one agent may be enhanced by another

2. Increased chances of suprainfections

3. If inadequate dose of non-synergistic drugs are used, then chances of resistance may be promoted

4. Increased cost of therapy

5. Provide casual outlook in diagnosis of infections (rather than rational)