Antimicrobial Therapy Notes

Antimicrobials

• Chapter 12

• Anti-biotics, Pro-biotics

Exam Preparation

• Focus on being familiar with:

  • Drug names

  • Classification of drugs

  • Mode of action (how medications work)

  • Applications of each drug

Principles of Antimicrobial Therapy

• Administer drugs to infected individuals to destroy microbes without harming the host's cells.

• Antimicrobial drugs are produced naturally or synthetically.

Characteristics of the Ideal Antimicrobial Drug

• Selectively toxic to the microbe but nontoxic to host cells

• Microbicidal rather than microbistatic

• Relatively soluble; functions even when highly diluted in body fluids

• Remains potent long enough to act and is not broken down or excreted prematurely

• Doesn't lead to the development of antimicrobial resistance

• Complements or assists the activities of the host's defenses

• Remains active in tissues and body fluids

• Readily delivered to the site of infection

• Reasonably priced

• Does not disrupt the host's health by causing allergies or predisposing the host to other infections

Terminology

• Antimicrobial: All-inclusive term for any antimicrobial, regardless of its origin.

• Semisynthetic drugs: Drugs that are chemically modified after being isolated from natural sources.

Origins of Antibiotic Drugs

• Antibiotics are common metabolic products of aerobic spore-forming bacteria and fungi.

  • Examples:

    • Bacteria in genera Streptomyces and Bacillus

    • Molds in genera Penicillium and Cephalosporium

Spectrum of an Antimicrobic Drug

• Spectrum: Range of activity of a drug.

• Narrow-spectrum: Effective on a small range of microbes, targeting specific cell components found only in certain microbes.

• Broad-spectrum: Greatest range of activity, targeting cell components common to most pathogens.

Classification of Drug Action

1. Cell Wall Inhibitors

2. Disruption of Cell Membrane Structure or Function

3. Inhibition of Nucleic Acid Synthesis, Structure, or Function

4. Inhibition of Protein Synthesis

5. Blocks on Key Metabolic Pathways

Cell Wall Inhibitors

• Block synthesis and repair of the cell wall.

• Examples:

  • Penicillins

  • Cephalosporins

  • Vancomycin

  • Bacitracin

  • Monobactams/carbapenems

  • Fosfomycin

  • Cycloserine

  • Isoniazid

Beta-Lactam Drugs

• Examples of cell wall inhibitors.

Beta-Lactam Antimicrobials

• All contain a highly reactive 3-carbon, 1-nitrogen ring (beta-lactam ring).

• The beta-lactam ring resembles components needed for peptidoglycan synthesis.

Antibiotics that Inhibit Cell Wall Synthesis: Penicillins

• Natural Penicillins:

  • Penicillin G (injectable)

  • Penicillin V (oral form)

• Resistance: Beta-lactamases (penicillinases).

Penicillins (Narrow Spectrum)

• Penicillin G:

  • Injectable form

  • Used to treat syphilis in adults and children

  • Not typically used to treat infections by Gram-negative rods

• Penicillin V:

  • Oral form

  • Application: Oropharyngeal infections

Cephalosporins

• Grouped into "generations" based on their properties.

• Mode of Action: Block enzymes called penicillin-binding proteins (PBPs).

• Route of administration: IV or IM (intravenous or intramuscular injection).

• All medications begin with prefixes: ceph-, kef-, cef-.

• Advantage over Penicillins:

  • The beta-lactam ring is more resistant to beta-lactamases.

  • Broader spectrum of activity.

• All are ineffective against MRSA, except for 5th generation cephalosporins.

Cephalosporin Generations

• First generation:

  • Cephalothin

  • Most effective against Gram-positive cocci (Streptococcus pyogenes, but NOT MRSA) and some Gram-negative bacteria (e.g., E. coli).

• Second generation:

  • Cefaclor

  • More effective against Gram-negative bacteria, used for respiratory tract infections and UTIs.

• Third generation:

  • Cefixime

  • Broad-spectrum activity against enteric bacteria and some beta-lactamases.

  • Used for nosocomial infections.

  • Ceftriaxone is the standard treatment for resistant gonorrhea.

  • Some can cross the blood-brain barrier.

• Fourth generation:

  • Cefepime

  • Widest range of activity.

  • Effective against Pseudomonas aeruginosa.

  • Can cross the blood-brain barrier (often used for pneumonia and UTIs).

• Fifth generation:

  • Ceftaroline

  • FDA approved in 2016.

  • Administered IV.

  • The only class effective against MRSA (skin & soft tissue infections-SSTI) & pneumonia

Semi-synthetic Penicillins

• Examples:

  • Methicillin

  • Amoxicillin

Amoxicillin

• Semi-synthetic penicillin.

• Moderate range of activity (mostly Gram-positive organisms).

• Advantage: Resistant to acid in the stomach.

• Application:

  • First drug of choice for otitis media ("inflammation of the middle ear"); 75% of children get it before age 3.

  • Also used for Streptococcal pharyngitis.

Methicillin

• Spectrum of activity: Narrow.

• Created to treat Staphylococcus aureus strains that produce beta-lactamase enzymes.

• Currently: Most S. aureus strains are resistant (MRSA).

• This drug is discontinued in the U.S.

Non-Beta-Lactam Cell Wall Inhibitors

• Vancomycin

• Anti-mycobacterial Drugs:

  • Isoniazid

  • Ethambutol

Vancomycin

• Spectrum of Activity: Narrow (injectable).

• Mode of Action: Interferes with alanine/alanine amino acids in cross bridges (binds to the end of the cross-bridge).

• Application:

  • Treatment of MRSA; must be given IV.

  • Can be used before surgery (e.g., hip replacement) or for treatment of endocarditis.

  • Only given orally for colitis.

• Disadvantage: Inactive against Gram-negative infections.

Anti-mycobacterial Drugs

• Used to treat Mycobacterium tuberculosis.

Isoniazid (INH)

• Mode of Action: Blocks the production of enzymes (fatty acid synthase) involved in the synthesis of mycolic acid.

• Safe during pregnancy.

• Disadvantage: Causes hepatotoxicity (i.e., hepatitis).

Ethambutol (Myambutol)

• Mechanism of Action: Interferes with the integration of mycolic acid into the cell wall.

• Used in combination with Isoniazid.

• Issue: Patient compliance.

• Directly Observed Therapy: Patients receive medications within the clinic!

Cell Membrane Inhibitors

• Polymyxins

Polymyxins

• 5 Polymyxins: A, B, C, D, and E.

• Polymyxin B is most common.

• Applied: Topical use only.

• Mode of Action: Disrupt cell membranes of bacteria; narrow range (only effective against Gram-negative bacteria).

• Disadvantage: Toxic when used internally!

Protein Synthesis Inhibitors

• 30S Inhibitors

Aminoglycosides

• Mode of Action: They change the shape of the 30S ribosome.

• Spectrum of Activity: Broad.

• The first discovered = streptomycin (1940s); limited use EXCEPT for TB.

Aminoglycosides

• Application: Serious Gram-negative infections & Pseudomonas.

• Two newer aminoglycosides: Tobramycin & Amikacin.

• Good diffusion qualities for bone, joint & endocarditis infections.

• Advantage: Can act synergistically with other drugs (e.g., beta-lactam medications).

• Disadvantage: Side effects can include ototoxicity (inner ear damage - watch out for dizziness & headaches).

Tetracyclines

• Mode of Action: They block the docking site for tRNA on the bacterial ribosomes.

• Broad-spectrum drugs.

• Examples: Tetracycline (natural), Doxycycline (semi-synthetic), Minocycline, Tigecycline (FDA approved in 2005).

Tetracyclines

• Application: Effective against "intracellular" parasites

• First drug of choice= Chlamydia (STD), and Rickettsia (Rocky Mountain Spotted Fever)

• Newer versions- helpful against pneumonia & MRSA

Rocky Mountain Spotted Fever

• Prevalent in Southeastern states

• After 2-4 days incubation:

• First symptoms are sustained fever, chills, headache, and pain

• Later rash appears over body (hands/wrists first)

• Can be fatal in first 8 days

Tetracyclines: Disadvantages

• Tetracyclines cause permanent discoloration of tooth enamel in children 8 years and younger.

• Tetracyclines are inactivated by calcium ions (in milk) and iron.

• Cannot be taken during pregnancy!

• High doses may impair liver function.

• Can become toxic when expired.

Protein Synthesis Inhibitors: 50S Inhibitors

Chloramphenicol

• Mode of Action: Blocks the activity of the 50S ribosome so that peptide bonds cannot form between amino acids.

• Spectrum of Activity: Broad.

• Application: "Back up" drug for severe infections by Salmonella (typhoid fever) & pink eye

• Severe Side Effects:

  • Reversible form of anemia

  • Aplastic anemia - irreversible & fatal.

  • Do not breastfeed while taking this medication.

Macrolides

• Mode of Action: They prevent the movement of ribosome along mRNA (elongation step).

• Examples: Erythromycin, azithromycin (Z-PAK), clarithromycin.

Azithromycin (Zithromax)

• Used to treat Gram-positive infections (Staph & Strep) for patients allergic to penicillin.

• Very effective against intracellular bacteria; often used for respiratory infections.

• Advantage: Short regimen (once daily for 5 days); patients complete the regimen; longer half-life (68 hours).

• Disadvantage: Drugs bind to receptors in GI tract (stimulates smooth muscle contractions) = Diarrhea!

Chlamydia trachomatis

• Can be transmitted from infected mothers to newborns, causing blindness.

• Bacteria can ulcerate cornea after birth.

• Most states mandate a 0.5% ointment/drops of Erythromycin applied to eyes of newborns (especially vaginal births) due to low risk of side effects.

Antimetabolites

• Mode of Action: Antimicrobials that interfere with metabolic pathways.

Sulfonamides

• Known as sulfa drugs; broad range.

• Mode of Action: Structural analogs to PABA (para-aminobenzoic acid; known as Vitamin B).

• Example: sulfisoxazole, sulfamethoxazole (SMX).

• Some used to treat protozoan infections.

• 3% of the population is allergic - don't necessarily avoid all 'sulfur' related meds.

Trimethoprim (TMP)

• Broad-spectrum.

• Mode of Action: Medication is an analog of the molecule dihydrofolic acid.

• Prescribed in combination with Sulfonamides.

Clinical Uses of Sulfonamides and Trimethoprim

• T (Tree): Respiratory "tree" infections (pneumonia).

• M (Mouth): Gastrointestinal tract infections (IBS).

• P (Pee): Genitourinary tract infections (acute & chronic UTIs, urethritis).

Nucleic Acid Inhibitors

Fluoroquinolones

• Broad-spectrum; -cidal effect.

• Mode of Action: Drugs work by targeting DNA gyrase; an enzyme required for DNA replication.

• Examples: Ciprofloxacin (Cipro), Norfloxacin, Levofloxacin, Ofloxacin.

Fluoroquinolones

• Clinical Use:

  • Gram-negative infections

  • Multi-resistant Pseudomonas aeruginosa

  • For urogenital & GI tract infections (diarrhea: Shigella, E. coli, Salmonella)

  • Drug-resistant pneumococci

• DO NOT take with multi-vitamins!

Ciprofloxacin: Prevention & Treatment of Inhalational Anthrax

Caution with Fluoroquinolones!

• Drugs should be used with caution!

• Side Effects: Tendon rupture; CNS toxicity (neurological effects 1-8% of cases).

• Can impair cartilage development - cannot be prescribed to individuals 18 years and under.

Rifampin (name used in U.S.)

• Inhibits RNA polymerase to block the synthesis of mRNA.

• Side effects: Red-orange urine & bodily fluids!

• Use: Used in tuberculosis "cocktail".

• Early in treatment; must be taken daily!