Antimicrobials and Chemotherapy

Antimicrobials and Chemotherapeutic Agents

• All chemotherapeutic agents are toxic.
• The goal is to target the pathogen selectively with minimal toxicity to the patient.
• Ideal chemotherapy is toxic to the pathogen and minimally toxic to the patient.

Targets for Chemotherapeutic Agents

• Selective toxicity is a consequence of the uniqueness of the target and specificity of the drug.
• The dose of active drug delivered to the target is important.
• Drugs targeting the cell wall (e.g., penicillins, cephalosporins, vancomycin) show good selectivity, as mammals lack cell walls. These drugs target structures unique to pathogens.
• Chemotherapeutic agents should have different targets in pathogens compared to the host.

Chemotherapeutic Spectrum

• Narrow spectrum agents are effective against a few species or classes of pathogens. Examples include penicillin G.

• Broad spectrum agents target many pathogens and are useful for mixed infections or when pathogen identification is uncertain.

• Static agents inhibit pathogen growth and proliferation.

• Cidal agents kill pathogens.

• Bactericidal agents are generally preferred for immunocompromised patients.

Inhibitors of Cell Wall Synthesis (ICWS)

• ICWS target the bacterial cell wall, affecting its structural integrity and leading to cell death.
• B-lactams work via time-dependent killing and are responsible for approximately 70% of anaphylactic reactions. Penicillins, Cephalosporins, Carbapenems, and Monobactams are examples.
• Glycopeptides (e.g., Vancomycin) are examples of another mechanism of inhibiting peptidoglycan crosslinking (often used in cases of penicillin resistance.) This also works via both time- and concentration-dependent killing.

Penicillinase-Resistant Penicillins

• Resistant to penicillin-splitting enzymes produced by some bacteria.
• Methicillin, oxacillin, nafcillin, cloxacillin, and dicloxacillin are examples.
• Administering a penicillinase inhibitor (e.g., clavulanic acid) may be necessary for use with penicillin.

Cephalosporins

• Inhibit bacterial cell wall synthesis.
• The rate of cross-sensitivity between penicillin and cephalosporins is relatively low (1-3%).
• Hypersensitivity is a common adverse reaction.
• Cefazolin is an example of a first-generation cephalosporin; used for procedures likely involving skin and GI tract flora.
• Cephalosporins cross the placenta and are distributed into the joints.

Other B-lactams

• Vancomycin.
• Administration and rapid infusion of IV vancomycin causes intense redness of the body from histamine release in some patients.

Inhibitors of Protein Synthesis (IPS)

• Inhibit protein synthesis by binding to 30S or 50S ribosomal subunits.
• Aminoglycosides (Gentamicin, tobramycin, amikacin, streptomycin, neomycin) inhibit 30S.
• Tetracyclines and Glycylcyclines bind to 30S.
• Tetracyclines should not be administered with dairy products.
• Macrolides (Azithromycin, clarithromycin, erythromycin) bind to 50S.
• Lincosamides (Clindamycin) bind to 50S.
• Oxazolidinones (Linezolid) work differently than the other IPS.

DNA Synthesis Inhibitors

• Interfere with DNA synthesis by inhibiting bacterial topoisomerases or affecting DNA structure.
• Fluoroquinolones (ciprofloxacin, levofloxacin, moxifloxacin) inhibit topoisomerases.

Other Inhibitors

• Nitroimidazoles (Metronidazole) are broad spectrum, targeting a variety of cellular functions rather than focusing specifically on a bacterial component.

Misc.

• Polymyxins (polymyxin B and colistin) are used topically (often for skin infections) due to their nephrotoxicity when delivered IV.
• Rifampin and Xifaxan are miscellaneous agents, with properties used for specific conditions (e.g., in some cases rifampin can be used as a prophylaxis).