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N6024 Antimicrobial Therapy Overview

Disclaimer

  • Information is current at presentation: healthcare is dynamic; use clinical judgment.
  • This document is for education, not standard of care.

Types of Microbes

  • Prokaryotes: No nucleus/organelles; Bacteria, Rickettsiae.
  • Eukaryotes: Unicellular (Yeast, Protozoa), Multicellular (Fungi, Helminths, Ectoparasites).
  • Viruses: Contain either RNA or DNA, not both; require host for replication.

Basic Bacterial Structure

  • Cell Wall: Present in most bacteria (except Mycoplasma); provides protection and shape.
  • Peptidoglycan (murein) cell wall & phospholipid bilayer cell (plasma) membrane form basic envelope.

Gram Stain

  • Gram-Negative: Red-orange after safranin counterstain. Has 3 layers: lipopolysaccharide (LPS) phospholipid bilayer, peptidoglycan cell wall, periplasmic space, phospholipid bilayer cell membrane. Endotoxins released on cell death.
  • Gram-Positive: Blue-purple after Gram stain. Has 2 layers: peptidoglycan cell wall, phospholipid bilayer cell membrane. Exotoxins secreted.

Bacterial Characteristics

  • Shape: Round (cocci), Rod-shaped (bacilli), Spiral-shaped (spirilla).
  • Oxygen Requirements:
    • Aerobic: Requires oxygen.
    • Microaerophilic: Requires low oxygen.
    • Anaerobic: Requires no oxygen.
    • Facultative: Can grow in either, prefers one.
    • Obligate: Must have a certain environment.
  • Ribosomes: Bacteria have 70S (50S & 30S subunits); humans have 80S (60S & 40S subunits).

Other Microbes

  • Fungi: Yeast (unicellular, budding), Molds (multicellular, hyphae, saprophytes). Examples: Tinea, Candida.
  • Protozoa: Single-cell eukaryotes with nucleus/organelles. Ingest nutrients. Can form cysts. Examples: Giardia, Trichomonas, Pneumocystis jiroveci, Malaria, Toxoplasmosis.
  • Helminths (Infestations): Flatworms (tapeworms), Roundworms. Live in/feed off host.
  • Ectoparasites (Infestations): Live on host surface. Examples: Lice, Scabies, Bedbugs.

Antibiotic Types

  • Bacteriostatic: Inhibits growth; requires intact immune system. Examples: Clindamycin, Tetracyclines, Macrolides, Sulfonamides.
  • Bactericidal: Kills bacteria; less reliant on host immune system. Examples: Beta-lactams, Glycopeptide inhibitors, Aminoglycosides, Fluoroquinolones.

Antibiotic Classifications (Mechanisms of Action)

  • Cell Wall Inhibitors:
    • Bind to cell wall proteins, prevent synthesis/repair, cause cell lysis. Minimal human side effects (no cell wall).
    • Beta-lactams: Penicillins, Cephalosporins, Monobactams, Carbapenems.
    • Beta-lactamases (e.g., penicillinase, cephalosporinase) destroy the beta-lactam ring, rendering drug ineffective.
    • Glycopeptide inhibitors: Vancomycin (blocks cell wall/membrane synthesis), Telavancin, Dalbavancin, Oritavancin.
    • Other: Daptomycin, Fosfomycin, Bacitracin (topical), Cycloserine.
  • Cell Membrane Inhibitors: Bind/inhibit membrane synthesis. Examples: Polymixin B (topical), Amphotericin B.
  • Nucleic Acid Synthesis Inhibitors: Fluoroquinolones, Rifampin, Metronidazole.
  • Ribosome (Protein) Synthesis Inhibitors:
    • 50S Subunit: Chloramphenicol, Macrolides, Lincosamides (Clindamycin), Oxazolidinones (Linezolid, Tedizolid).
    • 30S Subunit: Tetracyclines, Aminoglycosides.
    • Other: Mupirocin (topical).
  • Folic Acid Synthesis Inhibitors: Sulfonamides, Trimethoprim, Dapsone.
  • Mycolic Acid Synthesis Inhibitors: Isoniazid, Ethambutol.
  • Fatty Acid Synthetase Inhibitors: Pyrazinamide.

Specific Antibiotic Classes

  • Penicillins (PCN):
    • Natural: Penicillin G (IV/IM), Penicillin V (PO). Covers gram positives, some gram negative cocci, non-beta lactamase anaerobes. S. pneumoniae, S. pyogenes, Treponema pallidum.
    • Aminopenicillin: Ampicillin (IV/IM), Amoxicillin (PO). Broad gram negative coverage. Ineffective against beta-lactamases.
    • Beta-lactamase Resistant (Anti-staph): Nafcillin (IV), Oxacillin (IV/IM), Dicloxacillin (PO). Covers staph skin/bone infections.
    • Antipseudomonal (Extended Spectrum): Piperacillin (combined with inhibitors).
    • PCN + Beta-lactamase Inhibitor: Amoxicillin/clavulanate (Augmentin), Ampicillin/sulbactam (Unasyn), Piperacillin/tazobactam (Zosyn). Broad spectrum.
    • Pharmacokinetics: Generally well absorbed, widely distributed (minimal CSF unless inflamed), renal excretion.
    • Adverse Effects: GI upset, allergic reactions (urticaria, anaphylaxis, SJS), superinfections (C. difficile, candidiasis).
  • Cephalosporins: Cross-sensitizing/reacting with PCNs (<5% risk).
    • 1st Gen: Cephalexin (PO), Cefazolin (IV/IM). Mostly gram positives (strep, staph, pneumococcus); pre-op prophylaxis. Limited gram negative. No MRSA, Enterococcus, Pseudomonas.
    • 2nd Gen: Cefaclor (PO), Cefuroxime (PO/IV/IM). 1st gen + gram negatives (H. flu, Neisseria, Klebsiella). No Enterococcus, Pseudomonas.
    • 3rd Gen: Cefixime (PO), Ceftriaxone (IV/IM). Broader gram negatives, less gram positives than 1st/2nd. Ceftriaxone crosses BBB.
    • 4th Gen: Cefepime (IV). Gram negatives > positives. Resistant to some beta-lactamases. Good Pseudomonas coverage.
    • 5th Gen: Ceftaroline (IV). Gram positives > negatives. Effective against MRSA for ABSSSI, CAP. Does not cover Pseudomonas or VRE. May cause hemolytic anemia.
    • + Beta-lactamase Inhibitor: Ceftazidime/avibactam (Avycaz), Ceftolozane/tazobactam (Zerbaxa). For complicated UTIs, intra-abdominal infections, ESBL organisms.
    • Pharmacokinetics: Well absorbed, widely distributed (minimal CSF except ceftriaxone), renal excretion.
    • Adverse Effects: Cefazolin/cefotetan may cause disulfiram-like reaction or interfere with vitamin K metabolism.
  • Monobactams: Aztreonam (IV/IM). Only aerobic gram negatives (e.g., Pseudomonas). Useful for beta-lactam allergic patients (no cross-reactivity).
  • Carbapenems: Imipenem/cilastatin, Meropenem, Ertapenem. Broad spectrum (gram negative, positive, anaerobes). Do not cover MRSA, VRE. Side effects: N/V, phlebitis, seizures (imipenem).
  • Fluoroquinolones (Nucleic Acid Inhibitors): Ciprofloxacin, Levofloxacin, Moxifloxacin. Covers gram negative and aerobic gram positives. FDA BBW for disabling, potentially irreversible serious reactions (tendon/cartilage injury, CNS, hypoglycemia, myasthenia gravis, avoid in <16 yrs/pregnancy unless no alternatives). QT prolongation, photosensitivity. Renal adjustments needed (except moxifloxacin).
  • Rifampin (Nucleic Acid Inhibitor): Prophylaxis for Neisseria meningitis, H. flu; TB, leprosy. Side effects: elevated LFTs, orange bodily fluids, CYP450 inducer.
  • Metronidazole (Flagyl) (Nucleic Acid Inhibitor): Obligate anaerobes (Bacteroides, Clostridium), antiprotozoal. Disulfiram-like reaction (avoid alcohol). BBW for carcinogenicity in lab animals. Contraindicated in 1st trimester pregnancy. Alternative for C. difficile.
  • Nitrofurantoin (Nucleic Acid/Ribosome Inhibitor): Mainly lower UTI (E. coli). Contraindicated in severe renal disease and late 3rd trimester pregnancy.
  • Chloramphenicol (Ribosome Inhibitor): Wide spectrum. BBW for bone marrow suppression (reversible myelosuppression, rare aplastic anemia). "Gray Baby" syndrome in neonates.
  • Clindamycin (Lincosamide, Ribosome Inhibitor): Gram positives (Strep, Staph including MRSA), anaerobes. BBW for C. difficile.
  • Macrolides (Ribosome Inhibitors): Erythromycin, Azithromycin, Clarithromycin. Alternate for PCN allergic patients. Covers gram negatives/positives, atypical CAP. Side effects: GI upset, QT prolongation, photosensitivity. CYP450 inhibitor (erythromycin).
  • Tetracyclines (Ribosome Inhibitors): Doxycycline, Minocycline, Tetracycline. Broad spectrum. Avoid with calcium, magnesium, iron. Side effects: GI, superinfections, calcium chelation (bones/teeth, contraindicated in <8 yrs/pregnancy/lactation), photosensitivity. May interact with warfarin, digoxin, hormonal contraception.
  • Aminoglycosides (Ribosome Inhibitors): Gentamicin, Tobramycin, Amikacin. Aerobic gram negatives (e.g., Pseudomonas). Synergistic with beta-lactams/vancomycin. BBW for neuro/ototoxicity and nephrotoxicity.
  • Sulfonamides (Folic Acid Synthesis Inhibitors): TMP/SMX (Bactrim). Gram negative/positive coverage; prophylaxis in immunocompromised. Side effects: GI, photosensitivity, SJS, hemolytic anemia (G-6-PD deficiency). Avoid in 1st/3rd trimester pregnancy.
  • Isoniazid (Mycolic Acid Synthesis Inhibitor): For M. tuberculosis. Side effects: Pyridoxine ( ext{B}_6) deficiency, hepatotoxicity (BBW).

Antibiotic Stewardship & Resistance

  • Core Elements: Infection prevention, interdisciplinary approach, staff education, source control, appropriate prescribing (when needed, correct choice/dosage, shortest duration), reassessment, surveillance.
  • Resistance: Innate or acquired. Mechanisms: enzyme production (beta-lactamases, ESBLs), altered cell wall (MRSA, Pseudomonas), efflux pumps.

Patient Management Considerations

  • Empirical Therapy: Initial choice based on site of infection, Gram stain, regional resistance. De-escalation to definitive therapy based on culture and sensitivity.
  • Antibiogram: Chart showing microbe susceptibility/resistance to various antibiotics; aids in empiric and definitive therapy decisions.
  • Factors to Consider: Route, comorbidities (renal, hepatic, cardiac), other medications, prior adverse reactions, hydration, immune status.
  • Pregnancy: Avoid Aminoglycosides, Fluoroquinolones, Tetracycline, Chloramphenicol, Clarithromycin, Sulfonamides.
  • Renal Disease: Adjust/avoid Vancomycin, Fluoroquinolones, Aminoglycosides, Ethambutol, Nitrofurantoin, Amphotericin B, Acyclovir.
  • Hepatic Disease: Adjust/avoid Antivirals, Antifungals, Chloramphenicol, Metronidazole.

Empiric Treatment (General Examples)

  • Acute Otitis Media/Bacterial Sinusitis: High dose Amoxicillin, Amoxicillin-clavulanate, Doxycycline, 2nd/3rd gen cephalosporin.
  • Skin & Soft Tissue Infections (SSTI):
    • Cellulitis: 1st gen Cephalosporins, PCN, Clindamycin.
    • Abscess: I&D + antimicrobials (polymicrobial coverage).
    • CA-MRSA: TMP/SMX, Clindamycin, Tetracyclines.
    • Nosocomial MRSA: Vancomycin, Linezolid, Daptomycin, Ceftaroline, Telavancin, Tigecycline.
  • Tick-borne Illnesses (Borrelia burgdorferi, Rickettsia rickettsia): Doxycycline.
  • Community Acquired Pneumonia (CAP): Amoxicillin, Doxycycline, Macrolide (outpatient); Beta-lactam + macrolide/doxycycline or Fluoroquinolone (inpatient).
  • Nosocomial Pneumonia: 3rd/4th gen cephalosporin or carbapenem + Fluoroquinolone +/- Vancomycin.
  • M. tuberculosis: Rifampin + Isoniazid + Pyrazinamide + Ethambutol (combo for 3-6 months).
  • Meningitis: Ceftriaxone + Vancomycin. Neonates: Ampicillin + Gentamicin.
  • UTI: Nitrofurantoin, TMP/SMX, Amoxicillin/cephalexin (outpatient). Fluoroquinolone, Ceftriaxone/cefepime, Piperacillin/tazobactam, Carbapenem (inpatient).
  • Asymptomatic Bacteriuria: Treat only if pregnant or invasive urologic procedures.
  • Sexually Transmitted Infections (STI):
    • Gonorrhea & Chlamydia: Ceftriaxone + Doxycycline (or Azithromycin).
    • Trichomoniasis: Metronidazole.
    • Syphilis: Penicillin G (dose/duration depends on stage), Doxycycline for PCN allergic.

Prophylaxis

  • Surgical: Cefazolin, Ampicillin/sulbactam, Cefoxitin.
  • Medical: Meningitis exposure (Ciprofloxacin, Rifampin), Pertussis (Azithromycin), Anthrax (Ciprofloxacin, Doxycycline), Endocarditis (Amoxicillin, Clindamycin), Otitis media (Amoxicillin), UTI (TMP-SMX, Nitrofurantoin).

Tetanus

  • Tetanus immune globulin (TIG) IM, Tdap/Td immunization. Benzodiazepines for spasms. Antibiotics: PCN G, Doxycycline, Metronidazole.

Systemic Antifungals

  • Amphotericin B: Alters cell membrane. Broad spectrum for severe systemic infections. Side effects: fever, chills, nephrotoxicity. Premedicate.
  • Azoles (Imidazoles & Triazoles): Inhibit fungal CYP450 (ergosterol synthesis). Broad spectrum. Side effects: CYP450 interactions, elevated LFTs. Examples: Ketoconazole, Itraconazole, Fluconazole, Voriconazole.
  • Echinocandins: Inhibit eta(1-3)glucan synthesis in cell walls. For Aspergillus, Candida systemic infections. IV only. Examples: Caspofungin, Micafungin, Anidulafungin.
  • Systemic for Superficial: Griseofulvin, Terbinafine.
  • Topical: Nystatin, Clotrimazole, Miconazole, Ketoconazole, Terbinafine, Tolnaftate.

Antivirals

  • Herpes Simplex (HSV) & Varicella Zoster (VZV): Acyclovir, Valacyclovir, Famciclovir (initiate early for benefit).
  • Cytomegalovirus (CMV): Ganciclovir, Valganciclovir (for immunocompromised). BBW for toxicity.
  • Influenza: Always reference CDC guidelines. Baloxavir marboxil (Polymerase Acidic Endonuclease Inhibitor). Zanamivir, Oseltamivir, Peramivir (Neuraminidase Inhibitors). Start within 48 hrs of onset/exposure.
  • CoVID-19: Remdesivir (IV). Oral agents: Nirmatrelvir/ritonavir (Paxlovid, BBW for interactions), Molnupiravir (EUA only, likely teratogenic).

Anti-Retrovirals (HIV/AIDS)

  • Antiretroviral Therapy (ART) includes Reverse Transcriptase Inhibitors (NRTIs, NNRTIs), Protease Inhibitors (PIs), Integrase Inhibitors (INSTIs), Fusion Inhibitors, CCR5 receptor antagonists.
  • Post-Exposure Prophylaxis (PEP): Tenofovir disoproxil/emtricitabine + raltegravir or dolutegravir. Start within 72 hrs of exposure, continue $\geq 4$ weeks.
  • Pre-Exposure Prophylaxis (PrEP): Tenofovir disoproxil/emtricitabine or tenofovir alafenamide/emtricitabine. Cabotegravir IM. Requires HIV/STI testing.

Other Prophylaxis

  • Hepatitis A/B: Immune globulin if not immunized, then vaccine.
  • Rabies: Rabies Immune Globulin (RIG) if not immunized, then vaccine series.

Antiparasitic Agents

  • Antiprotozoal: Metronidazole, Tinidazole, Nitazoxanide (amebiasis, giardiasis, trichomoniasis).
  • Helminths (Anthelmintics): Mebendazole, Albendazole (inhibit glucose uptake); Pyrantel pamoate, Ivermectin (cause paralysis).
  • Ectoparasites: Permethrin (1% for lice, 5% for scabies), Malathion, Lindane. Ivermectin (topical/oral) used for both.