chemotherapy and suseptiblity testing

• Chemotherapy involves treating a disease with a specific chemical designed to target the exact cause of that disease
• Antimicrobial chemotherapy administers drugs with selective toxicity against pathogens involved in infections
• Selective toxicity is the ability of an antimicrobial agent to harm a pathogen without harming the host
• Fewer drugs are selectively toxic as the target cells become more like humans, e.g., fungi, viruses, cancer, protozoa, and worms
• Antibacterial drugs are derived from bacteria or molds or synthesized de novo
• Antibiotic producing microbes include:

  • Gram-Positive Rods: Bacillus subtilis, Bacillus polymyxa
  • Fungi: Penicillium notatum, Acremonium spp. (Cephalosporium spp.)
  • Actinomycetes: Streptomyces venezuelae, Streptomyces griseus, Streptomyces nodosus, Micromonospora purpurea
• Classification of antibiotics according to mechanism of action:

  • Inhibition of cell wall synthesis
  • Inhibition of protein synthesis
  • Inhibition of nucleic acid synthesis
  • Inhibition of cell membrane functions
  • Inhibition of folate synthesis
• Factors driving antibiotic resistance include inappropriate prescribing, overuse, lack of knowledge, substandard drugs, poor hygiene, and more
• Combination therapy can have synergistic, additive, or antagonistic effects
• Aminoglycosides have concentration-dependent bactericidal activity by binding to the 30S ribosome, inhibiting bacterial protein synthesis
• Aminoglycosides are poorly absorbed orally but well absorbed from the peritoneum, pleural cavity, and joints
• Aminoglycosides are contraindicated in cases of allergy and can cause renal, vestibular, and auditory toxicity
• β-Lactam antibiotics contain a beta-lactam ring and inactivate enzymes required for bacterial cell wall synthesis
• β-lactam antibiotics are bactericidal and act by inhibiting the synthesis of the peptidoglycan layer of bacterial cell walls
• The final transpeptidation step in the synthesis of the peptidoglycan is facilitated by DD-transpeptidases, also known as Penicillin Binding Proteins (PBPs)
• Cephalosporins penetrate well into most body fluids and the ECF of most tissues, especially when inflammation is present
• Cephalosporins that reach CSF levels high enough to treat meningitis are: Ceftriaxone, Cefotaxime, Ceftazidime, Cefepime
• Most cephalosporins are excreted primarily in urine, while Cefoperazone and Ceftriaxone have significant biliary excretion
• Ceftriaxone is contraindicated with Ca-containing IV solutions in neonates ≤ 28 days due to the risk of ceftriaxone-Ca salt precipitation
• Ceftriaxone should not be given to hyperbilirubinemic and preterm neonates because it can displace bilirubin from serum albumin, potentially triggering kernicterus
• Cephalosporins have limitations including lack of activity against Enterococci, methicillin-resistant staphylococci (except for Ceftobiprole), and anaerobic gram-negative bacilli (except for cefotetan and cefoxitin)
• Fluoroquinolones exhibit concentration-dependent bactericidal activity by inhibiting the activity of DNA gyrase and topoisomerase, essential for bacterial DNA replication
• Older fluoroquinolones include Ciprofloxacin, norfloxacin, and ofloxacin, while newer ones are Gemifloxacin, levofloxacin, and moxifloxacin
• Fluoroquinolones are widely distributed in most extracellular and intracellular fluids and are concentrated in the prostate, lungs, and bile
• Fluoroquinolones are no longer recommended for the treatment of gonorrhea in the US due to increasing resistance
• Fluoroquinolones are contraindicated in patients with previous allergic reactions to the drugs or certain disorders that predispose to arrhythmias
• Fluoroquinolones are traditionally considered contraindicated in children due to potential cartilage lesions if growth plates are open, but some experts challenge this view
• Lincosamides, Oxazolidinones, and Streptogramins are grouped together due to their similar mode of antibacterial action and spectra
• Clindamycin, a lincosamide, is primarily bacteriostatic and binds to the 50S subunit of the ribosome
• Clindamycin is effective for infections due to anaerobes, community-acquired MRSA, but not reliably active against Mycoplasmas, Chlamydiae, and Legionellae
• Macrolides are active against various microorganisms, including aerobic and anaerobic gram-positive cocci, Mycoplasma pneumoniae, Chlamydia trachomatis, and Legionella species
• Macrolides have adverse effects like GI disturbances, QT-interval prolongation by erythromycin, and inhibition of hepatic metabolism leading to numerous drug interactions
• Metronidazole is a bactericidal antibiotic that enters bacterial cell walls
• Azithromycin is the least likely antibiotic to interact with other drugs
• Metronidazole is bactericidal, entering bacterial cell walls to interrupt DNA, distributed widely in body fluids, penetrating into CSF, metabolized in the liver, and excreted mainly in urine
• Metronidazole indications:

  • All obligate anaerobic bacteria
  • Certain protozoan parasites (e.g., Trichomonas vaginalis, Entamoeba histolytica, Giardia intestinalis [lamblia])
  • Drug of choice for bacterial vaginosis (BV)
• Metronidazole contraindications:

  • Previous allergic reaction
  • Avoid during the 1st trimester due to mutagenicity concerns
  • Enters breast milk; not recommended during breastfeeding
• Metronidazole adverse effects:

  • GI disturbances
  • CNS effects and peripheral neuropathy
  • Disulfiram-like reaction
• Vancomycin is a time-dependent bactericidal antibiotic that inhibits cell wall synthesis, excreted unchanged by glomerular filtration
• Vancomycin adverse effects:

  • Hypersensitivity reactions (e.g., rash, fever, reversible neutropenia, and thrombocytopenia)
  • Nephrotoxicity is rare unless high doses are used or an aminoglycoside is given concomitantly
  • Red-person syndrome, a histamine-mediated reaction causing pruritus and flushing