antimicrobials

• Antibacterials can be classified into different groups, including cell wall inhibitors
• Cell wall is composed of a polymer called peptidoglycan
• Inhibitors of cell wall synthesis require actively proliferating microorganisms
• Beta-lactam antibiotics and Vancomycin are important members of the cell wall inhibitors group
• Penicillins are natural penicillins obtained from fermentations of the mold Penicillium spp
• Penicillin G (benzylpenicillin) is the cornerstone of therapy for infections caused by various bacteria
• Penicillin G inhibits bacterial cell wall synthesis by affecting penicillin-binding proteins (PBPs)
• Penicillin G is susceptible to inactivation by beta-lactamases (penicillinases)
• Antistaphylococcal penicillins, such as Methicillin, nafcillin, oxacillin, and dicloxacillin, are used to treat infections caused by penicillinase-producing staphylococci
• Extended-spectrum penicillins like Ampicillin and amoxicillin have a similar antibacterial spectrum to penicillin G but are more effective against gram-negative bacilli
• Antipseudomonal penicillins, including carbenicillin, ticarcillin, and piperacillin, are effective against many gram-negative bacilli
• Penicillins have synergistic effects with aminoglycosides, but they should not be placed in the same infusion fluid
• Resistance to penicillins can occur through beta-lactamase activity, decreased permeability to the drug, and altered penicillin-binding proteins (PBPs)
• Routes of administration for penicillins depend on stability to gastric acid and severity of the infection
• Pharmacokinetics of penicillins involve absorption, distribution, metabolism, and excretion
• Adverse reactions to penicillins include hypersensitivity, diarrhea, nephritis, neurotoxicity, and cation toxicity
• Penicillins are generally safe to use during pregnancy
• Cephalosporins have a similar mode of action as penicillins and are affected by the same resistance mechanisms
• Cephalosporins are classified into first, second, third, and fourth generations based on bacterial susceptibility patterns and resistance to beta-lactamases
• First-generation cephalosporins act as penicillin G substitutes and are resistant to staphylococcal penicillinase
• Second-generation cephalosporins have greater activity against additional gram-negative organisms
• Third-generation cephalosporins have enhanced activity against gram-negative bacilli and are used in the treatment of meningitis
• Fourth-generation cephalosporins like Cefepime & cefpirome have a wide antibacterial spectrum and are more resistant to hydrolysis compared to third-generation cephalosporins
• Pharmacokinetics of cephalosporins involve poor oral absorption and distribution into body fluids
• Cephalosporins:

  • Cephalosporins distribute well into body fluids
  • Adequate therapeutic levels in the CSF are achieved only with third-generation cephalosporins (ceftriaxone or cefotaxime) for meningitis by H. influenzae
  • Cefazolin is effective for most surgical procedures, including orthopedic surgery due to its ability to penetrate bone
  • All cephalosporins cross the placenta
  • Elimination of cephalosporins occurs through tubular secretion and/or glomerular filtration
  • Ceftriaxone is excreted through the bile into the feces and is safe in patients with renal insufficiency
• Adverse effects of cephalosporins:

  • Allergic manifestations: Cross sensitivity with penicillins
  • Antibiotic-associated colitis: superinfection
  • Bleeding tendency: hypoprothrombinemia with methylthioterazole/MTT containing group in 2nd/3rd generation cephalosporins (Cefoperazone, Cefmandole, Cefotetan, Cefmetazole)
  • Local effects: thrombophlebitis from IV injection
• Drug interactions with cephalosporins:

  • Probenecid
  • Alcohol: cephalosporins with MTT have a disulfiram-like reaction
  • Drugs that promote bleeding
• Cephalosporins during pregnancy:

  • Safely used to treat various infections during pregnancy
  • Older agents are preferred due to more data and experience in pregnancy
  • Pregnancy increases clearance (CL) and volume of distribution (Vd), decreased AUCs and shorter half-lives
  • Increased dose amounts and more frequent dosing may be needed to attain adequate drug concentrations for many cephalosporins
• Vancomycin:

  • Glycopeptide effective against multiple drug-resistant organisms like MRSA and enterococci
  • Mode of action: inhibits synthesis of bacterial cell wall
  • Vancomycin is effective primarily against Gram-positive organisms
  • Oral vancomycin is limited to the treatment of potentially life-threatening, antibiotic-associated colitis due to C. difficile or staphylococci
  • Vancomycin resistance mechanisms include changes in permeability to the drug and decreased binding of vancomycin to receptor molecules
• Vancomycin pharmacokinetics:

  • Not absorbed after oral administration
  • Slow IV infusion is employed for treatment of systemic infections
  • Inflammation allows penetration into the meninges
  • Combined with ceftriaxone for synergistic effects to treat meningitis
  • Metabolism of the drug is minimal
• Adverse effects of vancomycin:

  • Fever, chills, and/or phlebitis at the infusion site
  • Flushing (red man syndrome) and shock from histamine release with rapid infusion
  • Dose-related hearing loss in patients with renal failure
  • Ototoxicity and nephrotoxicity are more common when vancomycin is administered with another drug that can also produce these effects
• Aminoglycosides:

  • General properties: composed of two or more aminosugars connected by a glycoside linkage, polycations at physiological pH, water-soluble, stable in solution
  • Mechanism of action: transport through outer membrane by passive diffusion via porins, then actively transported across the cell membrane, binds to 30s ribosomal subunit leading to protein synthesis inhibition
  • Therapeutic uses: used against Gram-negative enteric bacteria in bacteremia and sepsis, TB, in combination with β-lactam antibiotics for increased coverage and synergism
• Adverse effects of aminoglycosides:

  • Cochlear toxicity: tinnitus, high-frequency hearing loss
  • Vestibular toxicity: vertigo, ataxia, loss of balance
  • Nephrotoxicity: risk factors include older patients, renal disease, large doses, frequent dosing interval, and concomitant drugs
• MIC & Time- vs Concentration-Dependent Killing:

  • Concentration-Dependent Killing: rate & extent of killing increases as peak drug concentration increases, largest for aminoglycosides & fluoroquinolones
  • Post-antibiotic effect: persistent suppression of bacterial growth after limited exposure to an antibiotic
  • Time-Dependent Killing: associated with cell wall synthesis inhibitors like β-lactams & vancomycin, bactericidal activity continues as long as plasma concentration is above the MIC
• Bacteriostatic inhibitors of protein synthesis:

  • Tetracycline
  • Macrolide
  • Lincosamides
  • Chloramphenicol
  • Spectinomycin
• Tetracyclines:

  • Mechanism: enter microorganism by passive & active transport, act by binding 30s ribosome to prevent addition of amino acid to growing peptide
  • Adverse effects: GI irritation, effect on bone & teeth, liver toxicity, kidney toxicity, photosensitization, vestibular reactions
• Macrolides:

  • Includes Erythromycin, Clarithromycin, Azithromycin
  • Mechanism of Erythromycin: inhibition of protein synthesis via binding to 50s ribosomal RNA, usually bacteriostatic
  • Therapeutic uses of Erythromycin
• Adverse effects of Erythromycin:

  • GI effects: ANVD
  • Liver toxicity: estolate salts cause acute cholestatic hepatitis due to hypersensitivity reaction
  • Drug interactions with Erythromycin
• Azithromycin and Clarithromycin:

  • Semisynthetic derivatives of erythromycin
  • Better oral absorption
• Azithromycin and Clarithromycin:

  • Semisynthetic derivatives of erythromycin
  • Better oral absorption
  • Longer half-life
  • Fewer gastrointestinal side effects
  • Expensive
  • Clarithromycin is more active against M. avium complex and also has activity against M. laprae & Toxoplasma gondii
  • Azithromycin is less active against staphylococci & streptococci, slightly more active against H. influenza, highly active against Chlamydia, and has a long half-life allowing for once daily dosing