Antimicrobials 1

• Antibiotics


  Substance that destroys or inhibits the growth of other pathogenic microorganisms and is used in the treatment of external or internal infections
• Antibiotics


  • Produced by micro-organism
  • Manufactured synthetically
• Inhibitors of Cell Wall Synthesis

  • Beta-lactam compound
  • Glycopeptides
  • Daptomycin
  • Fosfomycin
  • Bacitracin
  • Cycloserine
• Penicillins


  • Greatest activity against Gram-positive organisms, Gram-negative cocci and non-beta-lactamase producing anaerobes
  • Susceptible to hydrolysis by Beta-lactamase
• Classification of Penicillins


  • Penicillins
  • Anti-staphylococcal Penicillins
  • Extended Spectrum Penicillins
• Anti-staphylococcal Penicillins


  Resistant to staphylococcal beta-lactamases, active against staphylococci & streptococci
• Extended Spectrum Penicillins


  Retain antibacterial spectrum of penicillin, improved activity against Gram-negative organisms
• Extended Spectrum Penicillins


  • Aminopenicillins
  • Carboxypenicillins
  • Ureidopenicillins
• Extended Spectrum Penicillins are relatively susceptible to hydrolysis by β-lactamases
• Mechanisms of Resistance to Penicillins

  • Methicillin resistant staph
  • PNC resistant pneumococci and enterococci
  • Efflux mechanism
  • Occurs only in Gram-negative
• Beta-lactamase Inhibitors


  Clavulanic acid, Sulbactam, Tazobactam
• Carbapenems


  • Doripenem
  • Ertapenem
  • Imipenem
  • Meropenem
• Monobactam


  Aztreonam
• Mechanism of Action of Penicillins


  Binds and blocks peptidases involved in cross-linking the glycan molecules, hinders peptidoglycan elongation
• Vancomycin


  Inhibits the formation of the basic peptidoglycan subunits
• Cycloserine


  Inhibits the formation of the basic peptidoglycan subunits
• Penicillin Salts


  • Benzathine PNC 1.2 MU
  • Procaine PNC 600,000 MU
  • PNC-V
• Penicillin Units and Formulation

  • Crystalline Penicillin G - 1600 U, 1 U = 0.6 mcg, 1 MU = 0.6 g
  • Sodium or Potassium salt
  • Procaine and Benzathine salts - repository forms for IM injections
  • Dry Crystalline form - stable for years at 4°C, activity lost rapidly at 20°C in 24H, must be freshly prepared for administration
• Pharmacokinetics of Penicillins


  • Half-life of penicillin G is 30 min
  • Dicloxacillin, Ampicillin and Amoxicillin are acid-stable and well absorbed
  • Nafcillin has erratic absorption, not suitable for oral administration
  • Food impairs absorption of oral penicillins, taken 1-2 hr before or after meals
• Pharmacokinetics of Penicillins


  • Route: IV preferred than IM (irritation and local pain with large doses), absorption is complete and rapid
  • Poor penetration: eye, the prostate, and CNS, therapeutic penicillin concentrations can be achieved with a daily parenteral dose of 18-24 million units in inflamed meninges
  • Excretion - rapidly excreted by the kidneys, Nafcillin primarily by the biliary excretion, Oxacillin, dicloxacillin, cloxacillin are eliminated both by renal/biliary
• Adverse Reactions to Penicillins

  • Most adverse effects are due to hypersensitivity, all penicillins are cross-sensitizing and cross-reacting, less than 1% of persons who have received penicillin without incident will have an allergic reaction when given penicillin
  • Range of allergic reactions - Anaphylactic shock (0.05%), Serum sickness, A variety of skin rashes
  • In renal failure, high dose can cause seizures
  • Others: Nafcillin - neutropenia, Oxacillin - hepatitis, Ampicillin - vaginal candidiasis, pseudomembranous colitis
• Cephalosporins


  • First Generation
  • Second Generation
  • Third Generation
  • Fourth Generation
• First-generation Cephalosporins


  • Greatest activity against Gram-positive organisms and non-beta-lactamase producing anaerobes, may be used for the treatment of UTI and staphylococcal or streptococcal infections, including cellulitis or soft tissue abscess, Cefazolin - only parenteral first-generation still in general use, drug of choice for surgical prophylaxis, does not penetrate the CNS and cannot be used to treat meningitis
• Second-generation Cephalosporins


  • Have extended Gram-negative coverage compared to first generation, the oral are active against β-lactamase, activity against anaerobes (including B fragilis), can be used to treat such infections (peritonitis or diverticulitis)
• Third-generation Cephalosporins


  • Expanded Gram-negative coverage, for infections resistant to most other drugs, achieve sufficient levels in the CSF (NOT CEFOPERAZONE), excretion mainly renal, BILIARY CEFOPERAZONE
• Third-generation Cephalosporins


  • Cefoperazone
  • Cefotaxime
  • Ceftazidime
  • Ceftizoxime
  • Ceftriaxone
  • Cefixime
  • Cefpodoxime Proxetil
  • Cefdinir
  • Cefditoren pivoxil
  • Ceftibuten
  • Moxalactam
• Fourth-generation Cephalosporins


  • Highly effective: H. influenzae, Neisseria, useful in the treatment of enterobacter infections, clinical role similar to that of third-generation agents
• Monobactams


  Aztreonam - drugs with a monocyclic β-lactam ring, resistant to β-lactamases and active against Gram-negative rods (including pseudomonas), no activity against Gram-positive bacteria or anaerobes
• Carbapenems


  Ertapenem, Imipenem, Meropenem - activity: Gram-negative, Gram-positive, anaerobe organisms, used for P aeruginosa resistant to other drugs and mixed aerobic and anaerobic infections, inactivated by dehydropeptidases in renal tubules, resulting in low urinary concentrations (not meropenem/ertapenem), administered with an inhibitor of renal dehydropeptidase, cilastatin
• Beta-lactamase Inhibitors


  Clavulanic acid, Sulbactam, Tazobactam - bind with beta-lactamase and prevent the enzyme from breaking down the penicillin
• Penicillin-beta-lactamase inhibitor combination drugs

  • ampicillin + sulbactam = Unasyn
  • amoxicillin + clavulanic acid = Augmentin
  • ticarcillin + clavulanic acid = Timentin
  • piperacillin + tazobactam = Zosyn
• Miscellaneous drugs related to β-lactams

  • Vancomycin
  • Daptomycin
  • Fosfomycin
  • Bacitracin
  • Cycloserine
• Vancomycin


  Active against Gram-positive bacteria particularly staphylococci, β-lactamase producing staphylococci and those resistant to nafcillin and methicillin are killed, kills staphylococci slowly and only if cells are actively dividing, poorly absorbed from the GI tract, used orally only for antibiotic-associated enterocolitis caused by C difficile, reserved for refractory cases, parenteral vancomycin is used in sepsis caused by methicillin-resistant staphylococci
• Vancomycin Adverse Effects


  Irritating to tissue, resulting in phlebitis at the site of injection, a common reaction is "red man" or "red neck" syndrome caused by release of histamine, largely prevented by prolonging the infusion period to 1-2 hours or increasing the dosing interval
• Daptomycin


  Active against vancomycin-resistant enterococci and S aureus, mechanism of action: binds to and depolarizes the cell membrane, causing potassium efflux and rapid cell death, adverse effect: myopathy, monitoring creatine phosphokinase levels essential
• Fosfomycin


  Active against both Gram-positive and Gram-negative organisms, mechanism of action: inhibits the cytoplasmic enzyme, enolpyruvate transferase, resistance is due to inadequate transport of drug into the cell, used for treatment of uncomplicated lower urinary tract infections in women, appears to be safe for use in pregnancy, availability: oral and parenteral
• Bacitracin


  There is no cross-resistance between bacitracin and other antimicrobial drugs, highly nephrotoxic and is only used topically, bacitracin (with polymyxin or neomycin), is used for mixed bacterial flora in surface lesions of the skin or mucous membranes
• Cycloserine


  Used only to treat tuberculosis resistant to first-line agents, water soluble and very unstable to acid pH, causes serious CNS toxicity with headaches, tremors, acute psychosis, and convulsions