Lily

• Empiric therapy


  Immediate administration of drug(s) prior to bacterial identification and susceptibility testing, for acutely ill patients with unknown infections
• Broad-spectrum therapy


  May be indicated initially when the organism is unknown or polymicrobial infections are likely
• Some pathogens have predictable susceptibility patterns, while others require susceptibility testing due to unpredictable patterns
• Selecting a drug


  1. Broad-spectrum therapy may be indicated initially when the organism is unknown or polymicrobial infections are likely

  2. Gram-positive cocci in the spinal fluid of a newborn infant is most likely to be Streptococcus agalactiae which is sensitive to penicillin G

  3. Gram-positive cocci in the spinal fluid of a 40-year-old patient are most likely to be S. pneumoniae which is frequently resistant to penicillin G and often requires treatment with a high-dose third generation cephalosporin or vancomycin
• Some pathogens


  • Streptococcus pyogenes and Neisseria meningitidis usually have predictable susceptibility patterns to certain antibiotics
  • Most gram-negative bacilli, enterococci, and staphylococcal species often show unpredictable susceptibility patterns and require susceptibility testing to determine appropriate antimicrobial therapy
• Minimum inhibitory concentration (MIC)


  The lowest antimicrobial concentration that prevents visible growth of an organism after 24 hours of incubation
• Minimum bactericidal concentration (MBC)


  The lowest concentration of antimicrobial agent that results in a 99.9% decline in colony count after overnight broth dilution incubations
• Blood-brain barrier (BBB)


  • Formed by the single layer of endothelial cells fused by tight junctions that impede entry from the blood to the brain of virtually all molecules, except those that are small and lipophilic

  
• Factors affecting penetration and concentration of antibacterial agents in the CSF

  • Lipid solubility of the drug
  • Molecular weight of the drug
  • Protein binding of the drug

  
• Patient factors affecting antimicrobial selection

  • Immune system status
  • Renal function
  • Hepatic function
  • Perfusion
  • Age
  • Pregnancy and lactation
• Bacteriostatic drugs


  Arrest the growth and replication of bacteria at serum (or urine) levels
• Bactericidal drugs


  Kill bacteria at drug serum levels achievable in the patient
• Bactericidal agents are often the drugs of choice in seriously ill and immunocompromised patients due to their more aggressive antimicrobial action
• Narrow-spectrum antibiotics


  • Act only on a single or a limited group of microorganisms
• Extended-spectrum antibiotics


  • Modified to be effective against gram-positive organisms and also against a significant number of gram-negative bacteria
• Broad-spectrum antibiotics


  • Affect a wide variety of microbial species
• Advantages of drug combinations

  • Certain combinations show synergism, where the combination is more effective than either drug used separately
• Disadvantages of drug combinations

  • Bacteriostatic drugs may interfere with the action of bactericidal drugs
  • Unnecessary combination therapy can lead to antibiotic resistance
• Mechanisms of drug resistance

  • Modification of target sites
  • Decreased accumulation
  • Enzymatic inactivation
• Prophylactic use of antibiotics is restricted to clinical situations where the benefits outweigh the potential risks, and the duration should be closely observed to prevent unnecessary resistance
• Complications of antibiotic therapy

  • Hypersensitivity
  • Direct toxicity
  • Superinfections
• Beta-lactams


  Antibiotics that inhibit bacterial cell wall synthesis, including penicillins and cephalosporins
• Penicillin subclasses


  • Differences in antimicrobial activity, susceptibility to acid and enzymatic hydrolysis, and biodisposition
• Routes of penicillin administration

  • Oral
  • Intravenous
  • Intramuscular
  • Depot forms (procaine penicillin G, benzathine penicillin G)
• Penicillin absorption


  • Incompletely absorbed after oral administration
  • Food decreases absorption of penicillinase-resistant penicillins
• Penicillin distribution and excretion

  • Distribute well and cross the placental barrier
  • Insufficient penetration into bone or CSF unless inflamed
  • Primarily excreted by glomerular filtration
  • Nafcillin and oxacillin metabolized in the liver
  • Probenecid inhibits penicillin secretion

  
• Mechanism of action of beta-lactams

  1. Binding to penicillin-binding proteins

  2. Inhibition of transpeptidation reaction in cell wall synthesis

  3. Activation of autolytic enzymes causing cell wall lesions

  
• Mechanism of bacterial resistance to beta-lactams

  • Formation of beta-lactamases (penicillinases)
  • Use of beta-lactamase inhibitors (e.g. clavulanic acid, sulbactam, tazobactam) to prevent inactivation
• Nafcillin and oxacillin


  Metabolized in the liver
• Probenecid


  Inhibits the secretion of penicillins by competing for active tubular secretion via the organic acid transporter, thus can increase blood levels

  
• Mechanism of action of beta-lactam antibiotics

  1. Binding of the drug to specific enzymes (penicillin-binding proteins [PBPs]) located in the bacterial cytoplasmic membrane

  2. Inhibition of the transpeptidation reaction that cross-links the linear peptidoglycan chain constituents of the cell wall

  3. Activation of autolytic enzymes that cause lesions in the bacterial cell wall

  
• Mechanisms of bacterial resistance to beta-lactam antibiotics

  • Formation of beta-lactamases (penicillinases) by most staphylococci and many gram-negative organisms
  • Structural change in target PBPs responsible for methicillin resistance in staphylococci (MRSA) and for resistance to penicillin G in pneumococci (eg, PRSP, penicillin resistant Streptococcus pneumoniae) and enterococci
  • Changes in the porin structures in the outer cell wall membrane in some gram-negative rods (eg, Pseudomonas aeruginosa) may contribute to resistance by impeding access of penicillins to PBPs

  
• Penicillin G


  Prototype of a subclass of penicillins
• Penicillin G


  • Used for therapy of infections caused by common streptococci, meningococci, gram-positive bacilli, and spirochetes
  • Remains the drug of choice for syphilis
  • Activity against enterococci is enhanced by coadministration of aminoglycosides
• Penicillin V


  Oral drug used mainly in oropharyngeal infections
• Methicillin, nafcillin, oxacillin


  Very-narrow-spectrum penicillinase-resistant drugs, primary use is in the treatment of known or suspected staphylococcal infections
• Methicillin-resistant (MR) staphylococci (S. aureus [MRSA] and S. epidermidis [MRSE]) are resistant to all penicillins and are often resistant to multiple antimicrobial drugs
• Ampicillin and amoxicillin


  • Wider spectrum of antibacterial activity than penicillin G, used for infections resulting from enterococci, Listeria monocytogenes, Escherichia coli, Proteus mirabilis, Haemophilus influenzae, and Moraxella catarrhalis
  • When used in combination with inhibitors of penicillinases (eg, clavulanic acid), their antibacterial activity is often enhanced
  • In enterococcal and listerial infections, ampicillin is synergistic with aminoglycosides
• Piperacillin and ticarcillin


  • Have activity against several gram-negative rods, including Pseudomonas, Enterobacter, and in some cases Klebsiella species
  • Most drugs in this subgroup have synergistic actions with aminoglycosides against such organisms
  • Susceptible to penicillinases and are often used in combination with penicillinase inhibitors (eg, tazobactam and clavulanic acid) to enhance their activity

  
• Adverse effects of penicillins

  • Allergy (urticaria, severe pruritus, fever, joint swelling, hemolytic anemia, nephritis, and anaphylaxis)
  • Gastrointestinal disturbances (nausea and diarrhea, especially with ampicillin)