antibiotics

• new antibiotic - antibiotic not used clinically before, but belongs to an existing class of antibiotics
• novel antibiotic - new class of antibiotic [new mechanism of action]
• S. aureus usually produces 4 enzymes (penicillin binding proteins) for cell wall synthesis

  • PBP 1-4 can be modified by beta-lactam antibiotics resulting in their inhibition and apoptosis
  • MRSA produces an altered PBP 2a which is not inhibited by beta-lactam antibiotics
• as MRSA is resistant to all penicillins, other antibiotics such as vancomycin, linezolid [oxazolidinone class, inhibits cell wall synthesis], synercid [combo of drugs that inhibit protein synthesis] and Daptomycin [lipopeptide that both disrupts membrane function and affects protein and nucleic acid synthesis]
• vancomycin is a glycopeptide antibiotic that inhibits cell wall synthesis by blocking the substrate of GPTase
• Clostridium difficile is a gram-positive, spore-forming, obligate anaerobic bacterium that causes nosocomial diarrhoea

  • >90% of cases occur after or during antibiotic treatment
• treatments for clostridium difficile associated disease [CDAD] :

  1. discontinuation of inciting antibiotics
  2. specific antibiotic treatment [metronidazole, vancomycin]
• Metronidazole is a nitroaryl compound

  • prodrug activated by anaerobic organisms by reduction of nitro group to hydroxylamine group
  • during reduction, byproducts can damage bacterial cell DNA, proteins and membranes

  advantages : prevent selection of VRE
• vancomycin is prescribed in CDAD cases in place of metronidazole if:

  • failure to respond in 3-5 days
  • pregnancy and lactation
  • intolerance
  • metronidazole resistant pathogen
  • critically ill patients
• predominant gram-negative pathogens:

  • E. Coli
  • Kiebsiella Pneumoniae
  • enterobactor species
  • serratia
• main HAIs caused by gram negative organisms:

  1. Pneumonia - associated with mechanical ventilation
  2. Bloodstream Infection - caused by central vascular catheter
  3. UTIs - associated with urethral catheters
• MDR [multi-drug resistant] organisms are resistant to at least 3 different antibiotic classes e.g. staphylococcus aureus

  XDR [extreme-drug resistant] organisms are resistant to all available antibiotics e.g. acinetobacter baumannii
• mechanisms of resistance:

  • penicillins -> beta-lactamases
  • cephalosporins -> extended spectrum beta-lactamases
  • monobactams -> extended spectrum beta-lactamases
  • carbapenems -> carbapenemases
• carbapenemases inactivate all beta-lactam antioiotics and are not inhibited by beta-lactamase inhibitors
• antibiotic treatment to resistant bacteria:

  gram negative expressing ESBLs -> carbapenems e.g. meropenem

  gram negative expressing carbapenemases -> colistin or tigecycline
• meropenem has a similar structure to penicillin:

  • bicyclic -> beta-lactam and 5-membered ring
  • no sulphur in ring, but in side chain
  • c=c in ring
• colistin is a polymyxin and is a peptide antibiotic

  • mixture of 2 cyclic peptides produced by fermentation of bacillus polymyxa
  • cell membrane disrupter
  • cause nephrotoxicity
• tigecycline is a novel tetracycline class called gycyclyclins, characterised by additional glycylamido substituent

  • inhibits protein synthesis