Therapeutic Antimicrobials II

Question 1

describe the inhibitors of peptidoglycan/cell wall synthesis

Answer 1

B-lactams

• includes the groups: penicillin, cephalosporins, monobactams and carbapenems
• all are active only on growing cells

Question 2

summarize the mechanism of action of B-lactam antibiotics

Answer 2

• antibiotic binds to bacterial Pencillin Binding Proteins (PBPs)
  
  • bacterial enzymes normally involved in cross-linking of cell wall
• transpeptidation blocked
  
  • normal process in transpeptidation:
    
    • linkage of terminal glycine of pentaglycine bridge to fourth pentapeptide (D-alanine)
    • hydrolysis of terminal D-alanine generates necessary energy for the process
• active cell wall synthesis necessary for action
  
  • metabolically inactive or very slow growing = no or reduced effect respectively
• activation of bacterial autolytic enzymes/removal of autolysin inhibitor
• result = bacterial cell lysis

Question 3

describe the inhibitors of nucleic acid synthesis

Answer 3

quinolones & fluoroquinolones

• analogs of nalidixic acid; quinolone or derived ring
  
  • inhibitors of topoisomerase IV (gyrase homolog)
    
    • blocks DNA supercoiling
  • fluoroquinolone = modification of original structure with different side chain substitutions

Question 4

name the medically important resistant bacteria

Answer 4

• MRSA
  
  • Methicillin/Multiple Resistance Staphylococcus aureus
• VRE
  
  • Vancomycin Resistant Enterococci
• KPCs
  
  • Klebsiella pneumoniae Carbapenemases
• ESBL producers
  
  • extended spectrium B-lactamases producers
• Multidrug resistant (MDR) Mycobacterium tuberculosis

Question 5

describe inherent vs acquired resistance

Answer 5

• inherent resistance
  
  • natural absence of tatget for drug to act against
    
    • mycoplasmas lack cell wall -> resistant to penicillin
    • Enterococci lack folic acid synthesis pathway -> resistant to SMX-TMP
  • structural restriction
    
    • outer membrane (G-ve) blocks antibiotic access
• acquired resistance: via genetic diversity
  
  • transfer of resistance genes (plasmids, conjugation, etc.)
  • random mutation (single > multiple)

Question 6

give example of inherent resistance

Answer 6

Question 7

summarize antibiotic resistance mechanisms

Answer 7

Question 8

describe the mechanism of altered uptake

Answer 8

• altered uptake prevents intracellular accumulation of antibiotic to therapeutic levels
• often involves efflux pumps
  
  • can be antibiotic-induced
  • frequently encoded by mobile genetic elements
• membrane-located transport proteins
• present in Gram+ve and -ve
• can be:
  
  • specific for one substrate or
  • range of dissimilar classes (multiple antibiotics)

Question 9

describe the mechanism of altered target and give an example

Answer 9

change in structure of bacterial enzyme/target retains function but make it less able to e.g. bind the antibiotic

• example: mecA gene
• possessed by some species of S. aureus and S. pnuemoniae
• encodes for Penicillin Binding Protein 2a (PBP2a) = a modified transpeptidase
  
  • significantly lower binding affinity for B-lactam antibiotics
• impact: bacteria able to continue transpeptidation in presence of the antibiotic

Question 10

describe the mechanism of antibiotic inactivation by secreted enzymes

Answer 10

• bacterial hydrolytic enzymes that cleave the antibiotic
• e.g. B-lactamases
• convert active –> inactive antibiotic
• constitutive or inducible
• over 100 B-lactamases indentified
  
  • TEM B-lactamases (G-ve) are most common
  • range from broad –> specific
• partial solution: give antibiotic plus a B-lactamase inhibitor (e.g. Clavulanic acid)

Question 11

describe ESBLs

Answer 11

• extended-spectrium Beta-lactamases (ESBLs): confer resistance to:
  
  • all B-lactam antibiotics
    
    • except cephamycines and carbapenems
  • associated with high therapeutic failure and mortality rates of at least 50%
  • frequently to many other classes of antibiotics, including aminoglycosides and fluoroquinolones
• main producers are members of Enterobacteriacae, particularly:
  
  • E. coli
  • Klebsiella species

Question 12

describe the risk factors for ESBL exposure

Answer 12

Question 13

describe the carbapenemases (CPEs)

Answer 13

• Carbapenemases - produced by some Enterobacteriaceae
  
  • specific B-lactamases that target Carbapenem group of antibiotics
    
    • usually carbapenem antibiotics are relatively unaffected by B-lactamases
• e.g. MDR and XDR Mycobacterium tuberculosis
• impacts include:
  
  • increased cost in treatment
  • increased duration of treatment and hospital stay (costs $$)
  • need to use drugs with lower selective toxicity increases side effects

Question 14

describe the Kirby-Bauer sensitivity testing (disk diffusion technique)

Answer 14

Kirby Bauer tells you which antibiotic at which concentrations are effective

Question 15

describe establishing minimum inhibitory concentration (MIC)

Answer 15

Question 16

describe an antibiogram

Answer 16

• report of susceptibility profiles of isolates from patients across an institution to various antibiotics
• usually expressed as % susceptible
• produced and published annually
• use:
  
  • guides treatment in advance of individual susceptibility results
  • helps institutions/regions determine & track their susceptibility trends