Micro 3 - Antimicrobial Resistance and Clinical Antibiotics
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- What are the 4 mechanisms of antibacterial resistance?
- 1. Enzymes that destroy or inactivate antibiotics 2. Development of altered genes 3. Alterations in permeability of bacterial cell 4. Presence of pumps which remove antibiotics
- What is an example of an enzyme that destroy or inactivate antibiotics?
- Beta-lactamases = destroy Beta-lactam ring - H. influenzae and M. Catarrhalis = beta-lactamase enzyme makes them resistant to amoxicillin - S. aureus = penicillinase Extended spectrum beta-lactamases = affect advanced generation beta-lactams
- How do beta-lactamase enzymes mediate antibiotic resistance?
- Hydrolysis of the beta-lactam ring = opens the ring so it can't bind to the target = resistance
- What is involved in the "development of altered targets" form of resistance?
- modification of antibiotic target with resultant diminished affinity of the antibiotic for the target without loss of target's biological function
- What are 4 examples of the "development of altered targets" form of resistance
- 1. alterations in PBPs leading to beta-lactam resistance 2. presence of mutant peptidoglycan precursors resulting in vancomycin-resistance 3. alteration of DNA gyrase with consequent quinolone resistance 4. Alteration of ribosome resulting in macrolide resistance
- Which are the targets of quinolones?
- Quiolones bind to DNA gyrase and prevent its normal function = antimicrobial effect
- What is the most common way that permeability is altered in the bacterial cell? And how does that lead to antibiotic resistance
- mutation or loss of porins (Gram-neg) bacteria = prevent or slow antibiotic entrance into cell = decreased rates of entrance favors enzymes which modify antibiotics
- How are porins involved in the antibiotic resistance of Pseudomonas aeruginosa? Which drugs are involved?
- Quinolones enter P. aeruginosa through Opr D porin
- How biofilms protect organisms from antibiotics?
- 1. poor permeability of antibiotics through biofilms 2. very slow metabolic states of organisms living in biofilm
- What are clinical examples of antimicrobial resistant bacteria?
- 1. Escherichia coli 2. Enterococci = still susceptible to ampicillin and vancomycin 3. Staphylococcus aureus = most often fought with vancomycin 4. MSRA in healthy children 5. Glycopeptide resistance in S. aureus = evidence of VRE-transposon 6. Streptococcus pneumoniae = multiply-resistance strains 7. Group A Streptococci = ribosomal methylation, macrolide efflux pump, mutations in ribosomal sites
- What is NDM-1?
- carbapenemase gene with intrisic ability to destroy most known beta-lactams - transferable to many GNR (gram-neg rods)species - originally isolated in K. pneumoniae from India
- What are glycylcyclines?
- - derivative of tetracycline - new class of therapy against GNR (gram-neg rods)
- What are 3 ways that genes can be transferred in bacteria?
- 1. Genetic transformation 2. Transduction 3. Conjugation
- What is gene transformation?
- recipient cell takes up naked DNA released by donor - single-stranded DNA - homologous recombination - new DNA similar, but not identical to recipient DNA
- Why is important that bacteria can transfer genes?
- one bacteria can spread resistance to other bacteria
- What is transduction?
- gene transfer by bacterial virus (bacteriophage) - homologous recombination
- How is DNA integrated into the recipient DNA?
- homologous recombination
- What is conjugation?
- - gene transfer that occurs between sexually differentiated bacteria involving cell-to-cell contact - major source of Ab resistance transfer
- How do male cells differ from female cells in conjugation?
- males possess conjugative plasmids = extrachromosomal DNA elements - males (donors) form sex pillus and transfer plasmid to female (recipient) - recipient bacteria with plasmid = male
- What are the components of a bacterial plasmid and what are their functions?
- 1. DNA rep = required for DNA replication 2. Resistance genes = antibacterial resistance 3. IS = insertion sequence, can jump around genome 4. Transfer genes = allow plasmid to go from donor to recipient cell 5. oriT = origin of transfer, where DNA is nicked during initiation of DNA transfer
- What are 3 genes that make up a plasmid replicon
- 1. origin = site of initiation 2. rep gene = encodes initiator protein that is required for plasmid replication 3. copy control gene (cop) = controls replication and copy number of a plasmid
- What is "copy number"?
- - number of plasmid molecules per chromosome in a cell - fixed for a given plasmid
- What are compatible plasmids vs incompatible plasmids?
- compatible = can present in the same host and replicate independently of each other incompatible = are unable to coexist stably in descendants of the same host cell
- What are conjugation plasmids? What is a major example of one?
- Plasmids that initiate own transfer by cell to cell contact. Example = R-Plasmids (R-Factors) = antibody resistance gene - contain oriT, insertion sequences, and transposons
- What are virulence plasmids
- carry genes that encode toxins and other virulence factors
- What does an integron do?
- allows integration of foreign DNA
- What are transposable elements?
- jumping genes, movable genetic elements - do not occur independently in a cell, but always found as a part of a genome - Insertion sequences and transposons contain inverted repeats (IR) at their ends
- What are the 2 groups of transposable elements and what distinguishes them?
- 1. insertion sequences = small, carry only genes that are required for their movement 2. transposons = larger, carry genes for movement as well as additional genes that specify a phenotype - composite transposons carry insertion seequences at their ends
- What are 4 components of a typical transposon (Tn3) and what do they do?
- 1. tnpA = encodes transposase protein required for transposition 2. tnpR = encodes repressor of transposition 3. amp^r gene (bla) = encodes B-lactamase which makes bacteria resistant to ampicillin 4. inverted repeats (IRs) = DNA sequence at one end of transposon repeated at other end in inverted orientation (absolutely required for transposition)
- What are inverted repeats (IRs) and why are they important?
- DNA sequence at one end of transposon repeated at other end in inverted orientation - absolutely required for transposition
- What are 2 mechanisms of transposition?
- 1. replicative (net increase in element) or conservative (no net increase of element) 2. intramolecular (within same genome) or intermolecular (between 2 genomes)
- What are 5 different types of antibiotic prescribing?
- 1. Prophylaxis 2. Pre-emptive therapy 3. Empiric therapy 4. Pathogen-directed therapy 5. Susceptibility-guided therapy
- What is prophylaxis and what are some examples?
- Use of antimicrobial agents to prevent infection 1. Perioperative prophylaxis = used to prevent surgical site infections, given 1 hour before surgery 2. endocarditis prophylaxis = prevent endocarditis (infections of heart valves) with procedures that induct bacteremia 3. Travel prophylaxis = prevent travelers from getting malaria 4. Opportunistic infection prophylaxis = prevent infections in immunocompromised patients (ie Pneumocystis jirovenci)
- What is pre-emptive therapy?
- use of antibiotics in case of an asymptomatic infection which is likely to become symptomatic with serious consequences - starting valganciclovir in a transplant patient with evidence of cytomegalovirus (CMV)
- What is empiric therapy?
- use of antibiotics for the presumed infection but before the etiology of the infection is known - used in fever in neutropenic patients, community-acquired pneumonia, and ventilator associated pneumonia
- True or false, most infections justify the use of antibiotics?
- False. Many infections resolve due to the immune system of the host and do not justify the use of antibiotics
- What is pathogen-directed therapy?
- When the organism is known, but antibiotic susceptibility is awaited.
- What is susceptibility-guided therapy?
- When the organism and the antibiotic susceptibility are both known.
- What are 5 occasions in which antibiotics are not required?
- 1. suspected viral infection for which no effective antimicrobial medications exist (ie rhinitis) 2. contamination of the sample 3. colonization in the absence of infection 4. treatment has not shown to hasten the resolution of an infection (ie. bronchitis) 5. adequate surgical drainage of an abscess obviates the need for antibiotics
- What are the ways in which microbiology laboratories perform antibiotic susceptibility testing?
- 1. Disk diffusion 2. Broth macrodilution, microdilution and agar dilution 3. E-test = determine MIC 4. genetic testing
- What is disk diffusion?
- disks containing antibiotics are placed on an agar plate and zone of inhibition of bacterial growth are measured. - greater zone = more susceptible bacteria are to the antibiotics on the disk
- What is broth mactodilution, microdilution, and agar dilution?
- test tubes, microtiter plates, or agar plates containing various antibiotics are inoculated with the organism.
- What is the MIC?
- minimum inhibitory concentration = lowest concentration of the antibiotic at which there is no visible growth in the test tube
- What is the E-test?
- patented strip with different concentrations of antibiotics along its gradient. - placed directly on an agar plate with the organism. - MIC = zone of inhibition
- What is an important factor in determining MIC breakpoints for organisms and different infections?
- how easy it is for drug to get to the target - ie. diffusion of drug to CSF = lower achievable concentrations for PCN in CSF
- What does a larger MIC mean?
- the bacteria is resistant to the antibiotic
- What is the best way to administer concentration-dependent antibiotics?
- - larger dose once a day
- What is the best way to administer time-dependent antibiotics?
- - continuous infusions or multiple daily doses of concentrations just above the MIC
- What type of infection is commonly treated with combination therapy?
- tuberculosis = RIPE Rifampin, isoniazid, pyrazinamide, ethambutol