Bacterial Resistance Flashcards
Bacterial DNA
a single circular, double-stranded
chromosome that encodes for essential cellular functions (growth, cell division)
plasmids
- Encode for genes whose products are not essential for cell survival
- self-replicating DNA
- genes encoding resistance to multiple antibiotics can be located on a single plasmid
Gram positive organisms and peptidoglycan layers (cell wall)
thick peptidoglycan layers
Gram-negatives and peptidoglycan layers
cell wall
thin peptidoglycan layer, fewer peptide cross-linkages
enzymes vital for cell wall synthesis shape and structural integrity (cell wall)
Penicillin binding protein
most vital penicillin binding protein (cell wall)
transpeptidase (catalyzes the final cross link between
sugar and peptide in peptidoglycan molecule)
the outer membrane of gram-negative bacteria
- contains (LPS endotoxin)
- contains porins, (which are hydrophilic channels that allow for transport of small molecules
periplasmic space in gram negative organisms
located in-between cytoplasmic space (peptidoglycan layers) and the outer membrane (this is where beta lactamases in gram negative organisms are)
Human risk factors for emergence, transmission, of bacterial resistance.
- introduction of broad spectrum antibiotics
- elderly, immunocompromised
- homelessness, poor nutrition
- inadequate medical care
- reductions in public health care
Microbial risk factors for emergence, persistence, and transmission of bacterial resistance
- propensity to exchange genetic materials
- intrinsic resistance
- survival in multiple environments
- ability to occupy certain ecological niches and interact with other organisms in these niches
- previous antibiotic exposure
- selecting for resistant strains
mechanisms of intrinsic resistance
- absence of antibacterial target
- bacterial cell impermeability
acquired resistance
- a change in bacterial DNA acquired through a mutation in hosts DNA, or gaining new DNA
Mutations
occur spontaneously in every 10^6 bacterial cells
Conjugation
direct contact or mating via sex pili (most common)
Transduction
genes transferred between bacteria by bacteriophage (viruses)
Transformation
he transfer or uptake of “free floating” DNA from the
environment; then DNA is integrated into the host DNA
Transposons
- Genetic elements flanked by 2 insertion sequence elements that possess the ability to translocate from one location to another
- capable of moving from a plasmid to a chromosome or vice versa
- single transposons may encode multiple resistance factors
Phages
- viruses that can transfer DNA from organism to organism
beta-lactamases
enzymes that hydrolyze the beta lactic ring by splitting an amide bond and inactivating the drug.
Ambler classification
four molecular classes of beta-lactamases based on amino acid sequences
Ambler Classes A (ESBL, CRE), C (AmpC), and D utilize what mechanism of beta lactam inactivation
enzymes that hydrolyze the substrate by forming an acyl enzyme through an active serine site
Ambler Class B - utilizes what mechanism of beta lactic inactivation
metallo-beta-lactamases that utilize at least 1 active site zinc ion to facilitate hydrolysis
Ambler Class C target-
Amp-C
- substrate is cephalosporins (considered cephalosporinases since greater hydrolysis than penicillins)
- seen in SPICE organisms
SPICE Organisms (Serratia, Pseudomonas, Indole positive Proteus, Citrobacter, Enterobacter)
- klebsiella aerogenes (enterobacter)
- Indole + proteus (P. vulgaris, Providencia, Morganella)
Ambler Class C (Amp-C) and beta-lactamase inhibitors
- previous beta-lactamase inhibitors (clauvanic acid, tazobactam, sulbactam) do not work on Ambler Class C
Group 1 Beta Lactamases
AmpC
- inhibited by avibactam
Group 1 Beta Lactamases
AmpC
- inhibited by avibactam
- ## induction of beta-lactamase production (elevation in presence of Beta-Lactam agents)
Strong inducers of AmpC Beta Lactamases (weak activity)
Penicillin G
Ampicillin
1st generation cephalosporins
Cefoxitin
Strong inducers of AmpC (better activity)
Imipenem
Meropenem
Weak inducer of AmpC( less likely to increase beta-lactamase) less likely to affect antibiotic activity
2nd or 3rd generation cephalosporins
ureidopenicillins
monobactams
weak inducers of AmpC but better activity
carbenicillin
Selection of Group 1 (AmpC 1 beta-lactamases)
essentially we can select for these pre-existing mutants that are de-repressed and create a population of microbes that are constantly producing beta-lactamase
Extended Spectrum Beta-Lactamase-mediated resistance
- plasmid mediated hydrolysis enzyme (TEM & SHV)
- Seen in Klebsiella and E. coli
- similar resistance to ceftazidime, cefotaxime, ceftriaxone, and aztreonam; cefepime resistance is variable
- inhibited by avibactam, may be inhibited by tazobactam
risk factors for infection with exile producing pathogens
- exposure to 3rd gen cephalosporins
- exposure to ciprofloxacin
exposure to amino glycosides - total antibiotic use
- ventilator days and ARDS
Treatment of choice for ESBLs
- carbapenems (choice)
- ceftazidime-avibactam
- tigecycline
- high-dose piperacillin/tazobactam (less effective than carbs unless in urinary tract)
- fluoroquinolone - high prevalence of cross resistance
- aminoglycoside (not used as monotherapy)
- Bactrim
- Colistin only if multi drug resistant
Merino trial
determined that pip/tazo was inferior to meropenem in blood stream infections
Klebsiella Pneumoniae carbapenemases (Class A)
- plasmid mediated
- inhibited by bactams (AVycaz), (Vabomere), (Recarbrio)
- most fruent infection type in the United States
New Deli metallo-Beta-lactamase (Class B)
- spreading world-wide
- easily transmitted among gram negative bacteria
not inhibited by any current beta-lactamases - aztreonam is stable and active
Carbapenem resistance
- results in the loss of our safest last line of defense against resistant pathogens
- requires us to use more toxic agents
Carbapenem-resistant-Enterobacteriaceae
- not necessarily possessing carbapenemases as 50% are beta-lactam negative. there are other mechanisms besides bata-lactamases that could make an organisms resistant to carbapenem antibiotics
Treating Carbapenemase-producing gram-negative
- serine carbapenemase (Ceftazidime-avibactam, Meropenem-vaborbactam, Imipenem-cilastatin-relebactam, Plazomicin, Cefiderocol, Colistin + meropenem, Colistin + meropenem + tigecycline)
- metallo-β-lactamase (Aztreonam + ceftazidime-avibactam, Cefiderocol)
3 mechanisms of aminoglycoside-modifying enzymes
- acetylation
- neucleotidylation
- phosphorylation
Penicillin-binding proteins and altered target sites
- altered penicillin binding sites cause decreased binding affinity for target
- effect on MIC may vary, could be increased MIC or organism could become resistant
- caused the presence of methicillin resistant S. aureus
- cause of penicillin and cephalosporin resistance in S. npeumonia
Penicillin-binding proteins and altered target sites
- altered penicillin binding sites cause decreased binding affinity for target
- effect on MIC may vary, could be increased MIC or organism could become resistant
- caused the presence of methicillin resistant S. aureus (creates a new PBP (new target) by the mecA gene)
- cause of penicillin and cephalosporin resistance in S. pneumonia
altered cell wall precursors in vancomycin resistance in enterococci (altered target sites)
- vanc inhibits cell wall precursors by binding to the end of the D-alanine terminus of pentapeptide (peptidoglycan precursors). loss of the last alanine results in 1000 fold decrease in affinity of vanc
Ceftaroline
- only beta-lactam drug that has activity for MRSA. (usually treated with Vanc)
vancomycin resistance
most concerning is VanA, and VanB. as these are plasmid mediated and their modified target is D-Ala-D-Lac
Altered target sites (ribosomes)
- resistance of macrolide and azalide resistance in S. pneumonia is due to the fact that they both target the same ribosomal target.
- clindamycin also targets this ribosome and if the ribosome is identified with an ermB gene then it is resistant to macrolides, azalides, and clindamycin
altered target sites (dna gyrase and topoisomerase IV)
- FLuoroquinolone resistance in gram-negatives and S. pneumoniae. essentially the mutations in dna gyrase and topoisomerase IV cause less affinity to the drug and lead to a mechanism of resistance
Antibiotic efflux pumps
pump drugs out of the cell through the periplasmic space and into the environment
Chromosomal or plasmid mediated efflux pumps
- macrolides, azalides (S. pneumoonia, S. epidermis) from the mefA gene (susceptible to clindamycin)
- Carbapenems (P. aeruginosa – meropenem > imipenem)
mexAB-oprM
- an efflux pump associated with carbapenem resistance in Pseudomonas arginosa
- resistance is associated more with meropenem than imipenem
- this is also another place for FQ resistance (floxacin)
Porin alterations may manifest by 3 processes
- shift in porin type
- change in porin expression
- impairment or loss of porin expression
- most commonly seen in Enterobacteriacae and P. aeruginosa (imipenem > meropenem, doripenem)
Colistin Resistance and Heteroresistance
- MOA is the modification of lipopolysaccharide
- resistance described in A. baumannii, P. aeruginosa, and K. pneumoniae
- mcr-1 gene encodes resitance to colistin
- located on plasmid
