Lecture 7 - Resistance Mechanisms & Aminoglycosides, Polymyxins, Fosfomycin, Nitrofurantoin, & Methenamine Flashcards
Bacterial Resistance Risk factors
- Overuse of antibiotics
- Introduction & use of broad-spectrum antimicrobials
- Animal Antibiotic consumption
Intrinsic Resistance
some organisms are notorious for intrinsic ability to express multiple types of resistance
examples:
Vancomycin too large for Gram - porin channels
Beta Lactams need cell wall, mycoplasma dont have
Acquired Resistance
some organisms acquire genes, which enable a mechanism of resistance, from another species of bacteria that already had it through transfer of Millie genetic elements
Examples of Mechanisms of Resistance
Efflux
Immunity & Bypass
Target Modification
Inactivating enzymes
Mechanisms of intrinsic resistance
Absence of antibacterial target
Bacterial cell impermeability
Acquired Resistance can occur through…
Mutations
Genetic Exchange - Plasmids most common**
What are Plasmids
- Self replicating extrachromosomal DNA
- Genes encoding for resistance to many antibiotics can exist on 1
- Conjugative plasmids contain additional genes that can initiate transfer from one bacterium to another
Common Mechanisms of Resistance for Gram +
Modify target sites
Common Mechanisms of Resistance for Gram -
Some changes at target sites
More common to change Efflux pumps/ Porin channel / enzymes
3 Types of Beta-lactamases
ESBLs ( Extended-spectrum beta-lactamases)
AmpC beta-lactamases
Carbapenemases (KPC)
How do Beta-lactamase inhibitors work?
When combined to beta-lactams, bind to beta-lactamases and protect active antibiotic from inactivation
Activity is specific to certain Beta-lactamases depending on drug
Which antibiotics are ESBL able to hydrolyze?
Penicillins and cephalosporins up through 3rd gen
Carbapenemases work against these**
Hint that its an ESBL
Susceptible to.... Amox/Clav Ampicillin/Sulbactam Piperacillin/Tazobactam Carbapenems
Resistant to... Ampicillin Aztreonam Cefazolin Ceftriaxone
Treatment of ESBLs
Carbapenems are drugs of choice
Newer inhibitor combos work, but reserved for carbapenems resistant organisms
Pip/taz = not used due to worse outcomes
AmpC cause resistant in…
SPICE or SPACE
Space & Spice
Serratia Pseudomonas aeruginosa Proteus vulgaris, Providencia spp. Citrobacter freundii Enterobacter cloacae, Klebsiella aerogenes
A = Acinetobacter spp.
Difference between AmpC and ESBL
Susceptible to….
Ceftriaxone - dont use tho
Aztreonam
Resistant to…
Amox/Clav
Why worry about AmpC
Exposure to antibiotics causes a developed resistance during therapy
in up to ~40% of cases
3rd gen cephalosporins not recommended
AmpC treatment options
Carbapenems Fluoroquinolones TMP/SMX Cefepime Aminoglycosides
Avoid what drugs for AmpC
Ceftriaxone
Piperacillin-tazobactam
cause induction of resistance
Carbapenemases
Target carbapenems, most broad spectrum Beta-lactamases
become resistant to most other treatment options when becoming resistant
Carbapenemases found in many Gram -
Metallo-beta lactamases
Serine carbapenemases (KPC)
transmitted ia plasmid
found worldwide in many Gram -
Options for Carbapenemases
Tigecycline BL/BLI activate against KPC \+/- aminoglycosides Polymixins (colistin/ polymyxin B) data for double carbapenem therapy
BL/BLI active against KPC
Ceftazidime-avibactam
Meropenem-vaborbactam
Imipenem-relebactam
Mechanism of resistance in staph/strep (its Gram +)
Change in binding protein target site
penicillin binding proteins
resistance to Fluoroquinolone is due to….
Altered DNA gyros and/or topoisomerase IV
Ribosomal alterations responsible for resistance to….
Macrolides Azalides Aminoglycosides Tetracyclines Clindamycin
Reduced outer membrane permeability most common in….
Enterobacteriaceae and P. aeruginosa (gram -)
Antibiotic efflux pumps common in…
Huge problem among Pseudomonas aeruginosa
RND family of transporters responsible for this
Majority of RND efflux systems chromosomal encoded
Aminoglycosides include
Gentamicin
Tobramycin
Amikacin
Plazomicin
Aminoglycosides MOA
Inhibit protein synthesis
Bactericidal
Target for Aminoglycosides
A-site of 16S, part of 30S ribosomal subunit
Gentamicin Gram + Activity
** only one we use for Gram + synergy **
Must be used in combo with anti-staph penicillin or vancomycin as “synergy”
Never used alone
Gentamicin Gram - Activity
Good against susceptible Enterobacteriaceae
Good against Pseudomonas aeruginosa, used combo with beta-lactam often
common pathogens that cause UTI
Gentamicin Anaerobe + Atypical activity
Doesn’t really have any
Tobramycin, Amikacin, Plazomicin don’t have activity in…
Gram +
Anaerobic
Atypical
Tobramycin, Amikacin, Plazomicin Gram - activity
Tobra = 2nd gen Amik = 3rd gen Plazo = 4th gen
Broadens as gen increase
Good against ESBL & Carbapenem-resistant
Limited against non-fermentors, best against Pseudomonas.
Aminoglycoside Synergy
more than additive effect
true when add gentamicin w/ drugs active against cell wall
ie. give w/ penicillin for penicillin resistant strain and it will work against it
High Dose Aminoglycosides
Once-daily dosing, as efficacious as traditional multi-dose method but lowers risk of side effects
simpler, more cost effective, less time consuming
usually when using for gram - therapy
Aminoglycoside excretion & Metabolism
Most Renal excretion, no hepatic so have to adjust w/ poor renal function
Aminoglycoside Adverse effects
** nephrotoxicity **
accumulate in kidney
can develop dialysis dependent renal failure
need several days/doses for this to occur
** Ototoxicity **
Plazomicin appears to have less ototoxicity
** Neuromuscular blockade = rare**
Risk factors for Nephrotoxicity of Aminoglycosides
Older & preexisting renal disease
Hypotension, volume depletion
Hepatic dysfunction
Dose related risk factors for Nephrotoxicity of Aminoglycosides
Recent aminoglycoside therapy Larger doses treatment > 3 days Frequent dosing interval Gent>ami+tobra>strepto
Concomitant drugs associated with Nephrotoxicity risk
Vanco Amphotericin B Furosemide Clindamycin Piperacillin
Cochlear toxicity (Aminoglycosides)
anyone getting > 2 wks therapy should have baseline + followup audiology exams
3-14% incidence
Vestibular Toxicity (Aminoglycosides)
functional recovery in 53% of pts at 10 days - 9 months after stoping drug exposure
Polymyxins
Colistin (CMS,given as prodrug)
Polymyxin B
Polymyxins MOA
Permeabilize outer membrane via direct interaction with the lipid A component of the lipopolysaccharide
Bactericidal
Where do Polymyxins not have activity?
Gram +
Anaerobic
Atypical
Polymyxins Gram - activity
V.good against Enterobacteriaceae (ESBL + carbapenem-resistant organisms)
Good against nn-fermenters, even MDR strains
Polymyxin Antimicrobial Activity
Conc dependent killing
Post-antibiotic effect - for P.aeruginusa
Rapid in vitro resistance** always use in combo
Polymyxin Adverse effects
Nephrotoxicity ~ 30-60% occurrence, dose related, reversible
Neurotoxicity, rare, dose related, reversible
Nitrofurantoin MOA
Inhibit ribosomal translation
Bacterial DNA damage
Interference w/ kern cycle
Metabolized by bacterial nitroreductases turning it into reactive intermediate
Nitrofurantoin Gram + activity
none against Strep or Staph
Good against Enterococcus including VRE
Nitrofurantoin Gram - activity
E.coli
none against non fermentors
Nitrofurantoin doesn’t have activity in…
Atypical and Anaerobes
Nitrofurantoin Metabolism & Excretion
Metabolized to active metabolite and excreted into urine BUT doesn’t have high conc in kidney
** not used in upper tract disease, pyelonephritis, perinephric abscesses **
When is Nitrofurantoin not used
Upper tract disease
pyelonephritis
perinephric abscesses
Nitrofurantoin Adverse effects
Generally well tolerated
Some GI = most common
Some when used chronically ie Hepatic, hematologic, Peripheral neuropathy**
When is Nitrofurantoin not recommened
CrCl < 60 = package insert
> 65 or CrCl < 30 Beers Criteria
due to peripheral neuropathy
Fosfomycin MOA
Blocks cell wall synthesis by inactivating the enzyme perusal transferase
Req transport into cell
Fosfomycin Gram + activity
Good against staph, both MRSA/MSSA
none for Strep
Good against Enterococcus, including VRE
Fosfomycin Gram - activity
E.coli, including ESBL
Some K.pneumoniae
Not used against Pseudomonas
Fosfomycin dont have activity in…
Atypical
Anaerobic
Fosfomycin Metabolism & Excretion
Doesn’t have hepatic metabolism
Excreted in Urine but doesn’t achieve high conc in kidney…only urine
Not used in pyelonephritis but used in cystitus
Fosfomycin common side effects
Diarrhea
Nausea
Headache
overall well tolerated
Methenamine MOA
Hydrolyzed to formaldehyde and ammonia in acidic urine
** useful in suppressive therapy after infection is cleared **
Methenamine uses
suppressive therapy
Methenamine Adverse effects
Nausea
Vomiting
Rash
overall well tolerated
