Antimicrobials Flashcards
minimum inhibitory concentration
- lowest concentration of drug that can inhibit growth of a particular bacterial species
minimum bactericidal concentration
- smallest concentration of a drug to kill 50% of the bacterial population
if you have bacteriostatic
- MBC»_space;> MIC
If you have bactericidal
- MBC = MIC
culture based methods to determine microbial susceptibly/resistance
- disk diffusion
- E-test
molecular detection of resistance mutations
- PCR
- sequencing
antibiograms
- summaries of antibiotic susceptibilities of local isolates
- sent to clinical micro lab
- aid in selecting empiric therapy
efficacy of antimicrobial drugs limited by
- mechanism of action
- susceptibility of the target organism
- side effects on the host
- pharmacodynamics
- cost
- patient compliance
efficacy of antimicrobial drugs mechanism of action
- has to be able to get to the site of infection
efficacy of antimicrobial drugs cost
- if the prescription is more than your patient can afford
- they won’t take it
- won’t be efficacious
efficacy of antimicrobial drugs patient compliance
- will the patient actually take it
Cmax
- max concentration you can get from a dose
area under curve
- total concentration of drug that has accumulated in the patient during that dosing interval
time dependent killing
- maximize time above MIC
drugs that use TDK
Wall inhibitors - penicillins - cephalosporins Protein inhibitors - macrolides - clindamycin
concentration dependent killing
- maximize Cmax and therefore AUC
drugs that use CDK
DNA inhibitors
- fluoroquinolones
Protein inhibitors
- Aminoglycosides
post antibiotic effect
- the time it takes bacteria to return to log-phase growth following removal of antibiotic
post antibiotic effect TDK
- minimal because we have extended amount of time where the drug is above MIC
post antibiotic effect CDK
- quite long to extend amount of time before next drug needs to be administered
importance of long PAEs
- reduce required frequency of dosing
- reduce toxicities and cost
cefriaxone
- subclass: cephalosporin
- class: beta lactam
bacterial cell envelope includes
- cell membrane
- peptidoglycan layer
- outer membrane
bacterial cell envelope doesn’t include
- intracellular structures
- extracellular polysaccharide capsules
- secreted molecules
classes of agents that interfere with bacterial cell envelope
- beta lactamase
- glycopeptides
- isoniazid
- ethambutol
- bacitracin
- phosphomycin
- cycloserine
- lipopeptides
- polymyxins
beta lactam examples
- penicillins
- cephalosporins
- carbapenems
- monobactams
gram negative cell envelope
- small peptidoglycan layer
- lipopolysaccharide layer (important for gram negatives)
- Lipid A
LPS layer
- outer membrane of gram negative cell envelope
lipid A
- endotoxin
- toxic molecule of LPS
gram positive cell envelope
- lots of peptidoglycan
- lipotechoic acid unique to gram positives
peptidoglycan
- alternating units of NAG and NAM
what do beta lactams inhibit?
- transpeptidation
peptidoglycan amino acids
- D-Ala-D-Ala
- this what penicillin targets
penicillin binding proteins
- have the transpeptidase activity
- may also have the transglycosylation activity to put sugar backbone together
structural basis of beta lactams
- they look a lot like D-Ala-D-Ala
- drug named for beta lactam ring
- inhibits activity of enzyme that looks for D-Ala-D-Ala
Classes of B lactams
- penicillin
- cephalosporins
antibiotic resistance mechanisms
- enzymatically inactivate drug
- alter drug target
- alter drug exposure
enzymatically inactivate drug
- beta lactamases
- often on mobile genetic elements
alter drug target
- mutation
- can occur via horizontal exchange
alter drug exposure
- decreased uptake (gram negatives)
- increased efflux
how do gram negatives have decreased uptake?
- they can change the size of their pores to allow nutrients to get in
- exclude drugs because they are bigger
beta lactamases
- break bond in beta lactam ring of penicillin
- disables molecule
types of beta lactamases
- ESBL
- metal dependent (NDM-1)
ESBL
- mostly derived from active site mutations in TEM/SHV
- results in activity against extended spectrum cephalosporins
clavulanic acid
- resistance to cleavage by beta lactamases
- will deactivate beta lactamase
alternative penicillin resistant PBP
- have low affinity for B-lactams but retain transpeptidase activity
- can arise through mutation (gonorrhea)
- can be acquired horizontally (MRSA)
fitness cost of antibiotic resistance
- it costs the bacteria something to become resistance to antibiotic
- won’t grow as well as the susceptible drug
rationale for understanding mechanisms of resistance
- choose antibiotics with higher fitness cost for resistance
altered penicillin transport
- decreased membrane permeability
- increased efflux
altered penicillin transport decreased membrane permeability
- only relevant for gram negatives
- can arise via spontaneous mutations in porin genes
altered penicillin transport increased efflux
- horizontal acquisition of new pump
- mutation that alters specificity or expression
multiple mechanisms of resistance
- higher levels of resistance
multiple mechanisms of resistance examples
- alterations in porin (gram -)
- alternations in PBPs
- production of beta lactamases
- over expression of efflux pump
glycopeptide example
- vancomycin
- for gram positives
what do glycopeptides do?
- inhibit transglycosylation of peptidoglycan
- binds to D-ala-D-ala and blocks incorporation
vancomycin resistance mechanisms
- synthesis of D-ala-D-lac precursors that cannot bind vancomycin
bacitracin
- inhibits regeneration of PG lipid carrier
phosphomycin
- prevents attachment of NAG to NAM
cycloserine
- prevents attachment of peptide to NAM
mycobacterium species
- have mycolic acid
- and arabinogalactan
- acid fast stain
agents that work on mycobacterial species
- isoniazid
- ethambutol
isoniazid
- inhibits mycolic acid synthesis
ethambutol
- inhibits arabinotransferases
lipopeptides MOA
- form pores in cytoplasmic membrane of gram positive cell
- bind to phosphatidylglycerol which is abundant in bacterial cell membranes
- rare in eukaryotic cell membranes
lipopeptides example
- daptomycin
why don’t we use lipopeptides to treat pneumonia
- surfactant is coated in phosphatidylglycerol
- not good because lipopeptides break holes in this
bacterial folate synthesis inhibitors
- sulfonamides
- trimethoprim
- humans don’t synthesize their own folate.
- bacteria do
sulfonamides
- bacteriostatic on their own
- generally included trimethoprim
- sulfamethoxazole
resistance to sulfonamides altered drug target
- spontaneous mutation of dhps
- horizontal acquisition of alternate DHPS
resistance to sulfonamides swamp the system
- increased production of folate precursor PABA
resistance to sulfonamides altered drug exposure
- decreased uptake
combinatorial synergy
- lower amount of each drug we need to use and get same outcome
- each drug works better in presence of the other drug
trimethoprim
- bactericidal
- inhibits dihydrofolate reductase
Tmp/Smx
- synergistic combination
- smx becomes bactericidal with combined with tmp
quinolones/fluoroquinolones
- inhibit DNA gyrase (topo II and topo IV)
- bactericidal
- work best against gram negatives
quinolones/fluoroquinolones example
- ciprofloxacin
role of topoisomerase IV
- separates newly replicated chromosomes into daughter cells
problem with cipro
- may rupture tendons
resistance of quinolones altered drug target
- chromosomal mutation in gyrase and topoisomerase genes
resistance of quinolones altered drug exposure
- decreased uptake via mutations in gram negative porin proteins
- increased efflux due to mutations in efflux pump activity
- cross-resistance leading to multi drug resistance
rifamycins
- inhibit DNA synthesis
- can be bactericidal or static dependent on concentration
rifamycins MOA
- bind to bacterial DdRp with higher affinity than for human enzyme
rifamycins example
- rifampin
- mostly used for mycobacterium or meningococcal
resistance to monotherapy
- spontaneous mutations in RNA pol gene
- rarely used as mono therapy
nitroimidazole use
- bactericidal
- anaerobic microbes
nitroimidazole type of drug
- pro-drug - must be converted by microbial enzyme to active form
nitroimidazole MOA
- active drug forms toxic free radicals that damage DNA
nitroimidazole example
- metronidazole
resistance to nitroimidazole
- failture to enzymatically activate drug
- mutations in enzymes that convert the prodrug to the active compound.
