Chemotherapy and Antibiotic Resistnace - Kozel Flashcards
T/F: Antibiotics are naturally produced chemicals
true
Is the ideal antimicrobial bacteriocidal or bacteriostatic?
bacteriocidal
T/F: resistance can be caused by enzymatic inactiavation of the abx or simply a failure to convert it to its active form
true
T/F: overproduction of an abx target can cause resistance
true
(Pharmacokinetics/dynamics) describes the interaction between concentration and antimicrobial effect
dynamics
Concentration vs. time in tissue and other body fluids determines (blank)
pharmacologic or toxic effect
Concentration vs. time at site of infection determines (blank)
antimicrobial effect
What are the pharmacokinectic issues that prevent an abx from reaching the bacteria?
absorption from the site of administration
transfer from plasma to site of infection
elimination from plasma
elimination from the site of infection
What is the difference between bacteriostatic and bacteriocidal?
cidal= KILL the bacteria static= inhibit growth but does not kill
What are some examples of bacteriocidals?
beta lactams, vancomycin, fluoroquinolones, metronidazole, aminoglycosides
What are some examples of bacteriostatics?
tetracyclines, clindamycin, macrolides, sulfonamides
What type of abx relies on the host to kill the microbe?
bacteriostatics
A combination of antibiotics produces a 2-log10 increase in action relative to each agent alone is known as (blank)
syngergy
A synergistic relationship between penicillina nd gentamycin is used to treat (blank)
viridans streptococcal meningitis
What is the post-abx effect
suppresion of growth following exposure to abx
Hows does the post-abx effect work?
slows growth that the sub- minimum inhibitory concentration (MIC) and alters morphology
What effects does post-abx leukocyte enhancement have?
increases susceptibility to phagocytosis and phagocytic killing
Time > MIC is what type of killing?
time-dependent killing
Describe the persistent effects of time-dependent killing?
minimal to moderate
The AUC/MIC ratio shows us the (blank)
total exposure of microbe to antimicrobial agent
Describe the persistent effects of AUC/MIC?
prolonged persistent effects
Cmax/MIC ratio shows what type of killing?
concentration-dependent killing
Describe the persistent effects of Cmax/MIC type killing?
prolonged persistent effects
Absorption, distribution, and elimination are part of pharmaco(blank)
kinetics
What two ratios are predictors of outcome for concentration dependent mechanisms?
AUC/MIC and Cmax/MIC
IN plain english, what does it mean if something is concentration dependent when it kills?
higher drug concentrations have a higher rate and extent of bacteriocidal activity
What are some examples of concentration dependent abx?
aminoglycosides, fluoroquinolones, metronidazole
What type of killing is relatively slow
TIME dependent killing
In time dependent killing, (blank) occurs at low multiples of the MIC
saturation of killing
What are some examples of time dependent abx?
B-lactams and vancomycin
T/F: bacteriostatic agents have minimal post-abx effect
false; prolonged effect
What ratio predicts the outcome of bacteriostatic agents?
AUC/MIC
What are the natural penicillins?
B-lactams
What other categories of drugs fall under B-lactams besides penicillin?
cephalosporins, carbapenems, Beta lactamase inhibitors
The spectrum of the natural penicillins includes (blank)
ONLY GRAM POSITIVE
T/F: natural penicillins provide the starting material for semisynthetic penicillins
true
Carboxypeptidases Endopeptidases Transglycosylases Transpeptidases Are all examples of (blank) binding proteins
penicillin binding proteins
what is the function of the penicillin binding proteins?
construct the pentapeptide-pentaglycine bridges that cross-link peptidoglycan
Describe the MOA of penicillin?
Penicllin binds to penicillin binding proteins. PDG cross-linking blocked; cell lysis due to autolytic enzymes that destroy the cell wall
T/F: beta lactamase is carried by a plasmid
ture
T/F: beta lactamase is carried by a transposable chromosome gene
true
Gram (blank) have an intrinsic ability to block the access of penicillin to PBPs
gram negative
An altered (blank) protein in N. gonorrheoeae creates penicillin resistance
porin
Newly resistant strains of S. pneumoniae have what changes to their abx binding site?
reduction in number or affinity to the PBP
S. pneumoniae, N. gonorrheoeae, and MRSA are all examples of what type of abx resistance?
alteration in abx binding site
Penicillinase resistant penicillins work by (blank)
introducing a bulky R group near the site of hydrolysis
What are two examples of penicillinase resistant PCN?
methicillin and nafcillin
What is the trade off when using a PCNase resistant PCN?
they are 1/10th as potent as penicillin G
Where is lipoteichoic acid found in the gram pos wall?
in the PDG layer above the PM
Where is lipid A and O polysacc found in the gram neg wall?
OUTER layer of the OUTER membrane
Where is PDG found in gram neg?
in between the two membranes
Where are porins found in the gram neg wall?
outer layer of the outer membrane
What does O polysacc attach to in the gram neg wall?
Lipid A
The outer membrane of gram neg resists penetration of (hyrophobic/philic) molecules
hydrophobic
How do you enchance the penetration of PCN thru outer membrane porins?`
add a hydrophilic charged group
T/F: broad spectrum PCNs like ampicillin and carbenicillin have the same sensitivity to PCNases as natural PCN
true
T/F: PCN forms a covalent irreversible bond with PBPs
true
How do PBPs prep the PDG for crosslinking?
they remove the D-alanine precursor from PDG
Where in the bacteria do you find PBPs?
membrane bound and in the cytosol
How do PBPs aid in abx resistance?
overproduction of PBPs and formation of PBPs that have low affinity for PCN; b-lactamase production as well
Which PBP is responsible for causing MRSA ?
PBP 2A
Generally speaking, are PCNs cleared rapidly or slowly from the kidneys?
rapid secretion
Are PCNs generally distributed to most tissues?
yes
Do PCNs penetrate the blood brain barrier?
no
How do you maximize drug exposure for PCN that use time-dependent killing?
optimize your dosing strategy; lower doses more frequently; keep the dose above the MIC
Opening of the b-lactam ring allows for binding to host proteins causing the (blank) reaction and creating an allergic reaction
hapten
Disturbances of GI flora is most prominent with what abx?
ampicillin
An allergic reaction can occur with reactivity to the (blank) ring within PCN
thiazolidine ring
T/F: cephalosporins have high immunological cross reactivity with PCN
false
cephalosporins are resistant to what enzyme?
b-lactamases
Describe the characterization of the spectrum of cephalosporins from gen’s 1-4?
- narrrow
- expanded
- Broad
- Extended
MRSA-active
What generation of cephalosporin includes gram neg activity that will kill Pseudomonas?
3rd gen
High affinity for (blank) allows for MRSA-active cephalosporin
PBP 2A’
Which penicillins are acid labile?
PCN G, methicillin
which PCNs are acid stable?
PCN V; most semi-synthetic PCNs
Differences between acid labile or stable PCNs creates a large variation in (blank)
oral absorption
T/F: cephalosporins generally have good tissue distribution
false; distribution and metabolism varies widely from one to the other
T/F: cephaolosporins are capable of CNS penetratioN
TRUE
How are cephalosporins excreted? In what patients do you need to alter the dosage?
Renal excretion; pt’s with renal insufficiency
What is the most common side effect of cephalosporins?
diarrhea and nausea (GI symptoms)
(blank)-infections are possible with broad spectrum cephalosporins
superinfections
What are the three mechanisms by which N. gonorrheoeae is resistant to cephalosporins?
altered PBP2A
overexpression of efflux pump
mutation in porin reduces uptake
Carbapenems, imipenem, and muropenem have what structure?
B-lactam
the modified alpha ring in carbapenems eliminates (blank)
sulfur
What is the spectrum of carbapenems?
HIGH AFFINITY for essential PBPs of gram pos and neg
Carbapenems can penetrate the gram neg outer membrane via a specific (blank)
OMP (outer membrane protein)
Are carbapenems effective against MRSA?
NOPE
The hydroxyethyl at C-6 in carbapenem makes it highly resistant to (blank)
beta lactamase
T/F: carbapenems are only used when the specific microbe is known
false; used in empirical therapy
What is the preferred route of administration of carbapenem? why?
pareneterally; poor absorption after oral ingestion
Carbapenem is rapidly hydrolyzed by (blank) in the renal tubule
peptidase
What is the peptidase inhibitor that blocks renal degradation of imipenem?
Cilastatin
What are the side effects of carbapenems?
generally well tolerated; can cause allergic reactions
NDM-1 plasmid encoding extended spectrum beta lacatamase confers resistance to which abxs?
imipenems, all B-lactams, aminoglycosides, tetracyclines, and fluoroquinolones
T/F: NDM-1 plasmid is found in common enteric bacilli
true
In what setting do you typically see NDM-1 cause problems?
Pts getting elective surgery in SE asia
What are two common b lacatamase inhibitors?
clavulanic acid and sulbactam
Why do we use b lactamase inhibitors?
used with b lactams with little direct antibacterial action to improve their power
what is the MOA of b lactamase inhibitors?
SUICIDE INHIBITION; clavulanate will bind to the b-lactamase IRREVERSIBLY (suicide) to prevent it from functioning; forms an acyle enzyme intermediate that is hydrolyzed VERY slowly
B-lactamase inhibitors are used in conjuction with (blank)ase sensitive b-lactams
PCNase
What humongous class of abx inhibits cell wall synthesis?
b-lactams
what drug is used against M. tuberculosis that inhibits cell wall synthesis
cycloserine
What class of abx is vancomycin?
glycopeptide
Where does vancomycin bind on the cell wall?
terminal D-ala-D-ala
What function does vancomycin block?
transpeptidation
Is vancoymycin bactericidal or bacteriostatic?
bacteriocidal
Vancomycin resistance is (blank) mediated
plasma mediated
What are two bugs that are vancomycin resistant?
enterococcus spp. and S. aureus
How do VRE and VRSA avoid vancomycin?
they substitute lactate for alanine
VISA avoids vancomycin how?
multiple free ala-ala to act as decoys for vancomycin
What is the spectrum of vancomycin and glycopeptide abx?
gram pos ONLY
T/F: vancomycin is a firstline drug
false; drug of LAST RESORT
What is the usual route of administration of glycopeptide abx?
IV
What bug is vancomycin especially useful for?
C. diff
What is the mode of excretion of vancomycin? what kind of pts should you alter dose for?
renal; renal insufficiency
vancomycin is (blank)-toxic at high doses
ototoxic, nephrotoxic
Red Man syndrome is associated with what abx?
vancomycin; rapid IgE mediated mast cell degranulation causing red rash
Is VRSA or VISA the most common form of resistant S. aureus?
VISA
Is polymyxin useful againt gram pos or gram neg bacteria? why?
gram neg; fatty acid tail penetrates the phospholipid bilyater
What is the MOA of polymyxin?
leakage of metabolites and disruption of membrane function
Is polymyxin bacteriocidal or static?
cidal
The toxicity of polymyxin limits its use to (blank)
topical applications
highly resistant strains of Pseudomonas, Klebsiella, and Acinetobacter warrant of use of parenteral (blank)
polymyxin
Why is polymyxin given in parenterally?
not absorbed after oral administration
Polymyxin shows dose-related (blank)toxicity
nephrotoxicity
What abx should be used when an enteric carries that fucking god-awful NDM b lactamase plasmid?
Poly-fuckin-myxins
P. aeruginosa, A. baumanii, and enterobacteriacaeae that are resistant to all b-lactams, fluoroquinolones, and aminoglycosides should be treated with (blank)
polymyxins
What is the MOA of quinolones?
inhibits DNA synth via inhibition of DNA gyrase
are quinolones cidal or static?
cidal
How can a bug have resistance to quinolones?
mutation to DNA gyrase
what is the spectrum of quinolones?
gram neg and pos
what are the clinical uses of quinolones?
UTIs and other bacterial infections
do quinolones have good oral absorption?
yes
What is the method of clearance of quinolones?
renal
What is the most common cause of C. diff colitis?
Ciproflaxin!
What are the three classes of side effects with quinolones?
GI, CNS, and achilles tendon damage
what is the trade name of metronidazole?
flagyl
what is the MOA of metronidazole?
PRODRUG reduced to active form by electron transport protein
(aerobic/anaerobic) bacteria are able to convert metronizadole prodrug to active form
anaerobic via electron transport, strangely
T/F: some protozoa have a mechanism that makes them susceptible to metronizadole?
true
What does metronizadole do once it is converted to its active form?
produces cytotoxic compounds that DAMAGE DNA
What is the spectrum of mentronidazole
obligate anaerobes and many protozoa
Does metronidazole work in facultative anerobes or obligate aerobes?
nope
is metronidazole cidal or static?
cidal
What drug is given as a prophylaxis in colorectal surgery?
metronidazole
Trichomonas vaginalis is commonly treated with (blank)
flagyl
T/F: flagyl has roughly similar blood levels following oral and IV administration
true
What is the most common side effect of flagyl?
GI upset; mutagenic effects UNPROVEN, but possible
What is the mechanism of Rifampin?
binds to DNA-dependent RNA pol, blocks CHAIN INITIATION and RNA transription
T/F: Rifampin is active on eukaryotic polymerases
false; only on bacterial!
T/f: Rifampin is cidal or static depending on the concentration of the BACTERIUM
TRUE
How do bugs become resistant to Rifampin?
single step mutation in the beta subunit of RNA Pol; very rapid mutation
what are the clinical uses of Rifampin?
Tx of TB, leprosy, prophylaxis of N. meningitidis
What is the normal route of administration of Rifampin?
oral
Describe the distribution of Rifampin?
good throughout the body, limited CNS penetration
what is method of elimination of Rifampin?
30% urine and 60-70% feces!
What drug causes ORANGE DISCOLORATION of tears, sweat, and urine?
Rifampin
What are the most common side effects of Rifampin?
GI
Rifampin is (blank)toxic
hepatotoxic
Rifampin upregulates CYP450 and therefore decreases hormone and drug (blank)
half lives; need to check to see if there is a potential med interaction!
Is streptomycin cidal or static?
cidal
what is the MOA of streptomycin?
irreversibly binds to 30S unit
depletes ribosome pool
misreads the message
premature release from the ribosome
Aminoglycosides like streptomycin are syngergistic with (blank), that facilitate their uptake by gram pos bacteria
cell wall-active antimicrobials
What is the method that a bacteria becomes resistant to streptomycin?
Plasmid mediated enzymatic alteration: acetylation, phosphorylation, adenylation (most common) or reduced uptake or intrinsic resistance
Do aerobes or anaerobes have intrinsic resistance to aminoglycosides?
anaerobes
what is the spectrum of streptomycin?
BROAD spectrum: gram pos and neg, and TB
Streptomycin is a (first/second)line drug in TB Tx
second line
what other terrible diseases do you use streptomycin to treat?
tularemia, plague; more toxic than newer agents
Gentamycin, tobramycin, and amikacin are used in empiric therapy of (blank)
suspected aerobic, gram NEG bacteria
Once starting pt on empiric gentamycin and you get cultures back, do you continue therapy or switch abx?
switch abx
What is needed to make aminoglycosides more effective against gram pos bacteria?
combo therapy with cell wall active agents
T/F: aminoglycosides are minimally absorbed from the GI tract
true; must give IM or IV
what is the clearance mechanism of aminoglycosides?
renal
What pharmacodynamic ratio is a predictor of efficacy?
Cmax/MIC; CONCENTRATION DEPENDENT EFFECT
What type of toxicity is most common with aminoglycosides? 2nd most common? Any other side effects?
- Nephrotoxicity 5-25%
- ototoxicity –IRREVERSIBLE 2-10%
- neuromuscular blockade: rare
To what ribosomal subunit does tetracycline bind?
30s
Where on the 30s does tetracycline bind?
A-site, blocks binding of aminoacyl tRNA
is tetracycline binding reversible?
yes!
is tetracycline bacteriostatic or cidal?
STATIC
What is the most common mechanism for tetracycline resistance? Next most common?
Active efflux pump; ribosomal protection: cytoplasmic proteins bind to the ribosome to protect it
What is the spectrum of tetracylcine?
VERY BROAD; gram pos and neg, many anaerobes, spirochetes, mycoplasma, rickettsiae and chlamydia
(blank) is firstline Tx in chlamydia, rickettsia, and spirochetes,
tetracycline
What factors make tetracycline a second line choice?
toxicity, resistance, and availability of alternatives
What factors play into oral absorption of tetracyline?
varies from person to person and amongst various types, also impaired by MILK and divalent/trivalent cations
What are the two methods that tetracycline is excreted?
kidney and bile
T/F: tetracycline can cause superinfection
true
T/F: tetracyline may stain teeth and bones in early years
true
what are the side effects of tetracyline?
photosensitivity, GI problems, nephrotoxicity, bone/tooth staining, superinfection
Is chloramphenicol used in the US?
nope
What is the more common name for lincosamides?
clindamycin
to what ribosomal unit does clindamycin bind?
50s
what is the MOA of clindamycin?
blocks peptidyl transferase
is clindamycin static or cidal?
static
Describe the mechanism of resistance to clindamycin
plasmid mediated methylation of ribosome reducing abx binding
what is the spectrum of clindamycin?
Aerobic GRAM POSITIVE COCCI
ANAEROBES
Is clindamycin effective against gram negative?
nope
what is the clinical use for clindamycin?
anaerobic infections, alternative to PCN if allergy, MRSA is susceptible!
How do you deliver clindamycin?
Oral and pareneteral
how is clindamycin excreted?
urinary and fecal
The (blank) of clindamycin increases with renal failure
half life
Pseudomembranous colitis is associated with what bug?
C. diff; intrinsically resistant to clindamycin
What is the most common side effect of clindamycin?
GI disturbances
what part of the ribosome does linezolid bind to?
50s unit
what is the MOA of linezolid?
prevents formation of the 70s complex; unusual mechanism makes it SUPER EFFECTIVE! against resistant bacteria
is linezolid static or cidal?
static
what is the spectrum of linezolid?
most clinically important gram pos; limited with gram neg
What drugs do you use linezolid for?
MRA, multi-drug resistant strep pneumoniae, VRE, and as a reserve abx for difficult bacteria
What are the ways to give linezolid?
IV or orally
What is the bioavailability of linezolid?
FUCKING OUTSTANDING
how is linezolid excreted?
broken down in vivo and excreted in urine
Long term use of linezolid results in (blank)
myelosuppresion
What is the most common side effect of linezolid?
GI upset
Linezolid is a weak nonspecific inhibitor of monoamine oxidase and should therefore not be given with (blank)
SSRIs!!
What are the common macrolides?
erythromycin, azithromycin, and clarithromycin
where do the macrolides bind and what is there MOA?
to the 50s; blocks peptidyl transferase and translocation
are macrolides static or cidal?
static
T/F: macrolides also have a plasmid mediated resistance method
treu
what does the macrolide resistance plasmid carry?
gene for methylation of ribosome
Macrolides have cross resistance with (blank)
lincomycin/clindamycin
Besides being generally broad, define the spectrum of macrolides?
most active against aerobic, gram pos
What is the clinical use of macrolides?
firstline for mycoplasma and Legionella, alternative for PCN if allergic
(blank) inactivates macrolides, therefore oral dosing is givien as enteric-caoted or more-stable salts or esters
gastric acid
Which macrolide is acid stable?
azithromycin
What are the only areas where macrolides are not well distributed?
brain and CSF
what is the primary mode of excretion of macrolides?
BILIARY WTF
What are the side effects of macrolides? (think of mode of excretion)
hepatotoxicity
stimulates GI motility–i.e. GI upset
INHIBITOR OF CYP450; SIG. DRUG INTERACTIONS
CARDIAC ARRHYTHMIAS
sulfonamides and trimethoprim both function in what pathway?
folic acid metabolism
suflonamides block the synthesis of (blank)
dihydrofolic acid
Trimethoprim blocks the synthesis of (blank)
T for Tetrahydrofolic acid
THF is used in the synthesis of (blank)
DNA and RNA
while sulfonamides block the synth of DHF, they are analogs to (blank)
PABA
By what mechanism do sulfonamides block DHF synth?
competitive inhibitor
are sulfonamides cidal or static?
static
Plasmid resistance of sulfonamides mediates production of (blank) enzyme with decreased affinity for the drug
dihydropteroate synthetase
Gram pos, gram neg, chlamydia, and NOCARDIA are in the spectrum of (blank)
sulfonamides
T/F: you can use sulfonamides for UTIs
true
T/F: sulfonamides have good GI absorption
true
T/F: sulfonamides are excreted in feces
false; urine
What is the common side effect to sulfonamides?
hypersensitivity reactions – rash and hivez
Confluent dermatological necrosis is an emergency that is part of the (blank) syndrome in response to sulfonamides
Stevens-Johnson syndrome; shows with the confluent epidermal necrosis and immune reaction
Hemolytic anemia, agranulocytosis, aplastic anemia, and other hematopoietic disorders are rare side effects associated with (blank)
sulfonamides
T/F: trimethoprim is synergistic with sulfonamides
true
cotrimoxazole (Bactrim and Septra) is a combo of what?
trimethoprim and sulfamethoxazole
what is the drug of choice for Pneumocystis jirovecii??
trimethoprim
what is a firstline for MRSA?
sulfamethoxazole/trimethoprim
Impaired folate usage is a side effect of sulfa/trimeth?
trimeth
What is the MOA of Isoniazid?
PRODRUG that is activated in the bacteria; inhibits synthesis of mycolic acids
What is the very limited spectrum of Isoniazid?
only effective agains MYCOBACTERIA
T/F: Resistance against Isoniazid is very common
true
What is the mechanism of resistance against Isoniazid?
deletion of gene encoding the activating enzyme that takes it from prodrug to active drug
What is the use of isoniazid?
TB tx
What are the methods of administration of Isoniazid?
orally and IM
Isoniazid will inhibit Cyp450 so you need to check for drug interactions and potential (blank) as a side effect
hepatitis
What are the five general mechanisms of abx resistance?
- enzymatic inactivation of abx
- decreased permeability
- efflux of abx
- mod of molecular target
- failure to convert prodrug to active form
What are the two ways that an abx is enzymatically modified so it doesn’t work?
it is either destroyed or modded so it fails to reach/bind its target
What are the two locations for decreased permeability?
outer membrane permeability (gram neg) or inner (cytoplasmic) membrane permeability (gram neg or pos)
What are some of the modifications to the molecular target of an abx to create resistance?
- altered binding site for abx
- protection of binding site
- overproduction of target (think vancomycin)
- binding up of abx
Resistance to what types of abx is controlled by enzymatic alteration of the abx?
B-lactams and aminoglycosides
Resistance to what types of abx is controlled by efflux of abx?
tetracylcine
Resistance to what types of abx is controlled by altered abx binding site?
B-lactams, glycopeptides, quinolones, rifampin, macrolides, lincosamides, and sulfa/trimeth
T/F: it is always best to choose the shortest effective abx regimen
true
What factor should you consider when prescribing empirically?
local susceptibility trends
What is an abx diffusion test?
Spread isolate on plate, drop on the abx discs, and measure the diameter of inhibition
What does a diffusion test tell you?
estimates the minimum inhibitory concentration of an abx
WHat are the disadvantages to a diffusion test?
non-quantitative interpretation
does not measure bacteriCIDAL activity
inappropriate for slow growers and slow diffusers
In a dilution test, are you diluting solutions of bacteria or abx?
abx
What are you able to calculate using a dilution test?
minimum bactericidal concentratoin–the least amount of abx needed to kill the bacteria
Does a dilution or diffusion test determine bactericidal activity?
dilution test
The (blank) test is influenced by growth rate while the (blank) is not
diffusion is, dilution is not
Which bacterial assay provides quantitative results?
dilution testing
Automated tests are mechanized (blank) tests
dilution
in automated tests, bacterial growth is determined by (blank)
reduction in light transmittance or increase in scattering
What is the advantage of automated tests?
better standardization, produces more info, and rapid results
