Antimicrobials - Cell Wall synthesis inhibitors Flashcards
(67 cards)
1
Q
CW synth inhibitor generalizations
A
- maximum selective toxicity (inhib peptidoglycan synth and X-linking)
- inhibit Gram +++»_space; Gram - bc gram + more dependent on peptidoglycan for cell structure integrity
- narrow or extended spectrum
- bactericidal in general –> lysis
- poor penetration of BBB
- oral admin
- renal clearance
2
Q
Beta lactamase
A
-multiple types, enzyme outside cell wall, evolved to destroy antibiotic agents
3
Q
differences b/t gram + / gram - CW
A
gram + has an inner plasma membrane, outer layer of peptidoglycan with beta lactamases on outside of CW
gram - has an inner and outer phospholipid membrane, in between is peptidoglycan layer. beta lactamases surround peptidoglycan layer
4
Q
porins
A
membrane PRO that allow drugs in
5
Q
Penicillin binding protein
A
membrane PRO responsible for tansglycosylation and ranspeptidation of peptidoglycan
6
Q
fosfomycin MOA, PK, spectrum, resistance, toxicity
A
- structural analog of phosphoenol pyruvate, blocks step 1 PDG synthesis
- well absorbed and distributed, excreted unchanged in urine
- broad spectrum
- rapid resistance
- few adverse effects: diarrhea, vaginitis
7
Q
fosfomycin uses
A
single dose oral rx of uncomplicated UTI caused by E faecalis and E coli
8
Q
D-cycloserine MOA, PK, spectrum, toxicity
A
MOA: structural analog of D-alanine, blocks step 2 of PDG synthesis
PK: oral, good CNS penetration, active form in urine
-broad spectrum (both gram neg and positive)
-serious CNS effects, dose related and reversible
9
Q
D cycloserine use
A
restricted second-line M tuberculosis drug
10
Q
bacitracin MOA, PK, spectrum, SE
A
-depletes lipid carrier to PDG synthesis (interferes with recycling of lipid carrier)
-PK: topical application only, poorly absorbed
-narrow spectrum (gram +, neisseria, T. pallidum)
SE: severe nephrotoxicity
-bactericidal
11
Q
bacitracin uses
A
skin and ophthalmologic infections, good in combination w polymixin B (membrane inhibitor)
12
Q
vancomycin structure & MOA
A
-glycopeptide
-binds D-Ala-D-Ala terminus of pentapeptide
-blocks PDG synthesis by binding the substrate**
rapidly bactericidal for dividing bacterial cultures except enterococci (static)
13
Q
vancomycin PK
A
- IV admin (slow) [not IM except intestinal infection]
- rarely oral d/t poor absorption
- distribution excelling (bone, CNS if meninges inflamed)
- renal excretion
14
Q
vancomycin spectrum
A
- narrow
- gram + microbes, most MRSA
15
Q
2 mechanisms of resistance to vancomycin
A
- VRE: enterococci can have vanA, vanB, or van C genes (can be transferred b/t cell organisms), bacteria make diff cell wall subunits with reduced binding to vanco
- VRSA: S. aureus overexpresses D-Ala-D-Ala
16
Q
vanco SE
A
red man syndrome
-ototoxicity and nephrotoxicity
17
Q
vancomycin clinical uses
A
-reserved for serious gram + infections resistant to other less toxic drugs as determined by lab culture and sensitivity tests
-MRSA
-po for antibiotic associated C diff
-penicillin resistant S. pneumonia
combination with aminoglycosides = synergistic`
18
Q
beta lactam antibiotic categories
A
PCN
cephalosporins
carbapenems
monobactams
19
Q
structure of beta lactams
A
-all have B lactam ring (amide in 4 sided ring)
20
Q
beta lactam antibiotics generalizations
A
1- inhibitis transpeptidases (PBP)
- activate autolytic enzymes in CW
- bactericidal : bacteria must be dividing
- time dependent action (takes awhile to work)
- R amino groups have pharmacologic properties
21
Q
beta lactam antibiotics PK
A
various route of admin
- will distribution except in CNS
- renal excretion unmetabolized (except nafcillin, imipenim)
22
Q
spectrum beta lactam
A
gram + aerobes, csme gram - cocci and stones
23
Q
beta lactam resistance
A
- production of beta bactamases/peniucillinases
- alteration of targaret PFP (decreased affinity for job)
- alteration of outer membrane PRO, prevents drug from meeting PBP (gram neg)
- increased efflux pump activity
24
Q
beta lactam SE/toxicity
A
- allergy (1-10%) of patients, cross sensitization to chemically related drugs not as much as previously thought
- acute/anaphylactic; accelerated shock (30 mins to 2 days), delayed (2 or more days after admin, mild/reversible rash [80-90%])
- minimal toxicity, maximal selective toxicity
- tissue irritation, phlebitis with IV admin
- can lead to super infections
25
PCN G PK
-short half-life
-acid-labile, parenteral admin**
2 repository forms for IM injections**
26
PCN V PK
- short 1/2 life, dosing 4 x per day
- acid stable (better oral bioavailability)
- oral admin, absorption 65%
27
PCN G & V spectrum
- gram + and gram - cocci
| - not most gram neg rods/anaerobes
28
PCN G & V SE
allergies
- stevens-Johnson syndrom
- pcn g: dose dependent neurotox and seizures
29
clinical uses of PCN G & V
- S. PNA (many resistant)
- viridians group strep
- Neisseria meningitidis
- Clostridium
- treponema pallidum
30
beta lactamase resistant PCN; group includes
**oxacillin, dicloxacillin
31
PK of beta lactamase resistant PCN
oaxacillin, dicloxacillin
- most are acid stable
- food interferes with absorption
- can be given parenterally
32
beta lactamase resistant PCN spectrum/clinical use
penicillinase producing staphylococci and streptococci (methicillin sensitive)
33
beta lactamase resistant PCN resistance
- MRSA (not d/t B lactamsase prod)
| - due to PBP with lower affinity for drugs
34
beta lactamase resistant PCN adverse effects
- few more than PNC G/V
- some cross-reaction allergies
- oxacillin : hepatitis as high doses
35
PCN extended spectrum drugs: aminopenicillins
PK
ampicillin, amoxicillin
- spectrum extended vs PCN V/G
- can be destroyed by beta lactamase
- used with beta lactamase inhibitors
acid stable, oral admin, amoxicillin > ampicillin absoprtion (amoxi not affected by food)
t1/2 1.5h, BID/TID
36
PCN extended spectrum drugs: carboxypenicillins
ticarcillin
- spectrum extended vs PCN V/G
- can be destroyed by beta lactamase
- used with beta lactamase inhibitors
- parenteral admin
- antipsuedomonal
- rarely used alone
37
PCN extended spectrum drugs: ureidopenicillins
- piperacillin
- spectrum extended vs PCN V/G
- can be destroyed by beta lactamase
- used with beta lactamase inhibitors
- parenteral admin
- anti-pseudomonal
- reserved for serious systemic infections caused by klebsiella or psudomonas infections (often in combo with aminolycoside, to prevent resistance)
38
aminopenicillins spectrum/uses
non-lactamase producing gram - bacilli: E coli, H influenza, salmonella, shigella (PK superior to PCN V)
39
beta lactamase inhibitors
| MOA
calvulanic acid, sulbactam, tazobactam
MOA: structurally related to PCN, beta lactamase suicide inhibitors (irreversibly inhibit b lactamase)
-poor antibiotic activity alone
-used in fixed concentrations with extended spectrum PCN
40
augmentin
beta lactamase inhibitor used in fixed concentrations with extended spectrum PCN
-clavulanic acid + amoxicillin
41
timentin
clavulanic acid & ticarcillin
| beta lactamase inhibitor used in fixed concentrations with extended spectrum PCN
42
cephalosporins
PK
-most widely hospital-rx antibiotics
-similar to PCN in chemical structure and MOA and adverse effects (allergy most common)
4 generation based on spectra of activity
-pk: acidi stability better w 1st gen; not topical application, some orally or IV/IM
43
cephalosporin bacterial resistance
later gen resistant to beta lactamases
| -low affinity PBP, exteded spectrum B lactamases
44
cephalosporin adverse effects
- overall v safe
- cutaneous allergy, cross-allergy with PCN (not for pt with anaphylaxis to PCN)
- disulfiram-life reaction (antabuse effect) and bleeded d/o with 2nd/3rd gen
- pseudomembranous colitis (CDAC) w 3rd and 4th gen
45
cephalexin
1st generation cephalosporin
- more acid stability
- broadest spectrum against gram + cocci, effective against gram - bacilli
- prophylaxis against bacterial endocarditis in PCN-allergic pt
46
cefuroxime
2nd generation cephalosporin
- antabuse effect and bleeding d/o s.e.
- only group with significant activity against anaerobes
47
ceftriaxone
- can cause CDAC, antabuse effect and bleeding d/o
- use: antipseudomonal and penuococcal, serious gram - infections such as meningitis, PNA, gonorrhea
- prophylaxis against bacterial endocarditis in PCN-allergic pt
48
cefepime
- can cause CDAC
- antipseudomonal
- high resistance to B lactamases, useful to rx enterobacter and PCN-resistant strep
49
carbapenems
- imipenem and meropenem
- recent synthetic derivatives of natural prod
- have B lactam ring, same mech as PCN/cephs
50
carbapenems activity and spectrum
- bind more efficiently with PBP than PCN/Cephs
- penetrate outer membrane of gram - bacteria
- broadest activity of all B lactam drugs
- resistant to degredation by most B lactamases, but induce those than inactivate PCN/cephs
- antagonize action of PCN/cephs
- active against extended spectrum b lactamase prod organisms
51
carbapenems resistance
-alt of PBP, carbapenemases
52
carbapenems PK
- parenteral admin
- renal metabolisma nd inactivation of imipenem
- admin with cilastatin, inhibits dehydropeptidases, which rapidly dissolves carbapenems
53
imipenem PK
-admin with cilastatin, inhibits dehydropeptidases, which rapidly dissolves imipenem (primaxin) (not significant problem for meropenem)
54
carbapenems SE
cross allergenic rxn to PCN may be present
| rare: GI effects, superinfections, neurotox
55
clinical uses of carbapenems
2nd line therapy for serious nosocomial infections
56
```
monobactams
MOA
PK
spectrum
SE
```
aztreonam
- binds PBP, relatively resistant to beta-lactamases
- IM or IV, drug penetrates inflamed CNS
- no significant x-reactivity with PCN
spectrum: narrow--gram - aerobes like pseudomonals (not gram + or anaerobes)
57
uses for monobactams
-gram - UTI, lower RTI, systemic infections
58
```
cell membrane agents
-MOA
PK
-Spectrum/uses
-SE
```
- daptomycin
- MOA: novel cyclic lipopeptide, causes membrane depolarization
- pokes holes in cell membranes in presence of Ca
- bactericidal
- PK: IV admin (90% PRO bound)
- renal elim
spectrum: similar to vanco, but rx of VRE/MRSA
- myopathy
59
Why are mitochondrial ribosomes susceptible to PRO synthesis inhibitors
mitochondrial ribosomes are more like bacterial ribosomes (30 + 50) than mammalian (40 + 60 S)
60
Where do most PRO synthesis inhibitors work
50S subunit of the mitochondrial ribosome
61
tetracyclines MOA
- tetracycline, doxycycline, minocycline
- reversible binding to the 30S subunit of the bacterial ribosome
- blocks aminoacyl tRNAs from entering the A site of the ribosome
62
tetracyclines selective toxicity/spectrum
- affects 70S mitochondrial ribosomes, not cytoplasmic ribosomes
- very broad spectrum
- generally more active against gram + than -
- bacteriostatic
63
tetracyclines resistance
- decreased intracellular levels from decreased influx or increased efflux (pump)
- expression of PRO that protect ribosomes from drug
- enzymatic inactivation of drug
- widespread resistance has limited clinical use
64
tetracyclines PK
- absorption: oral admin yields variable absorption, decreased by divalent and trivalent cations (dairy, antacids, iron), decreased absorption when gastric pH is elevated
- distribution: wide, accumulation in liver, spleen, BM, bones, dentine, and enamel of unerupted teeth; good penetration into CNS and crosses placenta
- elim: excretion via kidneys, some passage into small intest via bile; except: doxycycline not eliminated via kidneys, elminated as an inactive chelate or conjugate in feces (reduced GI complications, lesser impact on normal flora)
- minocycline: metabolized by liver, passed in fecces
65
clinical uses of tetracycline
- acne
- drug of choice for rx of rickettsial diseases
- chlamydia, mycoplasma pneumoniae, yersinia pestis, borrelia (lyme disease)
- periodontitis: systemic tetracyclines for rx of periodontitis may have limited benefit and limited long-term efficacy; weigh against risk of propagating antibiotic resistance and efficacy of mechanical therapy
66
tetracyclines adverse effects
- GI irritation and superinfections (including CDAC)
- photosensitivity
- hepatotoxicity
- renal tox
- discoloration of teeth (fetal and childhood sisks, should not be given to pregnant women or to children
67
tetracyclines drug interactions
- may compromise efficacy of bactericidal antibiotics b//c they work best against dividing cells and tetracyclines slow division
- can alter phamacological activity of drugs (digoxin increased absoprtion, warfarin competition for plasma PRO binding)
