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Mandie Pharm IV > Antimicrobials - Cell Wall synthesis inhibitors > Flashcards

Antimicrobials - Cell Wall synthesis inhibitors Flashcards

1
Q

CW synth inhibitor generalizations

A
  • maximum selective toxicity (inhib peptidoglycan synth and X-linking)
  • inhibit Gram +++&raquo_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
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2
Q

Beta lactamase

A

-multiple types, enzyme outside cell wall, evolved to destroy antibiotic agents

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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

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4
Q

porins

A

membrane PRO that allow drugs in

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5
Q

Penicillin binding protein

A

membrane PRO responsible for tansglycosylation and ranspeptidation of peptidoglycan

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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
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7
Q

fosfomycin uses

A

single dose oral rx of uncomplicated UTI caused by E faecalis and E coli

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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

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9
Q

D cycloserine use

A

restricted second-line M tuberculosis drug

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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

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11
Q

bacitracin uses

A

skin and ophthalmologic infections, good in combination w polymixin B (membrane inhibitor)

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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)

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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
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14
Q

vancomycin spectrum

A
  • narrow

- gram + microbes, most MRSA

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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
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16
Q

vanco SE

A

red man syndrome

-ototoxicity and nephrotoxicity

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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`

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18
Q

beta lactam antibiotic categories

A

PCN
cephalosporins
carbapenems
monobactams

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19
Q

structure of beta lactams

A

-all have B lactam ring (amide in 4 sided ring)

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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
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21
Q

beta lactam antibiotics PK

A

various route of admin

  • will distribution except in CNS
  • renal excretion unmetabolized (except nafcillin, imipenim)
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22
Q

spectrum beta lactam

A

gram + aerobes, csme gram - cocci and stones

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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
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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
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25
Q

PCN G PK

A

-short half-life
-acid-labile, parenteral admin**
2 repository forms for IM injections**

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26
Q

PCN V PK

A
  • short 1/2 life, dosing 4 x per day
  • acid stable (better oral bioavailability)
  • oral admin, absorption 65%
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27
Q

PCN G & V spectrum

A
  • gram + and gram - cocci

- not most gram neg rods/anaerobes

28
Q

PCN G & V SE

A

allergies

  • stevens-Johnson syndrom
  • pcn g: dose dependent neurotox and seizures
29
Q

clinical uses of PCN G & V

A
  • S. PNA (many resistant)
  • viridians group strep
  • Neisseria meningitidis
  • Clostridium
  • treponema pallidum
30
Q

beta lactamase resistant PCN; group includes

A

**oxacillin, dicloxacillin

31
Q

PK of beta lactamase resistant PCN

A

oaxacillin, dicloxacillin

  • most are acid stable
  • food interferes with absorption
  • can be given parenterally
32
Q

beta lactamase resistant PCN spectrum/clinical use

A

penicillinase producing staphylococci and streptococci (methicillin sensitive)

33
Q

beta lactamase resistant PCN resistance

A
  • MRSA (not d/t B lactamsase prod)

- due to PBP with lower affinity for drugs

34
Q

beta lactamase resistant PCN adverse effects

A
  • few more than PNC G/V
  • some cross-reaction allergies
  • oxacillin : hepatitis as high doses
35
Q

PCN extended spectrum drugs: aminopenicillins

PK

A

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
Q

PCN extended spectrum drugs: carboxypenicillins

A

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
Q

PCN extended spectrum drugs: ureidopenicillins

A
  • 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
Q

aminopenicillins spectrum/uses

A

non-lactamase producing gram - bacilli: E coli, H influenza, salmonella, shigella (PK superior to PCN V)

39
Q

beta lactamase inhibitors

MOA

A

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
Q

augmentin

A

beta lactamase inhibitor used in fixed concentrations with extended spectrum PCN
-clavulanic acid + amoxicillin

41
Q

timentin

A

clavulanic acid & ticarcillin

beta lactamase inhibitor used in fixed concentrations with extended spectrum PCN

42
Q

cephalosporins

PK

A

-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
Q

cephalosporin bacterial resistance

A

later gen resistant to beta lactamases

-low affinity PBP, exteded spectrum B lactamases

44
Q

cephalosporin adverse effects

A
  • 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
Q

cephalexin

A

1st generation cephalosporin

  • more acid stability
  • broadest spectrum against gram + cocci, effective against gram - bacilli
  • prophylaxis against bacterial endocarditis in PCN-allergic pt
46
Q

cefuroxime

A

2nd generation cephalosporin

  • antabuse effect and bleeding d/o s.e.
  • only group with significant activity against anaerobes
47
Q

ceftriaxone

A
  • 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
Q

cefepime

A
  • can cause CDAC
  • antipseudomonal
  • high resistance to B lactamases, useful to rx enterobacter and PCN-resistant strep
49
Q

carbapenems

A
  • imipenem and meropenem
  • recent synthetic derivatives of natural prod
  • have B lactam ring, same mech as PCN/cephs
50
Q

carbapenems activity and spectrum

A
  • 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
Q

carbapenems resistance

A

-alt of PBP, carbapenemases

52
Q

carbapenems PK

A
  • parenteral admin
  • renal metabolisma nd inactivation of imipenem
  • admin with cilastatin, inhibits dehydropeptidases, which rapidly dissolves carbapenems
53
Q

imipenem PK

A

-admin with cilastatin, inhibits dehydropeptidases, which rapidly dissolves imipenem (primaxin) (not significant problem for meropenem)

54
Q

carbapenems SE

A

cross allergenic rxn to PCN may be present

rare: GI effects, superinfections, neurotox

55
Q

clinical uses of carbapenems

A

2nd line therapy for serious nosocomial infections

56
Q 
monobactams
MOA
PK
spectrum
SE
A

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
Q

uses for monobactams

A

-gram - UTI, lower RTI, systemic infections

58
Q 
cell membrane agents
-MOA
PK
-Spectrum/uses
-SE
A
  • 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
Q

Why are mitochondrial ribosomes susceptible to PRO synthesis inhibitors

A

mitochondrial ribosomes are more like bacterial ribosomes (30 + 50) than mammalian (40 + 60 S)

60
Q

Where do most PRO synthesis inhibitors work

A

50S subunit of the mitochondrial ribosome

61
Q

tetracyclines MOA

A
  • 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
Q

tetracyclines selective toxicity/spectrum

A
  • affects 70S mitochondrial ribosomes, not cytoplasmic ribosomes
  • very broad spectrum
  • generally more active against gram + than -
  • bacteriostatic
63
Q

tetracyclines resistance

A
  • 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
Q

tetracyclines PK

A
  • 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
Q

clinical uses of tetracycline

A
  • 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
Q

tetracyclines adverse effects

A
  • 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
Q

tetracyclines drug interactions

A
  • 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)

Mandie Pharm IV (12 decks)

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