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1. HDS Cardiology > Cell Wall Inhibtors and Abx Resistance > Flashcards

Cell Wall Inhibtors and Abx Resistance Flashcards

1
Q

Selective Toxicity

A

Antibacterial but not toxic to the host

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2
Q

Cell Wall Synthesis Inhibitors

A
  • β-lactams
    • Penicillins
    • Cephalosporins
    • Carbapenems
    • Monopenems
  • Glycopeptides
    • Vancomycin
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3
Q

30s subunit

Protein Synthesis Inhibitors

A
  • Aminoglycosides
    • Amikacin
    • Kanamycin
    • Gentamicin
  • Tetracyclines
    • Doxycycline
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4
Q

50S subunit

Protein Synthesis Inhibitors

A
  • Macrolides
    • Erythromycin
    • Clarithromycin
    • Azithromycin
  • Lincosamides
    • Clindamycin
  • Chloramphenicol
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5
Q

DNA Gyrase Inhibitors

A

Quinolones

e.g. Ciprofloxacin

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6
Q

RNA polymerase Inhibitors

A

Rifamycins

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7
Q

Folate Synthesis Inhibtors

A
  • Target dihydropteroate synthase
    • Sulfonamides
      • Sulfamethoxazole
  • Target dihydrofolate reductase
    • Trimethoprim
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8
Q

Other Abx Types

A
  • Nitroimidazoles
    • Metronidazole
      • Anaerobes
  • Daptomycin
    • Membrane
  • Mupirocin
    • Isoleucin tRNA synthetase
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9
Q

Agar Disk Diffusion Method

(Kirby-Bauer)

A

Provides qualitative results: S/I/R

  • Bacteria swabbed on agar plate
  • Antibacterial disk placed on surface
  • Incubate overnight
  • Measure diameter of zone of growth inhibition
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10
Q

Broth Dilution Method

(MIC)

A

Provides quantitative results in μg/ml.

  • Minimum inhibitory concentration (MIC) ⇒ Lowest concentration of abx that inhibits growth of test organism
  • Better guide to therapy
  • Look at the first well without growth
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11
Q

Minimum Bactericidal Concentration

(MBC)

A

Minimum concentration of abx that kills the organism.

  • Take 0.1 ml from MIC endpoint well
  • Grow for 48 hours
  • Drug concentration that reduced starting inoculum by 99.9%
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12
Q

Synergy

A

Effect of drug combo is greater than sum of the individual drugs independently.

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13
Q

Additive

(Indifferent)

A

Sum = components

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14
Q

Antagonism

A

Combo < more active drug alone

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15
Q

Antibacterial Resistance

Mechanisms

A
  1. Enzymatic inactivation of abx
  2. Modification of Abx target
  3. Altered membrane permeability
    • Dec. uptake or inc. efflux
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16
Q

Enzymatic Inactivation of Abx

A
  1. Hydrolysis
    • Beta-lactamase ⇒ PCN and cephalosporins
      • Plasmid & chromosomal
  2. Modification by acetylation, adenylation, phosphorylation
    • Aminoglycosides ⇒ chloramphenicol
      • Plasmid
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17
Q

PCN & Cephaloporins

Modification of Abx Targets

A

Altered penicillin-binding protein (PBP)

Chromosomal

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18
Q

Aminoglycosides

Modification of Abx Targets

A

Altered 30S Subunit

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19
Q

Macrolides

Modification of Abx Targets

A

Erythromycin, clarithromycin, etc.

methylation of 23S rRNA of 50S subunit

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20
Q

Quinolones

Modification of Abx Targets

A

Altered DNA gyrase

Chromosomal

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21
Q

Penicillins & Cephalosporins

Altered Membrane Permeability

A

Decreased outer membrane porin proteins

(OmpF)

Channels for abx entry

(Chromosomal)

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22
Q

Imipenem, Aminoglycosides, Quinolones

Altered Membrane Permeability

A

Decreased outer membrane permeability

(Chromosomal)

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23
Q

Tetracyclines

Altered Membrane Permeability

A

Efflux pump

(Plasmid & Chromosomal)

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24
Q

Macrolides

Altered Membrane Permeability

A

Efflux pump

(msrA gene)

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25
Q

Methicillin

A
  • First β-lactamase stable penicillin
  • Now 46% of S. aureus resistant
    • Use oxacillin or nafcillin
  • Often cross-resistant to non-β-lactams ⇒ “multiple-resistant S. aureus”
    • Use vancomycin
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26
Q

MRSA

Mechanism

A
  • Acquisition of mecA gene encoding PBP2a
    • Transpeptidase with very low β-lactam affinity
    • Cross resistant to non-β-lactam abx
    • Expression in bacterial populations may be low ⇒ heterogeneous resistance
      • Detect w/ PCR for mecA gene or agglutination test for PBP2a
  • β-lactamase overproduction
  • Modification of existing PBPs
27
Q

VRE

Mechanism

A

Vancomycin binds d-Ala-d-Ala.

  • High level resistance
    • Substitute D-lactate for terminal D-Ala
    • Incorporation into peptidoglycan can still occur
    • Vancomycin cannot bind and inhibit
    • VanA, VanB, VanD strains
  • Low level resistance
    • Substitute D-Ser for D-Ala
    • VanC, VanE, VanG strains
  • Resistance currently limited to Enterococci
    • May eventually transfer to Staph
28
Q

Abx Resistance

Genetic Origins

A
  • Chromosomal
    • Point mutations
    • Low frequency
  • Plasmid
    • Same or related species
    • Low freq. by transformation
    • High freq. by conjugation
  • Phage
    • Most common
    • Lytic phage ⇒ generalized transduction
    • Lysogenic phage ⇒ specialized transduction
  • Transposon
    • Abx resistance genes flanked by two IS
29
Q

Gene Transfer

Mechanisms

A
  • Transformation
    • Free DNA
    • Ex. Strep pneumoniae ⇒ chromosomal beta-lactamase genes
  • Transduction
    • Lytic phages
    • Ex. S. aureus ⇒ acquired beta-lactamase gene
  • Conjugation
    • Plasmids
    • Machinery encoded by Tra genes
    • Ex. Enterobacteria & other gram neg ⇒ most common method of transferring multidrug resistance
30
Q

Bacitracin

A
  • ⊗ Batoprenol
    • Prevents transport of cell wall monomers out of the cell
  • Only used topically
  • Treat minor skin and eye infections caused by Staph and Strep
31
Q

Glycopeptides

A
  • Vancomycin and Dalbavancin
  • Time-dependent
  • Poor bioavailability
  • Spectrum
    • Gram pos. aerobe and anaerobes including MRSA
  • Does NOT kill beta-lactam susceptible Staph as fast as beta-lactams
32
Q

Vancomycin

A
  • Binds a-alanyl-d-alanine ⇒ ⊗ cell wall synthesis
  • Covers many gram pos. resistant to other abx
    • MRSA
    • MSSA
    • Strep
  • Some enterococci resistant ⇒ VRE
  • PO only for C. diff
  • IV can cause flushing ⇒ “red man syndrome”
    • Slow infusion rate and give antihistamines
  • Associated with nephrotoxicity and ototoxicity
    • Inc. renal damage possible with concurrent nephrotoxins
33
Q

Penicillin Binding Proteins

(PBP)

A
  • Enzymes located on the cytoplasmic membrane
  • Responsible for cell wall synthesis
    • Some have transpeptidase activity
  • Inhibited by beta-lactam abx
34
Q

Beta-Lactams

A
  • All contain a beta-lactam ring
    • Opens up and binds PBPs
  • Substitutions alter pharmacologic profile
35
Q

Beta-Lactam

Pharmacokinetics

A
  • Most are time-dependent
  • Most eliminated via renal tubular secretion
    • Except nafcillin, aztreonam, and some cephalosporins
  • PCN widely distrubted to most tissues except CNS
    • Will cross BBB is meninges inflamed
      • Can be used to treat meningitis
36
Q

Probenecide

A
  • Used to treat gout
  • Inhibits tubular secretion
  • Prolongs half-life of renally excreted beta-lactams
37
Q

Beta-lactam

Hypersensitivity

A
  • Penicillioic acid combines with host proteins to form Ag
  • Results in hypersensitivity reactions
38
Q

Beta-lactam

Allergies

A
  • Patient reported drug allergies unreliable
    • True PCN allergies in 7-23% of pts reporting hx of allergy
    • PCN allergy can be confirmed through skin test
    • Desensitization protocol when PCN needed in pt with an allergy
  • Cephalosporins
    • Lower incidence of hypersensitivity than PCN
    • 5% cross-reactivity w/ PCN allergies
  • Carbapenems
    • 1% cross-reactivity w/ PCN allergies
  • Aztreonam
    • No cross-reactivity w/ PCN allergies
39
Q

Beta-Lactams

Adverse Effects

A
  • Hypersensitivity reactions
  • Ampicillin
    • Likely to cause skin rash in pts w/ certain viral infections like monomucleosis
  • PCN @ high doses
    • Seizures
    • Disrupt gut flora ⇒ diarrhea and superinfections like C. diff
      • Esp. 3rd/4th gen. cephalosporins, fluoroquinolones, carbapenems, clindamycin
40
Q

Penicillin Resistance

Mechanisms

A
  • Inactivation of abx by beta-lactamase
    • Chromosomal and plasmid expression
    • Constitutive or inducible expression
    • Ex. Staph to Penicillin G
  • Reduced affinity of PBP for abx
    • Ex. Staph to methicillin
  • Decreased entry of the drug into bacteria through outer membrane porins
    • Ex. Gram neg. to various beta-lactams
41
Q

Narrow-Spectrum Penicillins

A

“Natural Penicillins”

  • Meds:
    • Penicillin G ⇒ IV
    • Pencillin V ⇒ PO
    • Procaine and benzathine penicillin ⇒ long acting depot
  • 30 min half-life ⇒ frequent doses
  • Most bacteria are resistant
  • Useful spectrum:
    • Strep
    • Enterococci
    • Treponema pallidum
  • Main uses:
    • Susceptible strep infections
    • Syphilis
42
Q

Penicillinase-Resistant

Penicillins

A

“Antistaphylococcal”

  • Meds:
    • Nafcillin
      • Hepatically eliminated
      • High incidence of phlebitis
    • Oxacillin
    • Dicloxacillin
      • Not routinely used d/t dosing issues
  • Spectrum:
    • MSSA
    • Strep
  • Uses:
    • Suseptible staph infections
      • Endocarditis, osteomyelitis, cellulitis
  • If staph resistant to one, resistant to all ⇒ MRSA
  • Kill staph faster than vancomycin, should be used if suseptible
43
Q

Penicillinase-sensitive

Aminopenicillins

A

“Extended-spectrum penicillins”

  • Drugs:
    • Amoxicillin ⇒ IV, PO
    • Ampicillin ⇒ PO
  • Spectrum:
    • Strep
    • Enterococci
    • Listeria
    • H. pylori
    • Some non-beta-lactamase producing GNR
  • Uses:
    • URI
    • UTI
    • PUD
    • Enterococcal infections
  • Suseptible to beta-lactamases
  • Amino group ⇒ improved gram neg. activity
  • High incidence of diarrhea when given PO
44
Q

Amoxicillin

A
  • IV or PO
  • Higher bioavailability than ampicillin
  • Uses:
    • Prophylaxis for endocarditis in susceptible pts
    • Susceptible enterococci
45
Q

Ampicillin

A
  • Must be used w/ aminoglycoside for enterococci
    • Protein synthesis inhibitor
  • Used for serious infections
    • Endocarditis
46
Q

Beta-lactamase Inhibitor

Combinations

A
  • Aminopenicillins ⇒ intrinsic activity against GNR
  • Beta-lamtamase inhibitors ⇒ allow drug to exert effect
  • Good for empiric therapy for hospital acquired infections
    • Activity against aerobe and anaerobes
  • Good for mixed infections
    • Intra-abdominal infections
    • Diabetic ulcers
    • Aspiration PNA
47
Q

Antipseudomonal Penicillins

Penicillinase-sensitve

A
  • Meds:
    • Piperacillin ± tazobactam
    • Ticarcillin
  • Useful spectrum ⇒ parent drug + most beta-lactamase producing bacteria
    • Pseudomonas
    • Strep, MSSA, enterococci
    • Anaerobes
      • b. fragilis and other gut bacteria
    • Better GNR coverage than parent drug along
  • Active against pseudomonas and other drug-resistant GNR
    • Common hospital acquired infection
  • Tazobactam ⇒ beta-lactamase inhibitor
    • Restores coverage for MSSA
48
Q

Cephalosporins

A
  • Classified by generation
  • More resistant to beta-lactamase than PCN
  • Most have poor activity against anaerobes
49
Q

1st Gen

Cephalosporins

A
  • Meds:
    • Cefazolin ⇒ IV
    • Cephalexin ⇒ PO
  • Renal elimination
  • No CNS penetration
  • Useful spectrum:
    • MSSA
    • Strep
    • Some GNR
  • Main uses:
    • Surgical prophylaxis
    • Cellulitis
50
Q

2nd Gen

Cephalosporins

A
  • Meds:
    • Cefaclor
    • Cefuroxime
    • “Cephamycins”
      • Cefoxitin
      • Cefotetan
  • Better gram neg. and slightly weaker gram pos. activity compared to 1st gen
  • Most numerous, least commonly used
  • No CNS penetration
  • Main uses:
    • URIs
    • Surgical prophylaxis ⇒ cephamycins
51
Q

Cephamycins

A

Active against many anaerobes in GI tract.

Used for surgical prophylaxis in abdominal surgery.

  • Cefoxitin
  • Cefotetan
    • N-methylthiotetrazole (MTT) side chain
      • ⊗ Vit K production
        • Prolongs bleeding
      • ⊗ acetaldehyde dehydrogenase
        • Causes flushing with ETOH ⇒ disulfiram-like reaction
52
Q

3rd Gen

Cephalosporins

A

Broad spectrum agents

  • Meds:
    • Ceftriaxone
    • Cefotaxime
    • Cefpodoxime
    • Ceftazidime ± avibactam
      • No gram pos. coverage
      • Covers pseudomonas
  • Enters CNS
  • Compared with 2nd gen
    • ↑ Gram neg.
    • ↑ Strep
    • ↓ Staph
  • Main uses
    • Meningitis
    • CAP/HAP
    • Lyme disease
    • Skin and soft tissue infections
    • UTI
    • Febrile neutropenia
    • Gonorrhea
53
Q

Ceftriaxone

A
  • Dual elimination ⇒ liver and renal
    • No dose adj. for renal function
  • Uses:
    • Hospital aq. meningitis and HAP
      • Strep. pneumonae coverage
    • CAP
      • Strep. pneumonae most common
    • Lymes disease
    • Skin/soft tissue
      • Not great but convient qDay dose
    • UTI
    • Gonorrhea
  • Ceftriaxone + Azithromycin for chlamydia
54
Q

Cefpodoxime

A

Has MMT Side Chain.

⊗ Vit K production

⊗ acetaldehyde dehydrogenase ⇒ disulfiram-like reaction

55
Q

Ceftazidime

A
  • No gram + coverage
  • Does cover pseudomonas
  • Given with avibactam
    • Cephalosporin/beta-lactamase inhibitor combo
  • Combo active against many gram neg. bacteria
    • Treat complicated intraadominal and urinary tract infections
56
Q

4th Gen

Cephalosporin

A

Cefepime

  • Broadest spectrum cephalosporin
    • Gram neg
    • Gram pos
    • Pseudomonas
    • Not as good against anaerobes
  • More rapid penetration
  • Able to bind multiple PBPs
  • Lower affinity for several beta-lactamases
  • Given IV only
  • Enters CNS
  • Good for many hospital aq. infections
  • Overkill for community-aq. infections
57
Q

Advanced-Gen

Cephalosporin

A

Ceftaroline

  • Only cephalosporin with MRSA coverage
    • Designed to bind PBP 2a of MRSA
    • Think of it like Ceftriaxone + MRSA
  • Spectrum:
    • MRSA
    • MSSA
    • Strep
    • Enteric GNR
  • No pseudomonas coverage
  • Modest activity against Enterococcus faecalis
  • None against Enterococcus faecium
  • Uses:
    • Skin and soft tissue infections
    • CAP
58
Q

Monobactams

A

Aztreonam

  • Used for gram neg. infections in pts w/ beta-lactam allergies
    • Including pseudomonas
  • Safe to give to pts w/ beta-lactam allergies
    • Except if they are allergic to Ceftazidime
  • Enters CNS
  • Penetrates tissues well
  • Renally elimiated
59
Q

Carbapenems

A

The most broad spectrum antibiotic.

  • Meds:
    • Imipenem/cilastin
    • Doripenem
    • Ertapenem
    • Meropenem
  • 1% cross-reactivity w/ PCN allergies
  • All drugs have simiar spectrum except ertapenem
    • MSSA, Strep, E. faecalis, anaerobes
    • Many GNR including Pseudomonas
  • Drugs of choice for extended-spectrum beta-lactamase (ESBL) producing GNR
    • Including E. coli and Klebsiella pneumoniae
  • Main uses:
    • Nosocomial infections
    • Mixed aerobic/anaerobic infections
    • Febrile neutropenia
  • All given IV only
  • Renal elimination
  • Higher incidence of seizures
  • Causes nausea ⇒ rate-related
60
Q

Ertapenem

A
  • NOT effective against Pseudomonas and Acinetobacter
  • Longest half-life ⇒ used for outpatient infusion therapy for susceptible infections
61
Q

Imipenem

A
  • Highest incidence of seizures
    • Avoid in pts w/ meningitis
      • More likely to enter CNS
  • Metabolized in the kidneys to nephrotoxic product
    • ALWAYS given with Cilastin
      • Blocks this reaction
62
Q

Membrane Integrity Disruptors

A
  • Meds:
    • Daptomycin
    • Colistin, Polymixin B
  • Cyclic lipopeptides
    • Inserts into cell membrane
    • Bactericidal
63
Q

Daptomycin

A
  • Cyclic lipopeptide
  • Concentration-dependent
  • Poorly absorbed
    • Inactivated by surfactant ⇒ inactive in lungs
  • Excreted renally
  • Spectrum
    • Gram pos. aerobes and anaerobes
      • Including MRSA and VRE
  • Uses:
    • Bacteremia
    • Skin and soft tissue infections
    • Endocarditis
  • Adverse effects:
    • Creatine kinase elevation
    • Myopathy
    • Rhabdomyolysis
64
Q

Polymyxins

A

Colistin (Polymixin E) & Polymyxin B

  • MOA: Bind cell membrane of gram neg. distrupting permeability
  • Poor bioavilability
  • Colistin is excreted renally
  • Polymyxin B is not
  • Given by inhalation, IV, or topical
  • Spectrum:
    • Gram neg. organisms
      • MDR Pseudomonas
      • Acinetobacter
      • Klebsiella
  • Inactive against Serratia, Providentia
  • Uses:
    • MDR GNR infections
    • Topical infections
    • Prophylaxis of PNA in colonized CF patients
  • Adverse effects:
    • Nephrotoxicity ⇒ common
    • Neurotoxicity ⇒ uncommon

1. HDS Cardiology (7 decks)

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