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FM 2 > Cell Wall Active Antimicrobials > Flashcards

Cell Wall Active Antimicrobials Flashcards

1
Q

list the types of drugs active against bacterial cell walls

A 
Penicillins
Cephalosporins
Monobactam
Glycopeptides
Cyclic lipopeptides
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2
Q

Explain the mechanism of action for drugs that are active against the bacterial cell wall.

A

Beta-lactams
o Structure: thiazolidine ring, beta-lactam ring, and acyl side chain
o Acyl side chain gives different activity, susceptiblility to beta-lactamase enzymes, and pharmacokinectic properties
Includes:
• Penicillins
• Cephalosporins
• Carbapenems
• Monobactams
MOA:
• Penetrates bacteria and binds to bacterial enzymes called Penicillin Binding Proteins (PSPs)
• Gram-negative bacteria: must first pass through porin before penetrating the peptidoglycan and binding PBP
• Gram-positive bacteria: antibiotic diffuses directly across peptidoglycan and binds PBPs
• Inhibits transpeptidation → no peptidoglycan cross-linking
• Loss of cell wall integrity → cell autolysis (inhibition of the inhibitor for autolysis)
o Beta-lactams are cidal antibiotics

Glycopeptide
o Inhibit synthesis of peptidoglycan (act at earlier stage in cell wall synthesis)
o Ex: vancomycin

Cyclic lipopeptide
o Bind to cell membrane of Gram-positive organisms
o Ex: daptomycin

Lipoglycopeptide
o Telavancin

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3
Q

Describe the major mechanisms by which bacteria develop resistance to cell wall active agents.

A

Enzyme inactivation
o Beta-lactamases can inactivate drugs like penicillins and cephalosporins
o Example of resistant enterobacteriacae
• Klebsiella producing carbapenemase
• KPC and NDM-1 (new Delhi Metallo-beta-lactamase-1)
• Most common in Kebsiella
• Also in E. coli and other enterobacteriaeae
• Resistance to all antibiotics except polymyxins, tigecycline, and rarely aminoglycosides

Alteration in target site
o Altered Penicillin Binding Proteins (PBPs)
• With susceptible bacteria: antibiotic binds PBPs → bacteria cannot make adequate cell wall → growth stops
• With resistant bacteria: antibiotic cannot bind → bacterial growth continues

Altered bacterial membrane
o Ex: change charge/structure of membrane porins → antibiotic can’t penetrate outer membrane of Gram-negatives

Efflux pumps
o Antibiotic permeates cell but is actively pumped back out
o Gram-negative enteric bacilli
o S. pneumonia vs macrolides (relatively new)
o Antibiotics: tetracyclines, quinolones, macrolides

Environmental
o Oxygen tension
• Metronidazole = only in anaerobic environment
• Must get reduced to active form
• Aminoglycosides = enter bacteria through aerobic uptake mechanism
• Can’t enter (so can’t function) in anaerobic environment

More than one

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4
Q

Penicillins: Pharmacology

A

o Time-dependent killing
o Short half life → frequent dosing
• Exception = benathine penicillin G (IM form so longer acting)
o Location
• Oxacillin = good CNS penetration
• Penicillin G not very lipid soluble, but high doses can get it into CSF

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5
Q

Penicillins: sub-groups

A
  • -Natural penicillins (Penicllin G IV form and Penicillin G benzathine IM form)
  • -Aminopenicillins (Amoxicillin)
  • -Semi-synthetic penicillins (dicloxacillin, oxacillin)
  • -Extended spectrum Penicillins (Piperacillin)
  • -Penicillins + beta-lactamase inhibitors (amoxicillin-clavulanic acid; piperacillin-tazobactam)
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6
Q

Natural Penicillins: spectrum

A 
Gram-positives 
o	Streptococci, enterococci, pneumococci 
o	Peptostreptococcus 
o	Listeria, Clostrida 
Gram-negatives 
o	Pasturella, Neisseria meningitides
Spirochets 
o	T. pallidum (syphilis), Borrelia spp (Lyme)
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7
Q

Natural Penicillins: Clinical uses

A 
Streptococcal infections
o	Pharyngitis to cellulitis to endocarditis
Enterococcal infections 
Meningococcal infections 
Syphilis (all stages)
Gas gangrene (Clostridia perfringens)
o	Plus clindamycin to decrease organism toxin production 
Periodontal infections
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8
Q

Aminopenicillins: spectrum

A

Ex. Amoxicillin
Same as penicillin plus most E. coli, Proteus mirabilis, Hemophilus
o Unless beta-lactamase producing

Penicillin Spectrum:
Gram-positives 
o	Streptococci, enterococci, pneumococci 
o	Peptostreptococcus 
o	Listeria, Clostrida 
Gram-negatives 
o	Pasturella, Neisseria meningitides
Spirochets 
o	T. pallidum (syphilis), Borrelia spp (Lyme)
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9
Q

Aminopenicillins: Clinical use

A
  • Upper and lower respiratory tract
  • UTI
  • Enterococcal infections
  • Listeria
  • Endocarditis prophylaxis
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10
Q

Semi-synthetic penicillins: Spectrum

A

Penicillinase-resistant
Ex: dicloxacillin, oxacillin

Spectrum
• Staphylococci
• Streptococci
• NO Gram-negatives or anaerobes

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11
Q

Semi-synthetic penicillins: Clinical use

A
  • Staphylococcal infections (Drug of choice)

* Oxacillin = preferred drug for serious Staphylococcal infections

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12
Q

Extended spectrum penicillins: Spectrum

A

• Ex: Piperacillin

Spectrum 
•	Gram-negative aerobes 
•	Pseudomonas
•	Piperacillin covers enterococci 
•	Still good for Strept and Staph
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13
Q

Extended spectrum penicillins: Clinical use

A
  • Rarely used in this form
  • Instead = used beta-lactamase inhibitor combination forms
  • Pseudomonas infections
  • Polymicrobial infections (in combination with others)
  • Nosocomial infections
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14
Q

Penicillins + beta-lactamase inhibitors: Spectrum

A

Ex: amoxicillin-clavulanic acid; piperacillin-tazobactam
Function:
• Beta-lactamase inhibitor binds beta-lactamase → out of action
• Parent penicillin can now work

Spectrum
•	Same as parent penicillin PLUS beta-lactamase producers:
o	S. aureus
o	E. coli
o	H. influenza
o	Moraxella catarrhalis
o	Klebsiella
o	Bacteroides plus other anaerobes
o	Others
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15
Q

Penicillins + beta-lactamase inhibitors: Clinical use

A
  • Upper and lower respiratory tract
  • Head and neck
  • Cellultis/abscess
  • Intra-abdominal infections
  • Animal and human bites (amoxicillin/clavulanic)
  • Nosocomial infections including Pseudomonas (Piperacillin/tazobactam)
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16
Q

List the representative drug(s) from each generation of Cephalosporin

A 
o	1st: Cephalexin (oral), Cefazolin (IV)
o	2nd: Cefoxitin
o	3rd: Ceftriaxone
o	4th: Cefepime (IV)
o	5th: Ceftaroline (IV)
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17
Q

1st generation Cephalosporin spectrum

A

Cephalexin (oral), Cefazolin (IV)

Spectrum:
• Gram-positive cocci (Streptococci, Staphylococci)
• E. coli
• Klebsiella

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18
Q

1st generation Cephalosporin clinical uses

A

Cephalexin (oral), Cefazolin (IV)

  • Clinical uses:
  • Skin and soft tissue infections due to Staph and Strep
  • Surgical prophylaxis
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19
Q

2nd generation Cephalosporin spectrum

A

Cefuroxime group
o Spectrum= same as 1st generation + Hemophilus and Moraxella

Cephamycin group (includes Cefoxitin)
o	Spectrum = same as 1st generation + anaerobes and more aerobic GNR
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20
Q

2nd generation Cephalosporin clinical uses

A

Cefuroxime group
o Clinical uses = upper and lower respiratory tract infections,

Cephamycin group (includes Cefoxitin)
o	Clinical uses = intra-abdominal and pelvic infections
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21
Q

3rd generation Cephalosporin spectrum

A

Ex. Ceftriaxone

Broad spectrum:
• Excellent Gram-negative aerobe activity
• Excellent streptococcal activity
• Good for S. aureus
• Excellent N. gonorrheae (Ceftriaxone)
• Ceftazadime = excellent for pseudomonas, poor for staph and strep

22
Q

3rd generation Cephalosporin clinical uses

A

Ex. Ceftriaxone

Clinical uses
• Meningitis (ceftriaxone)
• Community acquired pneumonia (ceftriaxone)
• Viridans strep endocarditis (ceftriaxone)
• UTI (ceftriaxone)
• Gonorrhea (ceftriaxone IM, cefexime)
• Intra-abdominal (ceftriaxone + a drug for anaerobes)
• Pseudomonas (ceftazadime)

23
Q

3rd generation Cephalosporin pharmacology

A
  • Long half-life so once daily dosing
  • Dosed 2x daily for CNS infections (excellent CNS penetration)
  • Biliary excretion
24
Q

4th generation Cephalosporin spectrum

A

Ex: Cefepime (IV)

Spectrum
•	S. aureus
•	Streptococci 
•	GNR aerobes 
•	Pseudomonas
•	NO anaerobe
25
Q

4th generation Cephalosporin clinical uses

A

Ex: Cefepime (IV)

Clinical uses
•	Nosocomial infections
•	Febrile neutropenia
•	Pseudomonas infections
•	ESBL producing GNR (some)
•	Mixed Gram-positive and negative infections
26
Q

5th generation Cephalosporin spectrum

A

Ex: Ceftaroline (IV)

Spectrum
•	S. aureus
•	MRSA
•	MRSE
•	Strep
•	Good Gram-negative
•	NO pseudomonas
27
Q

5th generation Cephalosporin clinical uses

A

Ex: Ceftaroline (IV)

  • Pneumonia (Community-acquired)
  • SSTI
  • Many others to come
28
Q

Classes of organisms Cephalosporin does NOT have activity against

A 
NONE have activity against
o	Enterococci
o	Listeria
o	Chlamydia
o	Mycoplasma
29
Q

CNS penetration of Cephalosporin

A

o None in all 1st generation
o Almost all in 2nd generation
o Excellent: ceftriaxone, ceftazadime, cefepime

30
Q

Carbapenems: spectrum

A

Ex: Meropenem (IV)

Broad Spectrum
o Gram-positive
o Gram-negative (including Extended Spectrum Beta-lactamases [ESBL] producers)
o Pseudomonas (Doripenem > rest; NOT ertapenem)
o Anaerobes

31
Q

Carbapenems: do NOT cover these organisms

A 
o	MRSA
o	MRSE
o	E. faecium (including VRE)
o	C. difficile
o	Stenotrophomonas
o	Burkholderia 
o	Ertapenem misses pseudomonas and acinetobacter
32
Q

Properties of carbapenems

A

o Small molecules (able to pass through Gram-negative porins)
o Resistant to many beta-lactamases
o Affinity for PBP from a wide range of bacteria

33
Q

Carbapenems: clinical uses

A 
Serious infections in critically ill patients
•	Nosocomial infections
•	Pseudomonas infections
Meningitis/CNS (meropenem)
Mixed infections
•	Intra-abdominal 
•	Severe skin and soft tissue
34
Q

Monobactam (Aztreonam): spectrum

A

o Gram-negatives (including Pseudomonas)

o No gram-positive or anaerobes

35
Q

Monobactam (Aztreonam): clinical uses

A

o Safe to use with penicillin hypersensitivity
o Niche role: Pseudomonas infections when we cannot use a beta-lactam due to allergy
o Could be used for other GNF aerobes

36
Q

Glycopeptide (Vancomycin): mechanism of action

A

o Binds to D-alanyl-D-alanine portion of peptide precursor unit
o Prevent formation of peptidoglycan cross links
o Results in autolysis BUT cell death is slow

37
Q

Glycopeptide (Vancomycin): pharmacology

A

o Huge molecule = hard to get into CNS
o Poor GI tract absorption
• Oral vancomycin used only for C. difficile because stays in GI tract
o Higher dosing due to increasing MRSA MIC’s

38
Q

Glycopeptide (Vancomycin): spectrum

A 
Gram-positive bacteria 
•	Aerobic and anaerobic GPC
•	Most GPR (but not all)
Important activity against:
•	MRSA
•	MRSE
•	Enterococci (not VRE – vancomycin resistant)
•	Streptococci (including penicillin and cephalosporin resistant S. pneumoniae)
39
Q

Glycopeptide (Vancomycin): clinical uses

A

o MRSA and MRSE serious infections
o Enterococcal infections
o Alternative to beta-lactam when severe allergy present
o Penicillin and cephalosporin-resistant S. pneumoniae in meningitis and other serious pneumococcal infections
o Oral form to treat C difficile

40
Q

Cyclic Lipopeptides (Daptomycin): Mechanism of action

A

o Lipid portion inserts into cytoplasmic membrane
o Loss of membrane potential and ion conduction channel → cell death
o Rapid cidal activity

41
Q

Cyclic Lipopeptides (Daptomycin): pharmacology

A

o Once daily dosing

42
Q

Cyclic Lipopeptides (Daptomycin): spectrum

A 
Gram-positive bacteria:
•	MRSA and MRSE
•	VRE
•	Pneumococci
•	Other streptococci
43
Q

Cyclic Lipopeptides (Daptomycin): clinical uses

A

o Serious infections due to MRSA, MRSE, VRE

o Do NOT use for pneumonia because drug is inhibited by pulmonary surfactant

44
Q

Penicillins: Adverse Reactions

A 
o	Rash
o	Hypersensitivity
o	Diarrhea
o	Interstitial nephritis 
o	Nafcillin = neutropenia, phlebitis
o	Ticarcillin/Piperacillin = high salt load
o	Generally well tolerated
45
Q

Cephalosporins: Adverse Reactions

A

o Generally well tolerated
o Rash (cross reaction with penicillins in 3-7%)
o Diarrhea
o Ceftriaxone = biliary sludging with prolonged use
o Cefepime = mental status changes (be careful in elderly)

46
Q

Carbapenems: Adverse Reactions

A

o Rash and hypersensitivity (cross reaction with penicillins)
o Diarrhea
o Seizure and risk with imipenem (especially when improperly dose-adjusted for renal impairment)

47
Q

Monobactam (Aztreonam): Adverse Reactions

A

o Rash and hypersensitivity

48
Q

Vanomycin: Adverse Reactions

A 
o	Neutropenia
o	Nephrotoxin (when combined with other nephrotoxins)
o	Ototoxicity (rare)
o	“Red Man’s Syndrome”
•	Histamine release from rapid infusion
•	Rash and itching head and neck
49
Q

Daptomycin: Adverse Reactions

A

o Myopathy

50
Q

Concentration vs. Time-dependent Killing

A

Time-dependent killing
o Time above MIC is the parameter that predicts efficacy
o Beta-lactams

Concentration-dependent killing
o Peak/MIC and AUC/MIC ratios are the parameters that predict efficacy
o Aminoglycosides

FM 2 (8 decks)

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