4/9 Antibacterials I/II: Cell Wall Agents Flashcards
1
Q
what does Penicillin, Cephalosporin, Monobactam, Carbapenem have in common? What confers each specificity?
A
common structure: ß lactam ringspecificity
2
Q
Penicillin, Cephalosporin, Monobactam, Carbapenem all have a common function:
A
Antimicrobial agents that work by inhibiting cell wall synthesis
3
Q
in general, how are Penicillin, Cephalosporin, Monobactam, Carbapenem inactivated?
A
ß lactamase enzymes - cleave the ß-lactam ring (essential for activity)
4
Q
Why do carbapenems additional stability (more resistant to ß lactamases) over the rest of the drugs?
A
the H next to the keto group is oriented ABOVE the plane, and this configuration seems to stabilize the molecule, and make it more resistant to ß-lactamases (others: below)
5
Q
What type of hypersensitivity reaction does penicillin usually cause?What type of physical manifestations?
A
IgE Type I Hypersensitivity(rash, hives, angioedema, anaphylaxis).
6
Q
If one is severely allergic to penicillin, what other drugs are they likely to be allergic too as well?
A
Cephalosporin, Monobactam, Carbapenem
7
Q
Which one is the safest to use if if the patient had a mild allergic reaction? Why?
A
monobactam, since it looks the least like penicillin (it doesn’t have the second ring) and is least likely to trigger IgE compared to the other ones
8
Q
Structure of penicillin?
A
all contain Ring A (thiazolidine ring) attached to Ring B (ß-lactam ring)
9
Q
MoA of penicillin?
A
bind covalently to Penicillin-binding proteins (PBP’s) at the active site, thereby interfering with the transpeptidase reaction, a reaction that is critical in bacterial cell wall synthesis”bactericidal”
10
Q
how does resistance develop against penicillin?
A
1) Inactivation by ß-lactamase
2) Modification of target PBP
3) Impaired penetration of the cell (ex: ∆ porin channel)
4) Presence of a new efflux pump
11
Q
how does MRSA develop?
A
Modification of target PBP
12
Q
What drugs are in the Benzopenicillin class?
A
Penicillin G
Penicillin V
13
Q
sensitivity of penicillin G to ß lactamases?
A
sensitive
14
Q
How is Penicillin G administered?
A
parenteral (poor oral bioavailability)
- Procaine suspn (IM); duration 1-2 days
- Benzathine suspn (IV); duration 1-4 wks; great for kids
15
Q
How is Penicillin V administered?
A
PO; very stable in stomach acid
16
Q
Penicillins are effective in treating these bugs
A
- Gram (+)
- strep. pneumo
- S. pyogenes
- Actinomyces
- GNC
- N. meningitides
- Spirochetes (T. pallidum)
17
Q
what bugs are resistant to penicillin?
A
Staph (>85%)
Pneumococcus (10-30%)
bowel anaerobes
gonorrhea (Pen G)
most GNR’s
18
Q
Contraindications of penicillin?
A
Pen-allergic patients
19
Q
Side Effects of penicillins?
A
1) drug allergy especially rash, anaphylaxis
2) anemia (binds to RBC and induces hemolysis)
3) Seizures following high doses
20
Q
Drug interactions with penicillins?
A
- synergy with gentamicin against staph and enterococcus
- probenecid inhibits renal active tubular secretion
21
Q
What situations would warrant penicillin treatment?
A
- Streptococcal pharyngitis and skin infections
- Pneumonia
- Meningitis
- Endocarditis - if organism is sensitive
- Dental infection (by microaerophilic streptococcus)
- Syphilis
- Prevent rheumatic fever (GrpA ß hemolytic strep complication)
22
Q
Drugs in the Aminopenicillins class?
A
Ampicillin
Amoxicillin
23
Q
sensitivity of aminopenicillins to ß lactamases?
A
sensitive (its nearly identical to penicillin)
24
Q
mechanism of action of aminopenicillins?
A
binds PBP’s and inhibits the assembly of the bacterial cell wall, bactericidal
25
How is ampicillin different than amoxicillin?
Ampicillin - PO or IV
Amoxicillin - PO (higher oral bioavailability) - newer version of ampicillin with slightly wider spectrum of action; less likely to cause diarrhea
26
what bugs are sensitive to aminopenicillins?
extended spectrum of action
* Haemophilus influenza
* E. coli
* Listeria monocytogenes
* Proteus mirabilis
* Salmonella
* Shigella
* Enterococcus
Amp HELPSS to kill enterococci
27
What bugs are resistant to aminopenicillins?
1. most staph
2. some pneumococcus (\>30%)
3. some H. flu
4. bowel anaerobes
5. some GNRs
28
SE of aminopenicillins?
1. drug allergy especially rash, anaphylaxis
2. seizures following high doses
3. antibiotic-associated colitis
29
Contraindications of aminopenicillins?
Pen-allergic patients
30
drug interactions with aminopenicillins?
* synergy with gentamicin against enterococcus
* probenecid inhibits renal active tubular secretion of ampicillin
* ampicillin may inhibit tubular secretion of MTX
31
indications for aminopenicillins?
1. otitis media
2. neonatal sepsis
3. Lyme disease (early)
4. simple UTI's (GNRs, such as E. coli, klebsiella, enterobacter, proteus)
5. meningitis with sensitive pathogens
6. URI
7. endocarditis w. sensitive pathogens
32
What are examples of “semi-synthetic” penicillins?
1. Nafcillin
2. Dicloxacillin
3. Oxacillin
4. Methicillin - original
33
sensitivity of nafcillin to ß lactmases?
more resistant to ß lactamases (have more complex side chains; more stable)
34
MoA of nafcillin?
binds PBP’s and inhibits the assembly of the bacterial cell wall, bactericidal
35
There are various types of semi-synthetic penicillins. How would you use them clinically?
nafcillin or oxacillin - IV; serious infections with MSSA
dicloxacillin - PO; less severe infections
36
bugs sensitive to nafcillin?
Same as penicillin, but narrow spectrum
* S. aureus (except MRSA, resistant due to altered PBP target site)
“use naf for staph”
37
bugs resistant to nafcillin or within the same class?
1. MRSA (usually bc they have a different PBP)
2. pneumococcus
3. oral/bowel anaerobes
4. GNR (most)
38
contraindications for semi-synthetic pencillins?
Pen-allergic patients
39
SE of semi-synthetic penicillins (ie nafcillin)?
* drug allergy HSR
* neprotoxic - allergic interstitial nephritis
* Methicillin – highly nephrotoxic (causes allergic interstitial nephritis) and resistant to ß-lactamase; not used anymore
40
drug interactions with nafcillin?
* synergy with gentamicin against enterococcus
* probenecid inhibits renal active tubular secretion
41
indications for nafcillin or semi-synthetic pencillins within the same class?
Staph aureus infections, especially if pathogen is sensitive (in skin, soft tissue, bone, lung, endocarditis)
42
Drugs in the Anti-Pseudomonas class?
* Piperacillin
* Carbenicillin
* Ticarcillin
43
Piperacillin - sensitivity to ß lactamases?
sensitive
44
MoA of Piperacillin?
binds PBP’s and inhibits the assembly of the bacterial cell wall, bactericidal
45
What is one thing that you have to consider when dosing Piperacillin and Carbenicillin?
resistance w. monotherapy; given in combination therapy with gentamycin or tobramycin to decrease resistance
46
How is Piperacillin and Carbenicillin administered?
* Piperacillin - IV
* Carbenicillin - PO
47
bugs sensitive to Piperacillin and Carbenicillin?
Same as penicillin, but with extended spectrum
* Pseudomonas
* GNR
48
bugs resistant to Piperacillin and Carbenicillin?
1. GPC
2. Anaerobes
3. Enterococcus
4. pneumococcus
5. most S. aureus
6. increasing # of resistant pseudomonas and GNRs
49
contraindications of anti-pseudomonal agents??
Pen-allergic patients
50
SE of Piperacillin and Carbenicillin?
1. drug allergy especially rash, anaphylaxis
2. antibiotic-associated colitis
51
drug interactions of Piperacillin and Carbenicillin?
1. synergy with gentamicin against Pseudomonas
2. probenecid inhibits renal active tubular secretion of Piperacillin
3. Piperacillin may inhibit tubular secretion of MTX
52
indications for Piperacillin and Carbenicillin?
1. Pseudomonas infections (usually given in combination with gentamycin or tobramycin for synergy)
2. Carbenicillin – used treat non-life threatning infections (ie UTI) caused by Pseudomonas)
3. intra-abdominal infections (mixed GNR, anaerobes, and enterococcus)
4. nosocomial pneumonia (because often caused by GNR in the ICU)
53
What are some ß-lactamase inhibitors that are manufactured with penicillins?
Clavulanic acid, sulbactam, and tazobactam
54
How do ß-lactamase inhibitors work?
resemble ß lactam molecules and prevents cleavage of ß lactam rings, but have very weak antimicrobial activity themselves
thus they are added to amoxicillin or ampicillin or pipercillin, whose “range” is extended by the inhibitor
55
3 types of Penicillins w. ß-lactamase inhibitors?
1. Amoxicillin & clavulanate (Augmentin)
2. Ampicillin & sulbactam (Unasyn)
3. Piperacillin & Tazobactam (Zosyn)
56
bugs sensitive to Penicillins w. ß-lactamase inhibitors?
Augmentin (Amoxicillin & clavulanate): PO; broadest spectrum
Unasyn (Ampicillin & sulbactam): IV; broadest spectrum
Zosyn (Piperacillin & Tazobactam): IV; widest scope of activity
57
bugs resistant to Penicillins w. ß-lactamase inhibitors (ie clavulanic acids)?
ß-lactamases produced by
1. enterobacter
2. citrobacter
3. serratia
4. pseudomonas
58
indications for augmentin?
otitis media, sinusitis, lung, skin, urine infections, **bites**
59
indications for unasyn?
skin, intra-abdominal, pelvic, bite, head/neck infections
60
indications for Zosyn?
pneumonia, UTI, skin, gyn, bone, intra-abdominal, septicemia infections
61
How are cephalosporins similar than penicillins? different?
similar to penicillins in that they both have:
* structure (A ring + ß lactam ring)
* mechanism of action
* toxicities/allergic reactions
different in that cephalosporins are:
* more stable to many ß-lactamases
* broader spectrum of activity (good for polymicrobial infections or infections where you don’t know what it is)
* not as good as the penicillins against enterococcus and it is essentially worthless against listeria
62
What is the difference btwn the first generation cephalosporins and the later generations?
* 1st generation - more active against GP organisms (e.g. staph, streptococci)
* later drugs (2nd, 3rd, 4th gen) - are more active against GN aerobic organisms (e.g. E. coli, etc.)
63
Why is it bad to use cephalosporin if the bug is known?
bad to always use if the infection/pathogen is known because normal flora may be wiped out and cause c. diff, candidal infection, BV, or cause resistance! USE A MORE SPECIFIC ONE.
64
5 generations of cephalosporin? Which ones have good CSF penetration?
5 classes (know the highlighted ones)
* 1st gen: cefazolin iv, cephalexin po
* 2nd gen: cefuroxime – not that impt to know
* 3rd gen: ceftriaxone, ceftazidime, Cefotaxime, cefpodoxime
* 4th generation: cefepime
* 5th generation: ceftaroline
Good CSF penetration: 3rd, 4th, 5th
65
Drugs in the Cephalosporins 1st gen?
* Cefazolin
* cephalexin
66
MoA of Cefazolin?
binds PBP’s and inhibits the assembly of the bacterial cell wall, bactericidal
67
CSF penetration of Cephalosporins 1st gen?
poor
68
bugs sensitive to cefazolin?
broad spectrum of activity
* GPC
* Proteus mirabalis
* E. coli
* Klebsiella
**PEcK**
69
bugs resistant to cefazolin?
* MRSA (about 30% and growing)
* enterococcus,
* Listeria
* nosocomial GNRs
* some pneumococcus
* bowel anaerobes
70
contraindications of cefazolin?
Pen-allergic patients (cross-reactivity)
71
SE of cefazolin?
* drug allergy especially rash, anaphylaxis
* anemia
* vitamin K deficiency
* antibiotic-associated colitis
72
drug interactions of cefazolin?
* probenecid inhibits renal active tubular secretion, prolongs half-life
* increase nephrotoxicity of aminoglycosides
73
indications of cefazolin?
* soft tissue infections (strep and staph)
* UTI
* patients with mild allergies (but not anaphylaxis) to penicillins
* surgical prophylaxis (ie just before appendectomy or hysterectomy) to lower chance of developing wound infection against GNR
74
Rx in the Cephalosporins 3rd gen that we should know?
* Ceftriaxone
* Ceftazidime
75
MoA of Ceftriaxone?
binds PBP’s and inhibits the assembly of the bacterial cell wall, bactericidal
but it is more active against GNRs which produce ß-lactamases
76
Why is Cefotaxime/cefpodoxime given to pediatric patients in lieu of the standard 3rd generation ceftriaxone?
it is less likely to cause biliary sludging
77
bugs sensitive to ceftriaxone?
Given to serious GN infections that are resistant to other ß lactams
* meningitis
* gonorrhea
78
bugs resistant to ceftriaxone?
* MRSA (~30% and growing)
* pneumococcus (5-10%)
* enterococcus
* nosocomial GNRs
* bowel anaerobes
* pseudomonas
* Listeria
79
CI of ceftriaxone?
Pen-allergic patients
80
SE of ceftriaxone?
* drug allergy especially rash, anaphylaxis
* anemia
* antibiotic-associated colitis
* vitamin k deficiency
81
Drug interactions with ceftriaxone?
* probenecid inhibits renal active tubular secretion
* synergistic with gentamicin against some GNR
* may enhance effects of warfarin
* increase nephrotoxicity of aminoglycosides
82
indications for ceftriaxone?
* meningitis
* serious pneumonia
* otitis
* sinusitis
* neisseria gonorrhea
* GNR
* lyme dz
83
MoA for Ceftazidime?
binds PBP’s and inhibits the assembly of the bacterial cell wall, bactericidal, but more activae against GNRs which produce ß-lactamases
84
bugs sensitive to ceftazidime?
Given to serious GN infections that are resistant to other ß lactams
* Pseudomonas
85
bugs resistant to ceftazidime?
* large majority of staph
* some pneumococcus
* bowel anaerobes
86
CI for ceftazidime?
Pen-allergic patients
87
SE of ceftazidime?
* drug allergy especially rash, anaphylaxis
* antibiotic-associated colitis
* vitamin k deficiency
88
drug interactions with Ceftazidime?
* synergistic with gentamicin against some GNR, especially Pseudomonas
* may enhance effects of warfarin
* increase nephrotoxicity of aminoglycosides
89
indications for ceftazidime?
* infections where resistant GNRs and Pseudomonas are likely
* meningitis or sepsis where GNR is likely pathogen
* bacteremia
* UTI
* urosepsis
* empiric Rx of febrile neutropenic pts
90
What generation is Ceftaroline in?
Cephalosporins, 5th gen
91
MoA of ceftaroline?
binds PBP’s and inhibits the assembly of the bacterial cell wall, bactericidal, but more activae against GNRs which produce ß-lactamases
92
Why do you have to monitor ceftaroline in the elderly?
renal excretion – must monitor in elderly, who have reduced GFR
93
bugs sensitive to ceftaroline?
Broadest spectrum of activity
* GN
* GP – strep pneumonia, staph aureus (MSSA and MRSA)
* does not cover Pseudomonas
94
bugs resistant to ceftaroline?
still being defined
95
CI of ceftaroline?
Pen-allergic patients
96
SE of ceftaroline?
* drug allergy especially rash, anaphylaxis
* Clostridium difficile-associated diarrhea
* convert to a **positive direct Coombs test** (10% of patients)
97
ceftaroline drug interactions?
none reported
98
indications for ceftaroline use?
* community acquired bacterial pneumonia (CABP)
* acute skin infection
## Footnote
**but only for pathogens likely to be sensitive, and only used when a broad spectrum drug is needed**
99
drugs in the Carbapenems class?
* Meropenem
* Imipenem
* irbepenem
* ertapenem
* doripenem
100
How are carbapenems different than penicillins?
has an additional ring structure to the ß lactam ring
101
What do you often administer with Imipenem and why?
Imipenem - RESISTANT to ß lactamases; often given with cilastatin inhibitor of renal dehydropeptidase I) to reduce inactivation of drug in renal tubules “with imipenem, the kill is ‘lastin with cilastatin”
102
CSF penetration of Meropenem?
good
103
Why would you not use carbapenems as a first-line tx?
significant side effects and $$$ (not used as a first-line tx; use limited to life-threatening infections or after other drugs have failed)
104
bugs sensitive to carbapenem?
Broadest spectrum against the widest group of bacteria
* most GPC (including staph)
* most GNR (including pseumomonas)
* Anaerobes
105
bugs resistant to carbapenem?
* MRSA
* enterococcus
* rare pneumococcus; but can develop resistance rapidly
106
CI for using carbapenem?
Pen-allergic patients
107
SE of carbapenem?
* antibiotic-associated colitis
* seizures (at high plasma levels)
* GI distress
* skin rash
108
Rx interactions wtih carbapenem?
* probenecid inhibits renal active tubular secretion
* synergistic with gentamicin against some GNR
* may enhance effects of warfarin
109
Indications of carbapenem?
* mixed nosocomial infections with resistant GNRs (do not use for single-organism infections or when the infection is unknown (ie patient comes in with septic shock))
* complicated meningitis
* peritonitis
* serious pneumonia
* sepsis
110
drugs in the monobactam class?
Azetreonam
111
What is unique about Azetreonam?
* **resistant to ß lactamases**
* NO cross-allergenicity with penicillin
112
bugs sensitive to azetreonam?
* NARROW coverage - only aerobic GNR (e. coli, pseudomonas
113
side effects of azetreonam?
* Usually non-toxic
* Occasional GI upset
114
drug interactions of azetronam?
* synergistic with aminoglycosides
115
When is azetreonam used??
* penicillin allergic patients
* those with renal insufficiency who cannot tolerate aminoglycosides
116
Example of Glycopeptides?
Vancomycin
117
MoA of vancomycin?
binds to free carboxyl (COOH) end of the D-Ala-D-Ala chain, thereby preventing cross linking of peptidoglycan
118
How is vancomycin usually administered?
CSF penetration?
* IV, or PO only when it is used to treat a infection within the bowel lumen
* FAIR CSF penetration if the meninges are inflamed
119
How do VREs develop?
Remember the MoA of vancomycin is to bind the free carboxyl (COOH) end of the D-Ala-D-Ala chain, thereby preventing cross linking of peptidoglycan
resistance in enterococci and S. aureus occurs because they convert D-Ala --\> D-lactate, thereby reducing vancomycin efficacy (VRE)
120
bugs sensitive to vancomycin
GPC only – serious MDR organisms, including
* MSSA
* MRSA
* enterococcus
* C. diff (only PO)
* coagulase (-) staph
121
bugs resistant to vancomycin?
* All GNRs
* anaerobes other than clostridia sp,
* very rare S. aureus and enterococcus (VRE)
122
Why should you give vancomycin very slowly?
if given too fast, it can cause the **red man syndrome** (rapid rate of infusion can cause histamine release; trmt: slow infusion over 60min)
123
SE of vancomycin?
* nephrotoxicity
* neutropenia
* ototoxicity
* thrombophlebitis
* red man syndrome
124
Rx interactions with vancomycin?
* **additive nephrotoxicity** if given with other nephrotoxic drugs, including **aminoglycosides, amphotericin**
* synergistic when given with gentamicin against staph aureus, enterococcus, and staphylococci
125
Indiations of vancomycin?
* Empiric treatment of serious infections likely caused by GPC pending culture results (e.g meningitis, sepsis, pneumonia, endocarditis)
* treatment of serious infections caused by GPC resistant to other drugs (e.g. MRSA)
* oral treatment of C. difficile colitis
126
Example of Cyclic lipopeptides?
Daptomycin
127
MoA of Daptomycin?
antibacterial - binds to cell membrane, depolarizes the cell, which inhibits protein, DNA, and RNA synthesis, leading to cell death; does not enter the cytoplasm itself
128
why is daptomycin not used for pneumonia?
because it is inactivated by pulmonary surfactant
129
What must you do if you give a patient daptomycin?
check CPK weekly due to myopathy risk; stop Rx if CPK rise to 10x normal limit
130
bugs sensitive to daptomycin?
most GPC (strep, staph, enterococcus)
131
bugs resistant to daptomycin?
All GNR
132
SE of daptomycin?
* cardiac failure
* pseudomembranous colitis
* hypoglycemia
* myopathy
133
Drug interactions with daptomycin?
* cautiously with statins (may increase risk of myopathy)
* may alter levels of tobramycin
* may alter response to warfarin
134
indications for daptomycin?
serious infections caused by resistant GPC (ie MRSA, VRE) such as bacteremia, endocarditis, skin and soft tissue infections
135
MRSA - drugs that it is resistant to? senstive?
* resistant to all penicillins (penicillin, methacillin, nafcillin, oxacillin, and Dicloxacillin) and cephalosporins (except ceftaroline, 5th generation)
* sensitive to Ceftaroline, Vancomycin – use vanco because it is cheaper and it is more specific (wont encourage other bugs to develop resistance).
136
Pseudomonas treatments?
treatments = **pipercillin or ceftazidime**
very good at becoming resistant at every drug; can cause life threatening infections in compromised patients in a setting where antibiotics or chemotherapy are used; classic cases
* little old lady with indwelling foley who lives in a nursing home where antibiotics are widely used
* cancer patients on chemotherapy
137
organisms typically not covered by cephalosporins?
\*organisms typically not covered by cephalosporins are **LAME**:
Listeria
Atypicals (Chlamydia, Mycoplasma)
MRSA
Enterococci
*exception: ceftaroline covers MRSA*
