Exam 2 Flashcards
1
Q
What kind of cell is this?
A
Gram positive
2
Q
What kind of cell is this?
A
Gram negative
3
Q
What color are gram positive bacteria?
A
Purple
4
Q
What color are gram negative bacteria?
A
pink
5
Q
Which bacteria has a thicker cell?
A
gram negative
6
Q
Which bacteria has porins?
A
gram negative
7
Q
Where are beta lactamases located in gram positive bacteria?
A
External space, thus you need to create larger quantities
8
Q
where are beta lactamases located in gram negative bacteria?
A
Within in the cell in periplasmic space since it can go through porins
9
Q
What is the main barrier keeping drugs out of the cell in gram positive bacteria
A
Bacterial membrane
10
Q
How many membranes does gram positive bacteria have
A
1
11
Q
How many membranes do gram negative bacteria have
A
two –> inner and outer membranes
12
Q
What is in gram negative bacteria’s peptidoglycan and how is it cross-linked?
A
- meso-diaminopimelic acid residue (DAP)
- peptidoglycan is cross-linked by a bridge between the DAP residue of one strand and the terminal D-Ala of another
13
Q
What is in gram positive bacteria’s peptidoglycan and how is it cross-linked?
A
- L-lysine residue
- Bridge exists between the L-Lys strand and the terminal D-Ala of the second molecule
14
Q
What is the enzyme that cross-links the peptidoglycan strands?
A
transpeptidases
15
Q
beta lactam antibiotic mechanism of action
A
- inhibition of transpeptidases that glue the peptidoglycan strands together by cross-linking
- beta lactam antibiotics acylate the transpeptidase Ser residue in the enzyme active site to form stable product, which inactivates the enzyme, inhibiting peptiodglycan cross-linking, which results in a defective bacterial cell wall
16
Q
What is the reactivity of the beta lactam system due to
A
- highly strained four-membered ring
17
Q
Bacterial transpeptidases and catalyzation reactions of host cells
A
Bacterial transpeptidases do not catalyze reactions with host cell proteins because the bacterial substrate contains unnatural D-Ala amino acid residues that are not found in the host cell proteins
18
Q
How can resistance to beta lactam antibiotics occur (4)
A
- decreased cellular uptake of the drug
- mutation of the penicillin binding proteins to decrease their affinity for penicillins
- presence of an efflux pump that pumps the antibiotic out of the cell
- induction or elaboration of bacterial beta lactamases
19
Q
Rate of hydrolysis of the actylated beta lactamase
A
Fast, so the enzyme can hydrolyze many drug molecules rapidlyHyd
20
Q
How much of the US population is allergic to beta lactam antibiotics?
A
6-8%
21
Q
How does allergenicity of beta lactam antibiotics occur
A
Drugs acts like a hapten and acylates host cell proteins, which then raise antibodies that result in an allergic reaction
22
Q
Cross reactivity in mild reaction of beta lactams
A
Cephalosporin or carbapenen can be tried since cross-reactivity is 5-15%
23
Q
Cross reactivity in severe reaction of beta lactams
A
Cephalosporins and carbapenems are avoided, but aztreonam can be used
24
Q
*Under the acidic conditions, the main degradation of Pen G are:
A
- Benzylpenicillenic acid
- Benzylpenillic acid
- Benzylpenicilloic acid
uses achimeric assistance
25
\*Product of penicillin degradation under basic conditions
penicilloic acid
26
Antibiotic activity of penicillin hydrolysis products
no antibiotic activity
27
Is the hydrolysis of the beta lactam reversible or irreversible
Irreversible
28
Electronegative substituents and nucelophilicity of beta lactams
* Electronegative substituets on the side chain carbonyl reduce the nucleophilicity of the chain amide carbonyl oxygen atom
* This stabilizes the penicillin against hydrolysis under acidic conditions, since tgeh first step in the hydrolysis reaction is decelerated
29
Which medication is more stable to hydrolysis in the stomach and why? Penicillin V vs Penicillin G
Penicillin V is more stable to hydrolysis in the stomach than Penicillin G because the electronegativity of the ether oxygen dereases the nucleophilicity of the amide carbonyl
30
What catalyzes penicillin degradation reactions
Heavy metal ions- therefore keep away from penicillin solutions
31
Lipophilic side chains and protein bound relationship
penicillins with more lipophilic side chains are more highly protein bound
32
protein binding and bioavailability relationship
protein binding reduces bioavailability by reducing the effective concentration of the free drug
33
protein binding and degradation relationship
protein binding in general protects drug from degradation since they dont react with hydrophilic enzymes
34
what is rate-limit half life of penicillin
* Renal excretion rate
* half-lives of penicillins are generally not affected by protein binding, since their dissociation rates from the protein are fast
35
penicillin excretion routes
* rapidly excreted by the renal or biliaqry routes
* 10% of renal excretion is by glomerular filtration
* 90% is by tubular secretion
36
How does kidney disease or failure effect half-lives of penicillins
Half-lives are prolonged
37
Tubular secretion MOA of pencillins
The penicillins are anionic and competition with the anion probenecid for the secretion mechanism causes an increase in half life when probenecid is administered along with the penicillin
38
Dose range of penicillin
3-12 g per day for an average adult
39
Serum half-lives of penicillin
Serum half-lives are generally 0.5 to 2 hours
40
Penicillin G antimicrobial spectrum
Gram + cocci
N. gonorrhoeae and H. influenza
41
Pencillin beta lactamase sensitivity
Yes
42
Penicillin G administration
Orally in large doses, although the most effective route is parenteral
43
Penicillin G toxicity
Acute allergic reactions
44
Penicillin G precautions
Pen G should be used with caution in individuals with histories of signficant allergies and/or asthma
45
Penicillin Notes
Pen G is the drug of choice for treatment of more infections than any other antibiotic
46
How are synthetic penicillins made by
acylation of 6-APA
47
What structure is this?
penam
48
what structure is this?
penem
49
what structure is this?
carbapenem
50
what structure is this?
cephem
51
what structure is this?
monobactam
52
benylpenicillin benzathine and benzylpenicillin procaine PK
* because of low solubility, the drug is released slowly from the intramuscular injection site
* duration of action is longer and the blood levels are than with other parenteral penicillins
53
benylpenicillin benzathine and benzylpenicillin procaine administration
* Should only be administered by deep IM injection
* Inadvertent IV administration can result in cardiac arrest and death
* Injection near a nerve can result in permanent neurological damge
54
benylpenicillin benzathine and benzylpenicillin procaine therapuetic use
* moderately severe to severe infections of the upper-respiratory tract, scarlet fever, and skin and soft tissue infections due to susceptible streptococci
* Moderately severe pneumonia and otitis media due to susceptible pneumococci
55
Difference between penicillin V and penicillin G
* Pencillin V is more stable in acid
* the increase in stability in acid attributed to the electronegative ether oxygen which decreases the nucleophilicity of the side chain amide carbonyl and therefore decreases its participation in the beta lactam hydrolysis reaction
56
Does methicillin have beta lactamase sensitivity and why
No because of steric hindrance of nucleophilic attack by the enzyme on the beta lactan carbonyl
57
Is methicillin stable to acid
No because of electron donation toward the amide carbonyl oxygen by the o-methyoxygroups, making the amide carbonyl oxygen more nucleophilic
58
How is MRSA resistant to methacillin
* Mutation in a pencilin binding protein (transpeptidase)
* The gene coding for this protein is called methicillin resistance gene (mecA), and the penicillin binding protein that it codes for is PBP2A
59
Does nafcilin have beta lactamase sensitivity
No
60
Nafcillin stability in acid
Slightly more stable than methicillin in acid, but is clinically identical to methicillin
61
What drug is this?
oxacillin
62
what drug is this?
cloxacillin
63
what drug is this?
dicloxacillin
64
Does oxacillin, cloxacillin, and dicloxacillin have beta lactamase sensitivity?
No
65
Is oxacillin, cloxacillin, and dicloxacillin preferred treatment for septicemia and why?
No because they are highly protein bound
66
xacillin, cloxacillin, and dicloxacillin cross resistance
cross-resistant with methicillin
67
Ampicillin antimicrobial spectrum and how
* Many gram (-) microorganisms are sensitive, including Salmonella, shegella, proteus mirabilis, e. coli, h. influenza, and n. gonorrhoeae
* the inner surface of porirns in hydrophilic and porins all transport ionic compounds
* the charged amino group of ampicillin at physiological pH allows ampicillin to be transported into gram (-) bacteria through the porins
68
Is ampicillin stable in acid and why
* Yes because the amino group is protonated in the stomach, so the positively charged nitrogen is more electron-attracting
* This decreases the nucleophilicity of the amide carbonyl oxygen so that it does not participate in ring-opening of the lactam
69
Does amoxicillin or ampicillin have better absorption and why
Amoxicillin because it is an analog of ampicillin in which a phenolic hydroxyl group has been introduced into the aromatic ring
70
MOA of clavulanic acid and sulbactam
acylate the serine hydroxyl group in the active site of the beta lactamase to form a reactive intermediate that then inactivates the ezyme irreversibly
71
Does azlocillin, mezlocillin, and piperacillin have stronger or weaker potencies and why
Enhanced potencies because the added side chain fragments resemble a longer section of the peptidoglycan chain than ampicillin
72
How to treat piperacillin, resistant bacteria
Tazobactam
73
What is the main starting material for cephalasporins
cephalasporin c
74
what can cephalapsorin C be converted to to make a chemically useful cephalasporn
7-aminocephalosporic acid
75
Cephalosporin MOA
* Reaction with transpeptidases (penicillin-binding proteins) results in inhibition of peptidoglycan cross linking
* Many cephalosporins contain leaving groups that faciitate beta lactam ring opening
76
Hydrolysis of cephalosporins
Cephalosporins are hydrolyzed by beta lactamases
77
How does cephalosporin resistance occur
Cephalosporins are hydrolyzed by beta lactamases, rendering them inactive
78
beta-lactamase specificity
* There are over 340 different beta lactamases known
* They can be specific for certain antibiotics and classes of antibiotics
79
Allergenicity of cephalosporins
* allergic reactions are less common and less severe than with penicillin
80
cross allergenicity of cephalosporins
since allergenicity is common, cephalosporins should be used with caution, if at all, in patients who are allergc to penicillins
81
What medications are first generation cephalosporins
* Cefazolin
* cephanlexin
82
what are first generation cephalosporins primarily active against
* gram + cocci: staph aeureus and staph pyogenes
* group b streptococci: s agalactiae and s. pneumoniae
83
If the cephalosporin substituents at C-3 are chemiccaly reactive, how are they administered?
Parenterally
84
If the cephalosporin substituents at C-3 are not chemiccaly reactive, how are they administered?
orally
85
what medication is this and How is this medication administered?
cefazolin; parenteral
86
what generation is cefazolin
first generation
87
What is this medication how is this medication administered?
cephalexin; orally
88
What generation is cephalexin
first generatio
89
how is cephalexin able to confer oral activity
* Substituent at C-3 is not chemically reactive
* Contains an ampicillin-type side chain at C-7 that makes it more stable and helps to confer oral activity
90
what do second generation cephalosporins target
* Retain the anti gram (+) activity of the first generation and h. influenzae as well
* Some gram (-) activity including some strains of acinetobacter, citrobacter, enterobacter, e. coli, klebsiella, neisseria, proteus, providencia, and serratia
91
what generation if cefuroxime
second
92
What is special about cefuroxime
can be given parenterally and orally
93
Difference between syn and anti methoximino groups
* \*The syn methoximino group is more resistant than the anti isomer
* the syn isomer can be photochemically isomerized to the anti isomer in solution to for a 1:1 mixture of syn and anti isomers
94
Third generation cephalosporin activity
* less active against staphlocci than the first generation agents
* much more active vs gram (-) bacteria than either the first or second agents
95
what organisms are sensitive against third generation cephalosporins
* morganella
* bacteroides fragilis
* pneudomonas aeruginosa
* some enterobacteria
96
What is on almost all of the third generation cephalosporin structures
an aminothiazole substituent and contain an oxime ether at the 7-position
97
what drug class does ceftazidine belong to?
third generation cephalosporin
98
What moiety at C-7 conveys enhanced stability vs beta lacatamases
large oxime ether moiety
99
what drug class is cefixime
third generation cephalosporin
100
fourth generation cephalosporin antibacterial spectrum
retain the antibacterial spectrum of the third generation cephalosporins and also add pseudomonas aeruginosa and some enterobacteria that are resistant to third generation cephalosporins
more active against gram positive organisms
101
cefepine drug class
fourth gen cephalosporin
102
route of administration of cefepime
parenteral
103
what drug class is ceftolozane
fourth gen cephalosporin
104
what drug is ceftolozane combined with and what does it treat
* Tazobactam
* effective against many bacteria that are resistant to other antibiotcs
* treats both gram positive and gram negative bacteria
105
what drug class is ceftraoline
fifth generation cephalosporin
106
MOA of ceftraline fosamil
ceftraline fosamil is a prodrug that is hydrolyzed metabolically via phosphatase after IV infusion to ceftraroline
107
Ceftaroline spectrum of activity
broad-spectrum, fifth-generation cephalosporin antibiotic that is active vs MRSA and is used vs MRSA and community acquired bacterial pneumonia since it can inhibit the MRSA PBP2a
108
what drug class is cefiderocol
fifth gen cephalosporin
109
cefiderocol indication
complicated UTI
110
cefideroocol MOA
transpeptidase inhibitor
111
what structual unit does cephamycins have that make them special
7-alpha methoxyl group
112
cefoxitin spectrum activity
broad spectrum of gram positive and gram negative bacteria
113
MOA of cefoxitin
beta lacatamase inducer
114
cefoxitin drug class
cephalosporin
115
cefotetan drug class
cephalosporin
116
Caution point of cefotetan
releases N-methylthiotetrazole, which can cause hypothrombinemia, and can also cause a reaction to ethanol that is similar to disulfuram
117
why can't thienamycin be used as a drug and how has this been overcame
* thienamycin is too reactive to be used as a drug, since the primary amino group attacks the beta lactam intermolecularly
* Been overcame by removing n-formiminoyl group to create imipenem
118
Why are carbapenems more reactive than penicillins
* The sulfur that is present in the thiazolidine ring of the penicillins is replaced by a methylene
* This increases reactivity because a methylene is smaller than a sulfure, so the ring strain is greater in the carbapenems
119
MOA of imipenem
* reacts with penicillin binding proteins
* reacts with and inhibits beta lactamases
120
what is imipenem hydrolyzed by
renal dehydropeptidase-1, but this can be overcome by co-administration of the dehydropeptidase-1 inhibitor cilastatin
121
what is cilastatin and imipenem spectrum of activity
active against both gram + and gram - bacteria: used to treat of the gut, GI tract, bone, skin, and endocardium
122
meropenem drug class
carbapenem
123
does meropenem have to be administered with cilastatin
no because the 1-beta-methyl group confers stability to dehydropeptidase-1
124
why does ertapenem have an extended half life
highly protein bound so that it allows it to be administered iv once every 24 hours
125
aztreonam drug class
monobactams
126
origin of aztreonam
* aztreonam disodium is totally synthetic but the design was inspired by monocyclic beta lactam natural products called monobactams
* sulfamic acid group takes place of the c-2 carboxyl group in the penicillins and cephalosporins
* electronegativity of the sulfamic acid activates the beta lactam ring toward hydrolysis and to reaction with penicillin-binding proteins
127
aztreonam cross allergenicity
cross allergenicity with penicillins and cephalosporins has not been reported except for ceftazidine, which has an indentical oxime ether sidechain
128
what drug is this?
vancomycin
129
what drug is this?
teicoplanin
130
vancomycin mode of action and what makes it different from penicillins
* vancomycin involves binding to the peptidly side chain d-alanyl-d-alanyl terminus in the peptidoclycan precursor (before cross-linking)
* transpeptidase reaction that is required for cross-linking is inhibited by the high affinity binding of vancomycin to the the substrates
* vancomycin also inhibits the transglycosylation step in peptidoglycan synthesis, which penicillins do not do
131
vancomycin spectrum of activity
primarily bactericidal and is active against gram (+) bacteria
132
why is vancomycin not effective against gram negative bacteria
vancomycin is too big to get through the porins
133
how has vancomycin resistance occurred
* Mechanism of resistance appears to be mutation of the peptidoglycan cell wall precursor from D-Ala-D-Ala to D-Ala-D-lactate
* vancomycin does not inhibit the transpeptidase when the substrate is d-ala-d-lactate because vanomycin has 1000 times less affinity for the d-ala-d-lactate precursor
134
vancomycin PK and distribution
* vancomycin does afford appreciable blood levels after oral administration and is usually administered IV
* vancomycin is highly distributed and 90% eliminated by glomerular filtration with a half life of 4-11 hour
135
vancomycin therapeutic use
* given orally to treat c. diff
* strep-induced endocarditis
* MRSA
* MRSE
136
vancomycin toxicity and effects
* hypersensitivity
* nephrotoxicity
* ototoxicity
137
what drug is this?
oritavancin
138
oritavancin drug class
semisynthetic lipoglycopeptide antibiotic
139
oritavancin moa
inhibits transpeptidation and transglycosylation, which disrupts the membrane of gram-positive bacteria
140
oritavancin spectrum of activity
gram positive bacteria-MRSA skin infections
141
telavancin drug class
lipoglycopeptide antibiotic
142
what drug is this
telavancin
143
telavancin MOA
like vancomycin, telavancin binds to the D-Ala-D-Ala terminus of the peptidoglycan in the growing cell wall by inhibiting transpeptidation and transglycosylation
144
telavanvin therapeutic use
MRSA and other gram positive infections
145
what drug is this
dalbavancin
146
dalbavancin drug class
second generation lipoglycopeptide antibiotic
147
dalbavancin mechanisms
Identical to vancomycin: binds to the D-Ala-D-Ala residue on growing peptidoglycan chains and prevents transpeptidation and transglycosylation from occurring, thus preventing peptidoglycan elongation and cell membrane formation
148
what drug is this
daptomycin
149
what drug class is daptomycin
lipopeptide antibiotic
150
daptomycin moa
aggregation of daptomycin in the bacterial membrane creates holes that leak ions
151
daptomycin therpeutic use
used parenterally to treat systemic infections caused by gram-positive bacteria, including MRSA
152
What structure is this
penicillin
153
what structure is this
cephalosporin
154
what structure is this
monobactam
155
what structure is this
carbapenem
156
what are the four classes of beta lactams
1. penicillins
2. cephalosporins
3. monobactams
4. carbapenems
157
beta lactam MOA
inhibit cell wall synthesis
158
beta lactam mechanisms of resistance
* beta lactamase degradation
* PBP alteration
* Decreased penetration
159
Are beta lactams bacterialstatic or bacterialcidal and in what kind of manner
bactericidal in a time dependent manner
160
average half-life of beta lactams
less than 2 hours
161
how are beta lactams eliminated
primarily eliminated unchanged by the kidneys
162
is cross allergenicity possible in beta lactams
yes, except for aztreonam
163
what do all penicillins share
a beta lactam ring attached to a 5-membered thiazolidine ring
164
penicillin mechanism of action
interfere with cell wall synthesis by binding to and inhibiting penicillin-binding proteins PBPs located in bacterial cell walls
165
what does inhibition of PBPs lead to
inhibition of final transpeptidation step of peptidoglycan synthesis
166
Why are beta lactamases problematic for penicillins
The enzyme hydrolyzes the beta lactam ring, which inactivates the antibiotic
167
what gram positive bacteria produces beta lactamases
penicillin resistance staph. aureus
168
what gram negative bacteia produce beta lactamase enzymes
* h. influenzae
* moraxella catarhalis
* n. gonorrhoeae
* e. coli
* klebsiella pneumoniae
* enterobacter spp
169
what gram negative anaerobes produce beta lactamase
bacteroides fragilis
170
how are PBPs lead to penicillin resistance
* Alteration in structure of PBPs leading to decreased binding affinity
171
PBP Resistance Examples
MRSA and PRSP via that mECA gene
172
How do porins cause penicillin resistance
alteration of outer membrane porin proteins leading to decreased penetration
173
why were semi-synthetic penicillins developed
to provide enhanced antibacterial activity
174
what are the natural penicillins
1. aqueous penicillin G
2. benzathine penicillin G
3. procaine penicllin G
4. phenoxymethyl penicllin (penicillin VK)
175
natural penicillins are the drug of choice for what bacteria
treponema pallidum
176
what are penicillinase-resistant penicillins also known as
antistaphylococcal penicillins
177
what are the parenteral penicillinase-resistant penicillins
naficillin and methicillin (no longer used)
178
what is the oral penicillinase-resistant penicillins
dicloxacillin
179
what are penicillinase-resistant penicillins sensitive toward
methicillin-susceptible s. aureus (MSSA)
180
why were aminopenicillins developed
in response to the need for agents with some gram-negative activity
181
parenteral aminopenicllin
ampicillin
182
oral aminopenicillins
ampicillin and amoxicillin
183
what are aminopenicillins
semi-synthetic derivative of natural penicillin with the addition of an amino group
184
what is ampicillin the drug of choice for
enterococcus spp
185
what gram positive bacteria does aminopenicillin enhance activity against
listeria monocytogenes
186
what gram negative bacterias does aminopenicillin enhance activity against
* SHEP
* salmonella/shigella
* h. influenzae BL
* e. coli (some)
* proteus mirabilis
187
why were carboxypenicllins developed
in response to the need for agents with enhanced activity against gram negative bacteria
188
carboxypenicllin structure
semi-synthetic derivatives of natural penicillin with the addition of a carboxyl group
189
parental carboxypenicllin
ticarcillin
190
do carboxypenicllins have increased activity against gram positive aerobes
marginal
191
what gram negative aerobes do carboxypenicllins cover
* SHEPMEPP
* salmonella/shigella
* h. influenza BL+
* e. coli (some)
* proteus mirabilis
* morganella
* **enterobacter**
* **pseudomonas aeruginosa**
* proteus mirabilis
192
what penicllin do you use to treat MSSA
naficillin
193
what medication do we use to treat syphillis
IM benzathin penicllin
194
why were ureidopenicillins developed
in response to the need for agents with even more enhanced activity against gram-negative bacteria
195
ureidopenicillin structure
semi-synthetic derivatives of the amino-penicllins with acyl side chain adaptations
196
ureidopenicllin parenteral agent
piperacillin
197
what additionnal gram negative aerobes do ureidopenicillins cover
1. serratia marcescens
2. some klebsiella spp
198
MOA of beta lactamase inhibitors
irreversibly bind to catalytic site of beta lactamase enzyme
199
Parental beta lactamase inhibitor combinations
Unasyn and Zosyn
200
Unasyn component
ampicillin-sulbactam
201
Zosyn
Piperacillin-tazobactam
202
oral beta lactamase inhibitor
augmentin
203
augmentin components
amoxicillin-clavulanate
204
target organism of beta lactamase inhibitor combos
bacteroides spp
205
What bacterial killing depenedent on in penicllins
time
206
what correlated with efficacy of penicllins
time above MIC
207
Goal of penicllin dosing
Administer agents to maintain serum concentrations \> MIC of infection bacteria for 50% of dosing interval
208
Many penicllins are degraded by what
gastric acid
Lower concentrations achieve with PO versus IV so that oral penicllins should only be used for mild to moderate infections
209
Two best orally available penicillins
PEN VK and Amoxicillin
210
Do penicillins have csf permeabilit
Adequate CSF concetrations of penicillins (but NOT beta lactamase inhibitors) are achieved ONLY in the presence of inflamed meninges with high-dose parenteral administration
211
Penicllin primary elimination
most are eliminated unchanged by the kidney so that dosage adjustment is required in the presence of renal insufficiency; probenacid blocks tubular secretion
212
penicllin elimination exceptions
nafcillin and oxacillin are eliminated primarily by the liver- do not require adjustment in renal insufficiency
213
Why is sodium load in penicllin cause issues?
High contents of sodium must be used in caution in patients with CHF or renal insufficiency because of electrolyte abnormalities and fluid retention
214
Penicllins with sodium content (5)
* Sodium Penicllin G
* Nafcillin
* Carbenicillin
* Ticarcillin
* Piperacillin
215
Sodium Penicllin G sodium content
2.0 mEq per 1 million units
216
Nafcillin sodium content
2.9 mEq/gram
217
Carbenicllin sodium content
4.7 mEq/g
218
ticarcillin sodium content
5.2, which is the highest
219
piperacillin sodium load
1.85 mEq/gram
220
Which penicllin has the highest sodium load
ticarcillin
221
Natural penicillin clinical use
potential drug of drug for syphillis
222
penicillinase-resistant penicillins clinical uses
MSSA
223
augmentin clinical uses
sinusitis and otitis media, bite wounds
224
Unasyn, Zosyn, Timentin clinical uses
polymicrobial infections
225
Zosyn clinical use
empiric therapy for febrile neutropenia or hospital acquired infections
226
cross reactivity of penicillins
cross reactivity exists among all penicllins and even some other beta lactams
227
two main adverse effects of penicllins
neurologic and hematologic
228
how does penicllins cause neurologic adverse effects
direct toxic effect, especially in patients receiving high IV doses in the presence of renal insufficiency
seizures are common
229
hematolic penicllin adverse effects
netropenia and thrombocytopeni occur usually during prolonged therapy greater than 2 weeks but reversible upon discontinuation
230
GI adverse effects of penicllins
increased lfts, nausea, vomiting, diarrhea, C. diff
231
what is interstitial nephritis
immune mediated damage to renal tubules characterized by an abrupt increase in serum creatinine, eosinophilia, and eosinophiluria
232
what agents cause interstitial nephritis
methicillin or nafcillin
233
what classes fall under beta lactams
* penicillins
* cephalosporins
* monobactams
* carbapenems
234
what do cephalosporins contain
* contain a beta lactam ring attached to a 6-membered dihydrothiazine ring, which confers greater stability against some beta lactamase enzymes
235
how are cephalosporins active against anaerobes
cephamycins have methoxy group at C-7 and are active against anaerobes
236
cephalosporin mechanism of action
interfere with cell wall synthesis by binding to penicillin-binding proteins located in bacterial cell walls
237
how does cefiderocol enter the bacterial membrane
Acts as a siderophere by binding to free ferin that enters the bacterial cell well
238
What does inhibition of PBPs lead to
inhibition of the final transpeptidation step of peptidoglycan synthesis, which exposes a less osmotically stable cell wall that leads to decreased bacterial growth, lysis, and death
239
T/F: cephalosporins are bactericidal
true
240
cephalosporin mechanism of resistance
production of beta lactamase enzymes: most important and most common where enzyme hydrolyzes beta lactam ring causing inactivation
241
what is the one cephalosporin that is active against MRSA
cefteroline
242
which cephalosporin generation are the most active verses gram positive aereobes
first generation
243
how do you lose gram positive activity and increase in gram negativity within cephalosporin generations
Lose gram-positive activity with an increase in gram negative activity as you go from 1st -\> 2nd -\> 3rd to 4th
244
how does beta lactamase activity change with cephalosporin generations
greater beta lactamase stability as you go from 1st -\> 2nd -\> 3rd -\> 4th
245
what are the two main first generation cephalosporins
cefazolin and cephalexin
246
what gram positives are first gen cephalosporins active against
* pen-susc S. pneumoniae
* meth-susc S. aureus
247
what gram negatives are first generation cephalosporins are active against
p. mirabilis
e. coli
k. pneumoniae
248
what additional activity do several second generation cephalosporins have
several second generation agents have activity against anaerobes (the cephamycins)
249
are first or second generation cephalosporins better for treating meth-susc S. aueres
first generations
250
what gram negatives do second generation cephalosporins cover
* p. mirabilis
* e. coli
* k. pneumoniae
* h. influenzae
* enterbacter spp
* neisseria spp
* m. catarrhalis
251
what anaerobes are second geneneration cephalosporins active against
bacteroides fragilis
252
what are the three common second generation cephalosporins
1. cefuroxime
2. cefprozil
3. cefoxitin
253
what are the three most common third generation cephalosporins
1. ceftriaxone
2. ceftazidime
3. cefpodoxime
254
third generation cephalosporins are active against what gram negative aerobes
* p. mirabilis
* e. coli
* k. pneumoniae
* h. influenzae
* m. catarrhalis
* n. gonorrhoeae
* n. meningitidis
* citrobacter
* enterbacter
* acinetobacter
* morganella
* serratia
* providencia
* salmonella
* shigella
255
what third generation cephalosporins are active against pseudomonas aeruginosa
ceftazidime and cefoperazone
256
does ceftriaxone have activity against pseudomonas aeruginosa
NO
257
What are the three third generation cephalosporins
* ceftriaxone
* ceftazidime
* cefpodoxime
258
what is the only fourth generation cephalosporin available
cefpime
259
what are fouth generation cephalosporins poor inducers of
poor inducer of inducible AmpC beta lactamse enzymes
260
what is the anti-MRSA cephalosporin
ceftaroline
261
ceftaroline does or does not cover pseudomonas aeruginosa
does not
262
cefiderocol spectrum of activity
many ESBLs, AmpCs, CREs
263
what is ceftolozane and tazobactam sensitive to
pseudomonas aeruginosa
264
Overall, cephalosporins are NOT active against (6)
1. MRSA (except ceftaroline)
2. Enterococcus spp
3. listeria monocytogenes
4. stenotrophomonas maltophilia
5. clostridium difficile
6. atypical bacteria, including legionella
265
which cephalosporin is considered a potential drug of choice for infections due to MSSA
cefazolin
266
which cephalosporin does NOT have activity against pseudomonas aeruginosa
ceftriaxone
267
what is cephalosporins bactericidal activity dependent on
Time --\> Time \> MIC is PD parameter that correlates with efficacy
268
cephalosporins absorption
oral cephalosporins are well absorbed, but achieve lower serum concentrations than parenteral products; food decreases the absorption of cefaclor and loracarbef
269
cephalosporins distribution
* Widely distributed into tissues and fluids
270
cephalosporins CSF distribution
CSF concentrations achieved ONLY with PARENTERAL cefuroxime, 3rd and 4th generation agents
271
cephalosporin primary elimination
most are primarily eliminated unchanged by the kidney via glomerular filtration and tubular secretion; dosage adjustment of these agents is required in the presence of renal insuffiency
272
what cephalosporins are not eliminated by the kidney
* ceftriaxone (biliary)
* cefoperazone (liver)
273
what is the half life of most cephalosporins
\< 2 hours
274
what is the notable half life of cephalosporin
most cephalosporins have short elimination half-lives (\<2 hours)- on noteable exception is ceftriaxone whose half-life is 8 hours
275
ceftaroline clinical use
skin and soft tissue infections including those caused by MRSA
276
can you use caftaroline to treat pseudomonas aeruginosa
NOOOOOOO
277
cefiderocol clinical uses
use limited to infections caused by resistant Gram-negative bacteria (ESBL, AmpC, or carbapenemases), but current place in therapy is still being determined
278
cephalosporin hypersensitivity
5 to 15% cross-reactivity with penicillins (esp 1st generation)
279
Can you try cephalosporin with a rash/itching to penicllin
PK to try
280
which cephalosporins have MTT side chain and why is it a problem
* cefamandole, cefotetan, cefmetazole, cefoperazone, moxalactam
* hypoprothrombinemia- due to reduction in vitamin K-producing bacteria in GI tract
* Ethanol intolerance
281
cephalosporins other adverse effects
* IV calcium and ceftriaxone precipitate, nonconvulsive statis epilepticus
282
true/false: a patient who developed anaphylaxis to penicllin can safely receive any cephalosporin
FALSE: a patient who developed anaphylaxis to penicllin may develop anaphylaxis to a cephalosporin (esp 1st gen) due to common nucleus/side chains. Therefore, skin testing and/or desensitization may be necessary before using a cephalosporin in this patient
283
what are the four commericial carbapenems
imipenem, meropenem, ertapenem, doripenem
284
carbapenem basic structure and what does it result in
* beta lactam ring attached to a 5-membered ring like the penicillins
* structural changes result in extended spectrum of activity and greater beta lactamase stability
285
carbapenem mechanism of action
inhibitors of cell wall synthesis by binding to and inhibting PBPs; primary target is PBP-2
286
are carbenems bactericidal? If so, in what manner?
Bactericidal in time-dependent manner
287
carbapenems mechanisms of resistance
* beta lactamase production
* decreased permeability
* alteration in PBPs
288
carbapenems spectrum of activity
have activity against gram-positive and gram-negative aerobes AND anaerobes
289
what specific gram positive aerobe does carbapenems have activity against
enterococcus faecalis
290
do carbapenems have activity against pseudomonas aeruginosa?
Yes, all of them except ertapenem
291
are carbapenems active against c. difficile
no
292
what gram negative anaerobe is carbapenem active against
bacteroides spp
293
are carbapenems active against MRSA
nope
294
are carbapenems active against VRE?
no
295
True/False: Carbapenems are highly stable against many beta lactamase enzymes and are considered the drugs of choice for serious infections due to ESBL- and AmpC-producing bacteria
True
296
True/False: Meropenem-vaborbactam and imipenem-relebactam were developed to provide activity against KPC-producing Enterobacteriaceae
297
how do carbapenems display dependent bactericidal activity
Time-dependent --\> time \>MIC is PD parameter that correlates with efficacy
298
what are carbapenems bacteriostatic versus
enterococcus
299
carbapenem distribution
widely distributed into body tissues and fluids
300
do carbapenems penetrate CSF
Yes --\> meropenem is the best
301
how are carbapenems eliminated
all are primarily eliminated by the kidney; need dosage adjustment with renal dysfunction
302
carbapenems half lives
short: except ertapenem half-life= 4 hours
303
which carbapenem is co-formulated with cilastatin to prevent DHP degradation in the renal brush border and subsequent nephrotoxicity
imipenem
304
carbapenem clinical uses (4)
* empiric therapy for hospita acquired infections
* polymicrobial infections
* infections due to beta lactamase producing organisms
* complicated uti due to KPC-producing enterobacteriaceae
305
which carbapenem do you not use to treat ertapenem
306
do carbapenems have cross reactivity with penicllins
yes 5-15%
307
carbapenem central nervous system adverse effects
risk factors for seizures include pre-existing CNS disorder, high doses, and renal insufficiency
308
what is the only monobactam available
aztreonam
309
monobactam MOA
inhibits cell wall synthesis like other beta lactams by binding to PBPs (primarily PBP-3 of gram-negative aerobes)
310
are monobactams bactericidal or bacteristatic and in what manner
bactericidal in a time dependent manner
311
how does monobactam resistance occurs
through hydrolysis by beta lactamases or decreased permeability
312
what does monobactams have little to no activity against
little to no activity against gram-positive aerobes or anaerobes
313
what is monobactams target organism
pseudomonas aeruginosa
314
monobactams distribution
widely distributed into body tissues and fluids; penetrates the CSF in the presence of inflamed meninges
315
monobactams elimination
excreted in the urine as unchanged drug
316
when do monobactams need dose adjustment
doses need adjustment with renal dysfunction; is removed by hemodialysis
317
aztreonam clinical uses
susceptible gram negative aerobes and used in patients with significant penicillin allergies
318
which of the following antibiotics can be used in a patient who developed angioedema and hives after an IM injection of penicllin?
Aztreonam
319
what is the common streptogramin antibiotic
synercid
320
what is synercid made up of
quinupristin and dalfopristin
321
what is this structure
quinupristin
322
what structure is this?
dalfopristin
323
synercid mixture weight ratio
30% quinupristin and 70% dalfopristin
324
is quinupristin bacteriostatic or bactericidal
bacteriostatic
325
is dalfopristin bacteriostatic or bactericidal
bacteriostatic
326
what is synercid bacteriostatic against
enterococcus faecium
327
what is synercid bactericidal against
strains of mssa and mrsa
328
how is synercid administered
parenterally
329
dalfopristin MOA
* Dalfopristin directly interferes with the peptidyl transferase-catalyzed step in the 50S subunit
* During peptide synthesis, when the second tRNA base pairs with the appropriate codon in the mRNA, peptidyl transferase catalyzes the formation of a peptide bond between the two amino acids present
330
quinupristin MOA
binds in the ribosomal tunnel and causes blockage of the tunnel in the 50S subunit
331
pristinamycins parent nautral product mixture solubility
lacks suitable solubility for reliable dosages
332
quinupristin and dalfopristin solubility
they both have amino side chains that allow salt formation and enhance the water solubility needed to make a useful formulation
333
synercid therapuetic use (3)
1. vancomycin resistant e. faecium bacterim
2. skin infections caused by MRSA
3. vancomycin resistant by enteroccus faecium UTI
334
quinupristin resistance
adenine methylation of A2058 in the 23S rRNA as in the case of erythromycin and clindamycin. Susceptibility of the organism to dalfopristin is not affected by this rRNA modifaction, but renders synercid a bacteriostatic agent at the normal dose. Extension of the dosing to 3X a day is well tolerated and allows for more sustained tissue drug levels
335
synercid side effects
* No significant toxicity presented
* Several mild side effects have been reported and include inflammation and pain at the site of injection, nausea, diarrhea, muscle weakness and rash
336
synercid pharmacokinetics
complicated because of the different elimination rates for each component and their metabolites
337
Does synercid penetrate BBB
No
338
synercid clearance
clearance is 75% through biliary excretion (fecal matter) and the remainder appears in the urine
339
synercid drug interactions
synercid inhibits cytochrome 3a4, which metabolizes a long list of commonly used drugs
340
quinupristin metabolism
341
dalfopristin metabolism
342
what drug is an oxazolidinones
linezolid
343
oxazolidinones MOA
* linezolid acts early by potent interaction with 50S ribosomal subunit
* In the intiation step of bacterial translation, the 50S subunit associates with fMet-tRNA and a complex composed of the 30S ribosomal subunit and mRNA to form the functional 70S initiation complex
* Linezolid ineracts with the 50S subunit with micromolar affinity (and it has no affinity to the 30S subunit)
* This interaction prevents the formation of the 70S initiation complex
344
what does linezolid directly interact with
23S rRNA
345
linezolid therapeutic use
1. vancomycin resistant e. faecium
2. nosocomial pneumonia caused by methacillin resistant strains of staph aureus
3. skin infection caused by methicillin resistant strains of staph aureus
346
does linezolid have good oral bioavailability
yes- it is excellent
347
how to reduce development of drug-resistant bacteria and maintain the effectiveness of linezolid
should be used only to treat or to prevent infections that are proven or strongly suspected to be caused by multiply drug resistan gram (+) bacteria
348
how has linezolid resistance occur
target site modification
349
linezolid side effects
nausea, vomiting, diarrhea
350
linezolid metabolism
metabolism via morpholine ring oxidation
351
linezolid half life
4-6 hours
352
linezolid drug interactions
since linezolid is a moderately potent, reversible, nonselective inhibitor of monoamine oxidase. Therefore it has the potential for interaction with adrenergic and serotonergic agents
353
what drug is a second generation oxazolidinone
tedlizolid
354
is tedizolid and linezolid more potenent vs MRSA
tedizolid
355
vancomycin MOA
inhibits bacterial cell wall synthesis at a site diffeernt than beta lactams during the second stage of cell wall synthesis by binding firmly to D-alanyl-D-alanine portion of cell wall precursors to prevent cross-linking and further elongation of peptidoglycan --\> weakens cell wall
356
is vancomycin cidal or static and in what manner
time dependent bactericidal activity; slowly kills bacteria (static against enterococcus)
357
vancomycin mechanism of resistance
* Resistance in VRE and VRSA is due to modificatio of D-alanyl-D-alanine binding site of peptidoglycan
* VISA causes a thickened cell wall, leading to increased dose of vancomycin required
358
What does modification of D-alanyl-D-alanine cause
* terminal D-alanine replaced by D-lactate
* Loss of critical hydrogen bond
* Loss of antibacterial activity
359
Vancomycin spectrum of activity
Gram positive bacteria: MSSA, MRSA, C. diff
360
Vancomycin synergy
displays synergy with aminoglycosides
361
vancomycin absorption
absorption from GI tract is neglible after oral administration, except in patients with intense colitis
362
vancomycin distribution
widely distributed into body tissues and fluids, includising adipose tissue- use TBW for VD calculation
363
vancomycin CSF penetation
variable penetration into CSF, even in th epresence of inflames meninges
364
vancomycin elimination
primary eliminated unchanged by the kidney via glomerular filtration
365
what is vancomycin elimination half-life dependent on
* renal function
* 6-8 hrs with noram renal function
* 7-14 days with ESRD
366
vancomycin serum concentration monitoring
* AUC-based guided dosing and monitoring is recommended using peak and trough
367
when to pull vanco peak and target level
draw peak 60 minutes after end of infusion: target 30-40 mcg/mL
368
vanco target trough level
10-15 mcg/mL
369
vanco target AUC/MIC
400-600
370
vancomycin and hemodialysis
vanco is removed by hemodialysis (30-40% removed per 3-4 hour HD session with new membranes)
371
normal renal function vanco dosing
15-20 mg/kg/dose every 12 hours (typically 1 to 1.5g)
372
when do you use oral vanco
c. diff colitis
373
vancomycin clinical uses
* MRSA infections
* Endocariditis
* serious gram-positive infections in beta lactam allergic patients
* PRSP
374
vancomycin adverse effects
1. red-man syndrome
2. nephrotoxicity
3. ototoxicity
4. thrombophlebitis
5. interstitial nephritis
375
what causes red-man syndrome and treatment for it
* flushing and prutitis on upper torso related to rate of IV infusion
* No faster than 15mg per min
* resolves spontaneously after d/c
376
what drug is a streptogramin and why was it developed
synercid was developed in response to the need for antibiotics with activity against resistant gram positive bacteria, namely VRE
377
what is synercid a combo of
two semi-synthetic pristinamycin derivatives in a 30:70 w/w ratio: quinupristin and dalfopristin
378
synercid MOA
each agents acts individually on 50S (reversibly) ribosomal subunit to inhibit early and late stages of protein synthesis near the site where the macrolides and clindamycin bind
379
is synercid primarily static or cidal and in what manner
bacteriostatic in a time dependent manner
380
synercid MOR
* Alterations in ribosomal binding sites by erm gene
* enzymatic inactivation
381
synercid spectrum of activity
* s. pneumonia (PRSP)
* e. faecium ONLY (VRE)
* MSSA
* MRSA
* coag-negative staph
382
synercid absorption
only available parenterally
383
synercid distribution
penetrates into extravascular tissue, lung, skin/soft tissue
384
synercid CSF penetration
minimal CSF penetration
385
synercid elimination
both agents are metabolized: t 1/2 is 0.6-1 hour for quinu and 0.3 hours for dalfo
386
synercid drug interactions
* cytochrome p450 3A4 inhibitor
* HMG-COA reductase inhibitors
* Cyclosporin, tacrolimus
* carbamazepine
387
synercid adverse effects
1. venous irritation- esp when administered through a peripheral vein
2. severe myalgias, arthralgias
388
linezolid drug class
oxazolidinones
389
tedizolid drug class
oxazolidinones
390
why were oxazolidinones developed
in response to need for antibiotics with activity against resistant gram-positives (VRE, MRSA, VISA)
391
oxazolidinones MOA
binds to the 50S ribosomal subunit near the surface interface of 30S subinut (unique binding site) --\> causes inhibition of 70S initiation complex, which inhibits protein synthesis
392
are oxazolidinones primarily static or cidal
primarily bacteriostatic
393
oxazolidinones MOR
1. alterations in ribosomal binding sites- rare
2. cross-resistance with other protein synthesis inhibitors is unlikely
394
oxazolidinones spectrum of activity
1. PRSP strep pneumoniae
2. e. faecium
3. e. faecalis (VRE)
4. MRSA
5. MSSA
6. VRSA
395
linezolid absorption
100% bioavailable
396
tedizolid absorption
91% bioavailable
397
oxazolidinones distribution
readily distributes into well-perfused tissued
398
oxazolidinones CSF penetration
linezolid CSF penetration is 30%
399
oxazolidinones elimination
* both renally and nonrenally
400
oxazolidinones half-lives
* 4 to 5 hours for linezolid
* 12 hours for tedizolid
401
is dose adjustments needed for RI in oxazolidinones
NO
402
are oxazolidinones removed by HD
yes
403
oxazolidinones reserved use
* serious/complicated infections caused by resistant Gram-positive bacteria
404
linezolid and tedizolid drug interactions
serotonin syndrome with SSRIs
405
Linezolid AE
1. optic and peripheral neuropathy
2. thrombocytopenia or anemia
406
what drug class is daptomycin
lipopeptides
407
why was daptomycin developed
in response to the need for antibiotics with activity against Gram-positives (VRE, MRSA, VISA0
408
409
daptomycin MOA
binds to bacterial membranes and inserts lipophilic tail into cell wall to form trans-membrane channel --\> leakage of cellular contents and rapid depolarization of the membrane potential, which causes inhibition of protein, DNA, and RNA synthesis
410
is daptomycin static or cidal ande in what manner
concentration dependent bactericidal activity
411
daptomycin MOR
rarely reported in VRE and MRSA due to altered cell membrane binding
412
daptomycin spectrum of activity
1. s. pneumoniae (PRSP)
2. e. facecium and faecalis (VRE)
3. MSSA
4. MRSA
5. VRSA
6. coagulase-negative staphylococci
413
daptomycin distribution
readily distributes into well-perfused tissue: protein binding 90%
414
daptomycin CSF penetration
poor penetration
415
daptomycin elimination
excreted primarily by the kidneys
416
daptomycin half life
* 7.7 to 8.3 hours in normal renal function
417
daptomycin RI anda HD
* dosage adjustments are required in the presence of RI
* NOT removed by HD
418
daptomycin pneumonia treatment
daptomycin should not be used in the treatment of pneumonia
419
daptomycin adverse effects
1. myopathy and CPK elevation
2. acute eosinophilic pneumonia
420
daptomycin drug interactions
HMG CoA-reductase inibitors- may lead to increased incidence of myopathy
421
what drugs are lipoglycopeptides
1. telavancin
2. dalvance
3. orbactiv
422
why were lipoglycopeptides developed
to address the need for antibiotics with activity against resistant gram-positive (VRE, MRSA, VISA)
423
lipoglycopeptides MOA
all 3 interfere with polymerization and cross-linking of peptidoglycan by binding to D-Ala-D-Ala terminal
424
is lipoglycopeptides is static or cidal
concentration-dependent bactericidal acitivity
425
lipoglycopeptides MOR
* alteration in peptidoglycan terminus
426
lipoglycopeptides spectrum of activity
1. e. faecium and faecalis
2. MSSA
3. MRSA
4. Vanco-intermediate staph aureus
427
is lipoglycopeptides static or cidal and in what manner
concentration dependent bactericidal activity
428
lipoglycopeptide distribution
distributes fairly well into tissue
429
lipoglycopeptides CSF distribution
poor CSF penetration
430
lipoglycopeptides protein binding
90%
431
telavancin elimination
excreted primarily by the kidneys --\> dosage adjustments needed in the presence of RI
432
dalbavancin elimination
33% unchanged in urine --\> dose adjustment needed in RI
433
oritavancin elimination
Unknown --\> no adjustment needed in RI
434
are lipoglycopeptides removed by HD
no
435
lipoglycopeptide lab interactions
* telavancin and oritavancin interfere with coagulation tests (PT, INR, aPTT) by binding to artificial phospholipid surfaces
436
telavancin adverse effects
* nephrotoxicity
* QTc prolongation
* taste disturbances
437
lipoglycopeptides adverse effects
infusion related reactions --\> red man syndrome, N/V/D
438
lipoglycopeptide pregnancy category
* pregnancy category C
* telavancin with black box warning on use during pregnancy
* perform pregnancy test in women before use
439
T/F: vancomycin is the drug of choice for infections due to MRSA
True
440
aminoglycoside core structure
1,3-diaminocyclitol: aka streptidine and 2-deoxystreptamine
441
what structure is this
streptidine
442
what structure is this
2-deoxystreptamine
443
what drug is this
tobramycin
444
what drug is this
plazomicin
445
what drug is this
amikacin A
446
what drug is this
gentamicin C2
447
what drug neomycin B
neomycin b
448
what drug is this
streptomycin
449
aminoglycoside MOA
inibit protein synthesis by binding to the 30S ribosomal subunit
450
how do aminoglycosides result in cell death
* the binding to the 16S rRNA that forms the A site interferes with formation of the initiation complex, blocks further translation, and elicits premature termination
* It also causes impairment of the proofreading function of the ribosome and formation of nonsense proteins resulting form selectrion of the wrong aminco acids during translation
451
why are nonsense proteins problematic for bacteria
* Nonsense proteins impair bacterial cell wall function
* Damanged membranes have altered permeability characteristics and actually allow transport of larger amount aminoglycoside, and protein synthesis ceases altogether
* ultimately, the aminoglycosidees lead to leakage of ions and disruption of the cytoplasmic membrane, resulting in cell death
452
how does bacterial aminoglycoside uptake occur
* the intial entry of the positively charged aminoglycosides through the outer membrane involves the displacement of Mg and Ca ions that form salt bridges with phosphates of the phospholipids in the membrane
* This makes the membrane more permeable to the aminoglycosides
* Passage through the cytoplasmic membrane is an active transport process
453
how can metabolism cause aminoglycoside resistance
* bacteria inactivate aminoglycosides by acetylation, adenylation, and phosphorylation
* The genes responsible for metabolism can be transferred to other bacteria
454
how can altered ribosomes cause aminoglycoside resistance
The 16S rRNA binding site can be altered through point mutations
455
how can altered aminoglycoside cause aminoglycoside resistance
* the rate of emergence is far less than resistance due to metabolism, and the phenotype reverts after the drug is removed
456
aminoglycoside toxicities
* ototoxic (irreversible) --\> esp when taking loop diuretics/vanco
* nephrotoxic (reversible)
457
aminoglycoside drug interations
* concurrent use with loop diuretics (furosmide or ethacrynic acid) or other nephrotoxic antimicrobial drugs (vancomycin or amphotericin) can potentiate nephrotoxicity and should be avoided
458
aminoglycoside ototoxicity symptoms
1. tinnitus/high frequency hearing loss
2. vestibular damage resulting in vertigo, loss of balance, and ataxia
459
respiratory issues with aminoglycosides and how to treat it
* calcium increases the degree of depolarization at the NMJ caused by ACh, causing respiratory paralysis
* can usually be reversed by neostigmine or calcium gluconate, but mechanical respiratory assistance may be necessary
460
aminoglycoside toxicity risk relationship
likelihood of aminoglycoside toxicity increases with the treatment period, and is more likely to occur is treatment is extended more than 5 days
461
therapeutic use of aminoglycosides
although they have broad spectrum activity against both gram + and gram - bacteria, in practice their use is almost always reserved for **treatment of gram - bacteria**
462
what happens when you give aminoglycosides and penicillins together
chemical reaction render both drugs inactivated; therefore should be administered in different compartments
463
how is bacterial endocarditis treated
penicillin/aminoglycoside
464
what does streptomycin treat
TB
465
amikacin clinical use
* used competitively with gentamicin for treatment of mycobacterium tb, francisella tularnesis, and severe pseudomonas aeruginosa
* aminoglycoside resistant nosocomial infections in hospitals
466
tobramycin clinical use
widely used parenterally to treat gentamicin-resistnat p. aeruginosa infections, as well as other difficult infections
467
bacterial metabolism of tobramycin
* tobramycin is produced by fermentation of streptomyces tenebrarius
* lacks a 3'-hydroxyl group and cannot be phosphorylated at that position
* adenylated at c-2'
* acetylated at c-3
468
amikacin potency vs kanamycin potency
* the presence of the l-hydoxyaminobuteryl amide moiety inhibits bacterial metabolism by r-factors, so amikacin is more potent than kanamycin
469
gentamicin clinical use
* uti
* joint and bone infections
* skin infections/burns
* eye infections
470
why is gentamicin the most important aminoglycoside
low cost and reliable activity against all but the most resistant gram negative aerobes
471
what are the orally used aminoglycosides
* neomycin B
* paromomycin
472
why are macrolides polyketides
they are produced by sequential addition of propionate groups to a growing chain. This results in methyl groups on alternate carbon atoms in the macrolide ring
473
how is erythromycin more soluble
* the pKa of the amine in erythromycin is 8.8
* the amine can form salts that are more soluble
474
macrolide MOA
* macrolides inhibit bacterial protein synthesis by bind reversibly to the P site of the bacteria ribosome, thereby inhibiting translocation of peptidyl-tRNA from the A site to the P site
475
where does macrolide binding occur
bacterial 23S RNA
476
are macrolides mainly static or cidal
bacteriostatic
477
where do macrolides tend to accumulate
within leukocytes, and are therefore actually transported into the site of infection
478
hydrolase mechanism resistance in macrolides
lactone ester hydrolase induced to degrade the macrolides by hydrolysis of the macroycle
479
RNA methylase resistance in macrolides
* drug-induced production of RNA methylase
* a specific adenine base A2058 on the 23S RNA molecule of the 50S ribosomal subunit is methylated
* this inhibits the bidning of macrolides to the 50S subunit
480
Mutation resistance of macrolides
mutation of adenine to guanine at A2058 results in a 10,000 fold reduction in binding of erythromycin and clarthromycin to the 23S ribosomal RNA
481
efflux resistance of macrolides
an efflux pump ejects drugs from the cell by an active transport process
482
intrinsinc resistance of macrolides
* pseudomonas spp and enterobacteer spp. exhibit intrinsic resistance by not allowing entry of these drugs
* there are specific genes associated with these organisms that confer this intrinsic resistance
483
what route should erythromycin not be adminsitered and why
* should not be administered orally because the parent molecuple can be inactivated under acidic conditions by a process involving the 6-OH and the 12-OH groups
* the reaction is an intramolecular acid-catalyzed ketal formation that is inactive
484
how to achieve acid stabilitty in macrolides
* Using a 6-OCH derivative, which blocks ketal formation at low pH
485
what macrolide is formed when replacing 6-OH with OCH3
Clarithromycin
486
what macrolide is formed when replacing the C-9 ketone for an N-methylated methyleneamino moiety
azithromycin
487
main route of erythromycin metabolism
demethylation in the liver
488
erythromycin half life
1.5 hours
489
will enteric coated erythromycin be absorbed orally
yes
490
erythromycin and clarithromycin drug interactions
* bind and inhibit CYP3A and related P450 isoztmes
* carbamaepine, cyclosporin, quinidine
491
clinical use of erythromycins
primarily used for infections of skin and soft tissues primarily caused by gram (+) bacteria
492
erythromycin is drug of choice for what organisms (6)
1. mycoplasmA
2. Group A
3. Legionella
4. Bordetella
5. campylobacter
6. corynebacterium
493
what are macrolides used prophylactically for (3)
1. endocarditis
2. large bowel surgery
3. oral surgery
494
what do macrolides treat (5)
1. bronchitis
2. otitis media
3. acne
4. sinusitis
5. PID
495
macrolide GI side effects
the 14-membered macrolides strongly stimulate gastrointestinal motor activity and can cause vomiting, gastric cramps, and abdominal pain
496
macrolide biliary adverse events
* long term use (10-20 days) can induce a reversible cholestatic hepatitis which will manifest as a jaundice with cramping and fever
* relieved upon termination of the drug therapy
497
phagocytes use for macrolides
* erythromycin is very rapidly absorbed and diffuses into most tissues and phagocytes
* due to the high concentration in phagocytes, erythromycin is actively transported to the site of infection, where during active phagocytosis, large concentrations of erythromycin are released
498
why are aminoglycosides a special group of antibiotics
* dosed individually for each patient and require serum concentration monitoring due to:
* interpatient variability in Vd and Cl
* narrow therapeutic window/index
499
aminoglycoside derivatives
all derived from an actinomycete or are semisynthetic derivatives
500
aminoglycoside chemistry
* consist of 2 or more amino sugars linked to an aminocyclitol ring by glycosidic bonds
* are very polar compounds that are polycationic (PK), water soluble, and incapable of crossing lipid-containing cell membranes
501
aminoglycosides MOA
* irreversibly bind to 30S ribosomes
* disrupts the initiation of protein synthesis, decrease overall protein synthesis, and causes misreading of mRNA
* Must bind to and diffuse through outer membrane (passive) and cytoplasmic membrane (energy-dependent) to reach the ribosome
502
are aminoglycosides cidal or static and in what manner
bactericidal in a concentration-dependent manner
503
aminoglycoside MOR
1. alteration in aminoglycoside uptake
2. synthesis of aminoglycoside-modifying enzymes
3. alteration in ribosomal binding sites
504
Aminoglycoside spectrum of activity GPA (3)
1. enterococcus spp
2. s. aureus (most(
3. Coag negative staph
505
aminoglycoside spectrum of activity GNA (8)
1. e. coli
2. k. pneumonia
3. pseudomonas aeruginosa
4. providencia
5. serratia
6. salomonella
7. shigella
8. morganella
506
are aminoglycosides active against anaerobes
no
507
PAE of aminoglycosides
* suppression of bacterial growth after serum concentrations have fallen below MIC
* finite duration= 2 to 4 hours from gram-negatives
508
aminoglycoside synergy
observed with AGs and cell wall active agents against enterococcus, staph, viridans, gram negatives
509
True/False: aminoglycosides can be used as monotherapy for the treatment of infections due to gram positive aerobes
false
510
aminglycoside pharmacology
poorly absorbed from GI tract, must use parenteral administration for systemic infections
511
preferred aminoglycoside administration
intermittent IV infusion preferred- doses should be infused over 30 to 60 minutes
512
aminoglycoside distribution
primarily distribute into extracellular fluid volume --\> body fluids, urinary tract, bloodstream
513
poor distrubition sites for aminoglycosides
1. CSF
2. lungs
3. adipose tissue
514
IBW or TBW for dosing aminoglycosides
IBW
515
volume status for aminoglycosides
volume status must be taken into account to calculate appropriate dose- concentration dependent killers
516
aminoglycoside elimination
85-95% is eliminated unchanged by the kidney via glomerular filtration --\> high urinary concentrations
517
t 1/2 of aminoglycosides
* dependent on renal function
* normal is 2.5-4 hours
518
aminoglycosides and dialysis
* 30-50% removed by hemodialysis
* 25% removed by peritoneal dialysis
519
when to draw peak aminoglycoside level
30-60 minutes after end of infusion
520
when to draw trough aminoglycoside level
prior to next dose
521
gram positive synergy dosing aminoglycoside
1 mg/kg gent
522
gent/tobra dosing (LD+MD)
* LD= 2-2.5 mg/kg
* MD= 1.5-2 mg/kg/dose
523
amikacin dosing
7.5-10 mg/kg/dose
524
mod infection gent/tobra peak/trough
* Peak: 4-6
* Trough: 0.5-1.5
525
mod infection amikacin peak/trough
* PEAK: 20-25
* TROUGH: \<8
526
mod-severe infection gent/tobra peak/trough
* peak: 6-8
* trough: 1-1.5
527
mod-severe infection amikacin peak/trough
* 25-30
* \<8
528
severe infection gent/tobra peak/trough
* peak: 8-10
* trough: \<2
529
severe infection amikacin peak/trough
* peak: 25-30
* torugh: \<8
530
gent/tobra extended dosing
5-7 mg/kg q 24H
531
amikacin extended interval dosing
15 to 25 mg/kg q 24 h
532
gent/tobra peak/trough qd dosing
* peak: 13-20
* trough: \<0.5
533
amikacin peak/trough qd dosing
* peakL 40-50
* trough: \<8
534
True/False: all patients can receive the same aminoglycoside dose since there is little interpatient variability in Vd and Cl
False
535
plazomicin dosing
15mg/kg IV
536
amikasin, gentamicin, tobramycin clinical uses
infections to due gram negative aerobes (usually with beta lactams)
537
gentamicin, streptomycin clinical uses
* for syndergy with cell active antibiotics for serious infections due to gram positive aerobes
538
streptomycin clinical uses
tuberculosis
539
amingolycoside nephrotoxicity causes
nonliguric azotemia due to proximal tubular damange; increase in BUN and serum Cr
540
is aminoglycoside nephrotoxicity reversible or irreverible
reversible
541
amingolycoside nephrotoxicity risk factors (6)
1. prolonged high troughs
2. long duration of therapy
3. underlyding renal dysfunction
4. elderly
5. hypovolelmia
6. use of concomitant nephrotoxins
542
ototoxicity causes in aminoglycosides
8th cranial nerve damage- vestibular and/or auditory toxicity; irreversible
543
FQ MOA
* inhibit DNA synthesis by inhibiting bacterial topoisomerases necessary for DNA synthesis
544
How do FQs affect DNA gyrase and its target
* removes excess positive supercoiling helix
* forms stable complex with DNA and DNA gyrase, which blocks DNA replication
* primary target in gram negative bacteria
545
How do FQs affect topoisomerase IV and its target
* essential for separation of interlinked daughter DNA molecules, but interfere with separation of daughter cells
* primary target for many gram + bacteria
546
Are FQs static or cidal and in what manner
rapid, concentration-dependent bactericidal activity
547
4 MOR of FQ
1. altered binding sites
2. expression of active efflux
3. altered cell wall permeability --\> decreased porin expression
4. cross-resistance occurs between FQs
548
older FQs and route of admin
cipro: PO/IV
549
newer FQs and routes of administation
1. levofloxacin: PO/IV
2. moxifloxacin: PO/IV
3. Delafloxacin: PO/IV
550
FQs GPA
* group and viridans strep
* strep pneumoniae: PRSP
* enterococcus
* MSSA
551
what FQ is active against MRSA
delafloxacin
552
FQs Spectrum of Activity GNA
* h. influenzae, m. catarrhalis, neisseria
* enterobacteriaceae
* pneudomonas aeruginosa
553
what FQ is not active aginst p. aeruginosa
moxifloxacin
554
what atypical bacteria are FQs active against (4)
1. legionella
2. chalmydia
3. mycoplasma
4. ureaplasma
555
what other bacteria are FQs active against (2)
1. mycobatcerium tuberculosis
2. bacillus anthracis
556
delafloxacin oral bioavailability
59%- so higher dose has to be used
557
558
cipro oral bioavailability
70-75%
559
levo/moxifloxacin oral bioavailability
\>90%
560
FQs distribution
lung; skin/soft tissue and bone, urinary tract and prostate
561
FQs CSF penetration
minimal
562
FQs elimination
* most are renally eliminated thus dosage adjustment required in the renal insufficiency, but still would use to treat UTIs
563
which FQ is not renally eliminated
* moxifloxacin: hepatically eliminated
564
which FQ is removed during HD
NONE
565
which FQs treat community acquired pneumonia (2)
1. levo
2. moxi
566
which FQs treat nosocomial pneumonia
1. cipro
2. levo
567
FQ neurologic AE
peripheral neuropathy (new black box warning)
568
FQ cardiac AE
prolongation of QTC interval- case reports with current FQs- use with caution in pts with hypokalemia, pre-existing QT prolongation, concomitant antiarrhythmics (amiodarone/sotalol)
569
FQ and pregnancy relationship
contraindicated in pediatric patients and pregnant/breastfeeding women because of articular cartilage damage
570
other FQ AE
tendonitis and tendon rupture: \>60 years old, on corticosteroids, transplant
571
FQ Drug Interactions
* Divalent and trivalent cations
* Impairs absorption of orally-administered FQs --\> may lead to clinical failure
* Warfarin --\> Increases PT/INR
572
what are the three main macrolides
1. erythromycin
2. azithromycin
3. clarithromycin
573
Macrolide MOA
* inhibit protein synthesis by reversibly binding to the 50S ribosomal subunit
* induces dissociation of peptidyl transfer RNA from the ribosome during the elongation phases
574
macrolides are static or cidal and in what manner
* typically bacteriostatic
* time dependent for erythro and clarithro
* concentration dependent for azithro
575
Macrolides MOR
* active reflux
* altered binding sites
* cross-resistance occurs between all macrolides
576
macrolide spectrum of activity
1. group and viridans strep
2. PSSP
3. MSSA
4. bacillus, corynebacterium
577
what macrolide is best for gram positive aerobes
clarithro
578
what macrolide is best for gram negative aerobes
azithro
579
do macrolides have activity against enterobacteriaceae
580
what atypical bacteria do macrolides have activity against
1. legionella
2. chlamydia
3. mycoplasma
4. ureaplasma
581
macrolides are active against what other bacteria
mycobacterium avium complex
582
erythromycin absorption
* variable absorption (15-45%)- food may decrease absorption
* bases are destroyed by gastric acid
583
clarithromycin absorption
acid stable and well absorbed (52-55%) regardless of presence of food
584
azithromycin absorption
acid stable at 37% regardless of presence of food
585
macrolides distribution
extensive tissue and cellular distribution- clarithromycin and azithromycin with very large Vds
586
macrolides CSF penetration
minimal csf penetration
587
erythromycin elimination
exreted in bile and metabolized (cyp 450)
588
clarithromycin elimination
metabolized and also partially eliminated by the kidney; requies dose adjustment when CrCl \<30 mL/min
589
azithromycin elimination
biliary excretion
590
what macrolides are removed by HD
none
591
azithromycin half life
68 hours
592
macrolides clinical uses
1. commonity-acquired pneumonua
2. stds
3. MAC
4. alternative for penicillin-allergic patients
593
Macrolides AE
1. GI - take with food if possible
2. thrombophlebitis- dilute dose, slow admin, large vein
3. QTc prolongation
594
macrolides drug interactions
* erythromycin and clarithromycin are inhibitors of cytochrome P450 system in the liver and may increase concentrations of:
* theophylline
* cabamazepine
* cyclosporine
* phenytoin
* warfarin
* digoxin
* valproic acid
595
clindamycin synthesis
synthesized from the naturally occurring antibiotic lincomycin by treatment with chlorine and triphenylphosphine in acetonitrile
596
Clindamycin MOA
Inhibits protein synthesis by binding to the bacterial 50S ribosomes
597
can antagonism and cross-resistance between clinda and erythro occur and why
yes because clindamycin and erythromycin bind to the same site of the 50S ribosome
598
Clindamycin clinical use
* aerobic gram + cocci: Staph and streph
* anaerobic gram - bacilli: bacteroides and fusobacterium: MRSA
599
clindamycin metabolism
clindamycin is extensive metabolized by cytochrome P450 enzymes in the liver to the sulfoxide and N-demethylated derivative
600
what drug is this
clindamycin
601
clindamycin PK
90% of the administered dose is absorbed from the GI tract. It is widely distributed and penetrates the CNS in high enough concentrations
602
clindamycin elimination
clindamycin and its metabolites are mainly excreted in the urine and bile
603
clindamycin dose adjustment
accumulation of clindamycin can occur in patients with hepatic failure, and adjustment of the dosage may be required
604
clindamycin adverse effects
GI
605
What lethal condition can clindamycin cause
Pseudomembranous colitis is potentially lethat due to overgrowth of clostridium difficile, which results in the production of a toxin
606
what drug is this
tetracycline
607
tetracycline chemical properties
chelation: tetracyclines form stable chelates with polyvalent metal ions such as Ca, Al, Cu, Mg
608
tetracycline food cautions
should no tbe administerd with foods that are rich in calcium, should be administered 1 hour before or 2 hours after the tetracycline
609
should children be given tetracyclines
No, tetracyclines chelate calcium during formation of teethm resulting in permanently brown or gray teeth
610
why are tetracyclines injected with EDTA
to chelate the insoluble calcium, and they are buffered to acidic pH where chelation is suppressed to decrease pain
611
preferred route of tetracycline
oral
612
how do tetracyclines bind to heavy metals
through chelation
613
describe tetracycline epimerization, and the effect that this has on biological activity
* hydrogen on the amine-bearing carbon atom is acidic, resultin gin enolization and epimerization, which is inactive and loses half of their potencies
614
state the pH at which tetracycline epimerization is most rapid, and the relative
rate of epimerization in the solid state vs. in solution
* pH 4
* epimerization is slow in the solid state
615
describe tetracycline dehydration
the tertiary, benzylic hydroxyl group at c-6 has an antiperiplanar relationship with the proton at c-5a, so it is set up for elimination, leading to an inactive product of 4-epianhydrotetracycline, which is toxic to the kidneys
616
explain why minocycline and doxycycline lack the renal toxicity of tetracyclines
both lack a c-6 hydroxyl group annd are therefore completely free of this potential for toxicity
617
describe how tetracyclines cleave in under basic conditions
cleavage occurs at pH 8.5 or above, the lactone product is inactive
618
describe the mechanism of action of the tetracyclines
* bind to the 30S ribosomal subunit and inhibit bacterial protein sythnesis by blocking the attachment of the aminoacyl-tRNA to the A site of the ribosome, resulting in termination of peptide chain growth
619
describe the basis for selective toxicity of tetracyclines to bacteria, but not hosts
eukaryotic cells do not have a tetracyline uptake mechanism
620
do tetracyclines bind to the same spot as erythromycin
no
621
list the main therapeutic uses of the tetracyclines.
* acne
* chlamydia
* rickettsia
* spirochetal
* anthrax
* plague
* legionnaires
622
Be able to describe the main advantages of using tetracycline itself rather than one of the other antibiotics in the tetracycline class
generic and relatively inexpensive
623
is demeclocycline is more or less stable to dehydration than tetracycline
more
624
explain why demeclocycline is more stable to dehydration than tetracycline
it has a secondary hydroxyl group at c-6 instead of the tertiary hydroxyl group: secondary cation intermediate formed from demeclocycline in the dehydration reaction is less stable
625
do minocycline and doxycyline undergo dehydration
No
626
explain why minocycline and doxycycline do not undergo dehydration
they both lack a c-6 hydroxyl group and therefore do not undergo acid-catalyzed dehydration
627
describe the unique toxicities of minocycline in comparison with the other tetracyclines
vestibular toxicites
628
explain why doxycycline is widely considered to be the tetracycline of choice
fewer side effects and has 90-100% oral bioavailability, which permits once a day dosing
629
does why tigecycline have the potential for 4-epianhydrotetracycline-mediated toxicity and why
No because it lacks a c-6 hydroxyl group and therefore does not undergo acid-catalyzed dehydration. it therefore has no potential for 4-epianhydrotetracycline-mediated toxicity
630
tigecycline AE
1. hepatoxicity
2. pancreattis
3. anaphlactoid reaction
631
sarecycline main therapuetic use
moderate to severe acne
632
omadacycline clinical use
skin infections and community acquired bacterial pneumonia
633
can sarecycline and omadacycline be given while pregnant
no
634
chloramphenicol MOA
binds reversible to the 50S ribosomal subunit at a site that is near the site for erythromycin and clindamycin to block peptide bond formation between the P site and the A site
635
chloramphenicol and peptidyl transferase activity
chlorampenicol inhibits the peptidyl transferase activity of the ribosome and thus blocks peptide bond formation between the P site and the A site
636
chlorampenicol therapuetic use
1. bacterial meningitis
2. typhoid fever
3. ricketts
4. intraocular infections
637
metabolism of chloramphenicol sodium succinate
chloramphenicol sodium succinate is a prodrug for IV and IM administration that is hydrolyzed to chloramphenicol in the liver
638
solubility characteristics and distribution of chloramphenical
* lipid soluble, and it remains relatively unbound to plasma proteins
* penetrates effectively into all tissues of the body, including the brain
639
describe the main bacterial resistance mechanisms to chloramphen
1. reduced membrane permeability
2. mutation of the 50S ribosomal subunit
3. Elaboration of chloramphenicol acetyltransferase
640
describe how resistant bacteria metabolize chloramphenicol, and what effect this
has on biological activity
elaboration of chloramphenicol acetyltransferase, which acetylates one or both of the hydroxy groups to form metabolites that do not bind to the 50S ribosomal subunit
641
show how chloramphenicol is metabolized in humans
* metabolized to its glucoronide in the liver
* inactive and excreted by the kidneys
* reactions involves nucleophilic attack of the less hindered primary alcohol on UDPGA, catalyzed by glucuronyl transferase
642
describe the most serious potential toxicity of chloramphenicol, and how it limits
the use of chloramphenicol.
* aplastic anemia
* effect usually becomes apparent weeks or months after chloramphenicol treatment has been stopped
* bone marrow suppression due to impairment of mitochondrial function resulting from inhibition of protein synthesis
643
when should the dose of chloramphenicol be reduced
if hepatic function is impaired
644
Should neonates receive chloramphenicol
NO! they cannot metabolize chloramphenicol
645
compare the risk of serious toxicity of chloramphenicol eye drops vs. oral
chloramphenicol
* lowest risk occurs with eye drops
* highest risk is with oral chloramphenicol
646
describe how chloramphenicol toxicity can be minimize
Keep concentrations less than 25 ug/mL and give less than 20g
647
is chloramphenicol bone marrow suppression is a predictor of
aplastic anemia?
NO!
648
describe the relationship between chloramphenicol bone marrow suppression
and cumulative dose
the effect occurs quite predictably once a cumulative dose of 20 g has been given
649
describe the relationship between chloramphenicol-induced childhood leukemia
and length of treatment with chloramphenicol
there is an increased risk of childhood leukemia and the risk increases with length of treatment
650
specify the risk of drug interactions with chloramphenicol and the mechanism involved
chloramphenicol inhibits cytochrome p450 so drug interactions can be expected with drugs that are metabolized by cytochrome p450
651
describe the effect that inflammation of the meninges has on brain
concentrations of chloramphenic
* concentration achieved in brain and CSF is about 30 to 50% that of the plasma when the meninges are not inflamed; this increases to as high as 89% when the meninges are inflamed
652
recognize the core structures of the quinolone antibiotic
two rings with CO2H at C3 potition and o double bond at c4
653
state the characteristics of first, second, and third generation quinolones
* first generation
* d/c but gram (-)
* second generation
* fluorine substituent at c-6 and a heterolytic ring (usually piperazine) at c-7
* more potent for gram (-) but have extended activity again
* third generation/fourth generation
* gram +
* not as potent as gram - from cipro
654
specify the function of topoisomerases and gyrase
cleave DNA by carrying out a nucleophilic attack on a phosphodiester linkage, so one part of the strand becomes "free" and the other one becomes enzyme-linked
655
describe the difference between topoisomerase I and topoisomerase II enzymes
* topoisomerase 1 cuts one strand of the DNA helix
* topoisomerase 2 cuts both strands of the DNA helix
656
describe the common mechanistic features of bacterial gyrase, bacterial DNA
topoisomerase IV, and mammalian topoisomerase II.
* Bacterial Gyrase
* that catalyzes the ATP-dependent negative super-coiling of double-stranded closed-circular DNA
* Bacterial Toposiomerase IV
* Inhibition prevents separation of the daughter strands
* usually targets gram + bacteria
* Toposiomerase II
* prevent relaxation of supercoiled DNA
* ususally targeted by gram - bacteria
657
describe DNA unwinding by the strand passage mechanism catalyzed by gyrase,
bacterial DNA topoisomerase IV, and mammalian topoisomerase II
1. Cleavage of PD bond of each strand of DNA
2. dsDNA induce a conformation change
3. PD backbone is rejoined by nucelophilic displacement of the protein tyrosine residue by the 3'-OH of the cleaved strand
4. To repeat the cycle, the ATP has to be hydrolyzed
658
describe the mechanism of action of the quinolone
* inhibition of DNA replication
* Quinolones bind to the topoisomerase IV/DNA gyrase–DNA complexes and this results in the inhibition of DNA replication.
659
describe the therapeutic uses of the quinolones
1. UTI
2. prostatitis
3. STI
4. GI
5. RTI
6. Bone, joint, and soft tissue infections
660
describe the main bacterial resistance mechanisms to the quinolones
1. decreased cellular permeability
2. efflux pumos
3. mutation of the taregt enzymes
661
describe the main features of quinolone absorption, distribution, and elimination.
1. absorbed orally amd jabe a high degree of bioavailability
2. all are widely distributed --\> will reach brain more when meninges are inflamed
3. renal and hepatic clearance is important
662
describe how ciprofloxacin is metabolized
UDPGA attacks OH group of Cipro and uses UGT to make a major inactive metabolite (glucornide)
663
what are the main adverse effects of the quinolone antibioe main adverse effects of the quinolone antibiotics
nausea, vomiting, diarrhea
664
describe how the inactive prontosil can be converted to an active antibiotic after oral admiistration
actively directed fractionation causes to prontosil prodrug to be isolated to the active metabolite of p-aminobenzenesulfonamide
665
specify the therapeutic use of sulfanilamide
vaginal candida albicans
666
how is tetrahydrofolic acid formed, and why is it an important metabolite
* from dihyhydrofolate acid, you use DHFR to reduce dihydrofolic acid to tetrahydrofolic acid to use PABA
* incorporation of PABA into the folic acid nucleus in inhibited competitively by the sulfonamides, which are bioisoteres
667
explain why the sulfonamides are toxic to pathogenic bacteria but not humans
since mammalian cells utilize preformed folates in the diet and some bacterial cells are required to make their own folic acid, the sulfonamides have selective toxicity for bacterial cells as opposed to mammalian cells
668
sulfonamides MOA
sulfonamides inhibits PABA, which prevents the formation of thymine, which is necessary for the bacteria to make DNA
669
can sulfonamide activity be reversed
yes
670
describe how the antibiotic activities of the sulfonamides can be reversed
by adding large quantities of PABA to the diet
671
how does the acidity and pKa of p-aminobenzoic acid compares with that of sulfanulamide
* PABA has a pKa of 4.9 and is mainly anionic at physiological pH
* sulfanilamide has a pKa of 10.4 and is a week acid at physiological pH with anion:acid ration 1:1000
672
explain how aromatic substituents on the sulfonamide nitrogen can increase acidity and what does that increasing acidity cause
* the increase in acidity is due to the electronegativity of the aromatic substituent as well as resonance stabilization of the anion
* increased acidity means increased potency
673
how does the increase in the acidities of the sulfonamides can lead to a decrease in the incidence of crystalluria.
The increased acidity also greatly improves the water solubility of sulfonamide antimicrobials, which is important since the undissociated forms of these molecules and their acetate metabolites tend to have low solubility, which can be responsible for crystalluria.
674
what drug is this
sulfacetamide
675
what drug is this
sulfadiazine
676
what drug is this
sulfamethoxazole
677
what drug is this
sulfasalazine
678
characterize the antibiotic spectrum of the sulfonamides
inhibit both gram + and gram - bacteria
679
are sulfonamides used in combination? If so, why?
yes because the resistance factors are too widespread for these drugs to be used in a single drug therapy
680
1. AIDs infections (pneumocystis jiroveci)
2. Crohns/Colitis
3. acute tocoplasmosis
681
describe how sulfasalizine is metabolized by intestinal bacteria, and characterize the biological activities of the metabolites
* bacteria in the GI tract metabolize it to sulfapyridine and 5-aminosalicylic acid, which has antiinflammatory activity
682
describe the mechanism of action of pyrimethamine, and its therapeutic uses when combined with certain sulfonamides
* Pyrimethamine is an DHFR inhibitor
* saulfadiazine in combination with pyrimethamine to treat acute toxoplasmosis
683
describe the main bacterial resistance mechanisms to sulfonamid
1. mutations that cause overproductions of PABA
2. mutations in the taregt enzyme (dihydropteroate synthase) that decreases its affinity for the sulfonamides
3. muations that result in a decrease in cell permeability to the sulfonamides
684
characterize the pharmacokinetics of the main sulfonamides
* SMX is widely distributed in the body including the CSF and is also rapidly elimination
685
specify how the sulfonamides are metabolized in humans
* sulfonamides are generally metabolized by N-4 N-acetylation and in some cases N-1 glucuronidation
* Metabolites have no antibiotics activity
* hydroxylamine and nitroso metabolits are toxic
686
what drug is this
collstin
687
colistin MOA
* its ammonium cations are able to displace cations in the bacterial cell membrane (Mg and Ca) and facilitate binding of the antibiotic to anionic lipopolysaccharides in the cell membrane
688
what drug is this
metronidazole
689
metronidazole use
treatment of anerobic bacteria and protozoa: C. diff
690
metronidazole MOA
partial reduction of the nitro group in anaerobic bacteria leads to a radical anion that degrades bacterial DNA
691
what drug is this, its MOA, and therapeutic use
1. lefamulin acetate
2. selective binding to the peptidyl transferase center of the 50S ribosomal subunit to prevent bacterial protein synthesis
3. community acquired bacterial pneumonia
692
what drug is this, its MOA, and therapeutic use
1. pretomanid
2. inhibits mycolic acid biosynthesis through an unknown mechanism, and poisons respiration (mitochondria) through generation of nitric oxide
3. treatment resistant TB
693
what is a disinfectant
a compound that kills the vegetative form of microorganisms, but not spores, inanimate surfaces
694
what is a sterilant
compound that kills or removes all types of living microorganisms, including spores and viruses
695
what is an antispetic
compound that is applied to living tissue for the purpose of preventing infection
696
disinfectant examples
* alcohols
* phenols
* heavy metals
697
antiseptics examples
1. alcohols
2. chlorhexidine
3. oxychlorosene
698
Alcohol MOA
denature protein
699
chlorhexidine MOA
strongly adsorbs to bacterial membranes, causing leakage of small molecules, and it also causes precipitation of cytoplasmic proteins
700
iodine MOA
iodinates phenylalanyl and tyrosyl groups in proteins and oxidizes sulfhydryl groups in proteins
701
povidone-iodine MOA
free iodine that is liberated from the complex, causion ionation of phylalanyl and tyrosyl groups in proteins and oxidizes sulfhydryl groups in proteins
702
sodium hypochlorite MOA
variety of functional groups present in proteins and nucleic acids are oxidized by hypochlorous acid
703
halazone MOA
slowly liberates hyochlorous acid in water
704
chloroazodin MOA
diluted to liberate hypochlorous acid in water
705
oxychlorosene MOA
liberates HOCl in solution
706
phenol MOA
disrupt the cell wall and membranes, precipitate proteins, and inactivate enzymes
707
quaternary ammonium compounds MOA
inactivation of energy-producing enzymes, denaturation of proteins, and disruption of cell membranes
708
aldehydes MOA
react with amino groups in proteins and nucleic acids
709
hydrogen peroxide and peracetic acid MOA
powerful oxidizers
710
ethylene oxide MOA
reacts covalently with a variety of nucleophulic groups present in biological systems
711
alcohols use
antiseptic and disinfectant
712
chlorhexidine use
topical antiseptic against vegetative bacteria and has moderate activity vs fungi and virus, inhibits germination of spores
713
iodine use
* most active antisepctic for intact skin
* is bactericidal and kills spores, but can cause skin irritation
714
povidone-iodine use
* antiseptic that is available in aerosols, ointments, surgical scrubs, antiseptic gauze pads, sponges, and mouth washed
* kills bacteria, fungi, and lipid containing viruses
* prolonged exposure can kill spores
715
specify the chemical species that are present when sodium hypochlorite is
dissolved in water, and also when chlorine is dissolved in water
* hypochlorous acid is the active germicidal species that forms when chlorine is dissolved in water
* ammonia in urine can react with bleack to form chloramine, which is toxic
716
sodium hypochlorite use
* chlorine and its derivatives disinfect water
* disinfection of blood spils
* kill mircoorganisms at different concentrations
717
halazone and sodium dichloroisocyanurate uses
disinfect small quantities of water
718
chloroazodin use
dressing wounds, lavage, and irrigation
719
oxychlorosene use
used as an antiseptic to treat local infections, to remove necrotic tissue in massive infections, and to treat wounds
720
phenols use
disinfect hard surfaces
721
quaternary ammonium compounds use
Use as sanitizers
722
should quaternary ammonium compounds be used as antiseptics? Why or why not
no because they may contain infectious gram negative bacteria (pseudomonas)
723
aldehyde us
sterilize instruments such as fiberoptic endoscopes that cannot be sterilized by steam in an autoclave
724
which aldehyde is a carcinogen
formaldehyde
725
hydrogen peroxide use
sterilize respirators, acrylic resin implants, milk and juice cartons, plastic eating utensils, and contact lenses
726
ethlene oxide use
sterilize equipment that cannot be sterilized by heat in an autoclave (instruments with lenses, plastic, or rubber)
727
what are the tetracycline analogs
1. tigecycline
2. omadacycline
3. eravacycline
728
tetracycline and analogs MOA
inhibit bacterial protein synthesis by reversibly binding to the 30S ribosomal subunits by blocking the A site
729
tetracyclines and analogs display what type of activity
typically display bacteriostatic activity, but may be bactericidal when present at high concentrations against very susceptible organisms
730
tetracyclines and analogs mechanisms of resistance
1. decreased accumulation of tetracycline within bacteria due to decreased permeability or the presence of efflux
2. decreased access of tetracycline to the ribosome due to the presence of ribosomal protection proteins
3. enzymatic inactivation
