Chemotherapy and antibiotic resistance Flashcards
1
Q
What is this:
chemical substances produced by various species of microorganisms that are capable of inhibiting, in small amounts, the growth of other microorganisms.
A
Antibiotics
2
Q
What is an ideal antimicrobial?
A
- selective toxicity
- bactericidal rather than bacteriostatic
- absence of genetic or phenotypic resistance
- broad vs. narrow spectrum
- non-allergenic
- minimal adverse side effects
- remains active in body
- water soluble
- bactericidal levels can be reached in vivo
3
Q
What are the sites of antibiotic action?
A
cell wall synthesis membrane function or synthesis nucleic acid synthesis protein synthesis metabolic pathways
4
Q
What is the mechanism of resistance for antibiotics?
A
- enzymatic inactivation
- decreased permeability
- efflux
- modification of susceptible molecular target
- fail to convert an inactive precursor to its active form
5
Q
How d you get modification of susceptible molecular target?
A
- Alteration of antibiotic binding site
- Protection of target site
- Overproduction of target
- Binding-up of antibiotic
6
Q
What are the three components to pharmokinetics?
A
absorption
distribution
elimination
7
Q
What is pharmacodynamics?
A
relationship between concentration and pharmacologic or toxi effects
relationship between concentrations and antimicrobial effect
8
Q
When you are looking at concentration versus time in tissue and other body fluids-> what next do you look for?
A
pharmacologic or toxicological effect
9
Q
When you are lookinat at concentration versus time at site of infection-> what next do you look for?
A
antimicrobial effect versus time
10
Q
To be effective, an antibiotic needs to do what?
A
get to the microbe!
11
Q
What are some issues associated with getting the antibiotic to the microbe?
A
absorption from the site of administration
transfer from plasma to site of infection
elimination from plasma
elimination from site of infection
12
Q
What are the parameters of antimicrobial activity?
A
minimum inhibitory concentration (MIC) Minimum bactericical concentration (MBC) Bactericidal Bacteriostatic Synergy
13
Q
What is bactericidal?
Give me some examples of these
A
kills microbe
beta lactams, vancomycin, fluoroquinolones, metronidazole, aminoglycosides
14
Q
What is bacteriostatic?
Give me some examples of these
A
inhibit but do not kill the organism, relys on host to clear microbe
ex. tetracycline, clindamycin, macrolides, sulfonamides
15
Q
What is synergy?
Give me an example.
A
a combination of antibiotics produces a 2-log 10 increase in action relative to each agent alone
Penicilin + gentamycin for treatment of viridans streptococcal meningitis
16
Q
What is the postantibiotic effect?
A
persistent suppression of growth following exposure to an antimicrobial
17
Q
What is the mechanism behind the postantibiotic effect (PAE)?
A
slows growth at sub-MIC concentrations
alters morphology
18
Q
What is postantiobiotic leukocyte enhancement (PALE)?
A
increases susceptibility to phagocytosis
increases susceptibility to phagocytic killing
19
Q
What is Time > MIC and when do you use it?
A
How long a drug stays above the MIC. Displays TIme-dependent killing. For drugs with minimal to moderate persistent effects
20
Q
What is AUC/MIC and when do you use it?
A
Ratio of the 24-hour serum concentration curve to MIC.
Show total exposure of micobe to antimicrobial agent. For drugs with prolonged persistent effects.
21
Q
What is Cmax/MIC?
A
Maximum serum cencentration/ MIC.
Shows concentration- dependent killings. For drugs with prolonged persistent effects.
22
Q
In concentration dependent killing agents, what are the pharmacodynamic predictors of outcome and what drugs are the most effective?
A
higher drug concentrations have higher rate and extent of bactericidal activity
Cmax/MIC and AUC/MIC are pharmacodynamic predictors of outcome.
23
Q
What are some examples of concentration-dependent kiling agents?
A
aminoglycosides, fluroquinolones, metronidazole
24
Q
In time-dependent (concentration-independent) killing agents, what is the bactericidal action like? When does saturation of killing occur? What is the pharmacodynamic predictor of outcome?
A
relatively slow
saturation of killing occurs at low multiples of the MIC
T> MIC is pharmacodynamic predictor of outcome
25
What are some examples of Time-dependent (concentration-independent) kiling agents?
Beta lactams, vancomyocin
26
Why kind of post antibiotic effects (PAE) does bacteriostatic agents cause? what is the pharmacdynamic predictor of outcome for bacteriostatic agents?
prolonged
| AUC/MIC
27
What are some examples of bacteriostatic agents?
tetracyclines, clindamycin, macrolides, sulfonamides
28
What group of antibiotics inhibit cell wall synthesis?
beta lactam antibiotics
29
What beta lactam antibiotics inhibit cell wall synthesis?
```
natural penicillins
penicillin derivatives
(penicillinase resistant, broad spectrum)
cephalosporins
carbapenems
beta lactamase inhibitors
```
30
What is the spectrum of natural penicillins?
narrow, mostly gram positive
31
What is the clinical use of natural penicillins?
wide use; inexpenzive, drug of choice if sensitive
32
What are penicllin binding proteins?
proteins that bind beta lactam antibiotics
33
What is the function of penicillin binding proteins?
construction of pentapeptide-pentaglycine bridges that cross-link peptidoglycan
34
What are some examples of penicillin binding protiens?
carboxypeptidases
endopeptidases
transglycosylases
transpeptidases
35
What is the mechanism of action of penicillins?
Bind to penicillin binding proteins
Block peptidogycan cross-linking system
Bactericidal-> eventual lysis due to autolytic enzymes
36
What are the three ways to create resistance to penicillin?
Inactivation by beta lactamase
Prevent access of antibiotic to PBP
Alteraton in binding site-reduction in number or affinity of PBP
37
How do you get resistance to penicillin through inactivation by beta lactamase?
beta lactamase cleaves beta lactam ring and it is found
| carried by plasmid or a transposable chromosomal gene
38
How do you get resistance to penicillin by preventing access of antibiotics to PBP?
Gram negative have an ntrinisc resistance of to penicillin due to there double membrane.
Altered porin in N. fonorrhoeae
39
What pathogens do you get resistance to penicillin through alteration in binding site-reduction in number or affinity of PBP?
Newly resistant strains of S. pneumoniae
Some forms of penicillin-resistant N. gonorrhoeae
Methicillin-resistant S. ureus-MRSA
40
What is penicilinase-resistant penicilins? How potent is it?
its a penicillin witha bulk group near site of hydrolysis.
| It is 1/10th as potent as penicillin
41
How do broad spectrum penicillins work?
they have hydrophilicity (charged group) that enhances their ability to penetrate the outer membrane of gram negative bacteria and thus get into the porins.
42
Are broad spectrum penicillins sensitive to penicillinases?
yes, with the same amount of sensitivity as natural penicillins
43
What three things vary markely in oral absorption?
absoprtion, fate and excretion
44
What 2 things are acid labile (volatile)?
penicillin G, methicillin
45
What 2 things are acid stable?
penicillin V, most semi-synthetic penicillins
46
Are penicillins rapidly secreted renally or slowly secreted?
rapidly
47
Is penicillin well distributed to most tissues?
yes
48
Can penicillin penetrate the BBB?
NO
49
What kind of pharmacodynamic outcome parameters does pencillin use? knowing ths is the parameter that penicillin follows, how should you dose this drug?
time-dependent killing
| maximize exposures time of drug
50
What are the 2 side effects/ toxicity effects of penicillins/penicillin derivatives?
allergic reactions
| GI disturbances
51
Why can penicillins cause allergic reactions?
Can create haptens by having the beta lactam ring open up and bind to host protein
AND
you can get reactivity to thiazolidine ring
52
Why can penicillins cause GI disturbances?
disturbances of normal flora
| ***most prominent with ampicillin****
53
What are the beta lactam antibodies?
penicillin
cephalospirns
carbapenems
beta lactamase inhibitors
54
T or F
| cephalosporins I has limited immunological cross reactivity with penicillin
T
55
T or F
| cephalosporins are generally SENSITIVE to beta lactamases
FALSE
| they are generally RESISTANT to beta lactamases
56
What cephalosporin generation is this:
| Narrow spectrum- gram positives, some gram negatives
1st generation
57
What cephalosporin generation is this:
| Broad spectrum – Gram positives; improved gram negative activity, including Pseudomonas
3rd generation
58
What cephalosporin generation is this:
| Expanded spectrum- gram positives; improved gram negative activity
2nd generation
59
What cephalosporin generation is this:
| extended spectrum, gram positives, marginallly improved gram negative activity
4th generation
60
What cephalosporin is this:
| High affinity for PBP 2a'
MRSA-active cephalosporins
61
Tell me about the absorption, fate and excretion of cephalosporins
```
Oral and parental
Distrbution and metabolism vary
Some have good CNS penetration
Excreted via kidn
Dosage altered in patients with renal insufficiency
```
62
What are the toxicity and side effects of cephalosporin?
some (very low) cross reaction with penicillin
GI effects COMMON (diarrhea, nausea)
superinfections possible with broad spectrium cephalosporins
63
Resistance to broad spectrum cephalosporins is typically (blank)
multifactorial
64
Explain how you get resistance to broad spectrum cephalosporins.
altered penicillin binding protein 2 (altered penA gene)
overexpression of efflux pump (due to mutation in repressor mtrR)
mutation in porin reduces uptake (penB resistance determinant)
65
How do you treat uncomplicated gonorrhoea?
ceftriaxone and azithromycin
66
What are the 2 types of carbapenems?
imipenem, muropenem
67
What is the structure of a carbapenems?
beta lactam ring
| modified alpha ring- eliminates sulfur
68
What can carbapenems act upon?
high affinity for essental PBPs of most gram positives and gram negatives
Exceptionally broad spectrum- good penetration of outer membrane of gram negatives through a specific outer membrane porin (OMP)
69
Carbapenems are highly resistant to beta lactamase, why?
due to hydroxyethy at C6
70
Are carpabenems effective against MRSA?
NO
71
What is the clinical use of carbapenems?
- Useful for a wide array of infections due to broad antibacterial spectrum
- Empirical antibacterial therapy
72
What is the absorption, fate and excretion like with carbapenems?
poor absorption after oral ingestion;
administered parenterally
Rapidly hydrolyzed by peptidase in renal tubule
Can be given with Cilastatin to elongate antibiotic effects
73
Why does cilastatin elongate the effects of carbapenems ?
because it is a peptidase inhibitor therefore it blocks renal degredation of imipenem
74
What are the side effects and toxicity like in carbapenems?
generally well tolerated
| allergic reactions
75
What is NDM1?
extended spectrum beta lactamase
76
NDM1 is carried on a (blank) that carries multiple resistance genes . Why is this sooooo scary!!!!
plasmid
| because it is resistant to essentially all usuable antibiotics
77
What are 2 examples of beta lactamase inhibitors?
clavulanic acid
| sulbactam
78
What is the structure of beta lactams?
beta lactams with very limited direct antibacterial action
79
How do beta lactamase inhibitors work?
the are suicide inhibitors that bind to beta lactamase and form an acyl enzyme intermediate that is hydrolyzed very slowly
80
What do you use beta lactamse inhibitors for?
in combination with penicillinase sensitive beta lactams
| i.e amoxicillin-clavulanate (augmentin); sulbactam-ampicillin (unasyn)
81
What is vancomycin?
glycopeptide antibiotic
82
How does vancomycin work?
binds to terminal D-ala-D-ala and blocks transpeptidation AND it is a bactericidal
83
How do you get vancomycin resistance?
Plasmid mediated -multiple genes
Enterococcus sp. S. aureus
VRE and VRSA
VISA
84
What is VRE and VRSA?
they change the alanine-alanine on cell wall to lactate alanine so the bacteria go unharmed
85
What is VISA?
they are many free terminal ala-alas that float around and act as decoys for vancomycin
86
What is the spectrum of vancomycin?
gram positives
87
What is the clinical use of vancomycin?
alternative to penicillin
| often drug of last resort
88
What is the absorption, fate and excretion of glycopeptide antibiotics ?
Admin IV
(poorly absorbed orally, useful for C. diff)
Excreted primarily in kidney
Dosage altered in patients with renal insufficency
89
What are the toxicity and side effects of gycopeptide antibiotics ?
ototoxicity at high doses
nephrotoxicity at high doses
infusion-related reactions (i.e rash of red-person's syndrome)
90
What are the three forms of vancomycin resistance?
- vancomycin-resistant enterococcus (VRE)
- vancomycin-resistant S. aureus (VRSA) **rare***
- Vancomycin-intermediate S. aureus (VISA)
91
What is the most common form of resistance with vancomycin?
VISA!! (vancomycin-intermediate S. aureus)
92
Ampicillin and carbenicillin are examples of broad spectrum penicillins in which penicillin has been modified to enhance activity against gram negative bacteria. What is the function of the modifications that achieve the enhanced activity for gram negative bacteria?
Facilitates transit through outer membrane porins
93
How does Polymyxin (colistin) work?
It is a cell membrane inhibitor
94
What is the mechanism of Polymyxin (colistin)?
It's fatty acid tail penetrates phospholipid bilayer and you get leakage of metabolites and disruption of membrane function AND it is a bactericidal
95
What is the spectrum of polymyxin- colistin?
gram negative bacteria
96
What is the clinical use of polymyxin (colistin)?
toxicity limits use to topicals
| parental use when no alternative (i.e in highly resistant strains of pseudomonas, klebsiella, acinetobactor)
97
Can you give polymyxin (colistin) orally?
no, because it is not absorbed after oral admin
98
What is the adverse effect of polymyxin (colistin)?
dose-related nephrotoxicity
99
What is the potential use for polymixins?
pseudomonas aeruginosa, Acinetobacter baumannii and Enterobacteriaceae that are resistant to all beta lactams, fluoroquinolones and aminoglycosides; used when enterics carry NDM beta lactamase
100
What does quinolones do?
inhibitors of DNA synthesis
101
What is the mechanism of action of quinolones and fluoroquinolones I?
inhibits DNA gyrase
| acts as a bactericidal
102
How do you get resistance in quinolones and fluoroquinolones I?
via mutation to altered target (DNA gyrase)
103
What is the spectrum of quinolones and fluoroquinolones I?
gram-negative and gram-positive bacteria
104
What is the clinical use of Quinolones and fluoroquinolones?
urinary tract and a wide variety of other bacterial infections
105
What is the absorption, fate and excretion of Quinolones and fluoroquinolones?
good absorption via oral admin
renal excretion in high concentration
(Dosage altered in patients with renal insufficiency)
106
What are the adverse effects of quinolones and fluoroquinolones?
GI effects-nausea, vomiting, abdominal discomfort
CNS effects- mild headache, dizziness
Achilles tendon damage
107
What is the most common cause of Clostridium difficile colitis?
Ciprofloxacin
108
What does metronidazole do?
Inhibitors of DNA synthesis?
109
What is the structure of metronidazole (Flagyl) I?
synthetic 5-nitroimidazole derivative
110
What is the mechanism behind Metronidazole (Flagyl) I?
- prodrug
| - produces cytotoxic components that damage DNA-bactericidal
111
What is a prodrug?
reduced to active form by electron transport protein in anaerobic bacteria
NOTE: some protozoa have a similar protein
112
What is the spectrum of Metronidazole (Flagyl) I?
```
obligate anaerobes and many protozoa (active)
facultative aneraboes (inactive)
obligte aerobes (inactive)
```
113
What is the clinical use of metronidazole?
- treatment of anaerobic infections
- prophylaxis in colorectal surgery
- treatment of some protozoan infections- Trichomonas vaginalis
114
What is the absorption, fate, and excretion of metronidazole?
good absorption following oral admin
| similiar to blood levels following oral or IV admin
115
What are the side effects and toxicity of metronidazole?
generally well tolerated (not a lot of side effects)
GI effects most common (nausea, diarrhea)
possible mutagenic effects (largey unproven)
116
How does rifampin work?
it inhibits RNA synthesis
117
What is the mechanism behind rifampin I?
binds to DNA-dependent, RNA polymerase
Blocks chain initiation
It is inactive on polymerases from eukaryotic cells
IT can be bactericidal or bacteriostatic depending on concentration or bacterium
118
How do you get resistance to Rifampin I?
rapid single step mutation in beta subunit
119
What is the clinical use of Rifampin?
treatment of TB, leprosy, prophylaxis of N. meningitidis, many other applications
120
What is the absorption, fate and excretion of Rifampin?
Good absorption following oral admin
Good distribution through the body; Limited CNS penetration.
Elimination in urine 30%, in feces (60-70%)
121
What is the toxicity and side effects of Rifampin?
- orange discoloration of tears, sweat, and urine
- GI effects common-cramping, nausea, diarrhea
- Hepatic toxicity
- Powerful up-regulator of hepatic cytochrome P-450 enzymes
122
What happens if you upregulate hepatic cytochrome P450 enzymes?
alters hepatic metabolism of hormones and drugs (decreases the half life)
*****examine patient medications for potentia interactions****
123
What antiobiotics are inhibitors of 30S ribosomal subunit?
aminoglycosides
| tetracyclines
124
What antibiotics are inhibitors of the 50s ribosomal subunit?
Chloramphenicol
Lincosamides
Oxazolidinones
Macrolides (erythromycin)
125
How does tetracycline work?
it inhibits proteins synthesis by preventing bindind of tRNA to mRNA
126
How does Chloramphenicol and Lincosamides work?
In inhibits protein synthesis by preventing peptide bond formation
127
How do Macroides work?
inhibit protein synthesis by preventing translocation
128
What is the mechanism behind aminoglycosides (streptomycin)?
it is bactericidal
has multiple effects (irreversibly binds to 30s subunit, depletion of ribosomal pool, misreading of message, premature release of ribosome)
Synergy with cell wall-active antimicrobials Ii.e used with penicillin fciliates uptake of aminoglycosides by gram positives)
129
How do you get resistance to aminoglycosides (streptomycin)?
plasmid-mediated enzymatic alteration- acetylation, phosphorylation, adenylation (common)
reduced uptake by bacteria
intrinsic resistance-anaerobes
130
What is the spectrum of aminoglycosides (streptomycin)?
broad spectrum; gram positives, gram-negatives, TB
131
What are all the antibiotics you can use to fight TB?
Rifampin I
Aminoglycosides (streptomycin)
Isoniazid (INH)
132
```
What are these:
sisomicin
netilimicin
kanamycin A
amikacin
tobramycin
dibekacin
gentamicin complex
lividomycin A
```
Aminoglycosides
133
What are the 5 major aminoglycosides?
Streptomycin, gentamycin, tobramycin, amikacin, neomycin
134
What is the clinical use of the aminoglycoside streptomycin?
second line drug in Rx TB,
Tularemia, plague
NOTE: more toxic than newer agents
135
What is the clinical use of the aminoglycoside gentamycin, tobramycin, amikacin?
empiric therapy of suspected aerobic, gram-negative bacteria
| specific therapy once culutres and sensitivity are known
136
How do you use Neomycin?
as a topical ointment
137
How do you make aminoglycosides more effective with gram positive bacteria?
you use in combination with cell wall-active agents
138
What is the absorption, fate, and excretion of aminoglycosides?
minimally absorbed from GI tract (given IM or IV)
excreted primarily via kidney
(dosage alterned in patients iwth renal insufficiency)
concentration-dependent effect (Cmax/MIC) is predictor of efficacy
139
What are the adverese effects of aminoglycosides?
nephrotoxicity
ototoxicity
neuromuscular blockade (rare)
140
How is tetracycline?
an inhibitor of 30S ribosomal subunit
141
What is the mechanism of tetracycline?
blocks binding of aminoacyl tRNA to A-site of ribosome. Reversible binding.
142
Is tetracycline bacteriocidal or bacteriostatic?
bacteriostatic
143
How do you get tetracycline resistance?
```
Active efflux (pump; most common)
Ribosomal protection- cytoplasmic proteins that bind ribosome to protect from action of tetracyclines
```
144
What is the ribosomal protection that some bacteria have that keeps them safe from tetracycline?
cytoplasmic proteins that bind ribosome to protect from action of tetracyclines
145
What is the spectrum of tetracycline?
very broad, gram positive, gram negative, many anaerobes, many spirochetes, mycoplasma, rickettsiae and chlamydia
146
What is the clinical use of tetracycline?
variable depending on circumstance;
first line-> for chlamydia, ricketssia, spirochetes
Second line-> more common due to toxicity, resistance and availability of alternatives
147
What is the absorption, fate and excretion of tetracycline?
Absorption via oral admin
(variability among individuals and various tetracyclines)
Excreted via kidney and bile
148
How can oral absorption of tetracycline get impaired?
by ingestion of divalent and trivalent cations e.g. milk
149
What is the toxicity and side effects of tetracycline?
- Photosensitivity in skin
- GI disturbances
- Nephrotoxicity
- Stains teeth and bones during early development; not recommended for children under 8 years.
- Super infeciton.
150
What is chloramphenicol?
| Why dont we care about this?
inhibitor of 50s ribosomal subunit
| No longer used in USA
151
What is lincosamids (clindamycin)?
inhibitor of 50s ribosomal subunit
152
What is the mechanism behind Lincosamids (clindamycin)?
blocks peptidyl transferase
153
Is Lincosamids (clindamycin) a bacteriocidal or a bacteriostatic?
bacteriostatic
154
How do you get resistance to Lincosamids (clindamycin I)?
plasmid mediated methylation of ribosome to reduce binding of antibiotic
155
What is the spectrum of Lincosamids (cindamycin I)?
aerobic gram-positive cocci
anaerobes
NOTE: most gram negatives are resistant
156
What is the clinical use of clindamycin?
anaerobe infections
| alternative to penicillin if patient is hypersensitive
157
Many MRSA strains are suscpetible to what?
Clindamycin
158
What is the absorption, fate, and excretion of Clindamycin?
oral (most common) or parenteral use
Urinary and fecal excretion
Half-life increases with renal failure- requires changes in dosage
159
What is the toxicity and side effects of Clindamycin?
```
GI disturbances (diarrhea, nausea, vomiting, cramps)
Pseudomembraneous colitis (C. Diff)
```
160
What is Oxazolidinones (linezolid)?
an inhibitor of 50S ribosomal subunit
161
What is the mechanism behind Oxazolidinones (linezolid)?
- binds to 50s ribosomal subunit
| - prevents formation of 70S complex
162
Why is Oxazolidinones (linezolid) pretty awesome?
cuz it has an unusual mechanism which makes it effective against many resistant bacteria
163
Is Oxazolidinones (linezolid) bacteriocidal or bacteriostatic?
bacteriostatic
164
What is the clinical use of Oxazolidinones (linezolid)?
- Methicillin-resistant S. aureus (off label)
- Multidrug-resistant Streptococcus pneumoniae
- Vancomycin-resistant entercocci (VRE)
- Difficult bacteria resistant to other antibiotics - a "reserve antibiotic"
165
What is the absorption, fate, and excretion of Oxazolidinones (linezolid)?
Used IV or orally
Outstanding bioavailability
Broken down in vivo and excreted in urine
166
What is the toxicity and side effects of Oxazolidinones (linezolid)?
```
generally well tolerated
GI issues (diarrhea, nausea, vomiting)
Myelosuppression with long-term use
Weak nonspecific inhibitor of monoamine oxidase; should not be given with selective serotonin reuptake inhibitors (SSRI; antidepressants)
```
167
What do macrolides do and what are three of them?
they inhibit the 50S ribosomal subunit.
| Erythromycin, azrithromycin, clarithromycin
168
What is the mechanism behind Macrolides (erythromycin)?
binds to 50s ribosomal subunit and blocks peptidyl transferase and translocation
169
Are macrolides bacteriostatic or bacteriocidal?
bacteriostatic
170
How can you get resistance to Macrolides?
- Plasmid mediated methylation of ribosome
| - Cross resistance with lincomycin/clindamycin
171
What is the spectrum of Macrolides (erythromycin)?
generally broad; most active against aerobic, gram positives
172
What is the clinica use of Macrolides?
primary antibiotic for Mycoplasma, Legionella
| Alternative for penicillin if allergic
173
What is the absorption, fate and excretion of Macrolides?
Erythromycin is inactive by gastric acid
Azithromycin is acid stable
Well distributed throughout body except brain and CSF
Excretion varies with antibiotic; primarily billary excretion
174
How can you give erythromycin if is inactivated by gastric acid?
you give it orally with either enteric-coated or more-stable salts or esters
175
What is the toxicity and side effects of Macrolides?
- Hepatotoxicity
- Stimulates GI motility (diarrhea, nausea, abdominal pain)
- Inhibitor of cytochrome P450 system; significant drug interactions
- Cardiac arrhythmias
176
Rifamycins are highly effective against staphylococci. However, use of rifampin as a single agent for treatment of Staphylococcus aureus infections is limited due to the high rate of development of rifampin resistance during therapy. What is the most likely mechanism for resistance to rifampin?
Mutation in the DNA-dependent RNA polymerase
177
Cycloserine is an antibiotic that is a competitive inhibitor for incorporation of the terminal alanine into the pentapeptide that is attached to N-acetyl muramic acid in peptidoglycan. Which of the following antibiotics also targets the terminal alanine in the peptide attached to MurNAc?
vancomycin
178
Patients with possible exposure to Bacillus anthracis during the bioterrorism attack in 2001 were treated for 40 days with ciprofloxacin. What is the mechanism of action of ciprofloxacin?
inhibits subunit A of DNA gyrase
179
What are three metabolite analogs?
sulfonamides
trimethoprim
isoniazid
180
Folic acid is the precursor to DNA and RNA in bacteria, so why are sulfonamides awesome at killing bacteria?
because it competitively inhibits the synthesis of dihydrofolic acid from PABA
181
Folic acid is the precursor to DNA and RNA in bacteria, so why is trimethoprim awesome at killing bacteria?
because it competitively inhibits the synthesis of THF acid
182
What is the mechanism behind sulfonamides?
analog of p-aminobenzoic acid
competitive inhibtor
AND it is bacteriostatic
183
How do you get resistance to sulfonamides?
plasmid mediated production of dihydropteroate synthetase with decreased affinity for drug.
184
What is the spectrum of sulfonamides?
broad; gram positives, gram negatives, Nocardia, Chlamydia
185
What is the clinical use of sulfonamides?
urinary tract infections
| and "many special applications"
186
What is the absorption, fate and elimination of sulfonamides?
usually, oral admin; rapidly absorbed from GI tract
| Largely excreted in urine
187
What are the adverse effects of sulfonamides?
Disorders of hematopoietic system (generally rare)
Hypersensitivity reactions (common) -rash, hives
Stevens-Johnson syndrome
188
What are some disorders of the hematopoietic system?
hemolytic anemia
granulocytosis
aplastic anemia
189
What is Stevens-Johnson syndrome?
- immune reaction
| - confluent epidermal necrosis- dermatological emergency
190
What is the mechanism behind trimethoprim?
Structural analog of dihydrofolic acid
| Synergistic with sulfonamides
191
What is the spectrum of trimethoprim?
broad; similiar to sulfonamides
192
What are the clinical uses of Trimethoprim?
- combination with sulfamethoxazole-cotrimoxazole (bactrim, septra)
- urinary tract infection
- some gram negatives infection
- Drug of choice for Pneumocystis jirovecii
- MRSA with sulfamethoxazole
193
What is the drug of choice for trimethoprim?
Pneumocystis jirovecii
194
What is the absorption, fate and elimnation of trimethoprim?
oral administration
| high levels in urine
195
What is the toxicity and side effects of trimethoprim?
hypersensitivity
| impaired folate usage
196
What is trimethoprim?
metabolite analogs
197
What is Isoniazid (INH)?
metabolite analogs
198
What is the mechanism of Isoniazid (INH)?
prodrug activated in bacterium and it inhibits synthesis of mycolic acids
199
What is the spectrium of Isoniazid (INH)?
only effective against mycobacteria
200
How does resistance happen in Isoniazid (INH)?
very common and occurs by deletion of gene encoding activating enzyme
201
What is the clinical use of Isoniazid (INH)?
primary drug for tuberculosis
202
What is the pharmacology of Isoniazid (INH)?
well absorbed orally and IM
203
What are the adverse effects of Isoniazid (INH)?
heptatitis
| inhibitor of cytochrome P450s (drug interactions)
204
What is the mechanism of resistance for Isoniazid (INH)?
- enzymatic inactivation of antibiotics
- decreased permeability
- efflux of antibiotics
- modification of susceptible molecular target
- failure to convert an inactive precursor agent to its active form
205
How do you get enzymatic inactivation of antibiotics?
destruction of antibiotic
| modification of antibiotic so it fails to reach or bind target
206
How can you get modification of susceptible molecular targets?
- altered binding site for antibiotic
- protection of binding site
- overproduction of target
- binding up of antibiotic
207
What drugs have their major mechanism of resistance as enzymatic alteration?
Beta-lactam
aminoglycoside
chloramphenicol
208
What drugs have their major mechanism of resistance as efflux?
tetracycine
209
What drugs have their major mechanism of resistance as altered binding site?
glycopeptides, quinolone, rifampin, macrolides Lincosamides, SUlfonamide trimethoprim and beta lactam
210
How do you use antibiotics appropriately?
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give only when needed
use specific antiobiotc
use drug with shortest course and most efficacy
encourage patient compliance
use antibiotic combos only in specific situations
use high quality shit
discourage self-prescription
RELY On the CLINICAL microbilogy LAB
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211
What are the three antibiotic sensitivity testing?
diffusion tests
dilution tests
automated tests
212
What is this:
spread patient isolate on agar plate. Place antibiotic disc on plate. (creates con. gradient)
incubate
Read diameter of inhibition zone
use zone diameter and standard tables to estimate MIC
diffusion tests
213
What are the advantages of a diffusion test?
| What are the disadvantages?
simple, inexpensive, most widely used assay
non-quantitative interpretation
does not measure bactericidal activity
inappropriate for slow growers, slow diffusers
214
What is this
prepare serial dilutions of antibiotic
inoculate with standardized inoculum of clinical isolate
calculate MIC needed to inhibit growth
Dilution tests
215
What are the advantages to the dilution test?
| What are the disadvantages?
provides quantitative results
not influence by growth rate
avoids problems with diffusion properties of antibiotics
allows for determination of minimum bactericidal concentration.
Expensive, time consuming, requires rigid quality control
216
What is this:
Mechanized version of dilution test
Bacterial growth determined by reduction in light transmittance or increase in light scattering
automated tests
217
What are the advantages of the automated test?
| What are the disadvantages?
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Advantages
-Better standardization
-Usually produces more information
-Rapid results
Disadvantages
-Initial expense
-Promotes “blind” dependence on machines
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218
CDC’s Strategic National Stockpile includes enough antibiotics to treat several large cities at the same time in the event of a bioterrorism attack. One of the antibiotics in the stockpile is this antibiotic that would be used to treat individuals exposed to anthrax. In 2011, the FDA included a black box warning for this antibiotic due to the possibility of spontaneous tendon ruptures.
ciprofloxacin
219
A 6-year-old child was diagnosed with strep throat. The patient is allergic to penicillin and was treated with an antibiotic of this class that binds to the the bacterial 50S ribosomal subunit.
macrolide
220
Widespread use of tetracyclines for human therapy and in animal feeds has led to an increased number of resistant strains. Which of the following is a common mechanism for resistance to tetracycline?
acquistion of an efflux pump
221
The patient is a 32-year old gardener who was treated with streptomycin for ulceroglandular tularemia. Midway through the treatment, the infection stopped responding to the antibiotic. Further study might show that the bacterium had
Acquired a plasmid that encoded an enzyme that phosphorylated the antibiotic
