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Block 6 Week 4 > Chemotherapy and antibiotic resistance > Flashcards

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

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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
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3
Q

What are the sites of antibiotic action?

A 
cell wall synthesis
membrane function or synthesis
nucleic acid synthesis
protein synthesis
metabolic pathways
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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
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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
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6
Q

What are the three components to pharmokinetics?

A

absorption
distribution
elimination

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7
Q

What is pharmacodynamics?

A

relationship between concentration and pharmacologic or toxi effects
relationship between concentrations and antimicrobial effect

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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

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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

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10
Q

To be effective, an antibiotic needs to do what?

A

get to the microbe!

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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

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12
Q

What are the parameters of antimicrobial activity?

A 
minimum inhibitory concentration (MIC)
Minimum bactericical concentration (MBC)
Bactericidal
Bacteriostatic
Synergy
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13
Q

What is bactericidal?

Give me some examples of these

A

kills microbe

beta lactams, vancomycin, fluoroquinolones, metronidazole, aminoglycosides

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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

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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

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16
Q

What is the postantibiotic effect?

A

persistent suppression of growth following exposure to an antimicrobial

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17
Q

What is the mechanism behind the postantibiotic effect (PAE)?

A

slows growth at sub-MIC concentrations

alters morphology

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18
Q

What is postantiobiotic leukocyte enhancement (PALE)?

A

increases susceptibility to phagocytosis

increases susceptibility to phagocytic killing

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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

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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.

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21
Q

What is Cmax/MIC?

A

Maximum serum cencentration/ MIC.

Shows concentration- dependent killings. For drugs with prolonged persistent effects.

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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.

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23
Q

What are some examples of concentration-dependent kiling agents?

A

aminoglycosides, fluroquinolones, metronidazole

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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

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25
Q

What are some examples of Time-dependent (concentration-independent) kiling agents?

A

Beta lactams, vancomyocin

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26
Q

Why kind of post antibiotic effects (PAE) does bacteriostatic agents cause? what is the pharmacdynamic predictor of outcome for bacteriostatic agents?

A

prolonged

AUC/MIC

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27
Q

What are some examples of bacteriostatic agents?

A

tetracyclines, clindamycin, macrolides, sulfonamides

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28
Q

What group of antibiotics inhibit cell wall synthesis?

A

beta lactam antibiotics

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29
Q

What beta lactam antibiotics inhibit cell wall synthesis?

A 
natural penicillins
penicillin derivatives
(penicillinase resistant, broad spectrum)
cephalosporins
carbapenems 
beta lactamase inhibitors
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30
Q

What is the spectrum of natural penicillins?

A

narrow, mostly gram positive

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31
Q

What is the clinical use of natural penicillins?

A

wide use; inexpenzive, drug of choice if sensitive

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32
Q

What are penicllin binding proteins?

A

proteins that bind beta lactam antibiotics

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33
Q

What is the function of penicillin binding proteins?

A

construction of pentapeptide-pentaglycine bridges that cross-link peptidoglycan

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34
Q

What are some examples of penicillin binding protiens?

A

carboxypeptidases
endopeptidases
transglycosylases
transpeptidases

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35
Q

What is the mechanism of action of penicillins?

A

Bind to penicillin binding proteins
Block peptidogycan cross-linking system
Bactericidal-> eventual lysis due to autolytic enzymes

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36
Q

What are the three ways to create resistance to penicillin?

A

Inactivation by beta lactamase
Prevent access of antibiotic to PBP
Alteraton in binding site-reduction in number or affinity of PBP

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37
Q

How do you get resistance to penicillin through inactivation by beta lactamase?

A

beta lactamase cleaves beta lactam ring and it is found

carried by plasmid or a transposable chromosomal gene

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38
Q

How do you get resistance to penicillin by preventing access of antibiotics to PBP?

A

Gram negative have an ntrinisc resistance of to penicillin due to there double membrane.
Altered porin in N. fonorrhoeae

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39
Q

What pathogens do you get resistance to penicillin through alteration in binding site-reduction in number or affinity of PBP?

A

Newly resistant strains of S. pneumoniae
Some forms of penicillin-resistant N. gonorrhoeae
Methicillin-resistant S. ureus-MRSA

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40
Q

What is penicilinase-resistant penicilins? How potent is it?

A

its a penicillin witha bulk group near site of hydrolysis.

It is 1/10th as potent as penicillin

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41
Q

How do broad spectrum penicillins work?

A

they have hydrophilicity (charged group) that enhances their ability to penetrate the outer membrane of gram negative bacteria and thus get into the porins.

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42
Q

Are broad spectrum penicillins sensitive to penicillinases?

A

yes, with the same amount of sensitivity as natural penicillins

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43
Q

What three things vary markely in oral absorption?

A

absoprtion, fate and excretion

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44
Q

What 2 things are acid labile (volatile)?

A

penicillin G, methicillin

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45
Q

What 2 things are acid stable?

A

penicillin V, most semi-synthetic penicillins

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46
Q

Are penicillins rapidly secreted renally or slowly secreted?

A

rapidly

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47
Q

Is penicillin well distributed to most tissues?

A

yes

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48
Q

Can penicillin penetrate the BBB?

A

NO

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49
Q

What kind of pharmacodynamic outcome parameters does pencillin use? knowing ths is the parameter that penicillin follows, how should you dose this drug?

A

time-dependent killing

maximize exposures time of drug

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50
Q

What are the 2 side effects/ toxicity effects of penicillins/penicillin derivatives?

A

allergic reactions

GI disturbances

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51
Q

Why can penicillins cause allergic reactions?

A

Can create haptens by having the beta lactam ring open up and bind to host protein
AND
you can get reactivity to thiazolidine ring

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52
Q

Why can penicillins cause GI disturbances?

A

disturbances of normal flora

most prominent with ampicillin*

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53
Q

What are the beta lactam antibodies?

A

penicillin
cephalospirns
carbapenems
beta lactamase inhibitors

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54
Q

T or F

cephalosporins I has limited immunological cross reactivity with penicillin

A

T

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55
Q

T or F

cephalosporins are generally SENSITIVE to beta lactamases

A

FALSE

they are generally RESISTANT to beta lactamases

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56
Q

What cephalosporin generation is this:

Narrow spectrum- gram positives, some gram negatives

A

1st generation

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57
Q

What cephalosporin generation is this:

Broad spectrum – Gram positives; improved gram negative activity, including Pseudomonas

A

3rd generation

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58
Q

What cephalosporin generation is this:

Expanded spectrum- gram positives; improved gram negative activity

A

2nd generation

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59
Q

What cephalosporin generation is this:

extended spectrum, gram positives, marginallly improved gram negative activity

A

4th generation

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60
Q

What cephalosporin is this:

High affinity for PBP 2a’

A

MRSA-active cephalosporins

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61
Q

Tell me about the absorption, fate and excretion of cephalosporins

A 
Oral and parental
Distrbution and metabolism vary
Some have good CNS penetration
Excreted via kidn
Dosage altered in patients with renal insufficiency
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62
Q

What are the toxicity and side effects of cephalosporin?

A

some (very low) cross reaction with penicillin
GI effects COMMON (diarrhea, nausea)
superinfections possible with broad spectrium cephalosporins

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63
Q

Resistance to broad spectrum cephalosporins is typically (blank)

A

multifactorial

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64
Q

Explain how you get resistance to broad spectrum cephalosporins.

A

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)

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65
Q

How do you treat uncomplicated gonorrhoea?

A

ceftriaxone and azithromycin

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66
Q

What are the 2 types of carbapenems?

A

imipenem, muropenem

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67
Q

What is the structure of a carbapenems?

A

beta lactam ring

modified alpha ring- eliminates sulfur

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68
Q

What can carbapenems act upon?

A

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)

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69
Q

Carbapenems are highly resistant to beta lactamase, why?

A

due to hydroxyethy at C6

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70
Q

Are carpabenems effective against MRSA?

A

NO

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71
Q

What is the clinical use of carbapenems?

A
  • Useful for a wide array of infections due to broad antibacterial spectrum
  • Empirical antibacterial therapy
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72
Q

What is the absorption, fate and excretion like with carbapenems?

A

poor absorption after oral ingestion;
administered parenterally
Rapidly hydrolyzed by peptidase in renal tubule
Can be given with Cilastatin to elongate antibiotic effects

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73
Q

Why does cilastatin elongate the effects of carbapenems ?

A

because it is a peptidase inhibitor therefore it blocks renal degredation of imipenem

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74
Q

What are the side effects and toxicity like in carbapenems?

A

generally well tolerated

allergic reactions

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75
Q

What is NDM1?

A

extended spectrum beta lactamase

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76
Q

NDM1 is carried on a (blank) that carries multiple resistance genes . Why is this sooooo scary!!!!

A

plasmid

because it is resistant to essentially all usuable antibiotics

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77
Q

What are 2 examples of beta lactamase inhibitors?

A

clavulanic acid

sulbactam

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78
Q

What is the structure of beta lactams?

A

beta lactams with very limited direct antibacterial action

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79
Q

How do beta lactamase inhibitors work?

A

the are suicide inhibitors that bind to beta lactamase and form an acyl enzyme intermediate that is hydrolyzed very slowly

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80
Q

What do you use beta lactamse inhibitors for?

A

in combination with penicillinase sensitive beta lactams

i.e amoxicillin-clavulanate (augmentin); sulbactam-ampicillin (unasyn)

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81
Q

What is vancomycin?

A

glycopeptide antibiotic

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82
Q

How does vancomycin work?

A

binds to terminal D-ala-D-ala and blocks transpeptidation AND it is a bactericidal

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83
Q

How do you get vancomycin resistance?

A

Plasmid mediated -multiple genes
Enterococcus sp. S. aureus
VRE and VRSA
VISA

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84
Q

What is VRE and VRSA?

A

they change the alanine-alanine on cell wall to lactate alanine so the bacteria go unharmed

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85
Q

What is VISA?

A

they are many free terminal ala-alas that float around and act as decoys for vancomycin

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86
Q

What is the spectrum of vancomycin?

A

gram positives

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87
Q

What is the clinical use of vancomycin?

A

alternative to penicillin

often drug of last resort

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88
Q

What is the absorption, fate and excretion of glycopeptide antibiotics ?

A

Admin IV
(poorly absorbed orally, useful for C. diff)
Excreted primarily in kidney
Dosage altered in patients with renal insufficency

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89
Q

What are the toxicity and side effects of gycopeptide antibiotics ?

A

ototoxicity at high doses
nephrotoxicity at high doses
infusion-related reactions (i.e rash of red-person’s syndrome)

90
Q

What are the three forms of vancomycin resistance?

A
  • vancomycin-resistant enterococcus (VRE)
  • vancomycin-resistant S. aureus (VRSA) rare*
  • Vancomycin-intermediate S. aureus (VISA)
91
Q

What is the most common form of resistance with vancomycin?

A

VISA!! (vancomycin-intermediate S. aureus)

92
Q

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?

A

Facilitates transit through outer membrane porins

93
Q

How does Polymyxin (colistin) work?

A

It is a cell membrane inhibitor

94
Q

What is the mechanism of Polymyxin (colistin)?

A

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
Q

What is the spectrum of polymyxin- colistin?

A

gram negative bacteria

96
Q

What is the clinical use of polymyxin (colistin)?

A

toxicity limits use to topicals

parental use when no alternative (i.e in highly resistant strains of pseudomonas, klebsiella, acinetobactor)

97
Q

Can you give polymyxin (colistin) orally?

A

no, because it is not absorbed after oral admin

98
Q

What is the adverse effect of polymyxin (colistin)?

A

dose-related nephrotoxicity

99
Q

What is the potential use for polymixins?

A

pseudomonas aeruginosa, Acinetobacter baumannii and Enterobacteriaceae that are resistant to all beta lactams, fluoroquinolones and aminoglycosides; used when enterics carry NDM beta lactamase

100
Q

What does quinolones do?

A

inhibitors of DNA synthesis

101
Q

What is the mechanism of action of quinolones and fluoroquinolones I?

A

inhibits DNA gyrase

acts as a bactericidal

102
Q

How do you get resistance in quinolones and fluoroquinolones I?

A

via mutation to altered target (DNA gyrase)

103
Q

What is the spectrum of quinolones and fluoroquinolones I?

A

gram-negative and gram-positive bacteria

104
Q

What is the clinical use of Quinolones and fluoroquinolones?

A

urinary tract and a wide variety of other bacterial infections

105
Q

What is the absorption, fate and excretion of Quinolones and fluoroquinolones?

A

good absorption via oral admin
renal excretion in high concentration
(Dosage altered in patients with renal insufficiency)

106
Q

What are the adverse effects of quinolones and fluoroquinolones?

A

GI effects-nausea, vomiting, abdominal discomfort
CNS effects- mild headache, dizziness
Achilles tendon damage

107
Q

What is the most common cause of Clostridium difficile colitis?

A

Ciprofloxacin

108
Q

What does metronidazole do?

A

Inhibitors of DNA synthesis?

109
Q

What is the structure of metronidazole (Flagyl) I?

A

synthetic 5-nitroimidazole derivative

110
Q

What is the mechanism behind Metronidazole (Flagyl) I?

A
  • prodrug

- produces cytotoxic components that damage DNA-bactericidal

111
Q

What is a prodrug?

A

reduced to active form by electron transport protein in anaerobic bacteria

NOTE: some protozoa have a similar protein

112
Q

What is the spectrum of Metronidazole (Flagyl) I?

A 
obligate anaerobes and many protozoa (active)
facultative aneraboes (inactive)
obligte aerobes (inactive)
113
Q

What is the clinical use of metronidazole?

A
  • treatment of anaerobic infections
  • prophylaxis in colorectal surgery
  • treatment of some protozoan infections- Trichomonas vaginalis
114
Q

What is the absorption, fate, and excretion of metronidazole?

A

good absorption following oral admin

similiar to blood levels following oral or IV admin

115
Q

What are the side effects and toxicity of metronidazole?

A

generally well tolerated (not a lot of side effects)
GI effects most common (nausea, diarrhea)
possible mutagenic effects (largey unproven)

116
Q

How does rifampin work?

A

it inhibits RNA synthesis

117
Q

What is the mechanism behind rifampin I?

A

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
Q

How do you get resistance to Rifampin I?

A

rapid single step mutation in beta subunit

119
Q

What is the clinical use of Rifampin?

A

treatment of TB, leprosy, prophylaxis of N. meningitidis, many other applications

120
Q

What is the absorption, fate and excretion of Rifampin?

A

Good absorption following oral admin
Good distribution through the body; Limited CNS penetration.
Elimination in urine 30%, in feces (60-70%)

121
Q

What is the toxicity and side effects of Rifampin?

A
  • 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
Q

What happens if you upregulate hepatic cytochrome P450 enzymes?

A

alters hepatic metabolism of hormones and drugs (decreases the half life)
**examine patient medications for potentia interactions*

123
Q

What antiobiotics are inhibitors of 30S ribosomal subunit?

A

aminoglycosides

tetracyclines

124
Q

What antibiotics are inhibitors of the 50s ribosomal subunit?

A

Chloramphenicol
Lincosamides
Oxazolidinones
Macrolides (erythromycin)

125
Q

How does tetracycline work?

A

it inhibits proteins synthesis by preventing bindind of tRNA to mRNA

126
Q

How does Chloramphenicol and Lincosamides work?

A

In inhibits protein synthesis by preventing peptide bond formation

127
Q

How do Macroides work?

A

inhibit protein synthesis by preventing translocation

128
Q

What is the mechanism behind aminoglycosides (streptomycin)?

A

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
Q

How do you get resistance to aminoglycosides (streptomycin)?

A

plasmid-mediated enzymatic alteration- acetylation, phosphorylation, adenylation (common)
reduced uptake by bacteria
intrinsic resistance-anaerobes

130
Q

What is the spectrum of aminoglycosides (streptomycin)?

A

broad spectrum; gram positives, gram-negatives, TB

131
Q

What are all the antibiotics you can use to fight TB?

A

Rifampin I
Aminoglycosides (streptomycin)
Isoniazid (INH)

132
Q 
What are these:
sisomicin
netilimicin
kanamycin A
amikacin
tobramycin
dibekacin
gentamicin complex
lividomycin A
A

Aminoglycosides

133
Q

What are the 5 major aminoglycosides?

A

Streptomycin, gentamycin, tobramycin, amikacin, neomycin

134
Q

What is the clinical use of the aminoglycoside streptomycin?

A

second line drug in Rx TB,
Tularemia, plague
NOTE: more toxic than newer agents

135
Q

What is the clinical use of the aminoglycoside gentamycin, tobramycin, amikacin?

A

empiric therapy of suspected aerobic, gram-negative bacteria

specific therapy once culutres and sensitivity are known

136
Q

How do you use Neomycin?

A

as a topical ointment

137
Q

How do you make aminoglycosides more effective with gram positive bacteria?

A

you use in combination with cell wall-active agents

138
Q

What is the absorption, fate, and excretion of aminoglycosides?

A

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
Q

What are the adverese effects of aminoglycosides?

A

nephrotoxicity
ototoxicity
neuromuscular blockade (rare)

140
Q

How is tetracycline?

A

an inhibitor of 30S ribosomal subunit

141
Q

What is the mechanism of tetracycline?

A

blocks binding of aminoacyl tRNA to A-site of ribosome. Reversible binding.

142
Q

Is tetracycline bacteriocidal or bacteriostatic?

A

bacteriostatic

143
Q

How do you get tetracycline resistance?

A 
Active efflux (pump; most common)
Ribosomal protection- cytoplasmic proteins that bind ribosome to protect from action of tetracyclines
144
Q

What is the ribosomal protection that some bacteria have that keeps them safe from tetracycline?

A

cytoplasmic proteins that bind ribosome to protect from action of tetracyclines

145
Q

What is the spectrum of tetracycline?

A

very broad, gram positive, gram negative, many anaerobes, many spirochetes, mycoplasma, rickettsiae and chlamydia

146
Q

What is the clinical use of tetracycline?

A

variable depending on circumstance;
first line-> for chlamydia, ricketssia, spirochetes
Second line-> more common due to toxicity, resistance and availability of alternatives

147
Q

What is the absorption, fate and excretion of tetracycline?

A

Absorption via oral admin
(variability among individuals and various tetracyclines)
Excreted via kidney and bile

148
Q

How can oral absorption of tetracycline get impaired?

A

by ingestion of divalent and trivalent cations e.g. milk

149
Q

What is the toxicity and side effects of tetracycline?

A
  • Photosensitivity in skin
  • GI disturbances
  • Nephrotoxicity
  • Stains teeth and bones during early development; not recommended for children under 8 years.
  • Super infeciton.
150
Q

What is chloramphenicol?

Why dont we care about this?

A

inhibitor of 50s ribosomal subunit

No longer used in USA

151
Q

What is lincosamids (clindamycin)?

A

inhibitor of 50s ribosomal subunit

152
Q

What is the mechanism behind Lincosamids (clindamycin)?

A

blocks peptidyl transferase

153
Q

Is Lincosamids (clindamycin) a bacteriocidal or a bacteriostatic?

A

bacteriostatic

154
Q

How do you get resistance to Lincosamids (clindamycin I)?

A

plasmid mediated methylation of ribosome to reduce binding of antibiotic

155
Q

What is the spectrum of Lincosamids (cindamycin I)?

A

aerobic gram-positive cocci
anaerobes

NOTE: most gram negatives are resistant

156
Q

What is the clinical use of clindamycin?

A

anaerobe infections

alternative to penicillin if patient is hypersensitive

157
Q

Many MRSA strains are suscpetible to what?

A

Clindamycin

158
Q

What is the absorption, fate, and excretion of Clindamycin?

A

oral (most common) or parenteral use
Urinary and fecal excretion
Half-life increases with renal failure- requires changes in dosage

159
Q

What is the toxicity and side effects of Clindamycin?

A 
GI disturbances (diarrhea, nausea, vomiting, cramps)
Pseudomembraneous colitis (C. Diff)
160
Q

What is Oxazolidinones (linezolid)?

A

an inhibitor of 50S ribosomal subunit

161
Q

What is the mechanism behind Oxazolidinones (linezolid)?

A
  • binds to 50s ribosomal subunit

- prevents formation of 70S complex

162
Q

Why is Oxazolidinones (linezolid) pretty awesome?

A

cuz it has an unusual mechanism which makes it effective against many resistant bacteria

163
Q

Is Oxazolidinones (linezolid) bacteriocidal or bacteriostatic?

A

bacteriostatic

164
Q

What is the clinical use of Oxazolidinones (linezolid)?

A
  • Methicillin-resistant S. aureus (off label)
  • Multidrug-resistant Streptococcus pneumoniae
  • Vancomycin-resistant entercocci (VRE)
  • Difficult bacteria resistant to other antibiotics - a “reserve antibiotic”
165
Q

What is the absorption, fate, and excretion of Oxazolidinones (linezolid)?

A

Used IV or orally
Outstanding bioavailability
Broken down in vivo and excreted in urine

166
Q

What is the toxicity and side effects of Oxazolidinones (linezolid)?

A 
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
Q

What do macrolides do and what are three of them?

A

they inhibit the 50S ribosomal subunit.

Erythromycin, azrithromycin, clarithromycin

168
Q

What is the mechanism behind Macrolides (erythromycin)?

A

binds to 50s ribosomal subunit and blocks peptidyl transferase and translocation

169
Q

Are macrolides bacteriostatic or bacteriocidal?

A

bacteriostatic

170
Q

How can you get resistance to Macrolides?

A
  • Plasmid mediated methylation of ribosome

- Cross resistance with lincomycin/clindamycin

171
Q

What is the spectrum of Macrolides (erythromycin)?

A

generally broad; most active against aerobic, gram positives

172
Q

What is the clinica use of Macrolides?

A

primary antibiotic for Mycoplasma, Legionella

Alternative for penicillin if allergic

173
Q

What is the absorption, fate and excretion of Macrolides?

A

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
Q

How can you give erythromycin if is inactivated by gastric acid?

A

you give it orally with either enteric-coated or more-stable salts or esters

175
Q

What is the toxicity and side effects of Macrolides?

A
  • Hepatotoxicity
  • Stimulates GI motility (diarrhea, nausea, abdominal pain)
  • Inhibitor of cytochrome P450 system; significant drug interactions
  • Cardiac arrhythmias
176
Q

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?

A

Mutation in the DNA-dependent RNA polymerase

177
Q

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?

A

vancomycin

178
Q

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?

A

inhibits subunit A of DNA gyrase

179
Q

What are three metabolite analogs?

A

sulfonamides
trimethoprim
isoniazid

180
Q

Folic acid is the precursor to DNA and RNA in bacteria, so why are sulfonamides awesome at killing bacteria?

A

because it competitively inhibits the synthesis of dihydrofolic acid from PABA

181
Q

Folic acid is the precursor to DNA and RNA in bacteria, so why is trimethoprim awesome at killing bacteria?

A

because it competitively inhibits the synthesis of THF acid

182
Q

What is the mechanism behind sulfonamides?

A

analog of p-aminobenzoic acid
competitive inhibtor
AND it is bacteriostatic

183
Q

How do you get resistance to sulfonamides?

A

plasmid mediated production of dihydropteroate synthetase with decreased affinity for drug.

184
Q

What is the spectrum of sulfonamides?

A

broad; gram positives, gram negatives, Nocardia, Chlamydia

185
Q

What is the clinical use of sulfonamides?

A

urinary tract infections

and “many special applications”

186
Q

What is the absorption, fate and elimination of sulfonamides?

A

usually, oral admin; rapidly absorbed from GI tract

Largely excreted in urine

187
Q

What are the adverse effects of sulfonamides?

A

Disorders of hematopoietic system (generally rare)
Hypersensitivity reactions (common) -rash, hives
Stevens-Johnson syndrome

188
Q

What are some disorders of the hematopoietic system?

A

hemolytic anemia
granulocytosis
aplastic anemia

189
Q

What is Stevens-Johnson syndrome?

A
  • immune reaction

- confluent epidermal necrosis- dermatological emergency

190
Q

What is the mechanism behind trimethoprim?

A

Structural analog of dihydrofolic acid

Synergistic with sulfonamides

191
Q

What is the spectrum of trimethoprim?

A

broad; similiar to sulfonamides

192
Q

What are the clinical uses of Trimethoprim?

A
  • combination with sulfamethoxazole-cotrimoxazole (bactrim, septra)
  • urinary tract infection
  • some gram negatives infection
  • Drug of choice for Pneumocystis jirovecii
  • MRSA with sulfamethoxazole
193
Q

What is the drug of choice for trimethoprim?

A

Pneumocystis jirovecii

194
Q

What is the absorption, fate and elimnation of trimethoprim?

A

oral administration

high levels in urine

195
Q

What is the toxicity and side effects of trimethoprim?

A

hypersensitivity

impaired folate usage

196
Q

What is trimethoprim?

A

metabolite analogs

197
Q

What is Isoniazid (INH)?

A

metabolite analogs

198
Q

What is the mechanism of Isoniazid (INH)?

A

prodrug activated in bacterium and it inhibits synthesis of mycolic acids

199
Q

What is the spectrium of Isoniazid (INH)?

A

only effective against mycobacteria

200
Q

How does resistance happen in Isoniazid (INH)?

A

very common and occurs by deletion of gene encoding activating enzyme

201
Q

What is the clinical use of Isoniazid (INH)?

A

primary drug for tuberculosis

202
Q

What is the pharmacology of Isoniazid (INH)?

A

well absorbed orally and IM

203
Q

What are the adverse effects of Isoniazid (INH)?

A

heptatitis

inhibitor of cytochrome P450s (drug interactions)

204
Q

What is the mechanism of resistance for Isoniazid (INH)?

A
  • 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
Q

How do you get enzymatic inactivation of antibiotics?

A

destruction of antibiotic

modification of antibiotic so it fails to reach or bind target

206
Q

How can you get modification of susceptible molecular targets?

A
  • altered binding site for antibiotic
  • protection of binding site
  • overproduction of target
  • binding up of antibiotic
207
Q

What drugs have their major mechanism of resistance as enzymatic alteration?

A

Beta-lactam
aminoglycoside
chloramphenicol

208
Q

What drugs have their major mechanism of resistance as efflux?

A

tetracycine

209
Q

What drugs have their major mechanism of resistance as altered binding site?

A

glycopeptides, quinolone, rifampin, macrolides Lincosamides, SUlfonamide trimethoprim and beta lactam

210
Q

How do you use antibiotics appropriately?

A 
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
211
Q

What are the three antibiotic sensitivity testing?

A

diffusion tests
dilution tests
automated tests

212
Q

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

A

diffusion tests

213
Q

What are the advantages of a diffusion test?

What are the disadvantages?

A

simple, inexpensive, most widely used assay

non-quantitative interpretation
does not measure bactericidal activity
inappropriate for slow growers, slow diffusers

214
Q

What is this
prepare serial dilutions of antibiotic
inoculate with standardized inoculum of clinical isolate
calculate MIC needed to inhibit growth

A

Dilution tests

215
Q

What are the advantages to the dilution test?

What are the disadvantages?

A

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
Q

What is this:
Mechanized version of dilution test
Bacterial growth determined by reduction in light transmittance or increase in light scattering

A

automated tests

217
Q

What are the advantages of the automated test?

What are the disadvantages?

A 
Advantages
-Better standardization
-Usually produces more information
-Rapid results
Disadvantages
-Initial expense
-Promotes “blind” dependence on machines
218
Q

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.

A

ciprofloxacin

219
Q

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.

A

macrolide

220
Q

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?

A

acquistion of an efflux pump

221
Q

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

A

Acquired a plasmid that encoded an enzyme that phosphorylated the antibiotic

Block 6 Week 4 (9 decks)

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