Kozel: Antibiotic Resistance Flashcards
1
Q
What are some characteristics of the ideal antimicrobial?
A
selective toxicity bactericidal rather than bacteriostatic absence of genetic resistance broad spectrum non-allergenic minimal adverse side effects remains active in the body water soluble
2
Q
What are the 5 categories of antibiotic action?
A
cell wall synthesis membrane function nucleic acid synthesis protein synthesis metabolic pathways
3
Q
What are the 5 categories of mechanisms of resistance?
A
- enzymatic inactivation
- decreased permeability
- efflux
- modification of susceptible molecular target
- failure to convert an inactive precursor to its active form
4
Q
This term describes the absorption, distribution, and elimination of drugs
A
pharmacokinetics
5
Q
What does pharmacodynamics refer to? What relationships are observed?
A
relationship between concentration and toxic effects
relationship between concentration and antimicrobial effect
6
Q
What is the difference between the minimum inhibitory concentration (MIC) and the minimum bactericical concentration (MBC)?
A
MIC = minimum [drug] that inhibits GROWTH
MBC = minimum [drug] that KILLS
7
Q
What is the difference between bactericidal and bacteriostatic?
A
bactericidal: kills the microbe
bacteriostatic: inhibits microbe growth, but does not kill the organism - relies on the host to clear the microbe
8
Q
What does synergy refer to?
A
synergy is when you use two antibiotics in conjunction to increase the effectiveness and the action relative to each drug given alone
ex: viridans streptococcal meningitis is treated with penicillin and gentamycin
9
Q
What is the postantibiotic effect?
A
this refers to the persistent suppression of growth following exposure to an antimicrobial
10
Q
How LONG a drug stays above the MIC; TIME dependent killing; minimal to moderate persistent effects
A
Time > MIC
11
Q
A ratio of the 24hour serum concentration curve over the MIC; tells you about the total exposure of the microbe to antimicrobial agent; largely time-dependent killing; prolonged persistent effects
A
AUC/MIC
12
Q
A ratio of the MAXIMUM serum concentration over the MIC; CONCENTRATION-dependent killing; prolonged persistent effects
A
Cmax/MIC
13
Q
Higher drug concentrations have higher rate and extent of bactericidal activity
A
concentration-dependent killing agents
14
Q
Bactericidal action is relatively slow; saturation of killing occurs at low multiples of the MIC
A
time-dependent killing agents
15
Q
What do the beta lactam antibiotics do?
A
inhibit cell wall synthesis
16
Q
List some beta lactam antibiotics
A
penicillin penicillin derivatives cephalosporins carbapenems beta lactamase inhibitors
17
Q
Which type of bacteria do natural penicillins mostly target?
A
gram positives
18
Q
Narrow spectrum - mostly gram positives
Wide use clinically - drug of choice if sensitive
Provide the starting material for semisynthetic penicillins
A
natural penicillins
19
Q
Which natural penicillin cannot be taken orally?
A
penicillin G
20
Q
What are penicillin binding proteins? What do they do?
A
PBPs are normal proteins on many bacteria that bind beta lactam antibiotics; they form the pentapeptide-pentaglycine bridges that cross-link peptidoglycans - they are essential for bacterial cell wall synthesis
21
Q
What is the mechanism of action of penicillins?
A
they bind to penicillin binding proteins on the microbe
they block peptidoglycan cross-linking
22
Q
Are penicillins bactericidal or bacteriostatic?
A
they are bactericidal - they cause eventual lysis due to autolytic enzymes that “chew up” the cell wall
23
Q
What are some ways that bacteria can become resistance to penicillins?
A
- inactivation by beta lactamase - cleaves the beta lactam ring
- prevent access of the antibiotic to penicillin binding proteins on the bacteria
- alter the penicillin binding site by decreasing the number or affinity of PBPs
24
Q
Give an example of a bacteria that prevents access of the antibiotic to the penicillin binding protein
A
N. gonorrhoeae alters the porins of the outer membrane
25
Give an example of a bacteria that alters the penicillin binding site
MRSA - changes the penicillin binding proteins so methicillin is not effective
26
Why are penicillinase-resistant penicillins effective? Give an example of one such drug.
they introduce a bulky group near the B-lactam hydrolysis site and prevent penicillinase from binding and cleaving the B-lactam; methicillin
27
Why is it harder for antibiotics to traverse a gram negative cell wall vs a gram positive cell walls? What is one characteristic of broad spectrum penicillins that allows this molecule to penetrate the outer membrane porins?
antibiotic must traverse the OUTER membrane of the gram negative bacteria which resists penetration by hydrophobic molecules; broad spectrum penicillins have a charged group which enhances penetration of the outer membrane porins and allow for that penetration
28
What type of dosing strategy should you use with penicillin?
drug exhibits time-dependent killing, so maximize exposure to drug (time above MIC)
29
What are some toxicity and side effects of taking penicillins?
allergic reactions - forms a hapten
| GI disturbances - knocks out normal GI flora (esp ampicillin)
30
What is the structure of penicillins?
beta lactam ring - cut at C-N bond by beta lactamase (penicillase)
5 member thiazolidine ring
31
If a patient is allergic to penicillin, what might you consider first?
cephalosporins
32
What is the structure of cephalosporins?
B-lactam ring + a 6 membered ring (instead of 5 in penicillin)
33
Why are cephalosporins sometimes used in place of penicillin?
they are generally resistant to Beta-lactamases
34
There are "generations" of cephalosporins. What does this mean?
The different generations of cephalosporins have evolved to be able to treat a wider variety of bugs
1st generation: narrow spectrum antibiotic - only works on some gram negatives
2nd generation: expanded spectrum - works for more gram negatives
3rd generation: BROAD spectrum - designed to work against PSEUDOMONAS
4th generations: extended spectrum
35
Why would you want to take a cephalosporin parenterally (injection) vs. orally?
if the patient is very sick, they may not be able to take antibiotics by mouth
36
What are some toxicity concerns and side effects for cephalosporins?
cross-reaction with penicillin
GI effects most common - diarrhea, nausea
superinfections may result with use of broad spectrum cephalosporins if the GI flora is knocked out and bacteria are able to colonize
37
What is the structure of carbapenems?
Beta-lactam ring + a modified alpha 5 member ring without Sulfer
38
What are some unique features of carbapenems?
They have a high affinity for penicillin binding proteins on most gram positive and gram negative bacteria, so they are exceptionally broad spectrum. Also, they penetrate the outer membranes of gram negatives well. Furthermore, they are highly resistant to beta-lactamase b/c they have a large -CH2OHCH3 group that is bulky and prevents the enzyme from binding and cleaving the ring
39
When are carbapenems used clinically? What are two common carbapenems? Are they effective against MRSA?
used for a wide variety of infections (broad spectrum); imipenem, muropenem; not currently effective against MRSA
40
How are carbapenems administered? They are rapidly hydrolyzed in the kidney, so what other drug can be given in conjunction to slow down renal degradation?
parenterally (injected); Cilastatin is given which blocks the renal degradation
41
Allergic effects of carbapenems?
generally well tolerated
| allergic reactions may occur
42
What are two examples of Beta-lactamase inhibitors?
Cluvalanic acid
| Sulbactam
43
Do beta-lactamase inhibitors kill bacteria themselves? What do they do? When are they used?
no, they have very limited direct antibacterial action, but they are more like suicide inhibitors, bc they form an intermediate of the beta lactam that is hydrolyzed very slowly; they are used in conjunction with penicillase-sensitive beta-lactams
44
Give an example of a common beta-lactamase inhibitor: penicillinase-sensitive beta lactam combo
amoxicillin given with clavulanate (Augmentin)
45
List one glycopeptide antibiotic. What is its structure?
vancomycin; disaccharide with several amino acids
46
What is the mechanism of action of vancomycin? Is it bactericidal or bacteriostatic?
it prevents TRANSPEPTIDIZATION by binding to the terminal D-ala-D-ala of the cell wall of bacteria; bactericidal
47
How does resistance to vancomycin work? For vancomycin resistnat enterococcus vs vancomycin intermediate S. aureus?
it is plasmid mediated; for vancomycin resistant enterococcus, the target of vancomycin is altered such that a lactate is put in place of a terminal alanine so vancomycin cannot bind to ala-ala; for vancomycin intermediate staph aureus, there are many repeats of the terminal ala-ala which acts as a decoy for vancomycin
48
What is the spectrum of vancomycin?
used for gram positives - often the drug of last resort
49
How is vancomycin administered?
IV, unless you are treating C. difficile in which case it is given orally
50
What are the toxicity concerns and side effects with vancomycin?
ototoxicity at high dose
nephrotoxicity at high dose
infusion-related reactions, like rash
51
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?
Has a charged group which facilitates transit through outer membrane porins
52
What is one antibiotic that is a cell membrane inhibitor?
polymyxin
53
What is the structure of polymyxin?
peptide ring + long fatty acid tail
54
How does polymyxin work? Is it bactericidal or bacteriostatic?
fatty acid tail penetrates the phospholipid bilayer of bacteria; causes leakage of metabolites and disruption of membrane function; it is bactericidal
55
What is the spectrum of polymyxin?
works on gram negative bacteria by puncturing the phospholipid bilayer of the outer membrane
56
What is polymyxin used for clinically? How is it administered and what is the main adverse effect?
used as topicals only because they are very toxic; administered IV (no absorption if taken orally); causes dose-related nephrotoxicity
57
List three antibiotics that inhibit nucleic acid synthesis
Quinolones -DNA
Metronidazole -DNA
Rifampin -RNA
58
What is the structure of quinolones and fluoroquinolones?
two fused rings with F attached in the case of fluoroquinolones
59
What is the mechanism of quinolones? Is it bactericidal or bacteriostatic?
inhibits DNA gyrase; bactericidal
60
What is the spectrum of quinolones? What is its clinical use?
gram-negative and gram-positive bacteria; used for a wide variety of bacterial infections and UTI because it is excreted in the urine in large concentrations
61
How can bacteria become resistant to quinolones?
mutation that alters the target (DNA gyrase)
62
What are some adverse effects following use of quinolones or fluoroquinolones?
GI effects - nausea, vomiting, abdominal discomfort
CNS effects - mild headache, dizziness
Achilles tendon damage *Dr. Kozel's wife
63
Quinolones, esp Ciprofloxacin, can potentially knock out the normal GI flora and cause this infection...
Clostridium difficile --> colitis
64
What is the mechanism of action of metronidazoles? Bactericidal or bacteriostatic?
they are a prodrug which is converted to its active form in ANAEROBIC bacteria only - produces cytotoxic compunds that damage DNA; bactericidal
65
So what kind of bacteria specifically can be treated by metronidazole?
ANAEROBIC infections **requires these bacteria to convert the drug to its active form
66
What is the clinical use of metronidazole besides for anaerobic infections? Most common side effects?
prophylaxis in colorectal surgery
| treatment of some protozoan infections like Trichomonas vaginalis; GI effects
67
This is an inhibitor of RNA synthesis
Rifampin
68
What is the method of action of Rifampin? Bactericidal or bacteriostatic?
binds to DNA-dependent RNA polymerase and blocks chain initiation; either or depending on concentration or bacterium
69
What is rifampin used for clinically?
treatment of TB, leprosy, prophylaxis of N. meningitidis
70
What is different about the elimination of rifampin?
most is eliminated in the feces, not the urine
71
What are some side effects and toxicity problems with rifampin?
orange tears, sweat, urine
GI effects most common
hepatic toxicity
upregulates Cyto P450s so can cause adverse drug reactions if it affects the metabolism of other drugs
72
Some antibiotics inhibit translation via the 30S ribosomal subunit. Name 2.
aminoglycosides
| tetracyclines
73
Some antibiotics inhibit translation via the 50S ribosomal subunit. Name 4.
chloramphenicol
lincosamides
oxazolidinones
macrolides - erythromycin
74
What is the method of action of aminoglycosides? Which ribosomal subunit does it bind to? Bactericidal or bacteriostatic?
binds irreversibly to 30S subunit, depletes ribosomal pool, causes misreading of the message, and premature release of the ribosome; bactericidal
75
What are aminoglycosides given with synergistically?
given with cell wall-active antimicrobials like penicillins to facilitate their uptake by gram positive bacteria
76
What is the main mechanism of resistance by aminoglycosides?
plasmid-mediated enzymatic alteration - acetylation, phosphorylation, adenylation
77
What is the spectrum of aminoglycosides?
broad - gram positives and gram negatives
**less effective with gram positives, but used in conjunction with cell wall-active agents like penicillins
78
What are aminoglycosides used for clinically?
second line drug for TB
| tularemia, plague
79
List some aminoglycosides
gentamycin
tobramycin
amikacin
80
How are aminoglycosides administered? What can be used to dose?
IM or IV (not orally); use Cmax/MIC to dose effectively
81
Adverse effects of aminoglycosides?
nephrotoxicity
| ototoxicity
82
What is the structure of tetracyclines?
4 fused 6-member rings
83
What is the mechanism of action of tetracycline? Bactericidal or bacteriostatic?
REVERSIBLY binds to the A-site of the 30S ribosome to prevent binding of the tRNA; bacteriostatic
84
What is the most common method of resistance to tetracycline?
active efflux pump pumps the antibiotic out of the cell
85
What is the spectrum of tetracycline?
very broad - gram positives, negatives, anaerobes, spirochetes, mycoplasma, rickettsiae, chlamydia
86
Tetracyclines are used first line for what diseases? When are they used more commonly?
chlamydia, rickettsia, spirochetes; used more often as a second line defense bc of their toxic effects
87
Tetracyclines should not be taken with (blank) because it impairs the metabolism
milk (divalent/trivalent cations)
88
What are some toxic concerns and side effects with tetracyclines?
```
photosensitivity in skin
GI disturbances
nephrotoxicity
stains teeth and bones if under 8
superinfection
```
89
What should we know about Chloramphenicol?
it is an inhibitor of translation via the 50S ribosomal subunit
it is NO LONGER SOLD IN THE US, but may be sold in mexico
90
What is the mechanism of action of lincosamides, like clindamycin? Bactericidal or bacteriostatic?
binds to 50S subunit and blocks peptidyl transferase so no elongation of growing peptide can occur; bacteriostatic
91
What is the method of resistance to lincosamides?
plasmid mediated METHYLATION of ribosome to reduce binding of antibiotic - alters the target
92
What is the spectrum of lincosamides?
aerobic gram-positive cocci
anaerobes
most gram negatives are resistant
93
When is clindamycin, a lincosamide, used clinically?
anaerobe infections
MRSA
as an alternative to penicillin
94
What is the main side effect you should be concerned about with clindamycin?
Clostridium difficile infection
| Also, GI disturbances
95
What is the method of action of oxazolidinones? Is it bactericidal or bacteriostatic?
bind to 50S ribosomal subunit and prevent the formation of the combined 70S complex; bacteriostatic
96
What is the spectrum of oxazolidinones?
GRAM POSITIVES
| limited use with gram negatives
97
What are oxazolidinones used for clinically?
Difficult bacteria resistant to other antibiotics!
MRSA
multi-drug resistant S. pneumoniae
Vancomycin-resistant enterococci
98
What are some side effects of oxazolidinones? What should they NOT be given in conjunction with?
GI, myelosuppresion (long-term use); don't prescribe if patient is taking SSRIs
99
What are some MACROLIDES?
erythromycin
azrithromycin
clarithromycin
100
What is the mechanism of action of the macrolides? Bactericidal or bacteriostatic?
bind to 50S ribosomal subunit, blocking peptidyl transferase and translocation of growing polypeptide chain; bacteriostatic
101
What is the method of resistance of the macrolides?
methylation of ribosome
102
Spectrum of macrolides?
generally broad, mostly aerobic, gram positives
103
What is the clinical use of macrolides?
Mycoplasma and Legionella
| alternative to penicillin
104
Erythromycin is inactivated by gastric acid - how is this problem solved? Is this a problem with azithromycin?
oral doses are given as enteric-coated or more stable salts; no azithromycin is acid stable
105
What are some side effects of the macrolides?
hepatotoxicity
stimulates GI motility
inhibits cyto P450s leading to ADRs
cardiac arrhythmias
106
List the steps in DNA and RNA synthesis from PABA
PABA --> dihydrofolic acid --> tetrahydrofolic acid --> DNA and RNA
107
What step in DNA/RNA synthesis does sulfamethoxazole inhibit?
PABA --> dihydrofolic acid
**sulfamethoxazole is a structural analog of PABA, so it inhibits the synthesis of dihydrofolic acid
108
What step in DNA/RNA synthesis does trimethoprim inhibit?
dihydrofolic acid --> tetrahydrofolic acid
**it is a structural analog of DHF acid so it competitively inhibits the formation of THF acid
109
Again, what is the mechanism of action of the sulfonamides? Bactericidal or bacteriostatic?
they are structural analogs of p-aminobenzoic acid (PABA) so they act as a competitive inhibitor; bactericidal
110
What is the method of resistance of sulfonamides?
they produce dihydropteroate synthesis (enzyme that converts PABA to DHF) with decreased affinity for the drug or over produces the enzyme so that conversion occurs
111
What is the spectrum of sulfonamides?
broad - gram positives and gram negatives, like Nocardia and Chlamydia
112
What are sulfonamides used for? How are they usu administered?
UTIs; orally - excreted in urine
113
When is trimethoprim (structural analog of dihydrofolic acid) used clinically?
in combination with sulfamethoxazole for UTIs, otitis media, MRSA
Also, drug of choice for Pneumocystis jirovecii
114
What is Isoniazid (INH)? What is its mechanism of action?
it is another metabolite analog - its a prodrug that is activated inside the bacterium and inhibits the synthesis of mycolic acids - used exclusively for mycobacteria
115
What is isoniazid primarily used for?
primary drug for TB
116
What are the adverse effects of isoniazid?
hepatitis
| inhibits cyto P450s and causes ADRs
117
What are the primary mechanisms of resistance for Beta-lactams?
enzymatic alteration
| altered binding site
118
What is the primary mechanism of action of glycopeptides, quinolones, rifampin, macrolides, lincosamides, sulfonamides, and trimethoprim?
altered binding site
119
What is the mechanism of action of amino-glycosides?
enzymatic alteration
120
What is the mechanism of action of tetracyclines?
efflux
121
What are three tests that can be used for antibiotic sensitivity?
diffusion tests on agar plates
dilution tests with serial dilutions of antibiotic
automated tests with mechanized version of dilution test
122
What is this?
Spread patient isolate on agar plate
Place antibiotic disc on plate
Antibiotic sets up concentration gradient on plate
Incubate; read diameter of inhibition zone
Use zone diameter and standard tables to estimate minimum inhibitory concentration (MIC)
diffusion test
* *simple, inexpensive
* *non-quantitative, doesn't measure bactericidal activity, not good for slow growers
123
What is this?
Prepare serial dilutions of antibiotic
Inoculate with standardized inoculum of clinical isolate
Calculate minimal concentration needed to inhibit growth
dilution test
* *quantitative results, allows for MBC determination
* *expensive, time consuming
124
What is this?
Mechanized version of dilution test
Bacterial growth determined by reduction in light transmittance or increase in light scattering
automated test
* *rapid results, better standardization
* *expensive, blind dependence on machines
