microbio lecture 18 chapter 20 Flashcards
(185 cards)
1
Q
Who was Paul Ehrlich (165-1915)?
A
German physician and bacteriologist
2
Q
What did Ehrlich do?
A
Observed some dyes stain bacterial but not animal cells
3
Q
Ehrlich found fundamental difference between
A
cell types
4
Q
Ehrlich searched for ______ _______ that would kill microbial pathogens without harming human host
A
“magic bullet”
5
Q
Ehrlich tested _______ _____________ to treat syphilis, caused by spirochete Treponema pallidum
A
arsenic compounds
6
Q
The ______ _______ compound proved effective in laboratory animals
A
606th tested: it was Arsphenamine, named Salvarsan
7
Q
Arsphenamine, Salvarsan is potentially ________ for patients but did cure infections previously considered hopeless
A
lethal,
8
Q
Arsphenamine proved….
A
some chemicals could selectively kill microbes
9
Q
first documented case of antimicrobial medications
A
Salvarsan (Paul Ehrlich 1910)
10
Q
Red dye Prontosil
A
Gerhard Domagk, 1932; used to treat streptococcal infections in animals
11
Q
red dye prontosil has no effect in
A
test tubes: enzymes in blood split to produce sulfanilamide, the first sulfa drug
12
Q
red dye prontosil and salvarsan are
A
chemotherapeutic agents: chemicals used to treat disesase
13
Q
synonyms of chemotherapeutic agents
A
antimicrobial medications, antimicrobial drugs, antimicrobials
14
Q
Discovery of antibiotics
A
In 1928, Fleming identified mold Penicillium secreting compound toxic to Staphylococcus (penicillin) - he couldn’t purify it
15
Q
penicillin showed effective in
A
killing many bacterial species
16
Q
Chain and Florey purified penicillin and tested compounds in 1941 on police officer with
Staphylococcus aureus infection. It led to
A
Patient improvement but supply of purified penicillin ran out and he later died
17
Q
WWII spurred research and
development of penicillin G, the
A
first antibiotic
18
Q
antibiotic
A
naturally-produced antimicrobial
19
Q
Selman Waksman purified ________ from soil bacterium Streptomyces griseus
A
streptomycin
20
Q
researchers began screening
A
hundreds of thousands of
microbes for antibiotics
21
Q
pharmaceutical companies today examine
A
soil samples from around world
22
Q
Selective toxicity
A
causes greater harm to microbes than to
human host
23
Q
toxicity interferes with essential structures or properties common in
A
microbes
but not human cells
24
Q
toxicity is relative and expressed as
A
therapeutic index
25
therapeutic index calculated as the
lowest dost toxic to patient divided by dose used for therapy
26
penicillin g useful to humans and has high therapeutic index because it
interferes with cell wall synthesis, a process not present in humans
27
penicillin g also has a high therapeutic window, which is
the range between the therapeutic dose and the toxic dose
28
medications too toxic for systemic use may be used
topically (body surface application)
29
TI is the ratio of
the doses of toxic and the desired responses
30
TI is used as an
index of comparative toxicity of two different materials for relative safety of drug
31
larger the TI ratio, the _____ the relative safety
greater
32
bacteriostatic antimicrobial agents
chemicals inhibit bacterial growth
* Patient’s defenses must eliminate pathogen (sulfa drugs)
33
bactericidal agents
chemicals kill bacteria
* Sometimes only inhibitory depending upon drug
concentration and stage of microbial growth
34
Broad-spectrum antimicrobials
affect a wide range and are important for treating acute life-threatening diseases (especially when no time to culture for identification/susceptibility)
35
negative side effect of broad-spectrum antimicrobials
Can disrupt microbiome that helps keep out other
pathogens (dysbiosis)
36
narrow spectrum antimicrobials
affect limited range, requires identification and susceptibility of pathogen, less disruptive to microbiome
37
Patients may be started on broad-spectrum antimicrobial and later
switched to
narrow-spectrum once more is known about the pathogen
38
Antimicrobial behaviors differ in body
Only some can access the brain; only some can withstand stomach acid
39
Half-life of medication is
time it takes for serum concentration to
decrease by 50%
40
half-life dictates
frequency of doses required to maintain effective level in body
41
penicillin V is taken ___ times a day
4
42
azithromycin is taken no more than____ a day
once
43
Patients with kidney or liver dysfunction excrete or metabolize
medications more slowly; must adjust dosage to avoid toxic levels
44
Antimicrobials have saved countless lives when properly prescribed and used, however,
toxicity and intolerance can be significant issues
45
allergic reactions
May be life-threatening; may wear bracelet alert
46
Toxic effects
* Monitor those taking low therapeutic index drugs
* Some side effects are life-threatening (chloramphenicol may cause
aplastic anemia)
47
Dysbiosis
imbalance in the microbiome
48
dysbiosis example
broad-spectrum antimicrobials may allow growth of
Clostridium difficile without competition, resulting in diarrhea or colitis
49
Certain bacteria have
intrinsic (innate) resistance
50
example of innate resistance
Mycoplasma lack cell wall, resistant to penicillin that
interferes with peptidoglycan synthesis
51
Outer membrane of Gram-negatives
blocks many medications
52
Pseudomonas species have very narrow
porin diameter (channel through outer membrane)
53
Bacteria may develop acquired resistance through
* Spontaneous mutations
* Horizontal gene transfer (drug resistance plasmids, transposons, etc.)
54
Antibacterial medications target specific bacterial processes and structures* (Selective toxicity)
* Cell wall synthesis
* Protein synthesis
* Nucleic acid synthesis
* Metabolic pathways
* Cell membranes
55
antibacterial medications inhibiting cell wall synthesis due to unique bac cell walls w peptidoglycan
Include Beta-lactam
antibiotics, glycopeptide
antibiotics, and bacitracin
56
beta-lactam antibiotics all have
b lactam ring and high therapeutic index
57
beta lactam antibiotic examples
Penicillin, cephalosporins, carbapenems, monobactams
58
the beta-lactam antibiotics competitively inhibit with
penicillin-binding
proteins (PBPs) that
catalyze formation of
peptide bridges between
adjacent glycan strands;
disrupt cell wall synthesis
59
beta-lactam antibiotics are only effective against
actively growing cells
60
beta-lactam antibiotics also vary in
activity
61
when peptidoglycan of gram pos exposed, susceptible to
beta-lactam antibiotics, whereas outer membrane of gram-negatives block
62
PBPs different in Gram-positives versus
Gram-negatives; also aerobes
versus anaerobes, and in different species
63
some bacteria synthesize a b-lactamase which breaks
b-lactam ring destroying activity of antibiotic
64
penicillinase
inactivates members of penicillin family
65
extended spectrum b lactamases (ESBLS) inactivate
a wide variety of B lactam medications
66
gram negatives produce a more extensive array of __________ than gram positives
b lactamase
67
penicillinase is a
beta-lactamase
68
Broad-spectrum penicillins act against
Gram-positives and many Gram-
negatives (ampicillin, amoxicillin)
69
these penicillins inactivated by many
b lactamases
70
Extended-spectrum penicillins have
greater activity against
Enterobacteriaceae, Pseudomonas species
71
extended spec penicillins have reduced activity against
gram-positives
72
Augmentin: Penicillin + Beta-
lactamase inhibitor (clavulanic
acid) added to protect
penicillin from being degraded
by bacterial beta-lactamase
73
Cephalosporins
Structure makes resistant to some B lactamases
74
some cephalosporins have low affinity for
PBPs of gram-positives
75
chemical modifications have led to
five generations, where later generates more effect against gram-negs and resist b-lactamases
76
fifth generation is effective against
MRSA
77
other cephalosporins available with
B- lactamase inhibitor
78
zerbaxa was first medication approved under
GAIN act
79
Gain Act
Generating Antibiotic Incentives Now (GAIN) Act was passed by U.S. Congress in 2012
as part of the Food and Drug Administration Safety and Innovation Act (FDASIA). It
addresses the public health threat of antibacterial drug resistance by stimulating the
development and approval of new antibacterial and antifungal drugs.
80
Glycopeptide antibiotics
Bind to amino acid side chain of NAM molecules; block peptidoglycan synthesis
81
Glycopeptide antibiotics effective only against
Gram-positives; does not cross outer
membrane of Gram-negatives
82
side effects of glycopeptide antibiotics
give low therapeutic index
83
vancomycin is most widely
used glycopeptide
84
vancomycin poorly absorbed from
intestinal tract, usually administered via IV except
for intestinal infections
85
vancomycin often antibiotic of last resort to
treat Gram-positives resistant to beta-
lactam antibiotics
86
vancomycin can be VERY
toxic; requires close monitoring of dose and blood levels to
guard against acute renal failure and cardiac toxicity.
87
Bacitracin
toxicity limits to topical applications
88
bacitracin interferes with
transport of peptidoglycan precursors across
membrane
* Common in first-aid skin ointments
89
Inhibit protein synthesis
* Generally bacteriostatic
* aminoglycosides bactericidal
90
aminoglycosides bactericidal
Can exploit differences
between prokaryotic and
eukaryotic ribosomes
91
Prokaryotes have
70S ribosomes
92
eukaryotes have
80S ribosomes
93
mitochondria also have
70S ribosomes
94
differences in ribosomes may account for
toxicity of some of these
antibiotics
95
Aminoglycosides
gentamicin, amikacin, tobramycin, neomycin, and
streptomycin
96
Aminoglycosides inhibit
Protein Synthesis
97
Aminoglycosides Irreversibly bind to 30S ribosomal subunit, causing it to
malfunction; bacteriocidal
98
malfunctional binding blocks
initiation of translation; causes misreading of mRNA by ribosomes past initiation
99
aminoglycosides are often
toxic and generally used when alternatives unavailable
100
Aminoglycosides are generally ineffective against
anaerobes, enterococci, and streptococci because they do not enter these cells efficientyl
101
Sometimes aminoglycosides used synergistically with a penicillin that allows
the aminoglycoside to enter cells
102
Inhaled form of tobramycin treats
Pseudomonas lung infections
in cystic fibrosis patients
103
Neomycin too toxic for systemic use but common
in first-aid skin
ointments
104
Tetracyclines reversibly bind to
30S ribosomal subunit
(thus bacteriostatic
105
tetracyclines block
tRNA attachment; prevent translation
106
tetracyclines are effective against
certain Gram-positives and Gram-negatives
107
some tetracyclines have longer half-life meaning less
frequent doses
108
resistances comes from either
decreased uptake or increased excretion
109
the glycylcyclines are related to
the tetracyclines
110
relation of glycylcyclines and tetracyclines
Wider activity
* Effective against bacteria resistant to the tetracyclines
* Relatively new, so acquired resistance is rare
111
__________ is the only one currently approved
tigecycline
112
Macrolides: Erythromycin and Azithromycin
Reversibly bind to 50S subunit; prevent continuation of translation
113
Macrolides: Erythromycin and Azithromycin often antibiotic of choice for
patients allergic to penicillin
114
macrolides are bacteriostatic against
many Gram-positives and most common causes
of atypical pneumonia
* Outer membrane of Enterobacteriaceae blocks
115
resistance to macrolides occurs from
modification of ribosomal RNA target, enzyme
that modifies chemical, and decreased uptake
116
Chloramphenicol
Binds to 50S ribosomal subunit; blocks translation
* Active against wide range of bacteria
117
chloramphenicol used as last resort due to
rare but lethal side effect: may cause aplastic anemia, inability to form white, red blood cells
118
Fluoroquinolones and rifamycins
inhibit nucleic acid synthesis
119
fluoroquinolones
Inhibit topoisomerases, enzymes that maintain supercoiling of DNA; bactericidal against wide variety of bacteria
* DNA gyrase breaks, rejoins strands to relieve strain from localized unwinding of DNA; function is essential
120
resistant to Fluoroquinolones
due to alteration in DNA gyrase target
121
Rifamycin's
Block prokaryotic RNA polymerase; prevents initiation of transcription
122
Rifamycin is bactericidal against
Gram-positives, some Gram-negatives,
Mycobacterium
123
resistance to rifamycin develops quickly due to
mutation in RNA polymerase gene
124
folate inhibitors are most useful to
interfere with metabolic pathways
125
folate inhibitors inhibit steps in
synthesis
of folate and ultimately
synthesis of coenzyme
required for nucleotide
biosynthesis
126
animals lack enzymes to
synthesize folate; required in diet
127
sulfonamides, trimetoprim inhibit
different steps in synthesis
128
Sulfonamides and related are called
sulfa drugs
129
sulfonamides inhibit many
Gram-positives and Gram-negatives
130
sulfonamides structurally similar to
PABA, so enzyme binds chemical
* Example of competitive inhibition
* Human cells lack enzyme
131
trimethoprim inhibits
enzyme in later step and has little effect on enzyme's counterpart in human cells
132
Combination of trimethoprim and sulfonamide has
synergistic effect; co-trimoxazole
133
A few antimicrobials damage bacterial membranes causing cells to
leak, leading to cell death
134
Daptomycin
inserts into cytoplasmic membrane and is Used against Gram-positives resistant to other antibiotics
135
daptomycine ineffective against
Gram-negatives; cannot penetrate outer membrane
136
Polymyxins bind to membranes of
Gram-negatives, limits usefulness to topical applications
137
polymyxins also bind to
eukaryotic cells, though to a lesser extent
138
Newest glycopeptide antibiotics disrupt
cell membranes (albavancin, oritavancin)
139
Few antimicrobials effective against
Mycobacterium
140
waxy cells of mycobacterium
prevents entry of many chemicals; slow growth
141
First-line drugs are
most effective, least toxic
* Combination therapy decreases chance of development of resistant
mutants
142
Second-line drugs given for strains resistant
to first-line drugs
* Less effective or have greater toxicity risk1
143
some drugs target
unique cell wall of mycobacteria
144
examples of drugs targeting unique processes of mycobacteria
Isoniazid inhibits mycolic acid synthesis; ethambutol inhibits enzymes required for synthesis of other cell wall components; pyrazinamide
interferes with protein synthesis
145
Kirby-Bauer disc diffusion test
Conventional disc diffusion method routinely used to determine susceptibility of bacterial strain to antibiotics
146
Standard sample of strain uniformly spread on agar plate in Kirby-Bauer, discs
containing ________ __________- placed on surface
different antibiotics
147
in Kirby-Bauer test, drugs
diffuse outward, establish concentration gradients
148
diffusion of drugs results in
zone of inhibition
compared with specially
prepared charts to determine
whether strain is susceptible,
intermediate, or resistant
149
drug characteristics must be taken into acct, for example
molecular weight,
stability, amount
150
minimum inhibitory concentration (MIC) is
lowest concentration that prevents growth in vitro
151
Serial dilutions of chemical in suitable growth medium used;
cultures added, incubated, examined for turbidity
152
inhibition does not necessarily mean
successful treatment; level
may not be achieved in person’s blood
153
Microbes with MIC between susceptible (treatable) and resistant (untreatable) are
intermediate
154
Minimum bacterial concentration (MBC) is
lowest concentration that kills 99.9% of cells in vitro
155
MBC determined from plate count prepared from
tubes with no
growth in MIC test
156
MIC techniques precise but
labor-intense, expensive
157
Commercial modifications of susceptibility testing are
Less labor-intensive, often faster results
158
One automated system determines growth rate via
turbidity in cards,
interprets results to determine MICs in 6 to 15 hours
159
E test is modification of disc diffusion test, uses
strip with gradient of antibiotic; intersection of zone of inhibition indicates MIC
160
New systems detect
genes encoding antibiotic resistance
161
increasing use of antimicrobials, misuse selects for
resistant microorganisms
162
only 3% of S. aureus originally resistant to penicllin G; now,
more than 90% are resistant
163
Antimicrobial resistance alarming and has impact on
cost, complications, and
outcomes of treatment
164
dealing with problem requires
understanding of mechanisms and spread
of resistance
165
Mechanisms of acquired resistance
Antibiotic-inactivating enzymes & Antibiotic-inactivating enzymes & Decreased uptake of the
medication & Increased elimination of
medication
166
Antibiotic-inactivating enzymes
Bacteria produce enzymes
that interfere with drug
167
Antibiotic-inactivating enzymes examples
Penicillinase, extended
spectrum B lactamase,
chloramphenicol
acetyltransferase
168
Alteration in target molecule
Minor structural changes can
prevent binding
169
things that can cause alterations
PBPs (B lacatam antibiotics)
ribosomal RNA (macrolides,
lincosamides, streptogramins)
170
Decreased uptake of the
medication
Changes in porin
proteins of outer
membrane of Gram-
negatives
171
Increased elimination of
medication
* Efflux pumps remove
compounds from cell
* Increased production or
structural changes of pumps
allows faster removal
* Resistance to range of
antimicrobials
172
Acquisition of resistance
Spontaneous mutations that happen at low rate during replication that can still have significant effect
173
just a single base-pair change in gene encoding a ribosomal proteins yields
resistance to streptomycin
174
in a population of 10^9 cells, at least one likely has
that resistance mutation; if
streptomycin is added, only that cell and progeny will replicate,
yielding resistant population
175
Spontaneous resistance to antibiotics with several different targets
or multiple binding sites is
less likely
176
Combination therapy of multiple antibiotics is
often used; unlikely cells will simultaneously develop resistance
177
Gene transfer: Genes encoding resistance can spread to
different strains, species, even genera
178
most common spread through
conjugative transfer of R plasmids, which often carry several different resistance genes
179
Resistance genes on R plasmids originate from
* Spontaneous mutations
* Microbes that naturally produce the antibiotic
180
Gene coding for enzyme that modifies aminoglycoside likely originated from
the Streptomyces species that produces the antibiotic
181
Responsibilities of patients to prevent resistance
Carefully follow instructions even if inconvenient
* Essential to maintain adequate blood levels of antibiotic; skipping a dose may reduce levels, allowing less-sensitive microbes a chance to grow and
spread
* Failure to complete treatment may not kill least-sensitive organisms, allowing subsequent spread
182
The importance of an educated public
Antibiotics ineffective against viruses; cannot cure common cold!
* Misuse selects for antibiotic-resistant bacteria in normal microbiota; they
can eventually transfer R plasmids to pathogens
183
Global impacts of the use of antimicrobial medications
Overuse is a worldwide concern; resistant microbes recognize no political boundaries
* Antimicrobial antibiotics available without prescription in many parts of the world, may allow improper use
184
Antimicrobial antibiotics used in animal feeds at low levels to enhance growth;
selects for antibiotic-resistant microbes (ex. Resistant Salmonella strains linked to animals)
185
phage therapeutics
new dawn in combatting multi-drug resistant bacteria by killing them
