ICL 2.30: Antibiotics Flashcards
(126 cards)
1
Q
which drug groups are protein synthesis inhibitors?
A
- macrolides
- clindamycin
- tetracyclines
- chloramphenicol
- aminoglycosides
2
Q
what are the general steps of protein synthesis?
A
- 30S subunit, Initiation factors, and mRNA come together
- fMet-tRNA binds to mRNA
- 50S subunit binds to form initiation complex
- 2nd aminoacyl tRNA arrives at A site
- AA transferred from 1st tRNA to AA of new tRNA (peptide bond formed)
- uncharged tRNA moves to E site, then leaves
- translocation of ribosome puts tRNA with growing chain in P site; elongation continues
3
Q
what’s the difference between the ribosomes of prokarytoic and eukaryotic organisms?
A
prokaryotic = 50S + 30S = 70S
eukaryotic = 60S + 40S = 80S
4
Q
how does bacteria protein synthesis work?
A
simultaneous transcription/translation in bacteria!
even before transcription is completed, multiple ribosomes attach to mRNA creating polysomes
5’–> 3’ direction
5
Q
what is the MOA of macrolides?
A
macrolides bind to 50S ribosome subunit
binding is reversible!
so macrolides either prevent transfer of peptide or access by next tRNA, preventing elongation
*bacteriostatic activity!
6
Q
which drugs are macrolides?
A
- azithromycin
- clarithromycin
- erythromycin
7
Q
which infections is erythromycin used for? which bacteria specifically?
A
mainly used for respiratory infections and urethral infections
8
Q
which bacteria does erythromycin work on?
A
effective against:
1. Strep. pneumoniae
- Strep. pyogenes
- Chlamydia trachomatis
- Mycoplasma pneumoniae,
- Legionella pneumophila
9
Q
how is erythromycin given?
A
it’s unstable in stomach acid so it’s usually given orally as a drug ester which is more stable = erythromycin ethylsuccinate or estolate
also erythromycin base is very bitter and cannot be used in oral pediatric preparations – the ethylsuccinate and estolate are tasteless
10
Q
what are the adverse effects of erythromycin?
A
- liver injury –> caused only by estolate form but is reversible a few days after stopping treatment
- arrhythmias –> prolongation of the QT interval, increasing the risk of potentially fatal torsades de pointes-type arrhythmia
- temporary hearing loss: associated with doses > 4 grams/day
- impaired renal or hepatic function; age > 60 years
11
Q
what are the adverse GI effects associated with erythromycin?
A
erythromycin is a motilin agonist and stimulates migrating motor complex (MMC) activity = bands of intense contractile activity of intestinal smooth muscle
GI effects are the most common adverse effect observed with erythromycin
often >50% of patients in clinical studies have complained of abdominal cramps, nausea and diarrhea
12
Q
what can be used to treat the adverse GI effects of erythromycin?
A
antimuscarinic drugs like glycopyrrolate can be used to counteract the MMC response and therefore erythromycin-related GI problems
13
Q
which two drugs are “newer” macrolides? what’s different about them?
A
- clarithromycin
- azithromycin
about the same antimicrobial spectrum as erythromycin, but better tolerated because of fewer G.I. effects
they are also less likely to produce the other adverse effects associated with erythromycin
14
Q
what is azithromycin used to treat?
A
chlamydial urethritis
15
Q
what are azithromycin and clarithromycin used to treat?
A
used to treat mycobacterial pneumonia (MAC pneumonia in AIDS patients)
16
Q
what drug interaction do macrolides have?
A
erythromycin and clarithromycin inhibit cytochrome P450 drug metabolism in the liver –> you increase the half life of other drugs that are no longer being metabolized in the liver
azithromycin does so much less often
17
Q
what is the MOA of clindamycin?
A
binds to 50S ribosomal subunit – similar action as macrolides
binding is reversible!
so they either prevent transfer of peptide or access by next tRNA, preventing elongation
*bacteriostatic activity!
18
Q
clindamycin is used for the prophylaxis of what?
A
it’s used for prophylaxis of bacterial endocarditis in dental procedures for patients with valvular heart disease
a single dose of clindamycin is appropriate for prophylaxis prior to dental, oral, upper respiratory tract and esophageal procedures in at-risk, penicillin-allergic patients
19
Q
what type of bacteria is clindamycin good at targeting?
A
anaerobes
specifically severe infections outside the CNS caused by anaerobes including Bacteroides fragilis
20
Q
what is clindamycin used to treat?
A
- bacterial vaginal infections
- in combination with an aminoglycoside and cephalosporin for penetrating wounds of the abdomen or gut**
- treatment of aspiration pneumonia
21
Q
what are the adverse effects of clindamycin?
A
- skin rashes, and rarely Stevens-Johnson syndrome
- hepatotoxicity is possible (less than 0.1% of patients)
- diarrhea, including Pseudomembranous colitis in up to 10% of patients
22
Q
what is stevens-johnson syndrome?
A
a potential side effect of clindamycin
it’s a life-threatening skin condition, in which cell death causes the epidermis to separate from the dermis
23
Q
if someone gets diarrhea/pseudomembranous colitis from clindamycin, how do you treat it?
A
metronidazole
24
Q
what is the DOC for first episode of mild-moderate C. difficile infection?
A
metronidazole
25
which type of bacteria does metronidazole work on?
active only against anaerobes!
ferredoxin in sensitive bacteria chemically reduces metronidazole nitro group to produce toxic by-products which kill the bacteria!
26
what is metronidazole used to treat?
1. Clostridium difficile
2. Bacteroides fragilis
3. Trichomonas vaginalis (protozoa)
4. Giardia lamblia (protozoa)
27
what are metronidazole toxicities?
GI disturbances are the most common adverse effect
paresthesia and ataxia/convulsions may rarely occur
carcinogenic in rodents
28
what is the MOA of tetracyclines?
they bind to 30S ribosomal subunit and inhibits tRNA binding
this means they have a broad spectrum of activity against Gm + and Gm - bacteria
29
tetracyclines are the DOC for which diseases?
1. Rickettsial infections like Rocky Mountain spotted fever
2. cholera
3. chlamydial infections
4. acne
30
what are the adverse effects of tetracyclines?
1. hepatotoxicity
especially in pregnancy*
characterized by high blood bilirubin (jaundice)
frequently fatal
2. nephrotoxicity
in patients with renal disease
3. Fanconi syndrome
in people without renal disease
4. deposition in teeth and bones
5. GI irritation with oral use
6. phototoxicity
31
which tetracycline should you use in patients with renal disease?
doxycycline
32
what is Fanconi syndrome?
a possible adverse effect of tetracyclines in patients without a history of renal disease
this happens from outdated tetracyclines
it's a disease of the proximal renal tubules of the kidney where glucose, amino acids, uric acid, phosphate and bicarbonate are passed into the urine, instead of being reabsorbed
33
which tetracyclines can cause phototoxicity?
1. demethylchlortetracycline
| 2. doxycycline
34
what are the side effects of minocycline?
it's a type of tetracycline
1. vertigo
2. ataxia
3. nausea
4. vomiting
this is all due to damage to the vestibule in the middle ear --> it's reversible upon discontinuing the drug
35
what are the drug interactions of tetracyclines?
tetracyclines bind to calcium in dairy products, and calcium, magnesium or aluminum in antacids
this decreases absorption of the tetracycline
also tetracycline interferes with clotting
36
what are the contraindications of tetracyclines?
1. pregnancy
2. children 4 months to 8 years
3. patients with renal impairment (doxycycline is the possible exception)
37
what is tigecycline?
a glycylcycline derivative of minocycline
it's a tetracycline that's only administered IV
38
which bacteria does tigecycline work against?
it's NOT exported by energy dependent drug efflux pump in most bacteria
that makes it active against bacteria that have developed resistance to other tetracyclines!!
it's active vs methicillin-resistant and vancomycin-resistant Staph. aureus
also active against enterococci and extended spectrum B-lactamase producing Gm- pathogens
it's super broad spectrum....
39
what's the MOA of chloramphenicol?
binds to 50S ribosome and prevents binding of amino acid part of aminoacyl-tRNA
it's bacteriostatic
40
when is chloramphenicol used?
primarily used as a backup drug for β-lactams in treatment of H. influenzae or N. meningitidis meningitis in neonates and older children
it's also used as a backup drug for tetracyclines in children 4 months-8 years, renal insufficient patients and in pregnancy (except late stages)
41
what are the adverse effects of chloramphenicol?
1. BM depression; potential aplastic anemia = fatal
2. optic neuritis which may result in blindness
3. diarrhea, pseudomembranous colitis (because it's a broad spectrum antibiotic)
4. Gray baby syndrome
42
what is gray baby syndrome?
respiratory depression produced by high blood levels of chloramphenicol
can be fatal
43
what are aminoglycosides?
molecules comprised of amino sugars
they are highly polar molecules that do not distribute well into body compartments --> must be administered IV and IM only
narrow therapeutic index
44
which drugs are aminoglycosides?
1. streptomycin
2. gentamycin
3. kanamycin
4. tobramycin
5. amikacin
6. netilmicin
other drugs too
45
what's the MOA of aminoglycosides?
protein synthesis inhibitors that are bactericidal!! (rare)
they transport through the wall, through peptidoglycan of G+, through porins or directly through the outer membrane (OM) in G-, disrupting the OM
they transport through cell membrane by carrier, using electrochemical gradient (uses energy)
then they *covalently* bind to ribosomes!!! --> aminoglycosides bind various sites on both ribosomal subunits which freezes translation after initiation step, preventing polysome formation -- it also interferes with codon recognition resulting in misreading
the combination of membrane damage and inhibition of protein synthesis is bactericidal
46
how are aminoglycosides administered?
must be administered parenterally for systemic infections = i.v. or i.m., and tissue distribution is limited to extracellular space
47
how are aminolgycosides cleared from the body?
glomerular filtration
48
on which bacteria do aminoglycosides work?
aerobic bacteria only
they go through energy-dependent uptake which requires oxygen
therefore aminoglycosides do not work on anaerobes
49
what is streptomycin used to treat?
predominantly used for treatment of pulmonary tuberculosis
it's an aminoglycoside
50
what is gentamicin used to treat?
aminoglycoside of first choice --> it has good cost and it's wide spectrum than streptomycin
also hits psudomonas bacteria
51
what is tobramycin used to treat?
somewhat enhanced anti-Pseudomonas activity compared with gentamicin
it's an aminoglycoside
52
which two aminoglycosides have enhanced resistance to inactivating enzymes?
1. amikacin
| 2. netilmicin
53
when is amikacin used?
it's active against gentamicin and tobramycin-resistant organisms
it's only inactivated by bacterial N-acetyltransferase at the 6’position on the aminoglycoside structure
54
when is netilmicin used?
it's resistant to several of the bacterial enzymes that inactivate gentamicin and tobramycin
55
what are the adverse effects of aminoglycosides?
1. nephrotoxicity
2. ototoxicity
3. neuromuscular junction blockade
4. hypersensitivity
5. suprainfection
56
how can aminoglycosides cause nephrotoxicity?
it can cause proximal tubular necrosis -- severe toxicity in ~2% of patients
usually reversible, but sometimes permanent
there's increased BUN, decreased creatinine clearance, generally within a week or two of treatment
concurrent administration of lop diuretics will make the renal toxicity of the aminoglycosides even worse
57
how are aminoglycosides cleared from the body?
aminoglycosides are cleared predominantly by glomerular filtration
they are poorly protein-bound, and thus readily filtered
58
how are aminoglycosides ototoxic?
can be permanent!!
it happens when aminoglycosides accumulate in the perilymph = the fluid between the membranous labyrinth of the ear and the bone that encloses it
can cause vestibular damage = difficulty with balance and walking, resulting in dizziness
vestibular damage may only appear several weeks after termination of treatment
cochlear = high-pitched ringing in the ears (tinnitus)
as with nephrotoxicity, ototoxicity is exacerbated by the loop diuretics.
59
when can aminolgycosides cause neuromuscular junction blockade?
overdosage of aminoglycosides
can be reversed by neostigmine = a parasympathomimetic that acts as a reversible acetylcholinesterase inhibitor
60
how do nucleic acid synthesis inhibitors work?
they target enzymes required for nucleic acid synthesis
61
which drug groups are nucleic acid synthesis inhibitors?
1. fluoroquinolones
| 2. rifamycin
62
what do fluoroquinolones do?
they're nucleic acid synthesis inhibitors
they inhibit enzymes that maintain the supercoiling of closed circular DNA
63
what do rifamycins do?
they're nucleic acid synthesis inhibitors
they block prokaryotic RNA polymerase from initiating transcription
64
what is nalidixic acid?
a first generation quinolone used for
treatment of urinary
tract infections
65
which bacteria does nalidixic acid work on?
1. E. coli
2. Klebsiella
3. Enterobacter
4. Proteus spp.
66
what is ciprofloxacin?
a second generation fluoroquinolone useful for
treatment of many systemic infections
broad spectrum relative to nalidixic acid
67
what is levofloxacin?
third generation fluoroquinolone
specifically a respiratory fluoroquiniolone
68
which fluoroquinolones are fourth generation?
1. moxifloxacin
2. gatifloxacin
respiratory fluoroquinonlones
69
what is the MOA of quinolones and fluoroquinolones?
DNA gyrase (topoisomerase II) relieves tension in double-stranded DNA, relaxes supercoils
topoisomerase IV separates and unlinks DNA for the following DNA replication
Qs and FQs inhibit both enzymes so they inhibit DNA replication
70
are Qs and FQs bacteriastatic or bactericidal drugs?
bactericidal drugs
71
which bacteria are fluoroquinolones active against?
FQs enter into the host cells and therefore are active against intracellular pathogens:
1. Legionella
2. mycoplasma
3. chlamydia
they're really broad spectrum too though so they're rapidly bactericidal against many Gm+ and Gm- bacteria
72
is resistance a problem with fluoroquinolones?
yeahhh
resistance developes radpidly --> resistance to one fluoroquinolone usually means resistance to all of them
for example, with M. tuberculosis, the MfpA protein mimics DNA
in general, anaerobes are intrinsically resistant
73
which bacteria are intrinsically resistant to fluoroquinolones?
anaerobes
but moxifloxacin and gatifloxacin will hit anaerobes
74
what are fluoroquinolones used to treat?
1. UTIs
2. diarrhea caused by Campylobacter, E. coli, Salmonella, or Shigella
3. gonococcal infections
4. Prophylaxis of anthrax
5. respiratory tract infections
75
which FQs are used to treat gonococcal infections?
1. ciprofloxacin
| 2. ofloxacin
76
which FQs are used for prophylaxis of anthrax?
1. ciprofloxacin
| 2. levofloxacin
77
which FQs are used to treat respiratory tract infections?
for gram (-) bacteria use ciprofloxacin or levofloxacin
for anaerobes or pneumococcus use 4th generation FQs like gatifloxacin and moxifloxacin
78
what is ciprofloxacin used for?
it's the most potent of the fluoroquinolones for P. aeruginosa
it has a long post-antibiotic effect and is well absorbed in GI
***it's a potent CYP450 inhibitor
79
how is ciprofloxacin administered?
orally or IV
excreted in urine
80
what are the drug interactions associated with FQs?
1. antacids containing Ca2+, Mg2+, Zn2+, Bi2+, or Al3+ may reduce the oral bioavailability of fluoroquinolones
2. fluoroquinolones may increase the anticoagulant effect of warfarin
3. hepatotoxicity
4. hyper/hypoglycemia
5. allergic reaction
81
what is a potential complication associated with FQs inhibiting CYP450 enzymes?
due to inhibition of the CYP450 enyzmes, fluoroquinolones may increase the plasma concentration of theophylline
this can increase BP and heart rate
theophylline = drug used in therapy for respiratory diseases such as COPD and asthma
82
which FQ is linked to hepatotoxicity?
trovafloxacin
has been linked with 14 cases of liver failure
83
how do FQs mess with blood sugar?
can cause hypoglycemia in elderly diabetics
and can cause hyperglycemia in non-diabetics
especially gatifloxacin which is contraindicated in diabetes mellitus
84
what are some of the adverse effects of both quinolones and fluoroquinolones?
1. abnormalities of bone and cartilage formation
2. photosensitivity
3. tendonitis/tendon rupture
4. CNS issues
5. cardiac effects
85
what bone/cartilage abnormalities can Qs and FQs cause?
can cause cartilage damage in weight bearing joints in animal studies
bow legs in babies!
so because of this Qs and FQs are contraindicated in children under 18 and pregnant women
86
how do Qs and FQs cause CNS complications?
confusion, insomnia, fatigue, depression, drowsiness, seizures
they seizures are caused by binding to gamma-aminobutyric acid (GABA) receptors
87
what cardiac effects can Qs and FQs cause?
they prolong the QTc interval, increasing the risk of ventricular tachy-arrhythmias
88
which drugs are inhibitors of RNA synthesis?
1. rifampin
2. rifamycin
3. rifampicin
4. rifabutin
all bactericidal!!
89
what is the MOA of inhibitors of RNA synthesis?
these antimicrobials bind to DNA-dependent RNA polymerase and inhibit initiation of mRNA synthesis
90
what is the spectrum of activity of inhibitors of RNA synthesis?
broad spectrum but is used most commonly in the treatment of tuberculosis
resistance is common so combination therapy is often needed
91
what is the MOA of antimetabolites?
competitive inhibition by substance that resembles normal substrate of enzyme
ex. sulfa drugs
92
what is the MOA of folic acid synthesis inhibitors?
competitive inhibition by substance that resembles normal substrate of enzyme
ex. sulfamethoxazole is a sulfonamide
93
what does trimethoprim do?
it's a folic acid synthesis inhibitor
trimethoprim inhibits bacterial dihydrofolate reductase
94
what is a bactrim?
sulfonamid + trimethoprim
sulfonamides used to be mainstays of antimicrobial therapy, but now mainly used in combination with dihydrofolate reductase inhibitors (e.g. trimethoprim) for susceptible organisms
95
what are the adverse effects of sulfonamides?
1. hypersensitivity
2. blood disorders (e.g. aplastic anemia)
3. crystalluria (the presence of crystals in the urine)
4. jaundice and kernicterus of the newborn
96
what are the general characteristics of mycobacterium tuberculosis?
gram-positive aerobic rod-shaped bacilli
lack of spore formation and toxin production
no capsule, flagellum (non-motile)
“acid fast” bacteria
generation time of 18- 24 hours but requires 3-4 weeks for visual colonies
97
what are the pathological features of mycobacterium tuberculosis?
principle cause of Human Tuberculosis
intracellular pathogen (alveolar macrophages)
waxy, thick, complex cellular envelope
produces tubercles = localized lesions of M. tuberculosis
98
how do you treat TB?
combination of first and second line drugs for the first 2 months which could include:
1. isoniazid
2. rifampicin
3. pyrazinamide
4. streptomycin or ethamcutol
next 4 months, a combination of:
1. isoniazid
2. rifamicpin
99
what is isoniazid used for?
used for active disease in combination with other drugs & used alone for prophylaxis
it decreases mycolic acid synthesis
100
what's the spectrum of isoniazid?
narrow antimycobacterial spectrum: only hits M. tuberculosis and M. kansasii
101
how is isoniazid given?
orally available & widely distributed including CNS and caseous lesions
metabolism is different in fast vs slow acetylators
102
what is the MOA of isoniazid?
Isoniazid is a prodrug and must be activated by a bacterial catalase-peroxidase enzyme that in M. tuberculosis is called KatG
mutation of KatG peroxidase provides high level resistance
103
what are the adverse effects of isoniazid?
overall it's relatively safe
1. but can cause peripheral neuritis which can be prevented with bitamin B6
2. hepatitis - rare in individuals <35 years old
3. hypersensitivity
104
what environment does pyrazinamide require?
it's a nicotinamide analog like isoniazid
requires acidic environment
it's only effective vs intracellular mycobacteria that express the pncA gene --> mutation in the pncA gene causes resistance
105
what are the adverse effects of pyrazinamide?
liver damage is possible at only slightly higher than usual therapeutic doses
also causes urate retention & therefore may precipitate gout attacks --> allopurinol can be used for treatment of gout
106
what is the MOA of ethambutol?
inhibits mycolic acids attachment to D-arabinose residues and form mycolyl-arabinogalactan-peptidoglycan complex in the cell wall of M. tuberculosis
107
what is the spectrum of ethambutol?
M. tuberculosis and some atypical mycobacteria
not as potent as isoniazid, rifampin or pyrazinamide
108
what are the pharmacokinetics of ethambutol?
not widely distributed
but does cross inflamed meninges
109
what are the adverse effects of ethambutol?
1. optic neuritis = decreased visual acuity
| 2. urate retention
110
what is the MOA of rifampin?
inhibits RNA polymerase
111
what are the characteristics of rifampin?
has a broader spectrum than isoniazid
widely distributed, including CNS
usually well tolerated
*turns body fluids orange
induces expression of cytochrome P450
112
what are the adverse effects of rifampin?
1. hepatotoxicity
2. hypersensitivity
usually well tolerated though
113
what is rifabutin used to treat?
used to treat tuberculosis in AIDS patients
compared with rifampin, it causes less induction of cytochrome P450
114
what are the benefits of using rifapentine vs. rifampin?
longer half-life than rifampin, therefore can be administered twice weekly
115
how do you treat MAC respiratory infections?
MAC = mycobacterium avium complex
MAC respiratory infection is a real danger for immunocompromised patients (ex. AIDS)
treat with azithromycin or clarithromycin macrolide antibiotics & either ethambutol or rifabutin
116
which drugs can be used to treat leprosy?
1. dapsone
2. rifampin
3. clofazimine
used when the disease is resistant to dapsone and rifampin, or if the latter are not tolerated
MOA is unknown
117
what is the DOC for leprosy?
dapsone
it's a dihydropteroate synthetase inhibitor
major toxicities are related to blood = methemoglobinemia & hemolytic anemia
118
what is methemoglobinemia?
a disorder characterized by the presence of a higher than normal level of methemoglobin in the blood
heme group is in the Fe3+ (ferric) state, not the Fe2+ (ferrous) of normal hemoglobin so methemoglobin cannot bind oxygen
methemoglobin is an oxidized form of hemoglobin that has a decreased affinity for oxygen, resulting in an increased affinity of oxygen to other heme sites and overall reduced ability to release oxygen to tissues
119
why is tuberculosis naturally resistant to certain antibiotics?
M. tuberculosis: naturally resistant to certain antibiotics due to presence of:
1. drug-modifying enzymes
2. drug-efflux systems
3. hydrophobic cell wall
120
is antibiotic resistance a problem with TB?
yeah....
mycobacteria undergo natural mutations which can lead to development of drug resistance
so TB has to be treated with combination chemotherapy which decreases probability of development of drug resistance
development of increasingly resistant strains is mainly due to patient non-compliance
121
what does poly-resistant TB mean?
resistance to more than one drug, but not the combination of isoniazid and rifampicin
122
what is MDR TB?
multi-drug resistant TB
resistance to at least isoniazid and rifampicin
123
what is XDR TB?
extensively drug-resistant TB
MDR plus resistance to fluoroquinolones and at least 1 of the 3 injectable drugs (amikacin, kanamycin, capreomycin)
124
where are MDR and XDR TB most prevalent?
MDR and XDR-TB rates are higher in developed nations with access to anti-TB drugs.
MDR and XDR-TB: uncommon in developing nations lacking TB drugs (high drug-susceptible TB rates)
125
TB is related to which other virus?
HIV/AIDS
people with latent TB have a 10-20% of developing active TB in their lifetime
people with HIV and latent TB are 100 times more likely to develop active TB --> HIV infection can cause latent M. tuberculosis infection to become reactivated
a person with HIV/AIDS will have a harder time fighting off the M. tuberculosis infection due to a compromised immune system
126
which drugs are used to treat TB?
1. isoniazid
2. rifampin
3. pyrazinamide
4. ethambutol
