Aminoglycosides Flashcards
1
Q
Serratia
A
Gentamicin
2
Q
P. aeruginosa, Proteus
A
Tobramycin
3
Q
Aminoglycosides - What Bacteria
A
Aerobic, Gram Negative
4
Q
Aminoglycoside MOA
A
Bactericidal
5
Q
Bacterial killing
A
- Concentration-dependent
- Post-antibiotic effect
6
Q
The higher the concentration,
the greater is the rate at which bacteria is killed.
A
Concentration-dependent
7
Q
Is when residual bactericidal activity persist after serum conc. has fallen below MIC
(duration of this effect is conc.dependent)
A
Post-antibiotic effect
8
Q
t/f
Greater efficacy when administered as a SINGLE LARGE DOSE than when given as multiple smaller doses
A
true
9
Q
t/f
antibiotics that produce the:
longest PAEs
exhibit maximal PALEs
A
true
10
Q
Active in alkaline/acidic ph?
A
Alkaline
11
Q
Aminoglycosides are excreted rapidly in:
A
Kidneys
12
Q
T/F
Aminoglycosides are Nphrotoxic and Ototoxic
A
True
Auditory and vestibular functions of CN VIII
13
Q
AG is a Protein Synthesis Inhibitorthat acts where
A
ribosome level 30s
14
Q
Distinguished by
A
2 or more Aminosugars linked to:
an aminocyclitol ring in central position (hexose nucleus)
by GLYCOSIDIC BONDS
15
Q
Hexose ring
A
either streptidine
2-deoxystreptamine
16
Q
where aminocyclitol is not central and contains streptidine instead of 2-deoxystreptamine
A
Streptomycin
17
Q
What are the Aminoglycosides
A
Tobramycin, Amikacin, Netilmicin, Neomycin,
Gentamicin, Kanamycin, Streptomycin and Paromomycin
18
Q
Induce LYSOSOMAL PHOSPHOLIPIDOSIS where?
A
in Proximal Tubule cells
19
Q
interfere with mitochondrial functions
A
Produce ROS, deplete ATP
Several : induce site specific features of apoptosis
20
Q
MOA
A
Diffuse
- > aqueous channels (formed by porin proteins in outer mem. of G(-) bacteria)
- > periplasmic space
21
Q
depends on ELECTRON TRANSPORT
membrane elec. potential : interior negative
A
ENERGY-DEPENDENT phase 1 (EDP1)
- Rate-limiting
- Blocked by :
1. divalent cations eg. Ca++ & Mg++
2 hyperosmolarity (eg. Hyperosmolar Acidic urine)
3 Decrease ph (hyperosmolar, acidic urine)
4 Anaerobic Conditions
22
Q
Impair Ability of bacteria to maintain membrane potential
A
- divalent cations eg. Ca++ & Mg++
2 hyperosmolarity (eg. Hyperosmolar Acidic urine)
3 Decrease ph (hyperosmolar, acidic urine)
4 Anaerobic Conditions (Abscess)
23
Q
bacterial cell wall
A
(porin channels )
24
Q
periplasmic space
A
(passive diffusion)
25
cytoplasmic membrane
(active transport by proton pump-
an oxygen-dependent process)
26
linked to disruption of structure of cytoplasmic membrane disruption of cell envelope and other vital processes –
lethal action
energy-dependent phase II (EDP2)
27
primary IC site of action
30s ribosomal subunit
- primary IC site of action
- with 21 proteins and a single 16s molecule of RNA
- 50s ribosomal subunit for others
28
Microbial Resistance
(1) Mutations in bacterial ribosome
(2) Acquisition of plasmids or transposon-encoding genes for aminoglycoside-metabolizing enzymes (AME) - inactivate AGS
(3) Impaired transport of drug into cell (cytosol)
- Transport : O2 –dependent active process
- Strictly Anaerobic bacteria- resistant
- Facultative bacteria grown in anaerobic conditions - resistant
(4) Efflux pumps - expel AGs from bact’l cells
(5) Low affinity of drug for the bacterial ribosome
29
exhibit similar activity vs most gram(-)
Tobramycin and Gentamicin
30
ABSORPTION
highly polar cations (highly charged)
- DO NOT PERMIT THEIR MEMBRANE PERMEABILITY,
- as a result they have very poor oral bioavailabilty entire oral dose excreted in faeces.
31
ABSORPTION: solubility
Polar! water soluble
| do not penetrate most cells, CNS or eye (ex. Streptomycin)
32
Poorly absorbed where
GIT
< 1% absorbed after oral/rectal admin.
not inactivated in intestine & eliminated quantitatively in feces.
33
Long term administration
Renal impairment
34
absorption increased by GI dse. (ulcers/IBD)
Gentamicin
35
Rapid absorption?
1 absorption if instilled into body cavities with serosal surfaces
-toxic (ie. N-M blockade)
2 IM
36
Topical application for long a long time :
intoxication if with renal insufficiency
37
Peak conc. in plasma
30-90mins
38
Distribute poorly
Adipose Tse
39
Low concentrations in
secretions and tissues
40
High Conc in:
Renal cortex, endolymph & perilymph of inner ear
-Nephrotoxic & ototoxic
41
Increasing use of AGs via inhalation
Cystic fibrosis (w/chronic pseudomonas)
42
t/f
High sputum concentration
serum concentration remain LOW
True
43
For inhalation
tobramycin
44
Solutions for injections
Amikacin and tobramycin sol’ns
45
Active HEPATIC sec’n.
Conc in bile is 30% of those found in plasma (minor excretory route)
46
t/f Poor Penetration in respiratory sec’ns. or
true
47
increase penetration in peritoneal and
| pericardial cavities
Inflammation
48
hearing loss in children
Streptomycin & tobramycin
49
Distribution
In CSF- conc. (parenteral) – is subtherapeutic
Ocular fluid : penetration is poor
Pregnancy : accum. in fetal plasma & AF (NOT SAFE!!)
50
Excretion almost entirely by
Glomerular filtration
Urine conc. – 50-200 ug/ml achieved
- Nearly all of IV dose is excreted unchanged in urine.
- Cleared by kidneys through glomerular filtration resulting in fairly high urinary conc. which makes them useful in UTI.
- Use of urinary alkalinzer makes these drugs more effective.
51
Single dose : disappearance from plasma exceeds renal excretion by %??
10-20%
52
: 100% of subsequent doses
| - recovered in urine
After 1-2 days
53
t/f
| Rate of elimination is longer than plasma :
true
Tissue-bound aminoglycosides – 30-700 hrs.
10-20 days after : small amts seen in urine even after discontinuation
54
Removed from body by : (overdose)
Hemodialysis & peritoneal dialysis
-50% removed in 12 hrs by hemodialysis
- Peritoneal dialysis : less effective
- Add antibiotic to dialysate if with bacterial peritonitis
55
t/f
| Can be inactivated by penicillin in vitro
true
In vivo with end-stage renal dse patients
Amikacin – least affected by this
56
Half-lives prolonged in NB
8-11 hrs in 1st wk of life <2 kg
| 5 hrs > 2 kg
57
Normal Half life
1.5 -3 hrs
58
Clearance reduced in
Cystic Fibrosis
59
Require Large doses
burn patients
| - More rapid drug clearance 2ndary to drug loss thru burn tse.
60
Dosing
Before : 2 Or 3 equally divided doses based on short t1/2
Higher doses once daily
- is as effective & less toxic
for patients with normal renal func.
provide longer period when concentration falls below threshold for toxicity
```
for G(+) - Not used if in combination with a cell wall-active agent eg. endocarditis
Can give multiple daily doses with lower total daily dose
```
If >2-3 days : monitor plasma to avoid drug accumulation
61
Essential guide for proper admin. of drug
DETERMINATION OF CONC. OF DRUG IN PLASMA
In life-threatening systemic infxns. :
determined several times per week
w/in 24-48 hrs of a change in dosage
62
Creatinine clearance
< 80-100 mL/min
| Dose adjusted and plasma conc. monitored
63
most accurate method of monitoring plasma levels for dose adjustment :
(1) Measure conc. in 2 plasma samples drawn several hrs. apart
- eg. at 2 and 12 hrs after a dose
```
(2)
Nomograms
Target ranges of :
- 1-1.5 ug/mL for gentamicin at 18 hrs for patients with creatinine clearance >50 mL/min
- 1-2.5 ug/mL for <50 mL/min
Inaccurate
```
(3) Obtain a trough sample 24 hrs after dosing –
simplest method
but least desirable
64
Ototoxicity
- Dose-limiting adverse effect
- Irreversible, bilateral high frequency hearing loss
- temporary vestibular hypofunction
65
produce predominantly VESTIBULAR effects
Streptomycin & Gentamicin
66
Affect AUDITORY function
Amikacin, Kanamycin, Neomycin
67
Affect VESTIBULAR AND AUDITORY
Tobramycin
68
COCHLEAR TOXICITY (acute)
High pitched tinnitus
– often the first sx
Perception high-freq. sound lost first
– not aware of difficulty
69
Symptomless in while in bed
Difficulty walking or make sudden movements
ATAXIA : most prominent feature
Chronic Labyrinthitis
70
Chronic phase
persists for 2 months
71
Recovery
require 12-18 mos.
| Some with permanent residual damage
72
Nephrotoxicity
8-26 % mild
and ALMOST ALWAYS REVERSIBLE
Proximal cells capacity to regenerate
-Initial mx of damage : excretion of nzs of renal tubular brush border
```
-after a several days:
Defect of renal concentrating ability
Mild proteinuria
Hyaline & granular casts appearance
GFR : decreased after addn’l severaldays
non-oliguric phase : effect on distal portion of nephron
Mild Increase creatinine clearance
Infrequently : HYPO – K, Ca, PO4
```
73
Nephrotoxicity accumulate in
Accumulation and retention in proximal tubular cells
74
Decreasing potency for blockade
Neomycin, kanamycin, amikacin, gentamicin, tobramycin
75
NEUROMUSCULAR BLOCKADE
Intrapleural & intraperitoneal instillation of large doses
Also with IV, IM oral
Most episodes : anesthesia with other N-M blocking agents
76
Neuromascular Blockafe can be overcome by
Calcium can overcome this effect
| Preferred tx : Ca salt (IV)
77
Tx with ACHase inhibitors (NM blockage)
edrophonium & neostigmine
78
Inhibit prejunctional release of Ach
NEUROMUSCULAR BLOCKADE :
79
Uses
GRAM NEGATIVE INFECTIONS
DOC : lower cost & reliable activity vs all but the most resistant G(-) aerobes
Parenteral, opthalmic, topical
Gentamicin :
preferred agent but can be used interchangeably with :
Tobramycin, amikacin, netilmicin
80
Preferred Agent
Gentamicin
81
Used in combination with a cell wall-active agent (β-lactam or glycopeptide)
Rationale :
1 Expand spectrum of activity
For MDR G(-) : P. aeruginosa, Enterobacter, Klebsiella, Serratia
2 Provide synergistic bacterial killing
Improve microbial eradication & clinical response
in Endocarditis for G(+) eg. Enterococcus
3 Prevent emergence of resistance to individual agents
Only in Mycobacterial infections – data to prevent emergence
is supported by clinical data
82
UTI/ Pneumonia
Gentamicin
Uncomplicated UTI :5mg/kg SD
Pyelonephritis : use w/B-lactam
Pneumonia : alone is ineffective;
-(best tx using B lactam, macrolides or flouroquinolones than aminogly
83
used for asso. Cystic fibrosis
Gentamicin
84
If betalactam is weak for sepsis add what
Gentamicin
85
For burns
GENTAMICIN
Topical :
ointment- slow;
cream- more rapid;
> For burns
Meningitis : only for resistance to B-lactam (eg.Pseudo)
Peritonitis asso. w/ PD : 4-8 mg/L
Endocarditis : used w/ Penicillin
86
Same with Gentamicin;
Superior activity for P. aeruginosa;
Used w/ B-lactams
TOBRAMYCIN
87
Poor activity with Penicilin vs Enterococci (unlike gentamicin)
TOBRAMYCIN
88
E.faecium - highly resistant;
| Mycobacteria – ineffective;
TOBRAMYCIN
89
LESS nephrotoxic and Ototoxic
TOBRAMYCIN
90
IM/ IV /inhalation dose
Same dosages & serum conc. w/gentamcin;
Also Tobrex – an opthalmic ointment
TOBRAMYCIN
91
Meningitis : only for resistance to B-lactam (eg.Pseudo)
GENTAMICIN
92
Broadest spectrum of activity;
15 mg/kg/day
SD or div dose ( renal failure)
AMIKACIN
93
Absorbed rapidly IM;
Peak plasma conc.: 20 ug/mL after 7.5 mg/kg injection;
30 min inf. IV : 40 ug/mL
AMIKACIN
94
DOC for nosocomial G(-) infxns.
AMIKACIN
95
Active vs M.tuberculosis & aypical mycobacteria (eg.in AIDS pt)
AMIKACIN
96
Less effective vs Enterocci
| than genta
AMIKACIN
97
Renal/ Reversible
Gentamycin
98
Vestibular/ Irreversible
Streptomycin
99
Uncomplicated UTI : 1.5-2 mg/kg q 12h
| Serious infxns.: 4-7 mg/kg SD or div dose
NETILMICIN
100
For those resistant to genta; except Enterococci
NETILMICIN
101
Broad antibacterial activity vs aerobic G(-) bacilli
NETILMICIN
102
Latest drug;
| Similar to genta & tobra;
NETILMICIN
103
Bacterial Endocarditis :
| w/penicillin (but genta is less toxic)
STREPTOMYCIN
104
DOC (aside from Genta) :
| for TULAREMIA
STREPTOMYCIN
105
Plague
STREPTOMYCIN
106
TB : 2nd line agent & always should be in combination w/1-2 drugs;
15 mg/kg/day IM x 2-3 mos.;
OPTIC nn dysfunc.,
scotomas,
periph.neurirtis
STREPTOMYCIN
107
Rarely used because less effective than others
STREPTOMYCIN
108
One of the most toxic;
Injection & oral use
KANAMYCIN
109
OBSOLETE
Can be used orally as adjuntive tx for hepatic enceph.
KANAMYCIN
110
Topical/ oral;
Topical : Alone or in combination with polymyxin, bacitracin, corticosteroids
NEOMYCIN
111
Skin & mucous mem. : burns, wounds, ulcers, infected dermatoses
NEOMYCIN
112
Oral : usually w/erythromycin: bowel prep.
For surgery; rarely for hep.enceph.;
w/ polymyxin B - bladder irrigation
NEOMYCIN
113
```
Poorly absorbed in GIT;
excreted by kidney like others;
6-8 % hypersensitivity rxns;
Renal damage;
nerve deafness
```
NEOMYCIN
