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Aminoglycosides
고려대학교 의과대학 내과학교실
정 희 진
- Born of Streptomycin -
• S. griseus
• Selman Waksman
- by 1943
- New Jersey
History
Name year Source Product name
Streptomycin 1943 Streptomyces griseus Streptomycin (종근당)
Neomycin 1949 S. fradiae Neomycin sulfate (수입)
Kanamycin 1957 S. kanamyceticus Kanamycin (유한)
Gentamicin 1963 Micrommonospora purpurea Gentacin (건일)
Tobramycin 1968 S. tenebrarius Tobramcyin (동광)(유한)(대웅)
Amikacin 1972 derivative of Kanamycin A Amikin(보령), Akicin(환인)
Sisomicin 1970 M. inyoensis Sisomicin (종근당)
Dibekacin 1971 Dideoxy derivative of Kanamycin B
Netilmicin 1975 N=ethyl derivative of sisomicin Netromycin (건일)
Micronomicin 1975 M. samamiensis Micronomicin (녹십자)
Micronomicin (동광)
Miksin (제일제당), Sagacin (영진)
Astromicin 1977 M. olivoasterospora Fortimicin (영진)
Arbekacin 1973 Kanamycin B derivative
Isepamicin 1978 Gentamicin B derivative Isepacin (유한)
Nomination
• “ mycin” : derived from Streptomyces (ex: tobramycin)
• “ micin” : derived from Micromonospora (ex: gentamicin)
• “ kacin” : derived from S. kanamyceticus (ex: amikacin)
- derivatives of kanamycin
Q : Aminoglycosides는 어떤 균에 항균력이 있는가?
1) Stenotrophomonas maltophilia
2) Pseudomonas aeruginosa
3) Enterococcus faecium
4) Streptococcus pneumoniae
5) Bacteroides fragilis
Chemical Structures
H2N-C-NH
NH6-CH=NH
NH
NH2
Aminocyclitol
O
Aminosugars
CH3
OH O
OH NHCH3
H2N-C-NH NH6-CH=NH NH2
NH2
NH NH2 OH
STREPTIDINE OH OH 2-DEOXYSTREPTIDINE
OH R H
O OH H3C
O 4
H OH OH O
CH3 HOCH2 5 6
H
OH O R OH o
4 NH2
O H
H NH2
OH
OH NHCH3 OH
NH2
streptomycin neomycin kanamycin gentamicin
spectinomycin paromomycin tobramycin sisomicin
astromicin amikacin netilmicin
dibekacin
arbekacin isepamicin
Mechanism of Action
(+) AMG
passive diffusion, hole formation
ECF
(-) Outer memb.
Inner memb.
EDP O2DP low pH
EDP-1 low O2
EDP-2
ICF
high low
affinity affinity rRNa
Faulty protein
Cell death :- cidal ?
30S
sub-unit
mRNA
Donor
Acceptor
site
site
50S
sub-unit
Nascent
peptide
tRNA chain
Exit
channel Peptide
chain
Microbiological Activity of Aminoglycosides
Susceptible Resistant
G (-) rods Streptococci
(S. pneumoniae, S. pyogenes)
Enterococci
MRSA
Anaerobes
Stenotrophomonas maltophilia
Burkholderia cepacia
M. tuberculosis, Mycobacterium Kansasii,
selective atypical Mycobacteria (e.g. M. fortuitum) Mycobacterium avium intracellulare
Mycoplasma spp.
N. meningitidis, N. gonorrhoeae
Rickettsiae
MSSA Fungi
non-S. aureus spp. (e.g.Staphylococcus epidermidis) Viruses
Susceptibility (%) of Gram-Negative Bacilli to Aminoglycosides
Gentamicin Amikacin
Organism (≤4 ㎍/mL) (≤16 ㎍/mL)
Acinetobacter species 95 95
Alcaligenes species 67 75
Burkholderia cepacia 10 50
Citrobacter diversus 100 100
C.freundii 94 100
Enterobacter aerogenes 100 100
E. cloacae 99 99
Escherichia coli 98 100
Kllebsiella oxytoca 100 100
K. pneumoniae 100 100
Morganella morganii 97 100
Proteus mirabilis 95 100
P.vulgaris 100 100
Providencia rettgeri 100 100
P.stuartii 100 100
Pseudomonas aeruginosa 88 94
Serratia marcescens 100 100
Stenotrophomonas maltophilia 9 9
Yersinia enterocolitica 100 100
Mayo Clinic Rochester, 1998
Activity of Aminoglycosides to Microorganisms
Organism SM KM GM TOB AMK NET
Gram-negative
E.coli + + + + +
P. mirabilis + + + + +
Klebsiella sp. + + + + +
Enterobacter sp. 0 + + + +
Morganella sp. + + + + +
Citrobacter sp. + + + +
Serratia sp. + + + + +
Acinetobacter sp. 0 + 0
Ps. aeruginosa 0 + + + +
Ps. cepacia 0 0 0 0 0
S. maltophilia 0 0 0 0 0
Gram-positive
S. pneumoniae 0 0 0 0 0
S.aureus (MSSA) + + + + +
S.aureus (MRSA) 0 0 0 0 0
Miscellaneous
M. tuberculosis + 0 0 0 + 0
MAI 0 0 0 0 + 0
B. fragilis 0 0 0 0 0 0
Antimicrobial Activity
Susceptibility : variable with the drug, target organism
local/regional patterns of physician’s use
Organism No. of isolates % susceptible
GM TOB AMK
E. coli 1101 98 99 87
P. aeruginosa 730 71 95 88
A. baumanii
K. pneumoniae 319 99 99 100
E. cloacae 284 96 97 100
S. marcescens 92 100 99 92
E. aerogenes 56 98 100 56
Oregon HSU, 1992
Q : Aminoglycosides는 어떤 균에 항균력이 있는가?
Spectrum of Activity
• Wide range of aerobic G (-) bacilli
(not B. cephacia, S. maltophilia)
• Staphylococci ( not MRSA)
• Mycobacterium (not MAI, M. kanasasii)
A : Aminoglycosides는 어떤 균에 항균력이 있는가?
1) Stenotrophomonas maltophilia
2) Pseudomonas aeruginosa
3) Enterococcus faecium
4) Streptococcus pneumoniae
5) Bacteroides fragilis
Q : 다음중 gentamicin이 가장 효과적으로 사용될 수
있는 감염부위는?
1) Peritonitis
2) Pneumonia
3) Meningitis
4) Liver abscess
5) Prostatitis
Choice of Empirical therapy
: Factors related to Site of Infection
• Barriers to Antibiotic diffusion
: Blood-brain
: Blood-bronchi
: Blood-prostate
• Presence of foreign body
• Slime production
Absorption & Distribution
Polar structure (Cationic structure)
Oral IV (IM)
Low protein binding (<10%)
Intravascular Extravascular
• Low Intracellular conc.
• Poor penetration of biologic memb.
Elimination
• Aminoglycoside are not metabolized
• Poor biliary excretion (~1%)
Entirely (94-99%) urinary excretion (glomerular filtration)
Plasma half-life : 1.5-3.5 hr (in normal GFR)
30-60 hr (in renal failure)
Q : Aminoglycosides는 어떤 감염증에 효과적인가?
Pharmacokinetcs Site of Infection
• High Urine conc. • Prefered Use: UTIs
•G (-) bacilli Peritonitis,ostemyelitis
•Staphylococci
• Poor penetration of • Limited Use :
biologic membrane Meningitis,
Pneumonia
Prostatitis
Cholangitis
A : 다음중 gentamicin이 가장 효과적으로 사용될 수
있는 감염부위는?
1) Peritonitis
2) Pneumonia
3) Meningitis
4) Liver abscess
5) Prostatitis
Adverse drug reaction
Adverse reaction estimated frequency (%)
Nephrotoxicity 0- 50
Ototoxicity 0 - 62
cochlear 0- 62
vestibular 0- 19
Neuromuscular blockade exceedingly rare
Q : Aminoglycoside의 약제별 부작용에 차이가 있는가?
Isepamicin, netilmicin등은 과연 독성이 적은가?
Nephrotoxicity
• Reversible - Saturable Carrier-mediated Transport
Prox. tubular cell
: preferential uptake of AMG - accumulation in the lysosome
: inhibition of phospholipase
Myeloid body cell-necrosis
Myeloid
body
ATN
Nephrotoxicity
• Definition : increment of 15-50% from baseline s-creatinine level
• Nephrotoxicity of AMG
AMG Patients Nephrotixicity
Relative Nephrotoxicity index % mean (range)
Neomycin 4
Gentamicin 1055 163 15.5 (2.0-55.2)
Amikacin 7331 63 8.6 (0-27.6)
Tobramicin 709 98 13.8 (5.8-58.0)
Netilmicin 256 19 Isepamicin 7.4 (1.0-38.2)
(Wheaton, 1994)
Risk factors for aminoglycoside nephrotoxicity
Patient factors
Old age
Volume depletion, hypotension
Hepatic dysfunction
Aminoglycoside factors
Recent aminoglycoside therapy (6주이내)
Treatment of 10 or more days
Frequent dosing interval
Concomitant drugs
Other antibiotics: Vancomycin Amphotericin B Clindamycin
Furosemide
Chemotherapeutic agents: Foscarnet, cis-Platin
Intravenous radiocontrast agents
Ototoxicity
Irreversible - saturable carrier-mediated transport
1) Cochlear toxicity
• Outer hair cell at basal turn : high-frequency ( > 2kHz ) loss
: AMG - iron complex - (act as iron chelator) : activated AMG; cytotoxin
production of free radical
• Sx: no-symptoms
: ear-fullness, sudden conversational hearing loss
Clinical assessment of ototoxicity : difficult
Pure tone audiometer (PTA)
: Detection of Cochlear toxicity
- high-frequency sounds ( > 2kHz ) at initial phase
• Risk factor :
- age (> 60yrs)
- accumulated dose
- furosemide
Relative toxicity
Neomycin 4
GM, TOB, AMK 2
SM 1
Ototoxicity
2) Vestibular toxicity : days or weeks after stoping use
• Type I hair cell of the summit of the ampullar cristae
• Sx: nausea, vomiting vertigo
Relative toxicity
Streptomycin 4
Gentamicin 3
Tobramycin 2
Kanamycin 1
Neuromuscular blockade
Rapid IV administration
• Presynaptic block :block of Ca2+ entry into presynaptic region of axon
-- block of Ach release
• Risk factors: 1) muscular dystrophy, myasthenia gravis
2) hypo-calcemia, magnesemia
3) use of Ca-channel blocker
• Sx: 1) respiratory muscle weakness
2) flaccid paralysis
3) dilated pupil
• Tx: prompt administraion of Ca-gluconate
• Prevention: slow infusion
Adverse drug reaction
• Absences of side effect
– Hypersensitivity reaction
– coagulopathy
– hepatotoxicity
– hematopoietic side effect
Nephrotoxicity, Ototoxicity
Limited use of Aminoglycosides
G (-) bacilli: Cephalosporin, Carbapenems
Merit of Aminoglycosides : Steady - seller
Q: Aminoglycoside가 가지는 단점에도 불구하고
임상에서 계속 사용되는 특유의 장점은?
ㄱ. concentration - dependent bactericidal effect
ㄴ. post-antibiotic effect
ㄷ. low-level of resistance
ㄹ. synergism with cell wall active agent
Merit of AMG : Pharmacodynamics
Concentration effect Rate and extent of killing Maximun killing with
correlate with conc. large dose
Postantibiotic effect Persistent suppression Sustained efficacy despite
of bacterial growth after subinhibitory concentration
limted exposure
1st exposure effect Drug uptake by bacteria Organism less susceptible
less with subsequent to 2nd dose if given
drug exposure within 6-8 hrs
Pharmacodynamics
1) Concentration-dependent anti-bacterial activity
(Log
9
10 8
7
CFU)
50mg/L
6 25mg/L
5 12.5mg/L
4 7mg/L
3 1mg/L
2 no drug
1
0
0 1 2 3 4 5 6 (hr)
(P. aeurginsa with tobramycin, Jone EK, 1988)
Pharmacodynamics
Concentration-dependent anti-bacterial activity
Drug concentration rate of bacterial killing
: peak concentration / MIC = 10 - 12
maximize the bactericidal effect
decrease the selection & re-growth of resistant population
Pharmacodynamics
2) PAE (Post-antibiotic effect)
: A bacteriostatic phase without any re-growth
Dose Dose
Aminoglycoside
MIC
G(-) Bacteria
PAE
E. coli - Time-kill curve
Cefamandole Gentamicin
9 dose dose dose dose
Log
10 8
CFU/ml
7
6
concentration (ug/mL)
MIC
MIC
2 4 6 8 10 12 (hr) 2 4 6 8 10 12
PAE : -0.2 hr PAE: 1.8 hr
Pharmacodynamics
PAE (Post-antibiotic effect)
: A bacteriostatic phase without any re-growth
• Persistent suppression of bacterial re-growth under insuff. antibiotics conc.
after limited exposure of organisms to an antibiotics
: drug -induced nonlethal damage --- depletion of functional protein
for their metabolism & growth
: d/t irreversible binding to bacterial ribosome
A period of re-synthesis of functional protein
• Average duration: 0.5 - 7.5 hr
Pharmacodynamics
PAE (Post-antibiotic effect)
• Factors influencing PAE
1) Types of organism : G(-) bacilli, G (+) cocci (except enterococci)
2) Class & conc. of antibiotics
Drug concentration PAE duration
3) Duration of antimicrobial exposure
4) Synergism with other antibiotics : combination
• Longer PAE in vivo than in vitro : 1.5-10 times longer
Sub-MIC effect:
Post-antibiotic Leukocyte effect : d/t host leukocyte activity
Growth curve of P. aeruginosa ATCC 27583 in mice with tobramycin
10
Log
9
10
8
of CFU
7
6
dosage peak T>MIC PAE
5
(mg/kg) (mg/L) (hr) (hr)
4
3 control
2 4 4.7 1.1 2.2
1 12 15.5 1.5 4.8
20 25.6 1.7 7.3
0
0 2 4 6 8 12 16
(hrs) (Antibiotics in Lab. Medicine, 1991)
Synergism
Combination therapy
8
LOG
10 7
CFU/ml
6
5
CAZ (8HR)
4 TOB (8HR)
combination
3
2
1
0
0 5 10 15 20 (hr)
Growth and killing curve of P. aeruginosa (in vitro)
Synergism : G - rods
AMG + Cell wall active agent ( -lactam or glycopeptide)
• AMG: dominates during the early phase of the killing curve
: decrease the bacterial inoculum rapidly
: inoculum not-dependent
• -lactam: inoculum dependent
: dominates delaying bacterial regrowth
faster, longer killing process
(esp., simultaneous administration)
--- reduce the risk of AMG-resistant, -lactam resistant mutant
Synergism : Enterococci
AMG + Cell wall active agent ( -lactam or glycopeptide)
SM + Pn
• -lactam enhancement of AMG activity under low pH, O2
: to enhance the uptake of AMG
SM SM + Pn-G
In Vitro synergism of AMG + Cell Wall Active Agents
Organism Aminoglycoside(s) Cell Wall Active Drug(s)
Enterococci SM, KM, GM, TOB, NET, SIS,AMK Pn, AMC, CABC, NAFC, VAN
Viridans streptocci SM Pn
Streptococcus pyogenes GM Pn, AMC
MSSA KM, GM, TOB, NET, SIS NAFC, OXAC, CLOT, VAN
MRSA Teicoplanin ( + rifampin)
MSSE GM, TOB Teicoplanin ( + rifampin)
MRSE Vancomycin ( + rifampin)
Enterobacterriaceae GM, TOB, AMK PIPC, CLOT, CFOX, CTX
Pseudominas aeruginosa GM, TOB, AMK, NET, SIS Antipseudomonal penicillins,
aztreonam, CAZ, IMPM
Listeria monocytogenes SM, GM Pn, AMC, IMPM
Corynebacteria JK GM, TOB VAN, teicoplanin
In vivo Synergism (animal study)
Drug(s) Combined with
Organism (Animal) AMG Aminoglycoside Results
Enterococcus faecalis Endocarditis
Penicillin susceptible S, G Penicillin/ampicillin Combination synergistic
Penicillin resistant S, G Vancomycin Combination synergistic
HLR streptomycin, kanamycin G Penicillin/ampicillin Combination synergistic
HLR gentamicin S (?) Penicillin/ampicillin
Enterococcus faecium
Penicillin susceptible G Penicillin Combination synergistic
Penicillin resistant G Penicillin or vancomycin Pn- fail; VAN; success
Vancomycin resistant, high level G Teicoplanin Combination more effective
Viridans streptococci Endocarditis S Penicillin Combination synergistic
Staphylococcus aureus Endocardites
MSSA G Nafcillin Combination synersistic
MRSA None Vancomyinc+rifampin Combination effective
Staphylococcus epidermidis Endocarditis
MRSE G Vancomycin+rifampin more effective
In vivo Synergism (animal study)
Drug(s) Combined with
Organism (Animal) AMG Aminoglycoside Results
Enterobacteriaceae
Variety of organisms Peritonitis G, T Ticarcillin, carbenicillin Enhanced activity
Escherichia coli Endocarditis G Ceftriaxone+sulbactam Combination effective
Klegsiella pneumoniae Peritonitis A Imipenem Enhanced survival
Pseudomonas aeruginosa,
Serratia marcescens
Klbsiella pneumoniae Pneumonia G Ceftazidime Modest enhanced efficacy
Pseudomonas aeruginosa Peritonitis G, T Ticarcillin, carbenicillin Enhanced activity
(neutropenic & non-neutropenic)
Peritonitis A Pefloxacin No benefit of combination
Infected thigh N Azlocillin Combination more effective
Osteomyelitis Sis Carbenicillin Combination synergistic
Pneumonia T Ceftazidime Enhanced activity
Listeria monocytogenes Meningitis G Ampicillin Enhanced activity
Proven Synergism (in human)
1) Enterococcal endocarditis : GM + Pn -- improved survival (Mandell GL, Arch Intern Med, 1970)
2) S. aureus endocarditis : GM + cephalosporin -- microbiologic eradication rate
(Kosseniowski OM, Ann Intern Med, 1982)
3) P. aeruginosa infection :esp. in neutropenic patients
bacteremia : 47% vs 27% -- improved survival(Craig WA, 1994)
endocarditis
pneumonia : improved clinical response, -lactam resistance
4) Others G (-) bacteremia : mortality
Enterobacter bacteremia : 50% vs 29% (Chow JW, 1991)
Klebsiella bacteremia : 50% vs 24% (Korvick JA, 1992)
esp) Neutropenic pts with G (-) bacteremia : 2.8% vs 23% (Leonard L, 1997, AAC)
Q: Aminoglycoside가 가지는 단점에도 불구하고
임상에서 계속 사용되는 특유의 장점은?
ㄱ. concentration - dependent bactericidal effect
ㄴ. post-antibiotic effect
ㄷ. low-level of resistance
ㄹ. synergism with cell wall active agent
Aminoglycosides 사용량
A B C
Cephalosporins 548.49 411.80 588.11
Aminoglycosides 164.18 169.67 193.32
Penicillins 194.24 109.00 105.06
Quinolone 132.50 180.05 134.04
glycopeptide 10.25 22.89 10.47
(1999, 대한화학요법학회)
AMG use is Essential?
Risk
Benefit
Q; Aminoglycoside의 투여가 꼭 필요한 경우는?
1) Neutropenic fever
2) Staphylococcal catheter-related sepsis
3) Streptococcal endocarditis
4) Enterococcal endocarditis
5) Klebiella pneumoniae - intraabdominal abscess
Clinical Use of Aminoglycosides
AMG use is essential?
• Re-evaluation of the specific indications for aminoglycoside
Serious G - infection in compromised host
(P. aeruginosa, Serratia, Citrobacter, acinetobacter)
Systemic enterococcal infection : endocarditis
• Duration of AMG administration : as short as possible
Q : Aminoglycosides의 사용방법은?
Q : 최근 유행하는 Once-daily Dosing 의 배경은?
그리고 잇점은 ?
Dosing regimen
• Loading dose
: appropriate loading dose to attain “therapeutic” level rapidly
(1) calculation : ~ mg x Ideal Body weight (kg )
LD = desired Cmax / VoD
VoD : acute ill pts (ex: septic shock) LD
granulocytopenic, cancer pts
burn
obese pts
(2) independent on renal function
Dosing regimen
• Loading dose
Aminoglycosides Loading dose (mg/kg)
Streptomycin 7.5
Gentamicin 1.5-2
Tobramycin 1.5-2
Netilmicin 1.5-2
Amikacin 7.5-15
Isepamicin 7.5-15
Dosing regimen
• Maintenance dose ( Conventional, divided dosing)
: dependent on renal function
(1) modifying dose : Ccr/100 x normal maintenance dose
(2) changing the dose-interval : 100/Ccr x normal dose-interval
VoD renal clearance
Dosing regimen
• Divided Dosing
Maintenance Dose : dependent on Ccr
Aminoglycoside Maintenance Estimated Ccr (mL/min) supplement supplement
dose after HD during CAPD
(mg/kg) 80-90 50-80 10-50 <10 (mg/kg)
Gentamicin 1.7 q 8hr q12h q12-24h q24-48h q48-72h 1-2 3-4mg lost/L
Tobramycin 1.7 q 8hr q12h q12-24h q24-48h q48-72h 1-2 3-4mg lost/L
Netilmicin 2 q 8hr q12h q12-24h q24-48h q48-72h 1-2 3-4mg lost/L
Amikacin 7.5 q 12hr q12h q12-24h q24-48h q48-72h 1-2 3-4mg lost/L
Goal of therapy
: Therapeutic drug monitoring (TDM)
Target Serum level
Maximize Efficacy Conc. Dependent effect Peak conc./MIC: > 10
AMK : >20ug/mL
GM, TOB: >8-10ug/mL
Minimize Toxicity Sufficiently low Trough conc. :
AMK : <1-2ug/mL
GM, TOB: <0.5-1ug/mL
Saturable carrier of AMG uptake
Concentration 20 Once-daily regimen
(㎍/ml) Conventional regimen
16
12
8
4
0.5ug/mL
0
0 4 8 12 16 20 24
Time (hours)
Increased toxicity : trough > 2 ug/mL (amikacin)
Backgrounds of Extended Interval Dosing
200
Non-linear drug accumulation
150
100
50
10 20 30 40 50 60 70 80 90 100
Serum Gentamicin Concentration(㎍/mL)
Extended Interval Dosing
: meta-analyses of efficacy and safety of once-daily vs traditional dosing
(Proven in Clinical Trials)
No. of
trials clinical outcome nephrotoxicity ototoxicity
19 3.5% in efficacy 20% with OD 13% with OD
(p=0.027) (NS) (NS)
24 5.2% in efficacy 18% with OD 28% with OD
(p=<0.05) (NS) (NS)
16 2.7% in efficacy 0.1% with OD 0.1% with OD
(NS) (NS) (NS)
13 9% in mortality 15% with OD 33% with OD
(NS) (NS) (NS)
• Efficacy: superior to traditional dosing for wide variety of infection
• Toxicity: no difference in oto-, nephrotoxicity or reduced toxicity
Extended Intervals Dosing
Advantage
• Efficacy
1) Conc.-dependent killing effect : maximize the peak conc./MIC ratio
2) Conc.-dependent PAE
3) Prevent adaptive resistance : allow the 1st-exposure effect to dissipate
4) Cost saving
5) Facilitate tissue penetration : overcome the charge of chemical barrier
ex) endothelial capillary membrane
• Toxicity
: reduce the toxicity (-- saturable process of toxicity)
Extended interval Dosing
Indications Patients
Strong evidence of benefit G(-) infection : pneumonia, UTI
PID, bacteremia
Moderate, possible benefit G(+) infection: pneumonia, UTI
PID, bactermia
Abdominal infection,
Little or no benefit Meningitis
Skin&soft T infection with
Osteomyelitis
Inappropriate Enterococcal infection
* Not-used : variable VoD
burn pregnancy infective endocarditis
gross ascites neonate cystic fibrosis
renal failure neutropenic pts
Extended Intervals Dosing (Once-daily dosing)
Methods
: Administration - single daily infusion ( total daily amount)
ex) Tobramycin
100mg/IV q 8hrs 300mg
+) 5%DW 100cc
- bolus injection - infusion (30min-1 hr)
Extended Interval Dosing
• Loading Dose : same as conventional methods
• Maintenance dose
Dose (mg/kg) Dose interval (h)
Estimated creatinine Gentamicin
Clearance (mL/min) Tobramycin Amikacin
>80 5.0 15.0 24
60-79 4.0 12.0 24
50 3.5 7.5 24
40 2.5 4.0 24
<30 Use conventional dosing
• Nomogram (Extended Interval Dosing)
12 12
11 11
10 10
9 9
8 q48h 8
7 7
q36h
6 6
5
5
4 q24h 4
3 3
2 2
1 q12h 1
6 7 8 9 10 11 12 13 14
Hours After Start of infusion
Therapeutic Drug Monitoring
When we check?
• Not require rigorous measurement
Young patient with not prolonged therapy (< 5 days)
normal renal function ( Ccr > 60)
• Require rigorous measurement
Old age
Prolonged therapy
Co-administration of nephrotoxic agents
Patients with Severe infections
Therapeutic Drug Monitoring
When we check?
• Check after 2nd maintenance dose ( 5th day on once-daily)
serum creatinine : every 3 days
stable changed s- creatinine
TDM : 1 time/wk 2 times/wk
Conventional : Peak/Trough GM, TOB, NET : 8-10 (0.5-1)
Once-daily : Trough (6-14 hrs) AMK : 15-30 (1-4)
Q : Aminoglycosides 내성 기전은 ?
Mechasnism of Resistance
• Impaired drug uptake (Intrinsic/acquired)
• Target mutation (Ribosomal mutation)
• Synthesis of Modifying enzyme
Resistance
• Synthesis of modifying enzyme (: R-plasmid in cytoplasm) - M/C
: modification of AMG --> ineffective binding of AMG
: high level resistance
1) 3 of acetyltransferase (AAC-2’, AAC-3, AAC-6’)
2) 4 of adenyltransferase (AAD-2’’, AAD-3’’, AAD-4’, AAD-6)
3) 5 of phosphotransferase (APH-3’, APH-2’’, APH-3’’, APH-6, APH-5’’)
Resistance
• Synthesis of modifying enzyme
ex) GM, TOB
: susceptible to 5-6 types of enzyme
- cross resistance
- showing resistance frequently
AMK
: low level resistance
- susceptible only to AAC-6’
Hospitals with only-available AMG: Amikacin used
- GM, TOB resistant organism without increased AMK resistance
• G (-) bacilli resistance to AMG
GM TOB AMK
30 month 13% 6% 11% 4% 6% 3%
(Betts RF et al.-Veterans Affairs hospital, 1984)
Resistance of G (-) bacilli to aminoglycoside (KUGH)
80
70
70
60 60
60
50 50
50
E.coli
40 40
40 K.pneumo
P. aeru
30 30
30 S. marces
A. baum
20 20
20 E. cloac
10 10
10
0 0
0 1995 1996 1997
1995 1996 1997
1995 1996 1997
Gentamicin Tobramycin Amikacin
Summary
Aminoglycosides
:AMG remained useful antibiotics (despite of toxicity)
1) Higher efficacy: major, rapid, dose-dependent bactericidal effect
- effective even when the bacterial inoculum is large
2) Low incidence of resistance: rarely develop during the treatment
3) Combined therapy with cell wall-active agents in compromised pts
4) Relative in-expensive (reduced more with E-dosing)
Summary
Aminoglycosides
: Continued place for aminoglycoside
1) Resistance of G(-) bacilli to -lactam& quinolone
2) VRE, VRSA
3) Necessary as part of therapy for MDR tuberculosis
• Consider new-treatment methods of aminoglycoside
- Once-daily dosing
- Inhaled aminoglycoside
• Newer aminoglycoside
TOBI
: Inhaled Trobramycin
(by Chiron)
Less systemic toxicity
Delivery to site of action
Higher conc. In the lung
Improved PFT in CF
Arbekacin
: derivatives of Dibekacin
• In vitro synergistic killing against 8 of 13 VRE (Kak V, 2000)
• In vitro activity against MRSA
0.01 0.03 0.06 0.12 0.25 0.5 1 2 4 8
Arbekacin MRSA 2 4 4 49 165 34 13 7
MSSA 6 30 153 64 10 8
Total 2 10 34 202 229 44 21 7
Vancomycin MRSA 4 77 192 5
MSSA 67 197 7
Total 4 144 389 12
Gentamicin MRSA 3 11 2 2 1 8
MSSA 38 127 26 3 1 10
Total 41 138 28 3 2 2 18
Aminoglycoside
Consideration before Use AMG use is essential?
1. Use only when their unique potency is needed.
• Serious infection with Enterobacteriaceae
(P. aeruginosa, Serratia, Citrobacter, Acinetobacter)
- in compromised host : neutropenic patients
• Systemic Enterococcal infection
2. Predisposing potential risk factors - Correct, possible
Aminoglycoside
Consideration during Use AMG use is essential?
1. Change to less toxic antibiotics as soon as possible
- the infecting organism and it’s sensitivity have been determined
2. Duration of use
1) Empirical therapy : stop - after pt’s stabilization
2) Specific therapy : as short as possible
AMG use is Essential?
