1007165953 by lanyuehua

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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?

								
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