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Stretomyces Micromonospora
Suffix -mycin Suffix -micin
Inhalation
Tobramycin, Gentamicin : bronchopulmonary Ps.
aeruginosa
infections in cystic fibrosis
GENTAMICIN, TOBRAMYCIN, and AMIKACIN
Used for the following but is not the drug of
choice
H. influenzae
M. catarrhalis
Shigella species
Serious infections caused by aerobic gram (-)
bacteria
E. coli Enterobacter
Klebsiella Proteus
Providencia Pseudomonas
Serratia
ANTIBACTERIAL SYNERGY
Not effective for gram (+) cocci when
used alone
Combination of aminoglycoside and
cell wall synthesis inhibitors
Combined with penicillin in the treatment
Pseudomonal
Listerial
Enterococcal infections
STREPTOMYCIN
Tuberculosis
Plague
Tularemia
Multi-drug-resistant (MDR) strains of M. tb
resistant to streptomycin maybe susceptible
to amikacin
SPECTINOMYCIN
Aminocylitol related to aminoglycosides
Back-up drug
Intramuscular as single dose for gonorrhea
NEOMYCIN
Used topically
Locally
In the GIT
Eliminate bacterial flora
NETILMICIN
Reserved for serious infections resistant
to other aminoglycosides
Drug Use
Netilmicin septicemia
Lower respiratory tract infection
( NETROMYCIN )
Urinary tract infection
I.V
Streptomycin 25-30 mg/weak ( tuberculosis ) I.V , I.M
(Streptomycin Sulfate )
Oral
Paromomycin 500 mg po tid x7d Oral
( Humatin )
Oral
Neomycin For hepatic encephalopathy : Oral , topical
( mycifrdish ) 4-12 gm/d It is not given intravenously, as it is
As prophylactic in GI surgery : extremely nephrotoxic
1.0 gm po x3 with erythromycin
I.V
Tobramycin 5.1 ( 7 if critically ill ) mg/kg q24h I.V , I.M , inhalation
( Nebcin ) (Tobi)
I.V
Gentamicin 5.1 ( 7 if critically ill ) mg/kg q24h I.V , I.M , Topical
( garamycin )
I.V
Amikacin 15mg/kg q24h I.V , I.M
( Amikin )
I.V
Netilmicin 6.5 mg/kg q24h I.V , I.M
( NETROMYCIN ) The lowest ototoxic AGL
Tobramycin is superior to gentamicin for ttt of
P.aeruginosa .
Gentamicin is the preferred AGL used in combination
ttt of enterococcal endocarditis ( with ampicillin or
vancomycin).
Streptomycin has the greatest activity of all the AGL
against M.tuberculosis.
Capreomycin is an AGL use as alternative drug to ttt
mycobacterial infection
Streptomycin & gentamicin are drugs of choice to ttt
tularemia
Streptomycin is drug of choice to ttt plague &
brucellosis
A. OTOTOXICITY
Auditory or vestibular damage (or both) maybe
irreversible
Auditory impairment
Amikacin and kanamycin
Vestibular dysfunction
Gentamicin and tobramycin
Risk is proportionate to the plasma
levels
High if dosage is not modified in renal dysfunction
Increased with the use of loop diuretics
Contraindicated in pregnancy
B. NEPHROTOXICITY
Acute tubular necrosis
Reversible
Most nephrotoxic
Gentamicin and tobramycin
More common in elderly patients
Patients concurrently receiving
Amphotericin B
Cephalosporins
Vancomycin
C. NEUROMUSCULAR BLOCKADE
Rare
Curare-like block may occur at high doses
Respiratory paralysis
Reversible
Treatment
Calcium
Neostigmine
Ventilatory support
D. SKIN REACTIONS
Neomycin
Allergic skin reactions like contact dermatitis
Pharmacokinetics
Bioavailability
1. Oral: 0.2%
2. Intramuscular: complete, rapid
3. Aerosol: 1.5% to 34%
Duration of distribution
: 30 min. after the end of infusion
Total protein binding: 0% to 30%
Distribution sites
Good Synovial fluid, Urogenital tissue
Moderate Placenta
Poor Eye, Renal cyst
Limited Bone, Bronchial tree, CSF
Variable Saliva
Renal excretion
70% to 100%
Breast-feeding
Controversial
Bile
Variable
Some studies - biliary concentrations equal
to or greater than that of serum. No
correlation between liver function and drug
excretion in the bile.
For Adult:
There are two main principles for the use of the SDD of AGL:
1. Since the AGL bactericidal effect is related to peak concentrations,
higher doses will achieve a higher peak concentration and ensure
efficacy of therapy. With this dosing, it is possible to achieve the
desired peak:MIC ratio.
2. SDD may reduce the frequency of nephrotoxicity since low or
undetectable trough concentrations will be attained.
Dose ranges from 3 to 7mg/kg/day for gentamicin & tobramycin.
For children:
The use of SDD of AGL in children has some limitation
because of:
1. Rapid AGL clearance.
2. Unknown duration of post-antibiotic effect.
3. Safety concerns.
4. Limited clinical and efficacy data.
SDD relatively contraindications :
1. S.aureus or Enterococcal infection.
2. Bacterial pneumonia with pathogen having high MIC.
Toxicity with SDD:
1. Endotoxin like reactions with SDD AGLs therapy:
- many patients develop rigors, fever, tachycardia.
2. Ototoxicity: develop vestibular dysfunction with high dose.
3. Nephrotoxicity decreased with the use of SDD AGLs.
N.B:
- SDD of AGL not for every infection, pathogen, or patient.
- Must have therapeutic goal based on pathogen susceptibility & location
of infection.
- PKs remain useful tool to screen patients & to establish desired Cpx:MIC
ratio.
AGL dose depend on IBW & cretinine clerance.
Formula:
1. Creatinine clerance :
= (140-age)(IBW in kg) / (72)(Scr)=ml/min
x 0.85 for CrCl of women
2. Ideal Body Weight (IBW) :
males: 50kg + 2.3kg per inch over 5= weight in kg
females: 45kg +2.3kg per inch over 5= weight in kg
3. Obesity adjustment :
use if Actual Body Weight (ABW) is >30% above
IBW. To
calculate adjusted dosing weight in kg :
IBW+ 0.4 (ABW-IBW) = adjusted weight .
The pharmacokinetic dosing method
Literature-based recommended
dosing
The goal of initial dosing of
aminoglycosides is to compute the best dose
possible for the patient given their set of
disease states and conditions that influence
aminoglycoside pharmacokinetics and the
site and severity of the infection.
Vd 0.25 L/kg
Conc.
C1
C2
ti t1 t
n
Time
( Dose tin) S F 1 e Ketin e Ket 1
2) Vd
C1 Ke 1 e Ke
Vd
Dose Cmax
Conc.
C1
C2
ti t1 t
n
Time
1) Interval
1 Cpeakdesired
new Ln tin
Ke Ctroughdesired
2) Dose
Vd Cpeakdesired Ke tin (1 e Ke )
Dosenew
S F (1 e Ketin ) e Ket 1
Decide whether the following are appropriate:
Use alone or in combination with another antibiotic
Dose and Interval
Need for therapeutic serum concentration drug
monitoring
1. Will aminoglycoside levels be needed?
2. What type of study if any is needed
3. How many and when should levels be obtained
How should patient be monitored
Duration of therapy
Aminoglycoside serum concentration time
data (ASCTD) available:
No ASCT data available
1. Far more common situation
2. General rule for conventional aminoglycoside
therapy (Assume adult with normal renal
function)
- Daily dose for gentamicin or tobramycin ~ 5
mg/kg/d
*Amount per dose ~ 1.5 mg / kg
- Daily dose for amikacin ~ 15 mg/kg/d
*Amount per dose ~ 5 to 7.5 mg / kg
Parameters required for
evaluation:
Age
Height in inches
Weight
Serum creatinine
Patient weight:
a. Actual body weight (ABW)
b. Lean body weight (LBW) in Kg
1. Males = 50 + 2.3 (# inches over 5 feet)
2. Female = 45 + 2.3 (# inches over 5 feet)
3. Note if LBW > ABW use ABW
c. Dosing body weight (DBW)
1. For patients >30% over LBW
2. DBW = LBW + 0.4 (ABW LBW)
Calculated Creatinine Clearance(Crcl) in
ml/min
Method of Cockcroft and Gault