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The aminoglycoside antibiotics are widely used for the


treatment of severe gram-negative infections such as
pneumonia or bacteremia, often in combination with
a -lactam antibiotic.
Aminoglycosides are also used for gram-positive
infections such as infective endocarditis in
combination with penicillins when antibiotic synergy
is required for optimal killing.
Aminoglycoside antibiotics are bactericidal, and the
drugs exhibit concentrationdependent bacterial
killing.
Antibiotics with concentration-dependent
killing characteristically bacteria at a faster
rate when drug concentrations are higher.
Also, aminoglycosides have a concentration-
dependent postantibiotic effect.
The postantibiotic effect is the phenomenon
of continued bacterial killing even though
serum concentrations have fallen below the
minimum inhibitory concentration (MIC)
Aminoglycoside
(AGL)

Stretomyces Micromonospora
Suffix -mycin Suffix -micin

Streptomycin Paromomycin Gentamicin Amikacin

Neomycin Tobramycin Netilmicin


Most bacterial species are sensitive
aminoglycoside concentration varies widely among
species.

Intracellular concentration is dependent


upon a transport system located in the cell
membrane
Oxygen-dependent system ordinarily transports
polyamines and is absent in anaerobes

Therefore, only clinically useful against


organisms growing in aerobic conditions.
Bactericidal (irreversible) inhibitors of
protein synthesis
Penetration of bacterial cell wall is partly
dependent on O2-dependent active
transport
Minimal activity against strict anaerobes
Transport is enhanced by cell wall
synthesis inhibitors
Antimicrobial synergism
Bind to 30S ribosomal unit
Interfere with protein synthesis
1. Block formation of initiation complex
2. Cause misreading of the code on the
mRNA template
3. Inhibit translocation
Resistant due to failure to penetrate
into the cell
Streptococci, including S. pneumoniae
Enterococci
Resistant due to failure to penetrate
into the cell
Streptococci, including S. pneumoniae
Enterococci
Plasmid-mediated formation of inactivating
enzymes
Primary mechanism of resistance
Varying susceptibility to the enzyme
Plasmid-mediated formation of inactivating
enzymes
Group transferases
Catalyze the acetylation of amine functions
Transfer of phosphoryl or adenyl groups to the
O2 atoms of hydroxyl groups on the
aminoglycoside
Plasmid-mediated formation of inactivating
enzymes
Netilmicin is less susceptible and is active against
more strains of organisms
Plasmid-mediated formation of inactivating
enzymes
Transferases produced by enterococci
can inactivate
Amikacin
Gentamicin
Tobramycin
Not streptomycin
Parenteral
Septicemia, bone and joint infections, skin and
soft tissue infections, respiratory tract
infections, postoperative and intra-abdominal
infections
Tuberculosis and other mycobacterial diseases
: streptomycin, kanamycin, amikacin
In vitro synergism
- AGs + extended spectrum penicillin with
antipseudomonal activity or + -lactam
antibiotic/carbapenem or + expanded-spectrum
penicillin
- Gentamicin (or Streptomycin) + penicillin G (or
ampicillin) for Enterococci
Oral
Kanamycin, Neomycin: preoperative intestinal antisepsis
Paromomycin: intestinal amebiasis, various parasitic
infections

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

Streptomycin Second-choice medications: for


(Streptomycin Sulfate ) tuberculosis (TB)
streptococcal endocarditis (with B- lactam)

enterococcal endocarditis ( with penicillins )

Paromomycin Intestinal infections


Ttt of hepatic encephalopathy
( Humatin )
Ttt of amebiasis

Neomycin prophylaxis GI surgery


prevention of hepatic encephalopathy &
( mycifrdish )
hypercholesterolemia

Tobramycin Ttt of systemic infection


respiratory tract infection
( Nebcin ) , (Tobi)
Ttt of systemic infection
Gentamicin
life threatening infection
( garamycin )
eye infection

Amikacin Respiratory tract infection


Skin infection
( Amikin )
Urinary tract infection

Blood, abdomen or bones infection

Netilmicin septicemia
Lower respiratory tract infection
( NETROMYCIN )
Urinary tract infection

peritonitis and endometritis


Drug Dose regimen Available dosage form
(if creatinine clerance > 90ml/min) ( all aminglycosides have very
poor absorption from G.I.T )

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

The Hull and Sarubbi nomogram

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.

In order to do this, pharmacokinetic


parameters for the patient will be estimated
using average parameters measured in other
patients with similar disease state and
condition profiles.
For patients who do not have disease states
or conditions that alter volume of distribution,
the only two patient-specific factors that change
when using the pharmacokinetic dosing method
is patient weight and creatinine clearance.

Because of this, it is possible to make a


simple nomogram to handle uncomplicated
patients with a standard volume of distribution
(Table 4-3).
Because of the large amount of variability in
aminoglycoside pharmacokinetics, even when
concurrent disease states and conditions are
identified, many clinicians believe that the use of
standard aminoglycoside doses for pediatric patients
is warranted In general, the expected aminoglycoside
steady-state serum concentrations used to compute
these doses were similar to those for adults given
conventional dosing.

Suggested initial aminoglycoside doses for various


pediatric patients are listed in the Effects of Disease
States and Conditions on Aminoglycoside
Pharmacokinetics and Dosing section.
Clinical
PharmacoKinetics
Parameters
Therapeutic plasma concentration
Gentamicin, Tobramycin Peak 4-8 mg/L
Trough<2 mg/L
Amikacin Peak 20-30 mg/L Trough
<10mg/L

Vd 0.25 L/kg

Cl Normal renal function equal to Clcr


Functionally anephric patients 0.0043 L/kg/hr
Surgically anephric patients 0.0021 L/kg/hr
Hemodialysis 1.8 L/hr

T Normal renal function 2-3 hr


Functionally anephric patients 30-60 hr
Ln C1 / C2 0.693
1) Ke T1 / 2
t Ke
Dose
Cmax

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

Male = ((140 Age )* LBW) / (72* Scr)


Female = 0.85 ((140 Age )* LBW) / (72*
Scr)

Transform Crcl into Kd using Detli method


Kd (Hr-1) = 0.0024 (Crcl) + 0.01
Peak concentrations should be ~ 10 x MIC of the
likely bacterial pathogen
Troughs should be as low as possible given the
circumstances surrounding the patient
Dose should be evaluated on a mg/kg/day basis
and mg/kg per dose basis using the appropriate
body weight parameter
Dosing interval should be ~ 2 to 3 T1/2s plus the
hour for drug infusion
Try to limit total course of therapy to < 5 days to
reduce risk of nephrotoxicity or ototoxicity
General requirements are that patients renal function
and fluid status be stable
Trough / Peak Option
- Patient must be at steady state
*Received drug for 3-5 T1/2s
- If t1/2 is short in relation to doing interval, the
likelihood of having measurable trough is low
- Nurse has administered drug on time and on
schedule
during the 3 to 5 T1/2 period
- Note: If patient seriously ill with impaired renal
function, clinician may not be able to wait for
steadystate
Impact of preventing aminoglycoside toxicity through
TDM (traditional dosing)
TDM can reduce nephrotoxicityfrom 19.2%
to 7.9% (retrospective)
TDM reduces significantly nephrotoxicity from
14.4 to 8% and from 9.5 to 5.6 (prospective)
Nephrotoxicityin once-daily administration
occurs at a higher frequency (> 15%) in at risk patients
Long duration of therapy, high doses
Elderly
Co-existing liver/renal dysfunction
Co-administration nephrotoxicdrugs
(vancomycin), volume depletion, furosemide
Should always factor in the clinical condition of
the patient
The likely bacterial pathogen and level of
sensitivity to chosen aminoglycoside
The location of infection and how well the
aminoglycoside is likely to concentrate at that
site
Anticipate future
- Renal & fluid status
- Likely duration of therapy
Bauer, Larry A.2008. Applied Clinical
Pharmacokinetics Second Edition.
Washington : MacGrawHill Medical

Bauer, Larry A. Clinical Pharmacokinetics


Handbook. Washington : MacGrawHill
Medical