AMINOGLYCOSIDE ANTIBIOTICS

Presented by
Afreen Nasir
PharmD Intern
Introduction

• Streptomycin was the first member discovered in 1944 by Waksman and his col- leagues.
• It assumed great importance because it was active against tubercle bacilli.
Mechanism of action

Bactericidal action is achieved in 2 main steps.

Transport of AG through the bacterial cell wall & Binding to ribosomes resulting in inhibition of protein synthesis.
cytoplasmic membrane.

Penetrate outer coat of G-ve through porin channel.

Enters periplasmic space across cytoplasmic

membrane (O2 dependent).

• Penetrate in high pH alkaline > acidic.

• Antibiotics affecting bacterial cell wall (ß-
lactams, vancomycin) enhance entry of this
antibiotic.
Concentration-Dependent Killing
Due to their bactericidal activity, they exhibit conc-
dependent killing, i.e. higher the conc. the drug, the higher
the bacterial killing achieved.
Spectrum

.
Classification

.
Pharmacokinetic

• Absorption: Highly ionized, neither absorbed nor destroyed in g.i.t. Absorption from injection site in muscles is rapid: peak plasma
levels are attained in 30-60 minutes.
• Distribution: Extracellularly, so that Vd (~0.3 L/kg) is equal to the extracellular fluid volume. They cross placenta and can be found
in foetal blood/ amniotic fluid. Their use during pregnancy can cause hearing loss in the offspring; should be avoided.
• Metabolism: not metabolized; excreted by the kidneys.
• Elimination: eliminated mostly unchanged by the kidneys, plasma t1/2 of 2-4 hours in adults with normal renal function.

.
 Drugs PK
Absorption Distribution Elimination
GENTAMICIN Peak plasma time (PPT): IM (30- • Cross placenta • t1/2 : 2-3 hr
90min), IV (30 min after 30min • Normal CSF (minimal), • Excretion: urine (unchanged).
infusion) inflamed meninges (10-
30%).
• PB: <30%
.
STREPTOMYCIN • IM well absorbed, not from gut. • ECF • t1/2 : 2-4.7 hr prolong with renal
• PPT: 1 hr • PB: 34% impairment.
• Excretion: urine 90% unchanged.
KANAMYCIN Rapid IM Urine
TOBRAMYCIN • IM rapid • ECF • t1/2 : 2-3 hr
• PPT: IV 30 min, IM 30-60 min • PB: <30% • Excretion: 90-95% in urine in 24 hrs
(NRF)
AMIKACIN • IM • PB: 0-11% • t1/2 : 2-3 hr (NRF)
• PPT: IM 45-120 min • Excretion: urine 94-98%
NEOMYCIN • Oral: poor • t1/2 : 3 hr
• PPT: O 1-4 hr, IM 2 hr • Excretion: 97% unchanged in feces.
Dosing regimen
• Due to low safety margin, daily dose of systemically administered AGs must be calculated acc. to body weight and level of renal
function.
• Adult with normal RF (CLcr >70) dose will be:
Gentamicin/Tobramycin/ Sisomicin/Netilmicin – 3-5 mg/kg/day
Streptomycin/ Kanamycin/Amikacin – 7.5-15 mg/kg/day
• Single daily dose is more effective than divided dose.
 Drugs Formulations, dose Organisms Uses
GENTAMICIN Inj. sol ( 10, 40 mg/ml), • Aerobic G-ve bacilli (E. coli, Klebsiella • 1st line
IV sol.( 60, 70 mg/50 ml) pneumoniae. Enterobacter, H. injluenzae, • RTI, UTI, meningitis, septicemia,
0.3% eye/ ear drops, Proteus, Pseudomonas aeruginosa). endocarditis.
0.1% skin cream. • G +ve bacteria are susceptible (Staph. • Topical use on infected burns,
aureus, Strep.faecalis). conjunctivitis.
• Surgical prophylaxis.

STREPTOMYCIN 1g powder for inj. • Narrow spectrum: aerobic G-ve bacilli. M. TB, endocarditis, plaque, tularemia.
tuberculosis
• Resistance: E. coli, H. influenzae, largely
resistant.
KENAMYCIN Inj M. tuberculosis Resistant TB
TOBRAMYCIN Inj. sol (10,40 mg/ml). Proteus, Pseudomonas
0.3% eye drop.
AMIKACIN Inj. sol. 50, 250 mg/ml). Higher dose for Proteus, Pseudomonas. UTI, HAP
NEOMYCIN T 500mg. 0.3% oint, G-ve, +ve • Topical: ulcer, burn, ear infection,
0.5% skin cream, eye conjunctivitis, skin infection.
oint. • Oral:
Prepare bowel before surgery.
- Combined with METRONIDAZOLE
0.5 g 8 hourly on day before surgery)
may reduce postoperative infection.
Hepatic encephalopathy.
Dosing regimen
Drug Dosing
GENTAMICIN Administered IV/IM Infuse over 30-120 min when administering IV
STREPTOMYCIN Moderate-Severe Infections: 1-2 g/day IM divided q6-12hr; no more than 2 g/day.
TB: Daily therapy: 15 mg/kg IM qDay; no more than 1 g/day. Twice weekly therapy: 25-30 mg/kg IM 2 times/week;
no more than 1.5 g/day.
Streptococcal Endocarditis:1 g IM q12hr for 7 days, THEN 500 mg q12hr for 7 days, concomitant with
PENICILLIN. If >60 years old, 500 mg q12hr for entire 14 days.
Enterococcal Endocarditis:1 g IM q12hr for 2 weeks, THEN 500 mg q12hr for 4 weeks, concomitant with
PENICILLIN.

TOBRAMYCIN
AMIKACIN
NEOMYCIN
• neomycin/polymyxin
B/bacitracin/lidocaine
• Bacitracin
ophthalmic/neomycin/poly
myxin B/hydrocortisone
3-6 mg/kg/day IV/IM divided q8hr OR 4-7 mg/kg/dose IV/IM qDay
15 mg/kg/day divided IV/IM q8-12hr UTI: 250 mg IV/IM q12hr
HAP: 20 mg/kg/day IV; may administer with antipseudomonal beta-lactam or carbapenem.
Topical oint: (3.5mg/10,000units/500units/40mg)/g. Pre-Op Intestinal Antisepsis:1 g PO at 19, 18, and 9 hours pre-
op OR 1 g PO q1hr for 4 doses, THEN 1 g q4hr to complete 24
hours of dosing OR 88 mg/kg/day divided PO q4hr for 2-3 days
Ophthalmic oint: 400units/0.35%/10,000units/1%. pre-op. Maximum: Up to 12 grams 24 to 48 hours prior to surgery
Hepatic Encephalopathy:Acute: 4-12 g/day PO divided q6hr for
5-6 days OR 3-6 g/day for 1-2 weeks Chronic: Up to 4 g/day PO.
Renal dose adjustment

Drug Adjustment
GENTAMICIN Conventional dosing
Recommendations are based on doses of 1.7 mg/kg/dose q8hr or 5-7 mg/kg/dose once daily.
CrCl>50 mL/min: No dosage adjustment necessary CrCl 10-50 mL/min: Administer q12-48
hr
CrCl<10 mL/min: Administer q48-72 hr

STREPTOMYCIN Load: 1 g IM, THEN CrCl: 50-80 mL/min: 7.5 mg/kg IM q24hr. CrCl: 10-50 mL/min: 7.5 mg/kg IM q24-72hr
CrCl <10 mL/min: 7.5 mg/kg IM q72-96hr. Hemodialysis: 50-75% of initial loading dose at end of dialysis
period
TOBRAMYCIN Clcr >60 mL/min: q8hr. Clcr 40-60 mL/min: q12hr. Clcr 20-40 mL/min: q24hr. Clcr 10-20 mL/min: q48hr.
Clcr <10 mL/min: q72hr Following dialysis in ESRD
AMIKACIN CrCl >90 mL/min & aged <60 yr: q8hr. CrCl 60-90 mL/min OR aged ≥60 yr: q12hr. CrCl 25-60 mL/min: q24hr
CrCl 10-25 mL/min: q48hr. CrCl <10 mL/min: q72hr Administer after dialysis in ESRD
Mechanism of resistance
Acquisition of cell membrane bound inactivating enzymes which • The conjugated aminoglycosides do not bind to the target ribosomes
phosphorylate/ adenylate or acetylate the antibiotic. and are incapable of enhancing active transport like the unaltered
drug.
• This is the most important mechanism of development of resistance
to AG.
Mutation decreasing the affinity of ribosomal proteins that normally • This mechanism can confer high degree resistance.
bind AG.
Decreased efficiency of AG transporting mechanism. Either pores in the outer coat become less permeable or active transport
is interfered.
Toxicity

1)Ototoxicity: Cochlear damage (hearing loss), Vestibular damage (Headache, nausea, vomiting, dizziness, vertigo, ataxia).
2) Nephrotoxicity: AG interfere with the production of PGs in the kidney leading to reduced g.f.r.
3) Neuromuscular Blockade: AG reduce ACh release from the motor nerve endings. Streptomycin/Neomycin cause apnoea, fatalities.
Drug interactions
AG Drugs Mechanism
Gentamicin • Abacavir • ↓ excretion rate of Gentamicin which could result in nephrotoxicity.
• Acetylcholine • Therapeutic efficacy of Ach ↓ when used in combination with Gentamicin.

Nephrotoxic drugs (NSAIDs,

Amphotericin B, Vancomycin,
Cyclosporine, Cisplatin,
Cephalosporins).
Ototoxic drugs (Vancomycin,
Minocycline, Furosemide).
References
• Medscape
• Drug bank
• Tripathi 8th ed Pharmacology text book
• Goodman & Gilman’s Manual o f Pharmacology and Therapeutics book
THANK YOU