Please enable JavaScript.
Coggle requires JavaScript to display documents.
AMINOGLYCOSIDES - Coggle Diagram
AMINOGLYCOSIDES
GENERAL PROPERTIES
- AGs have a Hexose ring→
○ streptidine( in streptomycin)
○ 2-deoxystreptamine( in other AGs)
- Water soluble, stable in solution
MOA :check:
- Irreversible inhibitiors of protein synthesis
- Bactericidal
Events
- Passive diffusion via porin channels across outer membrane
- Drug actively transported across cell membrane into cytoplasm by O2-dep. process
○ Transmembrane EC gradient supplies energy & transport is coupled to a proton pump
○ Low extracellular pH & anaerobic conditions→ inhibit transport ( ↓ EC gradient_
○ Transport enhanced by cell wall active drugs→ Penicillin, vancomycin → Drug synergism
3. Inside bacterial cell→ AGs bind to 30S subunit ribosomal proteins
○ Additionally bind to 50S subunit or 30S-50S interface
- Protein synthesis inhibited in 3 ways:
○ Interference with initiation complex of peptide formation
○ Misreading of mRNA→ non functional proteins
○ Breakup of polysomes → non-functional monosomes
- Overall effect is irreversible→ cell death
MECHANISM OF RESISTANCE :recycle:
3 mechanisms established1. Pdn. of a transferase enzyme
- that inactivated AGs by adenylylation, acetylation, phophorylation
2. Impaired entry of AGs into cell
- Resulting from mutation/ deletion of a porin protein →
○ involved in transport & maintenance of EC grad.
○ or growth conditions where O2 dep. transport process is not functional
3. Receptor protein on 30S subunit may be deleted or altered as a result of mutation
SHARED TOXICITIES
Conc> 2mcg/ml predictive1. OTOTOXICITY
- Drugs are conc. in labyrinthine fluid & slowly removed as plasma conc. ↓
- Vestibular/ cochlear sensory cells can undergo conc. dependent destructive changes
- AG ear drops→ ototoxicity in patients with perforated eardrum : C/I
Cochlear damage
- Base→ apex
- High frequencies lost first
- No regeneration of sensory cells
- Retrograde degeneration of Auditory nerve fibers
- Asymptomatic→ tinnitus→ progressive hearing loss
- Older patients/ with preexisting hearing defect→ more susceptible
- Kanamycin & Amikacin
Vestibular damage
- Headache
- Nausea, vomiting, dizziness, nystagmus & vertigo, ataxia
- If drug is stopped then,
○ C/c phase lasting 6-10wks→
○ Patent asymptomatic
○ Compensation by visual & proprioceptive positioning allays symptoms
○ Recovery over 1-2yrs
- Permanence of damage depends on Extent of initial damage & age of patient
- Streptomycin & Gentamicin→ more vestibular toxicity
2. NEPHROTOXICITY
- Tubular damage→
○ loss of urinary conc.power
○ low GFR
○ Nitrogen retention
○ albuminuria & casts
- High conc. in renal Cortex( Prox. tubules)
- More in elderly & those with preexisting renal disease
- AG ind. nephrotoxicity→ ↓ clearance of drug→ persistent higher plasma conc.→ enhanced Ototoxicty
- Streptomycin→ least nephrotoxic
3. NM BLOCKADE
- All AGs→ ↓ Ach releasefrom motor nerve endings
- NM block by AGs can be
○ partially reversed by IV inj. of Ca salt
○ Neostigmine→ inconsistent reversing action
PRECAUTIONS & INTERACTIONS
- Avoid AGs in pregnancy→ risk of fetal toxicity
+ Avoid concurrent use of other nephrotoxic drugs
○ NSAIDs
○ Amphotericin B
○ Vancomycin
○ Cyclosporine
○ Cisplatin
- Cautious use of other ototoxic drugs
○ Vancomycin
○ inocycline
○ Furosemide
- Cautious use in patient > 60yrs & those with kidney damage
PHARMACOKINETICS
- Highly ionised
- GIT→ no absorption
- Absorption via IM→ rapid
- Extracellular distribution
- Vd~0.3L/kg= nearly equal to ECF vol.
- Low conc. in serous fluids - synovial, pleural, peritoneal. Significant levels attained on repeated dosing
- Relatively higher levels present in endolymph & renal cortex→ ototoxicity & nephrotoxicity
- AGs cross placenta & found in fetal blood/ amniotic fluid
○ Not used in pregnancy→ hearing loss
- Renal clearance of AGs parallels creatinine clearance ~⅓ of it
- T ½ prolonged upto 24hrs
○ Accumulation in patients→ RF
○ Elderly & neonates
○ Redn in dose or increase in dose interval is essential
○ Generally no need for dose redn. till CLcr> 70ml/min
DOSING REGIMEN
For an avg. adult with normal renal fn (CLcr>70ml/min)
- Gentamicin/ tobramycin/ sisomicin/ netilmicin
○ 3-5mg/kg/day
- Streptomycin/ kanamycin/ amikacin
○ 7.5-12mg/kg/day
ADMINISTRATION OF ENTIRE DAILY DOSE IN SINGLE INJ. :question: AGs exhibit Concentration dependent killing :check:
- Higher conc. kill larger portion of bacteria at rapid rate
Post Antibiotic Effect :check:
- Antibacterial activity persist beyond the time during which measurable drug is present
- PAE of AGs can last several hrs.
- Because of these 2 effects, given total amount of AGs may hav a better efficacy when administered as a Single large dose than when administered as multiple smaller doses
DRUGS
GENTAMICIN
- Higher potency & broader spectrum of activity
- Prototype
SPECTRUM :check:
- Aerobic G-ve bacilli
○ E.coli, K. pneumoniae, H. infl., Enterobacter, Proteus, Serratia, Ps. aeruginosa
- Brucella, Campylobacter, Citrobacter, Francisella, Yersinia→ sensitive
- Limited no. of susceptible G+ bacteria
- Ineff. against Myco. tuberculosis
- Cross resistance to Tobramycin & Sisomicin
Drug Synergism with ß lactam ABs
- Enterococcus- endocarditis
- Pseudomonas- meningitis
- With penicillin/ CS/ vancomycin
DOSE: 3-5mg/kg/day IM or IV
USES :check:
- Low TI→ restricted to serious G-ve bacillary infections
1. Resp. inf. in critically ill patients
- Mostly combined with penicillin/ CS
- Tobramycin/ amikacin also used
- Added to peritoneal dialysate → prevent/ treat peritonitis
2. Pseudomonas/ Proteus/ Klebsiella inf.
- Burns/ UTI/ pneumonia/ lung abscess/ osteomyelitis/ middle ear inf/ septicemia
- Combined with Piperacillin/ 3rd gen CS→ serious inf.
- Topical use on infected burns/ conjunctivitis→ permitted
3. Meningitis by G-ve bacilli
- 3rd gen CS + AG combination
4. SABE
- Gentamicin 1mg/kg 8hrly IM + penicillin/ ampicillin/ vancomycin
STREPTOMYCIN
- 1st AG from Streptomyces griseus
- Now use restricted to TB
- Less potent. MICs are higher
SPECTRUM :check:
- Aerobic G-ve bacilli
○ H. ducreyi, brucella, Yersinia pestis, Francisella tularensis, Nocardia, Calym. granulomatis, M. tuberculosis
- Few strains of E.coli, H. influenzae, V. cholerae, Shigella, Klebsiella, Enterococci, Some G+ cocci inhibited→ at High conc.
- Pseudomonas unaffected
RESISTANCE :recycle:
- One step mutation
- Or Aquisition of plasmid coding for modifying enzymes
- E.coli, H. influenzae, Str. pneumoniae, Str. pyogenes, Staph. aureus → largely resistant
- If streptomycin used alone→ M. tuberculosis→ resistant
- Cross resistance: partial & unidirectional b/w Streptomycin & other AGs
◘ Streptomycin dependence: Certain mutants grown in presence of streptomycin become dependent on it.
- Their growth is promoted than inhbited
- Antibiotic induced misreading of genetic code→ becomes normal feature of organism
ADVERSE EFFECTS :warning:
- Vestibular disturbances
- Auditory disturbance less common
- Least nephrotoxicity among AGs
○ Not conc. in renal cortex
- Pain at inj. site
- Paraesthesias & scotoma occasional
- HS reactions rare
- Superinfections not significant
- Topical use→ C/I d/t fear of contact sensitization
- Pregnancy C/I→ risk of fetal ototoxicity
USES :check:1. TB2. SABE
3. Plague
- Rapidly curative
- Alone/ combined with a Tetr.
4. Tularemia
KANAMYCIN
S. kanamyceticus
- 2nd systemically used AG developed
- Similar to strep in efficacy& all aspects
- More oto/nephrotoxic
- Irreversible hearing loss more common
- Replaced by other AGs
- Occassional use as 2nd line drug in Resistant TB
TOBRAMYCIN
S. tenebrarius
- AMA, PK, dosage ~gentamicin
- 2-4x more active against Pseudomonas & Proteus
- Not useful for combining with penicillin for enterococcal endocarditis
- Used as alt. to gentamicin
- Ototoxicity/ nephrotoxicity less
USES :check:
- Serious inf. by Pseudomonas & Proteus
AMIKACIN
- Semisynthetic derivative of kanamycin→ same PK, dose & toxicity
- Important feature→ resistance to bacterial AG modifying enzymes
- Widest spectrum of activity
- Relatively higher doses for Pseudomonas, Proteus & Staph. inf.
- Toxicity: hearing loss> vestibular disturbance
USES :check:
- ~gentamicin
- Reserve drug for empirical treatment of G-ve bacillary HAI → where gentamicin/ tobramycin resistance is high
- Effective in MDR-TB
SISOMICIN
- Natural AG from Micromonospora inyoensis
- PK & chemically~gentamicin
- Somewhat more potent on Pseudomonas, ß hemolytic streptococci
- Susceptible to AG inactivating enzymes
- Clinical use restricted
NETILMICIN
- Semisynthetic derivatve of gentamicin
- Broader spectrum & low toxicity alternative to gentamicin
+ Relatively resistant to few AG modifying enzymes
- Eff. against few gentamicin resistant strains
- Failed to gain clinical popularity
NEOMYCIN
S. fradiae
- Wide spectrum AG
- Active against most G-ve bacilla & some G+ cocci
- Highly toxic to internal ear & kidney
○ Not used systemically
- Abs. from GIT minimal
USES :check:
- Topically
○ Often combi with Polymyxin/ Bacitracin
○ For infected wound, ulcers, burns, ext. ear infections, conjunctivitis
- Orally
○ Preparation of bowel before surgery
○ Hepatic coma
ADVERSE EFFECTS :warning:
- Applied topically→ low sensitizing potential
- Oral neomycin→ damage on intestinal villi
○ Prolonged trt→ malabsorption syndrome with diarrhea, steatorrhea
- Superinfection by Candida
- Kidney damage & ototoxicity
○ C/I if renal fn. impaired
FRAMYCETIN
S. lavendulae
- Similar to neomycin
- Too toxic for systemic admn.
- Used topically on skin, eye, ear
PAROMOMYCIN
- Chemically related to neomycin
- Activity against protozoan parasites
- Was marketed for Intestinal amebiasis & giardiasis
USES :check:
- Alt. to neomycin for hepatic encephalopathy
- Parenterally→ visceral leishmaniasis
ARBEKACIN
- Semisynthetic AG of kanamycin family
- Broad spectrum activity
- Covers many G+ & G-ve
○ Incl. MRSA, E.coli, Ps. aeruginosa, K.pneumoniae, etc
- Stable to many AG modifying enzymes
- Synergises with ß lactam ABs
○ Combi. used for MDR pseudomonas & Acinetobacter infections
- Ototoxic & nephrotoxic
SPECTINOMYCIN
- **Aminocyclitol antibiotic structurally related to AGs
- In vitro action against many G+ & G-ve org.
- IM use - rapid abs.
USE :check:
- Antibiotic resistant gonococcal infections in penicillin allergic patients
ADVERSE EFFECTS :warning:
- Pain at inj. site
- Fever, nausea
- Rarely→ nephrotoxicity