aminoglycosides n.
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Aminoglycosides. Intro. Group of antibiotics used in the treatment of bacteria infections aerobic G-ve Consists of 2 or more amino sugars and a hexose nucleus Serious toxicity is a limiting factor for their application

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intro
Intro
  • Group of antibiotics used in the treatment of bacteria infections aerobic G-ve
  • Consists of 2 or more amino sugars and a hexose nucleus
  • Serious toxicity is a limiting factor for their application
  • Streptomycin was the first to be discovered in 1943 by Schatz, Bugie and Waksman
other examples are
Other examples are:
  • Gentamicin*
  • Streptomycin
  • Amikacin
  • Neomycin
  • Netilmicin*
  • Tobramycin
  • Kanamycin
  • Paromomycin+

*Not from Streptomyce spp (from Actinomycetes spp)

+ Antiparasitic ( amoebiasis, cryptosporidiosis)

slide4
Families:
  • Determined by the type of amino sugar
  • Neomycin – there are 3 amino sugars attached to 2-deoxystreptamine e.g Neo B, Paromomycin
  • Kanamycin family – 2 amino sugars attached to 2 deoxystreptamine. E.gs amikacin*. Kanamycin A & B, tobramycin
  • *a semisynthetic derivative of kanamycin A and netilmicin is also semisynthetic
aminoglycosides family
Aminoglycosides family
  • Gentamicin family-
    • Gent Ci,
    • Gent C1a and C2,
    • sisomicin and
    • Netilmicin (derivative of sisomicin)
  • Streptomycin family
    • Streptomycin and
    • dihydrostreptomycin.
    • Contains streptidine instead of deoxystreptamine
slide6
Spectrum of activity
  • Aerobic G-ve bacteria ( Citrobacter, Enterobacter, E. coli, proteus, Pseudomonas, Enterococci and Staph aureus *)
  • Lack activity against most anaerobic or facultative bacteria and activity against G+ve# organisms is limited

* in combination

# Strept pyogenes is highly resistant

slide7
Mechanism of Action
  • Bactericidal antibiotics
  • Penetration involves active transport
  • Inhibition of protein synthesis by binding to the 30S subunit of ribosomes
  • Causes misreading and premature termination of protein synthesis
slide8
Resistance-
  • May be plasmid mediated inactivation by microbial enzymes or failure of drug penetration
  • Synthesis of metabolizing enzymes
  • Mutation may alter ribosomal binding site for the aminoglycosides
  • Cross resistance with other aminoglycosides may occur
absorption distribution and elimination
Absorption, Distribution and Elimination
  • Polar agents with poor oral absorption
  • Usual routes: IM or I.V
  • Cmax achieved within 30-90 of IM
  • Absorption increases in inflammation
  • No significant amount in breast milk
  • Plasma protein binding is minimal
  • Vd approximates 25% of lean body weight
abs distr and elimination
Abs, Distr and Elimination
  • Penetration of CNS: 10-25% of plasma level
  • Accumulates in the perilymph and endolymph as well as renal cortex
  • Vd increases in – leukaemia
  • Clearance increases and T1/2 reduces in cystic fibrosis
  • T1/2 for most; 2-3 hours
  • Elimination is by glomerular filtration
  • Both haemo- and peritoneal dialysis remove aminoglycosides
unwanted effects
Unwanted effects
  • Ototoxicity: netilmicin is reputed to be mildest on both Vest and Audi. Functions*
  • Nephrotoxicity#
  • Other neurotoxic effects – optic neuritis, peripheral neuritis, neuromuscular blockade
  • Others: angioedema, skin rash, blood dyscrasia, eosinophilia, fever, stomatitis, anaphylaxis

*Neo/Amk/kan affect Audi more than others while Str/Gen tend to affect Vest fn more

# Gen/Tob/Neo are relatively more nephrotoxic than the others

NB: Nephrotoxic effects occurs in 5-10% of patients

therapeutic drug monitoring
Therapeutic drug monitoring

Necessary in:

  • Patients with life threatening infections
  • Renal impairment
  • 24 hours into new regimen
  • Neonates
  • Samples usually taken just before and 30 minutes after a dose
caution in
Caution in:
  • Pregnancy
  • Myasthenia gravis (MG)
  • Renal impairment
  • Parkinson’s dx
  • 8th cranial nerve disease
streptomycin
Streptomycin
  • Usual dosage: 15-25 mg per Kg body wt IM

Therapeutic applications in:

  • Bacterial endocarditis from enterococcal and group D Strep
  • Tularemia
  • Plague
  • Tuberculosis
gentamicin
Gentamicin
  • Inexpensive and reliable efficacy
  • Usual dose; 3-5 mg per Kg body wt in 3 divided doses daily
  • Therapeutic Applications: UTI, Pneumonia (nosocomial), Peritonitis, meningitis and sepsis
tetracyclines
Tetracyclines
  • Broad spectrum antibiotics (incl: Legionella spp, Ureaplasma, Mycoplasma, chlamydia plasmodium and rickettsial infections)
  • Origin: Streptomyces spp
  • Examples: Chlortetracycline, demeclocyline, oxytetracycline, doxycline*, tetracycline*, minocycline*

* semisynthetic

slide18
Mechanism of action:
  • Binding of the 30S subunit of ribosome, preventing the access of aminoacyl tRNA to the acceptor site on the mRNA-ribosome complex

Resistance

  • Plasmid mediated decrease accumulation of the drug
  • Blockade of access by ribosome protecting protein
  • Enzymatic inactivation of TCN
abs distr and elimination1
ABS, DISTR and ELIMINATION
  • Most are incompletely absorbed when taken orally*
  • Abs occurs mainly in the stomach and upper small intestine
  • Fasting improves abs while presence of food or divalent cations reduce
  • Peak conc ~ 2-4 hr
  • T1/2: 6-12 hrs+
  • Widely distributed (incl: RE cells in spleen, liver and bone marrow; also synovial and sinuses bone and dentine and prostate)

*Chlortetracycline is worst; minocycline and doxy are best

+ half life of mino and doxy very long 16-18 hr

slide20
Undergoes entero-hepatic cycling
  • Most tetracyclines are excreted in urine (doxicycline, an exception)
  • Clinical uses
  • Wide range of bacteria diseases+
    • Ricketsial infections
    • Mycoplasma
    • Chlamydia

+ Use often precluded by resistance

unwanted effects1
Unwanted effects
  • GI upset including abd pain, nausea, vomiting diarrhea
  • Photosensitivity
  • Hepatotoxicity
  • Renal toxicity
  • Teeth and bone discolouration
  • Skin rashes
  • Pseudomembraneous colitis
  • Thrombophlebitis (IV)
  • Pseudo-tumour cerebri
  • Leukopenia, Thrombocytopenic purpura
chloramphenicol
Chloramphenicol
  • Broad spectrum antibiotic (MIC for sensitive strains < 8 ug/ml)
  • Antimicrobial spectrum: Rickettsial, salmonella infections

Mechanism

  • Inhibition of protein synthesis via 50S subunit of ribosome**

Resistance

  • Plasmid mediated elaboration of inactivating enzymes (acetyl transferase)

** Other 50S: erythromycin Clindamycin

chloramphenicol1
Chloramphenicol
  • Introduced to clinical practice in 1949
  • Bacteriostatic
  • Fallen out favour in western countries cos it causes aplastic anaemia
  • Main use restricted as eye ointment/drops
  • Poorly dissolves in water requiring that IV is given as succinate ester.
  • The succinate ester is incompletely hydrolysed (70%); hence oral preferred to IV
chloramphenicol2
Chloramphenicol
  • Usual oral dose = 50 mg per kg
  • IV usually 75 mg per kg
  • Drug level to be monitored in neonates to < 4 yrs old, elderly, renal impaired patients
  • Recommended peak level 15-25 mg/ml (sample taken 1 hr after dose)
  • Trough level < 15mg/kg (sample taken b4 next dose)
abs distr excn
ABS DISTR EXCN
  • Well absorbed when given orally, (IM not advised as it is poorly absorbed)
  • Peak conc achieved within 2 hours
  • 60% of plasma found in CSF
  • T1/2 2 hours
  • 10% unchanged in urine, the rest is inactivated by glucuronidation in the liver
slide27
ADRs
  • Gray baby syndrome (consisting of: VDFlaccidityHypothermia Ashen-gray colour); Gray syndrome
  • Jarisch_Hexheimer reactions when used in brucellosis
  • Bone marrow suppression:
    • presents with low Hb;
    • does not predict Aplastic anaemia,
    • dose dependent (>20g)
  • Risk of leukaemia
slide28
ADRs
  • Bone marrow aplasia*
    • Not dose dependent
    • Unpredictable
    • commonest with oral (1:24000, least with eye preps (1: ~250000);
    • may begin weeks after stopping drug
  • Interactions: Phenytoin, phenobarb, Rifampicin, chlorpropamide, dicoumarol

*Such effect unknown with Thiamphenicol (a methyl-sulphonyl analogue of Chloramphenicol)

intro1
Intro
  • Group of broad spectrum antibiotics
  • Also known as DNA gyrase
  • Generally bactericidal
  • May be broadly divided into two groups
    • Fluoroquinolones
    • Other quinolones: Nalidixic acid, the oldest member, cinoxacin
mechanism
Mechanism
  • Penetrates bacterial cell easily
  • Inhibition of DNA gyrase
    • (in eukaroytes is called Topoisomerase II)
  • Prevents DNA replication
  • Blocks transcription
  • Resistance results from:
    • Increased efflux of drug
    • Altered DNA gyrase binding site
classes of quinolones
Classes of quinolones
  • 4 generations (plus!)
  • Earlier generations have narrower spectrum
  • 1st generation: Nalidixic acid, cinoxacin, oxolinic acid
  • 2nd generation: ciprofoxacin, enoxacin, ofloxacin, norfloxacin
  • 3rd : sparfloxacin, levofloxacin
  • 4th : gatifloxacin, sitafloxacin
slide33
ADME
  • General good absorption profile
  • Achieves peak plasma conc. 1-3 hrs
  • Food may reduce rate but not extent of absorption
  • Bioavailability ranges from 50-90%
  • Kidneys involved in excretion
clinical uses
Clinical uses
  • UTI
  • Travellers’ diarrhoea
  • Bone, joint soft tissues infections
  • Respiratory infections esp.
    • Legionella spp
    • Mycoplasma
  • Mycobacterium spp infections
  • Other organisms: Chlamydia, Brucella
slide35
ADRs
  • Peripheral neuropathy
  • Tendonitis and tendon rupture can occur
  • Rhabdomyolysis
  • SJS
  • Pseudomembranous colitis
  • Prolongation of QT interval
  • Not recommended in pre-pubertal b’cos of tendency to cause arthropathy
the macrolides1
The macrolides
  • Many membered lactone ring plus deoxy sugar
  • Bacteriostatic antibiotics
  • Inhibits protein synthesis (50S)
  • Resistance is usually plasmid mediated reduced
    • Erythromycin
    • Azithromycin
    • Clarithromycin
macrolides
macrolides
  • Spectrum of antibacterial activity
  • Mostly Gram +ve
  • Diphtheria
  • Mycoplasma
  • Legionella
  • Mycobacteria
  • Borrelia
macrolides1
Macrolides
  • Erythromycin base is susceptible to gastric acid inactivation
  • Thus, it is usually presented in enteric form
  • Poorly penetrates CNS but crosses placenta barrier
  • Plasma protein binding 70-90%
  • Half life is ~ 2 hours
  • Clinical uses include: Toxoplasmosis and cryptosporidiasis in HIV/AIDS
    • Chlamydia, mycoplasma, pertusis, tetanus, syphilis, H. pylori
erythromycin
Erythromycin

ADRs

  • Hypersensitivity reactions
  • Cholestatic jaundice*
  • Cardiac arrhythmias
  • Transient hearing loss

* Likened to hypersensitivity rxn. Starts ~10 days; GI disturbance; + fever; leukocytosis; eosinophilia; elevated liver enzymes

  • Interactions include inhibition of metabolism of: Digoxin, astemizole, carbamazepine, warfarin