Aminoglycosides

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Aminoglycosides
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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

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Other examples are

• Gentamicin
• Streptomycin
• Amikacin
• Neomycin
• Netilmicin
• Tobramycin
• Kanamycin
• Paromomycin
• Not from Streptomyce spp (from Actinomycetes
  spp)
• Antiparasitic ( amoebiasis, cryptosporidiosis)

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• 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

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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

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• 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 Gve
  organisms is limited
• in combination
• Strept pyogenes is highly resistant

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• 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

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• 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

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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

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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

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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

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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

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Caution in

• Pregnancy
• Myasthenia gravis (MG)
• Renal impairment
• Parkinsons dx
• 8th cranial nerve disease

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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

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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

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• Tetracyclines

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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

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• 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

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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

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• 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

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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

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• Chloramphenicol

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Chloramphenicol

• Broad spectrum antibiotic (MIC for sensitive
  strains lt 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

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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

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Chloramphenicol

• Usual oral dose 50 mg per kg
• IV usually 75 mg per kg
• Drug level to be monitored in neonates to lt 4 yrs
  old, elderly, renal impaired patients
• Recommended peak level 15-25 mg/ml (sample taken
  1 hr after dose)
• Trough level lt 15mg/kg (sample taken b4 next dose)

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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

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• 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 (gt20g)
• Risk of leukaemia

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ADRs

• Bone marrow aplasia
• Not dose dependent
• Unpredictable
• commonest with oral (124000, 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)

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The Quinolones
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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

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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

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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

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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

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Clinical uses

• UTI
• Travellers diarrhoea
• Bone, joint soft tissues infections
• Respiratory infections esp.
• Legionella spp
• Mycoplasma
• Mycobacterium spp infections
• Other organisms Chlamydia, Brucella

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ADRs

• Peripheral neuropathy
• Tendonitis and tendon rupture can occur
• Rhabdomyolysis
• SJS
• Pseudomembranous colitis
• Prolongation of QT interval
• Not recommended in pre-pubertal bcos of tendency
  to cause arthropathy

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The Macrolides
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The macrolides

• Many membered lactone ring plus deoxy sugar
• Bacteriostatic antibiotics
• Inhibits protein synthesis (50S)
• Resistance is usually plasmid mediated reduced
• Erythromycin
• Azithromycin
• Clarithromycin

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macrolides

• Spectrum of antibacterial activity
• Mostly Gram ve
• Diphtheria
• Mycoplasma
• Legionella
• Mycobacteria
• Borrelia

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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

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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