Aminoglycosides
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Transcript Aminoglycosides
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
Streptomycin was the first to be discovered
in 1943 by Schatz, Bugie and Waksman
Other examples are:
Gentamicin*
Streptomycin
Amikacin
Neomycin
Netilmicin*
Tobramycin
Kanamycin
Paromomycin+
*Not from Streptomyce spp (from Actinomycetes spp)
+ Antiparasitic ( amoebiasis, cryptosporidiosis)
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
Gentamicin family–
–
–
–
Gent Ci,
Gent C1a and C2,
sisomicin and
Netilmicin (derivative of sisomicin)
Streptomycin family
– Streptomycin and
– dihydrostreptomycin.
– Contains streptidine instead of deoxystreptamine
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
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
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
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
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
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
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:
Pregnancy
Myasthenia gravis (MG)
Renal impairment
Parkinson’s dx
8th cranial nerve disease
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
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
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 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
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 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
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
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
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
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
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)
The Quinolones
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
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
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
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
UTI
Travellers’ diarrhoea
Bone, joint soft tissues infections
Respiratory infections esp.
– Legionella spp
– Mycoplasma
Mycobacterium spp infections
Other organisms: Chlamydia, Brucella
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 Macrolides
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
Spectrum of antibacterial activity
Mostly Gram +ve
Diphtheria
Mycoplasma
Legionella
Mycobacteria
Borrelia
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
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