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:
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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
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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:
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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
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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)
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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
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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
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UTI
Travellers’ diarrhoea
Bone, joint soft tissues infections
Respiratory infections esp.
– Legionella spp
– Mycoplasma
 Mycobacterium spp infections
 Other organisms: Chlamydia, Brucella
ADRs
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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
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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