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CMR COLLEGE OF PHARMACY
SEMINOR ONAmino glycosides and antibiotic
GUIDED BYDr. T. Rama Mohan ReddyM. Pharm P.HD
BY
M. Santosh Kumar
10T21ROO58
B-Section.
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INDEX
Chloramphenicol
Aminoglycosides
Streptomycin
Gentamicin
Tetracycline's
The Quinolones
The Macrolides
Erythromycin
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Aminoglycosides
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Intro
Group of antibiotics used in the treatment ofbacteria infections aerobic G-ve
Consists of 2 or more amino sugars and ahexose nucleus
Serious toxicity is a limiting factor for theirapplication
Streptomycinwas the first to be discoveredin 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(fromActinomycetes spp)
+ Antiparasitic ( amoebiasis, cryptosporidiosis)
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Famil ies:
Determined by the type of amino sugar
Neomycinthere are 3 amino sugars attached to
2-deoxystreptamine e.g Neo B, Paromomycin
Kanamycin family2 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 G+ve# organisms islimited
* in combination
# Strept pyogenes is highly resistant
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Mechanism of Action
Bactericidalantibiotics
Penetration involves active transport
Inhibition of protein synthesis by binding to
the 30S subunit of ribosomes
Causes misreading and prematuretermination of protein synthesis
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Resistance-
May be plasmid mediated inactivation bymicrobial enzymes or failure of drugpenetration
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 aswell as renal cortex
Vd increases inleukaemia 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 removeaminoglycosides
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Unwanted effects
Ototoxicity: netilmicin is reputed to be mildest onboth Vest and Audi. Functions*
Nephrotoxicity#
Other neurotoxic effectsoptic neuritis, peripheralneuritis, 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 fnmore
# 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 30minutes after a dose
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Caution in:
Pregnancy
Myasthenia gravis (MG)
Renal impairment
Parkinsons dx
8thcranial nerve disease
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Streptomycin
Usual dosage: 15-25 mg per Kg body wt IM
Therapeutic applications in:
Bacterial endocarditis from enterococcal andgroup D Strep
Tularemia
Plague Tuberculosis
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Gentamicin
Inexpensive and reliable efficacy
Usual dose; 3-5 mg per Kg body wt in 3divided doses daily
Therapeutic Applications: UTI, Pneumonia
(nosocomial), Peritonitis, meningitis andsepsis
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Tetracyclines
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Tetracyclines
Broad spectrum antibiotics (incl: Legionella spp,Ureaplasma, Mycoplasma, chlamydia plasmodium and rickettsialinfections)
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 smallintestine
Fasting improves abs while presence of food or divalentcations 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 < 8ug/ml)
Antimicrobial spectrum: Rickettsial, salmonella infections
Mechanism
Inhibition of protein synthesis via 50S subunit ofribosome**
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 20g)
Risk of leukaemia
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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 analogueof 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 oldestmember, 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
1stgeneration: Nalidixic acid, cinoxacin,oxolinic acid
2ndgeneration: 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 ofabsorption
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 oftendency to cause arthropathy
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The Macrolides
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The macrolides
Many membered lactone ring plus deoxysugar
Bacteriostatic antibiotics
Inhibits protein synthesis (50S)
Resistance is usually plasmid mediatedreduced
ErythromycinAzithromycin
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 acidinactivation
Thus, it is usually presented in enteric form
Poorly penetrates CNS but crosses placentabarrier
Plasma protein binding 70-90%
Half life is ~ 2 hours
Clinical uses include: Toxoplasmosis andcryptosporidiasis 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
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1. ^Aminoglycosidesat the US National Library of Medicine Medical Subject
Headings(MeSH)
2. ^"Bacterial 'battle for survival' leads to new antibiotic"(Press release).
Massachusetts Institute of Technology. February 26, 2008. Retrieved December
1, 2010.
3. ^Ryden, R; Moore (1977). "BJ".J Antimicrob Chemother3(6): 609
613. doi:10.1093/jac/3.6.609. PMID340441.
4. ^Kroppenstedt RM, Mayilraj S, Wink JM (Jun 2005). "Eight new species of
the genus Micromonospora, Micromonospora citrea sp. nov., Micromonospora
echinaurantiaca sp. nov., Micromonospora echinofusca sp. nov.
Micromonospora fulviviridis sp. nov., Micromonospora inyonensis sp. nov.,Micromonospora peucetia sp. nov., Micromonospora sagamiensis sp. nov., and
Micromonospora viridifaciens sp. nov". Syst Appl Microbiol.28(4): 328
39. doi:10.1016/j.syapm.2004.12.011. PMID15997706.
5. ^Paul M. Dewick (2009).Medicinal Natural Products: A Biosynthetic
Approach(3rd ed.). Wiley. ISBN0-470-74167-8.
References
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6.Falagas, Matthew E; Grammatikos, Alexandros P; Michalopoulos,Argyris (2008). "Potential of old-generation antibiotics to address current
need for new antibiotics".Expert Review of Anti-infective Therapy6(5):
593600.doi:10.1586/14787210.6.5.593. PMID18847400.
7.^Durante- Mangoni, Emanuele; Grammatikos, Alexandros; Utili,
Riccardo; Falagas, Matthew E. (2009). "Do we still need the
aminoglycosides?".International Journal of Antimicrobial Agents33(3):
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8.^Merck Manual > Bacteria and Antibacterial DrugsLast full
review/revision July 2009 by Matthew E. Levison, MD9.^Gautam Mehta and Bilal Iqbal. Clinical Medicine for the MRCP
PACES. Volume 1. Core Clinical Skills. Oxford University Press. 2010.
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