amino glyc o sides 4444

8/13/2019 Amino Glyc o Sides 4444

1/25

A SEMINAR

ON

AMINOGLYCOSIDES-ANTIBIOTICSA REVIEW WORK

Submitted to Jawaharlal Nehru Technological University, Hyderabad

In partial fulfillment for the award of the degree of

BACHELOR OF PHARMACY

By

M.SANTHOSH KUMAR

(10T21R0058)

Under the Guidance of

DR.T.RAMA MOHAN REDDY. M.Pharm, PH.D

Dept. Of MEDICINAL CHEMISTRY

(Approved by AICTE & PCI, Affiliated to JNTU, Hyderabad)

Kandlakoya (V), Medchal Road, Hyderabad -501401.


2/25

CMR COLLEGE OF PHARMACY

(Approved by AICTE and PCI)

(Affiliated to JNTUH)

CERTIFICATE

This is to certify that the seminar described in this review entitled

AMINOGLYCOSIDES-ANTIBIOTICSis submitted to JNTU, Hyderabad in

partial fulfillment of award of the Bachelor of Pharmacy. It is also certified that the

work was carried out by, M.SANTHOSH KUMAR (10T21R0058)CMRCollege of Pharmacy, kandlakoya, Medchal Road, Hyderabad under my guidance

and supervision during the academic year 2013-2014.

PRINCIPAL GUIDE

V. Uma maheshwar rao M.pharm, Ph.D. DR.T.RAMA MOHAN REDDY.M.Pharm, PH.D


3/25

CMR COLLEGE OF PHARMACY(Approved by AICTE and PCI)

(Affiliated to JNTUH)

DECLARATION

I hereby declare that the seminar entitled AMINOGLYCOSIDES-

ANTIBIOTICS is carried out by me under the guidance of DR.T.RAMA

MOHAN REDDY. M.Pharm, PH.D,Associate professor.

M.SANTHOSH KUMAR(10T21R0058)


4/25

AMINOGLYCOSIDES-ANTI BIOTICS

An aminoglycosideis a molecule or a portion of a molecule composed of amino-

modified sugars

The aminoglycoside antibiotics constitute an important category of antibacterial agents in the

Therapeutic armamentarium, e.g., streptomycins, neomycins, paramomycins, kanamycins,gentamycinsand the corresponding derivatives of these antibiotics.

These are a bunch of closely related chemically basic carbohydrates that are mostly water-

soluble.Their respective hydrochlorides and sulphates are crystalline in nature. They are found to be

effective in

inhibiting the growth of gram-positive as well as gram-negative bacteria. They are also effective

to a great extent against mycobacteria.

Group of antibiotics used in the treatment of bacterial infections aerobic G-ve Consists of 2 or more amino sugars and a hexose nucleus Serious toxicity is a limiting factor for their application Streptomycinwas the first to be discovered in 1943 by Schatz, Bugie and Waksman

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 semisyntheticAminoglycosides family

Gentamicin family- Gent Ci, Gent C1a and C2,


5/25

sisomicin Streptomycin family

Streptomycin and Dihydrostreptomycin. Contains streptidine instead of deoxystreptamine

Other examples are

Gentamicin* Streptomycin Amikacin Neomycin Netilmicin* Tobramycin Kanamycin Paromomycin+

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+veorganisms is limited

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


6/25

Resistance

May be plasmid mediated inactivation by microbial 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

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 Penetration of CNS: 10-25% of plasma level Accumulates in the perilymph and endolymph as well 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 remove aminoglycosides

Therapeutic drug monitoring

Necessary in:

Patients with life threatening infections Renal impairment


7/25

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 Parkinsons dx 8thcranial nerve disease

In general, they are prepared biosynthetically exclusively from an admixture of carbohydratecomponents of the fermentation media.

They usually act by causing interference with the reading of the genetic code.

A few typical examples cited earlier shall be discussed below:

STREPTOMYCIN

Usual dosage: 15-25 mg per Kg body wt IMTherapeutic applications in:

Bacterial endocarditis from enterococcal and group D Strep Tularemia Plague Tuberculosis


8/25

Streptomycin is chiefly employed in the treatment of tuberculosis in conjunction with other

drugs such as isoniazid and rifampicin.

Streptomycin and penicillin exert a synergistic action against bacteria and are usually employed

together in the treatment of subacute bacterial endocarditis caused byStreptococcus faecalis

It exerts bacteriostatic action in low concentrations and bactericidal in high concentrationsagainst a plethora of Gram-negative and Gram-positive organisms.

The only infection wherein this drug alone is the drug of choice aretularemia and bubonicplague. A combination with a tetracycline it may be employed in the treatment of brucellosis and

infections produced by Pseudomonas mallei. It is also an alternative drug of choice in the

treatment of chancroid, rat-bite fever and tuberculosis.

Streptomycin INN, Streptomycin Sulphate BAN, Streptomycin Sulfate USAN,


9/25

STREPTOMYCIN

5-(2,4-diguanidino-3,5,6-trihydroxy-cyclohexoxy)- 4-[4,5-dihydroxy-6-(hydroxymethyl)

-3-methylamino-tetrahydropyran-2-yl] oxy-3-hydroxy-2-methyl

-tetrahydrofuran-3-carbaldehyde

Dose.

For non-tuberculosis infections, usual, 1g per day up to 5 to 10 days.

Mechanism of Action.

The drug exerts its maximum effectiveness against the organism Mycobacteriumtuberculosis. Interestingly, the antibiotic is not a cure itself but has proved to be anexcellent and valuable adjunct to other modalities of therapeutic treatment for

tuberculosis.

It acquires a rapid development with respect to certain strains of microorganisms. The combined administration of streptomycin and penicillinhas been suggested to combat

infections which may be due to organisms that are sensitive to both these antibiotics.

The drug is neither absorbed nor destroyed appreciably in the GI tract.


10/25

SAR of Streptomycin.

The drug serves as a triacidic basedue to the presence of two characteristic chemicalentities, namely:

(a) two strongly basic guanido moieties.

(b) rather weakly basic methylamino function.

Furthermore, hydroxy-streptomycin differs from streptomycin in essentially having astrategically positioned OH moiety in place of one of the H-atoms of the streptose methyl

function.

Besides, streptomycin B (i.e., mannisido streptomycin) possesses a mannoseresidueattached to a glycosidic linkage via a OH moiety at C-4 of the N-methyl-L-

glucosamine functional group. The designated stereo chemical structure of the drug hasbeen reconfirmed via the total synthesis.

Treatment of diseases

Infective endocarditis caused by enterococcus when the organism is not sensitivetoGentamicin

Tuberculosis in combination with other anti-TB drugs. It is not the first-line treatment,except in medically under-served populations where the cost of more expensive

treatments is prohibitive.

Plague (Yersinia pestis)has historically been treated with it as the first-line treatment. Itis approved for this purpose by theU.S. Food and Drug Administration.

Inveterinary medicine, streptomycin is the first-line antibiotic for use againstgramnegativebacteria in large animals (horses,cattle,sheep,etc.). It is commonly combined

with procainepenicillin for intramuscular injection.

Side Effects of Use

Fever and rashes result from persistent use. The Vestibular portion of cranial nerve VIII (the vestibulococlear nerve) can be

affected, resulting intinitus,vertigo andataxia.

It can also lead tonephrotoxicity.
http://en.wikipedia.org/wiki/Infective_endocarditishttp://en.wikipedia.org/wiki/Gentamicinhttp://en.wikipedia.org/wiki/Tuberculosishttp://en.wikipedia.org/wiki/Plague_(disease)http://en.wikipedia.org/wiki/Yersinia_pestishttp://en.wikipedia.org/wiki/U.S._Food_and_Drug_Administrationhttp://en.wikipedia.org/wiki/Veterinary_medicinehttp://en.wikipedia.org/wiki/Gram_negativehttp://en.wikipedia.org/wiki/Gram_negativehttp://en.wikipedia.org/wiki/Horseshttp://en.wikipedia.org/wiki/Cattlehttp://en.wikipedia.org/wiki/Sheephttp://en.wikipedia.org/wiki/Penicillinhttp://en.wikipedia.org/wiki/Tinitushttp://en.wikipedia.org/wiki/Vertigohttp://en.wikipedia.org/wiki/Ataxiahttp://en.wikipedia.org/wiki/Nephrotoxicityhttp://en.wikipedia.org/wiki/Nephrotoxicityhttp://en.wikipedia.org/wiki/Ataxiahttp://en.wikipedia.org/wiki/Vertigohttp://en.wikipedia.org/wiki/Tinitushttp://en.wikipedia.org/wiki/Penicillinhttp://en.wikipedia.org/wiki/Sheephttp://en.wikipedia.org/wiki/Cattlehttp://en.wikipedia.org/wiki/Horseshttp://en.wikipedia.org/wiki/Gram_negativehttp://en.wikipedia.org/wiki/Gram_negativehttp://en.wikipedia.org/wiki/Veterinary_medicinehttp://en.wikipedia.org/wiki/U.S._Food_and_Drug_Administrationhttp://en.wikipedia.org/wiki/Yersinia_pestishttp://en.wikipedia.org/wiki/Plague_(disease)http://en.wikipedia.org/wiki/Tuberculosishttp://en.wikipedia.org/wiki/Gentamicinhttp://en.wikipedia.org/wiki/Infective_endocarditis


11/25

NEOMYCIN

Neomycin is mostly used in a wide variety of local infection such as burns, ulcers,wounds,

Impetigo, infected dermatoses, furunculosis, conjunctivitis, etc. It is also employed as an adjuvant intopical steroid preparations to control secondary

infections in the case of inflammatory disorders.

The drug is employed to produce intestinal antisepsis prior to large bowel surgery, forthetreatment of gastroenteritis produced by toxigenic E. coli, and also to affordsuppression of ammoniaproducing bowel flora in the management of hepatic coma.

As it causes a rapid overgrowth of nonsusceptible organism, including staphylococci, oraltherapy must not be prolonged in any case formore than 3 days.

It displays broad-spectrum activity against a good number of pathogenic organisms. Besides, it demostrates a low incidence of toxic and hypersensitivity reactions.

Neomycin INN, Neomycin Sulphate BAN, Neomycin Sulphate USAN,


12/25

NEOMYCIN

2S,3S,4S,5R)-5-amino-2-(aminomethyl)-6-((2R,3S,4R,5S)-5-((1R,2R,5R,6R)-3,5-diamino-2-

((2R,3S,4R,5S)-3-amino-6-(aminomethyl)-4,5-dihydroxytetrahydro-2H-pyran-2-yloxy)-6-

hydroxycyclohexyloxy)-4-hydroxy-2-(hydroxymethyl)tetrahydrofuran-3-yloxy)tetrahydro-2H-pyran-3,4-diol

Dose:

Topical, to the skin, as 5% solution, aerosol or ointment 2 to 3 times a day.


The drug usually gets absorbed very rarely from the digestive system;Therefore, its oral administration primarily fails to produce any substantial systemic effect.

SAR of Neomycin.

The structures of neomycin A (neamine), neomycin B and neomycin C have beenestablished besides, the absolute configurational structures of neomycin and neamine

have been reported.


13/25

It has been demonstrated that neamine could be obtained by the methanolysis ofneomycin B and C respectively, whereby the glycosidic linkage existing between D-

ribose and deoxystreptamine undergoes cessation.

Spectrum

Similar to other aminoglycosides, neomycin has excellent activity againstGram-negative bacteria,and has partial activity againstGram-positive bacteria.

It is relatively toxic to humans, and many people have allergic reactions toit.Hypersensitivity. Physicians sometimes recommend using antibiotic ointments

without neomycin, such asPolysporin.

History

Neomycin was discovered in 1949 by the microbiologistSelman Waksmanand hisstudent Hubert Lechevalier at Rutgers University.

It is produced naturally by the bacteriumStreptomyces fradiae.Neomycin as a DNA binder

Neomycin belongs to the family of aminoglycosides. Aminoglycosides are known for their ability to bind to duplex RNA with high affinity. A study done by Daniel Pilch, Associate Professor Dept. of Pharmacology at Rutgers

University, and his coworkers determined the association constant for neomycin with A-site RNA was found to be in the ~10

9M

-1range.

However, more than 50 years after its discovery, its DNA-binding properties were stillunknown. In 2000, Dev P. Arya, currently Director of the Laboratory of Medicinal

Chemistry at Clemson University, and his coworkers discovered that neomycin inducesenormous thermal stabilization of triplex DNA while having little or almost no effect on

the B-DNA duplex stabilization.

They also showed that neomycin binds to structures that adopt A-form structure, triplexDNA being one of them. They later went on to show that neomycin even induces DNA:RNA hybrid triplex formation.

Molecular biology

Neomycin resistance is conferred by either one of two aminoglycosidephosphotransferase genes.

A neo gene is commonly included in DNAplasmids used by molecular biologists toestablish stable mammaliancell lines expressing cloned proteins in culture; manycommercially available protein expression plasmids contain neo as aselectable marker.

Non-transfectedcells will eventually die off when the culture is treated with neomycin orsimilar antibiotic. Neomycin orkanamycin can be used forprokaryotes,

butgeneticin (G418) is, in general, needed foreukaryotes.
http://en.wikipedia.org/wiki/Gram-negative_bacteriahttp://en.wikipedia.org/wiki/Gram-negative_bacteriahttp://en.wikipedia.org/wiki/Gram-positive_bacteriahttp://en.wikipedia.org/wiki/Hypersensitivityhttp://en.wikipedia.org/wiki/Polysporinhttp://en.wikipedia.org/wiki/Selman_Waksmanhttp://en.wikipedia.org/wiki/Selman_Waksmanhttp://en.wikipedia.org/wiki/Streptomyces_fradiaehttp://en.wikipedia.org/wiki/Streptomyces_fradiaehttp://en.wikipedia.org/wiki/Plasmidhttp://en.wikipedia.org/wiki/Cell_linehttp://en.wikipedia.org/wiki/Selectable_markerhttp://en.wikipedia.org/wiki/Transfecthttp://en.wikipedia.org/wiki/Kanamycinhttp://en.wikipedia.org/wiki/Prokaryoteshttp://en.wikipedia.org/wiki/Geneticinhttp://en.wikipedia.org/wiki/Eukaryoteshttp://en.wikipedia.org/wiki/Eukaryoteshttp://en.wikipedia.org/wiki/Geneticinhttp://en.wikipedia.org/wiki/Prokaryoteshttp://en.wikipedia.org/wiki/Kanamycinhttp://en.wikipedia.org/wiki/Transfecthttp://en.wikipedia.org/wiki/Selectable_markerhttp://en.wikipedia.org/wiki/Cell_linehttp://en.wikipedia.org/wiki/Plasmidhttp://en.wikipedia.org/wiki/Streptomyces_fradiaehttp://en.wikipedia.org/wiki/Selman_Waksmanhttp://en.wikipedia.org/wiki/Polysporinhttp://en.wikipedia.org/wiki/Hypersensitivityhttp://en.wikipedia.org/wiki/Gram-positive_bacteriahttp://en.wikipedia.org/wiki/Gram-negative_bacteriahttp://en.wikipedia.org/wiki/Gram-negative_bacteria


14/25

Uses

Neomycin is overwhelmingly used as atopicalpreparation, such asNeosporin. It can also be given orally, where it is usually combined with other antibiotics. Neomycin is not absorbed from the gastrointestinal tract and has been used as a

preventive measure forhepatic encephalopathy andhypercholesterolemia.

By killing bacteria in the intestinal tract, it keeps ammonia levels low and preventshepatic encephalopathy, especially prior to GI surgery.

It has also been used to treatsmall intestinal bacterial overgrowth. It is not given intravenously, as neomycin is

extremelynephrotoxic (causeskidney damage), especially compared tootheraminoglycosides.

The exception is when neomycin is included, in very small quantities, as a preservative insome vaccines - typically 0.025 mg per dose.

KANAMYCIN

Kanamycin(also known as kanamycin A) is anaminoglycosidebactericidalantibiotic,

available inoral,intravenous, and intramuscular forms, and used to treat a wide variety

ofinfections. Kanamycin is isolated from the bacteriumStreptomyces kanamyceticus and itsmost commonly used form is kanamycinsulfate.

It is effective against some Mycoplasma and gram-positive bacteria, for instance,Staphylococcus

Pyogenes and Staphylococcus epidermidis. Along with penicillinit is found to be effective against Streptomyces fecalis. It is used invariably either alone or in combination with other drugs for a variety of

disorders, namely: acute staphylococcal infections, gonorrhea, tuberculosis, acute urinary

tract infections, for bowl sterilization in hepatic coma and also prior to bowl surgery.

Side effects

Seriousside effects include tinnitus or loss of hearing,toxicity to kidneys,andallergic reactions to thedrug

pain or irritation where the injection was given; mild skin rash; headache; fever; or nausea, vomiting.
http://en.wikipedia.org/wiki/Topicalhttp://en.wikipedia.org/wiki/Neosporinhttp://en.wikipedia.org/wiki/Neosporinhttp://en.wikipedia.org/wiki/Hepatic_encephalopathyhttp://en.wikipedia.org/wiki/Hypercholesterolemiahttp://en.wikipedia.org/wiki/Small_intestinal_bacterial_overgrowthhttp://en.wikipedia.org/wiki/Nephrotoxichttp://en.wikipedia.org/wiki/Kidneyhttp://en.wikipedia.org/wiki/Aminoglycosidehttp://en.wikipedia.org/wiki/Aminoglycosidehttp://en.wikipedia.org/wiki/Bacteriocidalhttp://en.wikipedia.org/wiki/Antibiotichttp://en.wiktionary.org/wiki/oralhttp://en.wikipedia.org/wiki/Intravenoushttp://en.wikipedia.org/wiki/Infectionhttp://en.wikipedia.org/wiki/Streptomyces_kanamyceticushttp://en.wikipedia.org/wiki/Sulfatehttp://en.wikipedia.org/wiki/Adverse_effect_(medicine)http://en.wikipedia.org/wiki/Toxicity_to_kidneyshttp://en.wikipedia.org/wiki/Allergichttp://en.wikipedia.org/wiki/Medicationhttp://en.wikipedia.org/wiki/Medicationhttp://en.wikipedia.org/wiki/Medicationhttp://en.wikipedia.org/wiki/Allergichttp://en.wikipedia.org/wiki/Toxicity_to_kidneyshttp://en.wikipedia.org/wiki/Adverse_effect_(medicine)http://en.wikipedia.org/wiki/Sulfatehttp://en.wikipedia.org/wiki/Streptomyces_kanamyceticushttp://en.wikipedia.org/wiki/Infectionhttp://en.wikipedia.org/wiki/Intravenoushttp://en.wiktionary.org/wiki/oralhttp://en.wikipedia.org/wiki/Antibiotichttp://en.wikipedia.org/wiki/Bacteriocidalhttp://en.wikipedia.org/wiki/Aminoglycosidehttp://en.wikipedia.org/wiki/Aminoglycosidehttp://en.wikipedia.org/wiki/Kidneyhttp://en.wikipedia.org/wiki/Nephrotoxichttp://en.wikipedia.org/wiki/Small_intestinal_bacterial_overgrowthhttp://en.wikipedia.org/wiki/Hypercholesterolemiahttp://en.wikipedia.org/wiki/Hepatic_encephalopathyhttp://en.wikipedia.org/wiki/Neosporinhttp://en.wikipedia.org/wiki/Topical


15/25

Kanamycin INN, Kanamycin Sulphate BAN, Kanamycin Sulfate USAN,


16/25

KANAMYCIN

2-(aminomethyl) - 6-[4,6-diamino-3- [4-amino-3,5-dihydroxy-6-(hydroxymethyl)

tetrahydropyran-2-yl]oxy- 2-hydroxy- cyclohexoxy]- tetrahydropyran- 3,4,5-triol

In US the use of kanamycin is normally restricted to the infections related to theintestinal tract, such as: bacillary dysentry; systemic infections caused due to Gram-negative bacili, such as Klebsiella, Proteus, Enterobacter, and Serratia spp., which have

developed resistance to some other antibiotics. It has also been indicated for preoperative

antisepsis of the bowel. However, this drug could not be useful in tuberculosi s perhapsdue to the fact that it develops resistance to mycoorganism rather rapidly.

Dose :

(Base equivalent)-Oral, adult, for intestinal infection, 1g after every 8 hours for 5 to 7days ; For preparative preparations, 1g every hour for 4 doses followed by 1g every 6

hours for 36 to 72 hours.


Based on both clinical experience and experimental demonstration it has been dulyobserved that the drug develops cross-resistance overwhelmingly in the tubercle bacilli

specifically along with some other medicinal entities, such as: vincomycin,

dihydrostreptomycin and antitubercular drug substances.

SAR of Kanamycin.

Kanamycins A, B and C i.e., the three closely related analogues of kanamycin have beenduly established by the aid of chromatography.

Kanamycin A is the drug available for therapeutic usage.


17/25

It has been proved that the vital point of difference amongst the kanamycins residessolely in the sugar residuces strategically linked to the glycosidic oxygen at the C-4

position of the central deoxystreptamine.

Interestingly, the kanamycins do not essentially possess the D-ribose residue as ispresent in neomycins and paromomycins. In all the three structural variants of kanamycinthe presence of kanosamine entity is found to be attached glycosidically at the C-6

position of deoxystreptamine i.e., 3-D-glucosamine.

They also differ in the substituted D-glucoses which are observed to be attachedglycosidically at the C-4 position of the inherent deoxystreptamine ring.

Uses in research

Kanamycin is used in molecular biology as a selective agent most commonly toisolatebacteria (e.g.,E. coli)which have taken up genes (e.g., ofplasmids)coupled to a

gene coding for kanamycin resistance (primarily Neomycin phosphotransferase II [NPT

II/Neo]).

Bacteria that have beentransformed with a plasmid containing the kanamycin resistancegene are plated on kanamycin (50-100 ug/ml) containingagarplates or are grown in

media containing kanamycin (50-100 ug/ml).

Only the bacteria that have successfully taken up the kanamycin resistance gene becomeresistant and will grow under these conditions.

As a powder kanamycin is white to off-white and is soluble in water (50 mg/ml). Mammalian cells and othereukaryotes are screened usingG418, a similar

aminoglycoside antibiotic, which KanMX confers resistance against. At least one such gene,Atwbc19is native to a plant species, of comparatively large size

and its coded protein acts in a manner which decreases the possibility of transfer from the

plant to bacteria; it may be incapable of giving resistance to bacteria even if gene transfer

occurs.

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.
http://en.wikipedia.org/wiki/Bacteriahttp://en.wikipedia.org/wiki/E._colihttp://en.wikipedia.org/wiki/Plasmidhttp://en.wikipedia.org/wiki/Transformation_(genetics)http://en.wikipedia.org/wiki/Agarhttp://en.wikipedia.org/wiki/Eukaryotehttp://en.wikipedia.org/wiki/Geneticinhttp://en.wikipedia.org/wiki/Geneticinhttp://en.wikipedia.org/wiki/Eukaryotehttp://en.wikipedia.org/wiki/Agarhttp://en.wikipedia.org/wiki/Transformation_(genetics)http://en.wikipedia.org/wiki/Plasmidhttp://en.wikipedia.org/wiki/E._colihttp://en.wikipedia.org/wiki/Bacteria


18/25

TETRACYCLINES

Broad spectrum antibiotics (incl: Legionella spp, Ureaplasma, Mycoplasma, chlamydiaplasmodium and rickettsial infections)

Origin: Streptomyces spp Examples: Chlortetracycline, demeclocyline, oxytetracycline, doxycline, tetracycline,

minocycline

Mechanism of action:

Binding of the 30S subunit of ribosome, preventing the access of aminoacyltRNA to theacceptor 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


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

Ricketsial infections Mycoplasma Chlamydia

Unwanted effects

GI upset including abd pain, nausea, vomiting diarrhea Photosensitivity Hepatotoxicity Renal toxicity Teeth and bone discolouration Skin rashes Pseudomembranous colitis


19/25

Thrombophlebitis (IV) Pseudo-tumourcerebri Leukopenia, Thrombocytopenic purpura

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 ribosomeResistance

Plasmid mediated elaboration of inactivating enzymes (acetyl transferase) 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%); 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)


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); Graysyndrome


20/25

Jarisch_Hexheimer reactions when used in brucellosis Bone marrow suppression:

o presents with low Hb;o does not predict Aplastic anaemia,o dose dependent (>20g)

Risk of leukaemia

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

QUINOLONES

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


21/25

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


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.

o Legionella sppo 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 bcos of tendency to cause arthropathy


22/25

MACROLIDES

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

o Erythromycino Azithromycino Clarithromycin

Spectrum of antibacterial activity Mostly Gram +ve Diphtheria Mycoplasma Legionella Mycobacteria

Borelli 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 cryptosporidiosis in HIV/AIDS

o Chlamydia, mycoplasma, pertusis, tetanus, syphilis, H. pyloriARBEKACIN

Arbekacin(INN)is a semisyntheticaminoglycosideantibiotic. It is primarily used for the treatment of infections caused by multi-resistant bacteria

includingmethicillin-resistant Staphylococcus aureus (MRSA).

Arbekacin was originally synthesized fromdibekacin in 1973. It has been registered and marketed in Japan since 1990 under the trade name Habekacin. Arbekacin is no longer covered by patent and generic versions of the drug are also

available under such trade names as Decontasin and Blubatosine.

Mechanism of action

Aminoglycosides, such as 'Arbekacin, inhibit protein synthesis in susceptible bacteria byirreversibly binding to bacterial 30S and 16S ribosomal subunits.

Specifically Arbekacin binds to four nucleotides of 16S rRNA and a single amino acid ofprotein S12.

This interferes with decoding site in the vicinity of nucleotide 1400 in 16S rRNA of 30Ssubunit.

This region interacts with the wobble base in the anticodon of tRNA.
http://en.wikipedia.org/wiki/International_Nonproprietary_Namehttp://en.wikipedia.org/wiki/Aminoglycosidehttp://en.wikipedia.org/wiki/Antibiotichttp://en.wikipedia.org/wiki/Methicillin-resistant_Staphylococcus_aureushttp://en.wikipedia.org/wiki/Dibekacinhttp://en.wikipedia.org/wiki/Dibekacinhttp://en.wikipedia.org/wiki/Methicillin-resistant_Staphylococcus_aureushttp://en.wikipedia.org/wiki/Antibiotichttp://en.wikipedia.org/wiki/Aminoglycosidehttp://en.wikipedia.org/wiki/International_Nonproprietary_Name


23/25

This leads to misreading of mRNA so incorrect amino acids are inserted into thepolypeptide leading to nonfunctional or toxic peptides and the breakup of polysomes into

nonfunctionalmonosomes.

Toxicity

Ototoxicity and nephrotoxicity are the most serious adverse effects of aminoglycosidetherapy and are more likely to occur in patients with a history of renal impairment or who

are receiving other ototoxic and/or nephrotoxic drugs.

Normal duration of IM or IV aminoglycoside therapy is 7-10 days Although a longer duration may be necessary in some cases, toxicity is more likely to

occur when aminoglycoside treatment is continued for longer than 10 days.

PAROMOMYCIN

Paromomycinis anaminoglycoside antibiotic, first isolated from Streptomyces

krestomuceticus in the 1950s. It was discovered byParke Davis nowPfizer and introduced

asHumatin in 1960.It is also called monomycinand aminosidine;

Mechanism

Paromomycin is aprotein synthesis inhibitor in non-resistant cells by bindingto16Sribosomal RNA.This broad spectrum antibiotic soluble in water, is very similar in

action to Neomycin.

Antimicrobial activity of Paromomycin againstEscherichia coli andStaphylococcusaureus has been shown.

PAROMOMYCIN

6-diamino-2-[(2S, 3R, 4R, 5R)-4-[(2R, 3R, 4R, 5R, 6S)-3-amino-6-(amino methyl)-4
http://en.wikipedia.org/wiki/Aminoglycosidehttp://en.wikipedia.org/wiki/Parke_Davishttp://en.wikipedia.org/wiki/Pfizerhttp://en.wikipedia.org/wiki/Protein_synthesis_inhibitorhttp://en.wikipedia.org/wiki/16S_ribosomal_RNAhttp://en.wikipedia.org/wiki/Ribosomal_RNAhttp://en.wikipedia.org/wiki/Escherichia_colihttp://en.wikipedia.org/wiki/Staphylococcus_aureushttp://en.wikipedia.org/wiki/Staphylococcus_aureushttp://en.wikipedia.org/wiki/Staphylococcus_aureushttp://en.wikipedia.org/wiki/Staphylococcus_aureushttp://en.wikipedia.org/wiki/Escherichia_colihttp://en.wikipedia.org/wiki/Ribosomal_RNAhttp://en.wikipedia.org/wiki/16S_ribosomal_RNAhttp://en.wikipedia.org/wiki/Protein_synthesis_inhibitorhttp://en.wikipedia.org/wiki/Pfizerhttp://en.wikipedia.org/wiki/Parke_Davishttp://en.wikipedia.org/wiki/Aminoglycoside


24/25

Uses

It is an antibiotic used to treat intestinal infections suchascryptosporidiosis andamoebiasis,and other diseases likeleishmaniasis.

Paromomycin was demonstrated to be effective againstcutaneous leishmaniasis inclinical studies in theUSSR in the 1960s, and in trials withvisceral leishmaniasis in the

early 1990s.

The route of administration isintramuscular injection andcapsule.Paromomycin topical cream with or without gentamicin is an effective treatment for

ulcerative cutaneous leishmaniasis, according to the results of a phase 3, randomized,

double-blind, parallel groupcontrolled trial.
http://en.wikipedia.org/wiki/Cryptosporidiosishttp://en.wikipedia.org/wiki/Amoebiasishttp://en.wikipedia.org/wiki/Leishmaniasishttp://en.wikipedia.org/wiki/Cutaneous_leishmaniasishttp://en.wikipedia.org/wiki/USSRhttp://en.wikipedia.org/wiki/Visceral_leishmaniasishttp://en.wikipedia.org/wiki/Intramuscular_injectionhttp://en.wikipedia.org/wiki/Capsule_(pharmacy)http://en.wikipedia.org/wiki/Capsule_(pharmacy)http://en.wikipedia.org/wiki/Intramuscular_injectionhttp://en.wikipedia.org/wiki/Visceral_leishmaniasishttp://en.wikipedia.org/wiki/USSRhttp://en.wikipedia.org/wiki/Cutaneous_leishmaniasishttp://en.wikipedia.org/wiki/Leishmaniasishttp://en.wikipedia.org/wiki/Amoebiasishttp://en.wikipedia.org/wiki/Cryptosporidiosis


25/25

REFERENCES

1. Aminoglycosides at 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 PMID 340441

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., Micromonosporainyonensis 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. PMID 15997706

5. Paul M. Dewick (2009).Medicinal Natural Products: A Biosynthetic Approach (3rd ed.).

While. ISBN 0-470-74167-8

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. PMID 18847400

7.Durante- Mangoni, Emanuele; Grammatikos, Alexandros; Utili, Riccardo; Falagas, Matthew

E. (2009). "Do we still need the aminoglycosides?.International Journal of Antimicrobial

Agents33(3): 2015.doi:10.1016/j.ijantimicag.2008.09.001. PMID 18976888

8. Merck Manual > Bacteria and Antibacterial Drugs Last full review/revision July 2009 by

Matthew E. Levison, MD

9. Gautam Mehta and Bilal Iqbal. Clinical Medicine for the MRCP PACES. Volume 1. Core

Clinical Skills. Oxford University Press. 2010.

amino glyc o sides 4444

Documents