A SEMINAR ON

AMINOGLYCOSIDES-ANTIBIOTICS
A 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.

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-ANTIBIOTICS is 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) CMR College of Pharmacy, kandlakoya, Medchal Road, Hyderabad under my guidance and supervision during the academic year 2013-2014.

PRINCIPAL V. Uma maheshwar rao M.pharm, Ph.D.

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

CMR COLLEGE OF PHARMACY

(Approved by AICTE and PCI) (Affiliated to JNTUH)

DECLARATION

I hereby declare that the seminar entitled AMINOGLYCOSIDESANTIBIOTICS is carried out by me under the guidance of DR.T.RAMA

MOHAN REDDY.

M.Pharm, PH.D,

Associate professor.

M.SANTHOSH KUMAR

(10T21R0058)

AMINOGLYCOSIDES-ANTI BIOTICS

An aminoglycoside is a molecule or a portion of a molecule composed of aminomodified sugars The aminoglycoside antibiotics constitute an important category of antibacterial agents in the Therapeutic armamentarium, e.g., streptomycins, neomycins, paramomycins, kanamycins, gentamycins and the corresponding derivatives of these antibiotics. These are a bunch of closely related chemically basic carbohydrates that are mostly watersoluble. 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 Streptomycin was 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 semisynthetic

Aminoglycosides family
Gentamicin family Gent Ci, Gent C1a and C2,

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+ve organisms 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

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 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

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 Parkinsons dx 8th cranial nerve disease

In general, they are prepared biosynthetically exclusively from an admixture of carbohydrate components 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 IM

Therapeutic applications in:

Bacterial endocarditis from enterococcal and group D Strep Tularemia Plague Tuberculosis

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 by Streptococcus faecalis It exerts bacteriostatic action in low concentrations and bactericidal in high concentrations against a plethora of Gram-negative and Gram-positive organisms. The only infection wherein this drug alone is the drug of choice aretularemia and bubonic plague. 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,

STREPTOMYCIN
5-(2,4-diguanidino-3,5,6-trihydroxy-cyclohexoxy)-3-methylamino-tetrahydropyran-2-yl] -tetrahydrofuran-3-carbaldehyde 4-[4,5-dihydroxy-6-(hydroxymethyl) oxy-3-hydroxy-2-methyl

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 Mycobacterium tuberculosis. Interestingly, the antibiotic is not a cure itself but has proved to be an excellent 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.

SAR of Streptomycin.
The drug serves as a triacidic basedue to the presence of two characteristic chemical entities, namely: (a) two strongly basic guanido moieties. (b) rather weakly basic methylamino function. Furthermore, hydroxy-streptomycin differs from streptomycin in essentially having a strategically 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 mannose residueattached to a glycosidic linkage via a OH moiety at C-4 of the N-methyl-Lglucosamine functional group. The designated stereo chemical structure of the drug has been reconfirmed via the total synthesis.

Treatment of diseases
Infective endocarditis caused by enterococcus when the organism is not sensitive to Gentamicin 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. It is approved for this purpose by the U.S. Food and Drug Administration. In veterinary medicine, streptomycin is the first-line antibiotic for use against gram negative bacteria 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 in tinitus, vertigo and ataxia. It can also lead to nephrotoxicity.

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, for thetreatment of gastroenteritis produced by toxigenic E. coli, and also to afford suppression of ammoniaproducing bowel flora in the management of hepatic coma. As it causes a rapid overgrowth of nonsusceptible organism, including staphylococci, oral therapy 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,

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)-6hydroxycyclohexyloxy)-4-hydroxy-2-(hydroxymethyl)tetrahydrofuran-3-yloxy)tetrahydro-2Hpyran-3,4-diol

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

Mechanism of Action.
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 been established besides, the absolute configurational structures of neomycin and neamine have been reported.

It has been demonstrated that neamine could be obtained by the methanolysis of neomycin B and C respectively, whereby the glycosidic linkage existing between Dribose and deoxystreptamine undergoes cessation.

Spectrum
Similar to other aminoglycosides, neomycin has excellent activity against Gramnegative bacteria, and has partial activity against Gram-positive bacteria. It is relatively toxic to humans, and many people have allergic reactions to it.Hypersensitivity. Physicians sometimes recommend using antibiotic ointments without neomycin, such as Polysporin.

History
Neomycin was discovered in 1949 by the microbiologist Selman Waksman and his student Hubert Lechevalier at Rutgers University. It is produced naturally by the bacterium Streptomyces 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 Asite RNA was found to be in the ~109 M-1 range. However, more than 50 years after its discovery, its DNA-binding properties were still unknown. In 2000, Dev P. Arya, currently Director of the Laboratory of Medicinal Chemistry at Clemson University, and his coworkers discovered that neomycin induces enormous 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, triplex DNA 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 aminoglycoside phosphotransferase genes. A neo gene is commonly included in DNA plasmids used by molecular biologists to establish stable mammalian cell lines expressing cloned proteins in culture; many commercially available protein expression plasmids contain neo as a selectable marker. Non-transfectedcells will eventually die off when the culture is treated with neomycin or similar antibiotic. Neomycin or kanamycin can be used for prokaryotes, but geneticin (G418) is, in general, needed foreukaryotes.

Uses
Neomycin is overwhelmingly used as a topical preparation, such as Neosporin. 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 for hepatic encephalopathy and hypercholesterolemia. By killing bacteria in the intestinal tract, it keeps ammonia levels low and prevents hepatic encephalopathy, especially prior to GI surgery. It has also been used to treat small intestinal bacterial overgrowth. It is not given intravenously, as neomycin is extremely nephrotoxic (causes kidney damage), especially compared to other aminoglycosides. The exception is when neomycin is included, in very small quantities, as a preservative in some vaccines - typically 0.025 mg per dose.

KANAMYCIN
Kanamycin (also known as kanamycin A) is an aminoglycoside bactericidal antibiotic, available in oral, intravenous, and intramuscular forms, and used to treat a wide variety of infections. Kanamycin is isolated from the bacterium Streptomyces kanamyceticus and its most commonly used form is kanamycin sulfate. 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
Serious side effects include tinnitus or loss and allergic reactions to the drug pain or irritation where the injection was given; mild skin rash; headache; fever; or nausea, vomiting. of hearing, toxicity to kidneys,

Kanamycin INN, Kanamycin Sulphate BAN, Kanamycin Sulfate USAN,

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 the intestinal tract, such as: bacillary dysentry; systemic infections caused due to Gramnegative 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 perhaps due 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 7 days ; For preparative preparations, 1g every hour for 4 doses followed by 1g every 6 hours for 36 to 72 hours.

Mechanism of Action.
Based on both clinical experience and experimental demonstration it has been duly observed 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 been duly established by the aid of chromatography. Kanamycin A is the drug available for therapeutic usage.

It has been proved that the vital point of difference amongst the kanamycins resides solely 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 is present in neomycins and paromomycins. In all the three structural variants of kanamycin the 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 attached glycosidically 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 to isolate bacteria (e.g., E. coli) which have taken up genes (e.g., of plasmids) coupled to a gene coding for kanamycin resistance (primarily Neomycin phosphotransferase II [NPT II/Neo]). Bacteria that have been transformed with a plasmid containing the kanamycin resistance gene are plated on kanamycin (50-100 ug/ml) containing agar plates or are grown in media containing kanamycin (50-100 ug/ml). Only the bacteria that have successfully taken up the kanamycin resistance gene become resistant 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 other eukaryotes are screened using G418, aminoglycoside antibiotic, which KanMX confers resistance against. a similar

At least one such gene, Atwbc19 is 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.

TETRACYCLINES
Broad spectrum antibiotics (incl: Legionella spp, Ureaplasma, Mycoplasma, chlamydia plasmodium 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 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

Absorption, Distribution 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+ 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

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 ribosome

Resistance
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)

Absorption, Distribution and Elimination

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: 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

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

Absorption, Distribution and Elimination

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 spp o 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

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

ARBEKACIN
Arbekacin (INN) is a semisynthetic aminoglycoside antibiotic. It is primarily used for the treatment of infections caused by multi-resistant bacteria including methicillin-resistant Staphylococcus aureus (MRSA). Arbekacin was originally synthesized from dibekacin 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 by irreversibly binding to bacterial 30S and 16S ribosomal subunits. Specifically Arbekacin binds to four nucleotides of 16S rRNA and a single amino acid of protein S12. This interferes with decoding site in the vicinity of nucleotide 1400 in 16S rRNA of 30S subunit. This region interacts with the wobble base in the anticodon of tRNA.

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

Toxicity Ototoxicity and nephrotoxicity are the most serious adverse effects of aminoglycoside therapy 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
Paromomycin is an aminoglycoside antibiotic, first isolated from Streptomyces krestomuceticus in the 1950s. It was discovered by Parke Davis now Pfizer and introduced asHumatin in 1960.It is also called monomycin and aminosidine;

Mechanism
Paromomycin is a protein synthesis inhibitor in non-resistant cells by binding to 16S ribosomal RNA.This broad spectrum antibiotic soluble in water, is very similar in action to Neomycin. Antimicrobial activity of Paromomycin against Escherichia coli and Staphylococcus aureus has been shown.

PAROMOMYCIN
6-diamino-2-[(2S, 3R, 4R, 5R)-4-[(2R, 3R, 4R, 5R, 6S)-3-amino-6-(amino methyl)-4

Uses
It is an antibiotic used to treat intestinal infections as cryptosporidiosis and amoebiasis, and other diseases like leishmaniasis. such

Paromomycin was demonstrated to be effective against cutaneous leishmaniasis in clinical studies in the USSR in the 1960s, and in trials with visceral leishmaniasis in the early 1990s. The route of administration is intramuscular injection and capsule. 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.

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 613. doi:10.1093/jac/3.6.609 PMID 340441 Antimicrob Chemother 3 (6): 609

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. 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 Antiinfective Therapy 6 (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 Agents 33 (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.