Antibiotics Fmc

8/13/2019 Antibiotics Fmc

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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):

2015.doi:10.1016/j.ijantimicag.2008.09.001. PMID18976888.

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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