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ANTIBIOTICS
1.CHLORAMPHENICOL
2.MACROLIDES
INTRODUCTION
 Antimicrobial drugs differ from all others in that they are designed to inhibit the growth
or to kill the i...
ANTIBIOTICS
 Antibiotics are substances produced by microorganisms, which selectively suppress
the growth of microorganis...
CLASSIFICATION OF ANTIMICROBIAL DRUGS
Chemical structure – Presence of functional group
 Nitrobenzene derivative: Chloram...
CHLORAMPHENICOL
 Chloramphenicol was initially obtained from Streptomyces venezuelae in 1947.
It was soon synthesized che...
ANTIMICROBIAL SPECTRUM
BROAD
SPECTRUM
ANTIBIOTIC
Active against nearly the same range of organisms (gram-positive and nega...
MECHANISM OF ACTION
Chloramphenicol is a protein synthesis inhibitor in
bacteria.
It inhibits protein by binding irreversi...
RESISTANCE
Resistance is conferred by the presence of an
R factor that codes for an acetyl coenzyme A
transferase. This en...
Chloramphenicol may be administered either
intravenously or orally. It is rapidly and completely
absorbed via the oral rou...
THERAPEUTIC USES
 Because of potential toxicity, bacterial resistance, and the availability of many other
effective alter...
The clinical use of chloramphenicol is limited to life-threatening infections because of the
serious adverse effects assoc...
INTERACTIONS
 Chloramphenicol is able to inhibit some of the hepatic mixed-function oxidases and,
thus, blocks the metabo...
MACROLIDES
 The macrolides are a group of antibiotics with a macrocyclic lactone
structure to which one or more deoxy sug...
ERYTHROMYCIN
 It was isolated from Streptomyces erythreus in
1952.
 It has been widely employed, mainly as
alternative t...
Mechanism of
action
Erythromycin acts by
inhibiting bacterial
protein synthesis. lt
combines with 50S
ribosome subunits an...
Resistance to
erythromycin, mostly
by mechanisms which
render them less
permeable to
erythromycin or acquire
the capacity ...
Pharmacokinetics
Erythromycin base is acid labile. To protect it from
gastric acid, it is given as enteric coated tablets,...
Therapeutic uses
As an alternative to
penicillin
Diptheria
Tetanus
Leptospirosis
Syphilis and
gonorrhoea
As a first choice...
Hypersensitivity
Cholestatic
jaundice
Ototoxicity Hepatotoxicity
INTERACTION
• Erythromycin inhibits hepatic oxidation of ...
NEWER MACROLIDES
In an attempt to overcome the limitations of erythromycin like narrow spectrum, gastric
intolerance, gast...
CLARITHROMYCIN
 The antimicrobial spectrum of clarithromycin is
similar to erythromycin.
 in addition,it includes Mycoba...
THERAPEUTIC USES
 Clarithromycin is indicated in upper and lower respiratory tract infections, sinusitis, otitis
media, w...
AZITHROMYCIN
 Has an expanded spectrum, improved
pharmacokinetics, better tolerability and drug
interaction profiles.
 I...
THERAPEUTIC USES
Because of higher efficacy, better gastric tolerance and convenient once a day dosing,
azithromycin is no...
ADVERSE EFFECTS
Side effects are mild gastric upset, abdominal pain (less than erythromycin), headache
and dizziness. Azit...
Antibiotics   chloramphenicol and macrolides
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Antibiotics chloramphenicol and macrolides

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Antibiotics that acts as anti microbial by inhibiting the protein synthesis of microbes - eg, chloramphenicol and macrolides

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Antibiotics chloramphenicol and macrolides

  1. 1. ANTIBIOTICS 1.CHLORAMPHENICOL 2.MACROLIDES
  2. 2. INTRODUCTION  Antimicrobial drugs differ from all others in that they are designed to inhibit the growth or to kill the infecting organism and to have minimal effect or nil effect on the recipient.  This type of therapy which is administered for treating systemic infections that selectively suppress the pathogen without significantly affecting the host is called chemotherapy.  The selective microbial toxicity – action of drug on  a component of microbe (or)  the metabolic process that was not in the host (or)  high affinity for certain microbial biomolecules .  Due to analogy between the malignant cell and the pathogenic microbes, treatment of neoplastic diseases with drugs is also called 'chemotherapy'.
  3. 3. ANTIBIOTICS  Antibiotics are substances produced by microorganisms, which selectively suppress the growth of microorganism or kill other microorganisms at very low concentrations.  This excludes other natural substances which also inhibit microorganisms but are produced by higher forms (e.g. antibodies) or even those produced by microbes but are needed in high concentrations (ethanol, lactic acid, H2O2).  Initially the term 'chemotherapeutic agent‘ was restricted to synthetic compounds, since many antibiotics and their analogues have been synthesized, this criterion becomes irrelevant; both synthetic and microbiologically produced drugs need to be put together.  It would be more appropriate to use the term Antimicrobial agent (AMA) to designate synthetic as well as naturally obtained drugs that attenuate microorganisms.  The first antibiotic discovered was penicillin by Alexander Fleming in 1929
  4. 4. CLASSIFICATION OF ANTIMICROBIAL DRUGS Chemical structure – Presence of functional group  Nitrobenzene derivative: Chloramphenicol.  Macrolide antibiotics: Erythromycin, Clarithromycin, Azithromycin, etc Mechanism of action – on the microbes Inhibit protein synthesis: Tetracyclines, Chloramphenicol, Erythromycin, Clindamycin, Linezolid. Type of organism against which primarily active  Antibacterial - Erythromycin  Antiviral  Antifungal  Antiprotozoal  Antihelmintic Spectrum of activity - Broad spectrum -chloramphenicol Narrow spectrum-erythromycin Type of action - Primarily Bacteriostatic ( chloramphenicol, macrolides). Primarily bactericidal. Source of antibiotics- fungi, bacteria, Actinomycetes ( chloramphenicol, macrolides).
  5. 5. CHLORAMPHENICOL  Chloramphenicol was initially obtained from Streptomyces venezuelae in 1947. It was soon synthesized chemically and the commercial product now is all synthetic.  It is a yellowish white crystalline solid, aqueous solution is quite stable, stands boiling, but needs protection from light. It has a nitrobenzene substitution, which is probably responsible for the antibacterial activity and its intensely bitter taste.  It is soluble in alcohol but poorly soluble in water. Chloramphenicol succinate , which is used for parentral administration is highly water soluble. It is hydrolyzed invivo with liberation of free chloramphenicol
  6. 6. ANTIMICROBIAL SPECTRUM BROAD SPECTRUM ANTIBIOTIC Active against nearly the same range of organisms (gram-positive and negative bacteria, rickettsiae, mycoplasma, chlamydia) Gram-positive: Streptococcus sp., Staphylococcus sp., Enterococcus sp., Bacillus anthracis, Listeria monocytogenes. Gram- negative: Hemophilus influenzae, M. catarrhalis, N. meningitides, E. coli, P. mirabilis, Salmonella sp., Shigella sp., Stenotrophomonas maltophilia. Chloramphenicol has excellent activity against anaerobes. The drug is either bactericidal or (more commonly) bacteriostatic, depending on the organism. Bactericidal against H. influenzae, Neisseria meningitidis, and S. pneumoniae. The Enterobacteriaceae are variably sensitive to chloramphenicol. P. aeruginosa is resistant to even very high concentrations of chloramphenicol. Strains of V. cholerae have remained largely susceptible to chloramphenicol.
  7. 7. MECHANISM OF ACTION Chloramphenicol is a protein synthesis inhibitor in bacteria. It inhibits protein by binding irreversibly to the bacterial 50s ribosome subunit. It hinder the access of aminoacyl-tRNA to the acceptor site for amino acid incorporation by acting as a peptide analogue, it prevents formation of peptide bonds. Thus inhibits protein synthesis at the peptidyl transferase reaction At high doses, it inhibits protein synthesis in mammalian mitochondria via a similar mechanism, perhaps because their ribosomes somewhat resemble bacterial ribosomes; erythropoietic cells are particularly sensitive
  8. 8. RESISTANCE Resistance is conferred by the presence of an R factor that codes for an acetyl coenzyme A transferase. This enzyme inactivates chloramphenicol. Another mechanism for resistance is associated with an inability of the antibiotic to penetrate the organism. This change in permeability may be the basis of multidrug resistance Decreased permeability into the resistant bacterial cells (chloramphenicol appears to enter bacterial cell both by passive as well as facilitated diffusion) and lowered affinity of bacterial ribosome for chloramphenicol. Partial cross resistance between chloramphenicol and erythromycin/ clindamycin has been noted, because all these antibiotics bind to 50S ribosome at adjacent sites. Some cross resistance with tetracyclines also occurs, though the latter binds to 30S ribosome
  9. 9. Chloramphenicol may be administered either intravenously or orally. It is rapidly and completely absorbed via the oral route because of its lipophilic nature, and is widely distributed throughout the body. It is 50-60% bound to plasma proteins and very widely distributed, volume of distribution 1 L/kg. It freely penetrates serous cavities and blood-brain barrier: CSF concentration is nearly equal to that of unbound drug in plasma. It crosses placenta and is secreted in bile and milk. The drug inhibits the hepatic mixed- function oxidases. Excretion of the drug depends on its conversion in the liver to a glucuronide, which is then secreted by the renal tubule. Only about 10 percent of the parent compound is excreted by glomerular filtration Hepatic metabolism to the inactive glucuronide is the major route of elimination. This metabolite and chloramphenicol are excreted in the urine. Patients with impaired liver function have decreased metabolic clearance, and dose should be decreased. Since 50% of chloramphenicol is bound to plasma proteins , the dose should be reduced in cirrhotic patients and in neonates. PHARMACOKINETICS
  10. 10. THERAPEUTIC USES  Because of potential toxicity, bacterial resistance, and the availability of many other effective alternatives which are less toxic, chloramphenicol is rarely used.  It may be considered for treatment of serious rickettsial infections such as typhus and Rocky Mountain spotted fever.  It is an alternative to a b-lactam antibiotic for treatment of meningococcal meningitis occurring in patients who have major hypersensitivity reactions to penicillin or bacterial meningitis caused by penicillin-resistant strains of pneumococci.  Chloramphenicol is used topically in the treatment of eye infections because of its broad spectrum and its penetration of ocular tissues and the aqueous humor. It is ineffective for chlamydial infections.  Brucellosis: If tetracyclines are contraindicated, chloramphenicol is recommended.  Rarely used in the treatment of typhoid, when Third-generation cephalosporins and quinolones which are drugs of choice for the treatment of typhoid fever were contraindicated.
  11. 11. The clinical use of chloramphenicol is limited to life-threatening infections because of the serious adverse effects associated with its administration. Adverse effects Anemia Hemolytic anemia –less glucose 6-phosphate dehydrogenase. Reversible anemia- side effect , dose related Aplastic anemia - rare - idiosyncratic - usually fatal Hypersensitivity reaction Rashes, fever, atrophic glossitis angioedema Gastrointestinal irritative effects Nausea vomiting diarrhoea Gray baby syndrome Neonates have a low capacity to glucuronylate the antibiotic, and they have underdeveloped renal function. Therefore, neonates have a decreased ability to excrete the drug, which accumulates to levels that interfere with the function of mitochondrial ribosomes. This leads to poor feeding,depressed breathing, cardiovascular collapse, cyanosis and death. Adults who have received very high doses of the drug can also exhibit this toxicity.
  12. 12. INTERACTIONS  Chloramphenicol is able to inhibit some of the hepatic mixed-function oxidases and, thus, blocks the metabolism of such drugs as warfarin, phenytoin, tolbutamide, and chlorpropamide, thereby elevating their concentrations and potentiating their effects.  Severe toxicity and death have occurred due to these drug interactions. Concurrent administration of phenobarbital or rifampin, which potently induce CYPs, shortens chloramphenicol’s t1/2 and may result in sub therapeutic drug concentrations DOSAGE The commonest route of administration of chloramphenicol is oral-as capsules; 250-500 mg 6 hourly (max. total dose 28 g), children 25-50 mg/kg/ day. It is also available for application to eye/ear, but topical use at other sites is not recommended. CHLOROMYCETIN, ENTEROMYCETIN, PARAXIN, 250 mg, 500 mg cap, 1% eye oint, 0.5% eye drops, 5% ear drops, 1% applicaps.
  13. 13. MACROLIDES  The macrolides are a group of antibiotics with a macrocyclic lactone structure to which one or more deoxy sugars are attached.  Macrolides includes ,  Erythromycin  Clarithromycin  Azithromycin -methyl-substituted nitrogen in the lactone ring that improves acid stability and tissue penetration and broadens the activity spectrum.  Roxithromycin .  Macrolides are narrow spectrum antibiotic. More commonly bacteriostatic in nature ocassionaly bactericidal depends upon the microorganism.  Macrolides are also bacterial protein synthesis inhibitors.  Mechanism of action • The macrolides bind irreversibly to a site on the 50S subunit of the bacterial ribosome, thus inhibiting the translocation steps of protein synthesis . • They may also interfere at other steps, such as transpeptidation. • Their binding site is either identical or in close proximity to that for clindamycin and chloramphenicol.
  14. 14. ERYTHROMYCIN  It was isolated from Streptomyces erythreus in 1952.  It has been widely employed, mainly as alternative to penicillin.  Water solubility of erythromycin is limited, and the solution remains stable only when kept in cold. Antimicrobial spectrum • It is narrow, includes mostly gram-positive and a few gram-negative bacteria, and overlaps considerably with that of penicillin G. • Erythromycin is highly active against Str. pyogenes and Str. pneumoniae, N. gonorrhoeae, Clostridia, C. diphtheriae, Listeria. • Most penicillin-resistant Staphylococci and Streptococci were initially sensitive, but have now become resistant to erythromycin also. • In addition, Campylobacter, Legionella, Branhamella catarrhalis, Gardnerella vaginalis and Mycoplasma, that are not affected by penicillin, are highly sensitive to erythromycin. • Few others, including H. influenzae, H. ducreyi, B. pertussis, Chlamydia trachoma tis, Str. viridans, N. meningitidis and Rickettsiae are moderately sensitive.
  15. 15. Mechanism of action Erythromycin acts by inhibiting bacterial protein synthesis. lt combines with 50S ribosome subunits and interferes with 'translocation' . After peptide bond formation between the newly attached amino acid and the nacent peptide chain at the acceptor (A) site the elongated peptide is translocated back to the peptidyl (P) site, making the A site available for next aminoacyl tRNA attachment. This is prevented by erythromycin and the ribosome fails to move along the mRNA to expose the next codon. As an indirect consequence, peptide chain may be prematurely terminated: synthesis of larger proteins is especifically suppressed.
  16. 16. Resistance to erythromycin, mostly by mechanisms which render them less permeable to erythromycin or acquire the capacity to pump it out. Alteration in the ribosomal binding site for erythromycin by plasmid encoded methylase enzyme is an important mechanism in gram-positive bacteria. All the above types of resistance are plasmid mediated, while change in the 50S ribosome by chromosomal mutation has also been found. Bacteria that develop resistance to erythromycin are resistant to other macrolides as well. Cross resistance with clindamycin and chloramphenicol also occurs, because the ribosomal binding sites for all these are proximal to each RESISTANCE
  17. 17. Pharmacokinetics Erythromycin base is acid labile. To protect it from gastric acid, it is given as enteric coated tablets, from which absorption is incomplete and food delays absorption by retarding gastric emptying. Its acid stable esters are better absorbed. Erythromycin is widely distributed in the body, enters cells and into abscesses, crosses serous membranes and placenta, but not bloodbrain barrier. lt attains therapeutic concentration in the prostate. It is 70-80% plasma protein bound, partly metabolized and excreted primarily in bile in the active form. Renal excretion is minor; dose need not be altered in renal failure. The plasma half life is 1.5 hr, but erythromycin persists longer in tissues. Dose: 250-500 mg 6 hourly (max. 4 g/day), children 30-60 mg/kg/day. Erytluomycin (base): ERYSAFE 250, mg tabs, EROMED 333 mg tab, 125 mg/5 ml susp. Erytluomycin stearate: ERYTHROCIN 250, 500 mg tab, 100 mg/5 rnl susp.,. ETROCIN, ERYSTER 250 mg tab, 100 mg/5 rnl dry syr, EMTHRO 250 mg tab, 125 mg/5 ml susp. Erythromycin estolate (lauryl sulfate): ALTHROCIN 250, 500 mg tab, 125 mg kid tab, 125 mg/ 5 ml and 250 mg/5 rnl dry syr, 100 mg/rnl ped. drops, E-MYCIN 100, 250 mg tab, 100 mg/5 rnl dry syr; ERYC-5 250 mg tab, 125 mg/5 ml dry syr. Erythromycin ethylsuccinate: ERYNATE 100 mg/5 ml dry syr, ERYTHROCIN 100 mg/ml drops, 125 mg/5 rnl syr. A 30% ointment (GERY OINTMENT) is marketed for topical treatment of boils, carbuncles and skin infections, but efficacy is doubtful.
  18. 18. Therapeutic uses As an alternative to penicillin Diptheria Tetanus Leptospirosis Syphilis and gonorrhoea As a first choice drug Mycoplasma pneumoniae Whooping cough chancroid As a second choice drugs Chlamydia trachomatis infection of urogenital tract Penicillin-resistant Staphylococcal infections: Legionnaires' pneumonia: Campylobacter enteritis
  19. 19. Hypersensitivity Cholestatic jaundice Ototoxicity Hepatotoxicity INTERACTION • Erythromycin inhibits hepatic oxidation of many drugs. The clinically significant interactions are-rise in plasma levels of theophylline, carbamazepine, valproate, ergotamine and warfarin. • Several cases of Q-T prolongation, serious ventricular arrhythmias and death have been reported due to inhibition of CYP3A4 by erythromycin/ clarithromycin resulting in high blood levels of concurrently administered terfenadine/ astemizole/ cisapride ADVERSE EFFECTS
  20. 20. NEWER MACROLIDES In an attempt to overcome the limitations of erythromycin like narrow spectrum, gastric intolerance, gastric acid lability, low oral bioavailability, poor tissue penetration and short half-life, a number of semisynthetic macrolides have been produced, of which roxithromycin, clarithromycin and azithromycin have been marketed. ROXITHROMYCIN  It is a semisynthetic long –acting acid-stable macrolide whose antimicrobial spectrum resembles closely with that of erythromycin.  It is more potent against Branh. catarrhalis, Card. vaginal is and Legionella but less potent against B. pertussis.  Good enteral absorption and tissue penetration, an average plasma t½ of 12 hr making it suitable for twice daily dosing, as well as better gastric tolerability are its desirable features.  Though its affinity for cytochrome P450 is lower, drug interactions with terfenadine, cisapride and others are not ruled out.  Thus, it is an alternative to erythromycin for respiratory, ENT, skin and soft tissue and genital tract infections with similar efficacy. Dose: 150-300 mg BD 30 min before meals, children 2.5-5 mg/kg BD; ROXID, ROXIBID, RULIDE 150, 300 mg tab, 50 mg kid tab, 50 mg /5 ml liquid; ROXEM 50 mg kid tab, 150 mg tab
  21. 21. CLARITHROMYCIN  The antimicrobial spectrum of clarithromycin is similar to erythromycin.  in addition,it includes Mycobact. avium complex (MAC), other atypical mycobacteria, Mycobact. leprae and some anaerobes but not Bact. fragilis. It is more active against sensitive strains of gram-positive cocci, Moraxella, Legionella, Mycoplasma pneumoniae and Helicobacter pylori.  However, bacteria that have developed resistance to erythromycin are resistant to clarithromycin also.  Clarithromycin is more acid-stable than erythromycin, and is rapidly absorbed; oral bioavailability is -50% due to first pass metabolism; food delays but does not decrease absorption.  It has slightly greater tissue distribution than erythromycin and is metabolized by saturation kinetics-t1/2 is prolonged from 3--6 hours at lower doses to 6-9 hours at higher doses.  An active metabolite is produced. About 1/3 of oral dose is excreted unchanged in urine, but no dose modification is needed in liver disease or in mildto- moderate kidney failure.
  22. 22. THERAPEUTIC USES  Clarithromycin is indicated in upper and lower respiratory tract infections, sinusitis, otitis media, whooping cough, atypical pneumonia, skin and skin structure infections due to Strep. pyogenes and some Staph. aureus.  Used as a component of triple drug regimen (seep. 637) it eradicates H. pylori in 1-2 weeks. It is a first line drug in combination regimens for MAC infection in AIDS patients .  second line drug for other atypical mycobacterial diseases as well as leprosy. Dose: 250 mg BD for 7 days; severe cases 500 mg BD up to 14 days. CLARIBID 250, 500 mg tabs, 250 mg/5 ml dry syr; CLARIMAC 250, 500 mg tabs; SYNCLAR 250 mg tab, 125 mg/5 ml dry syr. ADVERSE EFFECTS  Side effects of clarithromycin are similar to erythromycin, but gastric tolerance is better.  High doses can cause reversible hearing loss.  Few cases of pseudomembranous enterocolitis, hepatic dysfunction or rhabdomyolysis are reported.  Its safety in pregnancy. The drug interaction potential is also similar to erythromycin.
  23. 23. AZITHROMYCIN  Has an expanded spectrum, improved pharmacokinetics, better tolerability and drug interaction profiles.  It is more active than other macrolides against H. influenzae, but less active against gram-positive cocci. High activity is exerted on respiratory pathogens- Mycoplasma,Chlamydia pneumoniae, Legionella, Moraxella and on others like Campylobacter, Ch. trachomatis, H. ducreyi, Calymm, granulomatis, N. gonorrhoeae.  However, it is not active against erythromycin resistant bacteria. Good activity is noted against MAC.
  24. 24. THERAPEUTIC USES Because of higher efficacy, better gastric tolerance and convenient once a day dosing, azithromycin is now preferred over erythromycin as first choice drug for infections such as:  Legionnaires' pneumonia  Chlamydia trachomatis  Donovanosis caused by Calymmatobacterium Granulomatis  Chancroid and PPNG urethritis PHARMACOKINETIC PROPERTIES  Acid-stability, rapid oral absorption, marked tissue distribution and intracellular penetration. Concentration in most tissues exceeds that in plasma.  Particularly high concentrations are attained inside macrophages and fibroblasts; volume of distribution is -30 L/kg.  Slow release from the intracellular sites contributes to its long terminal t1/2 of >50 hr. It is largely excreted unchanged in bile, renal excretion is - 10%.
  25. 25. ADVERSE EFFECTS Side effects are mild gastric upset, abdominal pain (less than erythromycin), headache and dizziness. Azithromycin has been found not to affect hepatic CYP3A4 enzyme. Interaction with theophylline, carbamazepine, warfarin, terfenadine and cisapride is not likely. Dose: 500 mg once daily 1 hour before or 2 hours after food (food decreases bioavailability); (children above 6 month-10 mg/kg/day for 3 days is sufficient for most infections. AZITHRAL 250, 500 mg cap and 250 mg per 5 ml dry syr; AZIWOK 250 mg cap, 100 mg kid tab, 100 mg/5 ml and 200 mg/5 rnl susp. AZIWIN 100, 250, 500 mg tab,200 mg/5 ml liq. Also AZITHRAL 500 mg inj. The other indications of azithromycin are pharyngitis, tonsillitis, sinusitis, otitis media, pneumonias, acute exacerbations of chronic bronchitis, streptococcal and some staphylococcal skin and soft tissue infections. In combination with at least one other drug it is effective in the prophylaxis and treatment of MAC in AIDS patients. Other potential uses are in typhoid, toxoplasmosis and malaria.

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