Drugs which act on 50s subunits.- Macrolides, Clindamycin and Chloramphenicol.

Also, Vancomycin which act on cell wall synthesis

 00Chloramphenicol
Isolated in 1947, from streptomyces venezuelae through the samples collected in Venezuela. It was used initially to treat outbreaks of epidemic typhus in Bolivia, gave
magnificent results and excellent success rate in scrub typhus. Nevertheless, it became clear in 1950 that this drug can cause serious blood dyscrasias. Hence the drug has only
special application for serious diseases like meningitis, typhus, typhoid for those people who cannot take safer alternative medication due to allergies or resistance. It is
contains nitrobenzene, derivative of dichloroacetic acid.

 00Mechanism of action: Chloramphenicol is a bacteriostatic drug, inhibit protein synthesis. It enters into bacteria by facilitated diffusion, binds with 50s ribosomal subunits &
prevent peptide bond formation by inhibiting peptidyltransferase. Chloramphenicol can inhibit human mitochondrial protein synthesis, particularly erythropoietic cells.
 00Antimicrobial spectrum of activity: It is effective against wide variety of organism G+ G-. Rickettsiae, Salmonella, Klebsiella, Bacteroides and H.influenzae. Mycoplasma,
Chlamydia are not effected clinically. Ineffective against mycobacterium tuberculosis, virus, fungus.
 00Resistance to chloramphenicol:
1. Plasmid mediated -production of acetyl transferase, which inactivates chloramphenicol by acetylating hydroxyl groups on the side chain.
2. B.fragilis and clostridium perfringens degrade chloramphenicol by reducing the nitro group of benzene ring.
3. Decrease permeation into microorganisms.
4. Decreased (binding.) sensitivity to ribosomes (mutation)
 00Pharmacokinetics. Chloramphenicol is rapidly and completely absorbed from g.i., well distributed through body fluids and crosses blood brain barrier. Concentration in c.n.s.
equals that of serum. It is conjugated with glucuronic acid in liver in presence of glucaronyl transferase and to some extent it is reduced to inactive aryl amine. Inactive products are
eliminated through tubular secretion. Avoid this drug in cirrhotic pts. & neonates because of decreased metabolic clearance
 Preparations: oral, parenteral and topical
 00Adverse effects:
1. Bone marrow disturbance: aplastic anemia a rare occurrence, an idiosyncratic reaction. People who survive may suffer from leukemia later life. An excess dose
may exhibit disturbances in red cell maturation characterized by vacuolated nucleated red cells in bone marrow, anemia & reticulocytopenia.
2. Gray baby syndrome is characterized by hypothermia, hypotension, abdominal distension, lethargic and patient appears ashen color, possible reasons are inadequate activity
of glucuronide transferase & inadequate excretion. In premature & in neonates both kidney & liver cannot handle to excrete the drug resulting in the blockade of electron
transport system in cardiac, liver and skeletal muscles. (alters their function)
3. Superinfection: inhibition of normal GI flora may be replaced by S.aureus, P.aeruginosa, or Candida albican.
4. Hypersensitivity reactions: macular or vesicular rashes, fever and angioedema can occur rarely.
5. G.I. irritation - nausea, vomiting and diarrhea. Diarrhea could be secondary to overgrowth of C.difficile.
6. Drug interactions: it can increase the half- lives of phenytoin, chlorpropamide, tolbutamide and warfarin by inhibiting hepatic microsomal cytochrome
P450. Chloramphenicol half life can be decreased by inducing hepatic microsomal enzymes by administration of phenobarbitone & rifampin.
7. Rare toxic effects include blurring of vision, digital paresthesias and optic neuritis.
8. Jarisch- Herxheimer reactions observed after administration of chloramphenicol in patient with syphilis, brucellosis & typhoid.
 00Therapeutic uses of chloramphenicol: The threat of the serious complication of fatal aplastic anemia, chloramphenicol is restricted to the treatment of severe infection in
which suitable alternative drug not available. Chloramphenicol used to be the choice for the treatment of typhoid now replaced by SMZ-TMP and quinolones.Treatment of CNS, PID,
infections, anaerobic infections involving B.fragilis. Rickettsial infections can also be treated with this drug. H.influenza, pneumococcal, meningococcal meningitis in persons intolerant to
betalactams. In eye, otic infection as topical agent.

 00ERYTHROMYCIN
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 * Discovered in 1952 by McGuire and coworkers in metabolic products of a strain of streptomyces erythreus. It was originally found in the soil sample of Philippine
archipelago.
*It contains a macro cyclic lactone ring to which deoxy sugar is attached.
*Clarithromycin & Azithromycin are new semisynthetic derivatives of erythromycin. Structural modification has improved acid stability, tissue penetration &
broaden the spectrum of activity.
 00Mechanism of action of erythromycin Bacteriostic drug binds with 50s ribosomal subunits & inhibit the translocation step from acceptor(A) site to donor site(P).
{the peptide fails to move from A site to P site.} Clarithromycin, azithromycin, clindamycin, lincomycin have similar mechanism of action.
 Resistance:
1. Plasmid mediated alteration resulting in ’ed permeation (accumulation.)
2. Ribosomal modification leading to decreased drug binding.
3. Hydrolysis of macrolides by esterases (Enterobacteriaceae)
 00Spectrum of activity: Erythromycin is a drug of choice in pneumonias caused by L.pneumophilia, M.pnemoniae and chlamydia pneumonia. It is also very effective
against campylobacter jejuni. The newer generation of macrolide Azithromycin and Clarithromycin are more effective, fewer side effects, and has increased activity . They
are also effective B.burgdorferi, N.gonorrhoea, MAC mycobacterium avium-intracellulare and some protozoa -toxoplasma gondii, crypto sporidium, and plasmodium spp.
 00Therapeutic uses: An alternate drug in penicillin allergy.
1. DOC in all pneumonias caused by mycoplasma, legionella & chlamydia; they are also v. effective in whooping cough (Bordatella pertussis) & diarrhea caused by
Campylobacter.
2. Streptococcal pharyngitis, mastoiditis, respiratory infection caused by pneumococcus, diphtheria, syphilis, tetanus and gonorrhea can be treated with these drugs.
3. Atypical mycobacteria- MAC, clarithromycin in toxoplasmosis encephalitis, diarrhoea due to cryptosporidium, peptic ulcer due to H.pylori.
 00Adverse effects:
1. Gastrointestinal: oral administration is associated with a high incidence of nausea, vomiting, dyspepsia and diarrhea. These are related to gastric irritation.
2. Allergic reactions: fever, eosinophilia & skin eruptions. Cholistatic hepatitis a hypersensitive reaction most commonly to erythromycin estolate & rarely w/ stearate or ethyl
succinate.
3. Drug interaction: erythromycin & to lesser extent newer drugs ’s effects of astemazole, terfenadine, theophylline, digoxin, cyclosporine, carbamazepine, corticosteroids, warfarin,
triazolam

 00CLINDAMYCIN & LINCOMYCIN

 Mechanism of action is similar to erythromycin.
 Spectrum of activity: clindamycin is more active against G+ cocci, anaerobic bacteria specially B.fragilis. It also shows good activity against PCP, toxoplasma encephalitis. It has some
activity against resistant forms of Pl.falsiparum and P.vivax -50% cure rate. Plasmid mediated resistance due to methylation of RNA.
 Kinetics: Clindamycin is widely distributed except CNS-does not cross blood brain barriers. Route of elimination is biliary.
 00Therapeutic uses.
1. It is the treatment of choice in mixed aerobic-anaerobic intra-abdominal & pelvic infections. Clindamycin usually combined w/ aminoglycoside & broad
spectrum penicillins or cephalosporins.
2. An alternative to penicillin in staphylococcal osteomyelitis.
3. Effective in infections caused by G+ cocci- S. aureus, S. epidermidis.
4. Certain forms of malaria and toxoplasmosis.
5. Used in acne vulgaris.
NB: Lincomycin is older & inferior to clindamycin.
 00Adverse effects: GI irritation - nausea, vomiting, diarrhea. Pseudomembranous colitis, hepatic dysfunction. Skin rashes, neutropenia could develop.

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 00VANCOMYCIN
It is a tricyclic glycopeptide acts by inhibiting cell wall synthesis, interfering D- alanyl- D- alanine cell wall precursor units. It is available for i.v. use and orally to
patients with pseudomembranous colitis. Employed only to methicillin resistant staph.cocci including pneumonias, empyema, endocarditis, osteomyelitis,
soft tissue abscesses and penicillin resistant pneumococcal infection.
 Adverse effects: T.Phlebitis, pain. chills, rash and fever, flushing, hypotension & extreme Flushing is referred as red-man or red neck syndrome. It is an
ototoxic & nephrotoxic agent. Neutropenia. “FONT"
 00Resistance Relatively uncommon.
1. Cytoplasmic protein that reduces the access of the drug to the site of its action.
2. VRE- Vancomycin resistant enterococci, use D-alanyl-D-lactate as a precursor to its cell wall synthesis & affinity to this wall is 1000 times less than
D- alanyl - D- alanine.

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Questions
All are true about vancomycin resistance except:
a) VRE vancomycin resistant enterococci has decreased affinity to cell wall precursors, D-alanyl-D-lactate.
b) Resistance could occur due to decreased access to the site of action.
c) Flushing, pruritus, redness of face & neck could occur with I.V. administration.
d) ancomycin is used in C.difficile infection & effective in MRSA.
e) It acts on non-growning, non-proliferting organism and a very good bacteriostatic agent.
f) It is also available as oral preparation.

00All statements about erythromycin are true except:

a) it can be used for the mild to moderate infections of pneumococcus in patients with history of penicillin allergy.
b) it is an effective drug in legionnaires' disease, mycoplasma pneumonia and whooping cough.
c) plasma levels of digoxin, cyclosporine, warfarin carbamazapine, theophylline can increase.
d) has good CSF penetration and could be used in CNS infections.
e) it can produce hepatitis, particularly in a pregnant woman.

00All statements about clindamycin are true except:

a) it is effective against anaerobic infections like B.fragilis
b) mechanism of action is similar to erythromycin.
c) it has very less CNS penetration
d) it is effective in the treatment of acne.
e) Bone marrow stimulation can be seen with this drug.  seen w/ erythropoeitin, G-CSF, GM-CSF

00All statements about chloramphenicol are true except:

a) can inhibit protein synthesis of inner mitochondrial membrane.
b) can produce Herxheimer reaction.
c) phenobarbitone can enhance the metabolism of chloramphenicol.
d) can be used in anaerobic infections and PID.
e) may produce staining of teeth.

00All statements about chloramphenicol are true except...

a) it acts by inhibiting peptidyltransferase.
b) in premature children it can produce c.v. collapse, hypothermia, hypotonia, distension of the abdomen, irregular respir. & ashen gray cyanosis.
c) photosensitivity is very frequent.
d) well distributed, crosses BBB, serous cavities & secreted into milk.
e) due to very serious toxic effect usually restricted to treatment of serious infection in which suitable alternative is not available.

00All the statements about chloramphenicol are true except...

a) use of chloramphenicol could be associated with idiopathic reaction leading to aplastic anemia, pancytopenia and most cases are fatal due to hemorrhage & infection.
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b) surviving people of aplastic reaction may develop leukemia in their later life.
c) it can be associated with pseudomembranous colitis.
d) alopecia is a specific feature.
e) can inhibit the metabolism of tolbutamide, cyclophosphamide and warfarin.