Macrolides and other protein inhibitors.ppt

Macrolides and other protein inhibitors.ppt

1. Macrolides
Dr.RamnarayanreddyDr.Ramnarayanreddy

2. Macrolides

These group of anti-microbials contains a These group of anti-microbials contains a
lactone ring.lactone ring.

These are used in patients allergic to beta-These are used in patients allergic to beta-
lactam antibiotics.lactam antibiotics.

These are bacteriostatic mainly.These are bacteriostatic mainly.

3. Mechanism of action

Binds to 50S ribosomal subunit and inhibits Binds to 50S ribosomal subunit and inhibits
the the translocationtranslocation of the newly synthesized of the newly synthesized
peptide from the acceptor site (A) to the peptide from the acceptor site (A) to the
donor site (P)donor site (P)

4. Macrolides
1.Chloramphenicol
2.Macrolides
3.Tetracycline

6. Anti-bacterial spectrum

Gram-positive - Gram-positive - Streptococcus,Streptococcus, C. diptheriaeC. diptheriae

Gram-negative Gram-negative –– N. gonorrhea, LegionellaN. gonorrhea, Legionella

Mycoplama, Spirochetes, Chlamydia Mycoplama, Spirochetes, Chlamydia

M. Avium-intracellulare, H.PyloriM. Avium-intracellulare, H.Pylori

7. Erythromycin

Erythromycin is inactivated by gastric acid. Erythromycin is inactivated by gastric acid.

Erythromycin esters are less susceptible to Erythromycin esters are less susceptible to
acid inactivation and are better absorbedacid inactivation and are better absorbed

It inhibits cytochrome P 450 It inhibits cytochrome P 450

It is mainly excreted in the bileIt is mainly excreted in the bile

8. Macrolides

Erythromycin & AzithromycinErythromycin & Azithromycin are excreted in are excreted in
bile.bile.

Clarithromycin appear in urine and bile.Clarithromycin appear in urine and bile.

AzithromycinAzithromycin has large Vd – high tissue has large Vd – high tissue
distribution – concentrated in neutrophils, distribution – concentrated in neutrophils,
macrophages.macrophages.

9. MACROLIDESMACROLIDES
OralOral
absorptionabsorption
Cytochrome Cytochrome
P450P450
SpectrumSpectrum Half Half
life life
(hours)(hours)
ErythromycinErythromycin yesyes InhibitsInhibits Penicillin Penicillin 2 2
ClarithromycinClarithromycinStable to Stable to
acidacid
Inhibits Inhibits MAC My, HP, MAC My, HP,
C,Leg C,Leg
44
AzithromycinAzithromycin Stable to Stable to
acidacid
NoNo H.Inf, Chl MACH.Inf, Chl MAC >40>40
RoxithromycinRoxithromycinStable to Stable to
acidacid
InhibitsInhibits Same as AzithroSame as Azithro1010

10. Adverse effects

Epigastric distress - erythromycinEpigastric distress - erythromycin

Cholestatic jaundice (mainly with Cholestatic jaundice (mainly with
erythromycin estolate) erythromycin estolate)

Ototoxicity Ototoxicity –– erythromycin at high dose. erythromycin at high dose.

11. Drug - drug interactions

Erythromycin, Clarithromycin and Erythromycin, Clarithromycin and
roxithromycin inhibit the cytochrome P450 roxithromycin inhibit the cytochrome P450
system.system.

so potentiate the activity of theophylline and so potentiate the activity of theophylline and
terfenadine terfenadine

12. THERAPEUTIC USES

Mycoplasma infections Mycoplasma infections

LegionnairesLegionnaires’’ disease disease

PertussisPertussis

Chlamydia infectionsChlamydia infections

Corynebacterium diphtheriae infectionsCorynebacterium diphtheriae infections

Atypical mycobacterium infectionsAtypical mycobacterium infections

13. Clindamycin

Active against gram +ve and anaerobes Active against gram +ve and anaerobes

Good activity against bacteroides Good activity against bacteroides
( including B. fragilis) & Penicillin resistant ( including B. fragilis) & Penicillin resistant
streptococcus.streptococcus.

No activity against most gram -ve bacteria No activity against most gram -ve bacteria

14. Clindamycin

Well absorbed orallyWell absorbed orally

Distribution in most tissues including bone. Distribution in most tissues including bone.

Excretion is mainly biliary and also in urine.Excretion is mainly biliary and also in urine.

15. Adverse effects

Gastrointestinal super-infections Gastrointestinal super-infections ––
potentially fatal pseudo-membranous colitis potentially fatal pseudo-membranous colitis
by C. difficile.by C. difficile.

Oral Metronidazole and Vancomycin are Oral Metronidazole and Vancomycin are
used for Ṛ of the fatal pseudo-membranous used for Ṛ of the fatal pseudo-membranous
colitis.colitis.

16. GLYCOPEPTIDE ANTIBIOTICS
Vancomycin
Bactericidal to gram-positive cocci, Bactericidal to gram-positive cocci, Neisseria, Clostridia Neisseria, Clostridia and and
diphtheroids. Extensively used for surgical prophylaxis, etc., diphtheroids. Extensively used for surgical prophylaxis, etc.,
VRSA and VRE have emerged. VRSA and VRE have emerged.
MoA: acts by inhibiting bacterial cell wall synthesis. It binds MoA: acts by inhibiting bacterial cell wall synthesis. It binds
to the terminal dipeptide units prevents cross linking to to the terminal dipeptide units prevents cross linking to
form the cell wall cannot take place. form the cell wall cannot take place.
Not absorbed orally. After i.v., widely distributed, penetrates Not absorbed orally. After i.v., widely distributed, penetrates
serous cavities, inflamed meninges and is excreted mainly serous cavities, inflamed meninges and is excreted mainly
unchanged by glomerular filtration. unchanged by glomerular filtration.

17. Toxicity: Toxicity:
Concentration-dependent permanent nerve Concentration-dependent permanent nerve
deafness. deafness.
Kidney damage is also dose-related. Kidney damage is also dose-related.
Aminoglycosides must be very carefully used. Aminoglycosides must be very carefully used.
Skin allergy and fall in BP during i.v. injection, Skin allergy and fall in BP during i.v. injection,
due to histamine release. due to histamine release.
Rapid i.v. injection - chills, fever, urticaria and Rapid i.v. injection - chills, fever, urticaria and
intense flushing-called 'intense flushing-called 'Red man syndromeRed man syndrome'.'.

18. Uses: Uses:
Given orally (125-500 mg 6 hourly), it is the second choice drug to metronidazole for Given orally (125-500 mg 6 hourly), it is the second choice drug to metronidazole for
antibiotic associated antibiotic associated pseudomembranous enterocolitis pseudomembranous enterocolitis caused by C. caused by C. difficile. difficile.
Systemic use (500 mg 6hourly i.v.) is restricted to Systemic use (500 mg 6hourly i.v.) is restricted to serious MRSA infectionsserious MRSA infections - most - most
effective drug, and as a penicillin substitute (in allergic patients) for effective drug, and as a penicillin substitute (in allergic patients) for enterococcal enterococcal
endocarditisendocarditis along with gentamicin. along with gentamicin.
For empirical therapy of For empirical therapy of bacterial meningitisbacterial meningitis, i.v. vancomycin is usually combined with , i.v. vancomycin is usually combined with
i.v. ceftriaxone/ cefotaxime. i.v. ceftriaxone/ cefotaxime.
Penicillin-resistant pneumococcal infections Penicillin-resistant pneumococcal infections and and diphtheroidsdiphtheroids respond very well to respond very well to
vancomycin. vancomycin.
Preferred surgical prophylactic in MRSA prevalent areas and in penicillin allergic patients. Preferred surgical prophylactic in MRSA prevalent areas and in penicillin allergic patients.

19. Quinupristin/Dalfopristin

It is a ratio of two streptogramins in the ratio It is a ratio of two streptogramins in the ratio
of 30:70of 30:70

Reserved for the treatment of Vancomycin Reserved for the treatment of Vancomycin
resistant Enterococcusresistant Enterococcus

20. Quinupristin/Dalfopristin
Mechanism of actionMechanism of action

Each component of this binds to separate Each component of this binds to separate
site on 50 S ribosome and thus interrupt site on 50 S ribosome and thus interrupt
protein synthesisprotein synthesis

Bactericidal and has long post-antibiotic Bactericidal and has long post-antibiotic
effect.effect.

21. Quinupristin/Dalfopristin
Anti-bacterial spectrum :Anti-bacterial spectrum :

Gram +ve bacteria resistant to other Gram +ve bacteria resistant to other
antibiotics like enterococcus faecium antibiotics like enterococcus faecium
infections including Vancomycin resistant infections including Vancomycin resistant
Enterococcus.Enterococcus.

22. Quinupristin/Dalfopristin
Kinetics :Kinetics :

It is available for parenteral route only.It is available for parenteral route only.

It penetrates macrophages and neutrophilsIt penetrates macrophages and neutrophils

It inhibits cytochrome P 450It inhibits cytochrome P 450

Most of the drugs are excreted by bileMost of the drugs are excreted by bile

23. Quinupristin/Dalfopristin
Adverse effects :Adverse effects :

Venous irritationVenous irritation

HyperbilirubinemiaHyperbilirubinemia

ArthralgiaArthralgia

24. Linezolid
First oxazolidone antibiotic
Blocks 70S ribosome assembly by
binding 50 S subunit

26. Linezolid
Anti-bacterial spectrum :
Gram positive bacteria only
Penicillin resistant streptococci
Methicillin and Vancomycin staphylococcus
Vancomycin resistant enterococcus
Lister monocytogenes, Corynebacterium spp
Also active against mycobacteria
tuberculosis and Clostridium

27. Linezolid
Linezolid
Orally absorbed
Well distributed
Excreted by renal and non-renal routes

28. Linezolid
Adverse effects :
Nausea and diarrhea
Thrombocytopenia
Inhibits MAO, avoid tyramine containing
foods

29. urinary antiseptics: urinary antiseptics: attain antibacterial concentration only attain antibacterial concentration only
in urine, with little or no systemic antibacterial effect.in urine, with little or no systemic antibacterial effect.
Nitrofurantoin and methenamine, Nalidixic acid also.Nitrofurantoin and methenamine, Nalidixic acid also.
Nitrofurantoin: Nitrofurantoin: bacteriostatic, its activity is enhanced bacteriostatic, its activity is enhanced
at lower pH. It inhibits many gram-negative bacteria, but at lower pH. It inhibits many gram-negative bacteria, but
due to development of resistance, activity is now due to development of resistance, activity is now
restricted largely to restricted largely to E. coli.E. coli.
Pharmacokinetics: Pharmacokinetics: well absorbed orally; half is excreted well absorbed orally; half is excreted
unchanged in urine; Renal excretion is reduced in unchanged in urine; Renal excretion is reduced in
azotaemic patients; contraindicated in renal failure.azotaemic patients; contraindicated in renal failure.
Adverse effects: Adverse effects: Commonest is Commonest is gi intolerancegi intolerance- nausea, - nausea,
epigastric pain and diarrhoea. Urine turns epigastric pain and diarrhoea. Urine turns dark browndark brown
on exposure to air. on exposure to air.
Use: Use: uncomplicated lower UTI, also for prophylaxis uncomplicated lower UTI, also for prophylaxis
when catheterization or instrumentation of the lower when catheterization or instrumentation of the lower
urinary tract is performed.urinary tract is performed.
50, 100 mg tab, 25 mg/5 rnl susp.50, 100 mg tab, 25 mg/5 rnl susp.

30. 
Methenamine: Methenamine: decomposes in acidic urine to decomposes in acidic urine to release release
formaldehydeformaldehyde which inhibits all bacteria. Methenamine is which inhibits all bacteria. Methenamine is
administered in enteric coated tablets to protect it from administered in enteric coated tablets to protect it from
decomposing in gastric juice. decomposing in gastric juice.

use is restricted to use is restricted to chronic, resistant type of utichronic, resistant type of uti, not involving , not involving
kidney substance. Resistance to formaldehyde does not occur.kidney substance. Resistance to formaldehyde does not occur.

Adverse effects: Adverse effects: Gastritis can occur due to release of Gastritis can occur due to release of
formaldehyde in stomach-patient compliance is often poor formaldehyde in stomach-patient compliance is often poor
due to this. Chemical cystitis and haematuria may develop due to this. Chemical cystitis and haematuria may develop
with high doses given for long periods.with high doses given for long periods.

contraindicated in renal failure and in liver disease. contraindicated in renal failure and in liver disease.

Phenazopyridine Phenazopyridine It is an It is an orange dye,orange dye,exerts exerts analgesic actionanalgesic action
in the urinary tract and affords symptomatic relief of burning in the urinary tract and affords symptomatic relief of burning
sensation, dysuria and urgency due to cystitis. Side effects are sensation, dysuria and urgency due to cystitis. Side effects are
nausea and epigastric pain.nausea and epigastric pain.

Dose: Dose: 200-400 mg TDS200-400 mg TDS