1. Broad spectrum AMAs 2. Macrolides 3. Misc.

AMAs Class I
Dr.U.P.Rathnakar
MD.DIH.PGDHM
21

Protein synthesis inhibitors

1. Broad spectrum AMAs Tetracyclines Chloramphenicol 2. Macrolides 3. Misc. AMAs Clindamycin, Streptogramins, Linezolid Aminogycosides

Vancomycin{Cell wall[-]}

Topical agents [Varied MOA] Mupirocin Fusidic acid Polymyxin B, Colistin, Bacitracin, Tyrothricin
20

BACTERIAL PROTEIN SYNTHESIS INHIBITORS

BROAD SPECTRUM SPECTRUM

MODERATE SPECTRUM

NARROW

TETRACYCLINES

MACROLIDES

KETOLIDES

LINCOSAMIDES STREPTOGRAMINS LINEZOLID Cell wall synthesis inhibtor

CHLORAMPHENICOL

1. 2. 3.

Topically used [Varied MOA] Mupirocin Fusidic acid Polymyxin B, Colistin, Bacitracin, Tyrothricin

Vancomycin

19

Protein synthesis in microorganisms

Ch

Exit

Peptidyl

Acceptor

AG

18

Protein synthesis in microorganisms

Step 1, the charged tRNA unit carrying amino acid 6 binds to the acceptor site

{TC}

Step 2 (transpeptidation), Peptidyl tRNA at the donor site, with amino acids binds the growing amino acid chain to amino acid 6.
AG

{CHLO}

Step 3, Uncharged tRNA left at the donor site is released

Step 4 (translocation), new 6-amino acid chain with its tRNA shifts to the peptidyl site

{E & C}

18-A

Tetracyclines

Tetracycline Oxytetracycline Demeclocycline Doxycycline Minocycline

Tablets,capsules, ointments, injections

17

Tetracyclines MOA
Bind to 30S ribosomes & prevent attachment t-RNA to A site Peptide chain fails to grow. The tetracyclines bacteriostatic;

TC 7

Tetracyclines MOA
Actively transported across membrane [G+ve] no transporter in hosts Through porin channels[G-ve] Doxycycline & Minocycline passive diffusion [lipid soluble] Inhibit protein synthesis

C 15

Tetracyclines Resistance
Not transported inside Efflux mechanism Binding site for tRNA protected
Inactivation enzymes

Cross resistance among other TCs Minocycline may be unaffected by cross resistance Partial cross resistance with chloramphenicol14

Spectrum Tetracyclines
[G+ve, G-ve, Aerobic, Leprae, anaerobic, ricketssiae, spirochetes, protozoa]
G-ve bacilliBrucella V.Cholera Y.Pestis B.Burgdoferi B.recurentis

Spirochetes

Mycoplasma pneumoniae

Ricketsia ricketsii

E.Histolytica

Chlamydia Calymm granulomatis H.ducreyi

Propioni bacterium acne Pseudomonas, proteus, Klebsiella, salmonella were never sensitive 13

Tetracyclines - Uses
1. Empirical therapy

2. First choice G-ve bacilliBrucella V.Cholera Y.Pestis B.Burgdoferi B.recurentis Brucellosis Cholera Plague Lymes disease Relapsing fever Atypical pneumonia

Spirochetes

Mycoplasma pneumoniae

Ricketsia ricketsii Chlamydia Calymm granulomatis H.ducreyi

Typhus, rocky mountain spotted fever, Q fever Non sp.urethritis Granuloma inguinale Chancroid 12

Tetracyclines - Uses
Second choice Listeria infections [To penicillin]

Gonorrhoea [To penicillins, Ceftriaxone] Symphilis [To penicillin]

Leptospirosis [To penicillin]

E.Histolytica [With other drugs]

Resistant malaria

Other uses Inappropriate secretion of ADHDemeclocycline

Propioni bacterium acneAcne vulgaris -

12

Tetracyclines
Tetracycline (T) Oxytetracycline(O) Source Absorption-GIT Excretion Fungus[O] Synthetic[T] Moderate Renal Demeclocycline Fungus Moderate Renal Doxycycline (D) Minocycline(M) Semisynthetic Complete, food does not interfere Dox-Faeces Mino-Bile and renal

Plasma half life

6-10h

10-18h
Moderate Highest 300mg BD

18-24h
Least High 200100mg OD

Suprainfection High Phototoxicity Dose Low 250-500 mg QID

Toxicity Renal Hepatic Suprainfection Bone & teeth

Less tooth discoloration[O]

Diabetes insipidus

[Dox]-less renal toxicity [M]-Vestibular 10 toxicity

Tetracyclines
Tetracycline (T) Oxytetracycline(O) Source Absorption-GIT Excretion Fungus[O] Synthetic[T] Moderate Renal Demeclocycline Fungus Moderate Renal Doxycycline (D) Minocycline(M) Semisynthetic Complete, food does not interfere Dox-Faeces Mino-Bile and renal

Plasma half life

6-10h

10-18h
Moderate Highest 300mg BD

18-24h
Least High 200100mg OD

Suprainfection High Phototoxicity Dose Low 250-500 mg QID

Toxicity Renal Hepatic Suprainfection Bone & teeth

Less tooth discoloration[O]

Diabetes insipidus

[Dox]-less renal toxicity [M]-Vestibular 10 toxicity

Irritation: GIT, i.m. sites, i.v. [phlebitis] Hepatotoxic- Jaundice[accumulate in liver], hepatic necrosis in pregnacy Kidney: Nephrotoxic [existing disease] except Doxy. Date expired-Fanconi syndrome Phototoxicity Teeth & Bones-[Pregnancy, lactation & children] Metabolism: catabolic effect Diabetes insipidus-Demeclocycline Vestibular toxicity-Mino Superinfection: Doxy & Mino less likely Hypersesitivity Intra cranial tension- infants

Tetracyclines ADEs

Glycyclines Tigecycline
Tigecycline, derivative of minocycline, Structurally similar to the tetracyclines Expanded broad-spectrum activity MRSA, multidrug-resistant Streptococcus pneumoniae, VRE, lactamase producing gram-negative bacteria, many anaerobic organisms. Not active against Proteus, and Pseudomonas species. 30- to 60-minute intravenous infusion every 12 hours Use- Serious community acquired pneumonia.

TC-Administration
Oral-preferred form Not in pregnancy, lactation & children Caution-hepatic & renal insufficiency Strict adherence to expiry date Do not mix with other agents Not intrathecally

17

Chloramphenicol MOA
Bind to 50S ribosomes & Prevents chain elongation Peptide chain fails to grow.

18

Chloramphenicol
[Mechanism of Action]

Chloramphenicol inhibits protein synthesis Prevents binding of peptide chain to new t-RNA Chain elongation inhibited Bacteriostatic [Cidal-H. influenzae, Neisseria meningitidis, and S. pneumoniae] Broad spectrum Can inhibit mitochondrial protein synthesis in mammalian cells

Chloramphenicol
[ADEs]

Dose related bone marrow suppressionreversible Aplastic anemia-Idiosyncratic-fatal Gray baby syndrome-overdose in neonates, especially if premature [vomiting, refusal to suck, irregular and rapid respiration, abdominal distention, periods of cyanosis, and passage of loose, green stools ] Hypersensitivity 5 GIT

Chloramphenicol
[DIs]

Enzyme inhibitor[DIs] oral antidiabetics, warfarin, phenytoin.

Rifampicin & phenobarbitone enhance metabolism of chloramphenicol

4

Chloramphenicol
[Precautions]

Never when others are available Do not repeat Less than 2 weeks, Daily<2-3grams, total dose less than 28 grams.

Chloramphenicol
[Uses] Chloramphenicol is an occasional alternative to more standard therapy for 1. Meningococcal, H influenzae, or pneumococcal infections of the CNS; 2. Anaerobic or mixed infections in the CNS, eg, brain abscess; 3. Alternative to tetracyclines in rickettsial infections, especially in pregnant women, in whom tetracycline is contraindicated.

Chloramphenicol
[Uses]

When other antimicrobial drugs that are equally effective and potentially less toxic are available, they should be used instead of chloramphenicol

Topically in eye-not in skin