PROTEIN SYNTHESIS INHIBITORS

Broad spectrum agents acting on the 30S subunit

• Tetracycline

• Aminoglycosides

Broad spectrum agents acting on the 50S subunit

• Ketolides/Macrolides

• Chloramphenicol

Narrow spectrum agents acting on the 50S subunit

• Linezolid

• Streptogramins

• Lincosamide

Chloramphenicol:

MOA 

Binds to 50S & inhibits formation of peptide bond

Tetracycline

MOA

Binds to 30S & interfere with binding of tRNA to ribosomal complex

Aminoglycosides

MOA

• Bind to 30S & causes mRNA codon to be misread

• Interfere with the initiation complex of 30S & 50S with mRNA

Macrolides, Clindamycin & Streptogramins:

MOA

Block polypeptide exit tunnel on 50S & prevent peptide chain elongation

Linezolid

• Binds to 50S & prevents formation of 50S/30S ribosomal complex

• Binds to the 23S ribosomal subunit of the 50s RNA subunit

TETRACYCLINE

• drugs

• doxycycline

• minocycline 

• demeclocyline

• tigecycline 

Free tetracycline

are crystalline amphoteric substance of low solubility

TETRACYCLINE

• Available as hydrochloride

• Chelates with divalent ions

TETRACYCLINE

spectrum & action

• Broad spectrum

• Bacteriostatic

• Inhibits protein synthesis

TETRACYCLINE

target bacteria

Active against gram-positive and gram-negative bacteria, including:

• anaerobes

• rickettsia

• chlamydia 

• mycoplasma

May also work against some protozoan infection

TETRACYCLINE

administration

• Often used orally

TETRACYCLINE

• Wide-spread resistance through major mechanisms

• Development of efflux pumps for active ejection of tetracycline

• Ribosomal protection proteins that prevent binding

• Enzymatic inactivation

Proteus and Pseudomonas

have multidrug pumps

Absorbed tetracycline

may remain in the gut and affect the normal flora and excreted in the feces

TETRACYCLINE

pk

• Absorption mainly occurs in the upper small intestine

• 40-80% bound to serum protein

• Excreted mainly in bile and urineall intestine

ABSORPTION AND ELIMINATION: CHLORTETRACYCLINE

30% 

TETRACYCLINE

ABSORPTION AND ELIMINATION: 

• TETRACYCLINE

• OXYTETRACYCLINE

• DEMECLOCYCLINE

• METHACYCLINE

60-70%

ABSORPTION AND ELIMINATION: 

• DOXYCYCLINE

• MINOCYCLINE

95-100%

DOXYCYCLINE

• long duration of action

• relatively low toxicity

• severe liver adverse effects

DOXYCYCLINE

Used in 

• acne

• bronchitis prevention and 

• leptospirosis prevention

MINOCYCLINE

also used in acne

DEMECLOCYCLINE

• also has a diuretic effect

• used in ADH (antidiuretic hormone) secreting tumor

TIGECYCLINE

• broad spectrum

• IV use only

• poorly absorbed in the GI

• administered IV

TIGECYCLINE

Used in:

• tetracycline resistance

• MRSA

• VRE

• β-lactamase producers

• anaerobes

• mycobacteria

• chlamydia

TETRACYCLINE ADVERSE EFFECTS 

• gi symproms

• photosensitivity 

• contrraindicates in pregnant, bf, and children <8 yrs

MINOCYCLINE ADR

• Vestibular 

  • dizziness

  • ataxia

  • N&V

• Skin and mucous membrane pigmentation

• Lupus-like symptoms

• cross-reactivity may occur 

TETRACYCLINE IV ADR

phlebitis

MACROLIDES

spectrum

• Broad-spectrum

• Active against gram-positive organisms including penicillin- resistant streptococci

• Effective against:

  • Chlamydia

  • Mycoplasma

  • Ureaplasma

  • and spirochetes

MACROLIDES

MECHANISM

• Bacteriostatic

• Binds to the 50S RNA subunit

• The binding site is near the peptidyl transferase center and peptide chain elongation is prevented by blocking of the polypeptide exit tunnel

MACROLIDES

drugs 

• azithromycin

• clarithromycin

• erythromycin 

• telithromycin 

MACROLIDES

STRUCTURE

• Macrocyclic lactone ring (usually 14 or 16 atoms) to which deoxy sugar is attached

TELITHROMYCIN

• greater in vitro activity against multidrug resistant gram-positive organism and Haemophilus influenzae compared to erythromycin

ERYTHROMYCIN BASE

problem 

Destroyed by stomach acid and must be administered with enteric coating

ERYTHROMYCIN BASE

pk

• Food interferes with absorption

• serum half life approximately 1.5 hours normally and 5 hours in patients with anuria

• Excreted in the bile and feces and only 5% is excreted in urine

• Widely distributed except in the brain and CSF

• Traverses placenta and reaches the fetus, non-dialysable

ERYTHROMYCIN BASE

• as traditional doc for

• corynebacterial infection

• chlamydial infection 

• CAP 

• penicillin substitute

• prophylaxis 

ERYTHROMYCIN BASE

• as traditional doc for corynebacterial infection

• diphtheria

• corynebacterial sepsis

• erythrasma

ERYTHROMYCIN BASE

• as traditional doc for CHLAMYDIAL INFECTION

• respiratory

• neonatal

• ocular or genital

ERYTHROMYCIN BASE

• as traditional doc for: used as _

• penicillin substitute in penicillin-allergic individual with infection caused by staphylococci and streptococci

ERYTHROMYCIN BASE

• as traditional doc for: prophylaxis against 

• endocarditis during dental procedure in individuals with valvular heart disease

CLARITHROMYCIN

srructure 

CLARITHROMYCIN

pk 

• Has improved acid stability and oral absorption

• 500 mg produces serum concentration of 2-3 mcg/mL

• Longer half-life (6 hours) compared to erythromycin

• Excreted in the urine

• Metabolized in the liver

• Penetrates most tissues well

CLARITHROMYCIN

More active against

• Mycobacterium avium complex

CLARITHROMYCIN

• Has activity against

• Mycobacterium leprae, Toxoplasma gondii and H. influenzae

CLARITHROMYCIN

Dose reduction in patients with

CrCl < 30 mL/min

AZITHROMYCIN

structure 

15-atom lactone macrolide ring compound

AZITHROMYCIN

STRUCTURAL MODIFICATION

Addition of methylated nitrogen into the lactone ring (similar with clarithromycin)

AZITHROMYCIN

clinical  use 

Similar clinical use like clarithromycin

AZITHROMYCIN

activity

Active against M. avium complex and T. gondii

AZITHROMYCIN

compared activity

• Slightly less active than erythromycin and clarithromycin against staphylococci and streptococci 

• slightly more active against H. influenzae

AZITHROMYCIN

SERUM CONCENTRATION

500 mg produces relatively low serum conc (0.4 mcg/mL)

AZITHROMYCIN

TISSUE PENETRATION

Penetrates into most tissues except CSF and phagocytic cells extremely well

AZITHROMYCIN

ELIMINATION HALF-LIFE

3 days 

AZITHROMYCIN

absorption & administration

• Rapidly absorbed and well-tolerated orally

• Administered one hour before or two hours after meals

MACROLIDES ADVERSE EFFECTS

adr

• gi 

• local effet carbiac

• toxicity 

MACROLIDES ADVERSE EFFECTS

gi

• Stimulates motility leading to abdominal pain and cramping, nausea, vomiting and diarrhea

• Clarithromycin

  • least stimulating to GIT

MACROLIDES ADVERSE EFFECTS

local effect

When given IV, it can cause venous irritation and thrombophlebitis (erythromycin lactobionate)

MACROLIDES ADVERSE EFFECTS

CARDIAC

QT interval prolongation and torsades de pointes

KETOLIDES

Semi-synthetic 14-membered ring macrolide

KETOLIDES

structural change 

Substitution of a 3-keto group for a neutral sugar L-cladinose

TELITHROMYCIN

use 

limited use 

TELITHROMYCIN

SPECTRUM / ACTIVITY Active against

• Streptococcus pyogenes, S. pneumoniae, 

• S. aureus, 

• H. influenzae, 

• Moraxella catarrhalis, 

• Mycoplasma sp., 

• L. pneumophila, 

• Chlamydia sp., 

• H. pylori, 

• Neisseria gonorrhea, 

• B. fragilis, 

• T. gondii, and 

• certain non-TB mycobacterium

TELITHROMYCIN

pk 

• Oral bioavailability (57%) and tissue and intracellular penetration is generally good

• metabolized in liver 

TELITHROMYCIN

enzyme effect

Reversible inhibitor of CYP3A4 enzyme

TELITHROMYCIN

cardiac effecct 

May slightly prolong QT interval

TELITHROMYCIN

ci 

Contraindicated in patients with myasthenia gravis

LINCOSAMIDE

DRUGS 

clindamycin 

CLINDAMYCIN

origin 

Chloride derivative of Lincomycin from Streptomyces lincolnensis

CLINDAMYCIN

mechanism of action 

Inhibits the 50S subunit

May be bacteriostatic or bactericidal

CLINDAMYCIN

• Active against

• most aerobic gram-positive and

• most anaerobic gram-negative bacteria

CLINDAMYCIN

No activity against

aerobic gram-negative bacteria

CLINDAMYCIN

pk 

• 90% protein bound

• Penetrates well in most tissues except CSF and BBB

• Metabolized in the liver, both active drug and active metabolite are excreted in bile and urine

• half life 2.5 hours in normal individual, 6 hours for patient with anuria

CLINDAMYCIN

dose adjustment 

No dose adjustment required for patients with renal failure

LINCOSAMIDE ADVERSE EFFECTS

gi 

N&V, diarrhea, abdominal pain, tenesmus

LINCOSAMIDE ADVERSE EFFECTS

iv admin 

Thrombophlebitis, erythema, pain, and swelling at the IV site

LINCOSAMIDE ADVERSE EFFECTS

• Transient leukopenia, neutropenia, eosinophilia, thrombocytopenia, and agranulocytosis

STREPTOGRAMINS

drugs

Quinupristin-dalfopristin

Quinupristin-dalfopristin

(combination of 2 streptogramins)

Quinupristin

(Streptogramin B),

Dalfopristin

Streptogramin A)

STREPTOGRAMINS

mechanism

• Shares same ribosomal binding site as macrolides and clindamycin

STREPTOGRAMINS

mechanism: quinupristin

inhibits late phase protein synthesis

STREPTOGRAMINS

mechanism: dalfopristin 

inhibits early phase protein synthesis

STREPTOGRAMINS

action

Bactericidal with post-antibiotic effect

STREPTOGRAMINS

• bacteria targeted

• Active against gram-positive cocci, including multidrug-resistant strains: 

  • streptococci, 

  • penicillin-resistant S. pneumoniae, 

  • methicillin-susceptible/ resistant staphylococci, 

  • E. faecium

STREPTOGRAMINS

• administration

Administered IV, 7.5 mg/kg every 8-12 hours

STREPTOGRAMINS

pk

• Rapidly metabolized in the liver, inhibits CYP3A4

• Quinupristin: 0.85 hours

• Dalfopristin: 0.7 hours

• excretion: fecal 

STREPTOGRAMINS

toxicity 

Painful injection site, myalgia, arthralgia, thrombophlebitis, hyperbilirubinemia

 CHLORAMPHENICOL

pk

• Soluble in alcohol but poorly soluble in water

• Wide distribution, crosses BBB

• Inactivated in the liver, minimal renal excretion

 CHLORAMPHENICOL

action 

Bacteriostatic (Haemophilus, Neisseria, Bacteroides)

 CHLORAMPHENICOL

• indicaions 

Back-up drug against Salmonella, Pneumococcal disease, meningococcus

 CHLORAMPHENICOL

• not active against 

chlamydia 

 CHLORAMPHENICOL

resistance 

• through a plasmid-mediated formation of an enzyme (acetyltransferase) that inactivates the drug

 CHLORAMPHENICOL

adr

• Direct irritation

• Superinfection

• Aplastic anemia

• Gray baby syndrome

LINEZOLID

• member of the

oxazolidinone

LINEZOLID

bacteria targeted

• Active against gram-positive organisms including:

  • Staphylococci,

  • Streptococci,

  • Enterococci,

  • Gram-positive anaerobic cocci and

  • Gram-positive rods such as 

    • corynebacterial, 

    • Nocardia sp., and 

    • L. monocytogenes

LINEZOLID

moa

• Binds to the 23S ribosomal subunit of the 50S RNA subunit

• Weak MAO inhibitor

LINEZOLID

pk 

• 100% bioavailable after oral administration

• half-life 4-6 hours

• Metabolized by oxidative metabolism