URDANETA CITY College of Pharmacy

UNIVERSITY
Owned and operated by the City Government of Urdaneta

ANTIBIOTICS
II. PROTEIN SYNTHESIS INHIBITORS
1. Aminoglycosides
- Poorly absorbed orally
- Used to treat systemic infections
- Basic compounds with good water solubility
- Spectrum of activity
 Aerobic gram- negative bacilli
 Less sensitive to aerobic gram negative and gram positive cocci except Staph
- Consists of two amino sugars joined in glycosidic linkage to a hexose nucleus
- The hexose may be Streptidine or 2- deoxystreptamine
- Spectinomycin: only aminoglycoside without an amino sugar

- History and source:

 Aminoglycosides are natural products or semi-synthetic derivatives of compounds
produced by a variety of soil actinomycetes
 Streptomycin: first antibiotic to be used in chemotherapy by Schatz and associates
 (- micin)- from Micromonospora spp, Fam. Actinomycetes
 (-mycin)- from Streptomyces spp, Fam. Actinomycetes

- Mechanism of action:
 Binds to 30s ribosomal subunit and interferes with initiation protein synthesis resulting
to blocking of initiation of protein synthesis, premature termination of translation
 Incorporation of incorrect amino acids leading to mutation
 AUG (methionine)- this is the start codon
 UAG, UGA, UAA - these are the stop codon

- Aminoglycosides are always BACTERIOSTATIC

- Microbial resistance:
 Failure of antibiotic to penetrate intracellularly
 Low affinity of drug to bacterial ribosome
 Inactivation by microbial enzymes

- Untoward effects:
 Ototoxicity:
 Cochlear: high pitched tinnitus, auditory impairment
 Vestibular: moderately intense headache, labyrinthine dysfunction, mental past
pointing, spontaneous nystagmus, balance
 Nephrotoxicity:
 Due to accumulation and retention of aminoglycoside in the renal proximal
tubular cells
 Neuromuscular blockade:
 Acute inability to move and may complicate to apnea
 Ca salts may be administered
 Allergic potential:
 Minimal; anaphylaxis and rash are unusual

Compiled by:
Maricar Grace F. Mararac, RPh
 URDANETA CITY College of Pharmacy
UNIVERSITY
Owned and operated by the City Government of Urdaneta

 Conraindication:
 Myasthenia gravis

 MNEMONIC ON UNTOWARD EFFECTS:

A-llergic potential
M-uscular blockade
I-ncompatible with penicillins (physical incompatibility).
N-ephrotoxic
O-totoxic

DRUGS CLASSIFIED AS AMINOGLYCOSIDES:

a. Streptomycin
- From Streptomyces griseus
- Administered deep IM or IV
- Poorly absorbed orally
- Uses: bacterial endocarditis, tularemia, plague, tuberculosis

b. Tobramycin
- From Streptomyces tenebrarius
- most active among Nebramycins
- 2- 4x activity against Pseudomonas aeruginosa than Gentamicin
- Brand names: Nebcin, Tobrex

c. Neomycin
- From Streptomyces fradiae
- Uses: treatment of GI infections, skin infections and peritonitis
- Decreased absorption, no systemic effect
- Combined with Polymyxin and Bacitracin
- Available topical and oral
- Nephrotoxic

d. Spectinomycin
- No amino sugar in the structure
- From Streptomyces spectabilis
- Most inferior aminoglycoside
- Use: uncomplicated gonorrhoea that is caused only be N. gonorrheae
- Has a least bactericidal effect

e. Gentamicin
- From Micromonospora pupurea
- Has string activity against Pseudomonas

f. Netilmicin
- From Micromonospora inyoensis
- Used to treat infections caused by Gentamicin resistant strains
- Latest aminoglycoside to be marketed
- Resistant to aminoglycosides modifying enzymes

Compiled by:
Maricar Grace F. Mararac, RPh
 URDANETA CITY College of Pharmacy
UNIVERSITY
Owned and operated by the City Government of Urdaneta

g. Kanamycin
- From Streptomyces kanamyceticus
- Obsolete with few indications
- Brand name: Kantrex

h. Amikacin
- Derivative of Kanamycin produced in Japan with broadest spectrum of activity
- Brand name: Amikin
- Preferred agent for the initial treatment of serious nosocomial gram negative bacillary infections
in hospitals.
- Agent is resistant to gentamicin and tobramycin has become significanr problem.

Other uses of aminoglycosides:

- Pneumonia
- Meningitis
- Urinary tract infections
- Peritoneal dialysis associated with peritonitis
- Bacterial endocarditis
- Sepsis

2. Tetracyclines
- History and source
 Chlortetracycline- prototype drug
 Semi- synthetic
 Doxycycline, Minocycline, Methacycline
 Natural source
 Oxytetracycline- from Streptomyces rimosus
 Demeclocycline- product of mutant strain of Streptomyces aureofaciens
- Broad spectrum, bacteriostatic agents
- Contain four fused rings with a system of conjugated double bonds
- Forms stable complexes with trivalent and divalent cations
- Close congeners of polycyclic naphthacene carboxamide
- Mechanism of action:
 Inhibit bacterial protein synthesis by binding to the 30s subunit and blocking tRNA binding
to the A site.
- Bacterial resistance:
 Decreased antibiotic influx or acquisition of an energy dependent efflux pathway
 Production of a ribosomoal protection protein that displaces tetracycline from its target
 Enzymatic inactivation of tetracyclines
- Untoward effects: Take not that tetracyclines should NOT be taken with Calcium
 Gastrointestinal irritation
 Photosensitivity
 Hepatic and renal toxicity
 Discoloration of the teeth- because TCN will bind with the calcium present in the teet
 Stunting of growth

Compiled by:
Maricar Grace F. Mararac, RPh
 URDANETA CITY College of Pharmacy
UNIVERSITY
Owned and operated by the City Government of Urdaneta

 Teratogenic- therefore is should not be taken by pregnant women as it may affect in the
development of baby’s skeletal system

3. Macrolides
 HISTORY
- Picromycin: 1st macrolide discovered
- Erythromycin: discovered in 1952 by McGuire and co- workers in the
metabolic products of Streptomyces erythraeus
- Ilotycin: Saccharopolyspora erythreus (Erythromycin succinate, an ester
prodrug which was discovered in Ilo- ilo

 CHEMISTRY
- Contain a many membered lactone ring
- 14- membered ring: Erythromycin and Clarithromycin
- 15- membered ring: Azithromycin
- Basic in nature due to the presence of a glycosidically linked amino sugar (bitter tasting)

 SPECTRUM OF ACTIVITY
- Used as an alternative to penicillins
- Active against aerobic and anerobic gram positive cocci EXCEPT for most Enterococci, many S.
aureus strains especially MRSA and some strains of S. pneumoniae and S. pyogenes strains
- Active against: M. pneumoniae, C. trachomatis, C. pneumoniae, Legionella spp, C. diphtheria,
Campylobacter spp, T. pallidum, Propionibacterium acnes, B. burgdorferi
- DOC: group A Streptococcal and Pneumococcal infections when penicillin cannot be used
- Low activity against gram negative bacteria

 MECHANISM OF ACTION
- Inhibits protein synthesis by binding reversibly to 50s ribosomal subunits of sensitive
microorganisms resulting to inhibition of translocation, conformational change that terminates
protein synthesis by interfering with transpeptidation and translocation.

 DRUGS CLASSIFIED UNDER MACROLIDES

A. ERYTHROMYCIN
- Free base is bitter and has irregular oral absorption which is destroyed by stomach acid. Food
interferes with absorption.
- Salts of Erythromycin: Lactobionate, Estolate, Stearate, Ethylsuccinate, Propionate, Gluceptate
- Salts can cause hepatotoxic effects such as cholestatic jaundice because bilirubin is not
metabolized properly
- Salts can increase the bioavailability even after oral absorption
- ADR: GI distress, hepatotoxicity, acute cholestatic hepatitis, fever, eosinophilia, rashes, CYP 450
inhibitor
- CLINICAL USES:
1. DOC: Corynebacteria infection such as diphtheria, corynebacterial sepsis, erythrasma
2. Respiratory neonatal, ocular or genital chlamydial infections
3. Treatment of CAP
4. Substitute in penicillin allergic individuals
5. Uncomplicated skin infections
6. Acne

Compiled by:
Maricar Grace F. Mararac, RPh
 URDANETA CITY College of Pharmacy
UNIVERSITY
Owned and operated by the City Government of Urdaneta

7. Bowel preparation before GI tract surgery (taken orally and used with an oral aminoglycoside)

B. CLARITHROMYCIN
 SPECTRUM OF ACTIVITY
- 6- methyl ether of erythromycin
- Increases stability and oral bioavailability than Erythromycin
- More active than Erythromycin against S. pneumoniae
- Presence of food does not significantly affect absorption
- CYP 3A4 enzyme inhibitor

C. AZITHROMYCIN
- Semi- synthetic analogue of Erythromycin
- Has unique pharmacokinetic properties (give it once a day for 3 days but sometimes can be given
for 5 or 7 days)
- Does not inactivate CYP 450 enzymes
- Not be administered with food

D. KETOLIDES (TELITHROMYCIN)
- Has more potent activity
- Semi- synthetic derivatives of erythromycin
- Effective against macrolide resistant gram positive strains
- Reversible inhibitor of CYP 3A4 enzyme system
- CI: should not be used in patients with myasthenia gravis because it can worsen the condition.

E. Fidaxomicin
- Minimal to no activity against gram negative bacteria but is bactericidal against Clostridioides
difficile

4. CHLORAMPHENICOL
 HISTORY
- Produced from Streptomyces venezuelae
- Introduced to clinical practice in 1948
- May cause fatal blood dyscrasias
- Contains nitrobenzene moiety and is a derivative of dichloroacetic acid

 MECHANISM OF ACTION
- Binds to the 50s ribosomal subunit at the peptidyl transferase site and inhibits the
transpeptidation reaction thereby inhibiting protein synthesis in bacteria but lesser extent to
humans
- It can also inhibit the mitochondrial protein synthesis in mammalian cells (70s ribosome)

 SPECTRUM OF ACTIVITY
- Primarily bacteriostatic
- Wide spectrum activity against gram positive and gram negative cocci and bacilli including
anaerobes
- Wide spectrum activity against Rickettsia, Mycoplasma, Chlamydia spp

Compiled by:
Maricar Grace F. Mararac, RPh
 URDANETA CITY College of Pharmacy
UNIVERSITY
Owned and operated by the City Government of Urdaneta

 UNTOWARD EFFECTS
- Bone marrow depression
- Nausea, vomiting, diarrhea
- Gray baby syndrome
- Hypersensitivity reactions
- Haematological disorders (blood dyscrasia)
- CYP 450 inhibitor

 SALT
- Chloramphenicol palmitate

5. LINCOMYCINS
 SPECTRUM OF ACTIVITY
- Sulphur containing antibiotics isolated from Streptomyces lincolnensis
- Resemble macrolides in spectrum of activity
- Distributed widely in tissues
- Primarily bacteriostatic

A. CLINDAMYCIN
 CHEMISTRY
- Chlorine substituted derivative of lincomycin

 MECHANISM OF ACTION
- Inhibits protein synthesis by interfering with the formation of initiation complexes and with
aminoacyl translocation reactions. It binds with 50s subunit of bacterial ribosome which then
inhibits protein synthesis.

 CLINICAL USES
- Effective for infections due to anaerobes particularly Bacteroides spp, community acquired
methicillin resistant S. aureus and macrolide resistant, Clindamycin susceptible S. pneumonia
- Treatment of skin and soft tissue infections caused by Streptococci and Staphylococci.
- Reserved for the treatment of Staphylococcal tissue infections, cellulitis, and osteomyelitis in
penicillin sensitive patients
- Cannot penetrate the cerebrospinal fluid

 UNTOWARD EFFECTS
- Antibiotic associated colitis
- Clindamycin, Erythromycin, Chloramphenicol interaction
- Neutropenia
- Skin rashes
- Diarrhea, nausea
6. STREPTOGRAMINS
 MECHANISM OF ACTION
- Same mechanism with macrolides and clindamycin which inhibits protein synthesis

A. Quinupristin- Dalfopristin
- Combination of 2 streptogramins: Quinupristin (Streptogramin B) and Dalfopristin (Streptogramin
A)

Compiled by:
Maricar Grace F. Mararac, RPh
 URDANETA CITY College of Pharmacy
UNIVERSITY
Owned and operated by the City Government of Urdaneta

- Has synergistic bactericidal activity for most susceptible organisms except Enterococcus faecium
which is killed slowly
- Active against Streptococci and Staphylococci including strains resistant to other antibiotic class,
some gram negative anaerobic bacilli, Clostridium perfringens, Atypical respiratory pathogens
caused by Mycoplasma pneumoniae, Chlamydophila pneumonia and Legionella pneumophila

 UNTOWARD EFFECTS
- Pain at the infusion site
- Arthralgia- myalgia syndrome
- CYP 3A4 inhibitor

7. OXAZOLIDINONES
 MECHANISM OF ACTION
- Inhibits protein synthesis by preventing formation of the ribosome complex that initiates protein
synthesis by binding to 23s ribosomal subunit of the 50s subunit, resulting to no cross resistance
with other drug classes.

A. Linezolid
- Has activity against Streptococci, Enterococci including the Vancomycin resistant E. faecium,
Staphylococci including MRSA and other strains resistant to other classes of antibiotics,
Mycobacteria, anaerobes such as Fusobacterium, Prevotella, Porphyromonas and Bacteroides spp

 CONTRAINDICATIONS
- Patients with a prior allergic reactions to it
- Risk factors for serotonin syndrome or hypertension

Compiled by:
Maricar Grace F. Mararac, RPh