UNIVERSITY OF ADEN

FACULTY OF PHARMACY
DEPARTMENT OF PHARMACOLOGY

ANTIMICROBIAL DRUGS
Part 2

Prepared by :Dr. Saba Adel

1
At the end of this lecture should be able to Understand:
 The pharmacological charactestics of Aminoglycoside
 2- The pharmacological charactestics of MACROLIDE
 3-The pharmacological charactestics of LINCOSAMIDE
 4The pharmacological charactestics of -
OXAZOLIDINONES
 5-The pharmacological charactestics of Tetracyclin
 6-The pharmacological charactestics of
Chloramphenicol
AMINOGLYCOSIDES
 AMINOGLYCOSIDES
 These are a group of natural and semisynthetic Antibiotics
 Unlike penicillin, which was a chance discovery,
aminoglycosides are products of deliberate search for
drugs effective against gram-negative bacteria.
 Streptomycin was the first member discovered
 All aminoglycosides are produced by soil actinomycete
1-Mechanism and mode of action
 all having the same general pattern of action
 which may be described in two main steps:
(a) Transport of the aminoglycoside through the bacterial cell wall
and cytoplasmic membrane.
(b) Binding to ribosomes resulting in inhibition of protein synthesis.
These drugs bind to 30S ribosomal units and prevent the formation
of“initiation complex” – a prerequisite for peptide synthesis.
 Rapidly acting bactericidal
2-PHARMACOKINETICS
 highly ionized, and are neither absorbed nor destroyed in the g.i.t .

 Aminoglycosides cross placenta .

 Don’t cross the BBB .
 Aminoglycosides are excreted unchanged in urine..
 Common properties of aminoglycoside
antibiotics

1. All are used as sulfate salts, which are highly water

soluble; solutions are stable for months.

2. They ionize in solution; are not absorbed orally;

distribute only extracellularly; do not penetrate brain
or CSF.

3. All are excreted unchanged in urine by glomerular

filtration.

4. All are bactericidal and more active at alkaline pH.

5. They act by interfering with bacterial protein synthesis.

6. All are active primarily against aerobic gram-negative
bacilli and do not inhibit anaerobes.

7. There is only partial cross resistance among them.

8. They have relatively narrow margin of safety.
9. All exhibit ototoxicity and nephrotoxicity

spectrum-3
Narrow spectrum: Aerobic gram negative bacilli, Not
effective against gram positive cocci & bacilli ,gram
negative cocci , and anaerobes
adverse effect-4
)SEE TABLE 53.1 about Comparative toxicity of aminoglycoside(
Nephrotoxicity-1
Ototoxicity -2
Neuromuscular blockade -3
 Classification of aminoglycoside
Systemic
aminoglycosides
 Streptomycin
 Amikacin Topical
 Gentamicin aminoglycosides
 Neomycin
 Sisomicin
 Kanamycin  Framycetin
Netilmicin
 Tobramycin
Paromomycin
 Streptomycin
The antimicrobial spectrum of streptomycin is
relatively narrow: primarily covers aerobic gram-
negative
Adverse effects
Streptomycin has the lowest nephrotoxicity
among aminoglycosides; probably why because it
is not concentrated in the renal cortex.
 Uses
1. Tuberculosis:
2. Sub acute bacterial endocarditis
3. Plague: effective agent for all forms of plague.
4. Tularemia:

streptomycin was used earlier, gentamicin or one of the newer

aminoglycosides is now preferred Due to widespread resistance to
streptomycin and its low potency
 Gentamicin
• quickly surpassed streptomycin because of
higher potency and broader spectrum of
activity

• It is active mainly against aerobic gram negative

pneumoniae, Enterobacter, H. influenzae,
bacilli, including E. coli, Klebsiella Proteus,
Serratia and Pseudomonas aeruginosa.
 Uses
1. Gentamicin is very valuable for preventing and treating
respiratory infections
2. Pseudomonas, Proteus or Klebsiella infections: burns,
urinary tract infection, pneumonia, lung abscesses
Meningitis caused by gram negative bacilli: (The third .3
generation cephalosporins alone or with an aminoglycoside
4. Subacute bacterial endocarditis (SABE):
Gentamicin (1 mg/kg 8 hourly i.m.) is generally
combined with penicillin/ampicillin/vancomycin.
TETRACYCLINE
Tetracyclins
1-Mechanism and mode of action
• Reversibly bind 30S ribosomal subunit
• Blocks attachment of tRNA to ribosome
• Prevents continuation of protein synthesis
• Bacteriostatic
2-Spectrum:
Effective against certain Gram (+) and
Gram (-), like rickettsia ,. amebic
parasites mycoplasma ,uroplasma
Chlamydia
 3-classification and pharmacoknetics :
Third group III second group II First group I

Doxycycline Democlocycline Tetracycline

Minocycline Methathcycline Oxytetracycline
Chlortetracycline
high intermediate low Potency

not affect by food intermediate intermediate Absorption

high high low Bind to plasma

protein:
side effects-4

• 1-Common : abdominal cramps or burning of the

stomach, diarrhea, sore mouth or tongue.
• 2- skin photosensitivity.
• 3-Teeth and bone deformity (chelating property)
brown discoloration of teeth.
• 4should not be used in children under the age of 8
years old
MACROLIDE
 MACROLIDE
These are antibiotics having a macrocyclic
lactone ring with attached sugars.
Erythromycin is the first member discovered
in the 1950s, Roxithromycin, Clarithromycin
and Azithromycin are the later additions.
 MACROLIDE

A) ERYTHROMYCIN
1- Mechanism & mode of Action
• Erythromycin is bacteriostatic at low levels
• cidal at high concentrations and (for certain bacteria only) depends
on the organism concerned & its rate of multiplication.
• It combines with 50S ribosome subunits and interferes with
‘translocation’ so the ribosome fails to move along the mRNA to
expose the next codon
2- Antimicrobial spectrum
- narrow, includes mostly gram-+ve and a few gram – ve bacteria
- Erythromycin is highly active against Str. pyogenes & Str. pneumoniae,
N. gonorrhoeae, Clostridia, C. diphtheriae

3- Resistance
- cocci : due to acquiring the capacity to pump it out
- gram-positive bacteria :due to alteration in the ribosomal binding site
a plasmid action

Note :Bacteria that develop resistance to erythromycin are

cross resistant to other macrolides
- Cross resistance with clindamycin & chloramphenicol also
occurs, because the ribosomal binding sites for all these
antibiotics are proximal to each other
4-Pharmacokinetics
• Erythromycin base is acid labile.
• enteric coated tablets, To protect it from gastric acid but incomplete
absorption
• food delays absorption by retarding gastric emptying.
• Its acid stable esters are better absorbed
• not pass blood brain barrier
• Excretion primarily in bile
5- Adverse effects
abdominal pain , diarrhea, Hypersensitivity: ( Rashes and
fever , infrequent )
7- Uses
A. As an alternative to penicillin
B. As a first choice :
1. Atypical pneumonia caused by Mycoplasma pneumoniae
2. Whooping cough (alternative Azithromycin, claritromycin)
3. Chancroid:2 g/day for 7 days (single dose azithromycin or
ceftriaxone)

New macrolides:
limitations of erythromycin
narrow spectrum, gastric intolerance, gastric acid
lability, low oral bioavailability, poor tissue
penetration short half-life,
B) Clarithromycin
1-antimicrobial spectrum: same to erythromycin
More active: Mycobact. avium complex (MAC),other atypical
mycobac. Helicobacter pylori Moraxella, Legionella
Mycoplasma pneumoniae
2- :Pharmacokinetics
• more acid-stable than erythromycin, rapidly absorbed;
• oral bioavailability ~50% due to first pass metabolism; less interactions
food delays but does not decrease absorption.
• larger tissue distribution than erythromycin
• An active metabolite is produced.
About 1/3 of an oral dose: excreted unchanged in urine (no change dose)
3- Uses:
upper &lower respiratory tract infections, sinusitis, otitis media,
whooping cough, atypical pneumonia, skin infections
c)Azithromycin
1-Expanded spectrum,
- Improved pharmacokinetics,
- better tolerability and drug interaction profile
- More active against H. influenzae, but less active against gram-
positive cocci ,High activity: on respiratory pathogens—
Mycoplasma, Chlamydia pneumonia , Legionella, Moraxella

2- :Pharmacokinetics

remarkable acid-stability, rapid oral absorption (from

empty stomach), larger tissue distribution & intracellular penetration
(inside macrophages)
• largely excreted unchanged in bile, renal excretion is ~ 10%.
3.Uses
• First choices antibiotics :
(a) Legionnaires’ pneumonia: 500 mg OD oral/i.v. for 2 weeks.
Erythromycin or a FQ (alternatives)
(b) Chlamydia trachomatis: nonspecific urethritis & genital
infections in both men and women —1 g single dose is curative
(c) Chancroid and NG urethritis: single 1.0 g dose is highly curative
• Other uses: pharyngitis, tonsillitis, sinusitis, otitis,
pneumonias,
prophylaxis and treatment of MAC in AIDS patients
Multidrug resistant typhoid fever in patients allergic to
cephalosporins; and in toxoplasmosis
NOTE :Because of higher efficacy, better gastric tolerance
and once a day dosing, azithromycin is now preferred
D) Spiramycin (resembles erythromycin)
• macrolide antibiotic
• limit risk of transplacental transmission of
Toxoplasma gondii infection
• for toxoplasmosis and recurrent abortion in
pregnant women;
3 week courses of 3 MU 2–3 times a day
Then repeated after 2 week gaps till delivery.
OXAZOLIDINONES
OXAZOLIDINONES
Linezolid
-First member /treat resistant gram-positive coccal (aerobic and
anaerobic) and bacillary infections. (not gram –ve bacteria )
- active against MRSA &penicillin-resistant Strep. pyogenes, Strep.
Viridans and Strep. pneumoniae.
- sensitive bacteria also: Clostridia, Bacr. fragilis and M. tuberculosis
- Primarily bacteriostatic, but cidal against some sensitive bacteria
- orally o r i.v. for uncomplicated &complicated skin & soft tissue
infections,
- use should be restricted to serious HAPs, febrile neutropenia, wound
infections and others caused by multidrug-resistant gram +ve bacteria
such as vancomycin resistant and MRSA,
- Being bacteriostatic, it is not suitable for treatment of enterococcal
endocarditis.
- Linezolid is used as a reserve drug for extensively drug resistant (XDR)
TB.
Dose: 600 mg BD, oral/ i.v
LINCOSAMIDE ANTIBIOTICS
LINCOSAMIDE ANTIBIOTICS : Lincomycin Clindamycin
• Similar in MOA and spectrum of activity to erythromycin
• the distinctive feature is its high activity against a variety of
anaerobes, especially Bact. fragilis.
• Oral absorption of clindamycin is good.
• It penetrates into most skeletal and soft tissues, but not in brain and
CSF; accumulates in neutrophils and macrophages.
• major problem is diarrhoea and pscudomembranous entcrocolitis
due to Clostridium difficile super-infection which is potentially fatal
• The drug should be promptly stopped and oral metronidazole(or
vancomycin)
• Because of the potential toxicity: use is restricted to anaerobic &
mixed infections 1st line,(involving Bact. fragilis causing abdominal,
pelvic and lung abscesses, septic abortion, penetrating injuries.
(comb. With aminog. Or cephalosp.)
• Topically it is used for infected acne vulgaris. Dose: 150-300 mg (children
3-6 mg/kg) QID oral;
200-600 mg i.v. 8 hourly
Chloramphenicol
Chloramphenicol
– Binds to 50S ribosomal subunit
• Prevents peptide bond formation
– Wide spectrum
– penetrate blood brain barrier,
wide distributed
– conjugate glucuronic acid in liver
& execrated unchanged in urine
Avoided repeated
– Cirrhotic and neonate has low course .daily dose
conjugating ability, require low should not exceed 2-3g.
dose Not more than 10
days.
Blood count should
require during therapy
Side effects:

1-Bone marrow depression .

2-Hypersesitivity reaction.
3-superinfection.
4-Gray baby syndrome:-
• specially in premature baby (stop feeding,
vomiting, hypnotic ,hypothermic, abdominal
distention, respiratory distress cyanosis
cardiovascular collapse &death)