ANTIBACTERIAL DRUGS

(INHIBITORS OF PROTEIN SYNTHESIS)

Lecturer University of Zambia

School of Health Sciences
Pharmacy Department

Kampamba .M
 Learning Objectives:

At the end of this session, YOU should be able to:

1. Classify inhibitors of protein synthesis antibacterial drugs

2. Explain correctly the mechanism of action of antibacterial

drugs

3. Explain correctly the pharmacokinetic considerations &

adverse effects of antibacterial drugs

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INHIBITORS OF PROTEIN SYNTHESIS
• Aminoglycosides
• Tetracyclines
• Macrolides
• Chloramphenicol
• Linconsamide
• Linezolid

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 Aminoglycosides
Mode of action:
• Bactericidal
• Bind irreversibly to 30S ribosomal bacterial subunits leading
to inhibition of protein synthesis
• Effective bactericidal activity against:
– Aerobic gram-negative bacilli
– Few Aerobic gram- positive bacteria
– Mycobacteria (streptomycin)
– Few Protozoa
– MDR TB. Kanamycin, Amikacin
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 Examples

– Gentamicin
– Amikacin ( widest antimicrobial activity)
– Neomycin
– Streptomycin
– Tobramycin ( preferred for P. Aeruginosa infection )
– Kanamycin
– Netilmycin

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Pharmacodynamics
• Resistance associated with drug failure
include:
– Inability to cross cell membrane
May be used with penicillin to aid entry of
aminoglycoside
– Altered ribosomes
– Destruction of drug by bacterial enzymes

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Spectrum of Activity

• Aminoglycosides are most effective against Gram-negative bacteria,

including:
• Escherichia coli
• Klebsiella pneumoniae
• Pseudomonas aeruginosa
• Enterobacter species
• Serratia species
• They have limited activity against Gram-positive bacteria and are usually
not effective against anaerobic bacteria.

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Pharmacokinetics
• Very poor GIT absorption
• Absorption complete and rapid after I.V./I.M administration
• Widely distributed in ECF
– Rapidly crosses placental barrier not BBB
• Not metabolized
– Excreted by kidneys unchanged
– Decreased renal function associated with increase serum t1/2

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 Lullmann, Color atlas of Pharmacology, 3ed

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Clinical Uses
• Treatment of infections by aerobic G(-) bacilli
• Nosocomial infections in critically ill patients
– Gram negative bacteremia/septicemia
– Peritonitis
– Pneumonia
– Sub-acute bacterial endocarditis
• UTI
– Enteric bacilli resistant to less toxic antibiotics such as penicillins and
cephalosporins
• Eye infections
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• Streptomycin used in TB regimens
• Kanamycin used for MDR-TB
• Neomycin used orally (to sterilize the bowel before surgery)
and topically in infected wounds. It is too toxic for systemic
use.

 Because of toxicity, Aminoglycosides are reserved for serious infections and usually
combined with Penicillins

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 Examples of Bacterial Coverage
Aminoglycoside Agent Bacteria

Streptomycin Mycobacteria including mycobacteria

tuberculosis
Gram- positive bacteria
Amikacin; Acinetobacter, Citrobacter, Enterobacter,
Gentamicin; Klebsiella, Proteus, pseudomonas
Tobramycin aeruginosa

Gentamycin; Used synergistically with penicillins

Tobramycin against gram positive organisms such as
staphylococci or enterococci

Bacterial spectrum dependent on susceptibility of bacteria (based on culture and

sensitivity tests)
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 Examples of Drug Interactions
Drug Interacting Drugs Possible Effects Monitoring aspects
All aminoglycosides Antiemetics Masked vestibular Hearing loss
ototoxicity
Loop diuretics Increased ototoxicity
Amikacin, Neuromuscular Increased blockade Administer
gentamicin, blockers anticholinesterases
streptomycin, and calcium;
tobramycin, cautious
neomycin, administration

Carbapenems; Decreased effect of Do not give

aminoglycoside together; give at
least 1 hour apart
Amikacin, Amphotericin B, Increased Monitor renal
gentamicin, cephalosporins, nephrotoxicity function
tobramycin acyclovir
Cyclosporines Increased Avoid combination;
nephrotoxicity monitor renal
function
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 Adverse Effects
• Most notably: Ototoxicity and Nephrotoxicity
– Commonly occurs in elderly due to impaired renal function & in
patients receiving ototoxic drugs
– Risk of nephrotoxicity increases with higher doses
The result, usually irreversible, may manifest as vertigo, ataxia and
loss of balance in the case of vestibular damage, and auditory
disturbances or deafness in the case of cochlear damage
• Can produce irreversible damage to cranial nerve VIII
• Renal tubular necrosis (↑Serum Cr and BUN)
• Neuromuscular paralysis: - Aminoglycosides inhibit Acetylcholine
release

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• Common adverse effects after oral administration:
– Nausea, vomiting, diarrhoea
• Allergic reactions rare:
– Rash, urticaria, stomatitis, fever

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Question ( True or False)
1. Which of the following aminoglycoside has widest antimicrobial activity?
a. Kanamycin
b. Gentamycin
c. Streptomycin
d. Tobramycin

2.Aminoglycoside that is too toxic for systemic use is

e. Tobramycin
f. Gentamycin
g. Neomycin
h. Kanamycine

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3. Preferred aminoglycosed for P. aeruginosa infections is:
a. Netilmycin
b. Gentamycin
c. Neomycin
d. Tobramycin

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 Tetracyclines
Tetracycline
oxytetracycline
Demeclocycline
Doxycycline
Minocycline
Limecycline

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 Pharmacodynamics
• Bacteriostatic
• Penetrate cell wall by energy-dependent processes
• Tetracycline is a short-acting antibiotic that inhibits bacterial growth by inhibiting
translation.
• It binds to the 30S ribosomal subunit and prevents the amino-acyl tRNA from
binding to the A site of the ribosome
– Prevents addition of new amino acids to peptide chain of bacteria  inhibition of
protein synthesis

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 Lullmann, Color Atlas of Pharmacology, 3ed

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 Pharmacokinetics
• Well absorbed from duodenum after oral administration
• Absorption impaired by Fe3+ preparations, antacids containing Ca2+, Mg2+
or aluminum salts
• Distributed widely into body tissue and fluids concentrated in bile , bind
to bones due to affinity to calcium
• Excreted primarily by kidneys

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 Spectrum of activity & Clinical Uses
• Spectrum of Activity:
• Tetracyclines have a broad spectrum of activity
• Activity against G(+), G(-), aerobic and anaerobic bacteria such as rickettsiae and
some protozoa
• Activity against atypical bacteria chlamydia, Legionella , mycoplasma and N.
Meningitides ( Minocycline)
• Brucellosis, lyme disease and anthrax
• Spirochaetes ( syphilis) and Coxiella burnetii

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 Common Drug Interactions
Drug Interacting Drugs Possible Effects Interventions
Doxycycline, Antacids- Inhibited absorption Administer 1 to 2
minocycline, magnesium, of tetracycline hours apart
tetracycline aluminum, calcium
salts

Doxycycline, Iron salts, zinc Decreased Administer 3 hours

minocycline, sulfate, bismuth absorption of before or 2 hours
tetracycline salicylate tetracycline after tetracycline

Doxycycline Barbituates, Increased Avoid concurrent

phenytoin doxycycline use or use different
metabolsm tetracycline
Tetracycline Oral contraceptives Altered GI flora Use alternative
decreases OC method of
absorption contraception
All tetracycline Penicillin Decreased Administer several
bactericidal activity hours apart
of penicillin
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 Adverse Effects
• Superinfection
• GI disturbances
– Nausea, vomiting, abdominal distress, distension and
diarrhoea
– Prolonged symptoms– pseudomembranous colitis
• Photosensitivity reactions
– Common in patients receiving demeclocycline but can also
occur with other tetracyclines
• Permanent discoloration of teeth during tooth formation
– Do not administer to children under age 8 (period of tooth
enamel formation)

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 • Hepatotoxicity
– Lipid infiltration of liver associated with IV administration
• Nephrotoxicity
– Develops in patients with renal failure
– Fanconi syndrome-associated with administration of
expired tetracycline
• CNS toxicity
– Vestibular disturbances—primarily with minocycline.
• Dental hypoplasis and bone deformities

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 4. The Tetracycline of choice in renal failure is :
a. Doxycycline
b. Limecycline
c. Demeclocycline
d. Tetracycline

5. The Tetracycline associated with vestibular disturbance is

e. Doxycycline
f. Limecycline
g. Demeclocycline
d. Minocycline

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 AMPHENICOLS

Chloramphenicol
• Limited clinical use due to drug-induced aplastic anaemia
• Reserved for treating serious infections and ampicillin-resistant H. influenzae
• Pharmacokinetics:
– Absorbed rapidly and completely from GIT
– Good penetration through biological barriers
– 10% excreted unchanged in the urine and 90 percent inactivated by the liver
• Pharmacodynamics:
– Bacteriostatic
– Binds to 50S ribosome subunit  inhibits peptide synthase  inhibition of protein
synthesis in susceptible organisms
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 Lullmann, Color atlas of Pharmacology, 3ed.

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 • Overcomes enzymatic acetylation
– Major mechanism of resistance in most gram-
negative bacilli
• Other Uses:
– Active against various organisms including
bacteria, spirochetes, rickettsiae, chlamydiae
– Very active against anaerobic bacteria
– DOC for treating ampicillin resistant typhoid fever
and other systemic Salmonella infections
– Quinlones are now mostly used in salmonellosis.
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 Drug Interactions
• Inhibits metabolism of oral hypoglycaemic agents,
anticonvulsants, and oral anticoagulation
– Symptoms include hypoglycaemia, phenytoin toxicity, haemorrhage
• Bone marrow suppression exacerbated by co-administration of
other drugs causing suppression

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 Adverse Effects
• Bone marrow suppression
• Aplastic anemia
• Grey baby syndrome in neonates (Vomiting, Flaccidity, Hypothermia, Grey
color, Shock and Collapse) resulting from decreased drug clearance due to
undeveloped liver and kidney functions in neonates.
• Optic neuritis
• GIT upset and super-infection

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 Lincosamide Antibiotic

Members: Clindamycin
• Pharmacokinetics:
– Absorbed well and distributed widely in body
– Eliminated primarily via hepatic metabolism including renal
metabolism and biliary excretion
• Pharmacodynamics :
– Bacteriostatic
– Clindamycin works primarily by binding to the 50s
ribosomal subunit of bacteria.
– This agent disrupts protein synthesis by interfering with the
transpeptidation reaction, which thereby inhibits early
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• Clinical Uses:
– Activity against aerobic gram-positive organisms including staphylococcus,
streptococcus, pneumococci, anaerobes
– Used for skin and bone infections
– Used specifically against anaerobic infections

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 • Drug interactions
– Enhances action of neuromuscular blockers

• Adverse effects
– Diarrhoea, stomatitis, nausea and vomiting from oral
administration
– Pseudomembranous colitis
• Symptoms include severe diarrhoea, abdominal pain, fever,
and mucus and blood in stools
– IV administration may damage tissue
– IM administration may produce pain, sterile abscess
– Hypersensitivity
• Stevens-Johnson syndrome (rare)
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 Macrolides
• Members: Erythromycin, azithromycin,
clarithromycin, roxithromycin, spiramycin
and Telithromycin
• Pharmacokinetics
– Absorption dependent on type of formulation,
influenced by presence of food in GIT
– Distributed to most tissues and body fluids except
cerebrospinal fluid
– Metabolized by liver
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 – Erythromycin primarily excreted in faeces; also excreted in urine in
small amounts
– Crosses placental barrier and secreted in breast milk

Pharmacodynamics:
• Bacteriostatic
• Inhibits protein synthesis
– Acts on 50S ribosomal units inhibiting RNA-dependent protein
synthesis
• Block advancement of ribosome unit and translocation of
peptides

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 Lullmann, Colot atlas of Pharmacology, 3ed

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 Spectrum of activity and clinical use

• Erythromycin is effective against Gram-positive bacteria

and spirochaetes, N. gonorrhoeae and, to a lesser extent,
H. influenzae.
• Mycoplasma pneumoniae, Legionella spp some chlamydial
organisms are also susceptible
• Azithromycin is less active agains gram + bacteria than
erythromycin but is considerably more effective against H.
influenza, Legionella.
• It has excellent action against Toxoplasma gondii, killing
the cysts
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 • Clarithromycin is as active against H. influenzae as
erythromycin.
• It is also effective against Mycobacterium avium-
intracellulare
• it may also be useful in leprosy and against
Helicobacter pylori
• also effective in Lyme disease.

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 Common Drug Interactions
• High dose macrolides decreases clearance of theophylline
– Increases serum levels– requires decrease of theophylline dosage
• Erythromycin lactobionate incompatible with vitamin B
complex, vitamin C, tetracycline, heparin, furosemide,
metoclopramide
• Clarithromycin increases plasma levels of carbamazepine

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 Adverse Effects
• GIT disturbances e.g.
– Epigastric distress, nausea, vomiting and diarrhoea
– Stomatitis, heartburn, anorexia and melena
• Allergic reactions
– Rash, fever, eosinophilia, anaphylaxis
• Rare: reversible sensorineural hearing loss
– Occurs in renally impaired patients receiving high dose
erythromycin
• Rare: cholestatic hepatitis
– Associated with erythromycin ethylsuccinate
– Characterized by nausea, vomiting, abdominal pain followed by
jaundice, fever
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 Azythromycin
• Less effective against G(+) but more effective against
G(-) organisms than Erythromycin.
• Potent against Chlamydia.
– Fewer GI adverse effects than erythomycin
– Palpitations, chest pain, dizziness, vertigo, fatigue,
rash
• Clarithromycin
– Fewer GI adverse effects
– Dyspepsia, headache
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 Questions.
6. Macrolyde with activity against Toxoplasma gondii:
a. Talithromycin
b. Erythromycin
c. Clarythromycin
d. Azithromycin

7. Macrolyde with activity against H.pylori and MAC

e. Talithromycin
f. Erythromycin
g. Clarythromycin
h. Azithromycin

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 4. Inhibitor of protein synthesis through binding to 30S subunit include:
a. Tetracycline
b. Chloramphenical
c. Aminoglycosides
d. Macrolydes

5. Bacteriocidal agent (s) include:

e. Doxycycline
f. Gentamycin
g. Erythromycin
h. Chloramphenicol

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Linezolid:

• Mechanism of Action: Linezolid is an oxazolidinone antibiotic that

inhibits bacterial protein synthesis by binding to the 23S ribosomal
RNA of the 50S subunit, preventing the formation of the 70S initiation
complex. This action ultimately leads to the inhibition of bacterial
protein synthesis, halting bacterial growth.

Spectrum of Activity
• Linezolid is effective against a wide range of Gram-positive bacteria,
including methicillin-resistant Staphylococcus aureus (MRSA),
vancomycin-resistant Enterococcus (VRE), Streptococcus
pneumoniae, and various other resistant strains.
• It is not effective against Gram-negative bacteria.

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Clinical Uses:
• Linezolid is primarily used to treat serious infections caused by resistant
Gram-positive bacteria.
• It is often used as a second-line agent for the treatment of MRSA
infections when other antibiotics are not effective.
• It is also employed in the treatment of complicated skin and soft tissue
infections, pneumonia (including hospital-acquired pneumonia), and
bloodstream infections.
Pharmacokinetics:
• Linezolid is available in both oral and intravenous (IV) forms.
• It is well-absorbed orally, allowing for convenient outpatient treatment of
certain infections.
• The drug is metabolized in the liver and excreted primarily in the urine.
• Dose adjustments may be necessary in patients with renal impairment.

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Adverse Effects:
• Linezolid is generally well-tolerated, but some common side effects include
nausea, vomiting, diarrhea, and headache.
• Long-term use or high doses may lead to bone marrow suppression,
resulting in anemia, thrombocytopenia, or leukopenia. Regular blood count
monitoring is necessary during treatment.
• Peripheral neuropathy has been reported with prolonged use, but it is rare.
• Linezolid has the potential to interact with certain medications, particularly
monoamine oxidase inhibitors (MAOIs), as it can increase the risk of
serotonin syndrome.
• Therefore, caution should be exercised when combining Linezolid with
other serotonergic drugs.

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Resistance: Resistance to Linezolid is relatively rare but can occur due to
mutations in the 23S rRNA binding site or other mechanisms. Combination
therapy or alternative antibiotics may be required in cases of resistance.

Special Considerations:
• Linezolid should be used judiciously due to concerns about the
development of antibiotic resistance.
• It is often reserved for severe infections caused by multidrug-resistant
Gram-positive bacteria.
• The duration of therapy and choice of oral or IV administration depend on
the specific infection being treated.

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• END OF LECTURE

Thank you for having me

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