INHIBITORS OF

BACTERIAL PROTEIN
SYNTHESIS

Dr. NDAYISABA CORNEILLE

CEO of CHG
MBChB,DCM,BCSIT,CCNA
Supported BY
 There are 2 subgroups of antibiotics
which inhibit bacterial protein
synthesis

a) Inhibitors of bacterial protein

synthesis by binding to 30s
ribosomal subunit

1. Aminoglycosides

2. Tetracyclines
Aminoglycosides
— Are bactericidal
— Inhibit protein synthesis by interfering with
ribosomal function
— Are very useful against aerobic gram-ve
microorganisms
Examples

1. Streptomycin

2. Neomycin

3. Kanamycin

4. Amikacin

5. Gentamicin

6. Tobramycin

7. Sisomicin
8. Netilmicin

9. Paramomycin etc
Antibacterial activity of aminoglycosides

 Mainly kill gram negative organisms

 Kill some gram positive bacteria
 Streptomycin is active against mycobacterium
tuberculosis & its currently reserved for tx of
TB
 Amikacin, gentamicn & tobramycin
are also active against pseudomonas
aeruginosa
 Mechanism of action of aminoglycosides
— All aminoglycosides irreversibly inhibit bacterial
protein synthesis
— This eventually lead to bacterial cell death
— These drugs act by binding to the 30s ribosomal
subunit
— This leads to interference with the formation of
initiation complex of the peptide chain
 Events that occur before drug action

1. Initial event is passive diffusion via porin channels

across the outer membrane.

2. Drug is then actively tpted across cell membrane into

cytoplasm by an oxygen-dependent process.

3. The transmembrane electrochemical gradient supplies

energy for this process & tpt is coupled to a proton
pump.
Protein synthesis is inhibited by in at least 3 ways;
 Interference with the initiation complex of peptide formation
 Misreading of mRNA, which causes incorporation of
incorrect amino acids into the peptide, resulting in a
nonfunctional or toxic protein;
 Breakup of polysomes into nonfunctional monosomes.

o Activities occur more or less simultaneously & overall

effect is irreversible & lethal for the cell.
 Mechanisms of resistance

a) Production of transferase enzyme or enzymes

inactivates the aminoglycoside by;
 adenylylation,
 acetylation, or
 phosphorylation.

o This is the principal type of resistance

encountered clinically.
 b) Impaired entry of aminoglycoside into the cell.
o May be genotypic, ie, resulting frm mutation or deletion
of a porin protein or proteins involved in tpt a
maintenance of electrochemical gradient
o May phenotypic e.g. resulting frm growth conditions
under which oxygen-dependent tpt process described
above is not functional.

c) The receptor protein on 30S ribosomal subunit may be

deleted or altered as a result of a mutation
 Pharmacokinetics
 These drugs are given;
— Intravenously
— Intramuscular
— Topical application on mucous membranes
 These drugs are not absorbed from the GIT thus
they are not given orally
— O.D dosing of aminoglycosides currently preferred

Why OD dosing is preferred

— Its more convenient to administer
— It provides large doses at once which results into
rapid killing of bacteria
— Aminoglycosides are excreted by kidneys
— These drugs accumulate in pts with renal failure
 Distribution of aminoglycosides
— They are poorly distributed to most body
tissues bcoz they are highly polar thus do
not enter cells readily
— These drugs can reach brain cells in
presence of active inflammation of the
meninges
 Clinical uses of aminoglycosides
— Given in combination with ampicillin or ceftriaxone
in tx of gram negative septicemia
— Given in combination with penicillin during tx of
bacterial endocarditis cozed by enterococci,
viridans streptococci & staph
— Given post-operatively after surgical operations
— Tx of septic wounds
— Tx of TB
 Clinical Uses
— Used in tx of plague
 Streptomycin
o Isolated from a strain of Streptomyces griseus.
o Ribosomal resistance develops readily, limiting its role as a single
agent.

Clinical Uses

1. Mycobacterial infections
o Used as a 2nd -line agent for tx of other forms of TB except TBM.
o Used as 1st line agent in tx of TB Meningitis
o Dosage is 0.5–1 g/d (7.5–15 mg/kg/d for children)
o Given IM or IV .
2. Nontuberculous infections

a) Plague

b) Tularemia

c) Sometimes brucellosis,
 Dosage 1 g/d (15 mg/kg/d for children)
 Given IM in combination with an oral tetracycline.

d) Enterococcal endocarditis
— For tx endocarditis due to viridans streptococci
e) Viridans streptococcal endocarditis
 Penicillin plus streptomycin is effective for and 2-week therapy of
Viridans streptococcal endocarditis
 Gentamicin has largely replaced streptomycin for these indications.

o Streptomycin remains a useful agent for treating

enterococcal infections

Contraindications
o Pregnancy, can cause deafness in the newborn
o Renal failure
o Vestibular disorders
 Gentamicin
o Isolated from Micromonospora purpurea.
o Effective against both gram-positives & gram-negative
o Many of its properties resemble those of other
aminoglycosides.

o Sisomicin is very similar to the C1a component of

gentamicin.
Clinical Uses

IM or IV administration

Used mainly in severe infections e.g.

1. Gram negative Septicemia

2. Pneumonia
o Such infections are usually caused by gram-negative bacteria that are
likely to be resistant to other drugs, esp
 Pseudomonas, - Enterobacter,
 Serratia - Proteus,
 Acinetobacter -Klebsiella.

o It usually is used in combination with 2nd agent, as alone may not be

effective for infections outside urinary tract.
 o Gentamicin shld not be used as a single agent to Rx
staphylococcal infections bcoz resistance develops
rapidly.
o Agents shld not be used for single-agent therapy of
pneumonia becoz penetration of infected lung tissue is
poor & local conditions of low pH + low oxygen
tension contribute to poor activity.
o Gentamicin 5–6 mg/kg/d traditionally is given IV TID,
but OD administration is just as effective
o Serum [gentamicin] & renal function shld be monitored
if given for more than a few days or if renal function is
changing (eg, in sepsis complicated by acute renal
failure).

Topical administration
o Creams, ointments & solutions containing 0.1–
0.3% gentamicin sulfate are used.
Indications include

I. Ocular infections

II. Infected burns

III. Infected wounds

IV. Infected skin lesions

V. Prevention of IV catheter infections.

o Topical gentamicin is partly inactivated by purulent

exudates.
 Intrathecal administration
o Meningitis cozed by gram-negative bacteria .
o Dose is 1–10 mg/d.
o Neither intrathecal nor intraventricular gentamicin was
beneficial in neonates with meningitis.
o Intraventricular gentamicin was toxic.
o 3RD generation cephalosporins for gram-negative
meningitis is currently preferred
 TOBRAMYCIN.

Clinical uses
oRx of Pseudomonas aeruginosa LRTIs complicating cystic fibrosis. A
300-mg dose regardless of the pt's age or weight by inhalation thus less
adverse effects
oGentamicin & tobramycin are otherwise interchangeable clinically.

Caution shld be used when administering tobramycin to pts with;

I.Preexisting renal diseases

II.Vestibular

III.Hearing disorders
 Amikacin
o Semisynthetic derivative of kanamycin;
o It is less toxic than the parent molecule.
o It is resistant to many enzymes that inactivate gentamicin &
tobramycin.
o Its therefore used against some microorganisms resistant to
the latter drugs.
Pharmacokinetics
o Dose is 500 mg BD (15 mg/kg/d)
o IM route
Clinical uses

1. Multidrug-resistant Mycobacterium tuberculosis.

Effective even to streptomycin-resistant strains.
Kanamycin-resistant strains may be cross-resistant to
amikacin.
o Dosage of amikacin for TB is 7.5–15 mg/kg/d as OD or
2-3 times weekly injection
o Always used in combination with other drugs to which
the isolate is susceptible.
 Netilmicin
o Shares many x-tics with gentamicin & tobramycin.
o However its resistant to enzymatic degradation due to
addition of an ethyl group to the 1-amino position of the
2-deoxystreptamine ring.
o Thus Netilmicin may be active against some
gentamicin & tobramycin-resistant bacteria.
Neomycin & Kanamycin
o Closely related.
o Paromomycin is also a member of this group.
o All have similar properties.

Antimicrobial Activity & Resistance

Drugs of neomycin group are active against;

I. Gram-positive & gram-negative bacteria

II. Some mycobacteria.

 Pseudomonas & streptococci are generally resistant.

Mechanisms of antibacterial action & resistance

o The same as with other aminoglycosides.
o Their in bowel preparation for elective surgery has
resulted in selection of resistant organisms & some
outbreaks of enterocolitis in hospitals.
o Cross-resistance btn kanamycin & neomycin is
complete.
 Pharmacokinetics
o Drugs of the neomycin group are poorly absorbed frm
GIT.
o After oral dose, intestinal flora is suppressed or
modified & the drug is excreted in the feces.
o Excretion of any absorbed drug is mainly thru
glomerular filtration into the urine.
Clinical Uses for Neomycin &kanamycin
o Clinical uses are now limited;

1. Topical

2. Oral use.
o Neomycin is too toxic for parenteral use.

A)Topical administration
o Solutions containing 1–5 mg/mL are used on;

1. Infected surfaces

2. Injected into joints, pleural cavity, tissue spaces, or

abscess cavities with infection .
o Total amount of drug given in this fashion must be
limited to 15 mg/kg/d bcoz at higher doses enough drug
may be absorbed to coz systemic toxicity.

B. Oral administration

1. Preparation for elective bowel surgery,

o 1 g of neomycin is given orally 6–8 hourly for 1–2 days
& often combined with 1 g of erythromycin base.
o This reduces aerobic bowel flora with little effect
on anaerobes.

2. In hepatic coma,
o Coliform flora can be suppressed
o Neomycin 1 g every 6–8 hours together with
reduced protein intake, thus reducing ammonia
intoxication.
o Use of neomycin for hepatic coma has been almost
entirely supplanted by lactulose, which is less toxic.
3. Intestinal amebiasis
o Paromomycin, 1 g every 6 hours orally for 2 weeks,
o Has been effective.

Adverse reactions

1. Nephrotoxicity

2. Ototoxicity.

3. Hypersensitivity is not common

4. Neuromuscular blockade & respiratory arrest

Ototoxicity
o Auditory function is affected more than vestibular.
o Deafness has occurred, esp in adults with impaired
renal function & prolonged elevation of drug levels.

Neuromuscular blockade & respiratory arrest.

o Due to sudden absorption of postoperatively instilled
kanamycin frm peritoneal cavity (3–5 g).
o Ca gluconate & neostigmine can act as antidotes.
 Hypersensitivity is uncommon,
o Prolonged application of neomycin-containing
ointments to skin & eyes has resulted in severe allergic
reactions.

Spectinomycin
o Aminocyclitol antibiotic that is structurally related to
aminoglycosides.
o It lacks amino sugars & glycosidic bonds.
Mechanism of action
o Inhibits protein synthesis

Antibacterial spectrum
o Active in vitro against many gram-positives & gram-negatives,
o Some strains of gonococci may be resistant

Clinical uses
o Almost solely as alternative Rx for drug-resistant gonorrhea
o Gonorrhea in penicillin-allergic patients

Pharmacokinetics
o Rapidly absorbed after IM.
o A single dose of 40 mg/kg up to a max of 2 g.
 Commonest S/E of aminoglycosides

1. Ototoxicity with features of vestibular & auditory

damage

Features auditory damage

– Tinnitus
– Hearing loss
Features vestibular damage

– Vertigo
  Ataxia
 Loss of balance
2.Nephrotoxicity with acute tubular necrosis

Other S/Es
— Hypersensitivity reactions like body rash
— Paralysis of respiratory muscles due to
neuromuscular junction blockade
— Hypomagnesaemia after prolonged use
Risk factors for S/Es of aminoglycosides

 Prolonged tx therapy with

aminoglycosides for > 5 days

 Giving large doses of aminoglycosides

 Old age

 Renal failure

 Concurrent use of loop diuretics with

aminoglycosides
 – Concurrent use of nephrotoxic drugs
like vancomycin, amphotericin B with
aminoglycosides
Contraindications

1. Pts with renal failure

2. Pts with vestibular damage

3. Pts with h/o hypersensitivity to

aminoglycosides
b) Inhibitors of protein synthesis by
binding to 50s ribosomal subunit

1. Amphenicols

– Chloramphenicol
2. Macrolides

– Erythromycin
– Azithromycin
3. Ketolides

– Telithromycin
4. Lincosamides

– Lincomycin
– Clindamycin
5. Streptogramins

– Quinupristin
– dalfopristin
6.Oxalizidonones

 Linezolid
7. Fusidic acid

 Sodium fusidate
 Azithromycin

 This is a semi synthetic derivative of erythromycin

o Its ½ life is 2–4 days thus its given O.D
o Its available inform of capsules ,tablets & syrups
for paediatrics
 It shld be administered 1 hour before or 2 hours
after meals
 Al & Mg antacids delay absorption of azithromycin
from the gut but they do not affect the drug
bioavailability
 Dosage

Adults;
— 500mgs od for 3 days
— 500mgs start then 250mgs od for 4 days
— 1g start

Paediatrics
— 10mg/kg od for 3 days
 Antibacterial activity ;
 Its active against
o Mycobacterium avium complex
o Toxoplasma gondii
o Chlamydia
o Haemophilus influenzae
o Slightly less active than erythromycin &
clarithromycin against staph & streptococci
 Indications

1. Chlamydial cervicitis

2. Chlamydial Urethritis (non gonococcal

urethritis)

3. CNS toxoplasmosis

4. Bacterial community acquired pneumonia

5. Treatment of streptococcal pharyngitis

6. Otitis media
 7. Mild to moderate typhoid fever due to
resistant s. typhi
8. Skin & soft tissue infections like
cellulitis ,boils
9. Prophylaxis against group A streptococcal
pharyngitis
10. Eradication of mycobacterium avium
complex which cozes severe wasting in ISS
pts
11. Uncomplicated genital chlamydia infections
 CLARITHROMYCIN

 This is a semi synthetic derivative of

erythromycin
 It has similar indications to those of
erythromycin
 It has lower incidence of GI intolerance
 Clarithromycin is more stable in gastric acid &
its well absorbed from the gut compared with
erythromycin
 Antibacterial activity
 Almost identical with erythromycin
 But clarithromycin is more active against

a. Mycobacterium avium complex

b. Mycobacterium leprae

c. Toxoplasma gondii
 Erythromycin-resistant streptococci & staph
are also resistant to clarithromycin
  Its ½ life is 6 hrs thus its given BD
 Its well distributed to most body tissues

Dosage

Adults
 250–500 mg bid

Paediatrics
 7.5 mgs/kg BD
 Indications

1. Otitis media

2. Respiratory tract infections

3. Used in triple therapy mgt of PUD by

eradicating helicobacter pylori

4. Tx of brain toxoplasmosis in ISS pts

5. Boils (Furunculosis);deep seated infection of

hair follicles
6. Carbuncles; a cluster of boils with spread of
bacterial infection to subcutaneous tissues

7. Chronic prostatitis

8. Septic wounds in combination with fragyl

9. Non Gonococcal urethritis due to

mycoplasma & chlamydia spp

10. Mastitis & breast abscesses

S/Es

1. Dyspepsia

2. Tooth & tongue discolouration

3. N+V, abdominal pains, diarrhoea

4. Smell & taste disturbances

5. Stomatitis

6. Glossitis

7. Headaches
 Erythromycin
 This is an antibiotic obtained from
a micro-organism known as Streptomyces
erythreus
 It can be safely given to;

1. Pregnant mothers

2. Breastfeeding women

3. Children
Antimicrobial activity of erythromycin
 It kills;

1. Gram +ve organisms like

 Streptococci e.g s. pneumoniae

 Staphylococci
 Corynebacteria
 2. Gram -ve organisms such as;

 Neisseria spp
 Chlamydia spp like C. trachomatis ,
C. psittaci, C. pneumoniae
 Legionella spp
 Helicobacter
 Listeria spp
 Campylobacter spp
  Bordetella pertussis
 Bartonella henselae & Bartonella
quintana etiologic agents of cat-scratch
disease + bacillary angiomatosis
 Haemophilus influenzae are less
susceptible
3. Mycoplasma spp
4. Some mycobacteria like M. kansasii& M.
scrofulaceum
5. Some rickettsia spp
6. Treponema pallidum
Dosage
Adults
 250–500 mg every QID
Paediatrics
 10-15 MG QID OR TDS
  It should be administered on an empty
stomach bcoz food interferes with its
absorption
 ½ life of erythromycin is about 1.5 hours
thus is given QID
Distribution
 Distributed widely to various body tissues
except to brain & CSF
 Its taken up by polymorphonuclear
leukocytes & macrophages
 It crosses the placenta & reaches fetus but
it has no teratogenic effects
 Indications; its indicated in treatment of
conditions like;

1. Vaginal d/c syndrome in pregnancy

2. Urethral discharge syndrome in pregnancy

3. Acute glomerulonephritis

4. Genital ulcer disease in pregnancy

5. Amnionitis
 6. Mastitis

7. Breast abscess

8. Puerperal sepsis

9. Obstructed labour in combination with

metronidazole

10. Ophthalmia neonatoram; pus d/c from eyes

of a neonate

11. Streptococcal pharyngitis

 12. Moderate to severe pneumonia

13. Whooping cough

14. Chronic prostatitis

15. Septic wounds in combination with fragyl

16. Non Gonococcal urethritis due to

mycoplasma & chlamydia spp
 12. Boils (Furunculosis);deep seated infection
of hair follicles

13. Carbuncles; a cluster of boils with spread of

bacterial infection to subcutaneous tissues

Other indications
 Impetigo; acute inflammation of outer
layer of skin
  Pemphigus; a rare potentially fatal skin
disease characterised by intra-epidermal
skin bullae on apparently healthy skin or
mucous membranes
 Cellulitis & erysipelas; acute inflammation of
skin & subcutaneous tissues
 Campylobacter enteritis
 Treatment of trachoma
  Acne vulgaris
 Rosacea
 Prophylaxis against diphtheria
 Prophylaxis against endocarditis during
dental procedures in individuals with
valvular heart disease
 Adverse reactions

GI S/Es

1. Anorexia

2. Nausea

3. Vomiting

4. Diarrhea

5. GI intolerance due to direct stimulation of

gut motility
 6. Hypersensitivity reactions like;

 Hepatitis with Jaundice & impaired liver

function
 Fever
 Urticaria
 Rashes
 Steven Johnson's syndrome
 Toxic epidermal necrosis
Drug interactions
• It inhibits cytochrome P450 enzymes
thus ↑ serum levels of drugs like;

– Aminophylline
– Oral anticoagulants
– Cyclosporine
– Methylprednisolone
– Digoxin
 AMPHENICOLS
 Chloramphenicol is the only example of
amphenicol antibiotics
Chloramphenicol
 A broad-spectrum antibiotic alongside the
tetracyclines
 This is a bacteriostatic antimicrobial
 Its no longer a 1st line antibiotic in most
developed countries due to its S/Es &
microbial resistance to the drug
Mechanism of action
o Potent inhibitor of microbial protein synthesis
o It binds reversibly to 50S subunit of bacterial ribosome
o This inhibits peptidyl transferase step of protein synthesis

Antimicrobial Activity;
o Its effective against a variety of;
 Gram +ve like H influenzae, N meningitidis
 Gram-ve bacteria
 Most anaerobic organisms like bacteroides to which CAF
isbactericidal
 Distribution
 Widely distributed to virtually all tissues & body fluids
including CNS & CSF
 This drug penetrates cell membranes readily

Metabolism
 Occurs in liver

Excretion
 Mainly by are kidneys
 Small amount of active drug is excreted into bile &
feces.
Dosage;

Adults; 500-1000mg every 6 hours

PO & IV;
 50mg/kg in 4 divided doses/d
 100mg/kg 4 divided doses in conditions like;
 Septicaemia
 Meningitis

Children;
 50-100mg/kg/d in 4 divided doses

Neonates < 2 wks;

 25mg/kg/d in 4 divided doses
Indications of chloramphenicol

1. Septicaemia esp due N. meningitidis

2. Pyogenic meningitis due strep pneumoniae,

N.meningitidis , H. influenzae

3. Epiglottitis due to H. influenzae

4. Septic wounds

5. Tx of bacterial conjunctivitis & keratitis

6. Tx of enteric fever /typhoid fever

7. Tx of bacillary dysentery in pregnancy as cipro &
cotrimoxazole are contraindicated

8. First choice drug tx for staphylococcal brain

abscesses

9. 2nd line drug in tx of tetracycline-resistant cholrea

10. Tx of typhus fever; an infection cozed by

rickettsiae which are transmitted by lice, rat fleas,
rodent mites
11. Tx of plague ;an acute severe bacterial infection
with high fatality rate cozed by yersinia pestis
which is transmitted by infected ground rodent
fleas

12. Rocky Mountain spotted fever due to

rickettsia
 Why CAF is rarely used now days

 Due to its potential toxicity

 Wide occurrence of bacterial resistance to

CAF

 Availability of many other effective antibiotics

Drug interactions of CAF

1. Inhibits cytochrome p450 enzymes that metabolize

several drugs thus leads to ↑ [serum] of;

– CCBs
– Antidepressants
– Anti-epileptic drugs
– Oral hypoglycemics
– PPIs
 2. Like other bacteriostatic inhibitors of
microbial protein synthesis, CAF
antagonizes bactericidal drugs like;
 Penicillins
 Aminoglycosides
Contraindications
1. Acute porphyria
2. Breast feeding mothers
 END
BY
DR NDAYISABA CORNEILLE
MBChB,DCM,BCSIT,CCNA,Cyber Security

contact: amentalhealths@gmail.com , ndayicoll@gmail.com

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