Aminoglycosides are a group of bactericidal antibiotics that were first discovered in 1944. They work by interfering with bacterial protein synthesis. They are effective against many gram-negative aerobic bacteria but have relatively low safety margins due to risks of ototoxicity and nephrotoxicity. Their structures contain amino sugars linked together. They enter bacteria and bind to the 30S ribosomal subunit, inducing misreading of mRNA and inhibiting protein synthesis. Resistance can develop through enzymatic modification or decreased drug uptake.

1. Aminoglycosides
Dr Farhan

2. • Streptomycin – 1944
• Actinomycetes – Streptomyces griseus
• Bactericidal antibiotics
• Interfere with protein synthesis
• Used to treat aerobic Gram –ve bacteria
• Resemble each other in MOA, pharmacokinetic
therapeutic and toxic properties
• Relatively low margin of safety
• Ototoxicity, nephrotoxicity & NM Blockade
Aminoglycosides

3. Chemistry
Amino sugar 2-deoxystreptamine Amino sugar
-o- -o-
Aminoglycosides Structure
Streptidine Streptose amino
sugar
N-Methyl-L
glucosamine
amino sugar
-o- -o-
Streptobiosamine
Streptomycin structure

4. Classification
 Systemic
 Streptomycin
 Gentamicin
 Kanamycin
 Amikacin
 Sisomicin
 Tobramycin
 Netilimicin
 Topical
 Neomycin
 Framycetin

5. Mechanism of Protein synthesis

6. Formation of the Initiation
Complex

7. Joining of 50S Ribosomal
Subunit

8. Protein Elongation

9. Termination of
Translation

10. Mechanism of action
• Initially they penetrate
bacterial cell wall, to reach
periplasmic space through
porin channels (passive
diffusion)
• Further transport across
cytoplasmic membrane takes
place by active transport by
proton pump; an oxygen-
dependent process

11. Mechanism of Action
• Bind 30S ribosomal
subunits and interfere
the initiation complex
• Induce misreading of
genetic code on
mRNA
• Breakup of polysomes
into monosomes

12. Post antibiotic effect
• Aminoglycosides exhibit concentration
dependent killing.
• They also possess significant Post-antibiotic
effect.
• Single daily dosing at least as effective as and
no more toxic than multiple dosing.

13. Mechanism of resistance
• Synthesis of plasmid mediated bacterial
transferase enzyme: Inactivate aminoglycosides
• ↓ transport into bacterial cytosol
• Deletion/alteration of receptor protein on 30 S
ribosomal unit by mutation: prevents
attachment

14. Antibacterial spectrum
• Primarily against Gm –ve aerobic bacilli
– Proteus, pseudomonas
– E.Coli,enterobacter
– Klebsiella
– Shigella
• Only few Gm +ve cocci:
– staph aureus, strepto viridans
• Not effective against Gm +ve bacilli, Gm-ve
cocci and anaerobes

15. Pharmacokinetics
• Highly polar basic drugs: poor oral BA
• Administered parenterally or applied locally
• Poorly distributed and poorly protein bound
• Do not undergo any significant metabolism
• Nearly all IV dose is excreted unchanged in
urine
• Dose adjustment is needed in renal
insufficiency

16. Clinical uses
• Gram –ve bacillary infection
– Septicaemia, pelvic & abdominal sepsis
• Bacterial endocarditis –
– enterococcal, streptococcal or staphylococcal infection of
heart valves
• Pneumonias, Tuberculosis
• Tularemia
• Plague, Brucellosis
• Topical – Neomycin, Framycetin.
• Infections of conjunctiva or external ear
• Tosterilize the bowel of patients who receive
immunosuppressive therapy, before surgery & in
hepatic coma

17. Shared toxicities
• Ototoxicity
– Vestibular damage
– Cochlear damage
• Nephrotoxicity
• Neuromuscular blockade

18. Precautions / Contraindications
• Pregnancy: foetal ototoxicity
• With other ototoxic drugs: furosemide, minocycline
• With nephrotoxic drugs: vancomycin ,cisplatin
• Elderly patients
• Those with kidney disease
• Cautious use of muscle relaxants
• Do not mix with any other drug in same
syringe

19. Tetracyclines

20. Contents
• Introduction
• Classification
• Structure of tetracycline
• Mechanism of action
• Mechanism of resistance
• Uses of tetracycline
• Side effects of tetracycline

21. Introduction
Tetracycline are broad spectrum antibiotics, which are chemical
substances produced by a microorganism that are able to kill other
microorganisms without being toxic to the person, animal or plant.
Tetracycline are derived directly from a bacterium knows as
Streptomyces coelicolor.
Tetracycline were discovered in 1940.

22. Tetracyclines
(according to the during of action)
Short-acting
(half-life is 6-8 hrs)
Tetracycline
chlortetracycline
Intermediate-acting
(half-life 12 hrs)
Demeclocycline
methacycline
Long-acting
(half-life 16 hrs)
Doxycycline
minocycline
Classification

23. Mechanism of action
• Inhibitors of bacterial protein synthesis

24. Mechanism of Resistance
Cell become resistant to tetracycline 3 mechanisms
• Enzymatic rarest type of resistance, where an acetyl group is added to
the molecule , causing inactivation of drug.
• Efflux resistance gene encodes a membrane protein that actively
pumps tetracycline out of the cell.
• Ribosomal protection which blocking tetracycline from binding to the
ribosome

25. Uses ofTetracycline
1. Antibacterial resistance
2. Non antibacterial resistance like inflammation
3. Tissue destructive disease like antifibrilogenics
4. Parkinson and other neurodegeneration disease
5. Antiviral and anti cancer
6. Upper/lower respiratory tract infections
7. Skin and soft tissue infections
8. Relapsing fever
9. Cholera
10.Urinary tract infection
11.Anthrax

26. Side effects
1. Upset stomach
2. Diarrhea
3. Itching of rectum or vagina
4. Sore mouth
5. Redness of the skin
6. Change in skin colour
7. Nail discoloratiom
8. Difficulty in breathing or swallowing
9. Extreme weakness
10.Premanent discoloration of teeth

27. Chloramphenicol

28. • Chloramphenicol was initially obtained from Streptomyces Venezuela
• It was soon synthesized chemically and the commercial product now is
all synthetic
• It has a nitrobenzene substitution, which is probably responsible for
the antibacterial activity and its intensely bitter taste.

29. • Chloramphenicol is primarily bacteriostatic, though high concentrations
Have been shown to exert cidal effect on some bacteria.
• Chloramphenicol was highly active against Salmonella including S. typhi, but
resistant strains are now rampant.
• It is more active than tetracyclines against H. influenzne (though many have
now developed resistance), B. pertussis, Klebsiella, N.meningitidis and
anaerobes including Bact. fragilis.
• It is less active against gram-positive cocci, spirochetes, certain
Enterobacteriaceae and Chlamydia. Entamoeba and Plasmodia are not
inhibited.

31. Inhibits protein synthesis
• Binds reversibly to 50s ribosome subunit
• Prevents formation of peptide bond
Chloramphenicol

32. Resistance
Ribosomal mutation
Decreased permeability of drug
Production of inactivating enzymes

33. • Duration: Typhoid: 8-10 days; meningitis: 7-10 days; brain abscess: Up to 4 wk.
• Absorption: Readily absorbed with peak plasma concentrations after 1 or 2 hr(oral).
• Distribution: Distributed widely into tissues and fluids, CSF, eye, crosses the
placenta and enters the breast milk. Protein-binding: 60%.
• Metabolism: Hydrolysed to the free drug in the GI tract (palmitate); liver by conjugation
with glucuronic acid, lungs and kidneys after parenteral admin (sodium succinate).
• Excretion: Via the urine, via the bile (3%), via the faeces (1% as inactive form); 1.5-4 hr
(elimination half-life).

34. • Hypersensitive reactions: skin rashes, fever, and angioedema
• GIT: nausea, vomiting, diarrhoea
• Anemias: Patients may experience dose-related anemia, hemolytic anemia (seen in
patients with glucose-6-phosphate dehydrogenase deficiency), and aplastic anemia.
[Note: Aplastic anemia is independent of dose and may occur after therapy has
ceased.]
•Bone marrow suppression:
• The most seriousADV of chloramphenicol, is on bone marrow, it occurs in two ways
 Dose dependent reversible suppression, which
manifests anemia, leukopenia, and thrombocytopenia.
 Non dose related: which is fatal

35. Gray baby syndrome (also termed Gray or Grey syndrome) is a
rare but serious side effect that occurs in newborn infants
Pathophysiology
Due to lack of The UDP- glucuronyl transferase enzyme system
of infants, especially premature infants, is immature and
incapable of metabolizing the excessive drug load.
Insufficient renal excretion of the unconjugated drug.

36. • Loss of appetite
• Vomiting
• Ashen gray color of the skin
• Hypotension (low blood pressure)
• Cyanosis (blue discolouration of lips
and skin)
• Hypothermia
• Cardiovascular collapse
• Abdominal distension
• Irregular respiration
• Increased blood lactate

37. 1. Paracetamol + chloramphenicol = enhances bioavailability of
chloramphenicol by 28 %
2. Chloramphenicol is potent enzyme inhibitor and inhibits metabolism
of
warfarin = increase risk of bleeding
Morphine = respiratory depression
Chorpropamide = increase hypoglycaemia
Chloramphenicol + Penicillins can cause antibiotic antagonism

38. • Anaerobic infections: B.fragilis, in combination with metronidazole for treatment of brain, lungs,
intra abdominal, or pelvic abscess
• Eye and ear infections
• Brucellosis
• Because of its toxic side effects, chloramphenicol is used only to suppress infections that cannot be
treated effectively with other antibiotics. Such infections typically include
• (1) Typhoid fever
• (2) Meningococcal infections in cephalosporin-allergic patients
• (3) Serious H. influenzae infections, particularly in cephalosporin-allergic patients
• (4) Anaerobic infections (e.g., those originating in the pelvis or intestines) Anaerobic
or mixed infections of the CNS
• (6) Rickettsial infections in pregnant patients, tetracycline-allergic patients, and renally impaired
patients
• Oral : 50mg/kg, ear drops: 5% 2-3 drops, eye drops: 0.5% drops