Pharmacology of tetracycline and chloramphenicol

1. Tetracycline and Chloramphenicol -
Broad Spectrum Antibiotics

2. Tetracycline - History
American Pharmaceutical Industry: In the 1940’s soil
actinomycetes were systematically
screened for the elaboration of antimicrobial substances

3. Broad spectrum – Why ??
• Name given as they contrasted to the existing
Antibiotics - Only Penicillin and Streptomycin
(1944) available
1. Orally effective
2. Wider spectrum of activity –
• gm+ve cocci
• gm+ve bacilli including anerobes (Clostridia)
• gm-ve bacilli including anerobes (Vibrio cholerae, H. pylori,
Brucella etc.)
• Spirochaetes (T. paalidum)
• Rickettsiae and chlamidiae
• Entamoeba Histiolytica and Plasmodia

4. Tetracyclines
• A class of antibiotics named for their nucleus
of four (“tetra-”) hydrocarbon rings
• All are obtained from soil actinomycetes
• 1948 first one – chlortetracycline
(aureomycin) – S. aureofaciens (Yellow
coloured colony)
– Oxytetracycline from S. rimosus (1950)
– Tetracycline (1953)

5. Tetracyclines - drugs
• Naturally occuring:
– Tetracycline, cholrtetracycline, oxytetracycline
and demeclocycline
• Semisynthetic occurring:
– Doxycycline, minocycline, tigecycline,
lymecycline, methacycline and rolitetracycline

7. Available drugs - characters
• Tetracycline, oxytetracycline, demeclocycline
– Lower potency (250-500 mg tid)
– Orally given, short acting (t1/2 – 6-8 Hrs)
– Incompletely absorbed from stomach (60-80%)
– Primarily excreted through the kidneys
• Minocycline, doxycycline, tigecycline
– Higher potency (100 - 200 mg)
– Lipid soluble, long acting (t1/2 – 18-24 Hrs)
– Completely absorbed from stomach (95-100%)
– Excreted through liver

8. Tetracyclines - MOA
• Inhibition of Bacterial Protein Synthesis by
binding to 30S ribosomes – aminoacyl-t-RNA
to mRNA-ribosome complex – interfered
• Why do not affect host cells ? – transport and
sensitivity

9. Tetracyclines - MOA
Inhibition of Bacterial Protein Synthesis

10. Resistance
• Develops slowly in graded manner
• Tetracycline concentrating mechanism lessens
• Efflux pump
• Plasmid mediated synthesis of “protection
protein”
• Tetracycline inactivating enzyme
Cross resistance

11. Tetracyclines – Antimicrobial spectrum
• Bacteriostatic drugs: originally all types of organisms
except viruses and fungi – Both, gm+ve and gm-ve
bacteria, Rickettsiae, Chlamydia, Mycoplasma,
actinomycetes and some protozo
• Cocci: All +ve and –ve cocci
– S. pneumoniae, gonococi, meningitidis are sensitive.
Resistance developed to Staph aureus, pyrogens and
enterococci
• Bacilli (+ve): clostridia, listeria, anthracis etc, but not
Mycobacteria
• Enterobacteriocae: resistant and not effective -
pseudomonas, klebsiella and salmonella

12. Tetracyclines - Kinetics
• Older ones less absorbed – 60-80% (food interferes) but doxy and
mino – completely
• Chelating property – milk, antacids and iron preparations
• Distribution: wide and variable protein binding (different members)
– Concentrated in liver, spleen and bone & teeth – minocycline in fats
– Good CSF penetration 1/4th of plasma) – no relation with inflammation
• Excretion: Primarily in urine (dose adjustment in renal failure)
– Doxycycline is exception (bile)
• Preparations: Oral capsules, ½ to 2 Hrs pre and post food
– No IM: painful (oxy and tetra available)
– Also cream, ointment and ocular etc. preparations – high risk of
sensitization

13. Adverse Effects
 GI disturbances: Due to Irritation
• Mild nausea and diarrhoea to severe, possibly life-threatening
colitis and Oesophageal ulcer etc.
 Superinfection: Disturbances in the normal flora (Diabetics)
– Candidiasis (oral and vaginal) – soreness and redness of
mouth black hairy tounge and inflammatory lesions in vulva,
vagina etc.
– Staphylococcal enteritis (S. aureus) – hospitalized patients –
loss of appetite, abdominal discomfort and watery diarrhoea,
– Pseudomembranous colitis - C. difficile (profuse diarrhoea
and fever) – Rare but dangerous
Difference of diarrhoea: Pus cell or RBCs (absent in irritation
type)
(Doxycycline and Minocycline – less likely to cause diarrhoea)

14. Toxicity – contd.
 Liver damage: fatty infiltration
 Kidney damage: accumulates except doxycycline
 Phototoxicity: Sunburn like - Skin rashes, mainly after topical
application
 Erythema, brown black discolouration of nails and loosening etc.
 Doxycycline and demeclycline - more
 Teeth and Bones: Brown discolouration - Calcium tetracycline
chelate (orthophosphate)
 Deciduous teeth – ill formed and prone to carries teeth
 Affect the crown of permanent anterior dentition
 Pregnancy and childhood - Temporary supression of Bone growth
 Antianabolic effect: reduction in Protein synthesis
 Diabetes Insipidus: antagonizes ADH and urine conc

15. Tetracyclines - uses
1. Empirical therapy: Mixed Infections
2. Rickettsial infections: Rocky Mountain
Spotted Fever, All forms of typhus and Q
fever (Coxiella burnetii)
3. Atypical pneumonia: due to mycoplasma.
4. Brucellosis: D 200+ R600/day X 6 weeks
5. Plague: Bubonic and Pneumonic plague

16. Tetracyclines – other uses
Other uses: UTI, Chloroquine Resistant
falciparum adjuvant to quinine, Amoebiasis,
Community aquired pneumonia, Acne vulgaris
and COPD

17. Chloramphenicol
Streptomyces venezuelae

18. Chloramphenicol
(streptomyces venezuelae)
• A natural product
(contains a nitrobenzene
moiety)
• Now all are synthetic
products
• Yellowish white crystalline
solid
• Stable aqueous solution
• Nitrobenzene –
antibacterial activity

19. Chloramphenicol - MOA
• Binds to 50S ribosomal
subunit
• Prevents peptide bonds
from forming and blocking
proteins synthesis
• Bacteriostatic - Effective
against a wide variety of
organisms
• Mainly like tetracycline -
+ve, -ve, Rikettsiae and
mycoplasma
• Generally used as drug of
last resort for life-
threatening infections

20. Chloramphenicol – Differences with
Tetracycline
• Highly effective against S. typhi (RESISTANT
NOW)
• More effective against H. influenzae, B.
pertissis, N. menigitidis
• Less active against gm+ve cocci and
spirochaetes
• Not effective against – chlamydia, entmoeba
and plasmodia

21. Resistance - chloramphenicol
• High incidence of Resistance due to
indiscriminate use in the past – developing
countries
• Resistant strains of S. typhi developed due to
transfer of R plasmid.
• R Plasmid mediated-formation of acetyl- transferases
that inactivate the drug
• Acetyl – chloramphenicol does not bind to ribosomes
• Other mechnisms –
• decreased permeability (passive and facilitated diffusion)
• Lowered affinity of ribosomes to chloramphenicol

22. Pharmacokinetics
• Given orally or parenterally
• Wide distribution – serous cavities and CSF
• Present in bile, milk, and placental fluid
• Conjugated in liver (glucoronic acid)
• Cirrhotics & neonates have low conjugating ability
• Little is excreted unchanged in urine
• T1/2 = 3-5 hrs
• Available as capsules 250mg – 500mg (maximum dose
28 gm in a course of less than 2 weeks)
• Also as inj. 0.25, 0.5 and 1 g per vial
• Eye drops 0.4% and ear drops

23. Adverse effects
• Irritative effects – Nausea, vomiting, diarrhoea and pain in injection
• Bone marrow depression: Notorious causes aplastic anaemia,
agrannulocytosis, thrombocytopenia
Hypersensitive effects – Rashes, fever, glossitis and angioedema
• Gray Baby Syndrome: (2-9 days after dose of 100mg/kg)
– Within 24 hours, baby starts to vomit, stops eating, rapid and irregular
respiration, abdominal distension, periods of cyanosis, and pooping
loose green stool
– Baby then turns ashen gray and becomes flaccid and hypothermic
– Also can occur in adults who are cirrhotics
– Death in 40% of cases (CVS collapse)
– Due to Inability to metabolised & excrete chloramphenicol

24. Chloramphenicol - Uses
• Enteric fever: Mainstay in the past
• meningitis as 2nd line to 3rd generation
cefalosporins – child and allergics
– Meningcoccal meningitis and H. influenzae
• Anaerobic infections – Bact. Fragilis
• Intraocular infections – endophthalmitis
• Second choice : brucellosis, UTI, rickettsial
infections, conjunctivitis, external ear
infections

25. Remember Adverse effects and
Resistance! - Preserve
Thank you