Chloramphenicol and tetracyclines are broad-spectrum antibiotics that are bacteriostatic. Their widespread use led to many resistant bacterial strains. Chloramphenicol works by reversibly binding to the 50S ribosomal subunit and inhibiting peptidyl transferase activity. Tetracyclines inhibit bacterial protein synthesis by binding to the 30S ribosomal subunit. Both experience resistance through ribosomal protection, decreased drug permeability/concentration, and enzymatic inactivation. They have many therapeutic uses but also potential adverse effects like bone/tooth discoloration and gastrointestinal issues. Tigecycline is a newer glycylcycline antibiotic with activity against resistant strains.

1. Broad Spectrum
Antibiotics:
Chloramphenicol &
Tetracyclines
Dr. Vikram Sharma
MD, Pharmacology
Maulana Azad Medical College

2. Introduction
o Chloramphenicol & Tetracyclines are
bacteriostatic antimicrobials.
o Their widespread use (or misuse) → many
resistant strains of bacteria → minimized
clinical usefulness.
o Recent surge in interest in clinical use → almost
complete lack of use loss of resistant bacteria
from environment

3. Chloramphenicol
(Chloromycetin)

4. Intro
o Isolated 1947; Streptomyces venezuelae
o Synthesized 1949; 1st completely synthetic
antimicrobial

5. Mechanism of Action
Reversible binding to 50s
↓
Inhibits peptidyl transferase
activity

6. MOA

7. 1. Ribosomal protection → decreased affinity to
ribosomal binding site.
2. Drug less permeable to mutants.
3. Plasmid encoded enzyme acetyltransferase →
inactivates drug
Resistance Mechanisms

8. Pharmacokinetics
• Rapid & complete oral absorption
• Can be given orally/ i.v.
• Widely distributed in body compartments
including CSF
• Glucuronyl Conjugation in liver inactivation
• Excretion: Urine
• t1/2 – 3 to 5 hr (6 hourly doses)

9. Pharmacokinetics
• Major excretion by urine (bile & faeces also)
• Dose decreased in new born & premature
infants.

10. Antimicrobial Spectrum
o Aerobic & anerobic; Gram Pos. & Gram Neg.
o Gram Neg. → S. typhi, H. influenzae, N. meningitidis
o Gram Pos. → S. pneumoniae
o Anaerobes → Bacteroides
o Spirochaetes, Mycoplasma, Rickettsiae ; not against Chlamydiae
o May be cidal → H. influenzae, N meningitides &
bacteroides.

11. Therapeutic Uses
 Bacterial meningitis: β-lactams resistant or allergic
pneumoccoci or meningococci (DOC: Ceftriaxone;
Cefotaxime)
 Topical ear/eye preps: conjunctivitis, otitis
externa, endophthalmitis.
 Pelvic & Brain Abscess (DOC: Clindamycin or
Metronidazole)
 Serious Rickettsial inf. :Typhus fever, Rocky mountain
spotted fever.
 Children <8yrs where Tetracyclines are
contraindicated.
 Earlier used to treat typhoid fever

12. Adverse Reactions
• Gastrointestinal disturbances: Nausea, Vomiting,
Diarrhoea, Oral/Vaginal candidiasis (Superinfection)
• Bone marrow depression: Dose related & reversible (monitoring
with periodic blood counts; Mech: inhibit host mitochondrial 70s ribosome)
• Aplastic anaemia: Non-dose related or idiosyncratic;
Rare(1:40k); Single oral dose
• Neonates: Toxicity due to deficient glucuronide
conjugation (>50mg/kg/d); Gray Baby Syndrome
(loss of hunger, abd distension, vomiting, grayish skin
discoloration; hypothermia, CVS collapse, death)

13. Drug Interactions
• Inhibits microsomal enzymes that metabolize
drugs.
• Chloramphenicol (static) antagonizes bactericidal
drugs: Penicillins, Aminoglycosides.
• PCM ↑ Bioavailability of drug by 28%

14. Tetracyclines

15. • Have a nucleus of four (tetra) cyclic rings
• Obtained from soil Actinomycetes
• Spectrum: Aerobes, Anaerobes, Chlamydia,
Rickettsiae, Mycoplasma, Protozoa (Plasmodium)
• Gram pos. → enter cytoplasm by Active transport
(Energy Dependent)
• Gram neg. → passes porin channels via passive
diffusion (Energy Independent)
Intro

16. MOA
• Inhibits bacterial protein synthesis.
• Binds to 30s bacterial ribosome, prevents
access of amino acyl tRNA to acceptor site on
mRNA–ribosome complex.
• Prevents addition of amino acids to growing
peptide.
• Selective Toxicity
Carrier involved in active transport absent in mammalian cells
don’t bind to mammalian 60s/40s ribosome units

17. Resistance Mechanisms
1.Decrease in intracellular concentration
2.Development of ribosomal protection proteins
3.Enzymatic inactivation
4.Efflux pump encoded on plasmid
(transmitted by transduction/conjugation)
 Cross resistance with other tetracyclines

18. A. Short acting: (6-8hrs)
Tetracycline, Chlortetracycline, Oxytetracycline
B. Intermediate acting:(12 hrs)
Demeclocycline, Methacycline
C. Long acting (16-18 hrs)
Minocycline, Doxycycline
D. Glycylcycline: Tigecycline

19. Pharmacokinetics
• Orally remains in gut lumen, modifies flora
• Absorbed in upper small intestine
• Widely distributed in body tissues & fluids, teeth,
bones, tumors with high Ca2+ (Gastric Carcinoma)
except CSF.

20. Drug Interactions
 Meals/Food
 Milk (Ca2+) ↓ Absorption of
 Antacids (Al3+, Zn2+, Mg2+) Tetracyclines
 Iron Preparations (Fe2+)
 (-) intestinal flora → ↓ vitamin K production → ↓ factor
2,7,9,10 → potentiate anticoagulant effect of warfarin →
↑bleeding tendency
 Doxy & Mino - absorption not affected by food; less affect
on intestinal flora

21. Pharmacokinetics
• Cross placenta, excreted in milk, chelate with Ca
→ affect bone & teeth development
• Excretion: Enterohepatic circulation; Urine(10-50%);
faeces(10-40%); Saliva & Tears (Minocycline)
 Doxycycline: non-renal excretion; tetracycline of
choice in renal insufficiency

23. Antimicrobial Spectrum
 Atypical Gram Neg. → Rickettsiae, Chlamydia (psittaci, trachomatis,
pneumoniae), Borrelia (burgdorferi, recurrentis), Mycoplasma
pneumoniae, Ureaplasma urealyticum
 Gram Neg. Bacilli → V. cholerae, Brucella abortis, Y. pestis, H. pylori,
Propionibacterium acne
 Gram pos. Bacilli → Bacillus anthracis, C. perfringens, C. tetani
 Protozoans → Entamoeba histolytica, Plasmodia (Adjuvant; high conc.)
X Gram pos. Cocci → S. pnemoniae, Staph. aureus
X Gram neg. Bacilli → E. coli, Enterobacter, Proteus, P. aeruginosa,
Klebsiella, Salmonella, Bacteroids fragilis

24. Therapeutic Uses
• Rickettsial infections – Rocky Mountain Spotted Fever,
Typhus Fever
• Mycoplasma infections - Atypical Pneumonia (x10-14d)
• Chlamydial infections –
o Psittacosis, Pneumonia
o Lymphogranuloma Venereum (Doxy; 100mg bd; x21d)
o Trachoma (Doxy; 100mg bd × 14d or Tetra; 250mg qid × 14d)
(Azithromycin single dose preferred)
• Ureaplasma urealyticum
o Non-specific urethritis (Doxy;100 mg BD x 7d)
(Azithromycin single dose preferred)

25. • Uncomplicated gonoccocal infections
C. trachomatis (Doxy 100mg bd × 7d)
• Pelvic inflammatory diseases: C. trachomatis
(Doxy; 100 mg iv 12hrly × 48 hrs followed by oral therapy x 14d)
Non-pregnant; Penicillin Allergic Patients
• 1○ /2○/ Latent Syphilis (2nd line agents)
(Doxy 100mg bd ×2 wks)
(not to be used in neurosyphilis)

26. • Brucellosis
• Tularemia
• Plague
• Malaria (Adjuvant; +Quinine; Chloroquine resistant P
. falciparum)
• Peptic Ulcer d/t H. pylori (Adjuvant)
• Amoebiasis (+ Metronidazole)
• Cholera (Doxy; 300mg; single dose)
• Acne – Propionibacteria (Tetra; 250 mg bd; Doxy 100mg od;
Minocycline (last resort)
X Fears of hepatitis/pneumonitis/pigmentation
X Cost
Therapeutic Uses (Effective)

27. Therapeutic Uses
 Doxycycline: Early stages of Lyme disease (i.v.);
Prophylxis of Anthrax
 Demeclocycline: (-) ADH action in renal tubules →
treatment of SIADH.
 Minocycline:
 Eradicate meningococcal carrier state from nasopharynx
 Swimming pool granuloma (Mycobacterium marinum)
 Chronic facial dermatoses

28. Adverse Effects
Gastrointestinal : epigastric burning, distress,
nausea, vomiting, abd. discomfort, stomatitis;
diarrhoea (affect intestinal flora)
Superinfection:
 Pseudomembranous Enterocolitis d/t C. difficile
(life threatening)
 Intestinal Candidiasis, Fungal esophagitis
Phototoxicity: Photosensitivity to U.V. light;
Demeclo & Doxy; sunburn-like rash

29. Hepatotoxicity: jaundice; more in
pregnancy (Oxytetra & Tetra – least among
group)
Renal toxicity: aggravate uraemia in pts with
renal disease (except Doxy & Mino)
Fanconi syndrome: nausea, vomiting, proteinuria,
polydipsia, acidosis, glycosuria, gross
aminoaciduria (due to outdated preps/use after expiry;
due to toxic metabolites)
Adverse Effects

30. Teeth : brown discoloration; deciduous (<10 years) &
permanent
Retardation of bone growth (teratogenic)
Nephrogenic Diabetes Insipidus - ADH Antagonism;
Demeclocycline-induced
Adverse Effects

31. Adverse Effects
 Vestibular Toxicity: Minocycline; Accumulate in
lipid rich cells of inner ear; Vertigo & Ataxia
 Skin pigmentation: Minocycline; thyroid staining
become visible over neck in light-skinned
patients.
 Pseudotumor cerebri (↑ICT; adults)
 Bulging fontanelles (chronic use)

32. Adverse Effects
 i.v. injection → phlebitis
 i.m. injection → painful; local irritation
 Pulmonary Eosinophilic Syndrome (Eosinophilia;
Hilar LAD; x 10d)

34. Contraindications
X Pregnancy & lactation
X Children before attainment of puberty (<10 years)
X Renal Impairment
X Hepatic Insufficiency
X Expired Products
X Intrathecal Injection

35. Glycylcycline: Tigecycline
• First member of new class of synthetic tetracycline analogue
(2005)
• Derivative of Minocycline
• Active against bacteria resistant to classical
tetracyclines.
• x20 times more potent in protein synthesis inhibition
than classical tetracyclines.
• Apart from usual tetracycline spectrum, also active against
MRSA, VRSA, VRE.
• X Pseudomonas, Proteus, Providencia

36. Pharmacokinetic advantages
 Excreted by Bile → Dose adjustment not
required in kidney disorders
 Don’t affect metabolism by CytP450 → fewer
drug interactions

37.  Lack of cross resistance b/w Tetracycline &
Tigecycline because efflux pumps are
unable to pump it out.
 Ribosomal protection is also less effective
against Tigecycline.
Lesser Resistance

38. • Only given by slow i.v. infusion.
• Approved only for serious pneumonia,
complicated skin & soft tissues infections,
complicated intra-abdominal infections.
• A/E – Nausea, vomiting, epigastric distress,
diarrhea, skin reactions, photosensitivity,
superinfections, pancreatitis.
• Contraindicated in children, pregnancy.