Broad Spectrum Antibiotics

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.