Broad Spectrum Antibiotics

(Tetracyclines & Chloramphenicol)

Dr. B. T. Rane
Tetracyclines
 Tetracyclines
 ‘A class of antibiotics having a nucleus of 4 cyclic rings’.

 Obtained from soil actinomycetes.

 Chlortetracycline (Aureomycin): 1st Tetracycline (1948).
 Classification of Tetracyclines
Natural Semi-synthetic
synthetic Synthetic
Tetracycline
Analogues
(Glycylcyclines)
Chlortetracycline Tetracycline Tigecycline
(Not used now) Doxycycline
Minocycline
Oxytetracycline Demeclocycline
 1. 2. 3. 4.
Aminoglycosides Tetracyclines Chloramphenicol Macrolides

Figure : Bacterial protein synthesis and the sites of action of antibiotics

 Mechanism of Action of Tetracyclines
 Primarily bacteriostatic.
 Inhibit protein synthesis in the susceptible microbes
as follows:
 Bind to the 30S ribosomes in the susceptible
microbes
→ Block the attachment of aminoacyl-t-RNA
aminoacyl to the
acceptor (A) site of mRNA-ribosome
mRNA complex
→ Peptide chain fails to grow
→ Protein synthesis is inhibited.
 Antimicrobial Spectrum of Tetracyclines
 Gram + ve Cocci: Some strains of:
• Streptococcus pyogenes
• Staphylococcus aureus (including MRSA)
• Enterococci.
 Gram - ve Cocci: Some strains of:
• Neisseria gonorrhoeae
• Neisseria meningitidis
(Minocycline may still have Significant activity
against these cocci)
 Gram + ve bacilli:
 Clostridia & other anaerobes,
Corynebacteria, Propionibacterium acnes,
Bacillus anthracis, Listeria,
Mycobacterium leprae (only to minocycline).
 Gram - ve bacilli:
 H. ducreyi, C. granulomatis, V. cholerae,
Y. pestis, Y. enterocolitica, C. jejuni, Brucella,
P. multocida, F. tularensis & many anaerobes.
 Spirochaetes:
Treponema pallidum, Borrelia (relapsing fever)
 Rickettsiae (typhus etc): All are highly sensitive.
 Chlamydiae: All are highly sensitive.
 Mycoplasma: Moderately sensitive.
 Actinomyces: Moderately sensitive.
 Protozoa: (Inhibited at high conc).
• Entamoeba histolytica, Plasmodia.
 Pharmacokinetics of tetracyclines
• Older tetra: Incomplete absorption from GIT.
• Doxycycline & Minocycline: Complete absorption
(irrespective of food).
• Chelating property:
Bind with calcium & other metals thereby forming
insoluble & unabsorbable complexes:
 Avoid / stagger the concurrent administration with
milk, iron, non-systemic
systemic antacids, sucralfate etc.
• Bind to the connective tissue in the bones &
teeth.
• Minocycline: highly lipid soluble.
 Accumulates in the body fat.
• Low CSF concentrations:
(even during meningeal inflammation).
• Dose reduction needed in renal failure:
(except doxycycline).
• Secreted in milk:
 may affect the suckling infant.
• Oral capsule:
 Most preferred dosage form.
• Doxycycline:
 Most commonly used tetracycline
 (100 mg / once or twice daily).
 Therapeutic uses of tetracyclines
I) Drugs of first choice in:
in
1. Venereal diseases:

 Chlamydial infections:: (Chlamydia

trachomatis):
 Nonspecific urethritis / Endocervicitis:
(Doxycycline 100 mg BD orally X 7 days).
 Lymphogranuloma venereum:
venereum
(Doxycycline 100 mg BD orally X 3 weeks).
  Granuloma inguinale (Donovanosis):
(Calymmatobacterium granulomatis)
(Doxycycline 100 mg BD orally X 3 weeks)
weeks

2. Rickettsial infections: Dramatic response in:

 Typhus
 Q fever
 Rocky mountain spotted fever.
3. Atypical pneumonia:
 Mycoplasma pneumoniae:
 ↓ Duration of illness.
 Chlamydia psittaci (Ornithosis/Parrot fever):
 Two weeks therapy is needed.
4. Cholera:
 ↓ Stool volume & DuraEon of diarrhoea.
5. Brucellosis:
(Malta /Mediterranean/ Undulant fever):
Doxycycline 200 mg/day + Rifampicin 600 mg/day
for 6 weeks (+ Gentamicin in acute cases)
 Highly effective  Rapid symptomatic relief.
6. Plague: Mass Rx of suspected cases in epidemic.
Effective in both bubonic & pneumonic plague.
7. Relapsing fever: (d/t: Borrelia recurrentis).
 II) As Second choice drugs in:
in
Conditions Second choice to:
Tetanus, Anthrax, Penicillin /Ampicillin
Actinomycosis, Listeriosis.
Gonorrhoea (in the patients Ceftriaxone/Amoxycillin/
allergic to penicillin) Azithromycin
Syphilis (in the patients allergic Ceftriaxone
to penicillin)
Leptospirosis Penicillin
(Doxy 100 mg BD X 7 days).
 III) Other situations in which tetracyclines are used:
used
• UTI: Odd cases if sensitive.
• Community Acquired Pneumonia:
Pneumonia
 If a selective antibiotic can’t be used.
• Chronic intestinal amoebiasis:
amoebiasis
 With other amoebicides.
• Chloroquine-resistant
resistant P. falciparum malaria:
malaria
 As adjuvant to Quinine / Artesunate.
• Acne vulgaris: Prolonged therapy with low doses.
 IV) As empirical therapy:
therapy
 If the nature & sensitivity of infecting
microorganism is not known.
 Initial Rx of mixed infections.
 Unreliable as empirical treatment of
serious / life threatening infections.
 Adverse effects of Tetracyclines
1. Teeth & Bones:
Tetracyclines have chelating property
 Calcium-tetracycline
tetracycline chelate gets deposited in
the developing teeth & bones.
 If given from midpregnancy to 5 months of
age,deciduous teeth are affected resulting in:
→ Brown discolouration, ill formed teeth &
↑ suscepEbility to dental caries.
• Given between 3 months to 6 years of age:
→ Damage to the crown of permanent anterior
dentition.
• Given during late pregnancy or childhood:
→ Temporary suppression of bone growth.
2. Phototoxicity:
 Sunburn like severe skin reaction on exposed parts
 Higher incidence with Demeclocycline & Doxycycline.
3. Superinfections:
• Occur commonly as tetracyclines cause marked
suppression of the resident flora.
• Intestinal superinfection by Candida albicans is most
prominent.
• More liability of Candidial diarrhoea d/t incomplete
absorption in the ileum.
• Pseudomembranous enterocolitis (Clostridium difficile)
(Rare but serious).
• Overgrowth of Pseudomonas & Proteus in the bowel.
4. Liver damage:
• Fatty infiltration of liver & jaundice occasionally.
• Given during pregnancy:
→ may precipitate fatal acute hepatic necrosis.
5. Kidney damage:
(esp. in patients with kidney disease):
• Worsening of renal failure (except doxycycline).
• Fanconi syndrome-like
like condition due to the use of
outdated & degraded tetracyclines (cause damage to
the proximal tubules).
6. Irritative effects:
• Irritant property of tetracyclines can cause:
→ Epigastric pain, nausea, vomiting &
diarrhoea.
• Accidental release of the material from
capsule
into the oesophagus during swallowing:
→ Odynophagia (pain while swallowing)
→ oesophageal ulceration
• Thrombophlebitis of the injected vein.
7. Vestibular toxicity: Minocycline can cause:
 Ataxia, vertigo & nystagmus.
 Subside on discontinuation.
8. Antianabolic effect:
 ↓ Protein synthesis
 - ve nitrogen balance
 ↑ Blood urea
9. Diabetes insipidus: Demeclocycline antagonizes ADH
acEon & ↓ urine concentraEng ability of the kidneys.
10. ↑ ICT: noted in some infants.
 Glycylcyclines
 A new class of synthetic tetracycline analogues.
 Active against most of the bacteria that have
developed resistance to the classical tetracyclines:
 Have the broadest spectrum of activity.
Tigecycline
• First glycylcycline (2005).
• Derivative of minocycline.
• Active against most of the gram + ve & gram – ve
cocci
as well as anaerobes (Tetra sensitive & resistant).
 Pharmacokinetics of Tigecycline:
Tigecycline
• Poor absorption on oral administration.
• Given by slow IV infusion (only).
• Wide tissue distribution.
• Long DOA: (Elimination t1/2 : 36-60 hours).
 MOA of Tigecycline:
 Same as tetracyclines.
 Dose:
 100 mg loading dose, followed by 50 mg BD
by IV infusion over 30-60
30 min, for 5-14 days.
 No cross-resistance
resistance with tetracyclines because:
because
 Tetracycline efflux pumps have low affinity for
Tigecycline.
 Bacterial ribosomal protection protein against
tetracycline has less capacity to protect the
ribosomal binding site from tigecycline.
 Approved therapeutic uses of Tigecycline:
Tigecycline
• Serious & hospitalized patients of community
acquired pneumonia.
• Complicated skin & skin structure infections
• Complicated intra-abdominal
abdominal infections
(caused by Enterococci, Anaerobes &
Enterobacteriaceae).
Chloramphenicol
 Chloramphenicol
 Broad spectrum antibiotic.
 Initially obtained from Streptomyces
venezuelae, now entirely synthetic.
 Antibacterial activity d/t its nitrobenzene
moiety.
 Primarily bacteriostatic action.
Mechanism of action:
 Inhibition of bacterial protein synthesis:
 1. 2. 3. 4.
Aminoglycosides Tetracyclines Chloramphenicol Macrolides

Figure : Bacterial protein synthesis and the sites of action of antibiotics

 MOA of chloramphenicol
 Attaches to the 50S ribosome near the acceptor (A)
site of the ribosome-mRNA
mRNA complex
→ Interferes with the transfer of elongating
(nascent) peptide chain from the peptidyl (P) site
to the at the acceptor (A) site (that has the newly
attached aminoacyl tRNA)
→ Prevents the peptide bond formation between the
nascent peptide chain & the newly attached amino acid
→ Inhibits the bacterial protein synthesis.
 Antimicrobial spectrum of chloramphenicol
 Broad spectrum antibiotic.
 Primarily bacteriostatic.
 Active against nearly the same range of microbes
as tetracyclines. Notable differences between these:
 Chloramphenicol is more active & has cidal effect
against H. influenzae & N. meningitidis (in high conc.)
 More active against B. pertussis & Klebsiella.
 Less active against gram + ve cocci & Spirochaetes.
 No inhibition of Entamoeba & Plasmodia.
 Therapeutic uses of chloramphenicol
1. Intraocular infections:
Attains high conc. in the ocular fluid on
systemic admn:
 Preferred drug for endophthalmitis caused
by sensitive bacteria.
2. Topically: (0.5-5 %):
 Conjunctivitis
 External ear infections
3. As second line drug for:
i) Pyogenic meningitis: (Bacterial meningitis):
(DOC: Third gen. cephalosporins + Vancomycin)
• Due to its excellent CSF penetration & proven
efficacy, Chloramphenicol may be used as second
line drug in:
 Haemophilus influenzae meningitis
 Meningococcal meningitis (N. meningitidis).
ii) Anaerobic infections: (B. fragilis etc):
(DOC: Clindamycin/Metronidazole + Penicillin/Cephalo)
 Wound infections
 Intraabdominal infections,
 Pelvic abscess
 Brain abscess.
iii) Whooping cough: (As second choice to erythromycin).
iv) Rickettsial infections & Brucellosis:
Brucellosis
(especially in young children & pregnant women,
as tetracyclines are contraindicated in them).
 Adverse effects of chloramphenicol
1. Bone marrow depression: Amongst all antibiotics,
Chloramphenicol is the most prominent cause of:
 Aplastic anaemia, Agranulocytosis,
Thrombocytopenia & Pancytopenia.
 Two forms:
i) Non-dose
dose related idiosyncratic reaction:
reaction
 Rare, unpredictable, fatal & based on genotype.
 Many victims, even if they survive, may develop
leukaemias later on.
 ii) Dose & duration of therapy related:
related
 Direct toxic effect, predictable, reversible &
d/t
inhibition of mitochondrial enzyme synthesis
in the erythropoietic cells.
 Often reversible (No long-term
long sequelae).
2. Gray baby syndrome:
• D/t inability of the newborn to adequately
metabolize
& excrete chloramphenicol
 Avoid in neonates.
3. Hypersensitivity reactions:
reactions
 Rashes, fever, atrophic glossitis,
angioedema.
4. Irritative effects:
 Nausea, vomiting, diarrhoea, pain on inj.
5. Superinfections:
 Similar to tetracyclines, but less common.
Thank You