Range of Secondary Electrons and Electron Build-Up: Impact on Scatter in Homo...
Broad spectrum antibiotics - drdhriti
1. TETRACYCLINE AND
CHLORAMPHENICOL - BROAD
SPECTRUM ANTIBIOTICS
Dr. D. K. Brahma
Associate Professor
Department of Pharmacology NEIGRIHMS, Shillong
2. BROAD SPECTRUM – WHY ??
Name given as they contrasted to the existing
antibiotics – e.g., Penicillin and Streptomycin (1944)
available
1. Orally effective
2. Wider spectrum of activity
Tetracycline and Chloramphenicol
3. TETRACYCLINE - HISTORY
American Pharmaceutical Industry: In the 1940’s soil
actinomycetes were systematically
screened for the elaboration of antimicrobial substances
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)
6. TETRACYCLINES – COMMON PROPERTIES
Nucleus of 4 hydrocarbon rings
Bitter solids and weakly water soluble – HCl salts
are more soluble
Aqueous solutions are unstable
Same antimicrobial activity – only minor differences
Newer ones – high lipid solubility and greater
potency
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
Higher diarhoeal
incidence
Phototoxicity - Low
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
Lower diarhoeal incidence
Phototoxicity - High
8. TETRACYCLINES - MOA
Inhibition of Bacterial Protein Synthesis by binding
to 30S ribosomes – aminoacyl-t-RNA to mRNA-
ribosome complex – interfered
Susceptible organisms: concentrating mechanism
Energy dependent active transport – concentrates TCN
intracellularly
By porin channels – gm-ve ones
Passive diffusion also by lipid soluble ones
Why do not affect host cells ? – transport (absence
of carrier) and sensitivity
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 protozoa
Cocci: All +ve and –ve cocci
S. pneumoniae, gonococi, meningitidis were sensitive. Resistance
developed to Staph aureus, Strep. pyrogens and enterococci
Now also active against N. gonorrhoeae ad N. meningitidis
Bacilli (+ve): clostridia, listeria, anthracis etc., but not
Mycobacteria
Gm-ve bacilli: Cholerae, Y. pestis, Helicobacter, Brucella etc. but
H. Influanzae become insensitive
Enterobacteriocae: resistant and not effective - pseudomonas,
proteus klebsiella and salmonella typhi and Bact. fragilis
Spirochaetes (T. pallidum, Borrelia)
All Rickettsiae (typhus), chlamydiae
Mycoplasma and actinomycetes etc.
Enterococci: histolytica and plasmodia
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
Intracellularly binds to mitochondria
Excretion: Primarily in urine (dose adjustment in renal failure)
Doxycycline is exception (bile) – enterohepatic circulation
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. PREPARATION AND ADMINISTRATION
Oral route is the most commonly used route – IM
not recommended – painful
Local preparations - sensitization
Oxytetracycline: Terramycin
250/500 Caps or 50 mg/ml vial
Also skin ointment and eye ointment
Tetracycline:
Hostacyclin/Restecyclin 250/500 Caps or skin and eye
ointment
Demeclocyclin: 130/300 mg caps
Doxycycline: 100 mg caps. and Minocycline – 50 or
100 mg caps.
14. ADVERSE EFFECTS
GI disturbances: Due to Irritation
• Mild nausea and diarrhoea to severe, possibly life-
threatening colitis and Oesophageal ulcer etc.
• Thrombophlebitis
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
15. TOXICITY – CONTD.
Liver damage: fatty infiltration – oxytetracycline safer; pregnancy –
acute hepatic necrosis
Kidney damage: accumulates except doxycycline – enhance existing
kidney disease
FANCONY LIKE SYNDROME – outdated tetracycline (epitetracycline,
anhydrotetracycline and anhydroepitetracycline) – glycosuria, proteinuria and
aminoaciduria etc.
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. property
Vestibular toxicity: Minocycline (ataxia, vertigo, nystagmus)
16. TOXICITY/CONTRAINDICATIONS
OF TETRACYCLINES
Because drug is deposited in
tooth dentine and enamel,
brown bands form
Do not give to children or
pregnant/nursing women
(bone growth, deformities, stature)
Misc. side effects
Thrombophlebitis
Various WBC dystrophies
Increased intracranial
pressure in neonates
Hypersensitivity reactions
(superinfections)
17. TETRACYCLINES - USES
1. Empirical therapy: No - Mixed Infections
2. 1st choice:
i. Venereal diseases:
Chlamydial urethritis/endocervicitis: Doxycycline – 7 days
Lymphogranuloma venereum (Chlamydia trachomatis) – 2-3
weeks
Granulloma inguinale (Klebsiella granulomatis) – 3 weeks
ii. Atypical pneumonia: due to mycoplasma - psittacosis
iii. Cholera: reduce stool volume
iv. Brucellosis: D 200+ R600/day X 6 weeks
v. Plague: Bubonic and Pneumonic plague
vi. Rickettsial infections: Rocky Mountain Spotted Fever, All
forms of typhus and Q fever (Coxiella burnetii)
vii. Relapsing fever due to Borrelia recurrentis
18. TETRACYCLINES – OTHER USES
2nd choice drugs:
To penicillins for tetanus,anthrax,actinomycosis and
listerias
To ceftriaxone/amoxy/azithro for gonorrhoea
To penicillins for syphilis (allergic to penicillins)
To pens for leptospirosis (doxy 100 mg BD 7 days)
To azithromycin for chlamydia pneumonia
To ceftriaxone and azithromycin for chancroid
To streptomycin for tularemia
Other uses: UTI, Chloroquine Resistant falciparum
adjuvant to quinine, Amoebiasis, Community aquired
pneumonia, Acne vulgaris and COPD
19. TETRACYCLINES - PRECAUTIONS
Pregnancy, lactation and children
Renal and hepatic insufficiency
Expiry Date
With diuretics
Intrathecal injection
21. CHLORAMPHENICOL
(STREPTOMYCES VENEZUELAE)
A natural product
(contains a nitrobenzene
moiety)
Now, all are synthetic
products
Yellowish white crystalline
solid
Stable aqueous solution –
stands boiling – sunlight !
Nitrobenzene –
antibacterial activity
BITTER
22. CHLORAMPHENICOL – DIFFERENCES WITH
TETRACYCLINE
Highly effective against S. typhi (RESISTANT
NOW)
More effective against H. influenzae, B. pertussis,
Klebsiella, N. menigitidis and Bact. fragilis
Less active against gm+ve cocci and spirochaetes
Not effective against – chlamydia, entmoeba and
plasmodia
Ineffective against Mycobacteria, Pseudomonas,
Proteus, fungi and viruses
23. CHLORAMPHENICOL - MOA
Binds to 50S ribosomal
subunit
Prevents peptide bonds from
forming and blocking proteins
synthesis
Prevents transfer of the
elongated peptide chain to
the newly attached
aminoacyl-tRNA at the
ribosome-mRNA complex
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
24. 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 factor
Resistance among gr-ve bacteria – by R Plasmid
encoded for acetyl- transferases acquisition -
inactivate the drug
• Acetyl – chloramphenicol does not bind to ribosomes
• Plasmid also carries resistance to – ampicillin and
tetracycline etc – multidrug resistance (S. typhi)
• Other mechnisms –
decreased permeability (passive and facilitated diffusion)
Lowered affinity of ribosomes to chloramphenicol
25. 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 250 mg – 500 mg (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
26. ADVERSE EFFECTS
Irritative effects – Nausea, vomiting, diarrhoea and pain in
injection
Bone marrow depression: Notorious causes aplastic anaemia,
agrannulocytosis, thrombocytopenia
1. Non dose related (idiosyncratic): genetic basis and unpredictable –
more common on repeated use - higher mortality - in long term
leukaemias
2. Dose and duration related – myelo-suppression – due to inhibition of
mitochondrial enzyme synthesis - predictable, reversible
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
27. CHLORAMPHENICOL - PRECAUTIONS
Minor infections and undefined etiology
Infections treatable by other AMAs
Avoid repeated courses
Should not use more than 2-3 gms per day, use for
less than 2 weeks and total dose should not exceed
28 gms
Regular peripheral blood smear – reticulocyte count
No combination with other antimicrobials
28. CHLORAMPHENICOL - USES
Enteric fever: Mainstay in the past
Pyogenic 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 & rickettsial infections,
UTI – sensitive ones ---- also topical in
conjunctivitis, external ear infections
Conjunctivitis and external ear infection - Not to be
used on skin or other areas
30. REMEMBER !
Toxicities of Tetracyclines - Superinfections, gum
and teeth deposits, Fanconi like syndrome,
pseudomembranous colitis – also GI disturbance,
liver damage, kidney damage and phototoxicity
Toxicities of chloramphenicol: Bone marrow
depression – aplastic anaemia, Gray Baby
syndrome and hypersensitivity