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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 â WHY ??
ď˘ Name given as they contrasted to the existing
antibiotics â 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 1940âs soil
actinomycetes were systematically
screened for the elaboration of antimicrobial substances
4. TETRACYCLINES
ď˘ A class of antibiotics named for their nucleus of four
(âtetra-â) hydrocarbon rings
ď˘ All are obtained from soil actinomycetes
ď˘ 1948 first one â chlortetracycline (aureomycin) â S.
aureofaciens (Yellow coloured colony)
ď Oxytetracycline from S. rimosus (1950)
ď Tetracycline (1953)
6. TETRACYCLINES â COMMON PROPERTIES
ď˘ Nucleus of 4 hydrocarbon rings
ď˘ Bitter solids and weakly water soluble â HCl salts
are more soluble
ď˘ Aqueous solutions are unstable
ď˘ Same antimicrobial activity â only minor differences
ď˘ Newer ones â high lipid solubility and greater
potency
7. AVAILABLE DRUGS - CHARACTERS
ď˘ Tetracycline,
oxytetracycline,
demeclocycline
ď Lower potency (250-500
mg tid)
ď Orally given, short acting
(t1/2 â 6-8 Hrs)
ď Incompletely absorbed
from stomach (60-80%)
ď Primarily excreted through
the kidneys
ď Higher diarhoeal
incidence
ď Phototoxicity - Low
ď˘ Minocycline,
doxycycline,
tigecycline
ď Higher potency (100 - 200
mg)
ď Lipid soluble, long acting
(t1/2 â 18-24 Hrs)
ď Completely absorbed
from stomach (95-100%)
ď Excreted through liver
ď Lower diarhoeal incidence
ď Phototoxicity - High
8. TETRACYCLINES - MOA
ď˘ Inhibition of Bacterial Protein Synthesis by binding
to 30S ribosomes â aminoacyl-t-RNA to mRNA-
ribosome complex â interfered
ď˘ Susceptible organisms: concentrating mechanism
ď Energy dependent active transport â concentrates TCN
intracellularly
ď By porin channels â gm-ve ones
ď Passive diffusion also by lipid soluble ones
ď˘ Why do not affect host cells ? â transport (absence
of carrier) and sensitivity
11. TETRACYCLINES â ANTIMICROBIAL SPECTRUM
ď˘ Bacteriostatic drugs: originally all types of organisms except
viruses and fungi â Both, gm+ve and gm-ve bacteria, Rickettsiae,
Chlamydia, Mycoplasma, actinomycetes and some protozoa
ď˘ Cocci: All +ve and âve cocci
ď S. pneumoniae, gonococi, meningitidis were sensitive. Resistance
developed to Staph aureus, Strep. pyrogens and enterococci
ď Now also active against N. gonorrhoeae ad N. meningitidis
ď˘ Bacilli (+ve): clostridia, listeria, anthracis etc., but not
Mycobacteria
ď˘ Gm-ve bacilli: Cholerae, Y. pestis, Helicobacter, Brucella etc. but
H. Influanzae become insensitive
ď˘ Enterobacteriocae: resistant and not effective - pseudomonas,
proteus klebsiella and salmonella typhi and Bact. fragilis
ď˘ Spirochaetes (T. pallidum, Borrelia)
ď˘ All Rickettsiae (typhus), chlamydiae
ď˘ Mycoplasma and actinomycetes etc.
ď˘ Enterococci: histolytica and plasmodia
12. TETRACYCLINES - KINETICS
ď˘ Older ones less absorbed â 60-80% (food interferes) but doxy
and mino â completely
ď˘ Chelating property â milk, antacids and iron preparations
ď˘ Distribution: wide and variable protein binding (different
members)
ď Concentrated in liver, spleen and bone & teeth â minocycline in fats
ď Good CSF penetration 1/4th of plasma) â no relation with inflammation
ď Intracellularly binds to mitochondria
ď˘ Excretion: Primarily in urine (dose adjustment in renal failure)
ď Doxycycline is exception (bile) â enterohepatic circulation
ď˘ Preparations: Oral capsules, ½ to 2 Hrs pre and post food
ď No IM: painful (oxy and tetra available)
ď Also cream, ointment and ocular etc. preparations â high risk of
sensitization
13. PREPARATION AND ADMINISTRATION
ď˘ Oral route is the most commonly used route â IM
not recommended â painful
ď Local preparations - sensitization
ď˘ Oxytetracycline: Terramycin
ď 250/500 Caps or 50 mg/ml vial
ď Also skin ointment and eye ointment
ď˘ Tetracycline:
ď Hostacyclin/Restecyclin 250/500 Caps or skin and eye
ointment
ď˘ Demeclocyclin: 130/300 mg caps
ď˘ Doxycycline: 100 mg caps. and Minocycline â 50 or
100 mg caps.
14. ADVERSE EFFECTS
ď˘ GI disturbances: Due to Irritation
⢠Mild nausea and diarrhoea to severe, possibly life-
threatening colitis and Oesophageal ulcer etc.
⢠Thrombophlebitis
ď˘ Superinfection: Disturbances in the normal flora
(Diabetics)
⢠Candidiasis (oral and vaginal) â soreness and redness of
mouth black hairy tounge and inflammatory lesions in vulva,
vagina etc.
⢠Staphylococcal enteritis (S. aureus) â hospitalized patients â
loss of appetite, abdominal discomfort and watery diarrhoea,
⢠Pseudomembranous colitis - C. difficile (profuse diarrhoea
and fever) â Rare but dangerous
ď˘ Difference of diarrhoea: Pus cell or RBCs (absent in
irritation type)
ď˘(Doxycycline and Minocycline â less likely to cause
15. TOXICITY â CONTD.
ďś Liver damage: fatty infiltration â oxytetracycline safer; pregnancy â
acute hepatic necrosis
ďś Kidney damage: accumulates except doxycycline â enhance existing
kidney disease
ďś FANCONY LIKE SYNDROME â outdated tetracycline (epitetracycline,
anhydrotetracycline and anhydroepitetracycline) â glycosuria, proteinuria and
aminoaciduria etc.
ďś Phototoxicity: Sunburn like - Skin rashes, mainly after topical
application
ďś Erythema, brown black discolouration of nails and loosening etc.
ďś Doxycycline and demeclycline - more
ďś Teeth and Bones: Brown discolouration - Calcium tetracycline chelate
(orthophosphate)
ďś Deciduous teeth â ill formed and prone to carries teeth
ďś Affect the crown of permanent anterior dentition
ďś Pregnancy and childhood - Temporary supression of Bone growth
ďś Antianabolic effect: reduction in Protein synthesis
ďś Diabetes Insipidus: antagonizes ADH and urine conc. property
ďś Vestibular toxicity: Minocycline (ataxia, vertigo, nystagmus)
16. TOXICITY/CONTRAINDICATIONS
OF TETRACYCLINES
ď˘ Because drug is deposited in
tooth dentine and enamel,
brown bands form
ď˘ Do not give to children or
pregnant/nursing women
(bone growth, deformities, stature)
ď˘ Misc. side effects
ď Thrombophlebitis
ď Various WBC dystrophies
ď Increased intracranial
pressure in neonates
ď Hypersensitivity reactions
(superinfections)
17. TETRACYCLINES - USES
1. Empirical therapy: No - Mixed Infections
2. 1st choice:
i. Venereal diseases:
ď˘ Chlamydial urethritis/endocervicitis: Doxycycline â 7 days
ď˘ Lymphogranuloma venereum (Chlamydia trachomatis) â 2-3
weeks
ď˘ Granulloma inguinale (Klebsiella granulomatis) â 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 â OTHER USES
2nd choice drugs:
ď§ To penicillins for tetanus,anthrax,actinomycosis and
listerias
ď§ To ceftriaxone/amoxy/azithro for gonorrhoea
ď§ To penicillins for syphilis (allergic to penicillins)
ď§ To pens for leptospirosis (doxy 100 mg BD 7 days)
ď§ To azithromycin for chlamydia pneumonia
ď§ To ceftriaxone and azithromycin for chancroid
ď§ To streptomycin for tularemia
Other uses: UTI, Chloroquine Resistant falciparum
adjuvant to quinine, Amoebiasis, Community aquired
pneumonia, Acne vulgaris and COPD
19. TETRACYCLINES - PRECAUTIONS
ď˘ Pregnancy, lactation and children
ď˘ Renal and hepatic insufficiency
ď˘ Expiry Date
ď˘ With diuretics
ď˘ Intrathecal injection
21. CHLORAMPHENICOL
(STREPTOMYCES VENEZUELAE)
ď˘ A natural product
(contains a nitrobenzene
moiety)
ď˘ Now, all are synthetic
products
ď˘ Yellowish white crystalline
solid
ď˘ Stable aqueous solution â
stands boiling â sunlight !
ď˘ Nitrobenzene â
antibacterial activity
ď˘ BITTER
22. CHLORAMPHENICOL â DIFFERENCES WITH
TETRACYCLINE
ď˘ Highly effective against S. typhi (RESISTANT
NOW)
ď˘ More effective against H. influenzae, B. pertussis,
Klebsiella, N. menigitidis and Bact. fragilis
ď˘ Less active against gm+ve cocci and spirochaetes
ď˘ Not effective against â chlamydia, entmoeba and
plasmodia
ď˘ Ineffective against Mycobacteria, Pseudomonas,
Proteus, fungi and viruses
23. CHLORAMPHENICOL - MOA
ď˘ Binds to 50S ribosomal
subunit
ď˘ Prevents peptide bonds from
forming and blocking proteins
synthesis
ď˘ Prevents transfer of the
elongated peptide chain to
the newly attached
aminoacyl-tRNA at the
ribosome-mRNA complex
ď˘ Bacteriostatic - Effective
against a wide variety of
organisms
ď˘ Mainly like tetracycline: +ve, -
ve, Rikettsiae and
mycoplasma
ď˘ Generally used as drug of
last resort for life-threatening
infections
24. RESISTANCE - CHLORAMPHENICOL
ď˘ High incidence of Resistance due to indiscriminate
use in the past â developing countries
ď˘ Resistant strains of S. typhi developed due to
transfer of R factor
ď˘ Resistance among gr-ve bacteria â by R Plasmid
encoded for acetyl- transferases acquisition -
inactivate the drug
⢠Acetyl â chloramphenicol does not bind to ribosomes
⢠Plasmid also carries resistance to â ampicillin and
tetracycline etc â multidrug resistance (S. typhi)
⢠Other mechnisms â
ď˘ decreased permeability (passive and facilitated diffusion)
ď˘ Lowered affinity of ribosomes to chloramphenicol
25. PHARMACOKINETICS
ď˘ Given orally or parenterally
ď˘ Wide distribution â serous cavities and CSF
ď˘ Present in bile, milk, and placental fluid
ď˘ Conjugated in liver (glucoronic acid)
ď˘ Cirrhotics & neonates have low conjugating ability
ď˘ Little is excreted unchanged in urine
ď˘ T1/2 = 3 - 5 hrs
ď˘ Available as capsules 250 mg â 500 mg (maximum
dose 28 gm in a course of less than 2 weeks)
ď˘ Also as inj. 0.25, 0.5 and 1 g per vial
ď˘ Eye drops 0.4% and ear drops
26. ADVERSE EFFECTS
ď˘ Irritative effects â Nausea, vomiting, diarrhoea and pain in
injection
ď˘ Bone marrow depression: Notorious causes aplastic anaemia,
agrannulocytosis, thrombocytopenia
1. Non dose related (idiosyncratic): genetic basis and unpredictable â
more common on repeated use - higher mortality - in long term
leukaemias
2. Dose and duration related â myelo-suppression â due to inhibition of
mitochondrial enzyme synthesis - predictable, reversible
ď˘ Hypersensitive effects â Rashes, fever, glossitis and
angioedema
ď˘ Gray Baby Syndrome: (2-9 days after dose of 100mg/kg)
ď Within 24 hours, baby starts to vomit, stops eating, rapid and irregular
respiration, abdominal distension, periods of cyanosis, and pooping loose
green stool
ď Baby then turns ashen gray and becomes flaccid and hypothermic
ď Also can occur in adults who are cirrhotics
ď Death in 40% of cases (CVS collapse)
ď Due to Inability to metabolised & excrete chloramphenicol
27. CHLORAMPHENICOL - PRECAUTIONS
ď˘ Minor infections and undefined etiology
ď˘ Infections treatable by other AMAs
ď˘ Avoid repeated courses
ď˘ Should not use more than 2-3 gms per day, use for
less than 2 weeks and total dose should not exceed
28 gms
ď˘ Regular peripheral blood smear â reticulocyte count
ď˘ No combination with other antimicrobials
28. CHLORAMPHENICOL - USES
ď˘ Enteric fever: Mainstay in the past
ď˘ Pyogenic meningitis as 2nd line to 3rd generation
cefalosporins â child and allergics
ď Meningcoccal meningitis and H. influenzae
ď˘ Anaerobic infections â Bact. Fragilis
ď˘ Intraocular infections â endophthalmitis
ď˘ Second choice : brucellosis & rickettsial infections,
UTI â sensitive ones ---- also topical in
conjunctivitis, external ear infections
ď˘ Conjunctivitis and external ear infection - Not to be
used on skin or other areas
30. REMEMBER !
ď˘ Toxicities of Tetracyclines - Superinfections, gum
and teeth deposits, Fanconi like syndrome,
pseudomembranous colitis â also GI disturbance,
liver damage, kidney damage and phototoxicity
ď˘ Toxicities of chloramphenicol: Bone marrow
depression â aplastic anaemia, Gray Baby
syndrome and hypersensitivity