Download Tobramycin

Tetracyclines
(Doxycycline and Minocycline)
Mechanism of Action
• The site of action of TET is the bacterial ribosome and all
TET function in the same manner. They are bacteriostatic
compounds.
• TET enter to susptible MO by Passive diffusion through
hydrophilic pores in the outer cell membranes.or by
Energy-dependent active transport system that pumps all
TET through the inner cytoplasmic membrane.
• TET inhibit protein synthesis by binding specifically to the
30S ribosome. This appears to prevent access of AA-tRNA
to the acceptor site on the mRNA-ribosome complex;
preventing the addition of AA to the growing peptide
chain.
Resistance
• Resistance to the TET for gram-ve and gram+ve
bacteria is mediated by inducible plasmid [the
bacteria become resistant only after exposure to the
drug].
Antibacterial spectrum(broad bacteriostatic ) •
These compounds also impair protein synthesis in:
mammalian cells at high concentration.
For gram (-) bacteria,
less understood for gram (+) bacteria.
Uses:
Treated Cholera , Chlamydia infection , Mycoplasma pneumonia
-
Pharmacokinetics
Absorption:
• All TET are adequately but incompletely absorbed from the G.I.
tract. Most absorption takes place from the stomach and upper
small intestine (greater in a fasting state).
• Absorption of TET is impaired by
• food in the stomach,
• milk products,
• aluminum OH gels, Na+ bicarbonate, Ca++ & Mg++, and Fe++
preparations.
• .
• They bind to tissue undergoing calcification ( teeth and bone)
.
• It enter CSF but level insufficient for therapeutic and it appear
in tears and saliva
• It cross placental barrier and concentrated in fetal bones and
dentine
• Doxycycline and minocycline are almost totally
absorbed on oral administration.
• doxycycline is the preferred tetracycline for
parenteral administration
• Minocycline enters the brain in the absence of
inflammation and also appears in tears and
saliva.
• useful in eradicating the meningococcal
carrier state
• minocycline is not effective for central nervous
system
Therapeutic uses in
dentistry
• The use of tetracyclines in the management of
acute orofacial infections is widely considered
inappropriate because of their bacteriostatic
activity and extensive microbial resistance.
• .
• Systemic tetracyclines in the management of
chronic periodontitis must be carefully
evaluated for risk/benefit ratio considering
their limited efficacy
• .
• Tetracyclines are effective in the management
of localized aggressive periodontitis and its
associated organism, A.
actinomycetemcomitans.
• Tetracyclines may also be used subgingivally
localized aggressive periodontitis
Excretion
• TET metabolized in liver
• excreted in bile and reabsorbed by entero hepatic
circulation
all the TET are excreted in the urine and the feces.
EXCEPT doxycycline , The drug is excreted by bile and
feces, largely as an inactive conjugate.
Thus one of the safest of the TET for the treatment of
extrarenal infections.
• TET also excreted in breast milk .
Adverse Effects
• TET can produce a variety of adverse effects ranging from
minor inconvenience to life-threatening.
• Wide safety margin, but many side effects
Gastrointestinal
TET produce GI irritation to a varying degree in some but not all
individuals. Nausea, vomiting, burning, diarrhea (common)
• Diarrhea must be promptly distinguished from that which
results from pseudomembranous colitis - caused by
overgrowth of clostridium difficile ( can be life-threatening) .
• TET like other antimicrobial agents administered orally may
lead to development super infections, usually due to strains of
bacteria or yeast resistant to these agents.
Hepatic Toxicity
• In Pregnant women are particularly sensitive to
TET -induced hepatic damage When received
high dose of TET .
Renal Toxicity
• TET may aggregate uremia in patients with
renal disease by Inhibition protein synthesis –
Effects on TEETH
• Children receiving long-or short term therapy with
TET may develop brown discoloration of the teeth.
The drug deposits in the teeth and bones probably
due to its chelating property and the formation of a
TET -calcium orthophosphate complex. This
discoloration is permanent. Avoid giving to pregnant
women and children under the age of 8 years .
Other effects
• Hypersensitivity : -Rash, hives with itching, itching anaphylactic
( decrease in BP, increase in HR, release of histamine, etc.)
• Photoxicity : darkening of skin & sunburn when patient
exposed to sunlight
Contra indication
• .
• 1. TET should not be used in pregnant
women and children under 8 years .
• 2. Tetracycline during 1st trimester of
pregnancy can cause birth defects
• 3. Should not be given to patient with severe
liver and renal disease.
Glycylcyclines
• Tigecycline is a derivative of minocycline,
• similar to the tetracyclines and has a broadspectrum activity against multidrug-resistant
gram-positive pathogens,
• some gram-negative organisms,
• anaerobic organisms.
• Tigecycline is indicated for treatment of
complicated skin and soft tissue infections as
well as complicated intra-abdominal
infections.
• Giving as intravenous infusion every 12 hours
Drug interactions
• tigecycline inhibit the clearance of warfarin..
• tigecycline decrease the effects of oral
contraceptives.
Aminoglycosides & Spectinomycin •
Aminoglycosides
Streptomycin
Amikacin ,gentamicin,Tobramycin
Tobramycin,Neomycin, Netilmicin
• Use to in restricted to treat serious infection due to
aerobic gram negative bacilli because of serious
toxicities so replace by more safe drug .
1.
Gram (-) Aerobic Bacilli
2. Beta-lactamase
Staph. aureus
N. gonorrhea
3. Mycobacteria
4. Pseudomonas
aeruginosa
All aminoglycosides are
bactericidal
I.
AMINOGLYCOSIDES
Older Aminoglycosides:
Streptomycin
Kanamycin
Newer Aminoglycosides:
Gentamicin
Tobramycin
Neomycin
Amikacin
Netilmicin
Sisomicin
MECHANISMS OF ACTION OF
ANTIBACTERIAL DRUGS
• Aminoglycosides
– Irreversibly binds to 30S
ribosomal subunit
• Causes distortion and
malfunction of ribosome
• Blocks translation
–Causes misreading of
mRNA
– Not effective against anaerobes,
enterococci and streptococci
Aminoglycosides
• irreversible inhibitors of protein synthesis, but the precise
mechanism for bactericidal activity is not known.
• The initial event is passive diffusion via porin channels across
the outer membrane
• Drug is then actively transported across the cell membrane
into the cytoplasm by an oxygen-dependent process.
• Low extra cellular pH and anaerobic conditions inhibit
transport by reducing the gradient.
.
Mechanism of action
• aminoglycosides bind to specific 30S-subunit
ribosomal proteins Protein synthesis is
inhibited by aminoglycosides through
• (1) interference with the initiation complex of
peptide formation
• (2) misreading of mRNA, which causes
incorporation of incorrect amino acids into the
peptide and results in a nonfunctional or toxic
protein and
Therapeutic uses
• 1- infection due to enterococci which is resistant to most
antibiotic classes and require two synergistic antibiotic for
effective therapy eg : Gentamycin or streptomycin +
Vancomycin or B- lactam (P group )
• 2- infected due to Pseudomonas aeruginosa which rarely
attack healthy individual like immunocompromised treated
include
Tobramycin + anti Pseudomonal pencillin (ticarcillin )
Resistance to aminoglycosides
•
due to:
1-failure of drug to penetrate intracellular
2-low affinity of drug for bacterial ribosome
3-drug inactivation
PHARMACOKINETICS
• Aminoglycosides are absorbed very poorly
from the intact gastrointestinal tract; almost
the entire oral dose is excreted in feces after
oral administration
• . intramuscular injection, are well absorbed,
giving peak concentrations in blood within 30–
90 minutes.
• Aminoglycosides are usually administered
intravenously as a 30- to 60-minute infusion.
• .
• once-daily aminoglycoside dosing may be preferred
in certain clinical situations. Aminoglycosides have
concentration-dependent killing; that is, increasing
concentrations kill an increasing proportion of
bacteria and at a more rapid rate. They also have a
significant postantibiotic effect, such that the
antibacterial activity persists beyond the time during
which measurable drug is present.
Side effect of Aminoglycosides
1- Ototoxicity(Vestibular and Cochlear )
related to high peak plasma level and duration of treatment :
deafness may be irreversible .
2- Nephrotoxicity :mild , reversible
3- neuromuscular paralysis : after direct intraperitoneal or
intrapleural application of high doses, aminoglycosides can
produce a curare-like effect with neuromuscular blockade that
results in respiratory paralysis. This paralysis is usually reversible by
calcium gluconate (given promptly) or neostigmine.
4- Allergic reaction : contact dermatitis when neomycin applied
topically .
streptomycin
• Used for Rx of certain unusual infections in combination with
others
• Given by deep i.m or i.v
• Indicated for Rx of;
1- bacterial endocarditis
2-Brucellosis
3-second choise in TB.
Gentamicin(garamycin)
• For gm –ve bacillary infection
• Given parentally , topical(solutions,ointment)
indications:
*Urinary tract infection(uTI)
*pneumonia
*meningitis
*bacterial endocarditis
*sepsis
*Meningitis caused by gram-negative bacteria has been
treated by the intrathecal injection of gentamicin
*Ocular infection
NEOMYCIN & KANAMYCIN
.
• Neomycin and kanamycin are closely related. are active
against gram-negative bacteria and some mycobacteria.
• Pseudomonas and streptococci are generally resistant.
• Given oral, topical
• Uses:
topical for skin and mucous membrane infections
e.g.burns,wound,ulcer
• Poorly absorbed from GIT
• Excreted by kidney
neomycin
• Side effects
-hypersensitivity
-renal damage
-deafness
-orally can cause intestinal
malabsorption and superinfection
Tobramycin
• has almost the same antibacterial spectrum as gentamicin
with a few exceptions. tobramycin is slightly more active
against pseudomonas; Enterococcus faecalis
• Like other aminoglycosides, tobramycin is ototoxic and
nephrotoxic. Nephrotoxicity of tobramycin may be slightly less
than that of gentamicin
• Tobramycin is also formulated in solution (300 mg in 5 mL) for
inhalation for treatment of Pseudomonas aeruginosa lower
respiratory tract infections
.
Amikacin
• a semisynthetic derivative of kanamycin; it is less
toxic than the parent molecule
• Act on Many gram-negative enteric bacteria,
including many strains of proteus, pseudomonas,
enterobacter, strains, are usually susceptible to
amikacin
• . Like all aminoglycosides, amikacin is nephrotoxic
and ototoxic (particularly for the auditory portion of
the eighth nerve).
SPECTINOMYCIN
• Spectinomycin is an aminocyclitol antibiotic
that is structurally related to aminoglycosides.
It lacks amino sugars and glycosidic bonds.
General notes on aminoglycosides
• Combined with Penicillin or cephalosporin for serious
gm-ve infections
• Should not be used more than few days.
• Never mix with P in same solution (inactivation)
• Contra indicated in pregnancy.