Chloramphenicol, Tetracycline and polypeptide antibiotics
TETRACYCLINES
History: Chlortetracyline was 1st introduced in 1948. 2 years later, oxytetracycline
became available.
Sources:
Chlortetracycline ----------------------Streptomyces
Oxytetracycline ----------------------streptomyces
Tetracycline
produced semi synthetically
from
chlortetracycline
Also
From a
Species of streptomyces
Demeclocycline
Product of
Streptomyces aureofaciens
a mutant of strain of
Metha cycline, doxycyclline, and minocycline
All semi synthetic derivatives
Chemistry and stability: They are closely congeneric derivatives of the polycyclic
naphtha cenecarboxamide.
The crystalline bases are faintly yellow, odourless, slightly bitter compounds. They
are only slightly soluble in H20 at pH 7 but their sodium salts -are soluble. These
drugs were initially effective against a wide range of aerobic and anaerobic grampositive and gram-negative bacterial organisms, however, extensive use including
irrational use in some cases has resulted in development of resistance to these drugs
by some bacteria, in addition, many antibacterial agents have since been developed,
hence, they are not usually drugs of choice for bacterial infections.
. The more
lipophilic drugs, minocycline and doxycycline usually are the most active by weight,
followed by tetracycline. Resistance of a bacterial strain to any one member of the
class usually results in cross resistance to other tetracyclines. Tetracyclines are
bacteriostatic agents. These drugs are effective against rickettsiae, miscellaneous
micro-organisms such as mycoplasma, Chlamydia, some atypical mycobacteria and
amebae.
Rapidly multiplying micro-organisms are mostly affected.
Order of activity
:
Minocycline
Doxycycline
Tetracycline
Oxytetracycline
In general gram-positive micro organisms are affected by lower conc. of tetracycline
than are grain – negative special agents.
Neisseria gonorrhoea and many strains of N.meningititis were initially inhibited by
tetracyclines though sensitivity patterns changed over the years. Mechanism of
Action: Site of action is the bacterial ribosome 30S, inhibiting protein synthesis.
Absorption, distribution, and Excretion
Most tetracyclines are adequately but in completely absorbed from the GIT. Most
absorption takes place from stomach and upper small intestine and is greater in the
fasting state, though more recent studies show that doxycycline is well absorbed
after food and this even prevents or ameliorates the GIT disturbance initially
associated with its administration. The drug accumulates with resultant high
concentrations in the GIT following repetitive dosing such that many aerobic and
anaerobic coliform micro-organisms and gram-positive spore-forming bacteria are
suppressed. Consequently, the intestinal flora is altered, the stools become softer,
odourless
and acquire a yellow-green colour. Diarrhea can also occur and
ocassionally, pseudomembranous colitis may occur.
Absorption is impaired by milk products, aluminium hydroxide gels, Nabicarbonate,
calcium salts, iron preparations. Chelation and increase in gastric pH are
mechanisms responsible)
There is irregularity of absorption from GIT hence a wide range of plasma conc in
different individuals ff oral administration.
They can be divided into 3 groups based on the dosage and frequency of oral
administration required to produce effective plasma concentration.
Oxytetracycline and Tetracycline – Adults 250mg 6 hly and methacycline – 150mg
6 hly.
Deoxycycloine and minocycline – 100mg every 12 hours in 1st 24 hours ff by 100mg
once a day or twice daily when infection is severe.
Food does not interfare with the absorption of doxycycline and minocycline.
The volume of distribution of many of the tetracycline is relatively larger than that
of the body water. They are all concentrated in the liver and excreted by way of the
bile into the intestine from which they are partially reabsorbed.
Decreased hepatic function or bilary obstruction leads to persistence in the blood.
Minocycline reaches a sufficient conc in tears and saline to eradicate the
meningococcal carrier state. High conc found in fetal circulation and breast milk.
They are stored in reticuloendothelial cells of the liver, spleen, and bone marrow and
in bone and the dentine and enamel of unerupted teeth.
main route of excretion is the kidney, also in feces. Generally, decrease in GFR as
in renal function leads to decreased
excretion with persistence in circulation
Preps, Routes – usually oral capsules and some by I.V injection. Topical
administration restricted to use on the eye because of a high risk of sensitization.
Never inject intrathecally and rarely given intramuscularly.
UNTOWARD EFFECTS: GIT irritation, Epigastric burning and stress, abdominal
discomfort, nausea, and vomiting. The larger the dose the greater the likelyhood of
an irritative reaction. Photocoxicity, hepatic toxicity. Renal toxicity. Yellowish then
Brownish discolouration of teeth if administered up to 8 years, however, generally
most authorities agree that it should not be administered to children up to 12 years
of age. The deciduous teeth are at the greatest danger affected if given from midpregnancy to 4/6 months of the postnatal period, while the greatest danger to the
permanent teeth coloration occurs if given between the ages of 2 months and 5 years.
Super infection.
CHLORAMPHENICOL
History: produced by streptomyces venezuelae
Chemistry: It contains a nitrobenzene noiety is a derivative of dichloroacetic acid
OH
02N
CH2OH
CHCH – NH – C – CHCl2
Mechanism of action: Chloramphenicol inhibits protein synthesis in bacteria by
binding reversibly to the 50S ribosomal subunit near the site of action of the
macrolide antibiotics and clindamycin, which it inhibits competitively. It also
inhibits mitochondrial protein synthesis in mammalian cells
Resistance has been growing, in the case of gram negative bacteria it is due to the
presence of a specific plasmid acquired, a specific acetyl transferase inactivates the
drug.
Absorption, Distribution, Fate and Excretion
Two forms are available for oral administration (1) the active drug and (2) the
prodrug chloramphenicol palmitate. Hydrolysis of (2) occurs rapidly and almost
completely by pancreatic lipases in the duodenum. Then absorption takes place.
Bioavailability is greater for (1) then (2) Absorption of I.M. is usually not predicable,
however, I.V. of the parenteral form succinate is as suitable as P.O. or I.M.,
Clearance is by the kidney hence renal insufficiency, poor renal fxn in neonates lead
to
conc. In plasma. This is well distributed in body fluids and readily reaches
therapettic conc in CSF (60% of plasma) in the presence or absence of meningitis.
It readily traverses the placental barrier and secreted in milk.
The major route of elimination is hepatic metabolism to the inactive glucoromide.
This metabolite as well as cholamphenicol is excreted in mine.
Preps etc: Capsules 250mg and 500mg oral use.
THERAPUTIC USES
Typhoid fever when the strains causing the organism are susceptible though the use
of other newer drugs which usually do not possess serious untoward effects and can
be administered for shorter periods has overtaken chloramphenicol in this regard.
It was very valuable against bacterial anaerobic infection especially intra-abdominal
and brain abscesses, but it is now rarely indicated because of the availability of
numerous equally effective and less toxic alternative.
Used in Rickettsial diseases when tetracycline cannot be used.
UNTOWARDS EFFECTS
Most effects are due to inhibition of the inner membrane of the mitochondrion and
mammalian tissues are also affected. Hypersensitivity reactions: macular, vesicular
rashes, fever, angioedema, Jarisch-Herxheimer reactions.
Hematological Toxicity: Type A ADVERSE DRUG REACTION presenting as dose
related anaemia.
Type B ADVERSE DRUG REACTION presenting as aplastic anemia, these
patients present in an unpredictable fashion. Who develops anemia cannot be
predetermined, the duration of drug use may not be commensurate with develop of
anemia or depth of anemia.
Type C ADVERSE DRUG REACTION presenting as anemia after chronic
administration
Type D ADVERSE DRUG REACTION presenting as aplastic anaemia. This occurs
sometime after the patient has taken the drug.
Gray baby syndrome in neonates because of decreased renal and hepatic functions
(failure of drug to be conjugated with glucuronic acid), similar reaction occur in
adults, fatalities are up to 40%.
It inhibits hepatic microsomal cytochrome P450 enzymes and may prolong the t1/2
of warfarin, dicumarol, phenytoin, chlorpropamide, antiretroviral protease
inhibitors, rifabutin, and tolbutamide leading to sever toxicity and death. Chronic
administration of phenobarbital or acute administration of rifampin shortens the t1/2
of chloramphnicol leading to sub-theraputic concentrations of the drug
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ythromycin (Erythromycin Base) - Description and Clinical Pharmacology
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To reduce the development of drug-resistant bacteria and maintain the effectiveness of
Erythromycin Base Filmtab tablets and other antibacterial drugs, Erythromycin Base
Filmtab tablets would be used only to treat or prevent infections that are proven or
strongly suspected to be caused by bacteria.
DESCRIPTION
Erythromycin Base Filmtab (erythromycin tablets, USP) is an antibacterial product
containing erythromycin, USP, in a unique, nonenteric film coating for oral
administration. Erythromycin Base Filmtab tablets are available in two strengths
containing either 250 mg or 500 mg of erythromycin base.
Erythromycin is produced by a strain of Saccharopolyspora erythraea (formerly
Streptomyces erythraeus ) and belongs to the macrolide group of antibiotics. It is basic
and readily forms salts with acids. Erythromycin is a white to off-white powder, slightly
soluble in water, and soluble in alcohol, chloroform, and ether. Erythromycin is known
chemically as (3R*, 4S*, 5S*, 6R*, 7R*, 9R*, 11R*, 12R*, 13S*, 14R*)-4-[(2,6dideoxy-3-C-methyl-3-O-methyl-α-L-ribo-hexopyranosyl)oxy]-14-ethyl-7,12,13trihydroxy-3,5,7,9,11,13-hexamethyl-6-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylohexopyranosyl]oxy]oxacyclotetradecane-2,10-dione. The molecular formula is
C37H67NO13, and the molecular weight is 733.94. The structural formula is:
shed StudiesCurr't
cal Trials
Inactive Ingredients
Colloidal silicon dioxide, croscarmellose sodium, crospovidone, D&C Red No. 30
Aluminum Lake, hydroxypropyl cellulose, hypromellose, hydroxypropyl methylcellulose
phthalate, magnesium stearate, microcrystalline cellulose, povidone, polyethylene glycol,
propylene glycol, sodium citrate, sodium hydroxide, sorbic acid, sorbitan monooleate,
talc, and titanium dioxide.
CLINICAL PHARMACOLOGY
Orally administered erythromycin base and its salts are readily absorbed in the
microbiologically active form. Interindividual variations in the absorption of
erythromycin are, however, observed, and some patients do not achieve optimal serum
levels. Erythromycin is largely bound to plasma proteins. After absorption, erythromycin
diffuses readily into most body fluids. In the absence of meningeal inflammation, low
concentrations are normally achieved in the spinal fluid but the passage of the drug across
the blood-brain barrier increases in meningitis. Erythromycin crosses the placental
barrier, but fetal plasma levels are low. The drug is excreted in human milk. Erythromycin
is not removed by peritoneal dialysis or hemodialysis.
In the presence of normal hepatic function, erythromycin is concentrated in the liver and
is excreted in the bile; the effect of hepatic dysfunction on biliary excretion of
erythromycin is not known. After oral administration, less than 5% of the administered
dose can be recovered in the active form in the urine.
Optimal blood levels are obtained when Erythromycin Base Filmtab tablets are given in
the fasting state (at least ½ hour and preferably 2 hours before meals). Bioavailability data
are available from Abbott Laboratories, Dept. 42W.
Microbiology
Erythromycin acts by inhibition of protein synthesis by binding 50 S ribosomal subunits
of susceptible organisms. It does not affect nucleic acid synthesis. Antagonism has been
demonstrated in vitro between erythromycin and clindamycin, lincomycin, and
chloramphenicol.
Many strains of Haemophilus influenzae are resistant to erythromycin alone but are
susceptible to erythromycin and sulfonamides used concomitantly.
Staphylococci resistant to erythromycin may emerge during a course of erythromycin
therapy.
Erythromycin has been shown to be active against most strains of the following
microorganisms, both in vitro and in clinical infections as described in the
INDICATIONS AND USAGE section.
Gram-positive organisms
Corynebacterium diphtheriae
Corynebacterium minutissimum
Listeria monocytogenes
Staphylococcus aureus (resistant organisms may emerge during treatment)
Streptococcus pneumoniae
Streptococcus pyogenes
Gram-negative organisms
Bordetella pertussis
Legionella pneumophila
Neisseria gonorrhoeae
Other microorganisms
Chlamydia trachomatis
Entamoeba histolytica
Mycoplasma pneumoniae
Treponema pallidum
Ureaplasma urealyticum
The following in vitro data are available, but their clinical significance is unknown.
Erythromycin exhibits in vitro minimal inhibitory concentrations (MIC's) of 0.5 µg/mL
or less against most (≥ 90%) strains of the following microorganisms; however, the safety
and effectiveness of erythromycin in treating clinical infections due to these
microorganisms have not been established in adequate and well-controlled clinical trials.
Gram-positive organisms
Viridans group streptococci
Gram-negative organisms
Moraxella catarrhalis
Susceptibility Tests Dilution Techniques
Quantitative methods are used to determine antimicrobial minimum inhibitory
concentrations (MIC's). These MIC's provide estimates of the susceptibility of bacteria to
antimicrobial compounds. The MIC's should be determined using a standardized
procedure. Standardized procedures are based on a dilution method1 (broth or agar) or
equivalent with standardized inoculum concentrations and standardized concentrations of
erythromycin powder. The MIC values should be interpreted according to the following
criteria:
MIC (µg/mL)
≤ 0.5
1-4
≥8
Interpretation
Susceptible (S)
Intermediate (I)
Resistant (R)
A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the
antimicrobial compound in the blood reaches the concentrations usually achievable.
A report of "Intermediate" indicates that the result should be considered equivocal, and,
if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the
test should be repeated. This category implies possible clinical applicability in body sites
where the drug is physiologically concentrated or in situations where high dosage of
drug can be used. This category also provides a buffer zone which prevents small
uncontrolled technical factors from causing major discrepancies in interpretation.
A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the
antimicrobial compound in the blood reaches the concentrations usually achievable;
other therapy should be selected.
Standardized susceptibility test procedures require the use of laboratory control
microorganisms to control the technical aspects of the laboratory procedures. Standard
erythromycin powder should provide the following MIC values:
Microorganism
MIC (µg/mL)
S. aureus ATCC 29213 0.12-0.5
E. faecalis ATCC 29212 1-4
Diffusion Techniques
Quantitative methods that require measurement of zone diameters also provide
reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One
such standardized procedure2 requires the use of standardized inoculum concentrations.
This procedure uses paper disks impregnated with 15-µg erythromycin to test the
susceptibility of microorganisms to erythromycin.
Reports from the laboratory providing results of the standard single-disk susceptibility
test with a 15-µg erythromycin disk should be interpreted according to the following
criteria:
Zone Diameter (mm)
≥ 23
14-22
≤ 13
Interpretation
Susceptible (S)
Intermediate (I)
Resistant (R)
Interpretation should be as stated above for results using dilution techniques.
Interpretation involves correlation of the diameter obtained in the disk test with the MIC
for erythromycin.
As with standardized dilution techniques, diffusion methods require the use of laboratory
control microorganisms that are used to control the technical aspects of the laboratory
procedures. For the diffusion technique, the 15-µg erythromycin disk should provide the
following zone diameters in these laboratory test quality control strains:
Microorganism
Zone Diameter (mm)
S. aureus ATCC 25923 22-30