Antibiotics

Document Sample
Antibiotics Powered By Docstoc
					Antibiotics

History

    1. As early as 500 to 600 B.C., the Chinese used a molded curd soybean to treat boils and
        carbuncles and similar infections
    2. The accidental discovery of Penicillin by Alexander Fleming in 1929.
    3. In 1940 Florey and Chain and their associates at Oxford undertook to apply antibiotic
        penicillin into therapy.
    4. In 1939, Dubos discovered that Bacillus brevis produced tyrothricin.
    5. Isolation of streptomycin from streptomyces griseus in 1944.

Definition

    1. An antibiotic or an antibiotic substance is a substance produced by
       microorganisms, which has the capacity of inhibiting the growth and even
       of destroying other microorganism. (Waksmann)

    2. An antibiotic is a chemical compound derived from or produced by a living organism,
       which is capable in small concentrations, of inhibitinbg the life processes of
       microorganisms. (Benedict and Langlykke)

    Therefore, a substance is classified as antibiotic if:

    1. It is a product of metabolism (although it may be duplicated or even have
        been anticipated by chemical synthesis)
    2. It is a synthetic product produced as a structural analog of a naturally occurring antibiotic.
    3. It antagonizes the growth and/or the survival of one or more species of microorganisms.
    4. It is effective in low concentrations

For an antibiotics to be successful in therapy, it should be decisively effective against a pathogen
without producing significant toxic effects. In addition it should be sufficiently stable so that it can
be isolated and processed and then stored for a reasonable length of time without appreciable
loss in activity. It is also important that it be amenable to processing into desirable dosage forms
from which it may be absorbed readily. Finally the rate of detoxification and elimination from the
body should be such as to require relatively infrequent dosage to maintain proper concentration
levels, yet sufficiently rapid and complete that the removal of drug from the body is accomplished
soon after administration has been discontinued.

The commercial production of antibiotics for medicinal use follows the general pattern, differing
detail for each antibiotic. The general scheme may be divided into 6 steps:

    1. preparation of a pure culture of the desired organism for use in inoculation of the
       fermentation medium.
    2. fermentation during which the antibiotic is formed.
    3. isolation of antibiotic from the culture media.
    4. purification
    5. assay for potency, test for sterility, absence of pyrogens, other necessary data
    6. formulation into acceptable and stable dosage form

Spectrum of activity:

    1. Broad spectrum has the ability to antagonize the growth of a large number of pathogens.
       Ex. Tetracycline and Chloramphenicol
    2. Narrow spectrum – has higher degree of specificity in antagonizing growth of pathogens.
       Ex. Bacitracin and Nystatin
Site of Action          Antibiotic               Process Interrupted       Type of Activity
Cell wall               Bacitracin               Mucopeptide               Bactericidal
                        Cephalosporin            synthesis                 Bactericidal
                        Cycloserine              Cell wall cross linking   Bactericidal
                                                 Cell   wall     peptide
                        Penicillin               synthesis                 Bactericidal
                        Vancomycin                                         Bactericidal
                                                 Cell wall cross-linking
                                                 Mucopeptide
                                                 synthesis
Cell membrane           Amphoteracin B           Membrane function         Fungicidal
                        Nystatin                 Membrane function         Fungicidal
                        Polymixin                Membrane integrity        Bactericidal
Ribosomes

50s subunit             Chloramphenicol          Protein synthesis         Bacteriostatic
                        Erythromycin             Protein synthesis         Bacteriostatic
                        Lincomycin               Protein synthesis         Bacteriostatic

30s subunit             Aminoglycosides          Protein synthesis and     Bactericidal
                                                 fidelity


Nucleic acids           Actinomycin              DNA     and     mRNA      Pancidal
                        Griseofulvin             synthesis                 Fungicidal
                                                 DNA     and     mRNA
DNA and/or RNA          Mitomycin C              synthesis                 Pancidal
                        Rifampicin                                         Bactericidal
                                                 DNA synthesis
                                                 mRNA synthesis


I. Penicillin

Structure contains fused ring system of unusual design, the beta lactam thiazolidine structure.
The 5 membered thiazolidine ring appears in other natural compounds, but the 4 membered beta
lactam ring is unique.

Systematic name: Bicyclo [3.2.0] heptane-2-carboxylic acid.

Over 30 penicillins have been isolated from fermentation mixtures. Some occurs by altering the
culture media so as to provide certain precursor that may be incorporated as acyl groups.
Commercial production penicillin depends chiefly on various strains of P.notatum and P.
chrysogenum.

Properties:
1. The crystalline penicillin must be protected from moisture, but when kept dry, the salt will
remain stable for years
  without refrigeration.
2. The free acid is not suitable for oral and parenteral administration.
3. Sodium and potassium salts of most penicillin are soluble in water and are readily absorbed
orally and parenterally.
4. Salts of penicillin with organic bases, such as benzathine and procaine have limited water
solubility and are therefore useful as depot forms to provide effective blood levels over a long
period in treatment of chronic infection
The procedure for assay was developed at Oxford, England, and the value become known as the
OXFORD UNIT.

One oxford unit is defined as the smallest amount of penicillin that will inhibit , in vitro, the
growth of strain of Staphylococcus in 50 mL of culture media under specified conditions.

The pure crystalline penicillin is now available in dose of “units”. The USP defines UNIT as the
antibiotic activity of 0.6 microgram of USP Penicillin G Sodium Reference Standard. The weight-
unit relationship of penicillin will vary with the nature of the acyl substituent and with the salt form
of the free acid.

1 mg Pen G Sodium = 1,667 units
1 mg Pen G Procaine = 1,009 units
1 mg Pen K = 1,530 units

4 Principal Classes of Penicillin:

1. Natural penicillin – such as Pen G, in which the acyl portion of the amide side chain consist of
a benzyl group or an
   alkyl group.

2. The acid resistant penicillin, such as Pen V and Phenethicillin, in which a phenoxy group is
attached to the alpha
   carbon of an alkyl group making up the acyl moiety of the amide side chain.

3. Penicillinase resistant penicillin, such as methicillin, nafcillin, oxacillin, cloxacillin etc., in which
the ring structure having
  aromatic properties is attached directly to the carbonyl carbon of the amide side chain.

4. The broad spectrum penicillin’s, such as ampicillin and carbenicillin. The acyl portion of the
amide side chain produce penicillin capable of inhibiting microorganisms resistant to penicillin G.

II. Cephalosporin

Antibiotic obtained from species of the fungus Cephalosporium                   and from semisynthetic
processes.

Compounds having 3 different chemical structures have been isolated from cephalosporium.
Different Chemical Structures:
1. Cephalosporin P – has steroidal stucture; possess low antibacterial properties and has not
been employed in clinical medicine.
2. Cephalosporin N – isolated from C.salmosynnematum and was given name synnematin and
the synnematin B. Its structure was determined to be D-(4-amino-4-carboxybutyl) penicillin and is
now frequently referred to as penicillin N.
3. Cephalosporic C – congener Penicillin N, containing a dihydrothiazine ring instead of
thiazolidine ring.

III. Aminoglycosides

         The discovery of streptomycin, the first aminoglycoside antibiotic to be used in
chemotherapy. From genus Streptomyces many antibiotic isolated from the genus, a number are
compounds. Four of them, kanamycin, neomycin, paromomycin, gentamicin. The five structurally
related antibiotics are poorly absorbed from the GIT and all but gentamicin are used to treat local
infections in that area.
       The organism that produces streptomycin, Streptomyces griseus, also produces a
number of other antibiotic compounds, 1.) hydrostreptomycin 2.) mannisidostreptomycin 3.)
cycloheximide.    The term streptomycin A           is commonly called streptomycin and
mannisidostreptomycin has been called streptomycin B.

        It is employed solely as an alternative to Penicillin G for the treatment of uncomplicated
gonorrhea. The aminoglycoside antibiotic, because of their potent bactericidal action against
gram (-) bacilli, are now preferred for the treatment of many serious infection caused by coliform
bacteria.
Chemistry:
        Acts as triacidic base through the effect of its two strongly basic guanidine groups and the
most weakly basic methylamino group. Aqueous solutions may be stored at room temperature for
1 week without loss of potency, but are more stable if the pH is adjusted between 4.5 and 7.0

IV. Chloramphenicol (unclassified antibiotic)

        The first of the widely used broad spectrum antibiotics, chloramphenicol, was isolated by
Ehrlich et.al in 1947. They obtained it from Streptomyces valenzuelae, an organism that was
found in a sample of soil collected in Valenzuela.


IV. Tetracycline

        The most important broad spectrum antibiotics are the members of the tetracycline
family. Eight such compounds – tetracycline, oxytetracycline, chlortetracycline, demeclocycline,
methacycline, doxycycline, minocycline and rolitetracycline – have been introduced into medicinal
use.

       The tetracycline are obtained by fermentation procedures from streptomyces species or
by chemical biotransformation of natural products.

Chemistry:

1. The important members of the group are derivatives of octahydronaphthacene, a hydrocarbon
made up of a system of 4 fused rings.

2. The affinity of tetracycline for calcium causes them to be laid down in newly formed bones and
teeth as tetracycline-calcium orthophosphate complexes. Deposits of these antibiotics in teeth
causes a yellow discoloration which darkens (a photochemical reaction) over a period of time.

3. Tetracycline are distributed into the milk of lactating mothers and also cross the placenta
barrier into the fetus. The possible effects of these agents on bones and teeth of the child should
be taken into consideration before their use in pregnancy or in children under 8 years of age is
instituted.

V. Macrolides

     1. Isolated from the actinomycetes and chemically related compounds.

     2. Picromycin was the first group to be identified as macrolide in 1950

     3. Erythromycin and Carbomycin were reported in 1952.

     4. At present more than 3 dozen such compounds are known.
Chemistry:

     Erythromycin is a very bitter, white or yellowish-white crystalline powder. It is soluble in
alcohol and in the other common organic solvents but only slightly soluble in water. Saturated
aqueous solutions develop an alkaline pH in the range of 8.0 to 10.5. It is extremely unstable at a
pH of 4 or lower. The optimum pH for stability of erythromycin is at nearly neutrality.

    As free base, erythromycin may be in oral dosage from and for topical administration.
However, to overcome its bitter taste and to provide more acceptable pharmaceutical forms for its
administration, derivatives of erythromycin commonly used.

2 Types of derivatives:

1. acid salts of the dimethylamino group such as glucoheptonate, lactobionate and stearate.
2. esters of the OH group on the desosamine moiety such as the ethyl carbonate, the ethyl
succinate and propionate (estolate)

* The glucoheptonate and lactobionate salts are water soluble, thus providing means of IV
administration of erythromycin.
* The stearate salt is water-insoluble and tasteless and is used in tablets and suspensions
* The ethyl carbonate ester is also water-insoluble and is used for pediatric suspensions
* Suspensions of the ethyl succinate and propionate esters are suitable for IM but not IV
injection.

VI. Lincomycin

      The lincomycin are sulfur containing antibiotics isolated from Streptomyces lincolnensis.
Lincomycin is the more active and medicinally useful of the compounds obtained from
fermentation. The structure contains a basic function, pyrrolidine nitrogen, by which water soluble
salts having an apparent pKa of 7.6 may be formed.

     Lincomycin HCl occurs as the monohydrate, a white crystalline solid that is stable in the dry
state. It is readily soluble in water and alcohol and its aqueous solutions are stable at room
temperature. It diffuses well into peritoneal and pleural fluids and into bone. It is excreted in the
urine and the bile. It is available in capsule form for oral administration and in ampules and vials
for parenteral administration.
Assignment:

1. Define antibiotics.
2. Give the 5 characteristics of antibiotics
3. Enumerate the antibiotics obtained from Streptomyces species
4. Give the 4 types of Penicillin and cite examples
5. Other term form Streptomycin A and Streptomycin B
6. Identify the antibiotic which causes yellow discoloration on teeth and explain the principle
   behind it.
7. Antibiotic used as alternative for penicillin.
8. Give the different salt preparations for erythromycin and identify the suitable dosage form for
   each.
9. Give the principle why tetracycline is not recommended during pregnancy or in children under
   years old.
10. Define Unit as defined by the USP and give the equivalent units of Pen G sodium, Pen G
    procaine and Pen K.
11. Complete the given below:
         2.5 mg Pen G Potassium = ________ units
         1 mg Pen G Sodium = _________ units
         2 mg Pen G Procaine = _______ units
12. Give the 8 members of the Tetracycline family.

				
DOCUMENT INFO
Shared By:
Categories:
Tags:
Stats:
views:63
posted:11/7/2012
language:simple
pages:6