Brotzu*, in 1948, was pioneer in isolating a novel microorganism
from the sea water meticulously sampled very close to a sewage outpours off the
coast of Sardinia. Interestingly, he noticed its marked and pronounced
antagonism to both Gram-positive and Gram-negative microorganisms.
Almost after seven years, Abraham** at Oxford first and foremost
gave the scientific world the report on the isolation of
three ‘antibiotic
substances’ from the culture of this specific organism, namely:
cephalosporin
P, penicillin N, and
cephalosporin C. Out of these three isolated
antibiotics, the
first:
cephalosporin P has practically
accomplished little therapeutic significance; the
second:
penicillin
N (originally termed as
cephalosporin N) obtained as the major
component and differs significantly from the common penicillin by its
antibacterial activity and hydrophilic character; and the
third:
cephalosporin
C showed low toxicity and
in vitro activity against the
penicillin-resistant
Staphylococci.
In view of the above statement of facts, it is quite evident that
there exist an apparent contrast with regard to the typical features of cephalosporin
C and the penicillins (viz., benzylpenicillin) besides
other possible structural modifications as given below:
Points
of Contrast Between Cephalosporin C and Penicillins
In the
broader perspective the semi-synthetic cephalosporins may be classified into three
different manners, namely: (a) chemical structure; (b) β-lactamase
resistance; and (c) antibacterial spectrum.
However,
in usual widely accepted prevailing practice the cephalosporins are logically
and legitimately classified by a more arbitrary system, dividing them into ‘generations,
such as: First generation;
Second
generation; and Third generation cephalosporins.
It is
pertinent to mention two important points with regard to the ‘cephalosporin
antibiotics’, namely:
(a)
All cephalosporins commence with the prefix ceph- or cef -;
however, the latter spelling now being preferred over the former, though both
spellings are usually encountered in certain branded drugs; and
(b)
The basis for the classification into the said three generations depends
primarily and solely upon the antibacterial spectrum shown by the drugs,
besides the year they were first introduced.
Note:
1. There are several instances in which the drugs belonging to the ‘second
generation’ may have been introduced after the ‘third generation’ of drugs had
been accomplished.
2.
Categorically, there is no prevalent practice or demarkation to suggest that
the drugs belonging to the ‘third generation’ automatically supercede second
and first genera tion ones. In fact, cephalosporins from all the three
aforesaid categories are still being used across the globe. Prodrugs (e.g.,
cefuroxime-axetil; cefpodoxime-proxetil) The prodrugs of some
cephalosporin antibiotics, for instance: cefuroxime-axetile and cefpodoxime-proxetil
have been duly developed having an additional ester moiety attached
to the C-4 carboxyl function. However, these tailor-made ‘prodrugs’ get
duly hydrolyzed to their respective active agents by the aid of esterases.
Cephamycins
These
represent another group of
cephalosporin antibiotics that are characterized
by a 7α-methoxy function, and are usually produced by two cosecutive reactions,
namely:
hydroxylation and
methylation.
Example
Caphamycin
C: In
this particular instance, the introduction of a carbamate function derived from
carbamoyl phosphate on the hydroxymethyl function.
A few
important and typical examples of the ‘Cephalosporin Antibiotics’ belonging
to the various recognized groups, such as: first generation, second generation,
third generation, prodrugs, and cephamycins have been duly summarized below
along with their structural variants, names, synonyms and special remarks:
Cephalosporin
Antibiotics: Typical Examples
A good
number of cephalosporins belonging to the three categorized generations
are available in the therapeutic armamentarium, besides the cephamycins, which
are given as under:
(i)
First generation Cephalosporins: Cefalotin (Cephalothin);
D-Cephalexin (D-Cefalexin); Cephapirin; Cefazolin; D-Cephradine (D-Cefradine);
D-Cefadroxil;
(ii)
Second Generation Cephalosporins: D-Cefactor; D-Cefamandole;
Cefuroxime; DCefonicid;
Ceforanide;
(iii)
Third Generation Cephalosphorins: Cefotaxime; Ceftizoxime;
D-Cefoperazone; Ceftazidime; Ceftriaxone; Cefmonoxime, Moxalactam;
(iv)
Prodrugs: Cefpodoxime proxetil; Cefuroxime axetil;
(v)
Cephamycins: Cephamycin C; Cefoxitin.
A few
of these important compounds representing the above said categories shall now
be discussed individually in the sections that follows:
----------------------------------------------
* Brotzu, G., Lav. Ist. Igiene Caligari, (1948)
** Abraham, Newton, Nature, 175, 548, (1955).
3.3.1
First Generation Cephalosporins
The first
generation cephalosporin antibiotics are found to be effective against a
host of Grampositive microorganisms, including penicillinase-producing Staphylococcus.
Besides, being resistant to penicillinase they are found to be
inactivated by another cephalosporinase termed as β-lactamase.
The
Gram-negative organisms that are observed to be highly sensitive to these
compounds are, namely: Escherichia coli; Proteus mirabilis; and Klebsiella
pneumoniae. These antibiotics are also found to be less active against Haemophilus
influenzae as compared to the extended-spectrum penicillins, such as: ampicillin.
A.
Cephalothin
Synonyms
Cefalotin;
7-(Thiophene-2-acetamido) cephalosporanic acid).
Biological
Source It is a semi-synthetic cephalosporin antibiotic derived
from Cephalosporium acremonium.
Chemical
Structure
(6R-trans)-3-[(Acetyloxy)
methyl]-8-oxo-7-[(2-thienylacetyl) amino]-5-thia-1-azobicyclo [4.2.0] act-2-ene-2-carboxylic
acid; (C16H16N2O6S2).
Preparation
First
of all the 7-aminocephalosporanic acid is N-acetylated with 2-thiopheneacetyl chloride
in a dehydro-chlorinating environment. The starting acid may be prepared from
the natural antibiotic, cephalosporin C, either by means of enzymatic
hydrolysis or by proton-eatalyzed hydrolysis. The cephalothin thus
obtained may be purified from acetonitrile.
Characteristic
Features
1. It
is obtained as a white amorphous powder having mp 160-160.5°C.
2. It
has specific optical rotation [α]D20 + 50° (C = 1.03 in
acetonitrile).
Cephalothin
Sodium [C16H15N2NaO6S2]
[Synonyms Averon-1; Cefalotin; Cemastin; Cephation; Ceporacin;
Cepovenin; Coaxin; Keflin; Lospoven; Microtin; Synclotin; Toricelocin].
1. It
is obtained as a white to off-white, crystalline powder, almost odourless,
moderately hygroscoic and has mp 204-205°C.
2. It
has dissociation constant pKa 2.2.
3. It
has specific optical rotation [α]D + 135° (C = 1.0 in water).
4. It
has uvmax: 236, 260 nm (ε 12950, 9350).
5. Solubility
Profile: It is freely soluble in water, normal saline or dextrose solution;
slightly soluble in ethanol; and practically insoluble in most organic
solvents.
Uses
1. It
is a potent antibacterial agent.
2. It
is a first-generation cephalosporin given IM and IV.
3. It
is found to be a short-acting antibiotic and exhibits the weakest spectrum of
its class.
B.
Cephazolin
Synonym
CEZ.
Biological
Source It is also a semi-synthetic antibiotic derived from 7-aminocephalosporanic
acid obtained from Cephalosporium acremonium.
Chemical
Structure
7-(1-(1H)-Tetrazolyl
acetamido)-3-[2-(5-methyl-1, 3, 4-thiadiazolyl) thiomethyl]-3-cephem-4-carboxylic
acid; (C14H14N8O4S3).
Preparation
The
sodium salt of 7-aminocephalosporanic acid is acylated with
1H-tetrazole-1-acetyl chloride. The acetoxy moiety present in the resulting
product is then displaced by reaction with 5-methyl-1, 3- 4-thiadiazole-2-thiol
to produce the desired product i.e., cephazolin. It is then further
purified from aqueous ethanol.
Characteristic
Features
1.
Cephazolin is obtained as needles from aqueous acetone having mp 198-200°C
(decomposes).
2. It
has uvmax (buffer pH 6.4): 272 nm (ε 13150).
3. It
is found to be freely soluble in DMF, pyridine; soluble in aqueous acetone,
aqueous dioxane, aqueous ethanol, slightly soluble in methanol; and practically
insoluble in benzene, chloroform, ether.
Cephazolin
Sodium [C14H13N8NaO4S3]
Synonyms Acef; Ancef; Atirin; Biazolina; Bor- Cefazol; Cetacidal; Cefamedin;
Cefamezin; Cefazil; Cefazina; Elzogram; Firmacef; Gramaxin; Kefzol; Lampocef;
Liviclina; Totacef; Zolicef]:
1. It
is obtained as white to yellowish white, odourless crystalline powder having a
bitter salty taste. It crystallizes out in α-, β-, and g-forms.
2. It
is found to be freely soluble in water; slightly soluble in methanol, ethanol;
and almost insoluble in benzene, acetone, chloroform.
Uses
1. Totacef
may be given IV or IM; however, its Gram-negative activity is essentially
limited to E. coli; Klebsiella; and Pr mirabilis.
2.
Some Gram-negative organisms and penicillinase-producing staphylococci which
are resistant to both Penicillin G and Ampicillin are found to be
sensitive to cefazolin.
3. It
may be used to treat infections of the respiratory tract skin, soft tissues,
tones, joints and urinary tract and endocarditis and septicemia caused
by suceptible organisms. However, amongst the UTIs, cystitis*
specifically responds much better than pyelonephritis**.
4. It
is one of the preferred cophalosporins for most surgical prophylaxis, by virtue
of its inherent long half-life (i.e., 1.5 to 2 hours in normal persons
but 3 to 42 hours in renal failure).
C.
Cefadroxil
Synonyms
BL-S578;
MJF-11567-3; Baxan; Bidocef; Cefa-drops; Cefamox; Ceforal; Cephos; Duracef;
Duricef; Kefroxil; Oracefal; Sedral; Ultracef.
Biological
Source It is also an orally active semi-synthetic cephalosporin antibiotic
obtained from the species Cephalosporium aeremonium.
Chemical
Structure
para-Hydroxycephalexine
monohydrate; (C16H17N3O5S.H2O).
Characteristic
Features It is obtained as white to yellow white crystals having mp
197°C (decomposes). It is found to be soluble in water, and fairly stable in
acidic medium.
Uses
1. It
is intermediate acting and quite effective against Staphylococcus and
certain enteric Gramnegative bacilli.
2.
Because of its prolonged exeretion criterion, it has an added advantage of
catering for more sustained serum and urine concentrations than are usually
obtained with other
oral cephalosporins.
3.
Clinical studies have revealed that cefadroxil administered, 1g twice
daily, is as effective as cephalexin given 500 mg four times daily.
----------------------------------------------
*
Cystitis: Inflammation of the bladder usually occurring secondary to
ascending urinary tract infections (UTIs).
**
Pyelonephritis: Inflammation of kidney and renal pelvis.
3.3.2
Second Generation Cephalosporins
Generally,
the ‘second generation cephalosporins’ exhibit the same spectrum of
antibacterial activity as that of the first generation cephalosporins. The
glaring exceptions being that these are comparatively much more active against
certain specific organisms, namely: Haemophilus influenzae, gonococcus, and
some enteric Gram-negative bacilli. Interestingly, most of the second
generation cephalosporins are adequately absorbed through the oral
administration. Some typical examples of second generation cephalosporins
shall now be described as under:
A.
Cefamandole
Synonyms
CMT;
Compound 83405.
Biological
Sources It is a broad-spectrum semi-synthetic cephalosporin
antibiotic obtained from
Cephalosporium
acremonium.
Chemical
Structure
7-D-Mandelamido-3-[[(1-methyl-1H-tetrazol-5yl)
thio]-methyl]-3-cephem-4-carboxylic acid; (C18H18N6O5S2).
Characteristic
Features
Cefamandole
Nafate [C19H17N6NaO6S2] [Synonyms Bergacef; Cedol, Cefam; Cefiran; Cemado;
Cemandil; Fado; Kefadol; Kefandol; Lampomandol; Mandokef; Mandol; Mandolsan;
Neocefal; Pavecef]:
1. It
is obtained or white odourless needles having mp 190°C (decomposes).
2. It
has uvmax (H2O): 269 nm (ε 10800).
3. Its
dissociation constant pKa 2.6-3.0.
4. It
is soluble in water, methanol; and almost insoluble in ether, chloroform,
benzene, cyclohexane.
It is
also found to be soluble in saline TS or dextrose solutions.
Uses
1. It
is administered effectively through IM and IV.
2. It
is found to be short-acting.
B.
Cefuroxime
Interestingly,
cefuroxime is available in two different versions; first—as its sodium
salt and secondly—as its prodrug cefuroxime axetil that are
hydrolyzed once they are absorbed and its absorption rate increased by
the intake of food in-take.
Chemical
Structure
(6R,
7R)-3-Carbamoyloxymethyl-7-[2-(2-furyl)-2-(methoxy-amino) acetamido]
ceph-3-em-4-
carboxylic
acid; (C16H16N4O8S).
Characteristic
Features
1. It
is obtained as a white crystalline solid.
2. It
has specific optical rotation [α]D20 + 63.7° (C = 1.0 in
0.2 m pH 7 phosphate buffer).
3. It
has uvmax (pH6 phosphate buffer): 274 nm (ε 17600).
Cefuroxime
Sodium [C16H15N4NaO8S]: [Synonyms
Anaptivan; Biociclin; Biofurex; Bioxima; Cefamar; Ceffoprim; Cefumax; Cefurex;
Cefurin; Curocef; Curoxim; Duxima; Gibicef; Ipacef; Kefurox; Kesint;
Lampsporin; Medoxim; Novocef; Spectrazole; Ultroxim; Zinacef ].
It is
a white solid; specific optical rotation [α]D20 + 60° (C
= 0.91 in water); uvmax (water): 274 nm (ε 17400). It is found to be freely
soluble in water and buffered solutions; soluble in methanol; very slightly
soluble in ether, ethyl acetate, octanol, benzene and chloroform. Its
solubility in water in 500 mg/2.5 ml. Its dissociation constant in water pKa
2.5; in DMF 5.1. The stability of cefuroxime sodium salt in water at room
temperature stands valid upto 13 hours; and at 25°C for 48 hours nearly 10%
decomposition takes place.
Uses
1. Its
activity against H. influenzae and ability to penetrate into the CSF
makes it specifically useful for the treatment, control and management of
meningitis caused by this organism. However, it is also recommended to treat
meningitis caused by Strep. pneumoniae, N. meningitidis and Staph.
aureus.
2. It
exhibits an excellent and super activity against all species of gonococci,
hence it is recommended for the treatment of gonorrhea.
3. It
may also be employed to treat lower respiratory tract infections normally
caused by H. influenzae and parainfluenzae, Klebsiella species, E.
coli, Strep pneumoniae and pyrogenes and Staph aureus.
4. It
is also approved for use against UTIs caused by E. Coli and Klebsiella;
of course, a rather more restricted approval as compared to other
second-generation drugs.
5. It
is also recommended for use in bone infections, septicemias and surgical
prophylaxis.
C.
Cefonicid
Biological
Source It is essentially an injectable semi-synthetic
cephalosporin antibiotic related to cefamandole which is obtained
from Cephalosporium acremonium.
Chemical
Structure
Characteristic
Features
Cefonicid
Disodium [C18H16N6Na2O8S3]
[Synonyms SKF-75073; Cefodie; Monocid; Monocidur; Praticef;] The pH
of 5% (w/v) solution is between 3.5 to 6.5.
Uses
1. It
is administered through IV and IM.
2. It
is an intermediate-acting second generation cephalosporin.
3.3.3
Third Generation Cephalosporins
The
‘third
generation cephalosporins’ are logically differentiated from the first and
second generation cephalosporins by virtue of their extended activity against a
wide spectrum of
enteric
Gram-negative
bacillii, along with the β-lactamase-producing strains.
A few
potent and typical examples of drugs belonging to this category shall be
discussed in the section that follows:
A.
Cefotaxime
Biological
Source It is a broad spectrum third generation cephalosporin antibiotic
derived from Cephalosporium acremonium. The name cefotaxime applies to
the isomer having a synmethoxyamino moiety.
Chemical
Structure It is the desacetyl active metabolite of cefotaxime i.e.,
another third generation cephalosporin.
7-[2-(2-Amino-4-thiazolyl)-2-methoxyimino
acetamido] cephalosporanic acid; (C16H17N5O7S2).
Characteristic
Features
Cefotaxime
Sodium [syn-Isomer]: [C16H16N5NaO7S2]
[Synonyms: Cefotax; Chemcef; Claforan; Pretor; Tolycar;
HR-756; RU-24756]:
1. It
is a white to off-white solid.
2. The
pH of a 10% (w/v) solution is approximately 5.5.
3. It
has specific optical rotation [α]D20 + 55° ± 2 (C = 0.8
in water).
4. Its
pKa (acid) is 3.75.
5. It
is found to be freely soluble in water; and almost insoluble in most organic
solvents.
Uses
1. It
is found to be active against a good number of Gram-negative bacilli and its
action is almost equivalent to the amino glycosides, except against Ps
aeruginosa, Acinetobacter and a few Enterobacter.
2. It
is highly resistant to the β-lactamases.
3. It
is found to be less active than either the first or the second
generation cephalosporins.
4. It
is a recognized and preferred third generation cephalosporin for
Gram-negative meningitis and other serious Gram-negative bacillary infections
outside the CNS.
5. It
is also recommended widely for surgical prophylaxis.
6. Cefatoxime
has a slightly longer half-life which permits 8 to 12 hour dosing in
comparison to 6 to 8 hours for cefotaxime.
B.
Ceftriaxone
Synonym
Cefatriaxone.
Biological
Source It is a parenteral third generation cephalosporin
antibiotic obtained from
Cephalosporium
acremonium.
Chemical
Structure [C18H18N8O7S3]
Characteristic
Features
Ceftriaxone
Disodium Hemiheptahydrate [C18H18N8Na2O7S3.3½H2O]:
[Synonyms Rocefin; Rocephin(e)]:
1. It
is obtained as white crystalline powder having mp > 155°C. (decomposes).
2. It
has specific optical rotation [α]D25-165° (C = 1 in
water) (calculated for anhydrous substance).
3. It
has uvmax (water): 242, 272 nm (ε 32, 300; 29530).
4. It
shows dissociation constant pKa : ~ 3 (COOH); 3.2 (NH3+), 4.1
(enolic OH).
5. Its
solubility in water at 25°C: ~ 40 g/100 ml.
6. The
colour of its solution varies from light yellow to amber depending solely on
the concentration (g. L–1) and the duration of storage (hrs.)
7. The
pH of a 1% (w/v) solution is nearly 6.7.
8. It
is found to be sparingly soluble in methanol; and very slightly soluble in
ethanol.
Uses
1. Ceftriaxone
sodium is considered as the drug of choice for uncomplicated and
disseminated gonococcal infections.
2. It
is also an effective alternative for meningitis in infants essentially caused
by H. influenzae, N. meningitidis and Streptococcus pneumoniae.
3. It
is also recommended for Gram-negative bacillary meningitis and some other
serious Gramnegative infections, including complications associated with Lyme
disease.*
4. It
may also be used for the treatment of bone and joint infections,
intra-abdominal infections, lower respiratory tract infections, pelvic
infections, skin and urinary tract infections (UTIs).
5. It
is also indicated for preoperative prophylaxis, for which its efficiency is
almost equivalent to that of cefazolin.
C.
Ceftazidime
Synonym
GR-20263;
Fortaz; Tazicef; Tazidime.
Biological
Source It belongs to the class of third generation cephalosporin
antibiotic.
Chemical
Structure The O-substituted oxime function certainly improves upon the
potency of the ‘third generation cephalosporin’, and ultimately exerts
resistance to β-lactamases. It is, however, pertinent to mention here
that the oximes with syn stereochemistry are appreciably more potent and
efficient than the corresponding anti isomers.
1-[[(6R,
7R)-7-[2-(2-(2-amino-4-thiazolyl) glyoxylamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4.2.0]
oct-2-en-3-yl] methyl] pyridinium hydroxide inner salt 72-(Z)-[0-(1-carboxy-1-
methylethyl) oxime]; (C22H22N6O7S2).
Characteristic
Features
1. It
is obtained as an ivory-coloured powder.
2. Its
pKa values are : 1.8, 2.7, 4.1.
3. It
has uvmax (pH6) : 257 nm (E1%1cm 348).
Uses
1. Ceftazidime
is a broad-spectrum antibiotic and is administered IV or IM.
2. It
is specifically of great interest because of its distinct high activity against
Pseudomonas and Enterobacteriaceae, but not enterococci.
3. It
is an alternative drug for the treatment of hospital-acquired Gram-negative
infections especially in immuno-compromised patients when Ps aeruginosa is
a potential causative organism.
4. It
is also recommended for use in the treatment, control, and management of bone
and joint infections, CNS-infections, gynecological infections, lower
respiratory tract infections, septicemia, skin and UTIs.
5. Its
activity is fairly comparable to that of cefotaxime and coftizoxime in
vitro but is much more active against Pseudomonas aeruginosa and
fairly less active against staphylococci and Bacteroides fragilis.
6. It
is an agent of choice for the ‘emperical antibiotic therapy’ when pseudomonas
happens to be one of the suspected pathogens.
---------------------------------
*
Lyme Disease: A multisystem disease caused by the tick-transmitted spirochete
Borrelia burgodorferi.
D.
Moxalactam
Synonyms
Lamoxactam;
Latamoxef.
Biological
Source It is an oxa-substituted third generation cephalosporin antibiotic
(oxacephalosporin).
Chemical
Structure [C20H20N6O9S]
Characteristic
Features
1. Moxalactam
is obtained as a colourless powder having mp 117-122°C (decomposes).
2. Its
specific optical rotation [α]D25–15.3 ± 2.6° (C = 0.216
in methanol).
3. It
has uvmax (methanol): 276 nm (ε 10200).
Moxalactam
Disodium [C20H18N6Na2O9S] [Synonyms Festamoxin; Moxalactam; Moxam; Shiomarin;
LY-12735; S-6059].
1. It
has specific optical rotation [α]D22-45° (water).
2. It
has uvmax (water): 270 nm (ε 12000).
Uses
1. Moxalactam
exhibits a spectrum of activity which is almost identical to that of
cefotaxime.
However,
its usage is very much restricted and limited on account of the occurrence of
bleeding disorders of serious nature.
Note:
The presence of methyltetrazolethiomethyl moiety may be responsible for causing
hypoprothrombinemia; and the a-carboxyl group may attribute to
the platelet dysfunction. Perhaps both these vital factors ultimately lead to
bleeding disorders.
2. It
has an extended Gram-negative spectrum, and are found to be most active against
enteric Gram-negative bacilli, but may be less active against certain
Gram-positive microorganisms, especially Staphylococcus aureus.
3.3.4
Prodrugs
A
major noticeable chief disadvantage of plethora of the current cephalosporins
is that they are not rapidly and effectively absorbed through oral route. This
specific serious drawback is perhaps due to the nature of the side-chain
present at C-3. An attempt has been made to design orally active prodrugs, namely:
cefuroxime-axetil and cefpodoxime-proxetil, which have been
developed meticulously by providing an additional ester function on the C-4
carboxyl moiety. Nevertheless, these prodrugs are designed in such a manner
that they are easily hydrolysed to the active agents i.e., drugs by the esterases.
A.
Cefpodoxime Proxetil
Synonyms
Banan;
Cefodox; Orelox; Otreon; Vantin; CS-807; U-76252;
Biological
Source It is a broad spectrum, orally absorbed third generation
cephalosporin, tailormade ester prodrug of the active-free-acid metabolite, cefpodoxime.
Chemical
Structure The skill and wisdom of a pharmaceutical chemist has made it
possible to design an ester of the metabolite, cefpodoxime, in which the
free carboxyl function located at C-4 of the thiazine ring i.e.,
the heterocyclic six-membered ring with one each of S and N atom studded at alternate
position in the ring.
1-(Isopropyloxy
carbonyloxy) ethyl (6R, 7R)-7 [2-(2-amino-4-thiazolyl)-(Z)-2-(methoxyamino) acetamido]-3-methoxymethyl-3-cephem-4-carboxylate;
(C21H27NO9S2).
Uses
1. It
is a ‘third generation cephalosporin’-prodrug administered orally.
2. It
is found to be an ‘intermediate acting cephalosporin’.
3. Its
pharmacologic activity is almost similar to that of cofixime.
3.3.5
Cephamycins
Streptomyces
clavuligerus gave rise to the isolation of the natural antibiotic known
as Cephamycin C, which essentially has an α-methoxy function at C-7
present in the basic cephalosporin ring system. It has
been observed that the steric hinderence caused due to the presence of
the additional methoxy moieties, affording thereby a possible resistance
to β-lactamase hydrolysis, might be solely responsible for the
weak antibacterial activity of both cephamycin C and other natural cephamycins.
Various
semi-synthetic structural analogues have been designed either:
(a)
By chemical introduction of the α-methyl moiety at C-7 of the basic
cephalosporin ring system, or
(b)
By modification of the side-chains of the naturally occurring cephamycins.
A.
Cefoxitin
Biological
Source It is a semi-synthetic derived from the
Cephamycin C through
the method ‘a’ stated above. The synthesis of
Cefoxitin has been
successfully carried out by Karady
et al.*
Chemical
Structure
3-Carbamoyloxymethyl-7α-methoxy-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylic
acid; (C16H17 N3O7S2).
Characteristic
Features
1. It
is obtained as crystals having mp 148-150°C (decomposes).
2. Its
dissociation constant pKa is 2.2.
3. Solubility
Profile: It is very soluble in acetone; soluble in aqueous NaHCO3; very
slightly soluble in water; and almost insoluble in ether and chloroform.
Cefoxitin
Sodium [C16H16N3NaO7S2]
[Synonyms Betacef; Farmoxin; Mefoxin; Mefoxitin;
Merxin;
Cenomycin;]:
1. It
is obtained as white crystals with a characteristic odour having mp 150°C.
2. It
has specific optical rotation [α]25 589nm + 210° (C = 1 in
methanol).
3. It
has dissociation constant pKa 2.2 (acid).
4. Solubility
Profile: It is found to be very soluble in water; soluble in methanol;
sparingly soluble in ethanol or acetone; and practically insoluble in aromatic
and aliphatic hydrocarbons.
Uses
1. It
is mostly used as an alternative drug for intra-abdominal infections,
colorectal surgery or appendectomy and ruptured viscus by virtue of the fact
that it is active against most enteric anaerobes including Bacteroides
fragilis.
2. It
is also recommended for use in the treatment of bone and joint infections
usually caused by S. aureus, gynecological and intra abdominal
infections by Bacteriodes species
3. It
is also approved for lower respiratory tract infections caused by Bacteroides
species; E. coli; H. influenzae; Klebsiella species; S. aureus etc.
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*
Karady et al. J. Am. Chem. Soc., 94, 1410, (1972).
