Summer placement

In
ABOTT Healthcare Pvt Ltd
(April 11 June 4, 2011 )


A Report


Sonali Sharma

Post Graduate Programme In Pharmaceutical Management
2010 2012







TABLE OF CONTENTS



1) ABBREVIATIONS
2) INTRODUCTION TO ANTIBIOTICS
3) CLASSIFICATION OF ANTIBIOTICS
4) COMPANY PROFILE
5) CEPHALOSPORINS
6) CEFIXIME
7) CLAVULANIC ACID
8) RESEARCH METHODOLOGY
9) DATA INTERPRETATION AND ANALYSIS
10) CONCLUSION
11) REFERENCES
12) ANNEXURE









ABBREVIATIONS


CSF : Cerebro Spinal Fluid
CV : Clavulanic Acid
ESBL : Extended Spectrum Beta Lactamase
FDC : Foods, Drugs and Chemicals
GI : Gastrointestinal
IM : Intra Muscular
IV : Intra Venous
MIC : Minimum Inhibitory Concentration
PBP : Penicillin Binding Protein
RTI : Respiratory Tract Infection
UTI : Urinary Tract Infection











Abbott's business in India prior to the acquisition of Piramal Healthcare
Solutions and True Care.
Abbott has been operating in India since 1910 and has a collection of businesses with a
diverse range of pharmaceutical, nutritional and medical products. Abbott currently employs
more than 2,500 people in India with the company's headquarters in Mumbai.
Pharmaceuticals - Abbott has primary care products in gastroenterology and
pain, and specialty care products in neuroscience, metabolics, urology and
hospital care. Key products include Digene (antacid), Cremaffin
(laxative) and Brufen (ibuprofen). Abbott has a pharmaceutical
manufacturing facility in Goa that produces liquids and tablets for India and
other countries in the region. Abbott plans to significantly expand its
pharmaceutical business in India with its pending acquisition of the Piramal
Healthcare Solutions and True Care businesses, and a licensing agreement
with Zydus Cadilla. These steps will make Abbott the No.1 pharmaceutical
company in India and increase the company's total number of employees in
India to more than 10,000 people.

Nutritional Products - Abbott offers a variety of nutritional products for
infants, children, active adults and people with special dietary needs. Key
products currently available in India include Isomil (soy-based formula for
infants and children), Ensure (adult nutritionals), Glucerna (nutrition for
people with diabetes) and PediaSure (complete, balanced nutrition for
children).

Medical Products - Lines of business include vascular, diagnostics, diabetes
care and vision care. Key products include the XIENCE VTM drug-eluting
stent, laboratory diagnostic instruments ARCHITECT and AxSYM, and
diabetes glucose monitoring devices Optium Xceed and Optium Omega.

Abbott's vision care business provides cataract, refractive and corneal care products,
including TECNIS monofocal and multifocal intraocular lenses.
Citizenship
Global citizenship is an integral part of Abbott's mission to improve people's lives, focused
on four key areas: innovating for the future, enhancing access to health care, safeguarding
the environment, and protecting patients and consumers. Working in partnership with
others, Abbott leverages its core business expertise and resources to create sustainable
solutions in India and countries globally.
Examples of local citizenship programs throughout India include:
Donating more than U.S. $3.7 million in vitamins, antibiotics, anesthesia and
nutritional products through volunteer medical missions and relief partners
since 2005.
Improving maternal and child health by training more than 50 attendants to
perform prenatal health services, conduct home deliveries and make high-risk
referrals.
Supporting life-changing corrective surgery for cleft lip/cleft palate for more
than 1,600 children and young adults.
Training more than 4,600 community health workers on home-based HIV
care, and serving more than 300,000 children and families impacted by
HIV/AIDS.
After acquisition
After the $3.72-billion acquisition of Piramal Healthcare in May, US-based Abbott plans to
make India a "prime focus target", outperform the industry growth of 15% and mop up a
turnover of $500 million in India by 2011. Sales of Piramal's domestic formulation business
acquired by Abbott stood at around $430 million for the year ended March 2010.
Abbott's acquisition of Piramal's domestic formulation division in May catapulted the lesser-
known MNC among the top 10 pharma companies in the country, in terms of market share in
the organized domestic retail market, surpassing the generic major, Cipla.
Piramal Healthcare Solutions will continue to operate as a standalone business, and will not
be merged with the existing Abbott India operations. The acquired business is split into two:
healthcare solutions and true care units.
Worldwide, EPD was formed to focus on branded generics and maximize the opportunity in
emerging markets, which contribute 20% of the global major's sales.
Talking about Abbott's strategy, India is a prime target for them. They want to focus on India
first as it is growing at 15% year-on-year, and outperforms the industry growth at over 20%.
Later, they are planning to look at export opportunities to the overseas markets.
In terms of sales, Abbott estimates the growth of its Indian pharmaceutical business
to approach 20% annually, with expected sales of more than $2.5 billion by 2020.
The company has retained all employees of the acquired unit and has manpower of 7,500-
odd people, with an overall staff strength of 10,000 across all its businesses in the country.
Besides the focus on branded generics portfolio (generics sold under a brand name), Abbott
is also keen on innovator or proprietary drugs from India. But these are outside the purview
of the EPD, which only focuses on branded generics.
They also have a strong R&D pipeline, which will see how to build the business by
identifying unmet commercial needs.
Though Abbott has been operating in India since 1910, it has become active over the last few
years with the parent acquiring Solvay last year. The Solvay deal gave Abbott a better
foothold in emerging markets in Eastern Europe and Asia, where the US Company has
limited sales.

















ANTIBIOTICS













ANTIBIOTICS

The word "antibiotics" comes from the Greek anti ("against") and bios ("life"). An antibiotic is a
drug that kills or slows the growth of bacteria. Antibiotics are one class of antimicrobials, a
larger group which also includes anti-viral, anti-fungal, and anti-parasitic drugs. Antibiotics are
chemicals produced by or derived from microorganisms (i.e. bugs or germs such as bacteria and
fungi). The first antibiotic was discovered by Alexander Fleming in 1928 in a significant
breakthrough for medical science. Antibiotics are among the most frequently prescribed
medications in modern medicine.
The term "antibiotic" was coined by Selman Waksman in 1942 to describe any substance
produced by a microorganism that is antagonistic to the growth of other microorganisms in high
dilution. This definition excluded substances that kill bacteria but are not produced by
microorganisms (such as gastric juices and hydrogen peroxide). It also excluded synthetic
antibacterial compounds such as the sulfonamides.
Antibiotics are used to treat many different bacterial infections. Antibiotics cure disease by
killing or injuring bacteria. Bacteria are simple one-celled organisms that can be found, by the
billions, all around us: on furniture and counter-tops, in the soil, and on plants and animals. They
are a natural and needed part of life. Bacteria cause disease and infection when they are able to
gain access to more vulnerable parts of our bodies and multiply rapidly. Bacteria can infect many
parts of the body: eyes, ears, throat, sinuses, lungs, airways, skin, stomach, colon, bones,
genitals.
Some antibiotics are 'bactericidal', meaning that they work by killing bacteria. Other antibiotics
are 'bacteriostatic', meaning that they work by stopping bacteria multiplying. Each different type
of antibiotic affects different bacteria in different ways. For example, an antibiotic might inhibit
a bacterium's ability to turn glucose into energy, or its ability to construct its cell wall. When this
happens, the bacterium dies instead of reproducing.
Some antibiotics can be used to treat a wide range of infections and are known as 'broad-
spectrum' antibiotics. Others are only effective against a few types of bacteria and are called
'narrow-spectrum' antibiotics.
With advances in medicinal chemistry, most of today's antibiotics chemically are semisynthetic
modifications of various natural compounds These include, for example, the beta-lactam
antibiotics, which include the penicillins (produced by fungi in the genus 'Penicillium), the
cephalosporins, and the carbapenems. Compounds that are still isolated from living organisms
are the aminoglycosides, whereas other antibacterialsfor example, the sulfonamides, the
quinolones, and the oxazolidinonesare produced solely by chemical synthesis.


HISTORY :-
Before the early twentieth century, treatments for infections were based primarily on medicinal
folklore. Mixtures with antimicrobial properties that were used in treatments of infections were
described over 2000 years ago. Many ancient cultures, including the ancient Egyptians and
ancient Greeks used specially selected mold and plant materials and extracts to treat infections.
More recent observations made in the laboratory of antibiosis between micro-organisms led to
the discovery of natural antibacterials produced by microorganisms. Louis Pasteur observed that,
"if we could intervene in the antagonism observed between some bacteria, it would offer perhaps
the greatest hopes for therapeutics".
Antagonistic activities by fungi against bacteria were first described in England by John Tyndall
in 1875. Synthetic antibiotic chemotherapy as a science and development of antibacterials began
in Germany with Paul Ehrlich in the late 1880s. Ehrlich noted that certain dyes would color
human, animal, or bacterial cells, while others did not. He then proposed the idea that it might be
possible to create chemicals that would act as a selective drug that would bind to and kill bacteria
without harming the human host. After screening hundreds of dyes against various organisms, he
discovered a medicinally useful drug, the synthetic antibacterial Salvarsan. In 1928, Alexander
Fleming observed antibiosis against bacteria by a fungus of the genus 'Penicillium'. Fleming
postulated that the effect was mediated by an antibacterial compound named penicillin and that
its antibacterial properties could be exploited for chemotherapy. He initially characterized some
of its biological properties, but he did not pursue its further development. Prontosil, the first
commercially available antibacterial antibiotic, was developed by a research team led by Gerhard
Domagk in 1932 (who received the 1939 Nobel Prize for Medicine for his efforts) at the Bayer
Laboratories of the IG Farben conglomerate in Germany. Prontosil had a relatively broad effect
against Gram-positive cocci but not against enterobacteria. The discovery and development of
this first sulfonamide drug opened the era of antibacterial antibiotics. In 1939, Rene Dubos
reported discovery of the first naturally derived antibiotic, gramicidin from B. brevis. It was one
of the first commercially manufactured antibiotics in use during World War II to prove highly
effective in treating wounds and ulcers.
Florey and Chain succeeded in purifying penicillin. Purified penicillin displayed potent
antibacterial activity against a wide range of bacteria and had low toxicity in humans.
Furthermore, its activity was not inhibited by biological constituents such as pus, unlike the
synthetic sulfonamides. The discovery of such a powerful antibiotic was unprecedented, and the
development of penicillin led to renewed interest in the search for antibiotic compounds with
similar efficacy and safety. For their discovery and development of penicillin as a therapeutic
drug, Ernst Chain, Howard Florey, and Alexander Fleming shared the 1945 Nobel Prize in
Medicine. Florey credited Dubos with pioneering the approach of deliberately and systematically
searching for antibacterial compounds, which had led to the discovery of gramicidin and had
revived Florey's research in penicillin.
ANTIBIOTIC RESISTANCE :-
Antibiotics are extremely important in medicine, but unfortunately bacteria are capable of
developing resistance to them. Antibiotic-resistant bacteria are germs that are not killed by
commonly used antibiotics. When bacteria are exposed to the same antibiotics over and over, the
bacteria can change and are no longer affected by the drug.
Bacteria have number of ways how they become antibiotic-resistant. For example, they possess
an internal mechanism of changing their structure so the antibiotic no longer works, they develop
ways to inactivate or neutralize the antibiotic. Also bacteria can transfer the genes coding for
antibiotic resistance between them, making it possible for bacteria never exposed to an antibiotic
to acquire resistance from those which have. The problem of antibiotic resistance is worsened
when antibiotics are used to treat disorders in which they have no efficacy (e.g. antibiotics are
not effective against infections caused by viruses), and when they are used widely as prophylaxis
rather than treatment.
Antibiotic-resistant strains and species, sometimes referred to as "superbugs", now contribute to
the emergence of diseases which were for a while well-controlled. For example, emergent
bacterial strains causing tuberculosis (TB) that are resistant to previously effective antibacterial
treatments pose many therapeutic challenges. Every year, nearly half a million new cases of
multidrug-resistant tuberculosis (MDR-TB) are estimated to occur worldwide. For example,
NDM-1 is a newly identified enzyme conveying bacterial resistance to a broad range of beta-
lactam antibacterials. United Kingdom Health Protection Agency has stated that "most isolates
with NDM-1 enzyme are resistant to all standard intravenous antibiotics for treatment of severe
infections.
Resistance to antibiotics poses a serious and growing problem, because some infectious diseases
are becoming more difficult to treat. Resistant bacteria do not respond to the antibiotics and
continue to cause infection. Some of these resistant bacteria can be treated with more powerful
medicines, but there some infections that are difficult to cure even with new or experimental
drugs.















CLASSIFICATION OF ANTIBIOTICS












CLASSIFICATION OF ANTIBIOTICS
The first classification is according to the spectrum. The spectrum means the number of the
organisms affected by the same drug. There are narrow and wide spectrum antibiotics. The wide
spectrum antibiotics affect several types of bacteria and fungi and it is usually used where the
specific type of the microorganism is unknown. For example, when we are treating an bacterial
caused inflammation, we know that we are dealing with a staphylococcus or streptococcus
microorganism so the doctor can proceed with the treatment without asking for more lab tests to
identify the specific type of the microorganism using the broad spectrum antibiotics but in other
cases, where we know the specific type of the microorganism, we can use the narrow spectrum
antibiotics that are more effective on specific microorganism but less effective on others.
The second classification is according to the type of the action of antibiotics. It could be
bactericidal or bacteriostatic. The bactericidal antibiotics kill the harmful microorganism while
the baceriostatic ones tend to slow down their growth and give the body the chance to use its
immune system against the microorganisms. In case of virulent microorganisms or in case of
weak immunity, bactericidal antibiotics are preferred because they will omit the problem from its
roots but they will affect the normal microorganisms in the body. In mild cases, bacteriostatic
antibiotics could be used because of their minor side effects.
The third classification of antibiotics is according to the route of administration of the drug. The
prevalent route of administration is the oral route but, there are other routes of administration that
are more effective in certain cases like injection or topical applications.
Antibiotic injection is used when the doctor wants to see a rapid onset of action and a quick
presence of antibiotic in the blood stream. It is used in severe cases and as a post operative
regime. Topical application of antibiotics is more used in cases of superficial inflammations and
skin infections. Direct application of antibiotics on the affected part make it more powerful in
combating the microorganism because when antibiotic is administered through oral or injection
route, some of it is degraded in the liver before it reach the peripheral circulation and superficial
legions.
Although there are several classification schemes for antibiotics, based on bacterial spectrum
(broad versus narrow) or type of activity (bactericidal vs. bacteriostatic), the most useful is based
on chemical structure. Antibiotics within a structural class will generally have similar patterns of
effectiveness, toxicity, and allergic potential.
The main classes of antibiotics are:
Beta-Lactams
o Penicillins
o Cephalosporins
Macrolides
Fluoroquinolones
Tetracyclines
Aminoglycosides
Penicillins
The penicillins are the oldest class of antibiotics. Penicillins have a common chemical structure
which they share with the cephalosporins. Penicillins are generally bactericidal, inhibiting
formation of the cell wall. Penicillins are used to treat skin infections, dental infections, ear
infections, respiratory tract infections, urinary tract infections, gonorrhea.
Cephalosporins
Cephalosporins have a mechanism of action identical to that of the penicillins. However, the
basic chemical structure of the penicillins and cephalosporins differs in other respects, resulting
in some difference in the spectrum of antibacterial activity. Like the penicillins, cephalosporins
have a beta-lactam ring structure that interferes with synthesis of the bacterial cell wall and so
are bactericidal. Cephalosporins are derived from cephalosporin C which is produced from
Cephalosporium acremonium.
Fluoroquinoloness
Fluoroquinolones (fluoridated quinolones) are the newest class of antibiotics. Their generic name
often contains the root "floxacin". They are synthetic antibiotics, and not derived from bacteria.
Fluoroquinolones belong to the family of antibiotics called quinolones. The older quinolones are
not well absorbed and are used to treat mostly urinary tract infections. The newer
fluoroquinolones are broad-spectrum bacteriocidal drugs that are chemically unrelated to the
penicillins or the cephalosporins. Because of their excellent absorption fluoroquinolones can be
administered not only by intravenous but orally as well.
Tetracyclines
Tetracyclines got their name because they share a chemical structure that has four rings. They are
derived from a species of Streptomyces bacteria. Tetracycline antibiotics are broad-spectrum
bacteriostatic agents, which inhibit bacterial protein synthesis. Tetracyclines may be effective
against a wide variety of microorganisms, including rickettsia and amebic parasites.
Macrolides
The macrolide antibiotics are derived from Streptomyces bacteria, and got their name because
they all have a macrocyclic lactone chemical structure. The macrolides are bacteriostatic, binding
with bacterial ribosomes to inhibit protein synthesis. Erythromycin, the prototype of this class,
has a spectrum and use similar to penicillin. Newer members of the group, azithromycin and
clarithyromycin, are particularly useful for their high level of lung penetration. Macrolide
antibiotics are used to treat respiratory tract infections (such as pharyngitis, sinusitis, and
bronchitis), genital, gastrointestinal tract, and skin infections.

Aminoglycosides
Aminoglycosides are derived from various species of Streptomyces. Aminoglycoside antibiotics
are used to treat infections caused by gram-negative bacteria. Aminoglycosides may be used
along with penicillins or cephalosporins to give a two-pronged attack on the bacteria.
Aminoglycosides work quite well, but bacteria can become resistant to them. Since
aminoglycosides are broken down easily in the stomach, they can't be given by mouth and must
be injected. Generally, aminoglycosides are given for short time periods .Aminoglycoside group
includes:






























CEPHALOSPORINS













CEPHALOSPORINS

The cephalosporins are a class of -lactam antibiotics that inhibit the synthesis of a structural
component of the bacterial cell wall, which was previously known as "Cephalosporium". The
cephalosporins were first isolated from cultures of the fungus Cephalosporium acremonium.
Together with cephamycins they constitute a subgroup of -lactam antibiotics called cephems..
Modifications of the -lactam ring have resulted in more than 20 derivatives with a range of
antibacterial properties.
Cephalosporins are semisynthetic antibiotics produced by fungi Cephalosporium. We may say
that cephalosporin antibiotics are "very close relatives" of penicillins, because cephalosporins
mechanism of action, mechanism of resistance, and some other properties are identical to
penicillins. Both cephalosporins and penicillins belong to -lactams (beta-lactam antibiotics.)The
main value of cephalosporins is their broad spectrum of antimicrobial activity. Cephalosporins
are widely and successfully used in medicine in the treatment of different bacterial infections.
Cephalosporins affect bacteria's cell wall. This leads to the death of a harmful bacteria.
Cephalosporins distribute in human body in satisfactory concentrations except central nervous
system. Only few of them achieve adequate concentration in cerebrospinal fluid (Cefuroxime,
Cefotaxime, Ceftriaxone, Ceftazidime) and can be used to cure meningitis or brain abscesses.
Cephalosporins are beta-lactam compounds in which the beta-lactam ring is fused to a 6-
membered dihydrothiazine ring, thus forming the cephem nucleus. Side chain modifications to
the cephem nucleus confers 1) an improved spectrum of antibacterial activity, 2)
pharmacokinetic advantages, and 3) additional side effects. Based on their spectrum of activity,
cephalosporins can be broadly categorized into four generations.
The cephalosporins are a group of semisynthetic derivatives of cephalosporin C, an antimicrobial
agent of fungal origin. They are structurally and pharmacologically related to the penicillins.
Because the cephalosporins are structurally similar to the penicillins, some patients allergic to
penicillin may also be allergic to cephalo- sporin drugs. The incidence of cross-sensitivity is
estimated to be 5 to 16 percent.
This group of antimicrobials, though similar to the penicillins in action, have different chemical
structures. They tend to be more stable than penicillins to many of the bacterial beta-lactamases,
and have a broader spectrum of activity than do the penicillins.
There are many cephalosporins that are different classes, and which vary in their spectrum of
activity, but all of the so called true cephalosporins derive from cephalosporin C produced by
Cephalosporium acremonium.
These drugs are usually bactericidal. They inhibit mucopeptide synthesis in bacterial cell walls.
Their advantage over the penicillins are that they resist hydrolysis by the enzyme penicillinase
which is secreted by a number of bacteria. The cephalosporins can be effective, but those that are
taken orally are not in most cases the drug of choice in systemic infections.
Their broad spectrum of activity and safety profile make the cephalosporins one of the most
widely prescribed class of antimicrobials. The earlier generation cephalosporins are commonly
used for community-acquired infections, while the later generation agents, with their better
spectrum of activity against gram-negative bacteria make them useful for hospital-acquired
infections or complicated community-acquired infections.

MECHANISM OF ACTION & PHARMACOLOGIC PROPERTIES:-
1. Prevents cell wall synthesis by binding to enzymes called penicillin binding proteins
(PBPs). These enzymes are essential for the synthesis of the bacterial cell wall.
2. Bactericidal.
3. Concentration-independent bactericidal activity, with maximal killing at 4-5 times the
MIC of the organism.
4. Clinically significant post-antibiotic effect is not observed.
Given these pharmacodynamic properties (concentration-independent bactericidal
activity and lack of a post-antibiotic effect), optimal dosing regimens should be designed
to continuously maintain drug levels above the MIC of pathogens.
.
THI RD GENERATI ON CEPHALOSPORI NS
Improved activity against Enterobacteriaceae associated with hospital-acquired infections; some
agents are also active against Pseudomonas aeruginosa which is a frequent cause of hospital-
acquired pneumonia.
SPECTRUM OF ACTIVITY- Gram-positive aerobic cocci: Cefotaxime, ceftriaxone, and
ceftizoxime are active against methicillin-susceptible Staphylococcus aureus (though less than
1st and some 2nd generation agents), very active against Groups A and B streptococci, and
viridans streptococci. Cefotaxime and ceftriaxone are more active than ceftizoxime against
Streptococcus pneumoniae, particularly intermediately-penicillin resistant Streptococcus
pneumoniae. None are active against methicillin-resistant Staphylococci, Enterococci, and
Listeria monocytogenes.
Gram-negative aerobes: Very active against Hemophilus influenzae, Moraxella catarrhalis,
Neisseria meningitidis, and Enterobacteriaceae (eg: Escherichia coli, Klebsiella species, Proteus
mirabilis, Providencia)found in hospital and community-acquired infections. Some Enterobacter
species have a tendency to become resistant during cephalosporin therapy, and thus
cephalosporins are not the drugs of choice for Enterobacter infections.
Only and ceftazidime and cefoperazone are active against Pseudomonas aeruginosa, and
ceftazidime is preferred because it is more potent than cefoperazone against gram-negative
bacteria.
Anaerobes: Cefotaxime, ceftriaxone, and ceftizoxime are adequate for oral anaerobes.
GENERAL CLINICAL USES -For infections involving gram-negative bacteria,
particularly hospital-acquired infections or complicated community-acquired infections of the
respiratory tract, blood, intra-abdominal, skin and soft tissue, and urinary tract. Because of their
activity includes the aerobic gram negative bacteria covered by aminoglycosides, they may be an
alternative to aminoglycosides in some patients with renal dysfunction.
The clinical situations requiring use of 3rd generation cephalosporins are likely to be
encountered in patients who are hospitalized, have recently received antibiotics, or are
immunocompromised.
SPECIFIC AGENTS:
A. Cefotaxime (Claforan), Ceftriaxone (Rocephin), Ceftizoxime (cefizox) . IV/IM
formulations. Activity against Enterobacteriaceae (eg: Escherchia coli, Klebsiella pneumoniae)
are similar. None are active against Pseudomonas aeruginosa. Only cefotaxime and ceftriaxone
achieve adequate drug levels in the cerebral spinal fluid to constitute reliable empiric therapy for
bacterial meningitis. Ceftriaxone is eliminated to a significant degree by the biliary system, and
as a result, biliary pseudo-lithiasis has been reported as a side effect of this agent.
B. Ceftazidime (Fortaz, Tazidime, Tazicef), Cefoperazone (Cefobid). IV/IM formulations.
Spectrum includes Pseudomonas aeruginosa (against which ceftazidime is more active) and
Enterobacteriaceae covered by the 3rd generation agents in item A above. Disadvantages of
cefoperazone are: 1) the least active 3rd generation agent against Enterobacteriaceae and 2)
contains MTT side chain .
C. Cefixime (Suprax), Ceftibuten (Cedax) .PO formulations administered once or twice daily.
Inactive against methicillin-susceptible Staphylococcus aureus, thus not good choices for skin
and soft tissue infections. Generally very active against gram-negative bacteria causing
community-acquired infections(Hemophilus influenzae, Moraxella catarrhalis). Cefixime is
effective as a single dose therapy for uncomplicated Neisseria gonorrhea infection. While used in
otitis media, cefixime may not routinely eradicate Streptococcus pneumoniae.















CEFIXIME















CEFIXIME

Cefixime, is an orally active third generation bactericidal cephalosporin(beta lactam antibiotic)
with broad spectrum of coverage .
It was sold under the trade name Suprax in the USA, until 2003 when it was taken off the market by drug
manufacturer Wyeth after its patent expired. The oral suspension form of "Suprax" was re-launched by
Lupin in the USA.In India its sold under the trade name Zifi 200.

As with other cephalosporins, bactericidal action of cefixime results from inhibition of cell- wall
synthesis. Cefixime is highly stable in the presence of betalactamase enzymes. As a result, many
organisms resistant to penicillins and some cephalosporins due to the presence of beta-
lactamases, may be susceptible to cefixime. However, cefixime was found to be ineffective
against bacteria which produces ESBL(Extended Spectrum Beta Lactam) enzyme and resistance
is seen in such types of bacteria.

Clavulanic acid is an irreversible suicide inhibitor of intracellular and extracellular -
lactamases, demonstrating concentration-dependent and competitive inhibition. It has a high
affinity for the class A -lactamases. This wide range of -lactamases, which includes the
plasmid-mediated TEM and SHV enzymes, is found frequently in members of the
Enterobacteriaceae, Haemophilus influenzae and Neisseria gonorrhoeae. The chromosomally
mediated -lactamases of Klebsiella pneumoniae, Proteus mirabilis, Proteus vulgaris,
Bacteroides fragilis and Moraxella catarrhalis are also inhibited, as are the extended-spectrum
-lactamases.

Pharmacokinetics:-

Combining clavulanic acid with beta lactam antibiotic causes no appreciable alteration of the
pharmacokinetics of either drug compared with their separate administration.

About 40-50% of cefixime is absorbed slowly following oral administration from the GIT.
Absorption is not significantly modified by the presence of food.
From in vitro studies, serum or urine concentrations of 1 mcg/mL or greater were considered to
be adequate for most common pathogens against which cefixime is active. Typically, the peak
serum levels following the recommended adult or paediatric doses are between 1.5 and 3
mcg/mL. Little or no accumulation of cefixime occurs following multiple dosing.

The pharmacokinetics of cefixime in healthy elderly (age> 64 years) and young volunteers (11-
35) compared the administration of 400 mg doses once daily for 5days.
Cefixime is predominantly eliminated as unchanged drug in the urine. Glomerular filtration is
considered the predominant mechanism. Metabolites of cefixime have not been isolated from
human serum or urine.

Serum protein binding is well characterised for human and animal sera; cefixime is almost
exclusively bound to the albumin fraction, the mean free fraction being approximately 30%.
Protein binding of cefixime is only concentration dependent in human serum at very high
concentrations which are not seen following clinical dosing.
Cefixime has been shown to be active against most strains of the following organisms both in
vitro and in clinical infections.
Gram-positive Organisms.
Streptococcus pneumoniae,
Streptococcus pyogenes.
Gram-negative Organisms.
Haemophilus influenzae
(beta-lactamase positive and negative strains),
Moraxella (Branhamella) catarrhalis
(most of which are beta-lactamase positive),
Escherichia coli,
Proteus mirabilis,
Neisseria gonorrhoeae
(including penicillinase- and non-penicillinase-producing strains).
Cefixime has been shown to be active in vitro against most strains of the following organisms;
however, clinical efficacy has not been established.


































CLAVULANIC ACID
























CLAVULANIC ACID

Clavulanic acid is a beta-lactamase inhibitor (marketed by GlaxoSmithKline, formerly Beecham)
combined with penicillin group antibiotics to overcome certain types of antibiotic resistance. It is used to
overcome resistance in bacteria that secrete beta-lactamase, which otherwise inactivates most penicillins.
In its most common form, the potassium salt potassium clavulanate is combined with amoxicillin (co-
amoxiclav [brand name Augmentin] or the veterinary formulation Synulox from Pfizer, or [Clavulox]) or
ticarcillin.
The name is derived from the Streptomyces clavuligerus, which produces clavulanic acid.
Clavulanic acid is biosynthetically generated from the amino acid arginine and the sugar
glyceraldehyde 3-phosphate.
Clavulanic acid was discovered around 1974/75 by British scientists working at the drug
company Beecham. After several attempts, Beecham finally filed for US patent protection for the
drug in 1981, and U.S. Patents 4,525,352, 4,529,720, and 4,560,552 were granted in 1985.
Although Clavulanic acid does have some degree of bacterial activity, its principal role is as a
beta-lactamase inhibitor. Beta-lactam antibiotics, such as the penicillins and cephalosporins, act
by disrupting the development of bacterial cells walls thus causing the disintegration of the
bacteria. However, some bacteria acquired the genes to produce enzymes which inactivated this
mode of action - so called beta-lactamases - drastically reducing the efficacy of this class
of antibiotics.
Clavulanic acid has a similar structure to the beta-lactam antibiotics but binds irreversibly to the
beta-lactamase enzymes. Used in combination with the beta-lactam antibiotics, it has become
one of the most prescribed antibiotics in the western world prolonging the effective life of
antibiotics such as Ampicillin (as in GSK's Augmentin)

MECHANISM OF ACTION :-
Clavulanic acid has negligible intrinsic antimicrobial activity, despite sharing the -lactam ring
that is characteristic of beta-lactam antibiotics. However, the similarity in chemical structure
allows the molecule to interact with the enzyme beta-lactamase secreted by certain bacteria to
confer resistance to beta-lactam antibiotics. Clavulanic acid is a suicide inhibitor, covalently
bonding to a serine residue in the active site of the beta-lactamase. This restructures the
clavulanic acid molecule, creating a much more reactive species that is attacked by another
amino acid in the active site, permanently inactivating it, and thus inactivating the enzyme. This
inhibition restores the antimicrobial activity of beta-lactam antibiotics against lactamase-
secreting-resistant bacteria. Despite this, some bacterial strains that are resistant even to such
combinations have emerged.










RESEARCH METHODOLOGY









Research Objective:-
To study the Role and Rational of Clavulanic acid used in combination with the
Cephalosporin (third generation) group of medicines.
The objective was to assess the knowledge of the doctors regarding the combination.
Doctors surveyed through Questionnaire
A total of 46 doctors were approached of different specialized areas as shown below
Specialization No. of Doctor
Physicians 29
Gynaecologists 05
Urologists 04
Paediatricians 08


Research Methodology-
A structured questionnaire was designed for the target population i.e. doctors and the survey was
done in Jaipur city in the months of April, May and June(2011).
An in-depth interview was conducted with the doctors belonging to different specializations and
a primary data was collected which was further analyzed and interpreted.
Sampling Techniques-Sampling technique used here are simple random sampling during
which visit to different hospitals(both public and private) and clinics was made in Jaipur. The
instrument which was used to gather the required information was a structured questionnaire
with open ended questions which were framed in a way to be filled by the doctors itself and
factors have taken into account to collect the required possible information in the minimum
possible time.
Study Area - The interviews were conducted in Bhagwan Mahaveer Cancer hospital, Jaipur
hospital, Sawai mansingh hospital, SDMH hospital ,Sardar Mal Khandaka hospital, Life care
hospital, K.G. memorial hospital, Brij clinic, Saket hospital, Dhanvantri hospital and Sharda
hospital.











DATA INTERPRETATION
AND
ANALYSIS

















DATA INTERPRETATION AND ANALYSIS

Doctors opinion regarding:-
PREFERRED BRANDS:-
Figure 1- Preferred Brands

N=46
Based on the respondent no. we can see that the most preferred brand for cefixime was Zifi
CV of FDC which was followed by Cefolac CV and Omnix CV.







INDICATION OF COMBINATION:-
32.6
17.39
13.04
10.86
10.86
8.69
6.52
Zifi CV
Cefolac CV
Omnix CV
Cefi CV
Milixm CV
Zimnic CV
Other
Figure 2-Indication of combination

N=46
The survey conducted revealed that majority of the doctors supported the view that major
indication of combination is because of its beta-lactamase inhibitor property while some doctors
believed that it also enhance drug potency when used in combination with the cephalosporin
group of medicines.


\




USAGE:-
65.27
13
6.52
15.21
-lactamase inhibitor
Enhance potency of drugs
For early curement
Broad spectrum
Figure 3-Usage

N=46
Based on the doctors opinion the main usage of clavulanic acid was there in the respiratory
and urinary tract infections along with its application in other areas like skin infections.









DURATION OF TREATMENT:-
34.78
19.56
17.39
13.04
8.69
6.52
RTI
UTI
OTITIS MEDIA
SKIN INFECTIONS
POST OPERATIVE CASES
OTHERS
Figure 4-Duration of treatment

N=46
Duration of the treatment from respondents view basically depends on the severity of the disease
but majority of them believes that duration of about 5-7 days are enough for the treatment.









CRITERIA:-
36.95
47.82
15.21
3-5 days
5-7 days
10-14 days
Figure 5-Criteria

N=46
Based on the data collected from various respondents, established brands plays a major role in
prescribing a particular medicine or drug. The other criteria include the cost effectiveness of
drugs and promotional strategy used by the companies to promote various drugs.









SIDE EFFECTS:-
23.91
26.08
19.56
21.73
8.69
Cost-effective
Brand(Company's name)
Better results
Promotional strategy
Availability
Figure 6-Side Effects

N=46
As per respondents view the main side effect of using clavulanic acid in combination with the
cephalosporin group of medicines was the GI disturbances which was followed by other side
effects like diarrhea, nausea ,etc.










28.26
19.56
21.73
17.39
13.04
GI Disturbances
Diarrhoea
Nausea
Skin rashes
Others






CONCLUSION



















Based on the above data interpretation and analysis it can be concluded that


The combination of cefixime and clavulanic acid (-lactamase inhibitor) provides a
solution for treatment of bacterial infections caused by beta lactam resistant pathogens as
clavulanic acid is mainly used because of its beta-lactamase inhibitor property which is
significant in reducing the bacterial infections.


Zifi CV, Cefolac CV and Omnix CV are among the most preferred brands used for
combination of clavulanic acid and cefixime(third generation group of medicines) by
doctors with varying specialization.


Cefixime in combination with clavulanic acid is used to treat multiple bacterial infections
in different parts of the body like in RTI, UTI, skin infections, etc. because of its broad
spectrum activity.


The prime reason behind prescribing a particular brand of cefixime with CV to a patient
is its reliability on a particular brand of a particular company along with factors like cost-
effectiveness and various promotional strategy used for promoting a particular brand.














REFERENCES


(1) "cephalosporin." Encyclopdia Britannica. Encyclopdia Britannica Online.
Encyclopdia Britannica, 2011. Web. 09 May. 2011.

(2) Stork CM (2006). "Antibiotics, antifungals, and antivirals". In Nelson LH, Flomenbaum
N, Goldfrank LR, Hoffman RL, Howland MD, Lewin NA. Goldfrank's toxicologic
emergencies. New York: McGraw-Hill. pp. 847. ISBN 0-07-143763-0.. Retrieved 2009-
07-03.

(3) US4110165, Process for the production of clavulanic acid, Beecham Group Limited
Inventor(s):Cole, Martin ; Howarth, Thomas T. ; Reading, Christopher.


(4) US4454069, Clavulanic acid salts and their preparation from the tertiary butyl amine salt,
Beecham Group Limited
Inventor(s):Cook, Michael A. ;Curzons, Alan D. ;Wilkins, Robert B.

(5) British National Formulary (54 ed.). September 2007













ANNEXURE 1
Questionnaire
Name of the doctor
Specialization
Contact No
E-mail Id
1. What are the brands you preferred of Cefixime [cephalosporin] in
combination with the clavulanic acid?
_____________________________________________________________
_____________________________________________________________

2. What is the role of clavulanic acid in this combination?
_____________________________________________________________
_____________________________________________________________

3. Where do you prefer such combinations?
_____________________________________________________________
_____________________________________________________________

4. What is the duration of the treatment with this/these brands?
_____________________________________________________________
_____________________________________________________________

5. What is the criteria behind selecting a particular brand?
_____________________________________________________________
_____________________________________________________________

6. Does it has any side effects? What are they?
_____________________________________________________________
_____________________________________________________________