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) ABBREVIATIONS2) INTRODUCTION TO ANTIBIOTICS3) CLASSIFICATION OF ANTIBIOTICS4) COMPANY PROFILE5) CEPHALOSPORINS6) CEFIXIME7) CLAVULANIC ACID8) RESEARCH METHODOLOGY9) DATA INTERPRETATION AND ANALYSIS10) CONCLUSION11) REFERENCES12) 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 antibacterials—for example, the sulfonamides, the quinolones, and the oxazolidinones—are 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 Penicillinso 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 β-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 β-lactam antibiotics called cephems.. Modifications of the β-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 β-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.

.

THIRD GENERATION CEPHALOSPORINS

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 β-lactamases, demonstrating concentration-dependent and competitive inhibition. It has a high affinity for the class A β-lactamases. This wide range of β-lactamases, which includes the plasmid-mediated TEM and SHV enzymes, is found frequently in members of the Enterobacteriaceae, Haemophilus influenzae and Neisseria gonorrhoeae. The chromosomallymediated β-lactamases of Klebsiella pneumoniae, Proteus mirabilis, Proteus vulgaris, Bacteroides fragilis and Moraxella catarrhalis are also inhibited, as are the extended-spectrum β-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 β-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 DoctorPhysicians 29Gynaecologists 05Urologists 04Paediatricians 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

Doctor’s opinion regarding:-

PREFERRED BRANDS:-

Figure 1- Preferred Brands

32.6

17.3913.04

10.86

10.86

8.69

6.52

Zifi CVCefolac CVOmnix CVCefi CVMilixm CVZimnic CVOther

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:-

Figure 2-Indication of combination

65.27

13

6.52

15.21

β-lactamase inhibitorEnhance potency of drugsFor early curementBroad spectrum

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:-

Figure 3-Usage

34.78

19.56

17.39

13.04

8.69

6.52

RTIUTIOTITIS MEDIASKIN INFECTIONSPOST OPERATIVE CASESOTHERS

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:-

Figure 4-Duration of treatment

36.95

47.82

15.21

3-5 days5-7 days10-14 days

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:-

Figure 5-Criteria

23.91

26.08

19.56

21.73

8.69

Cost-effectiveBrand(Company's name)Better resultsPromotional strategyAvailability

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:-

Figure 6-Side Effects

28.26

19.5621.73

17.39

13.04

GI DisturbancesDiarrhoeaNauseaSkin rashesOthers

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.

CONCLUSION

 

 

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

The combination of cefixime and clavulanic acid (β-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." Encyclopædia Britannica. Encyclopædia Britannica Online. Encyclopædia 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 LimitedInventor(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?__________________________________________________________________________________________________________________________