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Osteomyelitis-Symptoms, Causes and Treatment

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DOI: 10.5958/2349-2988.2018.00024.4

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 Research J. Science and Tech. 10(2): April- June, 2018

ISSN 0975-4393 (Print) Available online at

2349-2988 (Online) www.anvpublication.org
DOI:

Vol. 10| Issue-02|

Research Journal of Science and Technology
April- June | 2018 Home page www.rjstonline.com

RESEARCH ARTICLE

Osteomyelitis- Symptoms, Causes and Treatment

Debjit Bhowmik*, Rishab Bhanot, Darsh Gautam, Parshuram Rai, K. P. Sampath Kumar
Himachal Institute of Pharmaceutical Education and Research, Nadaun, Hamirpur, H.P.
Department of Pharmacy, Coimbatore government medical college, Coimbatore
*Corresponding Author E-mail: debjit_cr@yahoo.com

ABSTRACT:
Osteomyelitis is an infection and inflammation of the bone or the bone marrow. It can happen if a bacterial or
fungal infection enters the bone tissue from the bloodstream, due to injury or surgery. Around 80 percent of
cases develop because of an open wound. Symptoms include deep pain and muscle spasms in the inflammation area,
and fever. Bone infections commonly affect the long bones in the leg and upper arm, the spine, and the pelvis.In the
past, it was difficult to treat osteomyelitis, but now, aggressive treatment can often save the infected bone and stem
the spread of infection.

KEY WORDS: Osteomyelitis, Bone infections, Pyogenic bacteria.

INTRODUCTION:
Osteomyelitis is an infection of bone or bone marrow with a propensity for progression, usually caused by pyogenic
bacteria or mycobacteria. Osteomyelitis is inflammation of the bone and marrow, but, since it is always caused by an
infection, it implies an infection. When an infection develops inside the bone, the immune system will try to kill it.
Neutrophils, a type of white blood cell, will be sent to the source of the infection to kill the bacteria or fungus. If the
infection takes hold and is not treated, dead neutrophils will accumulate inside the bone, forming an abscess, or
pocket of pus. The abscess may block vital blood supplies to the affected bone. In chronic osteomyelitis, the bone
may eventually die. Bones are normally resistant to infection, but infection may enter a bone under certain
conditions. An infection in the bloodstream, complications of trauma or surgery, or pre-existing conditions, such as
diabetes, Reduce the person's ability to resist infection.

HISTORY:
There are numerous reports in the literature using animal models of osteomyelitis for investigating pathogenesis,
diagnosis, and treatment of bone infections. When designing an animal model of osteomyelitis, it is important to
learn the currently available models as well as their advantages and disadvantages. This article aims to concisely
introduce the history of osteomyelitis models, commonly used animals and models, basic procedures, basic
considerations during the period of model designing and conduction, and basic methods of evaluation. The
references used for this review were selected by a thorough search of MedLine and by reading previously published
articles including several well-known review articles by Mader (1985)[2], Norden (1988)[3], Rissing (1990)[4],
Crémieux and Carbon (1997)[5], and An and Friedman (1998)[6]. In general, only classic articles and selected recent
publications are included. It was noted that many publications are in languages other than English and copies are
difficult to obtain. Although the authors have put forth considerable effort, a number of key publications may have
been missed. The history of the development of animal osteomyelitis models is rather simple, with a scant list of
publications stretching from 1885 to 1970 and then a significantly increased number of articles after 1970. The latter

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is obviously correlated to the fast growing field of modern antibiotics. The first trials on animal models of
osteomyelitis can be traced back to the work by Rodet in 1885 [7] and Lexer in 1894 [8]. They injected staphylococci
intravenously to produce bone abscesses. These works were followed by only a few reports in the first half of the
19th century including those by Starr in 1922 [9], Haldeman in 1934 [10], and Thompson and Dubos in 1938 [11]. They
injected staphylococci either intravenously or directly into the bone and found only few osteomyelitis lesions which
were nonprogressive and did not mimic human conditions. Several years later, Scheman et al 1941 [12] reported their
chronic osteomyelitis model using rabbits, injecting staphylococci and sodium morrhuate directly into the tibia
metaphysis. This study established the basics for creating osteomyelitis in animals the use of a sclerosing agent

Types of Osteomyelitis:
It can be subclassified on the basis of the causative organism, the route, duration and anatomic location of the
infection. There are three types of osteomyelitis.

1. Acute osteomyelitis, where the bone infection develops within two weeks of an initial infection, injury or the
onset of an underlying disease.

2. Sub-acute osteomyelitis, where the bone infection develops within one ot two months of an initial infection,
injury or onset of an underlying disease.

3. Chronic osteomyelitis, where the bone infection develops two months or more after an initial infection, injury or
onset of an underlying disease.

Etiology of osteomyelitis:
Bacteria or fungus may cause the infection. Bloodstream-sourced osteomyelitis is seen most frequently in children,
and nearly 90% of cases are caused by Staphylococcus aureus.
In infants, S. aureus, Group B streptococci (most common[13]) and Escherichia coli are commonly isolated; in
children from 1 to 16 years of age, S. aureus, Streptococcus pyogenes, and Haemophilus influenzae are common. In
some subpopulations, including intravenous drug users and splenectomized patients, Gram-negative bacteria,
including enteric bacteria, are significant pathogens[14].

Hematogenously spread osteomyelitis usually results from a single organism usually affecting the metaphyses of the
tibia, femur, or humerus. Systemic mycotic (fungal) infections may also cause osteomyelitis. The two most common
pathogens involved in such infections are Blastomyces dermatitidis and Coccidioides immitis.

Tubercular osteomyelitis of the spine was so common before the initiation of effective antitubercular therapy that it
acquired a special name, Pott's disease, by which it is sometimes still known. The Burkholderia cepacia complex
have been implicated in vertebral osteomyelitis in intravenous drug abusers[15]

Pathogenesis:
In general, microorganisms may infect bone through one or more of three basic methods: via the bloodstream,
contiguously from local areas of infection (as in cellulitis), or penetrating trauma, including iatrogenic causes such
as joint replacements or internal fixation of fractures 9or root-canaled teeth. Once the bone is infected, leukocytes
enter the infected area, and, in their attempt to engulf the infectious organisms, release enzymes that lyse the bone.
Pus spreads into the bone blood vessels, impairing their flow, and areas of devitalized infected bone, known as
sequestra, form the basis of a chronic infection. Often, the body will try to create new bone around the area of
necrosis. The resulting new bone is often called an involucrum. On histologic examination, these areas of necrotic
bone are the basis for distinguishing between acute osteomyelitis and chronic osteomyelitis. Osteomyelitis is an
infective process which encompasses all of the bone (osseous) components, including the bone marrow. When it is
chronic it can lead to bone sclerosis and deformity. In infants, the infection can spread to the joint and cause
arthritis. In children, large subperiosteal abscesses can form because the periosteum is loosely attached to the surface
of the bone. Because of the particulars of their blood supply, the tibia, femur, humerus, vertebra, the maxilla, and the
mandibular bodies are especially susceptible to osteomyelitis. Abscesses of any bone, however, may be precipitated
by trauma to the affected area. Many infections are caused by Staphylococcus aureus, a member of the normal flora
found on the skin and mucous membranes. In sickle cell the causative agent is normally from the Salmonella

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species.

Mode of Transmission of bacteria-:

Bacteria can infect bones in a number of ways.

Through Bloodstream:
Bacteria can travel into the bone through the bloodstream from other infected areas in the body. This is called
hematogenous (hema refers to the blood) osteomyelitis, and is the most common way that people get bone
infections.

Direct infection:
when bacteria enter the body's tissues through a wound and travel to the bone (like after an injury). Open fractures
breaks in the bone with the skin also open— are the injuries that most often develop osteomyelitis.

Atherosclerosis:
A bone also can become infected when the blood supply to that area of the bone is disrupted. This can happen in
older people with atherosclerosis, which is a narrowing of the blood vessels, or in association with diabetes.

Common causes of Osteomyelitis:

It includes the following:
 A result of an injury to the bone.
 Intravenous drug users.
 Prosthetic bone devices, such as screws, plates, or wires.
 Poor circulation.
 An infection in the body carried by the blood to the bone.
 Artificial joints, such as a knee or hip.
 Trauma to the skin or bones, such as surgery, deep skin cuts, and bone fractures or breaks. Fungal infection
Table. No.- 1.The different aged group has different causting agent of Osteomyelitis are shown in this table.
S.No Age group Most common organism
1 Newborns (younger than 4 months) S.aureus, Enterobacter species and group A and B Streptococcus species
2 Childeren (aged 4 months to 4 years) S.aureus, group A Streptococcus species, Haemophilus influenza and Enterobacter
species
3 Childeren, aldolesents (aged 4yeras to adult) S.aureus (80%) group A streptococcus species, H. influenzae, Enterobacter species.
4 Adult S.aureus and occasionally Enterobacter or Streptococcus species

In children, the long bones are usually affected. In adults, the vertebrae and the pelvis are most commonly affected.
Acute osteomyelitis almost invariably occurs in children. When adults are affected, it may be because of
compromised host resistance due to debilitation, intravenous drug abuse, infectious root-canalled teeth, or other
disease or drugs (e.g. immunosuppressive therapy). Osteomyelitis is a secondary complication in 1-3% of patients
with pulmonary tuberculosis. In this case, the bacteria, in general, spread to the bone through the circulatory system,
first infecting the synovium (due to its higher oxygen concentration) before spreading to the adjacent bone. In
tubercular osteomyelitis, the long bones and vertebrae are the ones which tend to be affected. In infants, S. aureus,
Group B streptococci (most common) and Escherichia coli are commonly isolated; in children from 1 to 16 years of
age, S. aureus, Streptococcus pyogenes, and Haemophilus influenzae are common. In some subpopulations,
including intravenous drug users and splenectomized patients, Gram-negative bacteria, including enteric bacteria,
are significant pathogens.
The most common form of the disease in adults is caused by injury exposing the bone to local infection.
Staphylococcus aureus is the most common organism seen in osteomyelitis seeded from areas of contiguous
infection, but anaerobes and Gram-negative organisms, including Pseudomonas aeruginosa, E. coli, and Serratia
marcescens, are also common. Mixed infections are the rule rather than the exception. Systemic mycotic (fungal)
infections may also cause osteomyelitis. The two most common are Blastomyces dermatitidis and Coccidioides
immitis. In osteomyelitis involving the vertebral bodies, about half the cases are due to Staphylococcus aureus, and
the other half are due to tuberculosis (spread hematogenously from the lungs). The Burkholderia cepacia complex
have been implicated in vertebral osteomyelitis in intravenous drug users.

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Pathophysiology:
The infection associated with osteomyelitis may be localized or it may spread through the periosteum, cortex,
marrow, and cancellous tissue. The bacterial pathogen varies on the basis of the patient's age and the mechanism of
infection. The following are the 2 primary categories of acute osteomyelitis: hematogenous osteomyelitis and direct
or contiguous inoculation osteomyelitis. Hematogenous osteomyelitis is an infection caused by bacterial seeding
from the blood. Acute hematogenous osteomyelitis is characterized by an acute infection of the bone caused by the
seeding of the bacteria within the bone from a remote source. This condition primarily occurs in children. The most
common site is the rapidly growing and highly vascular metaphysis of growing bones. The apparent slowing or
sludging of blood flow as the vessels make sharp angles at the distal metaphysis predisposes the vessels to
thrombosis and the bone itself to localized necrosis and bacterial seeding. Acute hematogenous osteomyelitis,
despite its name, may have a slow clinical development and insidious onset. Direct or contiguous inoculation
osteomyelitis is caused by direct contact of the tissue and bacteria during trauma or surgery. Direct inoculation
(contiguous-focus) osteomyelitis is an infection in the bone secondary to the inoculation of organisms from direct
trauma, spread from a contiguous focus of infection, or sepsis after a surgical procedure. Clinical manifestations of
direct inoculation osteomyelitis are more localized than those of hematogenous osteomyelitis and tend to involve
multiple organisms. Additional categories include chronic osteomyelitis and osteomyelitis secondary to peripheral
vascular disease. Chronic osteomyelitis persists or recurs, regardless of its initial cause and/or mechanism and
despite aggressive intervention. Although listed as an etiology, peripheral vascular disease is actually a predisposing
factor rather than a true cause of infection. Disease states known to predispose patients to osteomyelitis include
diabetes mellitus, sickle cell disease, acquired immune deficiency syndrome (AIDS), intravenous (IV) drug abuse,
alcoholism, chronic steroid use, immunosuppression, and chronic joint disease. In addition, the presence of a
prosthetic orthopedic device is an independent risk factor, as is any recent orthopedic surgery or open fracture.

Symptoms of Osteomyelitis:
Patients with acute osteomyelitis of peripheral bones usually experience weight loss, fatigue, fever, and localized
warmth, swelling, erythema, and tenderness. Vertebral osteomyelitis causes localized back pain and tenderness with
paravertebral muscle spasm that is unresponsive to conservative treatment.Chronic osteomyelitis causes intermittent
(months to many years) bone pain, tenderness, and draining sinuses.

Diagnosis:
Diagnosis of osteomyelitis is often based on radiologic results showing a lytic center with a ring of sclerosis. Culture
of material taken from a bone biopsy is needed to identify the specific pathogen; alternative sampling methods such
as needle puncture or surface swabs are easier to perform, but do not produce reliable results.

Factors that may commonly complicate osteomyelitis are fractures of the bone, amyloidosis, endocarditis, or sepsis.
Symptoms and findings during a physical examination may suggest osteomyelitis. For example, doctors may suspect
osteomyelitis in a person who has persistent pain in part of a bone with or without a fever and feels tired much of the
time. Elevations in the erythrocyte sedimentation rate (ESR—a test that measures the rate at which red blood cells
settle to the bottom of a test tube containing blood), and an elevated level of C-reactive protein (a protein that
circulates in the blood and dramatically increases in level when there is inflammation) usually occur. Also, blood
tests often indicate elevated levels of white blood cells. However, these blood tests are not sufficient to diagnose
osteomyelitis. An X-ray may show changes characteristic of osteomyelitis, but sometimes not until more than 3
weeks after the first symptoms occur. Computed tomography (CT) and magnetic resonance imaging (MRI) can also
identify the infected area. However, these tests cannot always distinguish infections from other bone disorders. The
infected area almost always appears abnormal on bone scans (images of bone made after injecting radioactive
technetium), except in infants, because scans do not reliably indicate abnormalities in growing bones. White blood
cell scans (images made after radioactive indium–labeled white blood cells are injected into a vein) can help
distinguish between infection and other disorders in areas that are abnormal on bone scans. To diagnose a bone
infection and identify the organisms causing it, doctors may take samples of blood, pus, joint fluid, or the bone itself
to test. Usually, for vertebral osteomyelitis, samples of bone tissue are removed with a needle or during surgery.

Treatment:
Osteomyelitis often requires prolonged antibiotic therapy, with a course lasting a matter of weeks or months. Central
Venous Catheter is often placed for this purpose. Osteomyelitis also may require surgical debridement. Severe cases

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may lead to the loss of a limb. Initial first line antibiotic choice is determined by the patient's history and regional
differences in common infective organisms. In 1875, American artist Thomas Eakins depicted a surgical procedure
for osteomyelitis at Jefferson Medical College, in a famous oil painting titled The Gross Clinic. Prior to the
widespread availability and use of antibiotics, blow fly larvae were sometimes deliberately introduced to the wounds
to feed on the infected material, effectively scouring them clean. Hyperbaric oxygen therapy has been shown to be a
useful adjunct to the treatment of refractory osteomyelitis. A treatment lasting 42 days is practiced in a number of
facilities. For children and adults who have recently developed bone infections through the bloodstream, antibiotics
are the most effective treatment. If the bacteria causing the infection cannot be identified, then antibiotics that are
effective against Staphylococcus aureus and many types of bacteria (broad-spectrum antibiotics are used. Depending
on the severity of the infection, antibiotics may be given by vein (intravenously) for about 4 to 8 weeks but then may
be given by mouth later. Some people need months of antibiotic treatment. If a fungal infection is identified or
suspected, antifungal drugs are required for several months. If the infection is detected at an early stage, surgery is
usually not necessary.

For adults who have bacterial osteomyelitis of the vertebrae, the usual treatment is antibiotics for 6 to 8 weeks.
Sometimes bed rest is needed, and the person may need to wear a brace. Surgery may be needed to drain abscesses
or to stabilize affected vertebrae (to prevent the vertebrae from collapsing and thereby damaging nearby nerves, the
spinal cord, or blood vessels).

Prevention of osteomyelitis:
The prognosi s for people with osteomyelitis is usually good with early and proper treatment. However, sometimes,
chronic osteomyelitis develops, and a bone abscess may recur weeks to months or even years later. Certain people
who have artificial joints or metal components attached to a bone should take preventive antibiotics before surgery,
including dental surgery, because these people may be at increased risk of infection from bacteria normally present
in the mouth and other parts of the body. People can ask their health care practitioner for expert, detailed
recommendations regarding preventive antibiotics. People undergoing surgical or dental procedures should tell their
surgeon, orthopedist, or dentist that they have an artificial joint or metal component attached to a bone so that
preventive antibiotics can be taken. When osteomyelitis results from an adjacent soft-tissue infection (such as in a
foot ulcer caused by poor circulation or diabetes), treatment is more complex. Usually, all the dead tissue and bone
are removed surgically, and the resulting empty space is packed with healthy bone, muscle, or skin. Then the
infection is treated with antibiotics. When an abscess is present, it usually needs to be drained surgically. Surgery
may also be needed for people with persistent fever and weight loss. Usually, an artificial joint that has an infection
around it is removed and replaced. Antibiotics may be given several weeks before surgery to try to eradicate the
infection, so that the contaminated artificial joint can be removed and a new one can be implanted at the same time.
Rarely, treatment is not successful and the infection continues, requiring surgery to fuse the joint or amputate the
limb.

FIXED DOSE COMBINATION THERAPY[16]:

It would be generally agreed that scientific therapeutics ideally should employ only those drugs which modify
appropriately the target pathophysiological processes, and that both drug concentrations in the body and drug actions
should be monitored so that dose is adjusted to obtain an optimal response. Such exacting requirements are seldom
achievable in practice, so that various compromises are adopted in medical treatment which are not always agreed
upon and thus lead to controversy. Although simultaneous use of several drugs separately is generally accepted to be
commonly necessary, their combination in fixed doses in one medicine is still a controversial compromise. The
sustained popularity of combination products, especially in general practice, suggests that many prescribers and
patients have found them advantageous. By contrast, objections to such products are usually based on theories or
doctrinal statements with little supporting evidence. A medicine is a mixture of drug (or drugs) with other
substances in a formulation appropriate for the intended route and type of use and with desirable clinical or
therapeutic properties.

Pharmacological polymorphism:
The main criticism of combination medicines is the fixed ratio of the doses of the ingredients. The basis of this
criticism must be to the fixed ratio of pharmacological responses rather than of chemical doses alone. However, a
spectrum of pharmacological responses in fixed ratio is not confined to combination products since many, and

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possibly all, single-ingredient medicines have such a range of activities. For example, aspirin produces a number of
pharmacological effects with analgesic, anti-inflammatory, antipyretic and antithrombotic clinical properties. The
optimal dose required for each of these properties will differ and yet will carry the unwanted properties with it in
fixed ratio. Similar mixed responses are seen with many other pharmacologically active agents such as analgesics,
anti-inflammatory agents (steroidal and non-steroidal), psychotropic drugs, antihistamines, sex steroids, diuretics
and drugs acting on the cardiovascular and respiratory system. All of these classes of drugs have a range of disparate
effects, some of which are not only unwanted but troublesome. For example, systemic corticosteroids are used
clinically, apart from replacement therapy, for their inhibitory properties either on lymphoid tissue thus affecting the
immune responses, or on inflammatory responses. Different dosages and durations of therapy may partially
distinguish these effects, but there is no other method for dissociating the wanted from unwanted properties, nor for
avoiding the numerous potential side effects such as on the metabolism of water, electrolytes, carbohydrate, protein
and fat, on the function of the brain, of muscle and of the pituitary-hypothalamic adrenal axis, and on suppression of
the growth of children. Similarly, antihistamines have several useful different clinical properties such as inhibition
of allergic responses and central nervous system effects such as sedation, cough suppression and counteraction of
motion sickness. Additional unwanted effects are other central actions like dizziness, tinnitus, in coordination,
blurred vision, diplopia and tremors gastrointestinal effects like nausea, vomiting, discomfort, constipation and
diarrhoea; and atropine-like effects such as dry mouth. All of these effects, both useful and harmful, are linked
together in fixed ratio. Interestingly, some of these multiple actions from single drugs are equivalent to accepted
multiple therapy. For example, beta-blockers are commonly used with a peripheral vasodilator and these two
properties can be covered by a single drug labetalol. Also, night sedation is usefully combined with treatment of
some allergies either by two medicines or by the combined action of certain of the antihistamines given alone.
Turning from drugs to physiological systems, many 'natural' substances such as hormones, vitamins and biochemical
agents like adrenaline, noradrenaline, histamine, insulin, serotonin and cortisol also have multiple properties. The
range of receptors and actions of such substances is wide, and their secretion or liberation must give rise to a 'fixed
ratio' of responses, not all of which are answering physiological need. Serotonin, or 5-hydroxytryptamine (5HT), is
widely distributed in the body with numerous properties on smooth muscle and nerves giving a wide spectrum of
potential responses. These include actions on respiratory rate and volume, on bronchial smooth muscle, cardiac
output and blood vessel tone, on gastrointestinal tract motility and on gastric juice as well as in releasing
catecholamines from the adrenal gland and affecting other endocrine glands. The blood-brain barrier normally
prevents the penetration of 5HT into the brain, but various drugs such as reserpine and imipramine modulate its
distribution in that organ where it has important nerve-transmitter properties. Cell receptors for 5HT are thus
widespread and probably of distinctive types since there is a wide range in their susceptibilities to different blocking
drugs. Any single drug which mimics these physiological agents will induce a similar 'fixed ratio' of effects in areas
of its distribution. Physiological homeostasis commonly utilizes multiple pathways. Control of blood pressure is
effected by several cardiac and peripheral vascular responses mediated by many nervous and hormonal factors.
Similarly, regulation of other physical and biochemical functions, such as body temperature, blood glucose and
electrolytes, is mediated in each by a variety of channels. The powerful, acute, clinical response to such drugs is
suited to the symptomatic treatment of some disorders such as asthma. However, for long-term therapeutic control
of some physiological functions, such as blood sugar or blood pressure, a pharmacological approach which imitates
nature by utilizing a variety of pathways might have merit. Anti-infective medicines are employed for antimicrobial
activity rather than for any human pharmacological activity and some, such as penicillins and cephalosporins in
therapeutic doses, have few if any pharmacological effects. These drugs in combination would supply much less
pharmacological activity than most single drugs in other therapeutic classes.

Rationale for combination medicines:

Research with combination products has provided therapeutic advances in a number of different ways, and the
following examples may be cited where such products have proved to be more advantageous than single-drug
therapy. Protection of active drug. A decarboxylase inhibitor together with L-dopa prevents its destructive
metabolism. Amoxycillin can be preserved from the destructive action of bacterial, β-lactamase by simultaneous use
of clavulanic acid. Renal excretion of active nalidixic acid can be increased by raising urinary pH by the
administration of citrate. Enhancement of therapeutic effect. Antibacterial activity is enhanced and extended by
combinations of anti-infective agents such as trimethoprim with a sulphonamide, or ampicillin with flucloxacillin.
Improved therapeutic action: Use of a beta-blocker and a diuretic is synergistic in lowering blood pressure, but also
the unwanted effects are opposite in direction, and perhaps selfcancelling, on renin excretion, fluid retention and

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blood sugar levels. Oral contraception and post-menopausal replacement therapy achieved by oestrogen-progestogen
combinations give a better and different kind of response from that achieved by one drug alone. In both of these two
uses, clinical research has defined optimal fixed-ratio dosages which would be very difficult to provide reliably
other than by combination products, administered cyclically in calendar packs. Prevention of induction of microbial
drug resistance: In treating tuberculosis it is important to prevent the development of bacterial resistance to the
active drugs rifampicin or ethambutol by the concomitant use of isoniazid. Combination products of these drugs, in a
range of doses, avoid these dangers and provide safer regimes.

Alleviation of side effects:

Potassium loss during diuretic therapy can be alleviated by concomitant use of a potassium salt. Pyridoxine used
with isoniazid helps to prevent the development of neuropathy. Cyclizine reduces morphine vomiting. Simultaneous
treatment of coexisting disease: In pregnancy, iron deficiency commonly coexists with folic acid deficiency,
forming a valid indication for treatment of both deficiencies simultaneously with a combination of iron and folic
acid. Improved physicochemical properties: The intravenous steroid anaesthetic Althesin contains alphadolone (a
weak anaesthetic agent) to render the active drug, alphaxolone, sufficiently soluble by cosolubilization. In a sense
most medicines are combination products, being complex formulations of the active drug with other ingredients to
provide an appropriate vehicle with suitable stability, release characteristics, taste, colour, etc. The treatment of
multiple symptoms by a combination medicine, of which there are many examples, might also be considered an
appropriate rationale for this type of medicine. Some of these multiple therapies can be administered separately but
not with the convenience or other advantages of a single product. Also there are two other important practical
considerations in this context. The general theoretical advantages and disadvantages of fixed-dose combination
medicines have been reviewed frequently although firm data are still not available on most of these views. The
justification for a combination product as against a single one will be an improvement in some aspect of efficacy,
safety or quality. In comparison with a regime of multiple medicines, a combination product is justified by the
following advantages. From the patient's point of view, the simpler regime generates less anxiety; the uniformity of
ingredients and fixed doses provide greater safety and reliability; and the cost is reduced. From the doctor's
viewpoint, the combination will be easier than a multiple drug regime to describe to the patient, especially when
compliance is a problem; because the ingredients and doses are fixed into a fully-researched product they should
provide a more reliable performance and be more free from unexpected drug interactions compared with multiple
prescriptions; also the likelihood of a prescribing error in dose or of ingredient is reduced.

Treatment of osteomyeltis by fixed dose combination therapy:

Many aspects of the antibiotic treatment of osteomyelitis have not been completely investigated. Antibiotics kill
bacteria and prevent their invasive spread, while surgery aims to drain pus, remove necrotic soft and bone tissues
and bacterial slime, and restore blood supply. Levofloxacin is commonly referred to as a quinolone drug and is a
member of the fluoroquinolone class of antibacterials. VRP 1003 is a fixed dose combination of two antibiotic. A
fixed-dose combination (FDC) ; it is a formulation of two or more active ingredients combined in a single dosage
form available in certain fixed doses combination therapy is used to widen the antimicrobial spectrum, minimize
toxicity and prevent the emergence of resistant mutants. These antibiotics are reported to cause nephrotoxicity,
ototoxicity and neuromuscular blocks. Fixed-dose combination drug products may improve medication compliance
by reducing the pill burden of patients. Aminoglycosides (amikacin and tobramycin) are most important drugs in
clinical use and also essential for the treatment of severe infections caused by gram-negative bacteria. These
antibiotics are reported to cause nephrotoxicity, ototoxicity and neuromuscular blocks. Neuromuscular blocks are
rare, ototoxicity ranges from 0-62% and nephrotoxicity varies from 0-19% the binding of aminoglycosides in vivo as
well as in vitro with negatively charged membrane is associated with impairment of phospholipid catabolism,
change in membrane permeability and membrane aggregation. Aminoglycosides bind to membranes, where they are
endocytosed and accumulate with phospholipid within the tubular cell lysosomes. Due to increase accumulation of
aminoglycosides results in a stepwise alteration of cell function and ultimately causes cell necrosis. The adverse
effect of aminoglycosides has been attributed to the development of an array of alterations in proximal tubule
epithelium followed by its destruction, thereby causing kidney dysfunction. Aminoglycosides administration is also
reported to induce apoptosis. Free radical generation and glomerular basement membrane alterations. Free radicals
also plays an important role in drug-induced damage to the kidney failure. Cefepime and ceftazidime are
cephalosporin class of antibiotics having potential of free radical scavenging properties. A combination of
cephalosporins plus aminoglycosides has been used for many years as empirical therapy because of broad spectrum

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of activity against pathogens. There are several studies which suggest that cephalosporins in combination with
aminoglycosides prevent aminoglycosides induced toxicities. Chemical vector mediated technology was used to
form synergistic combination of aminoglycosides and cephalosporins with antioxidant potential. A fixed-dose
combination (FDC) is a formulation of two or more active ingredients combined in a single dosage form available in
certain fixed doses. Fixed-dose combination drug products may improve medication compliance by reducing the pill
burden of patients. Typically, fixed-dose combination drug products are developed to target a single disease (such as
with antiretroviral FDCs used against AIDS). However, FDCs may also target multiple diseases, such as Caduet
contains atorvastatin to treat hypercholesterolemia and amlodipine to treat hypertension. Since FDCs are reviewed
by the Food and Drug Administration, the active ingredients used in the FDC are unlikely to exhibit adverse drug
interactions with each other. However, FDCs may interact with other drugs that a patient is taking. While FDCs may
reduce pill burden, there are some disadvantages. If a dosing adjustment is warranted, there may not be an FDC
available in the most appropriate strength for the patient. In addition, if an adverse drug reaction occurs from using
an FDC, it may be difficult to identify the active ingredient responsible for causing the reaction. However, this
problem may be avoided by starting the medications individually and monitoring for reactions, and then switching to
an FDC when no problems have been observed.

Fixed dose combinations and rational drug therapy:

We read with interest the article on rational use of fixed dose combinations by Kastury et al in october 1999 issue of
Indian Journal of Pharmacology. The study was conducted as an auditing of prescriptions in Allahabad during 1997-
98 and evaluated the rationality of fixed dose combinations in such prescriptions according to the WHO's model list
of essential drugs which was revised in December 1997[17]. It showed 12 combination drugs and the prescriptions
were analyzed in accordance with the list. The study revealed that only 11% of the fixed dose combination were
according to the WHO's recommended list. We point out here that though the authors had made a sincere attempt,
the validity of the results are questionable. This is because the list of combinations drugs accordance with the WHO
model list revised in 1997 as cited. The WHO list has 18 fixed dose combination formulations. The discrepancies in
the published list of fixed dose combination drugs given by Kastury et al. are that it does not include Similarly the
combination of Isoniazid and ferrous sulphate included by these authors do not find a place in the revised WHO
model list. Most essential drugs should be formulated as single compounds. Fixed ratio combination products are
acceptable only when the dosage of each ingredient meets the requirements of a defined population group and when
the combination has a proven advantage over single compounds administered separately in its therapeutic effects,
safety or compliance[18]. Considering these criteria it is essential to weed out the irrational combinations
mushrooming in pharmaceutical industry at present. As early as 1988 itself (based on MIMS), there were 110
vitamin formulations, 71 cough remedies, 70 anti-diarrhoeals, 54 antimicrobial combinations and 49 analgesic
formulations available in the market[19]. An awareness needs to be created to allow only the rational combinations
based on the criteria above. We believe that this information will be of use to scientists involved in this area.

Synergism:
Interactiong between two or more agents, entities, factors, or substances that produces an effect greater than the sum
of their individual effects. Also called synergetic effect or synergistic effect, it is opposite of antagonism.
Combination therapy is used to widen the antimicrobial spectrum, minimize toxicity and prevent the emergence of
resistant mutants. These antibiotics are reported to cause nephrotoxicity, ototoxicity and neuromuscular blocks.
Staphylococcal infections pose an emerging problem with major economic impact [20, 21]. Osteomyelitis, a deep bone
infection, mostly staphylococcal, can result from trauma, nosocomial infection, or an orthopaedic operation [22,
23]
.This complicated infection has proven difficult to treat [24].Alleviating osteomyelitis presents an additional
challenge because the infecting bacteria form a biofilm mode of growth, which, on devascularized surfaces, shield
them from antibiotics [25]

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Cephalosporin:
The cephalosporins are a class of β-lactam antibiotics originally derived from Acremonium, which was previously
known as "Cephalosporium"[78].Cephalosporins is the most frequently prescribed class of antibiotics. They are
structurally and pharmacologically related to the penicillins. Like the penicillins, cephalosporins have a beta-lactam
ring structure that interferes with synthesis of the bacterial cell wall and so are bactericidal (which means that they
kill bacteria). Cefepime is a fourth-generation cephalosporin antibiotic developed in 1994. Cefepime has an
extended spectrum of activity against Gram-positive and Gram-negative bacteria, with greater activity against both
Gram-negative and Gram-positive organisms than third-generation agents. Cefepime hydrochloride was first
marketed in 1994 and is currently marketed under various trade names including Maxipime, Maxcef, Cepimax,
Cepimex, and Axepim. A 2007 meta-analysis suggested that when data of trials were combined, mortality was
increased in patients treated with cefepime compared with other β-lactam antibiotics[79]. In response, the U.S. Food
and Drug Administration performed their own meta-analysis which found that there was no mortality
difference.[80].`The cephalosporins are primarily bactericidal durg. They prevent the bacteria from biosynthesizing
the framework of their cell wall. The weakened cell wall will swell and burst causing cell death. The combination of
the syn-configuration of the methoxyimino moiety and the aminothiazolyl moiety confers extra stability to β-
lactamase enzymes produced by many bacteria. The N-methylpyrrolidine moiety increases penetration into Gram-
negative bacteria. These factors increases the activity of cefepime otherwise resistant organisms including
Pseudomonas aeruginosa and Staphylococcus aureus.

Structure of cefepime

Mechanisms of action of cephlosporin:

The cell walls of bacteria are essential for their normal growth and development. Peptidoglycan is a heteropolymeric
component of the cell wall that provides rigid mechanical stability by virtue of its highly cross-linked latticework
structure. In gram-positive microorganisms, the cell wall is 50 to 100 molecules thick, but it is only 1 or 2 molecules
thick in gram-negative bacteria. The peptidoglycan is composed of glycan chains, which are linear strands of two
alternating amino sugars (N-acetylglucosamine and N-acetylmuramic acid) that are cross-linked by peptide chains.
The biosynthesis of the peptidoglycan involves about 30 bacterial enzymes and may be considered in three stages.

Stage, 1- precursor formation:

It takes place in the cytoplasm. The product, uridine diphosphate (UDP)-acetylmuramyl-pentapeptide, accumulates
in cells when subsequent synthetic stages are inhibited. The last reaction in the synthesis of this compound is the
addition of a dipeptide, D-alanyl-D-alanine. Synthesis of the dipeptide involves prior racemization of L-alanine and
condensation catalyzed by D-alanyl-D-alanine synthetase. D-Cycloserine is a structural analog of D-alanine and acts
as a competitive inhibitor of both the racemase and the synthetase.

Stage, 2:
UDP-acetylmuramyl-pentapeptide and UDP-acetylglucosamine are linked (with the release of the uridine
nucleotides) to form a long polymer.

Stag 3:
It involves completion of the cross-link. This is accomplished by a transpeptidation reaction that occurs outside the
cell membrane. The transpeptidase itself is membrane-bound. The terminal glycine residue of the pentaglycine
bridge is linked to the fourth residue of the pentapeptide (D-alanine), releasing the fifth residue (also D-alanine). It is
this last step in peptidoglycan synthesis that is inhibited by the b-lactam antibiotics.

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The PBPs(penicillin binding proteins) vary in their affinities for different b-lactam antibiotics, although the
interactions eventually become covalent. The higher-molecular-weight PBPs of E. coli (PBPs 1a and 1b) include the
transpeptidases responsible for synthesis of the peptidoglycan. Other PBPs in E. coli include those that are necessary
for maintenance of the rodlike shape of the bacterium and for septum formation at division. Inhibition of the
transpeptidases causes spheroplast formation and rapid lysis. However, inhibition of the activities of other PBPs may
cause delayed lysis (PBP 2) or the production of long, filamentous forms of the bacterium (PBP 3)..Penicillin’s
disruption of the balance between PBP-mediated peptidoglycan assembly and murein hydrolase activity results in
autolysis. Nonlytic killing by penicillin may involve holin-like proteins in the bacterial membrane that collapse the
membrane potential. Cephalosporin bound to the essential PBP 3, inhibited DNA gyrase, and caused filamentation
in growing cells.

Adverse-effects:
Common adverse drug reactions (ADRs) (≥1% of patients) associated with the ctscephalosporin therapy include:
diarrhea, nausea, rash, electrolyte disturbances, and or pain and inflammation at injection site. Infrequent ADRs
(0.1–1% of patients) include: vomiting, headache, dizziness, oral and vaginal candidiasis, pseudomembranous
colitis, superinfection, eosinophilia, and/or fever.
Allergic reactions:
Allergic reactions to cephalosporins are infrequent, but range from a skin rash that may be itchy, red or swollen to
life-threatening reactions such as severe difficulty breathing and shock. Rarely, a specific type of allergic reaction
can occur with cefaclor involving a skin rash, joint pains, irritability, and fever. The patient should get medical
attention immediately if any of these symptoms develop while taking cephalosporins: induction of osteomylitis.
 shortness of breath
 pounding heartbeat
 skin rash or hives
 severe cramps or pain in the stomach or abdomen
 fever severe watery or bloody diarrhea (may occur up to several weeks after stopping the drug)
 unusual bleeding or bruise
Cotraindications-:
It is contra indicated in patients with a history of severe immediate allergic reaction(urticaria, anaphylaxis,
interstitial ephritis etc.)to cephalosporin. Several cephalosporins are associated with hypoprothrombinemia and
disulfiran-like reaction. Due to N-methylthiotetrazole side chain of cephalosporin which blocks thesnzyme vitamin
Kepoxide reductase and aldehyde dehydrogenase causing alcohol intolerance.
Aminoglycosides:
An aminoglycoside is a molecule composed of a sugar group and an amino group[81].Several aminoglycosides
function as antibiotics that are effective against certain types of bacteria. They include amikacin, arbekacin,
gentamicin, kanamycin, neomycin, netilmicin, paromomycin, rhodostreptomycin, streptomycin, tobramycin, and
apramycin.
Amikacin is an aminoglycoside antibiotic. it has been used extensively in humans and other animals to treat
infections produced by Gram-negative bacteria, as well as against Staphylococcus aureus, Pseudomonas auriginosa
and Mycobacterium tuberculosis. Aminoglycosides are used primarily for the treatment of life-threatening infections
such as peritonitis, bacteremia, pneumonia, endocarditis as well as urinary tract infections, cystic fibrosis and
tuberculosis. Energy is needed for aminoglycoside uptake into the bacterial cell. Anaerobes have less energy
available for this uptake, so aminoglycosides are less active against anaerobes. Aminoglycosides are useful
primarily in infections involving aerobic, gram-negative bacteria, such as Pseudomonas, Acinetobacter, and
Enterobacter. In addition, some Mycobacteria, including the bacteria that cause tuberculosis, are susceptible to
aminoglycosides. The most frequent use of aminoglycosides is empiric therapy for serious infections such as
septicemia, complicated intra abdominal infections, complicated urinary tract infections, and nosocomial respiratory
tract infections. Streptomycin was the first effective drug in the treatment of tuberculosis, though the role of
aminoglycosides such as streptomycin and amikacin has been eclipsed (because of their toxicity and inconvenient
route of administration) except for multiple drug resistant strains.

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Structure of Amikacin:

Mechanisms of action:
Amikacin acts through two main mechanisms
1. They interfere with the proofreading process, causing increased rate of error in synth with premature termination.
Also, there is evidence of inhibition of ribosomal translocation where the peptidyl-tRNA moves from the A-site to
the P-site. By binding to the ribosome, aminoglycosides inhibit the translocation of tRNA during translation and
leaving the bacterium unable to synthesize proteins necessary for growth.Although the eukaryotic cells of humans
also have ribosomes, these cellular protein factories differ in size and structure from the ribosomes of prokaryotes.
That is why aminoglycosides do not interfere with protein synthesis in human cells.They can also disrupt the
integrity of bacterial cell membrane. They bind to the bacterial 30S ribosomal subunit (some work by binding to
the50S subunit[87].

2. The protein synthesis inhibition of aminoglycosides does not usually produce a bactericidal effect,
Aminoglycosides competitively displace cell biofilm-associated Mg2+ and Ca2+ that link the polysaccharides of
adjacent lipopolysaccharide molecules. "The result is shedding of cell membrane blebs, with formation of transient
holes in the cell wall and disruption of the normal permeability of the cell wall. This action alone may be sufficient
to kill most susceptible Gram-negative bacteria before the aminoglycoside has a chance to reach the 30S
ribosome[88]. Aminoglycosides, like amikacin (AMK) and kanamycin, have been used as second-line drugs for the
treatment of resistant Mycobacterium infections. In particular, AMK has been effective as part of treatments for
patients with M. avium complex bacteremia and for the treatment of infections caused by organisms resistant to the
other aminoglycosides. Aminoglycosides are thought to penetrate the cells in a three-step process. Once they are
inside the cytosol, they bind to the 16S rRNA at the tRNA acceptor site (A site), which plays an important role for
the high fidelity of translation and act by interfering with the decoding process rather than by sterically hindering the
tRNA-ribosome interaction [94]. The recent resolution of complexes between aminoglycoside molecules and rRNA or
oligonucleotides has improved our understanding of the physicochemical basis of the interactions between the
amino glycosides and the RNA molecules However, although it is accepted that most amino glycosides exert their
action through the induction of misreading during protein synthesis, the precise mechanisms and effects of their
antimicrobial activities are still poorly understood. A series of metabolic perturbations, such as disturbances in DNA
and RNA synthesis, as well as altered membrane composition, permeability, and cellular ionic concentrations, have
been described; but most of them can be secondary to the presence of mistranslated proteins

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Flow chart of mechanism of action of Amino glycosides

Aminoglycosides

misreading of mRNA

aberran proteins in cell membrane

alter membrane permeability

Damage of protein, Lipid and Nucleic acid

potentiating the increased entry of drug

anaerobic environments and low external pH:

reduces transmembrane potential

effectiveness of aminoglycosides

Side effects:
shortness of breath; closing of the throat; hives; swelling of the lips, face, or tongue; rash; or fainting.
 little or no urine;
 decreased hearing or ringing in the ears;
 dizziness, clumsiness, or unsteadiness;
 numbness, skin tingling, muscle twitching, or seizures; or
 severe watery diarrhea and abdominal cramps.

Other, less serious side effects may be more likely to occur. I.e
 loss of appetite;
 nausea or vomiting;
 a rash.
Adverse effect of Amikacin:
The several adverse effect of amikacin such as-
 Nephrotoxicity (kidney failure)
 Ototoxicity (Hearing loss)
Mechanism of action of VRP 1003-:
Amikacin (aminoglycosides) antibiotics are glycosides formed from aminosugars (monosaccharides or
disaccharides) and aminocyclitols. They are alkaline in nature owing to their amino and oher basic functional
groups. The antibacterial mechanism of action aminoglycosides antibiotic is that after entering bacteria the
aminoglycoside antibiotic conjugates with the 30s subunit protein. Which causes error when tRNA translates mRNA
code and results in non functioning proteins inhibiting cell growth. Cefepime antibiotics are beta lactum antibiotics.
The antibacterial mechanism of action of beta lactum is entirely different from that of aminogycosides, it inhibit the
synthesis of bacterial cell wall by inhibiting the activity of D-alanyl-D-alanine traspeptidase inside bacteria. Beta
lactum are acidic where as aminoglycosides antibiotics are basic. When they combine to each other synergic
bacterial action can be achieved. Aminoglycosides are rich in primary amines and possess cytoprotective properties
but would not be excepted to protect extracellular sulf hydroxyl group against free radical mediated oxidation.

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Cephalosporins are thio ether group containing antibiotics which are very effective in preventing the free radical-
mediated oxidation of sulfhydryl group.VRP 1003 has one additional substituents i.e arginine that helps to detoxify
the liver by neutralizing the effects of ammonia and other toxic substances in body. It is required for the generation
of urea, which is needed for removal of toxic ammonia from the body during urination. Arginine maintains the pH
of constituent solution at 4 to 6. Arginine stabilizes two non compatible antibiotics as a single product. It is helpful
for the prevention of precipitation between cefepime and amikacin.

CONCLUSION:
The best way to prevent osteomyelitis is to keep things clean. If you or your child has a cut, especially a deep cut,
wash it completely. Flush out any open wound under running water for five minutes, then bandage it in sterile
bandages. If you have chronic osteomyelitis, make sure your doctor knows about your medical history so you can
work together to keep the condition under control. If you have diabetes, pay close attention to your feet and contact
your doctor at the first sign of infection. The sooner you treat osteomyelitis, the better. In cases of acute
osteomyelitis, early treatment prevents the condition from becoming a chronic problem that requires ongoing
treatment. Besides the pain and inconvenience of repeated infections, getting osteomyelitis under control early
provides the best chance for recovery. Treatment focuses on stopping infection in its tracks and preserving as much
function as possible. Most people with osteomyelitis are treated with antibiotics, surgery, or both. Antibiotics help
bring the infection under control and often make it possible to avoid surgery. People with osteomyelitis usually get
antibiotics for several weeks through an IV, and then switch to a pill form.

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Received on 03.12.2017 Modified on 28.12.2017

Accepted on 08.01.2018 ©A&V Publications All right reserved
Research J. Science and Tech. 2018; 10(2): .
DOI:

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