LINEZOLID - A ANTIBIOTICS OF OXAZOLIDINONE GROUP

LINEZOLID

 A ANTIBIOTICS OF OXAZOLIDINONE GROUP

Linezolid a antibacterial agent of  a new class of antibiotics, know as Oxazolidinone used for treatment of Gram-positive bacterial infection that are resistant to other antibiotics.

Linezolid is active against most Gram-positive bacteria that cause disease, including Streptococci, Vancomycin-resistant Enterococci(VRI), methicillin-resistant staphylococcus aureus (MRSA), Streptococcus pneumoniae (penicillin-susceptible strains only), Staphylococcus epidermidis(including methicillin-resistant strains), streptocovvus pyogenes, & Enterococcus faecalis. The main uses are infections of the skin and pneumonia.

Mechanism of Action:

Linezolid are a protein synthesis inhibitor that it stops the growth of bacteria by disrupting their production of proteins. Although many antibiotics work this way but linezolid appears to be unique in that it blocks the initiation of protein synthesis and not one of the later steps; therefore, cross-resistance between linezolid and other classes of antibiotics is unlikely.

Pharmacokinetics:

Plasma concentrations of linezolid at steady-state after oral doses of  600 mg given every 12 hours(q12 h).

Absorption :

Linozolid is rapidly and extensively adsorbed after oral dosing. Maximum plasma concentrations are reached approximately 1 to 2 hours after dosing and the absolute bioavailability is approximately 100%. Therefore, linezolid may be given orally or intravenously without dose adjustment. It may be administered without regard to the timing of meals. The time to reach the maximum concentration is delayed from 1.5 to 2.2 hours and Cmax is decreased by about 17% when high fat food is given with linezolid.

Distribution:

Linezolid readily distributes to well-perfuse tissue. The plasma protein binding of it is approximately 31% and is concentration-independent.

Metabolism :

Linezolid in not detectably metabolized by human cytochrome P450 and it does not inhibit the activities of clinically significant human CYP isoforms .

Excretion:

Nonrenal clearance accounts for approximately 65% of the total clearance of linezolid. Under steady-state conditions, approximately 30% of the dose appears in the urin as linezolid, 50% as metabolite. The renal clearance of linezolid is low (average 40 ml/min) and suggests net reabsorption. Virtually no linezolid appears in the feces.

Dosage:

Adult- 600 mg orally every 12 hours.

Geriatric:

The  pharmacokinetics of linezolid are not significantly altered in elderly patients (65 yrs or older). Therefore, dose adjustment for geriatric patients is not necessary.

Pediatric:

Information indicates that pediatric patients dosed with 10mg/kg IV have a similar Cmax but a higher average clearance when corrected by body weight and shorter apparent elimination half-life than adults receiving 625 mg of linezolide. Studies with dose higher than 10mg/kg or more frequent than every 12 hours have not been conducted in pediatric patients.

Gender:

Females have a slightly lower volume of distribution of linezolide than male. Plasma concentrations are higher in female than in males ,which is partly due to body weight difference. After a 600mg dose, mean oral clearance is approximately 38% lower in females than in males. However, there are no significant gender difference in means apparent elimination –rate constant or half-life. Therefore, dose adjustment by gender does not appear to be necessary.

Renal Insufficiency:

Linozolide pharmacokinetics is not altered in patients with any degree of renal insufficiency; no dose adjustment is recommended for patients with renal insufficiency.

Hepatic Insufficiency:

The pharmacokinetics of linezolide in not altered in patients with mild-to-moderate hepatic insufficiency. On the basis of the available information, no dosage adjustment is recommended for patients with mild-to-moderate hepatic insufficiency.

Pregnancy: Teratogenic Effects:

Linezolide was not teratogenic in mice or rate at exposure levels 4-fold (in mice) the expected human exposure level.However, embryo and fetal toxicities were seen there are no adequate and well-controlled studies in pregnant women. Linezolide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus

Nosocomial Infections

Nosocomial Infections

Infections which are acquired from hospitals are called nosocomial infection. These infection occurring with in 48 hours of hospital admission, 3 day of discharge or 30 days of an operation. If the organisms come from another patient it is called cross infections and if patient himself carries the infection to some other site then it is autoinfection. Infection may become apparent during the stay of the patient in the hospital or after his discharge from the hospital. There is actual increase in frequency and severity of infection especially due to antibiotic resistant enterobacteria, Staphylococcus aureus and Pseudomonas aeruginosa.Thus prolonged stay of the patient in the hospital is undesired and may be a serious matter for the patient and his family.

Patients Requiring Isolation:

Some patients really need isolation. Patients of tuberculosis, typhoid, diphtheria, lassa fever or smallpox should not be treated or nursed in open ward as these disease are serious and easily transmissible. Similarly infants with measles or whooping cough should not be nursed in general ward but may be treated at home. Staphylococcus aureus infection cases especially resistant to many antibiotics belonging to phase types (80/81 or 75/77) capable of causing serious epidemic of hospital sepsis, certainly require isolation. Isolation cubicles are suggested for these purposes which should be so designed, equipped and managed that no microorganism can pass from them to a ward. Attendant should use gown on entering the cubicle and remove on leaving. Washing facilities for the patient and attendant of the patient must be provided in the cubicle. Dressing should be discarded into paper bags which may be removed to incinerator. Bedding and clothing should be kept in disinfectant solution before sending to laundry. When the patient finally leaves the cubicle,it must be thoroughly washed with disinfectant and all equipment must be sterilized as far as possible.

Hospital Infection and Prevention:

We should be aware of some important hospital infections and their prevention:

1. Wounds and burns: It is important to remove all tissue debris from accidental wounds and burns as bacteria can establish more easily in damaged tissue. A careful and aseptic technique for dressing of wound preferable in dressing room reduces chances of cross infection.
2. Urinary tract infection: Catheter or other instruments into the bladder may cause urinary tract infection. Used catheters are difficult to sterilize and may be the cause of cross infection also, hence disposable sterilized catheter should be used aseptically.
3. Alimentary tract infections: Outbreak of E.coli gastroenteritis in children and Shigella sonnei, dysentery do occur quite oftenly  in hospital. Isolation, general hygiene and exclusion of carriers are important preventive measures.

Epidemiological Markers Useful in investigating Hospital Infection:

• Antibiogram and resistogram.
• Biotyping.
• Phage typing.
• Bacteriocin typing.
• Serotyping.
• Serum opacity factor.
• RNA electropharesis as in done in rotavirus.
• Cytotoxicity assay, e.g. Proteus mirabilis.
• Plasmid profile.

Prevention of Nosocomial Infections:

• Proper washing
• Isolation of patients, e.g. plague, influenza, measles, etc.
• Careful and appropriate use of instruments.
• Use of antibiotics only if required. It may be given to carrier staff or patient.
• Use of blood transfusion only if must. Disinfectants of excreta and infected material.
• Surveillance of infection properly and regularly.
• Use of vaccine, e.g. tetany gas sangrene, hepatitis – B, etc.

Factors Responsible for Hospital Infections:

• Neonates and aged patients have risk of getting hospital infection because of long stay and decreased immunity.
• Impaired defense mechanisms of patients due to disease or treatment.
• Hospital environment contains relatively heavy load of microorganisms.
• Major invasive diagnostic or therapy procedures.
• Advance treatment of cancer, organ transplantation, etc.
• Presence of multidrug resistant bacteria, etc.

Source of Hospital Infection :

• Infecting microorganisms from fellow patients which may be multidrug resistant.
• Infected organisms from hospital staff
• Infecting organisms from instruments, blood products, intravenous fluid, etc.
• From patient’s normal flora, etc.
• Insects are also source multidrug infection.
• Organism may be present in air, dust, water, antiseptic solution, food, etc.
• Surface contaminated by patient’s secretions, blood fluid, etc.

Mode of Infection :

• Airborne.
• Contact, e.g. hand, clothing, etc.
• Food and water.
• Hospital equipments and instruments.
• By parenteral routs.

Roll of Mycobacterium Tubercolosis Bacteria (TB) in HIV positive Person

Roll of Mycobacterium Tubercolosis Bacteria (TB) in HIV positive Person

When person has both HIV & TB , each disease speeds up the progress of other.

HIV positive person have weak immune system & therefore they are more prone to TB infection because TB bacteria get a conducive environment for their activation (its replication & growth). Generally TB does not affect normal person due to strong immune system of body.

Viruses do not have own enzymes which is necessary for protein & nucleic acid synthesis. For this reason virus depend upon synthetic machinery of host cells where they use host cell’s enzymes for their replication. When HIV positive person received TB cause bacteria, HIV found a new host cell in body for their replication.

Viruses that infect animal cells generally use cell-surface receptor that is found on those cell types in which the virus can replicate. Usually many viruses use a single type of receptor & some viruses can use several different receptor. Moreover, different viruses that infect the same cell type may each use a different receptor.  

However HIV requires both a primary receptor as a CD4 & a secondary co-receptor as a CCR5 OR CXCR4(a receptor for α-chemokines) depending on the particular variant of the virus for attachment & entry in to host cells. CD4 are protein involved in immune recognition which is found on the surface of many T-cells & macrophages. Macrophages are susceptible only to HIV variants that use CCR5 for entry, whereas T cells are most efficiently infected by variants that use CXCR4. The viruses that are found within the first few months after HIV infection almost invariably require CCR5, which presumably explains why individuals who carry a defective ccr5 gene are not susceptible to HIV infection. In the later stages of infection, viruses may either switch to use the CXCR4 co-receptor or adapt to use both co-receptors; in this way, the virus can change the cell types it infects as the disease progresses. 

After recognition and attachment to the host cell surface, the virus must next enter the host cell and release its nucleic acid genome from its protective protein coat or lipid envelope within so that the host's genetic coding can be altered to produce other HIV virions.