Cytovan

Uses

Cytovan is used for potentially life-threatening infections which cannot be treated with other effective, less toxic antimicrobial drugs including the penicillins and cephalosporins. Cytovan is useful in the therapy of severe staphylococcal infections in patients who cannot receive or who have failed to respond to the penicillins and cephalosporins or who have infections with staphylococci, resistant to other antibiotics. Cytovan is used in the treatment of endocarditis and as prophylaxis against endocarditis in patients undergoing dental or surgical procedures.Its effectiveness has been documented in other infections due to staphylococci including osteomyelitis, pneumonia, septicemia and soft tissue infections.

Cytovan is also used to associated treatment for these conditions: Clostridium Difficile-Associated Diarrhea (CDAD), Enterocolitis caused by Staphylococcus aureus, Infection caused by staphylococci, Severe Staphylococcal infection

How Cytovan works

The bactericidal action of vancomycin results primarily from inhibition of cell-wall biosynthesis. Specifically, vancomycin prevents incorporation of N-acetylmuramic acid (NAM)- and N-acetylglucosamine (NAG)-peptide subunits from being incorporated into the peptidoglycan matrix, which forms the major structural component of Gram-positive cell walls. Cytovan forms hydrogen bonds with the terminal D-alanyl-D-alanine moieties of the NAM/NAG-peptides, preventing the incorporation of the NAM/NAG-peptide subunits into the peptidoglycan matrix. In addition, vancomycin alters bacterial-cell-membrane permeability and RNA synthesis. There is no cross-resistance between vancomycin and other antibiotics. Cytovan is not active in vitro against gram-negative bacilli, mycobacteria, or fungi.

Dosage

Cytovan dosage

Concentrations of no more than 5 mg/ml and rates of no more than 10 mg/min are recommended in adults. In selected patients in need of fluid restriction, a concentration up to 10 mg/ml may be used.Patients with Normal Renal Function:

• Adults: Usual daily dose is 2 gm (in 4 or 2 divided doses).
• Children: Total daily dose is 40 mg/Kg (in 4 divided doses).
• Infants and Neonates: An initial dose of 15 mg/Kg is suggested followed by 10 mg/Kg every 12 hours in the first week, then every 8 hours up to 1 month.

Patients with Impaired Renal Function and Elderly Patients: Dosage adjustment must be made in patients with impaired renal function. In premature infants and the elderly, dosage reduction may be necessary to a greater extent than expected because of decreasing renal function. If creatinine clearance can be measured or estimated accurately, the dosage for most patients with renal impairment can be calculated using the following chart-

• CrCl 100 ml/min: Cytovan Dose 1545 mg/24 h
• CrCl 90 ml/min:Cytovan Dose 1390 mg/24 h
• CrCl 80 ml/min:Cytovan Dose1235 mg/24 h
• CrCl 70 ml/min:Cytovan Dose1080 mg/24 h
• CrCl 60 ml/min:Cytovan Dose925 mg/24 h
• CrCl 50 ml/min:Cytovan Dose770 mg/24 h
• CrCl 40 ml/min:Cytovan Dose620 mg/24 h
• CrCl 30 ml/min:Cytovan Dose465 mg/24 h
• CrCl 20 ml/min:Cytovan Dose310 mg/24 h
• CrCl 10 ml/min:Cytovan Dose 155 mg/24 h

The initial dose should be not less than 15 mg/kg even in patients with mild to moderate renal insufficiency. Above chart is not valid for functionally anephric patients. For such patients, an initial dose of 15 mg/kg of body weight should be given in order to achieve prompt therapeutic serum concentrations. The dose required to maintain stable concentrations is 1.9 mg/kg/24 h. Since individual maintenance doses of 250-1,000 mg are convenient, 1 dose may be given every several days rather than on a daily basis in patients with marked renal impairment. In anuria, a dose of 1000 mg every 7-10 days has been recommended. Intermittent infusion is the recommended method of administration. Intraperitoneal administration is not recommended.

Side Effects

Cytovan is well tolerated. However during or soon after rapid infusion of Cytovan, patients may develop anaphylactic reactions including hypotension, wheezing, dyspnoea, urticaria or pruritus. Rapid infusion may also cause flushing of the upper body ("red neck") or pain and muscle spasm of the chest and back. These reactions usually resolve within 20 minutes but may persist for several hours. Such events are infrequent if Cytovan is given by a slow infusion over 60 minutes.

Toxicity

The oral LD₅₀ in mice is 5000 mg/kg. The median lethal intravenous dose is 319 mg/kg in rats and 400 mg/kg in mice.

Conversely, the most common adverse effects associated with vancomycin appear to be nausea, abdominal pain, and hypokalemia . In particular, incidences of hypokalemia, urinary tracy infection, peripheral edema, insomnia, constipation, anemia, depression, vomiting, and hypotension are higher among subjects >65 years of than in those that are 65 years old or younger .

Additionally, nephrotoxicity involving reports of renal failure, renal impairment, elevated blood creatinine, and others has also occurred with vancomycin therapy during studies, and can occur during or after completion of a course of therapy . Risk of such nephrotoxicity is increased in patients greater than 65 years of age .

Ototoxicity has also occurred in patients receiving vancomycin treatment, and it can be transient or permanent. This effect has been reported primarily in patients who have been given excessive intravenous doses, who have kidney dysfunction, who have an underlying hearing loss, or who are receiving concomitant therapy with another ototoxic agent like an aminoglycoside . Potentially related adverse effects like vertigo, dizziness, and tinnitus have also been reported .

Neutropenia, often beginning one week or more after onset of intravenous vancomycin therapy or after a total dose of more than 25 mg has been observed for several dozen patients as well. This neutropenia however, appears to be promptly reversible when the vancomycin treatment is discontinued. Alternatively, thrombocytopenia has also been reported .

Additionally, a condition has been reported that is described as being similar to IV-induced symptoms involving symptoms consistent with anaphylactoid reactions, including hypotension, wheezing, dyspnea, urticaria, pruritus, flushing of the upper body (in what is known as the so-called 'Red Man Syndrome'), pain and muscle spasm of the chest and back. Although on average such reactions usually resolve within 20 minutes, they are just as likely to persist for hours .

In a controlled clinical study, the potential ototoxic and nephrotoxic effects of vancomycin on infants were assessed when the drug was given intravenously to pregnant women for serious staphylococcal infections complicating intravenous drug abuse. The results obtained demonstrated that vancomycin was found in cord blood but that no sensorineural hearing loss or nephrotoxicity attributable to vancomycin was noted. Ultimately however, because the number of subjects treated in this study was limited and vancomycin was administered only in the second and third trimesters, it is not formally known whether vancomycin causes fetal harm. Subsequently, vancomycin should be given to a pregnant woman only if clearly needed .

Although it is known that vancomycin is excreted in human milk based on information obtained from the intravenous administration of the medication, it is not known if vancomycin is excreted into human milk after oral administration. However, because of the overall potential for adverse events, caution must be exercised when vancomycin is given to a nursing woman and a decision must be made whether to discontinue nursing or discontinue the drug, taking into consideration the importance of the drug to the mother .

The safety and effectiveness in pediatric patients have not been formally established .

Patients older than 65 years of age may take longer to respond to therapy compared to patients aged 65 year or younger. Cytovan treatment in patients aged older than 65 years subsequently should not be discontinued or switched to an alternative treatment prematurely .

Furthermore, clinical studies have demonstrated that geriatric patients are at increased risk of developing nephrotoxicity following treatment with oral vancomycin, which can occur during or after completion of therapy. In patients aged older than 65 years, including those with normal renal function prior to treatment, renal function should be monitored during and following treatment with vancomycin to detect any potential vancomycin induced nephrotoxicity .

Precaution

Patients with borderline renal function and individuals over the age of 60 should be given serial tests of auditory function and of Cytovan blood levels. All patients receiving the drug should have periodic haematological studies, urine analysis and renal function tests. Cytovan is very irritating to tissue and causes injection site necrosis when injected intramuscularly. It must be infused intravenously. Injection site pain and thrombophlebitis occur in many patients receiving Cytovan and are occasionally severe.Prolonged use of Cytovan may result in the overgrowth of non-susceptible organisms. Careful observation of the patient is essential. If superinfection occurs during therapy, appropriate measures should be taken. In rare instances, there have been reports of pseudomembranous colitis due to C. difficile, developing in patients who received intravenous Cytovan.

Food Interaction

• Take with or without food.

Cytovan Drug Interaction

Moderate: sulfamethoxazole / trimethoprim, furosemideUnknown: diphenhydramine, duloxetine, metronidazole, insulin glargine, atorvastatin, enoxaparin, pregabalin, acetaminophen / hydrocodone, sodium chloride, acetaminophen, clopidogrel, pantoprazole, acetaminophen, cyanocobalamin, ascorbic acid, cholecalciferol, alprazolam, ondansetron

Cytovan Disease Interaction

Major: colitis, ototoxicity, renal dysfunctionModerate: neutropenia, GI inflammation

Volume of Distribution

The volume of distribution, as discussed in the literature, varies between 0.4-1 L/kg .

Elimination Route

Poorly absorbed from gastrointestinal tract, however systemic absorption (up to 60%) may occur following intraperitoneal administration .

Half Life

Half-life in normal renal patients is approximately 6 hours (range 4 to 11 hours). In anephric patients, the average half-life of elimination is 7.5 days .

Clearance

The mean plasma clearance of vancomycin is about 0.058 L/kg/h .

Elimination Route

In the first 24 hours, about 75-80% of an administered dose of vancomycin is excreted in urine by glomerular filtration .

Pregnancy & Breastfeeding use

It is not known whether it causes foetal harm or not. Cytovan should be given in pregnancy only if clearly needed and blood levels should be monitored carefully to minimise the risk of foetal toxicity.Cytovan Hydrochloride is excreted in human milk. Caution should be exercised when Cytovan is administered to a nursing woman. It is unlikely that a nursing infant can absorb a significant amount of Cytovan from its gastro-intestinal tract

Contraindication

Cytovan is contraindicated in Patients with known hypersensitivity to Cytovan

Acute Overdose

Supportive care is advised with maintenance of glomerular filtration. Cytovan is poorly removed from the blood by haemodialysis or peritoneal dialysis. Haemoperfusion with Amberlite resin XAD-4 has been reported to be of limited benefit

Innovators Monograph

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