vancomycin 1500 MG Injection

INDICATIONS AND USAGE Vancomycin Hydrochloride for Injection is a glycopeptide antibacterial indicated in adult and pediatric patients less than 18 years of age as follows: Vancomycin Hydrochloride for Injection administered intravenously is indicated for the treatment of: o Septicemia ( 1.1 ) o Infective Endocarditis ( 1.2 ) o Skin and Skin Structure Infections ( 1.3 ) o Bone Infections ( 1.4 ) o Lower Respiratory Tract Infections ( 1.5 ) Vancomycin Hydrochloride for Injection administered orally is indicated for the treatment of: o Clostridioides difficile -associated diarrhea ( 1.6 ) o Enterocolitis caused by Staphylococcus aureus (including methicillin-resistant strains) ( 1.7 ) Limitations of Use ( 1.8 ) Vancomycin Hydrochloride for Injection administered intravenously is not approved for the treatment of C. difficile -associated diarrhea and enterocolitis caused by susceptible isolates of Staphylococcus aureus because it is not effective. Vancomycin Hydrochloride for Injection administered orally is not approved for the treatment of septicemia, infective endocarditis, skin and skin structure infections, bone infections and lower respiratory tract infections because it is not effective. To reduce the development of drug-resistant bacteria and maintain the effectiveness of Vancomycin Hydrochloride for Injection and other antibacterial drugs, Vancomycin Hydrochloride for Injection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. ( 1.9 ) 1.1 Septicemia Vancomycin Hydrochloride for Injection administered intravenously is indicated in adults and pediatric patients less than 18 years of age for the treatment of septicemia due to: Susceptible isolates of methicillin-resistant Staphylococcus aureus (MRSA) and coagulase negative staphylococci. Methicillin-susceptible staphylococci in penicillin-allergic patients, or those patients who cannot receive or who have failed to respond to other drugs, including penicillins or cephalosporins. 1.2 Infective Endocarditis Vancomycin Hydrochloride for Injection administered intravenously is indicated in adults and pediatric patients less than 18 years of age for the treatment of infective endocarditis due to: Susceptible isolates of MRSA. Viridans group streptococci Streptococcus gallolyticus (previously known as Streptococcus bovis ), Enterococcus species and Corynebacterium species. For enterococcal endocarditis, use Vancomycin Hydrochloride for Injection in combination with an aminoglycoside. Methicillin-susceptible staphylococci in penicillin-allergic patients, or those patients who cannot receive or who have failed to respond to other drugs, including penicillins or cephalosporins. Vancomycin Hydrochloride for Injection administered intravenously is indicated in adults and pediatric patients less than 18 years of age for the treatment of early-onset prosthetic valve endocarditis caused by Staphylococcus epidermidis in combination with rifampin and an aminoglycoside. 1.3 Skin and Skin Structure Infections Vancomycin Hydrochloride for Injection administered intravenously is indicated in adults and pediatric patients less than 18 years of age for the treatment of skin and skin structure infections due to: Susceptible isolates of MRSA and coagulase negative staphylococci. Methicillin-susceptible staphylococci in penicillin-allergic patients, or those patients who cannot receive or who have failed to respond to other drugs, including penicillins or cephalosporins. 1.4 Bone Infections Vancomycin Hydrochloride for Injection administered intravenously is indicated in adults and pediatric patients less than 18 years of age for the treatment of bone infections due to: Susceptible isolates of MRSA and coagulase negative staphylococci. Methicillin-susceptible staphylococci in penicillin-allergic patients, or those patients who cannot receive or who have failed to respond to other drugs, including penicillins or cephalosporins. 1.5 Lower Respiratory Tract Infections Vancomycin Hydrochloride for Injection administered intravenously is indicated in adults and pediatric patients less than 18 years of age for the treatment of lower respiratory tract infections due to: Susceptible isolates of MRSA Methicillin-susceptible staphylococci in penicillin-allergic patients, or those patients who cannot receive or who have failed to respond to other drugs, including penicillins or cephalosporins. 1.6 Clostridioides difficile -Associated Diarrhea Vancomycin Hydrochloride for Injection administered orally is indicated for the treatment of C. difficile -associated diarrhea (CDAD) in adult and pediatric patients less than 18 years of age. 1.7 Enterocolitis Caused by S. aureus (including methicillin-resistant strains) Vancomycin Hydrochloride for Injection administered orally is indicated for the treatment of enterocolitis caused by susceptible isolates of Staphylococcus aureus in adults and pediatric patients less than 18 years of age. 1.8 Limitations of Use Vancomycin Hydrochloride for Injection administered intravenously is not approved for the treatment of the following conditions because it is not effective: C. difficile -Associated Diarrhea Enterocolitis caused by susceptible isolates of Staphylococcus aureus Vancomycin Hydrochloride for Injection administered orally is not approved for the treatment of the following conditions because it is not effective: Septicemia due to susceptible isolates of MRSA or methicillin-susceptible staphylococci Infective endocarditis due to susceptible isolates of MRSA, methicillin susceptible staphylococci, Viridans group streptococci Streptococcus gallolyticus , Enterococcus species and Corynebacterium species, or for the treatment of early-onset prosthetic valve endocarditis caused by Staphylococcus epidermidis in combination with rifampin and an aminoglycoside Skin and skin structure infections due to susceptible isolates of MRSA and methicillin susceptible staphylococci Bone infections due to susceptible isolates of MRSA and lower respiratory tract infections due to susceptible isolates of MRSA and methicillin susceptible staphylococci 1.9 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of Vancomycin Hydrochloride for Injection and other antibacterial drugs, Vancomycin Hydrochloride for Injection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

DOSAGE AND ADMINISTRATION Infusion-related events are related to both the concentration and the rate of administration of vancomycin. Concentrations of no more than 5 mg/mL and rates of no more than 10 mg/min, are recommended in adults (see also age-specific recommendations). In selected patients in need of fluid restriction, a concentration up to 10 mg/mL may be used; use of such higher concentrations may increase the risk of infusion-related events. An infusion rate of 10 mg/min or less is associated with fewer infusion-related events (see ADVERSE REACTIONS ). Infusion-related events may occur, however, at any rate or concentration. Patients with Normal Renal Function Adults The usual daily intravenous dose is 2 g divided either as 500 mg every 6 hours or 1 g every 12 hours. Each dose should be administered at no more than 10 mg/min or over a period of at least 60 minutes, whichever is longer. Other patient factors, such as age or obesity, may call for modification of the usual intravenous daily dose. Pediatric patients The usual intravenous dosage of vancomycin is 10 mg/kg per dose given every 6 hours. Each dose should be administered over a period of at least 60 minutes. Close monitoring of serum concentrations of vancomycin may be warranted in these patients. Neonates In pediatric patients up to the age of 1 month, the total daily intravenous dosage may be lower. In neonates, an initial dose of 15 mg/kg is suggested, followed by 10 mg/kg every 12 hours for neonates in the 1st week of life and every 8 hours thereafter up to the age of 1 month. Each dose should be administered over 60 minutes. In premature infants, vancomycin clearance decreases as postconceptional age decreases. Therefore, longer dosing intervals may be necessary in premature infants. Close monitoring of serum concentrations of vancomycin is recommended in these patients. 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, greater dosage reductions than expected may be necessary because of decreased renal function. Measurement of vancomycin serum concentrations can be helpful in optimizing therapy, especially in seriously ill patients with changing renal function. Vancomycin serum concentrations can be determined by use of microbiologic assay, radioimmunoassay, fluorescence polarization immunoassay, fluorescence immunoassay, or high-pressure liquid chromatography. If creatinine clearance can be measured or estimated accurately, the dosage for most patients with renal impairment can be calculated using the following table. The dosage of vancomycin hydrochloride for injection per day in mg is about 15 times the glomerular filtration rate in mL/min (see following table). DOSAGE TABLE FOR VANCOMYCIN IN PATIENTS WITH IMPAIRED RENAL FUNCTION (Adapted from Moellering et al. 1 ) Creatinine Clearance mL/min Vancomycin Dose mg/24 h 100 1,545 90 1,390 80 1,235 70 1,080 60 925 50 770 40 620 30 465 20 310 10 155 The initial dose should be no less than 15 mg/kg, even in patients with mild to moderate renal insufficiency. The table is not valid for functionally anephric patients. For such patients, an initial dose of 15 mg/kg of body weight should be given to achieve prompt therapeutic serum concentrations. The dose required to maintain stable concentrations is 1.9 mg/kg/24 hr. In patients with marked renal impairment, it may be more convenient to give maintenance doses of 250 to 1,000 mg once every several days rather than administering the drug on a daily basis. In anuria, a dose of 1,000 mg every 7 to 10 days has been recommended. When only serum creatinine is known, the following formula (based on sex, weight and age of the patient) may be used to calculate creatinine clearance. Calculated creatinine clearances (mL/min) are only estimates. The creatinine clearance should be measured promptly. Men: [Weight (kg) x (140 – age in years)] 72 x serum creatinine concentration (mg/dL) Women: 0.85 x above value The serum creatinine must represent a steady state of renal function. Otherwise, the estimated value for creatinine clearance is not valid. Such a calculated clearance is an overestimate of actual clearance in patients with conditions: (1) characterized by decreasing renal function, such as shock, severe heart failure, or oliguria; (2) in which a normal relationship between muscle mass and total body weight is not present, such as in obese patients or those with liver disease, edema, or ascites; and (3) accompanied by debilitation, malnutrition, or inactivity. The safety and efficacy of vancomycin administration by the intrathecal (intralumbar or intraventricular) routes have not been established. Intermittent infusion is the recommended method of administration. Compatibility with Other Drugs and IV Fluids The following diluents are physically and chemically compatible (with 4 g/L vancomycin hydrochloride): 5% Dextrose Injection, USP 5% Dextrose Injection and 0.9% Sodium Chloride Injection, USP Lactated Ringer’s Injection, USP 5% Dextrose and Lactated Ringer’s Injection Normosol ® -M and 5% Dextrose 0.9% Sodium Chloride Injection, USP Isolyte ® E Good professional practice suggests that compounded admixtures should be administered as soon after preparation as is feasible. Vancomycin solution has a low pH and may cause physical instability of other compounds. Preparation and Stability At the time of use, reconstitute the vials of Vancomycin Hydrochloride for Injection, USP with Sterile Water for Injection to a concentration of 50 mg of vancomycin/mL (see following table for volume of diluent). Concentration/Vial Volume of Diluent 500 mg 10 mL 1 gram 20 mL After reconstitution, the vials may be stored in a refrigerator for 14 days without significant loss of potency. Reconstituted solutions of vancomycin (500 mg/10 mL) must be further diluted in at least 100 mL of a suitable infusion solution. For doses of 1 gram (20 mL), at least 200 mL of solution must be used. The desired dose diluted in this manner should be administered by intermittent IV infusion over a period of at least 60 minutes. Compatibility with Intravenous Fluids Solutions that are diluted with 5% Dextrose Injection or 0.9% Sodium Chloride Injection may be stored in a refrigerator for 14 days without significant loss of potency. Solutions that are diluted with the following infusion fluids may be stored in a refrigerator for 96 hours: 5% Dextrose Injection and 0.9% Sodium Chloride Injection USP Lactated Ringer’s Injection USP Lactated Ringer’s and 5% Dextrose Injection USP Normosol ® -M and 5% Dextrose Isolyte ® E Acetated Ringer’s Injection Vancomycin solution has a low pH and may cause chemical or physical instability when it is mixed with other compounds. Mixtures of solutions of vancomycin and beta-lactam antibiotics have been shown to be physically incompatible. The likelihood of precipitation increases with higher concentrations of vancomycin. It is recommended to adequately flush the intravenous lines between the administration of these antibiotics. It is also recommended to dilute solutions of vancomycin to 5 mg/mL or less. Although intravitreal injection is not an approved route of administration for vancomycin, precipitation has been reported after intravitreal injection of vancomycin and ceftazidime for endophthalmitis using different syringes and needles. The precipitates dissolved gradually, with complete clearing of the vitreous cavity over two months and with improvement of visual acuity. Parenteral drug products should be visually inspected for particulate matter and discoloration prior to administration, whenever solution and container permit. For Oral Administration Oral vancomycin is used in treating antibiotic-associated pseudomembranous colitis caused by C. difficile and for staphylococcal enterocolitis. Vancomycin is not effective by the oral route for other types of infections. The usual a

WARNINGS AND PRECAUTIONS • Infusion Reactions: Hypotension, including shock and cardiac arrest, wheezing, dyspnea, urticaria, muscular, chest pain and “vancomycin infusion reaction” which manifests as pruritus and erythema that involves the face, neck and upper torso may occur with rapid intravenous administration. To reduce the risk of infusion reactions, administer Vancomycin Hydrochloride for Injection in a diluted solution over a period of 60 minutes or greater and also prior to intravenous anesthetic agents. ( 2.1 , 5.1 ) • Nephrotoxicity: Systemic vancomycin exposure may result in acute kidney injury (AKI) including acute renal failure, mainly due to interstitial nephritis or less commonly acute tubular necrosis. Monitor serum vancomycin concentrations and renal function. ( 5.2 ) • Ototoxicity: Ototoxicity has occurred in patients receiving vancomycin hydrochloride. Monitor for signs and symptoms of ototoxicity during therapy. Monitor serum vancomycin concentrations and renal function. Assessment of auditory function may be appropriate in some instances. ( 5.3 ) • Severe Dermatologic Reactions: Discontinue Vancomycin Hydrochloride for Injection at the first appearance of skin rashes, mucosal lesions, or blisters ( 5.4 ). • Clostridioides difficile -Associated Diarrhea: Evaluate patients if diarrhea occurs. ( 5.5 ) • Neutropenia: Periodically monitor leukocyte count. ( 5.7 ) • Phlebitis: To reduce the risk of local irritation and phlebitis administer Vancomycin Hydrochloride for Injection by a secure intravenous route of administration. ( 5.8 ) • Development of Drug-Resistant Bacteria: Prescribing Vancomycin Hydrochloride for Injection in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug resistant bacteria. ( 5.9 ) 5.1 Infusion Reactions Hypotension, including shock and cardiac arrest, wheezing, dyspnea, urticaria, muscular and chest pain may occur with rapid Vancomycin Hydrochloride for Injection administration. The reactions may be more severe in younger patients, particularly children, and in patients receiving concomitant muscle relaxant anesthetics. Rapid intravenous administration of Vancomycin Hydrochloride for Injection may also be associated with “vancomycin infusion reaction”, which manifests as pruritus and erythema that involves the face, neck and upper torso. Infusion-related adverse reactions are related to both the concentration and the rate of administration of vancomycin. Infusion-related adverse reactions may occur, however, at any rate or concentration. Administer Vancomycin Hydrochloride for Injection in a diluted solution over a period of 60 minutes or greater to reduce the risk of infusion-related adverse reactions. In selected patients in need of fluid restriction, a concentration up to 10 mg/mL may be used; use of such higher concentrations may increase the risk of infusion-related adverse reactions. Administer prior to intravenous anesthetic agents when feasible. Stop the infusion if a reaction occurs. 5.2 Nephrotoxicity Vancomycin Hydrochloride for Injection can result in acute kidney injury (AKI), including acute renal failure, mainly due to interstitial nephritis or less commonly acute tubular necrosis. AKI is manifested by increasing blood urea nitrogen (BUN) and serum creatinine (Cr). The risk of AKI increases with higher vancomycin serum levels, prolonged exposure, concomitant administration of other nephrotoxic drugs, concomitant administration of piperacillin-tazobactam [see Drug Interactions (7.2)] , volume depletion, pre-existing renal impairment and in critically ill patients and patients with co-morbid conditions that predispose to renal impairment. Monitor serum vancomycin concentrations and renal function in all patients receiving Vancomycin Hydrochloride for Injection. More frequent monitoring is recommended in patients with comorbidities that predispose to impairment in renal function or are concomitantly receiving other nephrotoxic drugs, in critically ill patients, in patients with changing renal function, and in patients requiring higher therapeutic vancomycin levels. If acute kidney injury occurs, discontinue Vancomycin Hydrochloride for Injection or reduce the dose. 5.3 Ototoxicity Ototoxicity has occurred in patients receiving Vancomycin Hydrochloride for Injection. It may be transient or permanent. Ototoxicity manifests as tinnitus, hearing loss, dizziness or vertigo. The risk is higher in older patients, patients who are receiving higher doses, who have an underlying hearing loss, who are receiving concomitant therapy with another ototoxic agent, such as an aminoglycoside or who have underlying renal impairment. Monitor for signs and symptoms of ototoxicity during therapy. Monitor serum vancomycin concentrations and renal function in all patients receiving parenteral vancomycin. Discontinue Vancomycin Hydrochloride for Injection if ototoxicity occurs. Dosage of Vancomycin Hydrochloride for Injection must be adjusted for patients with renal impairment [see Dosage and Administration ( 2.3 )] . Serial tests of auditory function may be helpful in order to minimize the risk of ototoxicity. 5.4 Severe Dermatologic Reactions Severe dermatologic reactions such as toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), and linear IgA bullous dermatosis (LABD) have been reported in association with the use of vancomycin. Cutaneous signs or symptoms reported include skin rashes, mucosal lesions, and blisters. Discontinue Vancomycin Hydrochloride for Injection at the first appearance of signs and symptoms of TEN, SJS, DRESS, AGEP, or LABD. 5.5 Clostridioides difficile -Associated Diarrhea Clostridioides difficile -associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Vancomycin Hydrochloride for Injection, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile , and surgical evaluation should be instituted as clinically indicated. Clinically significant serum concentrations have been reported in some patients being treated for active C. difficile -induced pseudomembranous colitis after multiple oral doses of vancomycin. Prolonged use of Vancomycin Hydrochloride for Injection may result in the overgrowth of nonsusceptible microorganisms. 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 Vancomycin Hydrochloride for Injection. 5.6 Hemorrhagic Occlusive Retinal Vasculitis (HORV) Hemorrhagic occlusive retinal vasculitis, including permanent loss of vision, occurred in patients receiving intracameral or intravitreal administration of vancomycin during or after cataract surgery. The safety and efficacy of vancomycin administered by the intracameral or the intravitreal route have not been est

CONTRAINDICATIONS • Vancomycin Injection is contraindicated in patients with known hypersensitivity to vancomycin. • Solutions containing dextrose including Vancomycin Injection, may be contraindicated in patients with a known allergy to corn or corn products. Hypersensitivity to vancomycin ( 4 )

CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Vancomycin is an antibacterial drug [see Microbiology (12.4)]. 12.2 Pharmacodynamics The pharmacodynamics of vancomycin is unknown. 12.3 Pharmacokinetics In subjects with normal kidney function, multiple intravenous dosing of 1 g of vancomycin (15 mg/kg) infused over 60 minutes produces mean plasma concentrations of approximately 63 mcg/mL immediately after the completion of infusion, mean plasma concentrations of approximately 23 mcg/mL 2 hours after infusion, and mean plasma concentrations of approximately 8 mcg/mL 11 hours after the end of the infusion. Multiple dosing of 500 mg infused over 30 minutes produces mean plasma concentrations of about 49 mcg/mL at the completion of infusion, mean plasma concentrations of about 19 mcg/mL 2 hours after infusion, and mean plasma concentrations of about 10 mcg/mL 6 hours after infusion. The plasma concentrations during multiple dosing are like those after a single dose. Distribution The volume of distribution ranges from 0.3 to 0.43 L/kg after intravenous administration. Vancomycin is approximately 55% serum protein bound as measured by ultrafiltration at vancomycin serum concentrations of 10 to 100 mcg/mL. After intravenous administration of vancomycin, inhibitory concentrations are present in pleural, pericardial, ascitic, and synovial fluids; in urine; in peritoneal dialysis fluid; and in atrial appendage tissue. Vancomycin does not readily diffuse across normal meninges into the spinal fluid; but, when the meninges are inflamed, penetration into the spinal fluid occurs. Elimination Mean plasma clearance is about 0.058 L/kg/h, and mean renal clearance is about 0.048 L/kg/h. The mean elimination half-life of vancomycin from plasma is 4 to 6 hours in subjects with normal renal function. In anephric patients, the mean elimination half-life is 7.5 days. Total body and renal clearance of vancomycin may be reduced in the elderly. Metabolism There is no apparent metabolism of the vancomycin. Excretion In the first 24 hours after intravenous administration, about 75% of an administered dose of vancomycin is excreted in urine by glomerular filtration. Renal impairment slows excretion of vancomycin. About 60% of an intraperitoneal dose of vancomycin administered during peritoneal dialysis is absorbed systemically in 6 hours. Serum concentrations of about 10 mcg/mL are achieved by intraperitoneal injection of 30 mg/kg of vancomycin. However, the safety and efficacy of the intraperitoneal use of vancomycin has not been established in adequate and well-controlled trials [see Warnings and Precautions (5.7)]. 12.4 Microbiology Mechanism of Action The bactericidal action of vancomycin results primarily from inhibition of cell-wall biosynthesis. In addition, vancomycin alters bacterial-cell-membrane permeability and RNA synthesis. Resistance Vancomycin is not active in vitro against gram-negative bacilli, mycobacteria, or fungi. There is no cross-resistance between vancomycin and other antibacterials. Interaction with Other Antimicrobials The combination of vancomycin and an aminoglycoside acts synergistically in vitro against many isolates of Staphylococcus aureus, Streptococcus gallolyticus (previously known as Streptococcus bovis ), enterococcus spp, and the viridans group streptococci. Antimicrobial Activity Vancomycin has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections [see Indications and Usage (1)]. Aerobic Gram-Positive Bacteria Corynebacterium spp. Enterococcus spp. (including Enterococcus faecalis ) Staphylococcus aureus (including methicillin-resistant and methicillin-susceptible isolates) Coagulase negative staphylococci (including S. epidermidis and methicillin-resistant isolates) Streptococcus gallolyticus (previously known as Streptococcus bovis ) Viridans group streptococci The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for vancomycin against isolates of similar genus or organism group. However, the efficacy of vancomycin in treating clinical infections caused by these bacteria has not been established in adequate and well-controlled clinical trials. Aerobic Gram-Positive Bacteria Listeria monocytogenes Streptococcus pyogenes Streptococcus pneumoniae Streptococcus agalactiae Anaerobic Gram-Positive Bacteria Actinomyces species Lactobacillus species Susceptibility Testing For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC. 12.1 Mechanism of Action Vancomycin is an antibacterial drug [see Microbiology (12.4)]. 12.2 Pharmacodynamics The pharmacodynamics of vancomycin is unknown. 12.3 Pharmacokinetics In subjects with normal kidney function, multiple intravenous dosing of 1 g of vancomycin (15 mg/kg) infused over 60 minutes produces mean plasma concentrations of approximately 63 mcg/mL immediately after the completion of infusion, mean plasma concentrations of approximately 23 mcg/mL 2 hours after infusion, and mean plasma concentrations of approximately 8 mcg/mL 11 hours after the end of the infusion. Multiple dosing of 500 mg infused over 30 minutes produces mean plasma concentrations of about 49 mcg/mL at the completion of infusion, mean plasma concentrations of about 19 mcg/mL 2 hours after infusion, and mean plasma concentrations of about 10 mcg/mL 6 hours after infusion. The plasma concentrations during multiple dosing are like those after a single dose. Distribution The volume of distribution ranges from 0.3 to 0.43 L/kg after intravenous administration. Vancomycin is approximately 55% serum protein bound as measured by ultrafiltration at vancomycin serum concentrations of 10 to 100 mcg/mL. After intravenous administration of vancomycin, inhibitory concentrations are present in pleural, pericardial, ascitic, and synovial fluids; in urine; in peritoneal dialysis fluid; and in atrial appendage tissue. Vancomycin does not readily diffuse across normal meninges into the spinal fluid; but, when the meninges are inflamed, penetration into the spinal fluid occurs. Elimination Mean plasma clearance is about 0.058 L/kg/h, and mean renal clearance is about 0.048 L/kg/h. The mean elimination half-life of vancomycin from plasma is 4 to 6 hours in subjects with normal renal function. In anephric patients, the mean elimination half-life is 7.5 days. Total body and renal clearance of vancomycin may be reduced in the elderly. Metabolism There is no apparent metabolism of the vancomycin. Excretion In the first 24 hours after intravenous administration, about 75% of an administered dose of vancomycin is excreted in urine by glomerular filtration. Renal impairment slows excretion of vancomycin. About 60% of an intraperitoneal dose of vancomycin administered during peritoneal dialysis is absorbed systemically in 6 hours. Serum concentrations of about 10 mcg/mL are achieved by intraperitoneal injection of 30 mg/kg of vancomycin. However, the safety and efficacy of the intraperitoneal use of vancomycin has not been established in adequate and well-controlled trials [see Warnings and Precautions (5.7)]. 12.4 Microbiology Mechanism of Action The bactericidal action of vancomycin results primarily from inhibition of cell-wall biosynthesis. In addition, vancomycin alters bacterial-cell-membrane permeability and RNA synthesis. Resistance Vancomycin is not active in vitro against gram-negative bacilli, mycobacteria, or fungi. There is no cross-resistance between vancomycin and other antibacterials. Interaction with Other Antimicrobials The combination of vancomycin and an aminoglycoside acts synergistically in vitro against many isolates of Staphylococcus aureus, Strep