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vancomycin hcl 250 mg capsule

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Uses

IV vancomycin hydrochloride is used in the treatment of potentially life-threatening infections caused by susceptible bacteria when other less toxic anti-infectives cannot be used or would be ineffective. Vancomycin is used principally for the treatment of severe infections caused by gram-positive bacteria in patients who cannot receive or who have failed to respond to penicillins and cephalosporins or for the treatment of gram-positive bacterial infections that are resistant to β-lactams and other anti-infectives.

Drug Use Guidelines for the Prevention of Vancomycin Resistance

Use of, and exposure to, anti-infectives are major risk factors for the emergence of anti-infective-resistant pathogens, and anti-infective resistance results in increased morbidity, mortality, and healthcare costs. Prevention of the emergence of drug resistance, its dissemination among pathogens, and the spread of such pathogens has become an increasingly important public health problem. Medical, pharmacy, and other staff and individuals responsible for drug-use policy and formulary decisions should review and restrict the use of certain anti-infectives, including vancomycin, and ensure that their use is appropriate. Clinicians should recognize that unnecessary and inappropriate use of anti-infectives has important, far-reaching implications for human health globally.

Because of the rapidly increasing prevalence of vancomycin-resistant enterococci in the US and concerns regarding the possibility of vancomycin-resistant strains of other gram-positive bacteria (e.g., Staphylococcus aureus) (see Resistance), a subcommittee of the US Centers for Disease Control and Prevention (CDC) Hospital Infection Control Practices Advisory Committee and others have made recommendations designed to prevent the spread of vancomycin resistance. The CDC recommends that hospitals in collaboration with quality improvement and infection control programs, pharmacy and therapeutics committees, and clinical, microbiology, nursing, administrative, and housekeeping departments develop comprehensive, institution-specific strategic plans for the detection, prevention, and control of infection and colonization with vancomycin-resistant enterococci and other bacterial pathogens. Since vancomycin use has consistently been reported to be a risk factor for colonization and infection with vancomycin-resistant enterococci, these strategic plans should include recommendations for the prudent use of vancomycin. In addition, all hospitals and other health-care delivery services (even those that have not had reports of vancomycin-resistant enterococci) should develop a comprehensive antimicrobial-utilization plan to provide education for their medical staff and medical students, oversee surgical prophylaxis, and develop guidelines for the appropriate use of vancomycin as applicable to their particular institution. Continuing education programs for hospital staff (e.g., attending and consulting physicians, medical students and residents, personnel in pharmacy, nursing, and laboratory departments) should include information on the epidemiology of vancomycin-resistant enterococci and the potential impact on cost and outcome of patient care. Enterococcal isolates obtained from blood, sterile body sites (with the possible exception of sterile urine), and other sites as clinically indicated should be evaluated for vancomycin resistance and high-level resistance to penicillin (or ampicillin) and aminoglycosides. If resources permit, laboratories may choose to routinely test wound and urine isolates for resistance to vancomycin, penicillin, and ampicillin.

Patients with vancomycin-resistant Enterococcus faecium (VREF) or staphylococcal infections that have not responded to appropriate anti-infective therapy or in whom vancomycin-resistant strains are suspected or documented may be candidates for treatment with linezolid (Zyvox) or the fixed combination of quinupristin and dalfopristin (Synercid). and in Linezolid may be active against vancomycin-resistant E. faecalis, but quinupristin and dalfopristin is not active against E. faecalis, and enterococcal species differentiation is important to avoid misidentification of this organism.

Based on recent reports of staphylococci, including oxacillin-resistant staphylococci, with reduced susceptibility to vancomycin and concerns about the possible appearance of staphylococci highly resistant to vancomycin,the CDC Hospital Infection Control Practices Advisory Committee also has issued interim guidelines designed to prevent and control the spread of infection caused by such strains. The interim guidelines include steps to decrease the likelihood of emergence of staphylococci with reduced susceptibility to vancomycin (e.g., limiting overuse and misuse of vancomycin), information on how to identify strains with reduced susceptibility to vancomycin (see Spectrum: In Vitro Susceptibility Testing), information on how to obtain an investigational antistaphylococcal anti-infective agent if use of such an agent is considered necessary (see Uses: Staphylococcal Infections), and information on infection control measures that should be used to prevent the spread of such strains within and between facilities and minimize the potential for the organism to become endemic.

The CDC recommends that vancomycin be reserved for use in the treatment of serious infections caused by gram-positive bacteria resistant to β-lactam anti-infectives; treatment of gram-positive bacterial infections in patients with severe hypersensitivity to β-lactam anti-infectives; prophylaxis in certain patients at high risk for bacterial endocarditis as recommended by the American Heart Association (AHA); treatment of antibiotic-associated pseudomembranous colitis that is severe or potentially life-threatening or that fails to respond to oral metronidazole; and for perioperative prophylaxis for major surgical procedures involving implantation of prosthetic materials or devices (e.g., cardiac and vascular procedures and total hip replacement) at institutions with a high rate of oxacillin-resistant (methicillin-resistant) S. aureus (ORSA; MRSA) or S. epidermidis. The CDC suggests that use of the drug in other situations be discouraged. Situation in which the use of vancomycin should be discouraged include: treatment of antibiotic-associated colitis when metronidazole would be effective; routine empiric therapy for febrile neutropenic patients, unless there is strong evidence that the infection is caused by gram-positive organisms (e.g., inflamed exit site of Hickman catheter) and the prevalence of ORSA in the hospital is substantial; continued use after results of in vitro tests indicate that an infection is not caused by gram-positive organisms resistant to β-lactam anti-infectives; selective decontamination of the GI tract; eradication of colonization with ORSA; routine prophylaxis in patients undergoing surgery, except in patients with life-threatening allergy to β-lactam anti-infectives; routine prophylaxis in patients undergoing continuous ambulatory peritoneal dialysis or hemodialysis; systemic or local (e.g., antibiotic lock) prophylaxis for infection or colonization of indwelling central or peripheral intravascular catheters; routine prophylaxis in very low birthweight neonates; use for topical application or irrigation; use for treatment of infections caused by gram-positive organisms susceptible to β-lactam anti-infectives; and use in response to a single blood culture positive for coagulase-negative staphylococci if other blood cultures drawn in the same time frame are negative (i.e., contamination of the blood culture with skin flora is likely).

Staphylococcal Infections

Although vancomycin hydrochloride is not effective by the oral route for the treatment of systemic infections, the drug is used orally for the treatment of enterocolitis caused by S. aureus (including oxacillin-resistant strains). Some clinicians consider vancomycin the drug of choice for staphylococcal enterocolitis because it does not affect the normal coliform bacteria present in the GI tract.

IV vancomycin has been used effective when used alone in the treatment of endocarditis, osteomyelitis, pneumonia, septicemia, and soft-tissue infections caused by S. aureus or S. epidermidis, including oxacillin-resistant strains.

IV vancomycin, alone or in conjunction with other anti-infectives, generally is considered the treatment of choice for infections caused by oxacillin-resistant staphylococci. Because oxacillin-resistant staphylococci are being reported with increasing frequency, initial therapy for suspected staphylococcal infections should include vancomycin if oxacillin-resistant strains are prevalent in the community or hospital. Patients with diabetes mellitus, peripheral vascular disease, or burn wounds appear to be at particularly high risk of acquiring oxacillin-resistant S. aureus or S. epidermidis has been reported frequently in patients with prosthetic valve endocarditis or infected CSF shunts and in granulocytopenic children with cancer. However, in a study of empiric therapy in a limited number of febrile, neutropenic cancer patients, addition of vancomycin to a regimen of ceftazidime and amikacin did not improve outcome and was associated with more frequent nephrotoxicity; it has been suggested that such vancomycin use generally be limited to patients with likely or documented gram-positive bacteremia or in institutions where gram-positive bacteremia (especially if caused by oxacillin-resistant staphylococci) is common. In addition, if empiric therapy initially includes vancomycin, it generally is recommended that the drug be discontinued 3-4 days later if a fulminant gram-positive infection is not confirmed.(See Uses: Empiric Therapy in Febrile Neutropenic Patients.)

Infections caused by oxacillin-resistant S. epidermidis generally are treated with vancomycin alone or vancomycin in conjunction with rifampin and/or an aminoglycoside. When ORSA is suspected in patients with bacteremia or sepsis, vancomycin (with or without gentamicin and/or rifampin) often is added to the empiric regimen. Vancomycin has been effective when given by instillation via the arteriovenous shunt for the treatment and prophylaxis of staphylococcal infections in hemodialysis patients. The drug also has been effective when given IV for the treatment of peritonitis caused by susceptible staphylococci or other gram-positive bacteria in peritoneal dialysis patients.

Vancomycin does not replace appropriate surgical measures when staphylococcal infections are localized and purulent.

IV vancomycin is considered the drug of choice for the treatment of endocarditis caused by oxacillin-resistant staphylococci. While a regimen of vancomycin administered alone is recommended for oxacillin-resistant staphylococcal endocarditis in patients with native cardiac valves, patients with a prosthetic valve or other prosthetic material should receive a combination regimen of IV vancomycin, oral or IV rifampin, and IV or IM gentamicin. Patients with endocarditis caused by oxacillin-susceptible staphylococci generally should receive a regimen that consists of a penicillinase-resistant penicillin (i.e., IV nafcillin or IV oxacillin) with or without IM or IV gentamicin; oral or IV rifampin is added if a prosthetic valve or other prosthetic material is present. Penicillin- allergic patients with oxacillin-susceptible staphylococcal endocarditis who have native cardiac valves usually can receive IV cefazolin with or without IM or IV gentamicin unless they have a history of immediate-type penicillin hypersensitivity; IV vancomycin usually is reserved for use as an alternative agent for the treatment of patients with a history of immediate-type hypersensitivity to penicillin. Patients with a prosthetic valve or other prosthetic materials who have staphylococcal endocarditis caused by oxacillin-susceptible strains should receive a regimen of a penicillinase-resistant penicillin (i.e., IV nafcillin or IV oxacillin) with oral or IV rifampin and IM or IV gentamicin; IV cefazolin or IV vancomycin should be substituted for the penicillin in those with penicillin hypersensitivity.

Because staphylococcal isolates with reduced susceptibility to vancomycin have recently been reported in patients who received the drug, staphylococci from patients who fail to respond to vancomycin therapy should be tested to determine if resistance to the drug has developed. Patients with staphylococcal infections that have not responded to appropriate anti-infective therapy may be candidates for treatment with quinupristin and dalfopristin (Synercid) if the causative organism is found to have reduced susceptibility to vancomycin.

Streptococcal Infections

While a regimen of IV penicillin G (with or without IM or IV gentamicin) or a regimen of IV or IM ceftriaxone usually is recommended for the treatment of endocarditis caused by viridans streptococci or S. bovis, IV vancomycin is the regimen of choice for patients with a history of immediate-type hypersensitivity to penicillin. For the treatment of enterococcal endocarditis, a regimen of either IV penicillin G or IV ampicillin with IM or IV gentamicin is preferred for most patients; however, a regimen of IV vancomycin with IM or IV gentamicin is considered the regimen of choice for the treatment of enterococcal endocarditis in patients with a history of immediate-type hypersensitivity to penicillins.

Vancomycin is used alone or in conjunction with a third generation cephalosporin (ceftriaxone, cefotaxime) with or without rifampin for the treatment of infections caused by Streptococcus pneumoniae that are highly resistant to penicillins. Highly penicillin-resistant S. pneumoniae also may have reduced susceptibility to third generation cephalosporins (e.g., cefotaxime, ceftriaxone). In areas where there have been reports of highly penicillin-resistantS. pneumoniae that also have reduced susceptibility to third generation cephalosporins, the CDC and many clinicians recommend use of vancomycin (with or without rifampin) in conjunction with a third generation cephalosporin (e.g., cefotaxime, ceftriaxone) for empiric treatment of severe, life-threatening infections (e.g., meningitis) pending results of in vitro susceptibility tests. Vancomycin should be discontinued if the causative organism is found to be susceptible to the cephalosporin. Vancomycin has been used in conjunction with rifampin for the treatment of pneumococcal meningitis in patients hypersensitive to penicillins. There is evidence that vancomycin used alone may not achieve effective CSF concentrations in some patients, and the drug should not be used alone for the treatment of pneumococcal meningitis. Although vancomycin has been administered intrathecally for the treatment of meningitis caused by susceptible organisms, the manufacturers state that safety and efficacy of intrathecal (intralumbar or intraventricular) administration have not been determined.

Endocarditis

IV vancomycin is used for the treatment of bacterial endocarditis and for prevention of bacterial endocarditis.

Treatment

IV vancomycin is used for the treatment of endocarditis caused by S. aureus or S. epidermidis, including oxacillin-resistant strains, and is considered the drug of choice for the treatment of endocarditis caused by oxacillin-resistant staphylococci.(See Uses: Staphylococcal Infections.) IV vancomycin also is used for the treatment of endocarditis caused by viridans streptococci or S. bovis in patients with a history of immediate-type hypersensitivity to penicillin.(See Uses: Enterococcal Infections.) Vancomycin also has been reported to be effective for the treatment of diphtheroid endocarditis.

Prevention

IV vancomycin is used as an alternative agent for prevention of enterococcal endocarditis in penicillin-allergic adults and children with congenital heart disease, rheumatic or other acquired valvular heart dysfunction (even after valvular surgery), prosthetic heart valves (including bioprosthetic and allograft valves), surgically constructed systemic pulmonary shunts or conduits, hypertrophic cardiomyopathy, mitral valve prolapse with valvular regurgitation and/or thickened leaflets, or previous bacterial endocarditis (even in the absence of heart disease), who undergo certain GI, biliary tract, or genitourinary surgery or instrumentation likely to cause transient bacteremia and increase the risk of endocarditis. These procedures include sclerotherapy for esophageal varices; esophageal structure dilation; endoscopic retrograde cholangiography with biliary obstruction, biliary tract surgery; surgical operations that involve intestinal mucosa; prostatic surgery, cystoscopy; and urethral dilation.

The AHA recognizes that its current recommendations for prophylaxis against bacterial endocarditis are empiric, since no controlled efficacy studies have been published, and that prophylaxis of endocarditis is not always effective. However, the AHA generally recommends routine use of prophylactic anti-infectives in patients with the cardiac conditions described above since these are associated with a high or moderate risk for bacterial endocarditis.

Prophylaxis against bacterial endocarditis is not considered necessary for adults or children with cardiac conditions considered to be associated with a negligible risk for endocarditis since these individuals are at no greater risk than the general population. Therefore, prophylaxis against bacterial endocarditis is not considered necessary for individuals with a history of isolated secundum atrial septal defect; surgical repair of atrial septal defect, ventricular septal defect, or patent ductus arteriosus (without residua beyond 6 months); previous coronary artery bypass graft surgery; mitral valve prolapse without valvar regurgitation; physiologic, functional, or innocent heart murmurs; previous Kawasaki disease without valvar dysfunction; previous rheumatic fever without valvar dysfunction; or cardiac pacemaker (intravascular and epicardial) and implanted defibrillators. When selecting anti-infectives for prophylaxis of bacterial endocarditis, the current recommendations of the AHA should be consulted.

Clostridium difficile-associated Diarrhea and Colitis

Although vancomycin hydrochloride is not effective by the oral route for the treatment of systemic infections, the drug is used orally for the treatment of Clostridium difficile-associated diarrhea and colitis (CDAD; also known as antibiotic-associated diarrhea and colitis, C. difficile diarrhea, C. difficile colitis, and pseudomembranous colitis) in seriously ill patients (i.e., with severe or potentially life-threatening colitis) or those who cannot tolerate or do not respond to oral metronidazole.

Oral metronidazole appears to be as effective as oral vancomycin for the treatment of pseudomembranous colitis caused by C. difficile. Therefore, because of cost considerations and concerns about increasing enterococcal and other (e.g., staphylococcal) resistance to vancomycin (see Resistance) and the risk of selection of such strains secondary to widespread and/or injudicious use of the drug, most experts and clinicians state that oral metronidazole therapy is preferred (unless a resistant strain of C. difficile is suspected or therapy with metronidazole is contraindicated or not tolerated) when anti-infective therapy is indicated for most cases of antibiotic-associated colitis and diarrhea. The relative efficacy of oral metronidazole for severe, potentially life-threatening cases of pseudomembranous colitis remains unclear, and some clinicians continue to consider vancomycin the drug of choice when anti-infective therapy is indicated for such cases (e.g., in critically ill patients). Most clinicians currently recommend that oral vancomycin only be used for the treatment of C. difficile-associated colitis in seriously ill patients (i.e., with severe or potentially life-threatening colitis) or those who cannot tolerate or do not respond to oral metronidazole.

After oral vancomycin therapy is initiated, fever may resolve within 24-48 hours and diarrhea generally remits gradually over about 3-5 days; however, resolution of fever and diarrhea occasionally may take a week or longer, probably because of persistent inflammation despite cessation of toxin production. Relapse, which usually is apparent within several weeks (occasionally up to several months) and probably is secondary to persistent germinating C. difficile spores or reinfection with the same or different strains, occurs in about 10-35% of patients treated with an effective anti-infective but generally responds to additional therapy with the same or an alternative anti-infective; true treatment failures (i.e., secondary to resistant strains) are rare. Although oral vancomycin also has been used in combination with oral rifampin for possible synergistic or other combined activity against C. difficile and/or its spores, the role, if any, of this approach in the treatment of multiple relapses remains to be established.

Oral vancomycin or oral metronidazole also has been used to prevent nosocomial outbreaks of C. difficile diarrhea and colitis in institutionalized patients who asymptomatically harbor the organism. However, current evidence suggests that the risks of such prophylactic therapy (e.g., in selecting potentially resistant organisms such as enterococci), particularly with vancomycin, outweigh any possible benefit. Most experts currently recommend that appropriate enteric and barrier precautions (e.g., isolation of patients, private bathroom facilities, strict hygiene) rather than prophylactic anti-infective therapy be implemented to prevent nosocomial transmission of the organisms.

For additional information on the management of this infection, , and also .

Respiratory Tract Infections

Although not considered a drug of choice for the treatment of community-acquired pneumonia (CAP), there may be some situations when IV vancomycin is included in anti-infective regimen used for empiric therapy of severe CAP that may be caused by S. aureus (e.g., in patients from a nursing home known to harbor this organism). In addition, use of IV vancomycin may be considered for the initial treatment of pneumonia caused by highly penicillin-resistant S. pneumoniae, especially when cephalosporins (e.g., ceftriaxone, cefotaxime) cannot be used.(See Uses: Streptococcal Infections.)

Bacillus Infections

Vancomycin is recommended by some clinicians as a drug of choice for the treatment of infections caused by Bacillus cereus or B. subtilis.

Capnocytophaga Infections

Vancomycin is used for the treatment of infections caused by Capnocytophaga. Optimum regimens for the treatment of infections caused by Capnocytophaga have not been identified; however, some clinicians recommend use of penicillin G or, alternatively, a third generation cephalosporin (cefotaxime, ceftizoxime, ceftriaxone), a carbapenem (imipenem and cilastatin sodium, meropenem), vancomycin, a fluoroquinolone, or clindamycin.

Corynebacterium Infections

Vancomycin is recommended by some clinicians as a drug of choice for the treatment of infections caused by Corynebacterium jeikeium (JK group). The drug has been used concomitantly with rifampin and/or an aminoglycoside for the treatment of early-onset prosthetic valve endocarditis caused by diphtheroids (e.g., C. jeikeium).

Rhodococcus Infections

Some clinicians suggest that infections caused by Rhodococcus equi be treated with a regimen of vancomycin used in conjunction with a fluoroquinolone, rifampin, imipenem (or meropenem), or amikacin. In at least one HIV-infected patient, vancomycin used in conjunction with imipenem was effective for the treatment of pulmonary infection caused by R. equi.R. equi has been identified as a cause of pulmonary infections (e.g., lung abscess) in immunocompromised individuals, including HIV-infected patients and solid organ transplant recipients. Although optimum regimens for the treatment of these infections have not been identified, combination regimens usually are recommended.

Prevention of Perinatal Group B Streptococcal Disease

IV vancomycin is used as an alternative to parenteral penicillin G or ampicillin for prevention of perinatal group B streptococcal (GBS) disease in certain women who are hypersensitive to penicillin. Pregnant women who are colonized with GBS in the genital or rectal areas can transmit GBS infection to their infants during labor and delivery resulting in invasive neonatal infection that can be associated with substantial morbidity and mortality. Intrapartum anti-infective prophylaxis for prevention of early-onset neonatal GBS disease is administered selectively to women at high risk for transmitting GBS infection to their neonates.

When intrapartum prophylaxis is indicated in the mother, penicillin G is the regimen of choice and ampicillin is the preferred alternative. When intrapartum prophylaxis to prevent GBS in the neonate is indicated in women who are hypersensitive to penicillins, the CDC recommends a regimen of IV cefazolin for those allergic to penicillins who are not at high risk for anaphylaxis. For those allergic to penicillins who are at high risk for anaphylaxis (e.g., those with a history of immediate penicillin hypersensitivity, such as anaphylaxis, angioedema, or urticaria; those with a history of asthma or other conditions that would make anaphylaxis more dangerous or difficult to treat, including individuals receiving β-adrenergic blocking agents), the CDC recommends a regimen of IV clindamycin or IV erythromycin. However, the fact that S. agalactiae (group B streptococci) with in vitro resistance to clindamycin and erythromycin have been reported with increasing frequency should be considered when choosing an alternative to penicillins for these patients. In addition, strains of GBS resistant to erythromycin often are resistant to clindamycin, although this may not be evident in results of in vitro testing. When use of erythromycin or clindamycin is being considered in a women hypersensitive to penicillin, in vitro susceptibility testing of clinical isolates obtained during GBS prenatal screening should be performed whenever possible to determine if the isolates are susceptible to these drugs. If in vitro susceptibility testing is not possible, results are unknown, or isolates are found to be resistant to erythromycin or clindamycin, a regimen of vancomycin should be used for intrapartum prophylaxis in women with penicillin allergy who are at high risk for anaphylaxis.

For additional information on prevention of perinatal GBS disease, see Uses: Prevention of Perinatal Group B Streptococcal Disease, in the Natural Penicillins General Statement 8:12.16.04.

Perioperative Prophylaxis

IV vancomycin is used for perioperative prophylaxis to reduce the risk of infection in patients undergoing cardiac surgery (e.g., placement of electrophysiologic devices, ventricular assist devices, ventriculoatrial shunts, arterial patches), neurosurgery (e.g., craniotomy, spinal surgery), orthopedic surgery (e.g., joint replacement, internal fixation of compound or open fractures with nails, plates, screws, or wires), thoracic (noncardiac) surgery (pulmonary resection, closed-tube thoracostomy for chest trauma with hemothorax or pneumothorax), or vascular surgery (arterial reconstructive surgery involving the abdominal aorta, leg procedures that include a groin incision, lower extremity amputation for ischemia) at institutions where oxacillin-resistant S. epidermidis are frequent causes of postoperative wound infection. Vancomycin also is used for perioperative prophylaxis in patients undergoing these procedures when the drugs of first choice (cefazolin, cefuroxime) cannot be used because the patient is hypersensitive to β-lactam anti-infectives. However, routine use of vancomycin for perioperative prophylaxis is not recommended since such use may promote emergence of vancomycin-resistant enterococci or staphylococci.

Empiric Therapy in Febrile Neutropenic Patients

IV vancomycin is used in conjunction with 1 or 2 other anti-infectives for empiric anti-infective therapy of presumed bacterial infections in febrile neutropenic patients. Vancomycin should never be used alone for empiric therapy in febrile neutropenic patients. Some clinicians suggest that it may be prudent to include vancomycin in an initial empiric regimen in selected patients with clinically suspected serious catheter-related infections (e.g., bacteremia, cellulitis); known colonization with penicillin- and cephalosporin-resistant S. pneumoniae or oxacillin-resistant S. aureus; initial blood culture results indicating presence of gram-positive bacteria; or hypotension or other evidence of cardiovascular impairment. However, if vancomycin is included in an initial empiric regimen, it should be discontinued within 24-48 hours if results of cultures do not identify gram-positive bacteria susceptible to the drug.

Successful treatment of infections in granulocytopenic patients requires prompt initiation of empiric anti-infective therapy (even when fever is the only sign or symptom of infection) and appropriate modification of the initial regimen if the duration of fever and neutropenia is protracted, if a specific site of infection is identified, or if organisms resistant to the initial regimen are present. No empiric regimen has been identified that would be appropriate for initial treatment of all febrile neutropenic patients. The initial empiric regimen should be chosen based on the underlying disease and other host factors that may affect the degree of risk and on local epidemiologic data regarding usual pathogens in these patients and data regarding their in vitro susceptibility to available anti-infective agents. The fact that gram-positive bacteria have become a predominant pathogen in febrile neutropenic patients should be considered when selecting an empiric anti-infective regimen.

The Infectious Diseases Society of America (IDSA) recommends use of a parenteral empiric regimen in most febrile neutropenic patients; use of an oral regimen (e.g., oral ciprofloxacin and oral amoxicillin and clavulanate) should only be considered in selected adults at low risk for complications who have no focus of bacterial infection and no signs or symptoms of systemic infection other than fever. At health-care facilities where gram-positive bacteria are common causes of serious infection and use of vancomycin in the initial empiric regimen is considered necessary, the IDSA recommends 2- or 3-drug combination therapy that includes vancomycin and either cefepime, ceftazidime, imipenem, or meropenem given with or without an aminoglycoside; vancomycin should be discontinued 24-48 hours later if a susceptible gram-positive bacterial infection is not identified. At health-care facilities where vancomycin is not indicated in the initial empiric regimen, the IDSA recommends monotherapy with a third or fourth generation cephalosporin (ceftazidime, cefepime) or a carbapenem (imipenem, meropenem) for uncomplicated cases; however, for complicated cases or if anti-infective resistance is a problem, combination therapy consisting of an aminoglycoside (amikacin, gentamicin, tobramycin) given in conjunction with an antipseudomonal penicillin (ticarcillin and clavulanate, piperacillin and tazobactam), an antipseudomonal cephalosporin (cefepime, ceftazidime), or a carbapenem (imipenem, meropenem) is recommended. Regardless of the initial regimen selected, patients should be reassessed after 3-5 days of treatment and the anti-infective regimen altered (if indicated) based on the presence or absence of fever, identification of the causative organism, and the clinical condition of the patient.

Published protocols for the treatment of infections in febrile neutropenic patients should be consulted for specific recommendations regarding selection of the initial empiric regimen, when to change the initial regimen, possible subsequent regimens, and duration of therapy in these patients. In addition, consultation with an infectious diseases expert knowledgeable about infections in immunocompromised patients is advised.

Dosage and Administration

Reconstitution and Administration

Vancomycin hydrochloride is administered by slow IV infusion for the treatment of systemic infections. Vancomycin hydrochloride is given orally as capsules for the treatment of enterocolitis caused by Staphylococcus aureus (including oxacillin-resistant [methicillin-resistant] strains) or for antibiotic-associated pseudomembranous colitis caused by Clostridium difficile; if necessary, the parenteral form of vancomycin hydrochloride may be diluted and administered orally or by nasogastric tube for the treatment of these infections.

Vancomycin is very irritating to tissue and must not be given IM.(See Cautions: Local Effects.) Safety and efficacy of intrathecal (intralumbar or intraventricular) or intraperitoneal administration of vancomycin have not been determined.

Oral Administration

Commercially available vancomycin hydrochloride capsules or the powder for IV administration can be used for oral administration.

When necessary, an oral solution for administration via a nasogastric tube can be prepared by diluting the appropriate dose of vancomycin hydrochloride powder for IV infusion in 30 mL of water. The 500-mg single-use vial should be used to prepare these oral solutions; ADD-Vantage vials should not be used. For patients who are too ill to receive oral therapy, administration via a long intestinal tube, via enema, or by direct instillation via a colostomy or ileostomy has been suggested.

IV Infusion

Vancomycin hydrochloride usually is administered by intermittent IV infusion, but has been administered by continuous IV infusion when intermittent infusions were not feasible.

Vancomycin hydrochloride powder for injection is reconstituted by adding 10 or 20 mL of sterile water for injection to a vial labeled as containing 500 mg or 1 g of vancomycin, respectively, to provide solutions containing 50 mg of the drug per mL. For intermittent IV infusion, the reconstituted solutions containing 500 mg or 1 g must be diluted further with at least 100 mL or at least 200 mL, respectively, of a compatible IV solution and administered over a period of at least 1 hour.

Alternatively, ADD-Vantage vials labeled as containing 500 mg or 1 g of vancomycin may be reconstituted according to the manufacturer's directions using 5% dextrose injection or 0.9% sodium chloride injection. ADD-Vantage vials of the drug should be used only when actual doses of 500 mg or 1 g are appropriate and should not be used in neonates, infants, or young children who require doses less than 500 mg.

The pharmacy bulk package is not intended for direct IV infusion; doses of the drug from the reconstituted bulk package must be further diluted in a compatible IV infusion solution prior to administration.

Thawed solutions of the commercially available frozen vancomycin hydrochloride injection in 5% dextrose should be administered only by IV infusion. The commercially available frozen vancomycin hydrochloride in 5% dextrose injection should be thawed at room temperature (25°C) or under refrigeration (5°C) and should not be thawed by immersion in a water bath or by exposure to microwave radiation. A precipitate may form while the commercially available injection in 5% dextrose is frozen; however, this usually will dissolve with little or no agitation upon reaching room temperature, and the potency of vancomycin hydrochloride frozen injection is not affected. After thawing at room temperature or under refrigeration, the container should be checked for minute leaks by firmly squeezing the bag. The injection should be discarded if the container seal or outlet ports are not intact or leaks are found or if the solution is discolored, cloudy, or contains a precipitate. The thawed injection should not be used in series connections with other plastic containers, since such use could result in air embolism from residual air being drawn from the primary container before administration of fluid from the secondary container is complete.

For continuous IV infusion when intermittent infusions are not feasible, 1-2 g of reconstituted vancomycin may be added to a sufficient volume of 0.9% sodium chloride or 5% dextrose injection to permit administration of the desired daily dosage over a 24-hour period.

The frequency and severity of thrombophlebitis can be minimized if vancomycin is administered slowly as a dilute solution (2.5-5 mg/mL) and administration sites are frequently rotated. Pretreatment with antihistamines (e.g., diphenhydramine hydrochloride 1 mg/kg IV and cimetidine 4 mg/kg IV) may attenuate but not eliminate the risk of certain adverse effects (e.g., red-man syndrome) associated with rapid IV infusion of vancomycin.(See Cautions: Dermatologic and Sensitivity Reactions.)

Rate of Administration

Intermittent IV infusions of vancomycin should be given over a period of at least 1 hour.

Rapid IV infusion (e.g., over several minutes) should be avoided, and patients should be monitored closely during infusion of the drug to detect a hypotensive reaction if it occurs.(See Dermatologic and Sensitivity Reactions: Red-man Syndrome, in Cautions.) To minimize adverse effects, vancomycin should be administered IV at a rate not exceeding 10 mg/minute; however, the possibility that adverse effects associated with vancomycin infusion could occur at any infusion rate should be considered.

Dosage

Dosage of vancomycin hydrochloride is expressed in terms of vancomycin.

Oral Dosage

Orally administered vancomycin is not effective for and should not be used for the treatment of systemic infections.

Adult Dosage

For the treatment of enterocolitis caused by S. aureus (including oxacillin-resistant strains), the usual adult oral dosage of vancomycin is 0.5-2 g daily given in 3 or 4 divided doses for 7-10 days.

For the treatment of C. difficile-associated diarrhea and colitis (CDAD; also known as antibiotic-associated diarrhea and colitis, C. difficile diarrhea, C. difficile colitis, and pseudomembranous colitis), the usual adult oral dosage of vancomycin is 0.5-2 g daily given in 3 or 4 divided doses for 7-10 days. Because clinical and bacteriologic responses in C. difficile-associated diarrhea and colitis generally appear to be similar for the low and high dosages in this range, most clinicians recommend using the lower dosage for cost considerations, unless ileus is impending or the infection is severe (e.g., in critically ill patients). Many clinicians recommend that oral vancomycin be given in a dosage of 125 mg 4 times daily for 7-10 days.

Pediatric Dosage

For the treatment of staphylococcal enterocolitis or antibiotic-associated pseudomembranous colitis in children, the usual oral dosage of vancomycin is 40 mg/kg daily given in 3 or 4 divided doses for 7-10 days. Dosage of oral vancomycin in children should not exceed 2 g daily.

IV Dosage

General Adult Dosage

For the treatment of potentially life-threatening systemic infections in adults with normal renal function, the usual IV dosage of vancomycin is 500 mg every 6 hours or 1 g every 12 hours.

General Pediatric Dosage

Numerous vancomycin dosage regimens have been suggested for pediatric patients, particularly neonates and young infants. The American Academy of Pediatrics (AAP) states that optimal vancomycin dosage in neonates should be based on serum concentrations of the drug, especially in those with low birthweight (i.e., less than 1.5 kg).

For neonates and young infants with normal renal function, the manufacturers recommend an initial IV dose of 15 mg/kg, followed by 10 mg/kg every 12 hours in neonates younger than 1 week of age and 10 mg/kg every 8 hours for infants 1 week to 1 month of age; close monitoring of serum vancomycin concentrations may be warranted in these patients. AAP recommends that neonates younger than 1 week of age receive 15 mg/kg every 24 hours if they weigh less than 1.2 kg, 10-15 mg/kg of vancomycin every 12-18 hours if they weigh 1.2-2 kg, or 10-15 mg/kg every 8-12 hours if they weigh more than 2 kg. For neonates 1 week of age or older, the AAP recommends 15 mg/kg every 24 hours in those weighing less than 1.2 kg, 10-15 mg/kg given every 8-12 hours in those weighing 1.2-2 kg, or 10-15 mg/kg every 6-8 hours in those weighing more than 2 kg.

For older children with normal renal function, the manufacturers recommend an IV dosage of 10 mg/kg every 6 hours. Alternatively, for older children, some clinicians suggest an IV dosage of 1.2 g/m daily given in divided doses. AAP suggests that children 1 month of age or older with mild to moderate infections receive IV vancomycin in a dosage of 40 mg/kg daily given in 3-4 divided doses and that those with severe infections receive 40-60 mg/kg daily given in 4 divided doses. For the treatment of meningitis in children 1 month of age or older, the AAP and other clinicians recommend that vancomycin be given in a dosage of 60 mg/kg daily (maximum 2 g daily) given in divided doses every 6 hours.

For specific information on other pediatric dosage regimens, published protocols and specialized references should be consulted.

Treatment of Endocarditis

For the treatment of native valve endocarditis caused by oxacillin-resistant staphylococci, the American Heart Association (AHA) and Infectious Diseases Society of America (IDSA) recommend that adults receive IV vancomycin in a dosage of 30 mg/kg daily given in 2 equally divided doses (maximum dose 2 g daily unless serum concentrations are inappropriately low) and that pediatric patients receive 40 mg/kg daily given in 2 or 3 equally divided doses for 6 weeks.

Adults with oxacillin-resistant staphylococcal endocarditis who have a prosthetic valve or other prosthetic material should receive IV vancomycin in a dosage of 30 mg/kg daily given in 2 equally divided doses (maximum dose 2 g daily unless serum concentrations are inappropriately low) given for at least 6 weeks in conjunction with oral or IV rifampin (300 mg every 8 hours given for at least 6 weeks) and IM or IV gentamicin (3 mg/kg daily in 2 or 3 equally divided doses during the first 2 weeks of vancomycin therapy). Pediatric patients with oxacillin-resistant staphylococcal endocarditis who have a prosthetic valve or other prosthetic material should receive IV vancomycin in a dosage of 40 mg/kg daily given in 2 or 3 equally divided doses for at least 6 weeks in conjunction with oral or IV rifampin (20 mg/kg daily in 3 equally divided doses given for at least 6 weeks) and IM or IV gentamicin (3 mg/kg daily in 3 equally divided doses during the first 2 weeks of vancomycin therapy).

For the treatment of endocarditis caused by viridans streptococci or Streptococcus bovis when penicillin G or ceftriaxone cannot be used, the AHA and IDSA recommend that adults receive IV vancomycin in a dosage of 30 mg/kg daily given in 2 equally divided doses (maximum dose 2 g daily unless serum concentrations are inappropriately low) and that pediatric patients receive 40 mg/kg daily given in 2-3 equally divided doses. Vancomycin should be given for 4 weeks for the treatment of native valve endocarditis or for 6 weeks for endocarditis that involves prosthetic valves or other prosthetic materials.

For the treatment of enterococcal endocarditis when penicillin G or ampicillin cannot be used, the AHA and IDSA recommend that adults receive IV vancomycin in a dosage of 30 mg/kg daily given in 2 equally divided doses for 6 weeks given in conjunction with IM or IV gentamicin (3 mg/kg daily given in 3 equally divided doses for 6 weeks). Pediatric patients with enterococcal endocarditis who cannot receive penicillin G or ampicillin should receive IV vancomycin in a dosage of 40 mg/kg daily given in 2 or 3 equally divided doses for 6 weeks in conjunction with IM or IV gentamicin (3 mg/kg daily in 3 equally divided doses given for 6 weeks).

If vancomycin is used in a multiple-drug regimen for the empiric treatment of culture-negative endocarditis involving native valves when the fixed combination of ampicillin and sulbactam cannot be used, the AHA and IDSA recommend that adults receive IV vancomycin in a dosage of 30 mg/kg daily given in 2 equally divided doses in conjunction with IM or IV gentamicin (3 mg/kg daily given in 3 equally divided doses) and ciprofloxacin (1 g daily given orally in 2 equally divided doses or 800 mg daily given IV in 2 equally divided doses). Pediatric patients should receive IV vancomycin in a dosage of 40 mg/kg daily given in 2 or 3 equally divided doses in conjunction with gentamicin (3 mg/kg daily given IM or IV in 3 equally divided doses) and ciprofloxacin (20-30 mg/kg daily given orally or IV in 2 equally divided doses). All 3 drugs should be given for 4-6 weeks.

Prevention of Bacterial Endocarditis

For prevention of enterococcal endocarditis in penicillin-allergic patients at high or moderate risk who are undergoing certain GI, biliary tract, or genitourinary tract surgery or instrumentation (see Uses: Endocarditis), the AHA recommends that adults receive a single 1-g dose of vancomycin and that pediatric patients receive a single 20-mg/kg dose of vancomycin given IV over 1-2 hours with the infusion completed within 30 minutes of the start of the procedure. While patients with cardiac conditions that put them at moderate risk of enterococcal endocarditis may receive vancomycin alone for prophylaxis, adults and pediatric patients with cardiac conditions that put them at high risk also should receive a single 1. 5-mg/kg dose of gentamicin (maximum dose 120 mg) given IM or IV within 30 minutes prior to the start of the procedure. When selecting anti-infectives for the prevention of bacterial endocarditis, the current recommendations published by the AHA should be consulted.

Prevention of Neonatal Group B Streptococcal Disease

If IV vancomycin is used for intrapartum anti-infective prophylaxis for prevention of perinatal group B streptococcal (GBS) disease in women with penicillin hypersensitivity who should not receive a β-lactam anti-infective and should not receive clindamycin and erythromycin because of known or suspected resistance, the CDC recommends that 1 g of vancomycin be given IV every 12 hours until delivery. When indicated, such prophylaxis is initiated at the time of labor or rupture of membranes.

Perioperative Prophylaxis

For perioperative prophylaxis in adults undergoing certain cardiac, neurosurgical, orthopedic, thoracic (noncardiac), or vascular surgical procedures when use of vancomycin is considered necessary because of a high incidence of oxacillin-resistant staphylococci at the institution or when cephalosporins (cefazolin, cefuroxime) cannot be used, a single 1-g dose of vancomycin should be given IV prior to the procedure.

The vancomycin infusion should be started 1-2 hours prior to the time of incision to minimize the risk of an adverse reaction occurring at the time of induction of anesthesia and to ensure adequate tissue concentrations of the drug at the time of incision.(See Drug Interactions: Anesthetics.) If surgery is prolonged (more than 4 hours), additional intraoperative doses of vancomycin may be given every 6-12 hours for the duration of the procedure. Additional doses may also be indicated if substantial blood loss occurs. However, postoperative doses generally are unnecessary and should not be used.

Dosage in Renal Impairment

In patients with impaired renal function, including premature infants and geriatric patients, doses and/or frequency of administration of vancomycin must be modified in response to the degree of impairment, severity of the infection, susceptibility of the causative organism, and serum concentrations of the drug. Several methods of calculating vancomycin dosage for patients with impaired renal function have been proposed; however, in these patients or patients undergoing hemodialysis or peritoneal dialysis, dosage should generally be based on actual serum concentrations of the drug.

In patients with impaired renal function, including geriatric and functionally anephric patients, an initial IV dose of 15 mg/kg should be given. Subsequent dosage must be based mainly on renal function and serum concentrations of the drug. Clinicians should consult published protocols and specialized references for information on specific methods of dosage adjustment. Some clinicians have recommended that 1 g of vancomycin be administered at 12-hour intervals in patients with serum creatinine concentrations less than 1.5 mg/dL, at 3- to 6-day intervals in patients with serum creatinine of 1.5-5 mg/dL, and at 10- to 14-day intervals in patients with serum creatinine greater than 5 mg/dL. Others have recommended that the usual individual dose be administered every 3-10 days in patients with glomerular filtration rates of 10-50 mL/minute and every 10 days in patients with glomerular filtration rates less than 10 mL/minute.

Cautions

Otic and Renal Effects

Ototoxicity and nephrotoxicity are the most serious adverse effects of parenteral vancomycin therapy. The incidences of ototoxicity and nephrotoxicity have not been well established, but clinical experience to date suggests that these adverse effects occur relatively infrequently.

Ototoxicity and nephrotoxicity are most likely to occur in patients with renal impairment, patients receiving IV vancomycin in high doses or for prolonged periods, or patients receiving other ototoxic and/or nephrotoxic drugs. (See Drug Interactions: Ototoxic and Nephrotoxic Drugs.) Although ototoxicity and nephrotoxicity have been associated with serum or blood vancomycin concentrations of 80-100 mcg/mL, these reactions have occurred with concentrations as low as 25 mcg/mL. Correlations between serum vancomycin concentrations and ototoxicity and nephrotoxicity still remain to be clarified.

Ototoxicity may be transient or permanent. Vancomycin may cause damage to the auditory branch of the eighth cranial nerve and permanent deafness has occurred. Vertigo, dizziness, and tinnitus have been reported rarely. Tinnitus may precede the onset of deafness and necessitates discontinuance of the drug. Deafness may progress despite cessation of vancomycin therapy.

Vancomycin-induced nephrotoxicity may be manifested by transient elevations in BUN or serum creatinine concentrations, and the presence of hyaline and granular casts and albumin in the urine. Fatal uremia has occurred. Rarely, the drug has been associated with acute interstitial nephritis.

Local Effects

Vancomycin hydrochloride is very irritating to tissue and causes necrosis when given IM; therefore, it must be administered IV and care must be taken to avoid extravasation. Pain and thrombophlebitis occur after IV administration in many patients, and occasionally may be severe.

Dermatologic and Sensitivity Reactions

Urticaria, exfoliative dermatitis, macular rashes, eosinophilia, vasculitis, a shock-like state, transient anaphylaxis, and, occasionally, vascular collapse have been reported in patients receiving vancomycin. The drug also has been associated with Stevens-Johnson syndrome in at least one patient.

Hypersensitivity reactions reportedly occur in 5-10% of patients receiving vancomycin. Successful desensitization was reported in some patients who had experienced severe systemic allergic reactions to vancomycin but required further therapy with the drug.

Red-man Syndrome

Rapid IV administration of vancomycin has resulted in a hypotensive reaction frequently referred to as the ''red-man syndrome'' or ''red-neck syndrome''. The reaction is characterized by a sudden decrease in blood pressure which can be severe and may be accompanied by flushing and/or a maculopapular or erythematous rash on the face, neck, chest, and upper extremities; the latter manifestations may also occur in the absence of hypotension. Wheezing, dyspnea, angioedema, urticaria, and pruritus may also occur. Rarely, cardiac arrest or seizures have occurred.

Vancomycin-induced hypotension appears to result from a negative inotropic and vasodilating action produced in part by a release of histamine, which is directly related to the rate of infusion; the release of histamine also appears to be responsible for the usual manifestations (e.g., erythema, rash, pruritus) of the ''red'' characterization. The reaction usually begins a few minutes after the vancomycin infusion is started, but may not occur until after the infusion is completed, and usually resolves spontaneously over one to several hours after discontinuance of the infusion. If the hypotensive reaction is severe, the use of antihistamines, corticosteroids, or IV fluids may be necessary. The hypotensive reaction is related to the rate of infusion of vancomycin and has been reported most frequently when the drug was administered over a period of 10 minutes or less; however, the reaction may also occur rarely when the drug is infused over a period of 1 hour or longer.

To minimize the risk of a hypotensive reaction, vancomycin should be infused over a period of at least 1 hour and the patient's blood pressure should be monitored during the infusion. In patients who have had the reaction, subsequent doses of vancomycin can usually be given without adverse effect if administered at a slow rate (e.g., over several hours). Pretreatment with antihistamines may be of benefit. If attempts to minimize the reaction fail, use of another anti-infective agent may be necessary. The reaction reportedly has occurred in more than 50% of healthy individuals given vancomycin but less frequently when the drug is used therapeutically.

In one study, intradermal skin tests with vancomycin were used to assess the possibility of predicting the severity of vancomycin-associated anaphylactoid reactions (i.e., ''red-man syndrome'' or ''red-neck syndrome''). Although the intradermal tests were positive (wheal and flare) in all patients and all patients subsequently experienced anaphylactoid reactions following an IV dose of the drug, the magnitude of cutaneous response was of little value in predicting the severity of ''red-man syndrome''. Desensitization, employing sequential incremental concentration and dose increases (in a manner typical for drug desensitization procedures) and pretreatment with an antihistamine and corticosteroid, has been performed successfully in a few patients in whom vancomycin therapy was considered necessary.

In at least one patient, oral administration of vancomycin resulted in the ''red-man syndrome''. This reaction was characterized by intense pruritus on the arms, scalp, and face; flushing on the face and neck; and erythema on the face, neck, chest, and arms. Administration of a parenteral antihistamine provided some relief.

Evidence from at least one patient suggests possible cross-sensitivity between teicoplanin administration and vancomycin-induced red-man syndrome.

Hematologic Effects

Adverse hematologic effects reported in patients receiving vancomycin include neutropenia, eosinophilia, and, rarely, thrombocytopenia. Neutropenia, which appears to be rapidly reversible following discontinuance of the drug, usually has occurred beginning 7 or more days after initiation of vancomycin therapy or after a total dose of more than 25 g of the drug.

Although a causal relationship to vancomycin has not been established, reversible agranulocytosis (granulocytes less than 500/mm) has been reported rarely in patients receiving vancomycin.

GI Effects

Antibiotic-associated pseudomembranous colitis, caused by toxin-producing clostridia (e.g., C. difficile), has been reported with the use of nearly all anti-infectives, including IV vancomycin, and should be considered in the differential diagnosis of patients who present with diarrhea subsequent to administration of anti-infectives. Pseudomembranous colitis may occur during or following discontinuance of anti-infective therapy and ranges in severity from mild to life-threatening. Mild cases of colitis may respond to discontinuance of the drug alone, but diagnosis and management of moderate to severe cases should include appropriate bacteriologic studies and treatment with fluid, electrolyte, and protein supplementation as indicated. If colitis is moderate to severe and is not relieved by discontinuance of the drug, appropriate anti-infective therapy (e.g., metronidazole) should be administered.

Nausea also has been reported in patients receiving vancomycin therapy.

Other Adverse Effects

A throbbing pain in the muscles of the back and neck has been reported with vancomycin and can usually be minimized or avoided by slower administration of the drug. In patients undergoing continuous ambulatory peritoneal dialysis (CAPD), intraperitoneal administration of vancomycin has been associated with chemical peritonitis, a syndrome consisting of a cloudy dialysate, which may be accompanied by abdominal pain and fever. Chemical peritonitis usually disappears shortly after discontinuance of intraperitoneal vancomycin.

Other adverse effects of vancomycin include chills and fever. Priapism after a second IV dose of vancomycin, with recurrence on inadvertent rechallenge, occurred in a 37-year-old man with severe underlying diabetes mellitus; bilateral phlebotomy of the corpus cavernosum resulted in resolution of the priapism.

Precautions and Contraindications

Vancomycin is contraindicated in patients with known hypersensitivity to the drug. The manufacturer of the commercially available frozen vancomycin hydrochloride injection in 5% dextrose states that solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products.

Because vancomycin is ototoxic and nephrotoxic, the drug should be used with caution in patients with impaired renal function and should be avoided in patients with previous hearing loss. If it is necessary to use vancomycin in such patients, dosage should be reduced. Patients with borderline renal function and those older than 60 years of age should be given serial tests of auditory function, and serum or blood vancomycin concentrations should be determined regularly during treatment with the drug. All patients receiving vancomycin should have periodic urinalysis and renal function tests. The manufacturers also recommend periodic monitoring of the leukocyte count in patients receiving prolonged vancomycin therapy and in those receiving concomitant therapy with drugs that may cause neutropenia.

The possibility that infusion reactions, including potentially severe hypotension, may occur with IV vancomycin should be considered.(See Dermatologic and Sensitivity Reactions: Red-man Syndrome, in Cautions.) Rapid IV administration (e.g., over several minutes) of the drug should be avoided since it may be associated with exaggerated hypotension, including shock, and may rarely be with associated with cardiac arrest.

Because reversible neutropenia has been reported in patients receiving vancomycin, leukocyte counts should be monitored periodically in patients receiving prolonged vancomycin therapy and in those who are receiving concomitant therapy with drugs that may cause neutropenia.

To reduce development of drug-resistant bacteria and maintain effectiveness of vancomycin and other antibacterials, the drug should be used only for the treatment or prevention of infections proven or strongly suspected to be caused by susceptible bacteria. When selecting or modifying anti-infective therapy, use results of culture and in vitro susceptibility testing. In the absence of such data, consider local epidemiology and susceptibility patterns when selecting anti-infectives for empiric therapy. Patients should be advised that antibacterials (including vancomycin) should only be used to treat bacterial infections and not used to treat viral infections (e.g., the common cold). Patients also should be advised about the importance of completing the full course of therapy, even if feeling better after a few days, and that skipping doses or not completing therapy may decrease effectiveness and increase the likelihood that bacteria will develop resistance and will not be treatable with vancomycin or other antibacterials in the future.

Prolonged use of vancomycin hydrochloride may result in overgrowth of nonsusceptible organisms. The patient should be carefully monitored and appropriate therapy should be instituted if a superinfection occurs. Because antibiotic-associated pseudomembranous colitis has been reported with the use of anti-infective agents, including IV vancomycin, it should be considered in the differential diagnosis of patients who develop diarrhea during therapy with the drug.

Pediatric Precautions

Safety and efficacy of oral vancomycin have not been established in pediatric patients.

IV vancomycin should be used with caution in premature neonates and young infants because of the renal immaturity of these patients and the potential for increased serum concentrations of the drug. Close monitoring of serum vancomycin concentrations may be warranted in pediatric patients, especially neonates and young infants.

Concomitant administration of vancomycin and anesthetic agents in children has been associated with erythema and histamine-like flushing. The occurrence of infusion-related adverse effects may be minimized by infusing vancomycin over a period of at least 1 hour prior to induction of anesthesia.

Safety of the chemical components that may leach out of the plastic container for commercially available frozen vancomycin injections has not been established in children.

Geriatric Precautions

Clinical studies of oral vancomycin hydrochloride did not include sufficient numbers of patients 65 years of age or older to determine whether they respond differently than younger adults. Other reported clinical experience has not identified any differences in response between geriatric and younger adults.

Vancomycin dosage for geriatric patients should be selected with caution, usually starting at the low end of the dosing range, because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.

Vancomycin dosage in geriatric patients should be adjusted based on the degree of renal impairment.(See Dosage: Dosage in Renal Impairment.) Because geriatric adults may have decreasing glomerular filtration with increasing age, increased serum vancomycin concentrations may occur if dosage is not adjusted in these patients.

Mutagenicity and Carcinogenicity

Vancomycin was not mutagenic in vitro in the mouse lymphoma forward mutation assay or the primary rat hepatocyte unscheduled DNA synthesis assay or in vivo in the Chinese hamster sister chromatid exchange assay or the mouse micronucleus assay.

No long-term animal carcinogenicity studies have been performed.

Pregnancy, Fertility, and Lactation

Pregnancy

There was no evidence of teratogenicity when vancomycin was administered IV to rats in dosages up to 200 mg/kg daily (1180 mg/m or equivalent to the recommended maximum human dosage based on mg/m) or to rabbits in dosage up to 120 mg/kg daily (1320 mg/m or 1.1 times the recommended maximum human dosage based on mg/m). There were no effects on fetal weight or development in rats at the highest dosage tested or in rabbits given 80 mg/kg daily (880 mg/m or 0.74 times the maximum recommended human dosage based on mg/m).

In one study, no sensorineural hearing loss or nephrotoxicity was reported in neonates born to women who received IV vancomycin for severe staphylococcal infections associated with IV drug abuse during pregnancy. In one infant whose mother received IV vancomycin in the third trimester of pregnancy, conductive hearing loss was reported; however, a causal relationship to vancomycin has not been established. Because the number of pregnant women in this study was limited and vancomycin was only administered during the second and third trimester of pregnancy, it is not known whether the drug can cause fetal harm when administered to pregnant women. Vancomycin should be used during pregnancy only when clearly needed.

Lactation

Vancomycin is distributed into milk following IV administration. Systemic absorption of oral vancomycin is very low and it is not known whether the drug distributes into human milk following oral administration. However, IV and oral vancomycin should be used with caution in nursing women. Because of the potential for serious adverse reactions from the drug in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of vancomycin to the woman.

Drug Interactions

Ototoxic and Nephrotoxic Drugs

Because of the possibility of additive toxicities, the concurrent or sequential systemic or topical use of other ototoxic and/or nephrotoxic drugs (e.g., aminoglycosides, amphotericin B, bacitracin, cisplatin, colistin, polymyxin B) and vancomycin requires careful serial monitoring of renal and auditory function. These drugs should be used with caution in patients receiving vancomycin therapy.

Aminoglycosides

In vitro, the antibacterial effects of vancomycin and aminoglycosides are synergistic against many strains of Staphylococcus aureus, nonenterococcal group D streptococci (Streptococcus bovis), enterococci (Enterococcus faecalis), and viridans streptococci. However, concomitant use of vancomycin and aminoglycosides is associated with an increased risk of ototoxicity and/or nephrotoxicity.(See Drug Interactions: Ototoxic and Nephrotoxic Drugs.)

Anesthestics

Concomitant use of vancomycin and anesthetic agents has been associated with anaphylactoid reactions and an increased frequency of infusion reactions (e.g., hypotension, flushing, erythema, urticaria, pruritus). Erythema and histamine-like flushing has occurred in pediatric patients receiving vancomycin and anesthetic agents concomitantly. The risk of infusion-related adverse effects may be minimized if vancomycin is given as a 1-hour IV infusion prior to induction of anesthesia.

Pharmacokinetics

Absorption

Vancomycin hydrochloride is not appreciably absorbed from the GI tract in most patients and must be given parenterally for the treatment of systemic infections. Oral bioavailability usually is less than 5%; however, limited data suggest that clinically important serum concentrations of the drug may result following enteral or oral administration of vancomycin in some patients with colitis and/or in those with renal impairment.

In adults with normal renal function who received multiple 1-g doses of vancomycin (15 mg/kg) given by IV infusion over 1 hour, mean plasma concentrations immediately after completion of the infusion are approximately 63 mcg/mL and mean plasma concentrations 2 and 11 hours later are approximately 23 or 8 mcg/mL, respectively. When multiple 500-mg doses are given by IV infusion over 30 minutes, mean plasma concentrations are about 49 mcg/mL immediately following the infusion and about 10 mcg/mL 6 hours after infusion.

Serum vancomycin concentrations are higher in patients with renal dysfunction than in those with normal renal function, and toxic serum concentrations may result.

Distribution

Following IV administration, vancomycin is widely distributed in body tissues and diffuses readily into pericardial, pleural, ascitic, and synovial fluids. Small amounts of the drug are distributed into bile.

Vancomycin does not readily distribute into CSF in the absence of inflammation unless serum concentrations are exceedingly high. Low concentrations of the drug may be present in CSF if meninges are inflamed, but negligible amounts are detected in the CSF of most patients with uninflamed meninges. In a limited number of adults and children with meningitis who received IV vancomycin in a dosage of 10-15 mg/kg daily, average CSF concentrations 1-3 hours after a dose were 3.3-3.8 mcg/mL and were 21-22% of concurrent serum concentrations. However, the relationship between CSF concentrations and clinical efficacy of vancomycin in the treatment of meningitis is unclear.

Vancomycin is 30-60% bound to serum proteins. Protein binding may be lower (19-29%) in patients with hypoalbuminemia (e.g., burn patients, those with end-stage renal disease).

Vancomycin readily crosses the placenta and is distributed into cord blood. Vancomycin is distributed into milk.

Elimination

The serum elimination half-life of vancomycin in adults with normal renal function has been reported to average 4-7 hours; accumulation tends to occur after 2-3 days of IV administration at 6- or 12-hour intervals. In geriatric adults 65 years of age older, the mean half-life of the drug has been reported to be 12.1 hours.

The mean half-life of vancomycin is 6.7 hours in full-term neonates and 4.1 hours in infants 1 month of age or older but younger than 1 year of age. In children 2.5-11 years of age, half-life of the drug is reported to be 5.6 hours.

The serum elimination half-life of vancomycin is increased in patients with renal dysfunction. In one study, the elimination half-life averaged 32.3 hours (range: 10.1-75.1 hours) in patients with creatinine clearances of 10-60 mL/minute and 146.7 hours (range: 44.1-406.4 hours) in those with creatinine clearances less than 10 mL/minute. However, because of increased clearance, half-life of vancomycin averages 4 hours in burn patients.

Vancomycin does not appear to be metabolized. Following oral administration, the drug is excreted mainly in feces. Following IV administration, about 75-90% of a dose is eliminated unchanged in urine by glomerular filtration and only small amounts are excreted in bile.

Vancomycin is only minimally removed by hemodialysis or peritoneal dialysis, including continuous ambulatory peritoneal dialysis. The drug is substantially removed by hemofiltration.

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