VA Class:AM900

AHFS Class:

• Glycopeptides 8:12.28.16

Generic Name(s):

• Vancomycin Hydrochloride

Molecular Formula:

• C₆₆H₇₅Cl₂N₉O₂₄•HCl

Vancomycin is a tricyclic glycopeptide antibiotic.159,266,274,275,294

Gram-Positive Bacterial Infections

Vancomycin is used orally for the treatment of diarrhea caused by Clostridioides difficile (formerly known as Clostridium difficile ) infection (CDI; C. difficile -associated diarrhea [CDAD]).197,266,267,268 Oral vancomycin is also used for the treatment of enterocolitis caused by Staphylococcus aureus (S. aureus ), including methicillin-resistant S. aureus (MRSA),197,266,267,268 The parenteral form of vancomycin hydrochloride may be administered orally for the treatment of antibiotic-associated pseudomembranous colitis produced by C. difficile and for staphylococcal enterocolitis.266 Orally administered vancomycin is not effective for the treatment of other types of infections.197,268

IV vancomycin is used for the treatment of infections caused by susceptible bacteria when other anti-infectives cannot be used or would be ineffective.155,266,267 IV vancomycin is used principally in the treatment of severe infections caused by gram-positive bacteria in patients who cannot receive or who have failed to respond to penicillins or cephalosporins or for the treatment of gram-positive bacterial infections that are resistant to β-lactams and other anti-infectives.155,266,267

The effectiveness of IV vancomycin has been documented in infections due to staphylococci, including staphylococcal endocarditis, septicemia, bone infections, lower respiratory tract infections, skin and skin structure infections.155,266,267 When staphylococcal infections are localized and purulent, antibiotics are used as adjuncts to appropriate surgical measures.155,266,267 IV vancomycin is used for initial therapy when MRSA is suspected;155 after susceptibility data are available, therapy should be adjusted accordingly.155

IV vancomycin also is used alone or in conjunction with an aminoglycoside for the treatment of endocarditis caused by enterococci (e.g., Enterococcus faecalis ), viridans streptococci, or Staphylococcus bovis (also known as S. gallolyticus) .266,450

See individual sections below in Uses for additional details on the use of vancomycin for specific gram-positive infections.

C. difficile -associated Diarrhea

Vancomycin is used orally for the treatment of diarrhea caused by Clostridioides difficile (formerly known as Clostridium difficile ) infection in adults and pediatric patients.12,122,178,180,181,197,211,212,213,215,216,217,218,219,266,268

Efficacy and safety of oral vancomycin (125 mg 4 times daily for 10 days) for the treatment of C. difficile -associated diarrhea (CDAD) were evaluated in 2 clinical trials.197,268 The studies included a total of 266 adults with C. difficile -associated diarrhea, defined as ≥3 loose or watery bowel movements within 24 hours prior to study enrollment, and the presence of either C. difficile toxin A or B, or pseudomembranes on endoscopy within 72 hours preceding enrollment.197,268 Patients with fulminant CDAD, sepsis with hypotension, ileus, peritoneal signs, or severe hepatic disease were excluded.197,268 The median age of patients was 67 years, 93% were white, and 52% were male.197,268 CDAD was classified as severe (defined as ≥10 unformed bowel movements per day or white blood cell counts ≥15,000/mm³) in 25% of patients; 47% of patients were previously treated for CDAD.197,268 The rate of clinical success with vancomycin (defined as resolution of diarrhea and absence of severe abdominal discomfort due to CDAD) on day 10 was 81% in both trials.197,268 The median time to resolution of diarrhea was 5 days in one trial and 4 days in the other trial.197,268

Results of 2 randomized controlled studies that compared oral vancomycin to fidaxomicin for the treatment of CDAD found that resolution of diarrhea was similar between the 2 agents; however, fidaxomicin was superior to vancomycin for sustained clinical response (defined as resolution of diarrhea at the end of treatment without recurrence 25 days after treatment).7

Clinical Perspective

C. difficile can cause asymptomatic colonization in the intestinal tract or symptomatic intestinal C. difficile infection (CDI) that can range in severity from mild to moderate diarrhea to more severe complications.7,122C. difficile is the most commonly recognized cause of infectious diarrhea in healthcare settings.12 Risk factors include advanced age, duration of hospitalization, immunosuppression as the result of disease or drug therapy, exposure to antibiotic agents, cancer chemotherapy, and GI surgery or manipulation of the GI tract.7,122 The most important modifiable risk factor for development of CDI is exposure to antibiotic agents.7 Antibiotics can alter the normal intestinal flora, providing an environment for overgrowth of C. difficile .7 CDI has been reported with nearly all systemic antibiotic agents and should be considered in the differential diagnosis in patients who develop diarrhea during or after anti-infective therapy.7 The risk of CDI from disruption of intestinal flora is increased during antibiotic therapy and for 3 months after such therapy is discontinued.7 Discontinuance of the inciting antibiotic is recommended as soon as possible to prevent recurrence of CDI.7

The Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA) have published guidelines on the management of CDI.7,12 The guidelines state that either oral vancomycin (125 mg 4 times daily for 10 days) or fidaxomicin (200 mg twice daily for 10 days) may be used for the initial treatment of CDI.7,12 When both agents are available, fidaxomicin may be preferred because of its favorable efficacy and safety profile; however, this recommendation is based on a moderate certainty of evidence and vancomycin remains an acceptable alternative.12 When vancomycin and fidaxomicin are not available, metronidazole (500 mg 3 times daily orally for 10-14 days) may be used for treatment of an initial CDI episode.12

For treatment of the first recurrent CDI episode, IDSA/SHEA states that fidaxomicin (standard or extended-pulsed regimen) is preferred; however, oral vancomycin (in a tapered and pulsed regimen or standard 10-day course) is an acceptable alternative.12 For patients with multiple recurrences, oral vancomycin (in a tapered and pulsed regimen), oral vancomycin followed by rifaximin, and fecal microbiota transplantation are options in addition to fidaxomicin.12

Vancomycin is the treatment of choice for fulminant CDI (characterized by hypotension or shock, ileus, or megacolon) in adults; a regimen that includes vancomycin (given orally, by nasogastric tube, and/or rectally as clinically indicated) in conjunction with IV metronidazole is recommended for the treatment of such infections, especially if ileus is present.12

Enterocolitis Caused by S. aureus

Vancomycin is used orally for the treatment of enterocolitis caused by S. aureus (including MRSA) in adults and pediatric patients.197,268

Clinical Perspective

Enterocolitis caused by S. aureus is rare, but several cases have been described in the literature.277,278,279,280,281,282 Patients often present with high fever, abdominal distension, and watery and/or bloody diarrhea that may lead to dehydration, shock, or multi-organ failure.277,278,279,280 In the reported cases, patient characteristics often included recent gastric surgery, underlying disease of the colon, recent antibiotic use, advanced age, immunocompromised state, decreased gastric acid production, or colonization with MRSA.277,278,279,280,281 Usually, patients were successfully treated with oral vancomycin,277,278,280,282 but in some cases required other antibiotic therapy or surgical intervention.279,281

Endocarditis

IV vancomycin is used for the treatment of endocarditis caused by staphylococci (e.g., S. aureus or S. epidermidis , including methicillin-resistant strains [MRSA]), streptococci (e.g., viridans streptococci, S. bovis [currently known as S. gallolyticus ]), or enterococci (e.g., E. faecalis ).155,266,267,450,452 Vancomycin also has been reported to be effective for the treatment of diphtheroid endocarditis.155,266,267

Clinical Experience

The American Heart Association (AHA) has published guidelines on the management of infective endocarditis in adults.450 A separate guideline is available for the treatment of infective endocarditis in children.452 Initial therapy of infective endocarditis is generally empiric; selection of an appropriate empiric antibiotic regimen is based on patient characteristics, prior antimicrobial exposures, microbiological findings, and other factors that help predict the presumed causative microorganism (e.g., injection drug use, indwelling cardiovascular medical devices, genitourinary disorders, chronic skin disorders, prosthetic valve replacement).450 Consultation with an infectious diseases specialist is recommended to define an appropriate empiric regimen.450 Once cultures are available and a pathogen is defined, the antimicrobial regimen should be adjusted accordingly.450 S. aureus is the most common cause of infective endocarditis in much of the developed world.450 Infective endocarditis also may be caused by coagulase negative staphylococci (e.g., S. epidermidis ).450 It is important to consider both pathogen groups in a patient with suspected staphylococci infection.450

Vancomycin is generally recommended for the treatment of endocarditis caused by MRSA.450 While a regimen of vancomycin administered alone is recommended for MRSA endocarditis in patients with native cardiac valves, adults with a prosthetic valve should receive a combination regimen (e.g., IV vancomycin, oral or IV rifampin, and IV or IM gentamicin) because of the high mortality rate associated with S. aureus -associated prosthetic-valve endocarditis.450 Those with native-valve endocarditis caused by methicillin-susceptible staphylococci generally should receive a regimen containing a β-lactam antibiotic (e.g., IV nafcillin, IV oxacillin, or IV cefazolin for penicillin-allergic patients); additional agents (e.g., oral or IV rifampin and IV or IM gentamicin) should be considered in patients with a prosthetic valve.450

Vancomycin has been effective alone or in combination with an aminoglycoside for the treatment of endocarditis caused by S. viridans or S. bovis (currently known as S. gallolyticus) .266 While a regimen of IV penicillin G (with or without IM or IV gentamicin) or IV or IM ceftriaxone (with or without IM or IV gentamicin) usually is recommended for the treatment of endocarditis caused by viridans streptococci or S. bovis ( S. gallolyticus) , IV vancomycin is a reasonable alternative for adults who cannot tolerate penicillin or ceftriaxone therapy.450

For endocarditis caused by enterococci (e.g., E. faecalis ), vancomycin has been reported to be effective only in combination with an aminoglycoside.155 For the treatment of enterococcal endocarditis, AHA guidelines state that a regimen of either IV penicillin G or IV ampicillin with IM or IV gentamicin is preferred for most adults;450 a regimen of IV vancomycin and IM or IV gentamicin is recommended for the treatment of enterococcal endocarditis only when the patient is unable to tolerate penicillin or ampicillin or in cases of endocarditis caused by E. faecalis resistant to penicillin.450

For information on management of endocarditis in pediatric patients, consult the most recent guidelines from AHA.452

Respiratory Tract Infections

Community-acquired Pneumonia

IV vancomycin has been used in the treatment of lower respiratory tract infections due to staphylococci.266

The American Thoracic Society (ATS) and Infectious Diseases Society of America (IDSA) have published guidelines on the management of adults with community-acquired pneumonia (CAP).512 Although not considered a drug of choice for empiric treatment of CAP, there are some instances when IV vancomycin is included in anti-infective regimens for CAP treatment.512

The guidelines recommend empiric coverage for MRSA (e.g., vancomycin or linezolid) in hospitalized adults with CAP only if locally validated risk factors for MRSA are present (e.g., prior isolation of MRSA from the respiratory tract).512 Appropriate blood cultures, sputum cultures, and/or nasal polymerase chain reaction (PCR) should be obtained to allow de-escalation or confirmation of the need for continued MRSA coverage.512

Nosocomial Pneumonia

IV vancomycin also has been used for empiric coverage against MRSA in patients with nosocomial pneumonia.315

For empiric treatment of ventilator-associated pneumonia or hospital-acquired pneumonia ( non -ventilator-associated), ATS and IDSA recommend use of anti-infectives that have a broad spectrum of activity against gram-positive (e.g., S. aureus ) and gram-negative (e.g., Pseudomonas aeruginosa ) bacteria.315 For the treatment of ventilator-associated pneumonia, an antibiotic active against MRSA (e.g., vancomycin, linezolid) should be included in the initial empiric regimen in patients with certain risk factors (i.e., risk of antimicrobial resistance, treatment in units where 10-20% of S. aureus isolates are methicillin-resistant, treatment in units where the prevalence of MRSA is not known).315 For the treatment of hospital-acquired pneumonia, an anti-infective active against MRSA should be included in the initial empiric regimen in patients with certain risk factors for MRSA infection (i.e., IV antibiotic use in the previous 90 days, hospitalization in units where over 20% of S. aureus isolates are methicillin-resistant, hospitalization in units where the prevalence of MRSA is not known, high risk of mortality).315

Skin and Skin Structure Infections

IV vancomycin is used in the treatment of various skin and skin structure infections due to staphylococci.155,266,267,543

The Infectious Diseases Society of America (IDSA) has published guidelines on the management of skin and skin structure infections.543 Such infections include purulent skin and soft tissue infections (e.g., cutaneous abscesses, furuncles, carbuncles, inflamed epidermoid cysts); an antibiotic that is active against MRSA is recommended in patients with these infections who have failed initial antibiotic treatment, have markedly impaired host defenses, or have systemic inflammatory response syndrome (SIRS) and hypotension.543

For patients with cellulitis associated with penetrating trauma, evidence of MRSA infection in another location, nasal colonization with MRSA, injection drug use, purulent drainage, or SIRS, vancomycin or another antibiotic effective against both MRSA and streptococci is recommended.543

Vancomycin is recommended for MRSA coverage in surgical site infections where risk factors for MRSA are high (e.g., nasal colonization with MRSA, prior MRSA infection, recent hospitalization, recent antibiotic use, high local prevalence of MRSA).543

Vancomycin also is recommended for broad-spectrum coverage in the treatment of necrotizing fasciitis.543

IDSA recommends use of vancomycin for initial empiric treatment of pyomyositis.543 For immunocompromised patients or in those with open trauma to the muscles, empiric treatment should also include an antibiotic active against gram-negative bacilli.543

Broad spectrum coverage with vancomycin plus either ampicillin/sulbactam, piperacillin/tazobactam, or a carbapenem is recommended in the treatment of clostridial gas gangrene or myonecrosis in the absence of definitive etiologic diagnosis.543

Antimicrobial Prophylaxis in Surgery

IV vancomycin (usually administered as a single preoperative dose) has been used for the prevention of surgical site infections.360,374 However, routine use of vancomycin for antimicrobial surgical prophylaxis is not recommended since such use may promote emergence of vancomycin-resistant enterococci or staphylococci.360,374

The American Society of Health-System Pharmacists (ASHP), Infectious Diseases Society of America (IDSA), Surgical Infection Society (SIS), and Society for Healthcare Epidemiology of America (SHEA) have published a joint guideline on antimicrobial prophylaxis in surgery.374 The guideline states that routine use of vancomycin is not recommended for any procedure; however, vancomycin may be included in the regimen of choice when a cluster of MRSA cases (e.g., mediastinitis after cardiac procedures) or methicillin-resistant coagulase negative staphylococci surgical site infections has been observed at a particular institution or in patients with known MRSA colonization or at high risk for MRSA colonization in the absence of surveillance data (e.g., recent hospitalization, nursing-home residents, patients receiving hemodialysis).374 Each institution is encouraged to develop guidelines for the proper use of vancomycin.374

Meningitis and Other CNS Infections

Vancomycin has been used for the empiric treatment of healthcare-associated ventriculitis and meningitis† in conjunction with an anti-pseudomonal β-lactam (e.g., cefepime, ceftazidime, meropenem).416

For the treatment of healthcare-associated ventriculitis and meningitis caused by MRSA, IDSA states that IV vancomycin is considered the drug of choice.416 However, if the vancomycin MIC is ≥1 mcg/mL, an alternative anti-infective agent (e.g., linezolid, daptomycin, trimethoprim/sulfamethoxazole) should be considered.416

Corynebacterium Infections

Vancomycin has been used for the treatment of infections caused by Corynebacterium †, including pulmonary infections, central venous catheter-related infections, osteomyelitis, endophthalmitis, and orthopedic infections.149,287,288,289,290,291,292,293 There also are case reports of intravitreal injection† of vancomycin to treat ocular infections caused by Corynebacterium ; however, safety and efficacy of this method of administration have not been established.155 289

Prevention of Perinatal Group B Streptococcal Disease

IV vancomycin has been used for prevention of perinatal group B streptococcal (GBS) disease† in certain women with a high-risk penicillin allergy and whose GBS isolate is not susceptible to clindamycin.158 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.158 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.158

Febrile Neutropenia

Although IV vancomycin is generally not recommended as a standard part of the initial antibiotic regimen for empiric anti-infective therapy in patients with febrile neutropenia†, consideration may be given to adding vancomycin to recommended empiric anti-infective therapy for other specific clinical conditions (e.g., suspected catheter-related infection, skin or soft-tissue infection, pneumonia, hemodynamic instability).787

General

Patient Monitoring

• Monitor renal function, especially in patients with underlying renal impairment, patients with risk factors for renal impairment, and patients receiving concomitant therapy with nephrotoxic drugs.197 Nephrotoxicity has been reported following both oral and IV administration of vancomycin and can occur during or after completion of therapy.197
• Therapeutic drug monitoring of vancomycin is recommended in certain patients and situations (e.g., serious methicillin-resistant S. aureus [MRSA] infections, pediatric patients).197,316
• Monitor patient's blood pressure during IV infusion of vancomycin.118,119,120,136,155

Administration

Vancomycin hydrochloride is administered by IV infusion for the treatment of systemic infections.155,157,266,267,269,270

Vancomycin hydrochloride is administered orally as capsules or solution for the treatment of Clostridioides difficile (formerly known as Clostridium difficile -associated diarrhea or enterocolitis caused by Staphylococcus aureus (including MRSA).12,197,268 If necessary, the parenteral form of vancomycin hydrochloride may be diluted and administered orally by mouth or nasogastric tube for these indications.157,266,267,272 Orally administered vancomycin is not effective for and should not be used for the treatment of systemic infections.197,268

Vancomycin has been administered rectally† in the treatment of fulminant CDI in adults.12

Safety and efficacy of intrathecal (intralumbar or intraventricular), intracameral, intravitreal, or intraperitoneal administration of vancomycin have not been established.155,266,267

Oral Administration

Commercially available vancomycin hydrochloride capsules,197 powder for oral solution,268 or the powder for IV administration157,266,267,272 can be used for oral administration.

Preparation of Oral Solution Using Commercially Available Powder for Oral Solution

Each bottle of commercially available vancomycin hydrochloride powder for oral solution must be reconstituted by a healthcare professional.268 The manufacturer-supplied premeasured diluent should be used to reconstitute the powder.268 Prior to reconstitution, tap the bottle on a hard surface to loosen the powder.268 Shake the bottle of diluent and then add approximately half of the diluent to the powder.268 Shake the mixture for approximately 45 seconds.268 Then, add the remaining diluent and shake the bottle for approximately 30 seconds.268 The final concentration of the solution is 25 or 50 mg/mL.268

Preparation of Oral Solution Using Parenteral Form of Vancomycin

When necessary, a solution for oral administration can be prepared by diluting the appropriate dose of the parental form of vancomycin hydrochloride lyophilized powder in 30 mL of water.267,272 Common flavoring syrups may be added to the solution to improve the taste.267,272 The 500-mg single-use vial should be used to prepare these oral solutions;267 ADD-Vantage^® vials should not be used to prepare such oral solutions,266 and premixed solutions of vancomycin hydrochloride injection should not be administered orally.155,269

IV Administration

Vancomycin hydrochloride usually is administered by intermittent IV infusion,266,267 but has been administered by continuous IV infusion.316 Various commercial IV preparations of the drug are available.155,157,267,269,270,271,272

Commercially available lyophilized powder in single-dose vials must be reconstituted and further diluted prior to administration.266,267,270,272 Each 250 mg of vancomycin hydrochloride powder for injection should be reconstituted with 5 mL of sterile water for injection to provide a solution containing 50 mg/mL.267,270,272 The reconstituted solution must be further diluted in at least 100 mL of a compatible diluent to a achieve a final vancomycin concentration of 5 mg/mL.267,270,272

Alternatively, ADD-Vantage^® vials labeled as containing 500 mg, 750 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.266 ADD-Vantage^® vials of the drug should be used only when actual doses of 500 mg, 750 mg, or 1 g are appropriate and should not be used in neonates, infants, or young children who require doses less than 500 mg.266

Vancomycin hydrochloride is also available as a pharmacy bulk packa reconstitution of the lyophilized powder contained in the bag and further dilution are required prior to administration.157,271 Consult the manufacturer's prescribing information for detailed instructions on preparation of this dosage form.157,271

Vancomycin hydrochloride is also commercially available as a frozen premixed solution containing 500 mg/100 mL, 750 mg/150 mL, or 1 g/200 mL in 5% dextrose injection or 0.9% sodium chloride injection in single-dose Galaxy plastic containers.155 The premixed solution 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.155 A precipitate may form in the frozen state; however, this will usually dissolve with little or no agitation upon reaching room temperature, and the potency of the drug is not affected.155 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.155

Vancomycin injection is also commercially available in premixed single-dose flexible bags containing 500 mg, 750 mg, 1 g, 1.25 g, 1.5 g, 1.75 g, and 2 g vancomycin in 100 mL, 150 mL, 200 mL, 250 mL, 300 mL, 350 mL, and 400 mL, respectively, of liquid (consisting of water and PEG together with the excipients NADA and lysine).269 This formulation of vancomycin should only be used in patients who require the entire dose of the drug contained in the bags and not any fraction thereof.269

Rate of Administration

Vancomycin should be administered as intermittent IV infusions. IV infusion should be given over a period of at least 1 hour to reduce the risk of infusion reactions.266,267

Avoid rapid IV infusion (e.g., over several minutes) which can cause exaggerated hypotension, including shock and rarely cardiac arrest.266,267 To minimize adverse effects, IV vancomycin should be administered at a rate not exceeding 10 mg/minute.266,267

Therapeutic Drug Monitoring

To achieve optimal serum vancomycin concentrations while minimizing toxicity in the treatment of serious infections, therapeutic drug monitoring of IV vancomycin is recommended in certain clinical situations.294,300,307,316 A consensus guideline on therapeutic monitoring of vancomycin for serious MRSA infections (e.g., bacteremia, sepsis, infective endocarditis, pneumonia, osteomyelitis, meningitis) has been published by the American Society of Health-System Pharmacists (ASHP), the Infectious Diseases Society of America (IDSA), the Pediatric Infectious Diseases Society (PIDS), and the Society of Infectious Diseases Pharmacists (SIDP).316

The primary predictive pharmacokinetic/pharmacodynamic parameter for vancomycin efficacy is the AUC/minimum inhibitory concentration (MIC) ratio.294,300,307,311 Based on in vitro, animal, and human data, an AUC/MIC ratio ≥400 mg×h/L (MIC determined by broth dilution [BMD]) has been established as the current accepted critical target for optimum vancomycin activity.300,307,308,310,311,312,313,314,316 Because of difficulty in estimating AUC in clinical practice, previous guidelines recommended monitoring trough concentrations as a surrogate marker for the AUC/MIC ratio.316 In this method of monitoring, an initial trough vancomycin level is evaluated after steady state has been reached (i.e., after approximately 4 doses).300,307,310 Then, the vancomycin dosage may be adjusted, if needed, to achieve the desired therapeutic trough concentration by calculating an optimized dose based on patient specific parameters (e.g., creatinine clearance, body weight).300,307,310 The risk of acute kidney injury with vancomycin increases as a function of the trough concentration, especially when the concentration exceeds 15-20 mg/L.316 Therefore, therapeutic monitoring has traditionally focused on maintaining trough concentrations between 15 and 20 mg/L for serious infections due to MRSA.316

The utility of trough vancomycin concentration monitoring is limited, and therefore this method may be insufficient to guide vancomycin dosing in all patients.307,308,310,311,313,316 Trough concentrations of 15-20 mg/L do not guarantee optimal exposures in patients with infections due to MRSA with a vancomycin MIC >1 mg/L and, conversely, trough concentrations of 15-20 mg/L may lead to AUCs associated with an increased risk of nephrotoxicity.308,311,312,313 Additionally, in some instances when trough vancomycin concentrations are considered to be subtherapeutic (i.e., <10 mg/L), the AUC may be in the therapeutic range.311 Therefore, trough-only monitoring, with a target of 15-20 mg/L, is no longer recommended based on efficacy and nephrotoxicity data in patients with serious infections due to MRSA.316 Current guidelines recommend AUC-guided therapeutic monitoring of vancomycin in both adults and pediatric patients with serious MRSA infections.316 There is insufficient evidence to provide recommendations on vancomycin therapeutic drug monitoring for patients with MSSA, noninvasive MRSA, or other infections.316

AUC-based monitoring targets a vancomycin AUC/MIC ratio of ≥400 mg×h/L while limiting high exposures associated with nephrotoxicity (i.e., vancomycin AUC/MIC ratio ≥ 600 mg×h/L).308,310,311,312,313,314 Two AUC-based therapeutic monitoring methods have been described.308,309,311,312,316 The first is the Bayesian method in which population pharmacokinetic modeling is done by software programs to optimize the dosage of vancomycin based on the collection of a single vancomycin serum concentration.294,308,311,313,316 The second method utilizes first-order pharmacokinetic equations based on the collection of 2 timed steady-state serum vancomycin concentrations to estimate the AUC.308,312,316 Although AUC-based therapeutic drug monitoring methods present logistical and clinical challenges, they may be emerging as preferred dosing strategies because of their potential to increase the proportion of patients who obtain vancomycin AUC/MIC ratios within therapeutic range, decreasing unnecessary high exposures to vancomycin and preventing associated toxicities.311,312,313,314,316

The current consensus guideline issued by ASHP, IDSA, PIDS, and SIDP recommends vancomycin monitoring to achieve sustained targeted AUC values for patients with serious MRSA infections.316 Vancomycin monitoring is also recommended for all patients at high risk for nephrotoxicity, patients with unstable renal function, and those receiving prolonged courses of therapy (more than 3 to 5 days) regardless of whether they have a MRSA infection.316 Given the narrow vancomycin AUC range for therapeutic effect and minimal risk of acute kidney injury, the most accurate and optimal way to manage vancomycin dosing should be through AUC-guided dosing and monitoring.316 The guideline states that in patients with suspected or definitive serious MRSA infections, an individualized target AUC/MIC_BMD ratio of 400-600 mg×h/L (assuming a vancomycin MIC_BMD of 1 mg/L) should be advocated to achieve clinical efficacy while improving patient safety.316 When transitioning to AUC/MIC monitoring, clinicians should conservatively target AUC values for patients with suspected or documented serious infections due to MRSA assuming a vancomycin MIC_BMD≤1 mg/L at most institutions.316 Given the importance of early appropriate therapy in patients with suspected or documented serious infections due to MRSA, vancomycin targeted exposure should be achieved early during the course of therapy, preferably within the first 24-8 hours.316 In such cases, use of the Bayesian method may be prudent since vancomycin concentrations can be collected more rapidly (within the first 24-48 hours rather than at steady state) to allow for early assessment of AUC target attainment.316

For additional information, consult the guideline document at [Web].316

Dosage

Dosage of vancomycin hydrochloride is expressed in terms of vancomycin.197,266,267

Oral Vancomycin

Clostridioides difficile (formerly known as Clostridium difficile ) Infection (CDI)

For the treatment of diarrhea caused by CDI, the usual adult oral dosage of vancomycin is 125 mg 4 times daily for 10 days.12,197,268

For the treatment of a first recurrence of CDI in adults, vancomycin in a tapered and pulsed regimen or vancomycin as a standard course may be given.12 An example of a tapered and pulsed regimen is as follows: vancomycin 125 mg 4 times daily for 10-14 days; followed by 125 mg twice daily for 7 days; then, 125 mg once daily for 7 days; then, 125 mg once every 2-3 days for 2-8 weeks.12

For the treatment of diarrhea caused by CDI in children, the usual oral dosage of vancomycin is 40 mg/kg daily given in 3 or 4 divided doses for 7-10 days.122,197,268 Dosage of oral vancomycin in children should not exceed 2 g daily.122,197,268

Enterocolitis Caused by S. aureus

For the treatment of enterocolitis caused by S. aureus (including MRSA), the usual adult oral dosage of vancomycin is 0.5-2 g daily given in 3 or 4 divided doses for 7-10 days.197,268

For the treatment of staphylococcal enterocolitis in pediatric patients, the usual oral dosage of vancomycin is 40 mg/kg daily given in 3 or 4 divided doses for 7-10 days.12,122,197,268 The total daily dosage should not exceed 2 g.122,197,268

IV Vancomycin

General Adult Dosage

For the treatment of serious or severe 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.155,266,267

A consensus guideline published by the American Society of Health-System Pharmacists (ASHP), the Infectious Diseases Society of America (IDSA), the Pediatric Infectious Diseases Society (PIDS), and the Society of Infectious Diseases Pharmacists (SIDP) provides recommendations for vancomycin dosing and monitoring in the treatment of serious MRSA infections (e.g., bacteremia, sepsis, infective endocarditis, pneumonia, osteomyelitis, meningitis).316 In critically ill patients with suspected or documented serious MRSA infections, a vancomycin loading dose of 20-35 mg/kg (based on actual body weight with a maximum dose of 3 g) can be considered for intermittent-infusion administration.316 A vancomycin loading dose of 20-25 mg/kg using actual body weight, with a maximum dose of 3 g, may be considered in obese adult patients with serious infections.316 Consult the guidelines for additional information ([Web])

General Pediatric Dosage

For neonates, the manufacturers suggest an initial IV vancomycin dose of 15 mg/kg, followed by 10 mg/kg either every 12 hours (in neonates <1 week of age) or every 8 hours (in infants 1 week to 1 month of age); close monitoring of serum vancomycin concentrations is recommended in these patients.155,266,267 Longer dosing intervals may be necessary in premature infants.155,266,267

The American Academy of Pediatrics (AAP) provides recommendations for vancomycin dosing in neonates based on serum creatinine concentrations.122 An initial IV loading dose of 20 mg/kg is recommended followed by a maintenance dosage in Table 1.122

For older infants and children with normal renal function, manufacturers recommend an IV vancomycin dosage of 10 mg/kg every 6 hours.155,266,267 AAP suggests that children ≥1 month of age receive IV vancomycin in a dosage of 45-60 mg/kg daily given in 3-4 divided doses.122

For children with normal renal function and suspected serious MRSA infections (e.g., pneumonia, pyomyositis, multifocal osteomyelitis, complicated bacteremia, necrotizing fasciitis), the consensus guideline published by ASHP, IDSA, PIDS, and SIDP recommends an initial IV vancomycin dosage of 60-80 mg/kg per day, in divided doses given every 6 hours for children 3 months to <12 years of age, or an initial vancomycin dosage of 60-70 mg/kg per day, in divided doses given every 6 to 8 hours, for pediatric patients ≥12 years of age.316 The consensus guideline states that the maximum empiric daily dose of IV vancomycin is usually 3.6 g in children with adequate renal function.316 Consult the guidelines for additional information ([Web])

Prevention of Neonatal Group B Streptococcal Disease

If IV vancomycin is used for intrapartum anti-infective prophylaxis of perinatal group B streptococcal (GBS) disease† in women with penicillin hypersensitivity who cannot receive clindamycin, the American College of Obstetrics and Gynecologists (ACOG) recommends an IV dosage of 20 mg/kg (not exceeding 2 g) administered every 8 hours until delivery.158 When indicated, such prophylaxis is initiated at the time of labor or rupture of membranes.158

Antimicrobial Prophylaxis in Surgery

For antimicrobial prophylaxis† in adults undergoing certain cardiac, neurosurgical, orthopedic, thoracic (noncardiac), or vascular surgical procedures when use of vancomycin is considered necessary, a single 15-mg/kg dose of IV vancomycin should be given.374

Because vancomycin should be administered by IV infusion over 1-2 hours, the infusion should be started within 120 minutes prior to the time of incision.374

Special Populations

Hepatic Impairment

Limited data suggest dosage adjustments of vancomycin are not necessary based on hepatic impairment.264

Renal Impairment

In patients with impaired renal function, doses and/or frequency of administration of vancomycin must be modified.266

The consensus guideline published by ASHP, IDSA, PIDS, and SIDP recommends vancomycin loading and maintenance doses for patients with serious MRSA infections who are receiving hemodialysis (see Table 2).316

The guideline recommends an IV loading dose of 20-25 mg/kg based on actual body weight in patients with serious MRSA infections who are receiving continuous renal replacement therapy (CRRT) at conventional, KDIGO-recommended effluent rates.316 The initial vancomycin maintenance dosage for such patients should be 7.5-10 mg/kg every 12 hours.316 Consult the guidelines for additional information ([Web])

Geriatric Patients

Vancomycin dosage should be adjusted accordingly in geriatric patients; consider the greater frequency of renal impairment in this age group.266

Obese Patients

The consensus guideline published by ASHP, IDSA, PIDS, and SIDP recommends an IV vancomycin loading dose of 20-25 mg/kg (up to a maximum dose of 3 g) based on actual body weight in obese adult patients with serious infections.316 Initial maintenance doses of vancomycin can be calculated using a population pharmacokinetic estimate of vancomycin clearance and the target AUC in obese patients.316 Empiric maintenance doses for most obese patients usually do not exceed 4.5 g/day, depending on renal function.316 Early and frequent monitoring of AUC exposure is recommended for dosage adjustment, especially when empiric doses exceed 4 g/day.316 Consult the guidelines for additional information ([Web])

Contraindications

• Hypersensitivity to vancomycin.197,266,267,268
• Commercially available frozen vancomycin hydrochloride injection in 5% dextrose may be contraindicated in patients with known allergy to corn or corn products.155

Warnings/Precautions

Warnings

Risk of Embryo-Fetal Toxicity Due to PEG 400 and NADA Excipients

Certain formulations of vancomycin injection contain the excipients polyethylene glycol (PEG 400) and N -acetyl D -alanine (NADA), which may cause fetal malformations.269 A boxed warning about this risk is included in the prescribing information for these formulations.269 Formulations of vancomycin containing PEG 400 and NADA should be avoided in pregnant patients.269

Other Warnings and Precautions

Nephrotoxicity

Nephrotoxicity has occurred during parenteral vancomycin therapy; such toxicity rarely has been observed during oral vancomycin therapy.146,155,197,266,267,268,294

Vancomycin-induced nephrotoxicity (i.e., acute kidney injury) 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. Rarely, the drug has been associated with acute tubular necrosis and acute interstitial nephritis.133,134,155,266,267,307 In clinical studies, the reported rate of nephrotoxicity associated with vancomycin is highly variable ranging from 0 (when the drug is not used concomitantly with other nephrotoxic drugs) up to 40% (when vancomycin is used concomitantly with other nephrotoxic drugs).294,307 Patient characteristics that increase the risk of vancomycin-associated nephrotoxic adverse effects include advanced age, reduced kidney function, dehydration, reduced renal mass, female sex, obesity, hypoalbuminemia, and sepsis.307 An increased risk of acute kidney injury is associated with increased duration of therapy and increased exposures or serum concentrations of vancomycin.155,266,267,307,311,312 Although there is conflicting data regarding the causal relationship between vancomycin exposures and nephrotoxicity, many studies have demonstrated an increased risk of nephrotoxicity in patients with trough serum vancomycin concentrations ≥15 mg/L when compared with those with trough concentrations <15 mg/L.294,307,308 With regard to vancomycin AUC, limited data indicate that an AUC ≥600 mg×h/L may be associated with increased risk of nephrotoxicity.308,312,314

Because vancomycin may cause nephrotoxic effects, the drug should be used with caution in patients with impaired renal function.155,266,267 Renal function should be monitored in all patients receiving vancomycin.155,266,267

Ototoxicity

Ototoxicity has occurred during parenteral vancomycin therapy; such toxicity rarely has been observed during oral vancomycin therapy.146,155,197,266,267,268,294 Reported ototoxicity included damage to the auditory branch of the eighth cranial nerve and permanent deafness, vertigo, dizziness, and tinnitus.132,134,266,267

Ototoxicity may be transient or permanent.155,197,266,267 It has been reported mostly in patients who receive excessive doses or prolonged IV therapy, patients with underlying hearing loss, or those receiving concomitant therapy with another ototoxic agent, such as an aminoglycoside.266,267 The incidence of ototoxicity associated with vancomycin use has been variable between 1-9%.307 Ototoxicity usually has been associated with serum or blood vancomycin concentrations of 80-100 mcg/mL, but has occurred with concentrations as low as 25 mcg/mL.132 Serial auditory function tests may be used to minimize the risk of ototoxicity.155,266,267

Local Effects

Vancomycin 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.266 Pain and thrombophlebitis may occur after IV administration; to minimize this, it is recommended that the drug be administered slowly as a dilute solution (2.5 to 5 g/L) and that venous access sites be rotated.266

Infusion-related Reactions

Rapid IV administration of vancomycin has resulted in a hypotensive reaction known as vancomycin flushing syndrome (previously referred to as “red man syndrome”).112,118,119,120,136,137,138,139,143,155,238,244,247,294 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;112,118,119,120,135,136,137,142,143 the latter manifestations may also occur in the absence of hypotension.120,135,136,142,238,244,247 Wheezing, dyspnea, angioedema, urticaria, pruritus, and shock may also occur; rarely, cardiac arrest121,138,155 or seizures139 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;136,140,141,142,294 the release of histamine also appears to be responsible for the usual manifestations (e.g., erythema, rash, pruritus) of the “red” characterization.135,136,142 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.118,120,135,136,143,155,238 If the hypotensive reaction is severe, the use of antihistamines, corticosteroids, or IV fluids may be necessary.118,120,136 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;112,118,119,120,136,138,139,244,247 however, the reaction may also occur rarely when the drug is infused over a period of ≥1 hour.120,143,247

To minimize the risk of a hypotensive reaction, vancomycin should be infused over a period of at least 1 hour at a rate ≤10 mg/minute, and the patient's blood pressure should be monitored during the infusion.118,119,120,136,155 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).118,119,120,139,144,294 Pretreatment with antihistamines may be of benefit.136,141,144,244,294 If attempts to minimize the reaction fail, use of another anti-infective agent may be necessary.144 The reaction reportedly has occurred in more than 50% of healthy individuals given vancomycin but less frequently when the drug is used therapeutically.238

In one study, intradermal skin tests with vancomycin were used to assess the possibility of predicting the severity of vancomycin-associated anaphylactoid reactions.166 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 the reaction.166 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.165,167

Concomitant administration of vancomycin and anesthetic agents has been associated with an increased frequency of infusion-related events (e.g., hypotension, flushing, erythema, urticaria, pruritus).155,266,267 Infusion-related events may be minimized by the administration of vancomycin as a 60-minute infusion prior to anesthetic induction.155,266,267

In at least one patient, oral administration of vancomycin resulted in the vancomycin flushing syndrome.147 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.147 Administration of a parenteral antihistamine provided some relief.147

The possibility that infusion reactions, including potentially severe hypotension, may occur with IV vancomycin should be considered.112,118,119,120,136,137,138,139,143,238,244,247 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.155

Other Dermatologic and Sensitivity Reactions

Urticaria, exfoliative dermatitis, macular rashes, eosinophilia, vasculitis, a shock-like state, transient anaphylaxis, linear IgA bullous dermatosis,155,266,267 toxic epidermal necrolysis,155,266,267 vasculitis associated with IV administration,155,266,267 inflammation at the injection site,155,266,267 and, occasionally, vascular collapse have been reported in patients receiving vancomycin. The drug also has been associated with Stevens-Johnson syndrome.131,155,266,267 Skin and subcutaneous disorders and drug rash with eosinophilia and systemic symptoms (DRESS) have been observed in postmarketing experience.155,266,267

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.113,165

Ocular Effects

Hemorrhagic occlusive retinal vasculitis (HORV), including permanent blindness, has occurred in patients receiving vancomycin by intracameral or intravitreal injection during or after cataract surgery.155 Safety and efficacy of vancomycin administered by the intracameral or intravitreal route have not been established by adequate and well-controlled trials, and vancomycin is not indicated for prophylaxis of endophthalmitis.155

Hematologic Effects

Adverse hematologic effects reported in patients receiving vancomycin include neutropenia, eosinophilia, and thrombocytopenia.155,266,267 Neutropenia, which appears to be rapidly reversible following discontinuance of the drug, usually has occurred 7 or more days after initiation of vancomycin therapy or after a total dose of more than 25 g of the drug.155,266,267

Although a causal relationship to vancomycin has not been established, reversible agranulocytosis (granulocytes <500/mm³) has been reported rarely in patients receiving the drug.130,155,266,267

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.155,266,267

C. difficile-associated Diarrhea and Colitis

Treatment with anti-infectives alters normal colon flora and may permit overgrowth of Clostridioides difficile (formerly known as Clostridium difficile ).12,213,215

C. difficile infection (CDI) and C. difficile -associated diarrhea and colitis (CDAD; also known as antibiotic-associated diarrhea and colitis or pseudomembranous colitis) have been reported with the use of nearly all anti-infectives, including IV vancomycin, and may range in severity from mild diarrhea to fatal colitis.12,155

Selection and Use of Anti-infectives

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.155,197,266,267,268 When selecting or modifying anti-infective therapy, use results of culture and in vitro susceptibility testing.155,197,266,267,268 In the absence of such data, consider local epidemiology and susceptibility patterns when selecting anti-infectives for empiric therapy.155,197 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).155,197,266,267,268 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.155,197,266,267,268

Information on test methods and quality control standards for in vitro susceptibility testing of antibacterial agents and specific interpretive criteria for such testing recognized by the FDA is available at [Web].265 For most antibacterial agents, FDA recognizes the standards published by the Clinical and Laboratory Standards Institute (CLSI).265

Prolonged use of vancomycin may result in overgrowth of nonsusceptible organisms.155,197,266,267,268 The patient should be carefully monitored and appropriate therapy should be instituted if a superinfection occurs.155,197,266,267,268 Because antibiotic-associated CDI 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.155,266,267

Use of, and exposure to, anti-infectives are major risk factors for the emergence of anti-infective-resistant pathogens,115,217,218,219,220,221,222,223,225 and anti-infective resistance results in increased morbidity, mortality, and healthcare costs.217,225 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.115,217,219,220,221,222,223 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.115,217,219,220,221,222,223 Clinicians should recognize that unnecessary and inappropriate use of anti-infectives has important, far-reaching implications for human health globally.217,223,225

Subsequently, other updated guidance regarding implementation of antibiotic stewardship programs, therapeutic vancomycin monitoring, and treatment of specific infections has been published to aid in the appropriate use of antibiotics, including vancomycin.299,300,301,315,416,450,512,543 For additional information, the current IDSA clinical practice guidelines available at [Web] should be consulted.

Warning and Precautions Related to Oral Formulations

Orally administered vancomycin capsules or solution must be used for the treatment of Clostridioides difficile (formerly known as Clostridium difficile ) infection (CDI; C. difficile -associated diarrhea [CDAD]) and enterocolitis caused by S. aureus .197,268 Parenterally administered vancomycin does not effectively treat such infections.197,268 Because vancomycin is not systemically absorbed following oral administration, vancomycin capsules and oral solution are not effective for other types of infections.197,268

Following oral administration of vancomycin for diarrhea caused by CDI, clinically important vancomycin serum concentrations have been reported.197,268 Systemic absorption of vancomycin following oral administration may occur in patients with inflammatory disorders of the intestinal mucosa.197,268 Such patients receiving high doses of oral vancomycin may be at risk for experiencing systemic adverse effects and serum concentration monitoring may be warranted in certain situations (i.e., patients with renal insufficiency and/or colitis, concomitant use with an aminoglycoside antibiotic).197,268

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.155,266,267 Chemical peritonitis usually disappears shortly after discontinuance of intraperitoneal vancomycin.155,266,267

Other adverse effects of vancomycin include chills and fever.155,266,267 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.239

Specific Populations

Pregnancy

There was no evidence of teratogenicity when vancomycin was administered IV to rats in dosages up to 200 mg/kg daily (1180 mg/m² or equivalent to the recommended maximum human dosage based on mg/m²) or to rabbits in dosages up to 120 mg/kg daily (1320 mg/m² or 1.1 times the recommended maximum human dosage based on mg/m²).197 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/m² or 0.74 times the maximum recommended human dosage based on mg/m²).197,268

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 injection drug abuse- during pregnancy.155,197,266,267,268 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.155,197,266,267 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.155,197,266,267

In a prospective study, no major adverse effects were observed in mothers or their newborns when IV vancomycin was administered at the time of delivery.268 This study included 55 pregnant women with positive group B Streptococcus culture with resistance to clindamycin or unknown sensitivity and a high-risk penicillin allergy.268 Vancomycin dosage ranged from 1 g every 12 hours to 20 mg/kg (maximum individual dose 2 g) every 8 hours.268 None of the newborns had sensorineural hearing loss; although renal function of the neonates was not assessed, all neonates were discharged in good condition.268

Vancomycin should be used during pregnancy only when clearly needed.155,197,266,267

Lactation

Vancomycin is distributed into milk following IV administration.155,266,267 Systemic absorption of oral vancomycin is very low and it is not known whether the drug distributes into human milk following oral administration.197 However, IV and oral vancomycin should be used with caution in nursing women.155,197,266,267 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.155,197,266,267

Pediatric Use

Safety and efficacy of oral vancomycin have not been established in pediatric patients.197

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.266,267 Close monitoring of serum vancomycin concentrations may be warranted in pediatric patients,155,266,267 especially neonates and young infants.266,267

Safety of the chemical components that may leach out of the plastic containers of commercially available frozen vancomycin injections has not been established in children.155

Geriatric Use

In clinical studies of oral vancomycin, 54% of patients were >65 years of a 197,268 of these, 40% were >65-75 years of age and 60% were >75 years of age.197,268 In these studies, geriatric patients treated with oral vancomycin capsules for diarrhea associated with CDI were more likely to develop nephrotoxicity during or after completion of therapy.197,268 Renal function should be monitored during and after treatment with oral vancomycin in all geriatric patients, including those with normal renal function.197,268

Geriatric patients >65 years of age may take longer to respond to oral vancomycin therapy compared with younger patients.197,268 Clinicians should be aware of the appropriate duration of oral vancomycin treatment in geriatric patients and therapy should not be prematurely discontinued or prematurely switched to an alternate therapy.197,268

IV vancomycin dosage in geriatric patients should be adjusted based on the degree of renal impairment.266,267 Because geriatric patients may have decreasing glomerular filtration with increasing age, increased serum vancomycin concentrations may occur if dosage is not adjusted in these patients.266,267

Renal Impairment

Vancomycin is only minimally removed by hemodialysis when a low-flux capillary is used (e.g., cuprophan)107,108,307 or peritoneal dialysis,109,110,123 including continuous ambulatory peritoneal dialysis.124,125,126 Hemodialysis using a high-flux capillary (e.g., polysulfone, polyacrylonitrile, polymethylmethacrylate) results in removal of approximately 30-46% of the drug with a subsequent rebound effect of 16-36% after completion of hemodialysis due to recirculation of vancomycin from protein binding sites over a 3-6 hour period.307 The drug is substantially removed by hemodiafiltration.127,307

Common Adverse Effects

IV: Local effects (pain and thrombophlebitis); infusion reactions; hypersensitivity reactions.

Oral solution: Nausea, abdominal pain, and hypokalemia.268

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.155,266,267 These drugs should be used with caution in patients receiving vancomycin therapy.164

Aminoglycosides

In vitro, the antibacterial effects of vancomycin and aminoglycosides are synergistic against many strains of Staphylococcus aureus , Streptococcus bovis (also known as S. gallolyticus) , enterococci ( Enterococcus faecalis ), and viridans streptococci.155,266,267

Anesthetics

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).155,266,267 Erythema and histamine-like flushing has occurred in pediatric patients receiving vancomycin and anesthetic agents concomitantly.155,266,267 Infusion-related events may be minimized by the administration of vancomycin as a 60-minute infusion prior to anesthetic induction.155

Description

Vancomycin is bactericidal and binds to the bacterial cell wall causing blockage of glycopeptide polymerization. This effect, which occurs at a site different from that affected by the penicillins, produces immediate inhibition of cell wall synthesis and secondary damage to the cytoplasmic membrane. Magnesium, manganese, calcium, and ferrous ions reduce the degree of adsorption of vancomycin to the cell wall, but the in vivo importance of this interaction is unknown.

Spectrum

Vancomycin is active in vitro and in vivo against many gram-positive bacteria, including Staphylococcus aureus (including methicillin-resistant S. aureus [MRSA]),155,197,266,267,268,294 S. epidermidis (including methicillin-resistant strains),155,266,267,294 nonenterococcal group D streptococci ( Streptococcus bovis [also known as S. gallolyticus ]),155,266,267,294 enterococci ( Enterococcus faecalis ),155,266,267,294 viridans streptococci,155,266,294 Corynebacterium ,155,266,267,294 and Clostridioides (including C. difficile ).197,268,294 The drug also is active in vitro against S. pyogenes (group A β-hemolytic streptococci),155,266,267,294 S. agalactiae (group B streptococci),155,266,267,294 S. pneumoniae (including penicillin-resistant strains),155,266,267 Listeria monocytogenes ,155,266,267,294 Actinomyces ,155,266,267,294 and Lactobacillus .155,266,267,294

Vancomycin is not active against gram-negative bacteria, mycobacteria, or fungi.155,266,267,294

Resistance

Resistance in Enterococci

Resistance to vancomycin has been reported in Enterococcus faecalis , E. faecium (VREF), E. gallinarum , E. casseliflavus , and E. flavescens 169,170,171,172,173,174,175,176,177,217,219,222,223,225,256 and strains of enterococci resistant to vancomycin have been reported with increasing frequency.169,172,173,174,175,176,217,222,223,225,301,302

Several different forms of vancomycin resistance have been identified in enterococci, including high-level resistance and low-level resistance.169,173,175,176,223,225,256,303,304 Strains of enterococci with high-level resistance generally require vancomycin concentrations of 128 mcg/mL or more and strains with low-level resistance generally require concentrations of 16-64 mcg/mL for in vitro inhibition.176,256 High-level vancomycin resistance has been reported in E. faecium and E. faecalis , appears to be plasmid mediated, and can be induced by exposure to vancomycin and, to a lesser extent, exposure to teicoplanin.169,170,173,175,223 Low-level vancomycin resistance has been reported in E. faecium , E. faecalis , E. gallinarum , E. casseliflavus , and E. flavescens 169,256 and may also be induced by exposure to vancomycin, but may or may not be induced by exposure to teicoplanin.169,170,173,175

High-level vancomycin resistance most frequently has been associated with the presence of a certain protein and a phenotype, VanA; high- to variable-level resistance usually has been associated with the presence VanB.159,169,173,175,176,223,256,294,303,304 Other phenotypes, (i.e., VanC, D, E, G, L, M, N) also have been identified.159,170,173,223,256,303 VanA, VanB, and VanD are associated with synthesis of the altered D-ala D-lac target;294 VanC, VanE, VanG, and VanL are associated with the altered D-ala D-ser target.294 In general, VanA resistance is high level, transferable (i.e., acquired resistance), and accompanied by high-level teicoplanin resistance.256 VanB resistance is variable in level, transferable, and not accompanied by teicoplanin resistance; VanC resistance is low level, not transferable (i.e., intrinsic resistance), and not associated with teicoplanin resistance; and VanD is associated with low- to high-level resistance to vancomycin and teicoplanin.223,256,303 Transferable genes (e.g., VanA, VanB) can be spread from organism to organism whereas non-transferable genes (e.g., VanC) are less likely to cause serious infections and have not been associated with outbreaks.256

Some strains of E. faecium or E. faecalis resistant to vancomycin may be susceptible in vitro to linezolid, daptomycin, or tigecycline.253,254,255,303 Strains of vancomycin-resistant enterococci may also be resistant to other drugs (e.g., aminoglycosides, ampicillin, penicillin G, imipenem, tetracyclines, synergistic combinations of β-lactam anti-infectives).149,168,173,175,176,177,223 Enterococci resistant to linezolid also has been observed.303 These multidrug-resistant strains of enterococci have been reported with increasing frequency.172,173,175,176,177,223 Although telavancin and dalbavancin are inactive against VanA enterococci, oritavancin retains activity against VanA-type vancomycin-resistant enterococci.159 Newer oxazolidinones (e.g., tedizolid) also have demonstrated efficacy against multi-drug resistant gram-positive isolates, including vancomycin-resistant enterococci.303

Resistance in Staphylococci

In vitro exposure of staphylococci to increasing concentrations of glycopeptide anti-infectives can produce strains with decreased susceptibility and emergence of vancomycin-resistant strains of S. haemolyticus and S. epidermidis have been reported in patients receiving the drug.114,115,168,220,221,226,227,228,229,230,231 The first vancomycin-resistant S. aureus isolate in the United States was reported in 2002 and other isolates have been subsequently reported.159,294,305,306

Although the mechanisms of vancomycin intermediate-resistant S. aureus have not been fully elucidated, several mutations are known to contribute to the development of these resistant isolates including genes encoding 2 component regulatory systems controlling transcription of genes in cell wall synthesis (e.g., graRS, vraSR, walKR) and genes encoding DNA-dependent RNA polymerase β-subunit (e.g., rpoB).276,305,306 Isolates with intermediate resistance to vancomycin have thicker cell walls containing subunits that are able to bind vancomycin extracellularly and have several altered metabolic pathways.159,276,294 Vancomycin-resistant S. aureus (i.e., MIC ≥16 mcg/mL) is conferred by VanA encoded on transposing Tn1546, which was originally a part of a vancomycin-resistant enterococci conjugative plasmid.294,276,305,306 Oritavancin retains activity against vancomycin-resistant S. aureus .159

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.101,117,197,294 Oral bioavailability usually is less than 5%;264 however, limited data suggest that clinically important serum concentrations may occur following enteral or oral administration of vancomycin in some patients with colitis and/or in those with renal impairment.101,117,197,264

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.155 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.155

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.155 Small amounts of the drug are distributed into bile.102

Vancomycin does not readily distribute into CSF in the absence of inflammation unless serum concentrations are exceedingly high.155,237 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.155,237 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.237 However, the relationship between CSF concentrations and clinical efficacy of vancomycin in the treatment of meningitis is unclear.237

Vancomycin is 30-60% bound to serum proteins.103,155,264 Protein binding may be lower (19-29%) in patients with hypoalbuminemia (e.g., burn patients, those with end-stage renal disease).264

Vancomycin readily crosses the placenta and is distributed into cord blood.155 Vancomycin is distributed into milk.155

Elimination

The serum elimination half-life of vancomycin in adults with normal renal function has been reported to average 4-7 hours;155,264 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.264

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.264 In children 2.5-11 years of age, half-life of the drug is reported to be 5.6 hours.264

The serum elimination half-life of vancomycin is increased in patients with renal dysfunction.104,105,106,155,264 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.106 However, because of increased clearance, half-life of vancomycin averages 4 hours in burn patients.264

Vancomycin does not appear to be metabolized.155,264 Following oral administration, the drug is excreted mainly in feces.197 Following IV administration, about 75-90% of a dose is eliminated unchanged in urine by glomerular filtration155,264 and only small amounts are excreted in bile.

Advice to Patients

• Advise patients that vancomycin should only be used to treat bacterial infections and not used to treat viral infections (e.g., the common cold).155,197
• Importance of completing full course of therapy, even if feeling better after a few days.155,197
• Advise patients that skipping doses or not completing the full course of 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.155,197
• Importance of reporting possible manifestations of adverse effects to the clinician, including ototoxicity, nephrotoxicity, infusion site reactions, and hypersensitivity.266,267
• Risk of diarrhea; usually ends when vancomycin is discontinued.269 If watery and bloody stools (with or without stomach cramps and fever) occur as late as two or more months after having taken the last dose of the drug, advise patient to contact their physician as soon as possible.269
• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, and any concomitant illnesses.266,267
• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.266,267
• Importance of advising patients of other important precautionary information. (See Cautions.)

Additional Information

Overview^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

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