Vancomycin

Mechanism of Action

Vancomycin is a glycopeptide antibiotic that exerts its bactericidal effect by inhibiting the polymerization of peptidoglycans in the bacterial cell wall.[9] The bacterial cell wall contains a rigid peptidoglycan layer with a highly cross-linked structure composed of long polymers of N-acetylmuramic acid (NAM) and N-acetylglucosamine (NAG). Vancomycin binds to D-alanyl D-alanine, which inhibits glucosyltransferase (peptidoglycan synthase) and the P-phospholipid carrier, thereby preventing the synthesis and polymerization of NAM and NAG within the peptidoglycan layer. This inhibition weakens bacterial cell walls and ultimately causes leakage of intracellular components, resulting in bacterial cell death.[10] Vancomycin is only active against gram-positive bacteria.[11]

Pharmacokinetics

Absorption: Oral vancomycin has a bioavailability of less than 10%. Vancomycin has a rapid onset of action with a serum peak concentration immediately following the completion of the intravenous infusion. The onset of action of oral vancomycin is currently unknown.

Distribution: Vancomycin is distributed widely (0.4 to 1.0 L/kg) in body tissues and fluids, excluding cerebrospinal fluid (CSF) with non-inflamed meninges. The drug exhibits a protein binding of approximately 55%.

Metabolism: Vancomycin does not undergo any signification metabolism and is primarily excreted unchanged. Vancomycin exhibits a biphasic elimination half-life, with a relatively quick initial phase and a terminal half-life of 4 to 6 hours in healthy adults with normal renal function. The elimination half-life is significantly prolonged in patients with renal dysfunction, and close monitoring is necessary for these patients.

Elimination: Intravenous vancomycin injection is primarily eliminated by glomerular filtration in the kidney (75% via urine). Vancomycin's clearance ranges from 0.71 to 1.31 mL/min/kg in adults with normal renal function. Oral vancomycin is predominantly excreted in feces.

Administration

Available Dosage Forms and Strengths 

Vancomycin is typically administered intravenously or orally and is available in 5 mg/mL IV solution, 10 mg/mL in NaCl 0.9% solution, or 5 mg/mL in dextrose 5% or NaCl 0.9% solution. Vancomycin is also available in 500 mg, 1 g, 1.25 g, 1.5 g, and 10 g vials of sterile powder for reconstitution before intravenous administration. Vancomycin hydrochloride should be diluted using a secure intravenous route to avoid local irritation and phlebitis reactions. Rectal administration is also possible for patients with Clostridium difficile infection; this is an off-label use. The selection of an appropriate administration method depends on the type and location of the infection. Vancomycin has poor oral bioavailability; it is typically administered intravenously to treat most infections.[12] 

Adult Dosage

Intravenous

Intravenous vancomycin injection can treat MRSA infections and other susceptible gram-positive organisms. However, it is not effective for the treatment of C difficile infections. The dose of vancomycin required depends on the type and severity of infection, the patient's overall clinical presentation, renal function, and body weight. The desired intravenous dose should be administered slowly over at least 60 minutes. The frequency of administration ranges from every 8 to 24 hours.

• The usual daily IV dose is 2 grams divided as 1 g every 12 hours or 500 mg every 6 hours. Each dose is administered over 60 minutes or longer. Diluted vancomycin hydrochloride concentrations of no more than 5 mg/mL are recommended for adults. A concentration of up to 10 mg/mL may be used in patients needing fluid restriction.
• Subsequent doses should be adjusted based on renal function, age, and serum trough concentrations. Serum trough concentrations require close monitoring in all patients.[13] Infusion-related events may occur at any rate or concentration.

Oral

Oral vancomycin exhibits poor systemic absorption and is only effective for treating intestinal infections. Therefore, its only indications are for the treatment of Clostridioides difficile-associated diarrhea (CDAD), pseudomembranous colitis, and staphylococcal enterocolitis. Oral vancomycin is not an appropriate treatment option for systemic infections affecting other organs or parts of the body. Oral vancomycin is available in 125 mg and 250 mg capsules and 250 mg/5 mL oral solution.

• The recommended dose for CDAD is 125 mg, administered orally 4 times daily for 10 days.
• The total daily dosage for staphylococcal enterocolitis is 500 mg to 2 g, administered orally in 3 to 4 divided doses for 7 to 10 days.

Determining the exact dose and length of therapy depends on multiple factors, including indication, assessment of the patient's clinical presentation, and the severity of an infection. Due to its low systemic absorption, oral vancomycin does not require dosage adjustment for patients with renal impairment. Moreover, routine serum trough monitoring is not recommended for patients who only receive oral vancomycin.[14]

Specific Patient Populations

Renal impairment: Reduced renal function can cause vancomycin to accumulate in the body, thereby increasing the risk of adverse effects. Dosing adjustments and close monitoring of vancomycin trough concentrations are necessary for all patients with renal impairment. These patients should be advised to contact their provider if they experience symptoms of reduced kidney function, such as decreased urine output, swelling, and abdominal pain, as vancomycin may exacerbate renal impairment.[13]

Pregnancy considerations: Oral vancomycin capsules are categorized as a pregnancy category B drug. Intravenous vancomycin is category C. Vancomycin should not be used during pregnancy unless the benefits outweigh the risks of the medication. If treatment with vancomycin is necessary, close monitoring of maternal blood is recommended to reduce the risk of ototoxicity and nephrotoxicity in the fetus. Animal studies have not yet determined any evidence of fetal harm from maternal vancomycin use. However, vancomycin crosses the placenta and has been detected in fetal serum, amniotic fluid, and cord blood. Patients who become pregnant while taking vancomycin should contact their healthcare provider immediately. Moreover, it is essential to note that pregnant patients may require higher doses of vancomycin to achieve therapeutic concentrations due to alterations in pharmacokinetics, such as an increased volume of distribution and total plasma clearance.

Breastfeeding considerations: Vancomycin is excreted in breast milk following intravenous administration. In contrast, oral vancomycin is minimally absorbed and exhibits limited excretion through breast milk. Breastfeeding patients who receive intravenous vancomycin should consult with their provider before continuing, as it may affect their baby's health. Nevertheless, vancomycin is recommended to treat C difficile infections in breastfeeding patients. Careful assessment regarding the discontinuation of breastfeeding is recommended before initiating vancomycin therapy in patients who are nursing.

Pediatric patients: For patients 1 month and older, the usual intravenous vancomycin dosage is 10 mg/kg every 6 hours. Each dose should be administered over at least 60 minutes. Close monitoring of serum vancomycin concentrations may be warranted in these patients.

• Patients younger than 1 month: An initial dose of 15 mg/kg is recommended for neonates, followed by 10 mg/kg every 12 hours for pediatric patients in the first week of life and every 8 hours after that up to the age of 1 month. Each dose should be administered over 60 minutes.
• Premature infants: Vancomycin clearance is reduced with postconceptional age. Therefore, longer dosing intervals may be necessary. Close monitoring of serum vancomycin concentrations is recommended in these patients.

Older patients: Older adults are more prone to toxicity during IV vancomycin administration due to age-related changes in renal function, volume of distribution, and accumulation. These patients must be carefully monitored and require a more conservative regimen.

Adverse Effects

Intravenous

Common adverse effects of intravenous vancomycin injection include nephrotoxicity, hypotension, and hypersensitivity reactions (eg, anaphylaxis).[15][16]

According to the Infectious Diseases Society of America, the American Society of Health-System Pharmacists, and the Pediatric Infectious Diseases Society, the risk of potential toxicity, including acute kidney injury, is highest if the trough concentration exceeds 15 mg/L and the AUC exceeds 650 mg·h/L.[17]

Vancomycin infusion reaction, previously known as vancomycin flushing syndrome or red man syndrome, is a reaction associated with rapid intravenous infusion of vancomycin. Symptoms include flushing, pruritus, and an erythematous rash on the face, neck, and upper torso. Signs of this infusion reaction often appear 4 to 10 minutes after starting or shortly after completing an infusion. The incidence of this reaction varies between 3.7% and 47%. However, there is a direct correlation between the increased incidence of vancomycin infusion reaction and faster vancomycin administration rates. Rapid infusion of vancomycin can also result in accompanying angioedema and hypotension. Therefore, prolonging the infusion time is the primary mitigation strategy. Premedication with antihistamines, such as diphenhydramine or hydroxyzine, can also aid in preventing the occurrence of vancomycin infusion reaction. The most severe forms of this reaction frequently occur in children and patients younger than 40.

Less common adverse effects include local phlebitis, chills, drug fever, skin rash, eosinophilia, and reversible neutropenia. Rarely, DRESS syndrome (drug rash with eosinophilia and systemic symptoms), ototoxicity, thrombocytopenia, vasculitis, and Stevens-Johnson syndrome have been reported.[18]

Oral

Gastrointestinal adverse effects, such as abdominal pain and nausea, are commonly observed in patients receiving oral vancomycin. Dysgeusia, or distorted sense of taste, is another common adverse reaction unique to oral vancomycin administration. Patients should seek medical attention if these adverse effects become bothersome. Many of these adverse effects are temporary.

Less common adverse effects of oral vancomycin include peripheral edema, fatigue, headache, diarrhea, flatulence, vomiting, back pain, urinary tract infection, and fever. Reports exist of rare cases of increased serum creatinine, VFS, interstitial nephritis, nephrotoxicity, ototoxicity, thrombocytopenia, and vasculitis using oral vancomycin.

Drug-Drug Interactions

Coadministration of other medications, along with vancomycin, may increase the risk of adverse effects and toxicity. Therefore, dosing adjustments, additional monitoring, and consideration of alternative treatment should merit attention when combining vancomycin with certain medications. Caution is necessary when administering vancomycin with other nephrotoxic agents such as aminoglycosides, amphotericin products, and IV contrast. Diluted vancomycin hydrochloride should be administered before any intravenous anesthetic agents to reduce the risk of infusion-related adverse reactions.

Contraindications

Vancomycin is contraindicated for patients with a known hypersensitivity to the drug or any component within the formulation.[19]

Bacterial Resistance

As with other antimicrobials, prolonged or inappropriate treatment with vancomycin can lead to bacterial resistance, such as vancomycin-resistant enterococci (VRE).[20] Providers must be aware of increased antimicrobial resistance patterns and practice appropriate antimicrobial stewardship. Moreover, patients should receive counseling on the importance of medication adherence to prevent the development of multidrug-resistant infections.

Warnings and Precautions

Nephrotoxicity: Vancomycin IV or oral can lead to acute kidney injury (AKI) and renal failure due to tubulointerstitial nephritis or acute tubular injury. AKI is characterized by increased serum creatinine (Cr) and blood urea nitrogen (BUN). The risk of AKI is higher with prolonged exposure, increased vancomycin serum levels, concomitant administration of other nephrotoxic drugs, including piperacillin-tazobactam, preexisting renal impairment, volume depletion, critical illness, and comorbid conditions that predispose patients to renal impairment. Serum vancomycin concentrations and renal function monitoring are recommended for all patients receiving vancomycin hydrochloride intravenously.

Nephrotoxicity has also been reported during and following oral vancomycin hydrochloride capsule therapy. The risk of nephrotoxicity is elevated in patients older than 65. In these patients, renal function should be monitored before, during, and following treatment to detect potential vancomycin-induced nephrotoxicity.

Ototoxicity: Transient or permanent ototoxicity has been reported during intravenous and oral vancomycin therapy. This condition manifests as dizziness, hearing loss, tinnitus, or vertigo. If ototoxicity occurs, discontinue the use of vancomycin hydrochloride for injection.

Severe dermatologic reactions: Drug reaction with eosinophilia and systemic symptoms (DRESS), toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), acute generalized exanthematous pustulosis (AGEP), and linear IgA bullous dermatosis (LABD) can occur during vancomycin therapy. Cutaneous signs or symptoms include mucosal lesions, skin rashes, and blisters.

Vancomycin should be discontinued at the first appearance of signs and symptoms of the following reactions:

• Neutropenia: Reversible neutropenia may occur in patients administered vancomycin orally or intravenously. 
• Infusion reactions: Rapid IV administration may cause hypotension, wheezing, dyspnea, muscular and chest pain, shock and cardiac arrest, and urticaria. The severity may be higher in younger patients, particularly children, and with concomitant administration of muscle relaxant anesthetics. Rapid IV administration of vancomycin may also cause an infusion reaction, manifested as pruritus and erythema involving the face, neck, and upper torso. The reaction depends on both the concentration and the vancomycin administration rate. 

Unapproved administration routes: Inflammation at vancomycin injection sites has been reported. Vancomycin irritates tissue and must be administered using a secure intravenous route to reduce the risk of local irritation and phlebitis. Thrombophlebitis may occur; slow drug infusion and rotating venous access sites can minimize the severity and frequency.

Administration of vancomycin injection via intrathecal, intraventricular, intraperitoneal, intramuscular (IM), or intravitreal routes is not FDA-approved or recommended. Pain, tenderness, and necrosis can occur with IM injection of vancomycin or inadvertent extravasation. Intraperitoneal administration during continuous ambulatory peritoneal dialysis (CAPD) can result in chemical peritonitis, identified from cloudy dialysate with or without variable degrees of abdominal pain and fever. Chemical peritonitis would be resolved after discontinuation of intraperitoneal vancomycin.

Hemorrhagic occlusive retinal vasculitis (HORV) causing permanent vision loss has occurred in patients receiving vancomycin intracamerally or intravitreally during or after cataract surgery. Vancomycin is not approved or indicated for endophthalmitis prophylaxis.

C difficile-associated diarrhea (CDAD): CDAD has been reported for almost all antibacterial drugs, including IV vancomycin, leading to overgrowth of C difficile productive of toxins A and B. This condition ranges in severity from mild diarrhea to fatal colitis. Infections involving toxin-producing strains of C difficile are associated with higher morbidity and mortality, as these strains are resistant to antimicrobial drugs and may necessitate colectomy. CDAD must be ruled out in all patients with diarrhea following antibacterial use. Careful medical history is required as CDAD may be present for over 2 months after administering antibacterial drugs. If CDAD is suspected or confirmed, ongoing antibacterial medicine may need to be discontinued. Appropriate protein supplementation, electrolyte and fluid management, antibacterial treatment of C difficile, and surgical evaluation may be indicated. Pseudomembranous colitis due to C difficile developing is reported in patients who received intravenous vancomycin. 

Drug-resistant bacteria: Administering vancomycin (orally or IV) without a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to benefit the patient and can increase the risk of developing drug-resistant bacterial strains. 

Absorption after oral administration: After multiple oral doses of vancomycin, clinically high serum concentrations are reported in some patients being treated for active C difficile-induced pseudomembranous colitis. Patients with gastrointestinal inflammatory disorders may also have more systemic vancomycin absorption and a higher risk for developing adverse reactions associated especially at high doses or prolonged use of oral vancomycin; therefore, serum concentration monitoring should be recommended for specific situations (eg, concomitant aminoglycoside administration) or patients with renal insufficiency or colitis.

Monitoring

Patients receiving vancomycin therapy require monitoring to ensure the safety and efficacy of the medication. Periodic renal function tests and complete blood cell counts can help monitor the patient’s response to the drug.[2]

Assessment of vancomycin trough concentrations is strongly recommended for patients receiving intravenous vancomycin injections and the following conditions:

• A severe or invasive infection
• Critical illness
• Impaired or unstable renal function
• Morbid obesity (BMI ≥40 kg/m²)
• Advanced age
• Inadequate response to therapy after 3 to 5 days
• Concomitant use of nephrotoxic agents (ie, aminoglycosides, piperacillin-tazobactam, amphotericin B, cyclosporine, loop diuretics, nonsteroidal anti-inflammatory drugs, contrast dye). 

Monitoring vancomycin trough concentrations in stable patients with normal renal function is also recommended to assess clinical response. Obtaining vancomycin serum trough concentrations allows healthcare professionals to evaluate the efficacy of the dosing regimen and clearance of the drug. The target therapeutic serum trough concentration varies depending on the indication and typically ranges between 10 to 20 μg/mL.

Serum trough concentrations should ideally be obtained within 30 minutes before administering a dose at steady-state conditions. Steady-state is typically achieved after the third dose of vancomycin.

Guidelines: According to the IDSA guidelines, obtaining serial trough concentrations is generally used for therapeutic monitoring. However, monitoring the AUC is preferred for severe MRSA infections (eg, infective endocarditis, bacteremia, osteomyelitis, meningitis, sepsis, and pneumonia). Therapeutic monitoring is generally not required for uncomplicated skin and soft tissue infections in patients who are not obese and have normal kidney function.[17]

Unlike intravenous vancomycin injection, oral vancomycin typically does not require serum concentration monitoring due to a lack of significant systemic absorption.

Clinicians must monitor patients receiving vancomycin therapy for signs and symptoms of ototoxicity. Serial auditory function testing may be used to minimize the risk of cytotoxicity. Clinicians should also periodically obtain a leukocyte count in patients undergoing prolonged vancomycin therapy or receiving concomitant medicines that cause neutropenia.

Toxicity

Vancomycin therapy is correlated with nephrotoxicity and ototoxicity.[2]

Although there are numerous case reports of acute renal failure attributed to vancomycin use, there is currently limited data suggesting a direct causal relationship. The proposed nephrotoxicity mechanism involves vancomycin's oxidative effect on cells of the proximal renal tubule, causing tubular ischemia. Common risk factors for nephrotoxicity include preexisting kidney disease, concurrent administration of nephrotoxic medications, advanced age, and dehydration. Although vancomycin-induced nephrotoxicity is commonly reversible, it can be challenging to differentiate this condition from acute tubulointerstitial nephritis and worsening renal function due to uncontrolled infection. In the absence of a causative explanation, vancomycin-induced nephrotoxicity may be identified by elevated serum creatinine levels. Adjusting vancomycin dosages based on the patient's estimated creatinine clearance is a common method to prevent nephrotoxicity. Patients who exhibit signs of acute renal failure precipitated by vancomycin therapy should promptly discontinue treatment. Nephrotoxicity has been reported in patients receiving oral and intravenous vancomycin. Cases of nephrotoxicity associated with oral vancomycin have typically been encountered in patients older than 65.

Ototoxicity is a rare complication of vancomycin monotherapy and is common in patients receiving excessive vancomycin doses, concurrent ototoxic medications (eg, aminoglycosides, loop diuretics, antineoplastic agents), and those with underlying hearing loss conditions. Treatment should stop if patients experience signs of cytotoxicity, such as tinnitus, loss of hearing, and unbalanced movements. Vancomycin-induced ototoxicity may be irreversible for some patients. Serial auditory function testing may be beneficial in identifying early symptoms.[21]

Enhancing Healthcare Team Outcomes

Vancomycin has been available for more than 70 years. Until recently, it was an empiric therapy for treating most gram-positive organisms. Vancomycin is a very effective medication, provided it is administered intravenously. However, bacterial strains resistant to vancomycin are becoming more common, necessitating its conservative use today. The pharmacist should ensure the clinician does not empirically order vancomycin when other alternatives are available.

Most hospitals have a drug committee composed of physicians and pharmacists who ensure that vancomycin use is under controlled circumstances. In many hospitals, permission is required from the infectious disease expert or the pharmacist before administering vancomycin. Vancomycin is one of the few drugs that are still effective against MRSA. Vancomycin concentrations require monitoring as it is both ototoxic and nephrotoxic; the pharmacist must ensure the provider orders laboratory testing of serum drug concentrations.[22] Staff may adjust the dose of vancomycin based on these concentrations or the patient's renal function. Nursing is typically the first staff member to see a vancomycin order and should always speak to the pharmacist to determine if the order is appropriate. The pharmacist should verify the patient's medication administration record before granting permission to administer. Finally, the nurse should educate the patient on the adverse drug reaction associated with vancomycin administration (eg, VFS) and the possibility of ear and renal dysfunction. Without an interprofessional team approach involving specialists, nurses, and pharmacists, the empirical use of vancomycin will eventually render the drug useless for most infections.

The only way to control drug costs and empirical prescribing is through a committee that oversees what drugs providers prescribe and why. The committee should have a list of drugs that cannot be prescribed without a particular need when less expensive alternatives are available to control healthcare costs.[23] Accomplishing these goals for vancomycin therapy requires an interprofessional team approach, including clinicians, nurses, and infectious disease specialists (doctors and pharmacists) working collaboratively to achieve optimal patient outcomes.