Continuing Education Activity

Vancomycin is a medication used in the treatment of serious Gram-positive bacterial infections. It is in the cell wall synthesis inhibitor class of antimicrobial medications. This activity reviews the indications, action, and contraindications for vancomycin as a valuable antimicrobial in treating Gram-positive bacterial infections. This activity will highlight the mechanism of action, adverse event profile, pharmacokinetics, and drug interactions pertinent for members of the interprofessional team in the treatment of patients with clinically significant Gram-positive bacterial infections.

Objectives:

• Describe the mechanism of action of vancomycin.
• Review the therapeutic uses of vancomycin.
• Explain the potential side effects of vancomycin.
• Outline the importance of collaboration and coordination among the interprofessional team to enhance patient care when dosing and monitoring vancomycin therapy.

Indications

Vancomycin is a tricyclic glycopeptide antibiotic originally derived from the organism Streptococcus orientalis. Vancomycin is used to treat and prevent various bacterial infections caused by gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). It is also effective for streptococci, enterococci, and methicillin-susceptible Staphylococcus aureus (MSSA) infections.[1] Vancomycin has numerous FDA-approved and off-label clinical uses.[2]

FDA-approved Clinical Uses

• Clostridioides difficile-associated diarrhea (oral administration)[3]
• Staphylococcus enterocolitis
• Pseudomembranous colitis
• Endocarditis: Diphtheroid, Enterococcal, Staphylococcal, and Streptococcal species
• Staphylococcal infections: septicemia, skin and soft tissue infections, bone infections, lower respiratory tract infections, etc.

Off-Label Clinical Uses

• Catheter-related infections[4]
• Community-acquired bacterial pneumonia
• Clostridioides difficile infection
• Neonatal prophylaxis for Group B streptococcus
• Intra-abdominal infections due to MRSA or ampicillin-resistant enterococci
• Bacterial meningitis
• Bacterial endophthalmitis (systemic or intravitreal administration)
• Native vertebral osteomyelitis
• Peritonitis
• Prosthetic joint infection
• Necrotizing skin and soft tissue infections
• Surgical prophylaxis
• Surgical-site infections

Mechanism of Action

Vancomycin is a glycopeptide antibiotic that exerts its bactericidal effect by inhibiting the polymerization of peptidoglycans in the bacterial cell wall.[5] 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.[6] Vancomycin is only active against gram-positive bacteria.[7]

Administration

Vancomycin is FDA-approved for administration by either intravenous injection or oral route. Rectal administration is an off-label use of vancomycin useful in treating Clostridium difficile infection. The administration is dependent on the type and location of the infection. Vancomycin has poor oral bioavailability; therefore, its administration is via the intravenous route to treat most infections.[8]

Intravenous vancomycin injection can treat MRSA infections and other susceptible gram-positive organisms. It 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. It is also available as a sterile powder for reconstitution in 500 mg, 1 g, 1.25 g, 1.5 g, and 10 g per vial. The dose of vancomycin required is dependent 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 and should be adjusted based on renal function, age, and serum trough concentrations. Serum trough concentrations require close monitoring in all patients.[9]

Oral vancomycin has low 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 currently available as 125 mg and 250 mg capsules and 250 mg / 5 mL oral solution. It is typically administered four times a day for 7 to 10 days. However, the determination of the exact dose and length of therapy is dependent 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 renal impairment. Moreover, routine serum trough monitoring is not a recommendation for patients who are only receiving oral vancomycin.[10]

Pharmacodynamics/Kinetics

Route of administration: Intravenous, oral, rectal administration (off-label)

Inhibition of bacterial growth: Slowly bactericidal

PK/PD parameter: AUC: MIC

Absorption: Oral vancomycin has a bioavailability of less than 10%.

Onset of action: 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: Large volume of distribution (0.4 L/kg to 1.0 L/kg) in body tissues and fluids, excluding cerebrospinal fluid (CSF) with non-inflamed meninges

Protein Binding:  approximately 55%

Metabolism: No evident metabolism (excreted unchanged)

Clearance: 0.71 mL/minute/kg to 1.31 mL/minute/kg in adults with normal renal function

Half-life: Vancomycin has a bi-phasic elimination half-life, with its initial half-life being relatively quick 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. Close monitoring is necessary for these patients.

Excretion:  Intravenous vancomycin injection is primarily eliminated by glomerular filtration in the kidney (75% via urine). Oral vancomycin predominantly gets excreted in feces.

Adverse Effects

Intravenous Vancomycin Injection

Common adverse effects of intravenous vancomycin injection include nephrotoxicity, hypotension, and hypersensitivity reactions.[11] Anaphylaxis is a type of hypersensitivity reaction that can occur with vancomycin.[12]

Vancomycin flushing syndrome (VFS), previously known as redman syndrome, is an infusion-related 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 VFS often appear 4 to 10 minutes after starting or shortly after completing an infusion. The incidence of VFS varies between 3.7 and 47% in patients. However, there is a direct correlation between the increased incidence of VFS with faster rates of vancomycin administration. Rapid infusion of vancomycin can lead to angioedema and hypotension, which accompany VFS. Reports show that the most severe forms of this reaction frequently occur in children and patients younger than age 40. Initially, the infusion can be held. Therefore, prolonging the infusion time is the primary management strategy used to mitigate VFS. Nevertheless, premedication with antihistamines, such as diphenhydramine or hydroxyzine, can be useful in preventing the occurrence of VFS.

Less common adverse effects include local phlebitis, chills, drug fever, skin rash, eosinophilia, and reversible neutropenia. In rare situations, patients have reported DRESS syndrome (drug rash with eosinophilia and systemic symptoms), ototoxicity, thrombocytopenia, vasculitis, and Stevens-Johnson syndrome.[13]

Oral Vancomycin

Gastrointestinal adverse effects, such as abdominal pain and nausea, are commonly seen with oral vancomycin. In addition, dysgeusia or distorted sense of taste is a common adverse effect unique to vancomycin oral solution. Patients should seek medical attention if these adverse effects are severe and bothersome. Note that 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.

Contraindications

Vancomycin is contraindicated in patients with a known hypersensitivity reaction to the drug or any component within the formulation.[14]

Clinical Considerations

Although vancomycin does not have many contraindications, there are some important clinical considerations to keep in mind during patient care.

Geriatric Considerations

Elderly patients are more prone to vancomycin toxicity with IV administration due to age-related changes in renal function, volume of distribution, and accumulation. These patients need to be carefully monitored and require a more conservative dosage regimen.

Pregnancy Considerations

Oral vancomycin capsules are categorized as a category B drug for use in pregnancy. In contrast, intravenous vancomycin injection 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 researchers have detected it 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 comparison, oral vancomycin has minimal systemic absorption and, therefore, limited excretion through breast milk. Breastfeeding mothers 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 Clostridioides difficile infections in breastfeeding women. Careful assessment regarding the discontinuation of breastfeeding is recommended before initiating vancomycin therapy in nursing mothers.

Renal Impairment                                                                                      

The reduced renal function can cause vancomycin to accumulate in the body, thereby increasing the risk of adverse effects. Dosing adjustments are necessary for renal impairment. Close monitoring of vancomycin trough concentrations is necessary for all patients with renal impairment. Patients should receive counsel 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.[9]

Bacterial Resistance

As with other antimicrobials, prolonged or inappropriate treatment with vancomycin can lead to bacterial resistance, such as vancomycin-resistant enterococci (VRE).[15] Providers need to 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.

Drug Interactions

Co-administration 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.

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 a strong recommendation in the following patients receiving intravenous vancomycin injections:

• A severe or invasive infection
• Critical illness
• Impaired or unstable renal function
• Morbid obesity (body mass index greater than or equal to 40 kg/m)
• Advanced age
• Inadequate response to therapy after three to five days
• Concomitant use of nephrotoxic agents (i.e., 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 satisfactory clinical response. Obtaining vancomycin serum trough concentrations allows healthcare professionals to evaluate the efficacy of the vancomycin dosing regimen and clearance of the drug by the individual patient. The target therapeutic serum trough concentration varies depending on the indication and typically ranges between 10 mcg/mL to 20 mcg/mL.

Serum trough concentrations should ideally be drawn immediately (30 minutes or less) before administering a dose at steady-state conditions. Typically, steady-state occurs after the third dose of vancomycin. Unlike intravenous vancomycin injection, oral vancomycin typically does not require serum concentration monitoring due to a lack of systemic absorption.

Toxicity

Nephrotoxicity and ototoxicity have correlations with the use of vancomycin.[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 mechanism of nephrotoxicity is renal tubular ischemia due to the oxidative effect of vancomycin on cells of the proximal renal tubule. Common risk factors for nephrotoxicity include preexisting renal impairment, concurrent use of nephrotoxic medications, advanced age, and dehydration. Although vancomycin-induced nephrotoxicity is commonly reversible, it can be challenging to differentiate it from acute interstitial nephritis and worsening renal function due to uncontrolled infection. Vancomycin-induced nephrotoxicity is identifiable by increases in serum creatinine in the absence of a causative explanation. Dosing vancomycin based on estimated creatinine clearance is a commonly used technique to prevent nephrotoxicity. Patients who experience signs of acute renal failure precipitated by vancomycin use should promptly discontinue their therapy. It is also important to note that there are reports of cases of nephrotoxicity with both oral and intravenous vancomycin use. Cases of nephrotoxicity associated with oral vancomycin have typically been in patients over 65.

Ototoxicity is a rare complication associated with vancomycin monotherapy. It is common in patients receiving excessive vancomycin doses, concurrent ototoxic medications (e.g., 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. It merits noting that vancomycin-induced ototoxicity may be irreversible in some cases. Auditory function testing may be beneficial to identify early symptoms.[16]

Enhancing Healthcare Team Outcomes

Vancomycin has been available for more than 70 years. It was an empiric therapy to treat most gram-positive organisms until recently. It is a very effective drug but requires intravenous administration. However, drug resistance to vancomycin is becoming more common, and there need to be limitations on its use. The pharmacist is vital for ensuring that 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 fact, in many hospitals, one has to require permission from the infectious disease expert or the pharmacist before using vancomycin. Vancomycin is one of the few drugs that are still active against MRSA. The other issue with vancomycin is that the drug concentrations require monitoring as it is both ototoxic and nephrotoxic; the pharmacist has to ensure the healthcare provider orders serum drug concentrations.[17] The medical staff must check these concentrations, and the dose adjusted based on renal function. The nurse is probably the first 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 giving the green light. Finally, the nurse should educate the patient on the side effects of vancomycin, like VFS, and the possibility of ear and renal dysfunction. Without an interprofessional team approach involving clinicians, specialists, nursing, and pharmacists, the empirical use of vancomycin will render the drug useless for most infections.

The only way to control drug costs and empirical prescribing is by having a drug committee that oversees what drugs healthcare providers prescribe and why. Finally, the committee should have a list of drugs that cannot be prescribed without a special need when less expensive alternatives are available to control healthcare costs.[18] Accomplishing these goals for vancomycin therapy requires an interprofessional team approach, including clinicians, nurses, and infectious disease specialists (both doctors and pharmacists), all working collaboratively to achieve optimal patient results. [Level 5]