Vancomycin


Article Author:
Shivali Patel
Charles Preuss


Article Editor:
Fidelia Bernice


Editors In Chief:
Venkat Minnaganti
John Brusch
Janak Koirala


Managing Editors:
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Frank Smeeks
Kristina Soman-Faulkner
Benjamin Eovaldi
Radia Jamil
Sobhan Daneshfar
Pritesh Sheth
Hassam Zulfiqar
Steve Bhimji
John Shell
Matthew Varacallo
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Hajira Basit
Phillip Hynes
Kavin Sugumar


Updated:
5/18/2019 2:22:40 PM

Indications

Vancomycin is a tricyclic glycopeptide antibiotic originally derived from the organism Streptococcus orientalis. Vancomycin is used for the treatment and prevention of various bacterial infections caused by gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). It is also utilized for streptococci, enterococci, and methicillin-susceptible Staphylococcus aureus (MSSA) infections. Vancomycin has numerous FDA-approved and off-label clinical uses.[1][2][3]

FDA-approved Clinical Uses of Vancomycin:

  • Clostridium difficile-associated diarrhea (oral administration)
  • 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 of Vancomycin include:

  • Catheter-related infections
  • Community-acquired bacterial pneumonia
  • Clostridium 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. The bacterial cell wall contains a rigid peptidoglycan layer that has 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 (peptidylglycan synthase) and the P-phospholipid carrier, thereby preventing the synthesis and polymerization of NAM and NAG within in the peptidoglycan layer. This inhibition weakens bacterial cell walls and ultimately causes leakage of intracellular components, resulting in bacterial cell death. Vancomycin is only active against gram-positive bacteria.[4][5]

Administration

Vancomycin is FDA-approved for administration by either intravenous injection or oral route. Rectal administration is an off-label use of vancomycin that can be used to treat Clostridium difficile infection. Administration is dependent on the type and location of the infection. Vancomycin has poor oral bioavailability; therefore, it must be administered intravenously in order to treat most infections.[6][7]

Intravenous vancomycin injection can be used to treat MRSA infections as well as other susceptible gram-positive organisms. 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 should be closely monitored in all patients.

Oral vancomycin has low systemic absorption and is only effective for treating intestinal infections. Therefore, it is only indicated for treatment of Clostridium 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 capsules and an oral solution. It is typically administered four times a day for a period of 7 to 10 days. However, the exact dose and length of therapy are determined by multiple factors, including indication, assessment of the patient’s clinical presentation, and the severity of an infection. Oral vancomycin does not require dosage adjustment for renal impairment due to its low systemic absorption. Moreover, routine serum trough monitoring is not recommended for patients who are only receiving oral vancomycin.[8]

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-inflammed 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 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 required in these patients.

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

Adverse Effects

Adverse Effects of Intravenous Vancomycin Injection:

Common adverse effects of intravenous vancomycin injection include nephrotoxicity, hypotension, and hypersensitivity reactions. Anaphylaxis is a type of hypersensitivity reaction that can be seen with vancomycin.[7][9][10]

Red man 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 red man syndrome often appear 4 to 10 minutes after starting or shortly after the completion of an infusion. The incidence of red man syndrome varies between 3.7% and 47% in patients. However, there is a direct correlation between the increased incidence of red man syndrome with faster rates of vancomycin administration. Rapid infusion of vancomycin can lead to angioedema and hypotension, which accompany red man syndrome. Reports show the most severe forms of this reaction frequently occur in children and patients younger than the age of 40. Prolonging the infusion time is the primary management strategy used to mitigate red man syndrome. Nevertheless, premedication with antihistamines, such as diphenhydramine or hydroxyzine, can be used to prevent the occurrence of red man syndrome.

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.

Adverse Effects of Oral Vancomycin:

Gastrointestinal adverse effects, such as abdominal pain and nausea, are commonly seen with oral vancomycin. Dysgeusia or distorted sense of taste is a common adverse effect unique to vancomycin oral solution. Patients should be told to 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. 

Rare cases of increased serum creatinine, red man syndrome, interstitial nephritis, nephrotoxicity, ototoxicity, thrombocytopenia, and vasculitis have also been reported with the use of oral vancomycin.

Contraindications

Vancomycin is contraindicated in patients with a known hypersensitivity reaction to the drug or any component within the formulation.[11]

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, the volume of distribution, and accumulation. These patients need to be carefully monitored and may require a more conservative dosage regimen.

Pregnancy Considerations:

Oral vancomycin capsules are currently listed as a category B drug for use in pregnancy whereas the intravenous vancomycin injection is listed as 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 important 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.

Breast-Feeding 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 be advised to consult with their provider before continuing as it may affect the health of their baby. Nevertheless, vancomycin is recommended for the treatment of Clostridium 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 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.

Bacterial Resistance:

Similar to other antimicrobials, prolonged or inappropriate treatment with vancomycin can lead to bacterial resistance such as Vancomycin-resistant enterococci (VRE). Providers need to be aware of increased antimicrobial resistance patterns and practice appropriate antimicrobial stewardship. Moreover, patients should be counseled 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 be considered when combining vancomycin with certain medications. Caution is advised when administering vancomycin with other nephrotoxic agents such as aminoglycosides, amphotericin products, and IV contrast.

Monitoring

Patients receiving vancomycin therapy should be monitored to ensure safety and efficacy of the medication. Periodic renal function tests and complete blood cell counts are frequently used to monitor the patient’s response to the medication.[3]

Assessment of vancomycin trough concentrations are strongly recommended in the following patients receiving intravenous vancomycin injection:

  • 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 in order 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) prior to administration of a dose at steady-state conditions. Typically, steady-state is achieved after the third dose of vancomycin.

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

Toxicity

Nephrotoxicity and ototoxicity have been associated with the use of vancomycin.[3]

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 an uncontrolled infection. Vancomycin-induced nephrotoxicity can be identified 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 cases of nephrotoxicity have been reported with both oral and intravenous vancomycin use. Cases of nephrotoxicity associated with oral vancomycin have typically been reported in patients over 65 years of age.

Ototoxicity is a rare complication associated with vancomycin monotherapy. It is commonly reported 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 be discontinued if patients experience signs of ototoxicity such as tinnitus, loss of hearing, and unbalanced movements. It should be noted that vancomycin-induced ototoxicity may be irreversible in some cases. Auditory function testing may be beneficial to identify early symptoms.

Enhancing Healthcare Team Outcomes

Vancomycin has been around for more than 70 years. Up until recently, it was empirically used to treat most gram-positive organisms. It is a very effective drug but has to be administered intravenously. However, drug resistance to vancomycin is now very common and its use has to be controlled. The pharmacist is vital for ensuring that the drug is not empirically ordered when other alternatives are available.

Most hospitals have a drug committee composed of physicians and pharmacist who ensure that vancomycin is not routinely prescribed. In fact, in many hospitals, one has to require permission from the infectious disease expert or the pharmacist prior to use of vancomycin. Vancomycin is one of the few drugs that is still active against MRSA. The other problem with vancomycin is that the drug concentrations have to be monitored as it is both ototoxic and nephrotoxic; the pharmacist has to ensure that serum drug concentrations are ordered by the healthcare provider. These concentrations have to be checked and the dose adjusted based on renal function. The nurse is probably the first person to see the order of vancomycin and should always speak to the pharmacist to determine if the order is appropriate. Finally, the nurse should educate the patient on the side effects of vancomycin like the red man syndrome and the possibility of ear and renal dysfunction. Without a team approach, 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, to control health care costs, the committee should have a list of drugs that cannot be prescribed without a special need, when there are less expensive alternatives available.[12][13] (Level V)


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Vancomycin - Questions

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Which of the following about vancomycin is false?



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A 2-year-old previously healthy boy develops orbital cellulitis with positive blood culture for methicillin-resistant Staphylococcus aureus (MRSA). The child is treated with vancomycin at an initial dose of 40 mg/kg/day in four divided doses and serum concentrations of vancomycin are monitored. Which of the following is not an adverse reaction requiring monitoring?



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Which of the following is not an appropriate use of vancomycin?



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Which of the following can be an adverse effect of rapid intravenous administration of vancomycin?



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In a patient on intravenous vancomycin, which of the following is unlikely?



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Which of the following is a common adverse effect of vancomycin?



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Which clinical feature is not associated with vancomycin?



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What is the most common adverse effect of vancomycin?



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Which of the following inhibits cell wall synthesis?



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What is the mechanism of action of vancomycin?



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Which is least likely to occur during vancomycin therapy?



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A 45-year-old woman develops pruritis, erythematous rash on the face and neck, and hypotension during initial intravenous antimicrobial treatment. Which of the following most likely caused this patients presentation?



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A 54-year-old woman is admitted with MRSA sepsis. The provider decides to initiate treatment with vancomycin. He notices that there are two formulations of vancomycin available on formula and questions if vancomycin is an appropriate treatment for the patient. He discusses this issue with you. How would you respond?



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Which of the following micro-organisms is not included in vancomycin's antimicrobial spectrum?



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A client has been diagnosed with septicemia and started on a regimen of intravenous vancomycin by a licensed independent practitioner. The nurse prepares to administer the ordered dose. What steps before and during the administration should the nurse take to ensure the drug is administered safely? Select all that apply.



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Vancomycin - References

References

Ishii H,Hirai K,Sugiyama K,Nakatani E,Kimura M,Itoh K, Validation of A Nomogram for Achieving Target Trough Concentration of Vancomycin: Accuracy in Patients with Augmented Renal Function. Therapeutic drug monitoring. 2018 Aug 27     [PubMed]
Kampmeier S,Kossow A,Clausen LM,Knaack D,Ertmer C,Gottschalk A,Freise H,Mellmann A, Hospital acquired vancomycin resistant enterococci in surgical intensive care patients - a prospective longitudinal study. Antimicrobial resistance and infection control. 2018     [PubMed]
Monteiro JF,Hahn SR,Gonçalves J,Fresco P, Vancomycin therapeutic drug monitoring and population pharmacokinetic models in special patient subpopulations. Pharmacology research     [PubMed]
Lee T,Pang S,Abraham S,Coombs GW, Antimicrobial Resistant CC17 Enterococcus faecium: The Past, the Present and the Future. Journal of global antimicrobial resistance. 2018 Aug 24     [PubMed]
Bartoletti M,Giannella M,Tedeschi S,Viale P, Multidrug-Resistant Bacterial Infections in Solid Organ Transplant Candidates and Recipients. Infectious disease clinics of North America. 2018 Sep     [PubMed]
Butler-Laporte G,De L'Étoile-Morel S,Cheng MP,McDonald EG,Lee TC, MRSA colonization status as a predictor of clinical infection: A systematic review and meta-analysis. The Journal of infection. 2018 Aug 11     [PubMed]
Levitus M,Perera TB, Vancomycin-Resistant Enterococci (VRE) null. 2018 Jan     [PubMed]
Gerding DN,Sambol SP,Johnson S, Non-toxigenic {i}Clostridioides{/i} (Formerly Clostridium) {i}difficile{/i} for Prevention of {i}C. difficile{/i} Infection: From Bench to Bedside Back to Bench and Back to Bedside. Frontiers in microbiology. 2018     [PubMed]
Vancomycin null. 2006     [PubMed]
Gerstein W,Colombo E,Harji F, Documented vancomycin-induced severe immune-mediated thrombocytopaenia. BMJ case reports. 2018 Aug 27     [PubMed]
Cieslak PR,Strausbaugh LJ,Fleming DW,Ling JM, Vancomycin in Oregon: who's using it and why. Infection control and hospital epidemiology. 1999 Aug     [PubMed]
Chan JOS,Baysari MT,Carland JE,Sandaradura I,Moran M,Day RO, Barriers and facilitators of appropriate vancomycin use: prescribing context is key. European journal of clinical pharmacology. 2018 Jul 28     [PubMed]
Xu G,Chen E,Mao E,Che Z,He J, [Research of optimal dosing regimens and therapeutic drug monitoring for vancomycin by clinical pharmacists: analysis of 7-year data]. Zhonghua wei zhong bing ji jiu yi xue. 2018 Jul     [PubMed]

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