Vancomycin Monograph

Introduction/Overview

Vancomycin is a glycopeptide antibiotic that has maintained a pivotal role in the treatment of serious Gram‑positive infections for several decades. Its continued relevance is underscored by the rise of methicillin‑resistant Staphylococcus aureus (MRSA) and other multidrug‑resistant organisms, for which vancomycin remains one of the few effective systemic agents. The pharmacologic profile of vancomycin—including its potent bactericidal activity, relatively predictable pharmacokinetics, and established therapeutic monitoring protocols—renders it a cornerstone of antimicrobial therapy in many clinical settings.

Key learning objectives for this chapter include:

• To delineate the classification and chemical characteristics of vancomycin.
• To explain the molecular mechanisms underlying its bactericidal action.
• To summarize the pharmacokinetic parameters that guide dosing and monitoring.
• To enumerate approved therapeutic indications and common off‑label uses.
• To identify major adverse effects, drug interactions, and special patient considerations.

Classification

Drug Class and Category

Vancomycin is classified as a glycopeptide antibiotic. Within the broader class of glycopeptides, it is the most widely used agent in clinical practice, particularly for severe Gram‑positive infections. The drug is typically available in three formulations: intravenous (IV) solution, oral delayed‑release tablets, and powder for reconstitution (IV or oral). The IV formulation is the preferred route for acute infections and in patients with impaired gastrointestinal absorption.

Chemical Classification

Vancomycin is a cyclic peptide composed of 18 amino acid residues, including several unusual amino acids such as 2,4‑dimethyl‑3,5‑diaminopentanoic acid and N‑methyl‑L‑tyrosine. The molecule contains several aromatic rings that confer high affinity for the D‑alanine‑D‑alanine termini of peptidoglycan precursors. Its molecular weight approximates 1,449 daltons, and its structure is stabilized by intramolecular hydrogen bonds and disulfide bridges. The compound is hydrophilic, with limited lipid solubility, which influences its distribution and elimination characteristics.

Mechanism of Action

Pharmacodynamics

Vancomycin exerts its antibacterial effect by binding with high affinity to the D‑alanine‑D‑alanine (D‑Ala‑D‑Ala) dipeptide termini of the nascent peptidoglycan chain. This interaction sterically hinders the transglycosylation step catalyzed by transglycosylase enzymes, thereby preventing the polymerization of glycan strands. Concurrently, vancomycin inhibits transpeptidation (cross‑linking) by blocking access of transpeptidase enzymes to their peptidoglycan substrates. The dual blockade leads to a rapid collapse of cell wall integrity, culminating in osmotic lysis of the bacterial cell. The activity is bactericidal, with a time‑dependent killing profile; the area under the concentration–time curve (AUC) relative to the minimum inhibitory concentration (MIC) is a key pharmacodynamic driver.

Receptor Interactions

Vancomycin does not interact with human cellular receptors. Its target is a bacterial cell wall component, and thus host toxicity is primarily mediated through off‑target effects on renal tubular cells and auditory pathways rather than receptor binding. This lack of receptor interaction contributes to a relatively narrow spectrum of activity, focusing on Gram‑positive organisms that possess D‑Ala‑D‑Ala termini.

Molecular and Cellular Mechanisms

At the cellular level, vancomycin binding to D‑Ala‑D‑Ala residues disrupts the cross‑linking of peptidoglycan strands, leading to a weakened cell wall matrix. The resulting loss of turgor pressure causes cell lysis. In addition, vancomycin can inhibit the formation of the lipid II intermediate, a pivotal substrate for peptidoglycan synthesis. Resistance mechanisms, such as the substitution of the terminal D‑Ala with D‑lactate (D‑Ala‑D‑Lac), reduce vancomycin binding affinity and are not the focus of this monograph, which concentrates on the drug’s typical pharmacologic properties.

Pharmacokinetics

Absorption

Intravenous administration achieves complete bioavailability (100%). Oral absorption is limited; the drug is poorly absorbed in the gastrointestinal tract due to its hydrophilic nature and large molecular size. Consequently, oral therapy is reserved for selected outpatient settings with delayed‑release formulations designed to enhance mucosal contact time. Oral bioavailability is typically <10 % in healthy individuals, although variability can be substantial.

Distribution

Vancomycin displays a volume of distribution (V_d) of approximately 0.4–0.6 L/kg, reflecting limited tissue penetration. The drug distributes extensively in extracellular fluid but poorly penetrates into adipose tissue, the central nervous system, and ocular fluids. Protein binding is modest, ranging from 10–15 %, which results in a relatively low fraction of free drug in plasma. The limited penetration into the central nervous system is a consideration when treating meningitis, where higher doses or alternative agents may be required.

Metabolism

Vancomycin undergoes minimal hepatic metabolism. The majority of the drug is excreted unchanged, with negligible formation of active metabolites. Consequently, hepatic impairment has a limited impact on vancomycin clearance, and dose adjustments for liver dysfunction are generally unnecessary.

Excretion

Renal clearance accounts for the predominant elimination pathway. The drug is primarily filtered by the glomerulus and is not significantly reabsorbed in the renal tubules. Therefore, creatinine clearance (CrCl) is the principal determinant of vancomycin elimination. In patients with normal renal function, the elimination half‑life (t_1/2) is approximately 4–8 hours. In patients with impaired renal function, t_1/2 can extend to 12–24 hours or longer, necessitating dose interval adjustments.

Half‑Life and Dosing Considerations

Because vancomycin clearance is directly proportional to CrCl, dosing regimens are frequently expressed as mg/kg administered over a 3–4 hour infusion. The target trough concentration (C_min) is typically 15–20 mg/L for severe infections (e.g., endocarditis, osteomyelitis) and 5–10 mg/L for less severe infections (e.g., skin and soft‑tissue infections). Therapeutic drug monitoring (TDM) is essential to ensure adequate exposure while minimizing toxicity. The loading dose is often calculated as 25 mg/kg to rapidly achieve target concentrations before the maintenance dose is initiated.

Therapeutic Uses/Clinical Applications

Approved Indications

• Severe Gram‑positive infections, including MRSA bacteremia, endocarditis, osteomyelitis, and meningitis.
• Immunocompromised patients with suspected or confirmed invasive Gram‑positive infections.
• Pneumonia caused by high‑risk Gram‑positive organisms when other agents are contraindicated.
• Prevention of graft‑versus‑host disease in bone marrow transplantation settings.

Off‑Label Uses

Vancomycin is frequently employed off‑label for:

• Infections caused by vancomycin‑susceptible but not vancomycin‑resistant organisms where other antibiotics are unsuitable.
• Treatment of certain anaerobic infections, particularly when resistance patterns favor vancomycin.
• Combination therapy with β‑lactams or aminoglycosides for synergistic effects against highly resistant strains.

Adverse Effects

Common Side Effects

• Nephrotoxicity: Acute tubular necrosis or cortical interstitial nephritis, typically manifesting as a rise in serum creatinine after 24–48 hours of therapy.
• Ototoxicity: Sensorineural hearing loss, often reversible upon drug discontinuation, with risk increasing in patients receiving concurrent aminoglycosides or high trough concentrations.
• Red Man Syndrome: An infusion‑related reaction characterized by flushing, pruritus, and hypotension, often occurring when the infusion rate exceeds 10 mg/min.
• Hypotension and tachycardia: Less common but documented, particularly during rapid IV administration.

Serious or Rare Adverse Reactions

Severe hypersensitivity reactions, including anaphylaxis, are rare but can occur. Additionally, the drug may trigger severe cutaneous adverse reactions such as Stevens–Johnson syndrome or toxic epidermal necrolysis, though these events are exceedingly uncommon. Long‑term use may result in nephrotoxic complications such as interstitial nephritis, which can progress to chronic kidney disease if not promptly addressed.

Black Box Warnings

Nephrotoxicity and ototoxicity are highlighted in the product labeling, underscoring the necessity for therapeutic drug monitoring and dose adjustments in patients with renal impairment. The potential for Red Man Syndrome necessitates slow infusion rates and pre‑medication with antihistamines in susceptible individuals.

Drug Interactions

Major Drug‑Drug Interactions

• Aminoglycosides: Concomitant use increases the risk of nephrotoxicity and ototoxicity, necessitating careful monitoring of serum drug levels and renal function.
• Non‑steroidal anti‑inflammatory drugs (NSAIDs): NSAID use can diminish renal perfusion, thereby exacerbating vancomycin nephrotoxicity.
• Calcineurin inhibitors: Cyclosporine and tacrolimus can potentiate vancomycin nephrotoxicity and increase trough concentrations.
• Diuretics: Loop diuretics may alter renal clearance of vancomycin and should be used cautiously.
• Phosphonic antibiotics (e.g., fosfomycin): Potential for additive nephrotoxic effects exists.

Contraindications

Vancomycin is contraindicated in patients with known hypersensitivity to the drug or to any of its excipients. Additionally, it should be avoided in patients with severe renal impairment (CrCl <10 mL/min) unless dose adjustments are meticulously applied and TDM is performed.

Special Considerations

Use in Pregnancy and Lactation

Vancomycin is classified as a category C drug in pregnancy. While animal studies have not demonstrated teratogenicity, human data are limited, and the drug should be reserved for situations where the benefits outweigh potential risks. The drug is excreted into breast milk in negligible amounts; however, nursing mothers should be advised to monitor infants for signs of ototoxicity or nephrotoxicity if long‑term therapy is anticipated.

Pediatric and Geriatric Considerations

Pediatric dosing is based on weight, with an initial loading dose of 25 mg/kg followed by maintenance doses of 15–20 mg/kg every 6 hours, adjusted for renal function. Geriatric patients often exhibit reduced renal clearance; therefore, dose intervals may need extension, and TDM is crucial. Age‑related changes in volume of distribution and renal function can complicate therapeutic target attainment.

Renal and Hepatic Impairment

In patients with renal impairment, vancomycin clearance decreases proportionally to CrCl. Renal dosing tables recommend extending the dosing interval or reducing dose based on measured serum creatinine and estimated CrCl. Hepatic impairment has minimal effect on vancomycin pharmacokinetics; dose adjustments are generally unnecessary. Nevertheless, caution is advised in patients with concurrent hepatic and renal dysfunction.

Summary/Key Points

• Vancomycin is a glycopeptide antibiotic with a unique mechanism targeting the D‑Ala‑D‑Ala termini of peptidoglycan precursors.
• Intravenous administration provides complete bioavailability; oral absorption is limited and reserved for specific outpatient indications.
• Renal clearance is the primary determinant of pharmacokinetics; therapeutic drug monitoring is essential to balance efficacy and toxicity.
• Nephrotoxicity and ototoxicity represent the most significant adverse effects; infusion rate should be moderated to avoid Red Man Syndrome.
• Drug interactions with aminoglycosides, NSAIDs, and calcineurin inhibitors necessitate vigilance and dose adjustments.
• Special populations—including pregnant women, nursing mothers, children, and the elderly—require individualized dosing strategies and close monitoring.

References

1. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.
2. Trevor AJ, Katzung BG, Kruidering-Hall M. Katzung & Trevor's Pharmacology: Examination & Board Review. 13th ed. New York: McGraw-Hill Education; 2022.
3. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.
4. Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 14th ed. New York: McGraw-Hill Education; 2023.
5. Golan DE, Armstrong EJ, Armstrong AW. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. 4th ed. Philadelphia: Wolters Kluwer; 2017.
6. Katzung BG, Vanderah TW. Basic & Clinical Pharmacology. 15th ed. New York: McGraw-Hill Education; 2021.
7. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.
8. Trevor AJ, Katzung BG, Kruidering-Hall M. Katzung & Trevor's Pharmacology: Examination & Board Review. 13th ed. New York: McGraw-Hill Education; 2022.