Vancomycin David R. McNamara, MD, and James M. Steckelberg, MD Despite use that spans more than four decades, vanco- mycin remains one of the most important antibiotics in orthopaedic practice. It has increased in importance in the last decade because of the growing r esistance of many gram-positive bacteriato β-lactam antibiotics, such as pen- icillins and cephalosporins. These gram-positive bacte- ria, especially Staphylococcus aureus and coagulase- negative staphylococci, cause a large proportion of the infections encountered in orthopaedic surgical practice, especially those involving implanted hardware. Structure and Mechanism of Action Vancomycin is a large, complex, tricyclic glycopeptide mol- ecule (Fig. 1). It works primarily through disruption of the biosynthesis of peptidoglycan, the major structural polymer of the gram-positive bacterial cell walls, thr ough binding to the D-alanyl-D-alanine terminal of cell wall pre- cursor units. Penicillins and cephalosporins also inhibit bacterial cell wall synthesis; however, unlike those drugs, cross-resistance with vancomycin does not develop be- cause vancomycin acts against different stages of cell wall synthesis and different specific targets. Although vanco- mycin possesses activity against nearly all gram-positive bacteria, its large molecular weight keeps it from pen- etrating the outer cell membrane of gram-negative ba- cilli, and it has no useful activity against these or ganisms. 1 Pharmacokinetics Vancomycin is poorly absorbed from the gastrointesti- nal tract and requires IV administration for the treatment of systemic or orthopaedic infections. (The only role for oral vancomycin is treatment of Clostridium difficile coli- tis.) After an IV dose, the first distributive phase has a half-life of approximately 0.4 hours; the second distrib- utive phase half-life is approximately 1.6 hours. Clear- ance is primarily through renal glomerular filtration, with hepatic metabolism only a minor contributor to drug elim- ination. In the pr esence of normal renal function, the elim- ination half-life is appr oximately 6 hours. Within 24 hours, 70% to 90% of the dose is excreted unchanged in the urine. 1 Drug dosing requires significant adjustment for both patient size and renal function. The efficacy of vancomycin in bacterial killing prima- rily correlates with the duration of exposure of suscep- tible bacteria to a sufficient concentration of the drug. This is expressed as the ratio of the area under the plasma con- centration curve to minimal inhibitory concentration (AUC:MIC). Antibacterial effects that persist after drug exposure (postantibiotic effect) also contribute to its an- tibacterial effect. 2 The goal of vancomycin dosing is to optimize exposure of susceptible bacteria to a sufficient concentration of the drug while avoiding drug toxicity. Indications for Use Vancomycin is active against staphylococci, both S au- reus and coagulase-negative staphylococci, including iso- lates resistant to β-lactams (so-called methicillin- or oxacillin-resistant strains). For many years, vancomycin was the only substantial therapeutic option for serious infections caused by these strains. Also in the last few years, a handful of strains of both S aur eus and coagulase- negative staphylococci with r educed susceptibility to van- comycin have been reported, an ominous development given the paucity of options for these strains. In addition to activity against staphylococci, vancomycin is active in vitro against most strains of corynebacterium, propioni- bacterium, streptococcal species, and clostridial species. A significant number of enterococci are now resistant, and susceptibility testing is required for this organism. 3 Dr. McNamara is Instructor of Medicine, Mayo Clinic College of Medi- cine, Rochester, MN. Dr. Steckelberg is Professor of Medicine, Mayo Clinic College of Medicine. None of the following authors or the departments with which they are af- filiated has received anything of value from or owns stock in a commercial company or institution related directly or indirectly to the subject of this article: Dr. McNamara and Dr. Steckelberg. Reprint requests: Dr. Steckelberg, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905. Copyright 2005 by the American Academy of Orthopaedic Surgeons. J Am Acad Orthop Surg 2005;13:89-92 Advances in Therapeutics and Diagnostics Vol 13, No 2, March/April 2005 89 Vancomycin should not be used routinely for the tr eat- ment of infections caused by gram-positive organisms known to be sensitive to cephalosporins, penicillins, or other antimicrobials (eg, clindamycin). Inappropriate use of vancomycin is a great concern. The emergence of resistant bacterial pathogens common- ly encountered in health care settings is associated with selective pressure from antimicrobial use. In particular, colonization with vancomycin-resistant enterococci has been associated with receipt in hospitalized patients of oral and parenteral vancomycin, cephalosporins, and anti- anaerobic drugs. 3 Among the recommendations issued by the Centers for Disease Control to prevent the spread of vancomycin resistance is pr udent use of the dr ug. 4 Spe- cifically discouraged are routine surgical prophylaxis in patients without life-threatening allergy to β-lactam an- tibiotics; continued empiric use for presumed infections in patients whose cultures are negative for β-lactam–re- sistant microorganisms; and use of vancomycin for dos- ing convenience in patients with renal insufficiency. Vancomycin is used for perioperative antimicrobial prophylaxis in patients with a history of type 1 hyper- sensitivity reaction (urticaria, laryngeal edema, broncho- spasm, or anaphylaxis) to penicillins or cephalosporins. Cefazolin is the preferred agent for patients able to tol- erate β-lactam antibiotics. Perioperative antimicrobial pro- phylaxis should be administered not more than 1 hour before surgery and should continue for less than 24 hours’ total duration (cefazolin 1 to2gIVevery 8 hours for not more than three doses, or vancomycin 15 mg/kg IV ev- ery 12 hours for two doses). 5 Allergy skin testing may be able to reduce the unnecessary use of vancomycin for perioperative prophylaxis in orthopaedic surgical patients with a reported history of allergy to penicillins or ceph- alosporins. A study using targeted penicillin allergy skin testing to identify patients at increased risk of a hyper- sensitivity reaction to β-lactam antibiotics reduced the use of vancomycin in patients with a reported history of al- lergy to β-lactam agents from 30% to 11%. 6 Randomized controlled prospective clinical trials of vancomycin compared to other antibiotics for the treat- ment of orthopaedic infections have not been reported. Despite this, vancomycin, with penicillins and cepha- losporins, has been used extensively in the treatment of osteomyelitis and soft-tissue infections for several de- cades. As an adjunct to appropriate surgical débridement, it has an established record as an accepted agent for these infections when they are caused by susceptible bacteria. Use of vancomycin for treatment of bone and joint in- fection is not specifically approved by the Food and Drug Administration (FDA). However, treatment of serious in- fection caused by organisms such as methicillin-resistant S aureus is an approved indication. Rigorous data are limited on optimal duration of an- timicrobial therapy of musculoskeletal infections. Because of the lack of prospective randomized trials and the het- erogenous nature of bone and joint infections, r ecommend- ed duration typically follows expert opinion and data from case series. Decisions on treatment duration normally in- volve consideration of factors such as response to initial medical and surgical therapy, adequacy of débridement in removing infected bone, systemic and local host fac- tors, and the identity and antimicrobial susceptibility of the involved microorganisms. Soft-tissue infections com- monly are treated for approximately 2 weeks. Osteomy- elitis typically is treated for 4 to 6 weeks, and intra-articular infections, for 2 to 4 weeks, with longer treatment for more virulent organisms, such as S aureus. 7 Several authors have measured the penetration of van- comycin into bone. In a study by Graziani et al, 8 14 pa- tients undergoing total hip arthr oplasty received a 15 mg/kg IV vancomycin dose 1 hour before surgery. Vancomycin concentration was found to range from 0.5 to 16.0 µg/mL (average, 2.3 µg/mL) in cancellous bone, and the drug was detectable in 10 of 14 cortical bone specimens (av- erage concentration, 1.1 µg/mL). Vancomycin was de- tectable in only two of five cortical bone specimens from patients undergoing débridement for osteomyelitis. 8 An- other study measured a mean vancomycin concentration of 9.3 µg/mL in healthy sternal bone samples from 10 patients undergoing sternotomy for cardiac surgery. 9 In an experimental S aureus osteomyelitis model, vancomy- cin had a concentration in infected bone of 5.3 ± 0.8 µg/ mL. By comparison, clindamycin had a concentration of 11.9 ± 1.9 µg/mL after a 70 mg/kg dose; cefazolin, a con- centration of 4.1 ± 0.7 µg/mL after a 15 mg/kg dose; and nafcillin, a concentration of 2.1 ± 0.3 µg/mL after a 40 mg/kg dose. 10 The clinical significance of animal studies evaluating bone concentrations of antimicrobials and the Figure 1 Structural formula of vancomycin. From the National Library of Medicine, accessed January 16, 2005, at http:// www.nlm.nih.gov/pubs/techbull/ma00/ma00_chemid_fig8.html. Vancomycin 90 Journal of the American Academy of Orthopaedic Surgeons bone-to-serum concentration ratio is less clear because of differences in methods between studies, limitations in extrapolating data from animal models using S aureus as the infecting agent, and the lack of long-term follow-up inherent in experimental animal models. 11 In addition to systemic parenteral vancomycin ther- apy, local delivery of antibiotics via impregnated poly- methylmethacrylate (PMMA) beads is commonly used in the treatment of chronic osteomyelitis or pr osthetic joint infection. The heat stability of vancomycin, in contrast to that of β-lactam antibiotics (which are degraded dur- ing the PMMA polymerization process), makes it a use- ful drug for this application. 10 Vancomycin-impregnated PMMA beads have not been approved by the FDA and are not commercially avail- able in the United States. For use in the treatment of in- fected bone as antibiotic-impregnated cement beads or spacer, in which structural strength of the cement is not of primary importance, up to 4 g vancomycin into 40 g PMMA cement can be used, often in combination with an aminoglycoside antibiotic. Increasing concentrations of vancomycin may have a negative effect on the mechan- ical strength and stability of the cement. For use in which the structural integrity of the cement is important (eg, prosthesis fixation), only 0.5 to1gofpowdered antibi- otic per 40 g of PMMA cement is recommended to avoid weakening the bone cement. 5 Also, the use of vancomycin- impregnated bone cement should be avoided in prophy- lactic applications and limited to the treatment of estab- lished infection. 5 An in vitro evaluation of drug release from PMMA beads in a continuous flow chamber showed that vancomycin-impregnated PMMA beads had a sim- ilar percentage of antibiotic release to that of gentamicin- and tobramycin-impregnated PMMA beads. 12 Various commercially available PMMA products may differ in their vancomycin elution characteristics. The in vivo significance of in vitro findings in studies compar- ing different PMMA products is unclear. In addition, elu- tion characteristics for vancomycin may change in com- bination with other antibiotics. One study found the in vitro elution of vancomycin in combination with tobra- mycin via Palacos R cement (Biomet, Warsaw, IN) to be greater than that of CMW 1 or CMW 3 cement (DePuy, Warsaw, IN). 13 Another study evaluating the in vitro elu- tion of vancomycin in Palacos R, CMW, and Simplex P cement (Stryker, Kalamazoo, MI) found that the addition of imipenem-cilastatin significantly (P < 0.5) increased the elution of vancomycin from all three cements. 14 Drug Interactions and Adverse Effects Common adverse effects include infusion-related pruri- tis and erythema as well as phlebitis. Red man syndrome involves a pr uritic, erythematous rash on the upper trunk, neck, and face associated with rapid vancomycin infu- sion causing histamine release. Vancomycin should be infused at a rate of 1,000 mg over 60 minutes, with larger doses taking proportionately longer to infuse. Red man syndrome can be ameliorated with a slower rate of in- fusion and antihistamine pr emedication. 15 Peripheral vein phlebitis with vancomycin therapy is common and can be avoided by infusion via a central venous catheter, such as a peripherally inserted central catheter (PICC), when therapy is anticipated to last longer than 10 to 14 days. More serious adverse effects include ototoxicity and nephrotoxicity. Cranial eighth nerve damage may result in permanent equilibrium or hearing loss. Vestibular tox- icity can be particularly troublesome for patients who al- ready have gait difficulty as a result of orthopaedic prob- lems. Concomitant aminoglycoside use has been linked with increased risk of both ototoxicity and nephrotox- icity. 16 Other potentially serious complications of vanco- mycin therapy include hypersensitivity rash, reversible neutropenia, and, rarely, drug fever. Vancomycin does not significantly interact with other medications, although concomitant administration of other potentially nephro- toxic or ototoxic drugs may incr ease the risk of these com- plications. Dosage and Cost Dosing nomograms use both estimated creatinine clear- ance and body weight to determine a dose and dosing frequency (Table 1, available at http://www5.aaos.org/ jaaos/pdf/v13n2a1t1.pdf). Empiric nomograms may not accurately guide dosing for patients with changing re- nal function, anuria, or dialysis who will require serum drug concentration monitoring to adjust doses. The av- erage wholesale price of daily doses of vancomycin com- pared with other antibacterials commonly used in ortho- paedic surgical practice is shown in Table 2. Patients with end-stage renal failure on dialysis have often been dosed with once-weekly vancomycin because of low clearance with traditional dialysis membranes. Newer dialysis techniques incorporating high-flux mem- branes, in addition to continuous renal replacement ther- apies used in hospitalized patients, clear vancomycin more rapidly and require more frequent dosing and of- ten larger vancomycin doses. Input from infectious dis- ease specialists and health-system pharmacists with ex- pertise in therapeutic drug monitoring and antibiotic dosing during renal replacement therapy is often valu- able in achieving accurate dosing of vancomycin in re- nal impairment. Measurement of vancomycin concentration in serum is often performed to guide dosing, especially in patients David R. McNamara, MD, and James M. Steckelberg, MD Vol 13, No 2, March/April 2005 91 who will remain on vancomycin therapy for long peri- ods (several weeks or more). This is typically performed after a pharmacokinetic steady state has been achieved, usually after the third empirically determined dose in pa- tients with a dosing interval of 24 hours or less; it should be repeated weekly in stable patients. Trough concentra- tions are measured on serum obtained immediately be- fore administration of a dose of the drug; peak concen- trations are measured on serum obtained 60 minutes after the end of a dose infusion. Trough serum concentrations of 5 to 10 µg/mL and peak serum concentrations of 20 to 40 µg/mL typically are desir ed. In determining treatment outcome, evidence for monitoring trough concentrations is stronger than for monitoring peak concentrations. 17 Some institutions rely mainly on trough measurements to guide dosing in pa- tients who are stable and at steady state. Measurement of creatinine level and complete blood count should be performed at baseline, several days after beginning van- comycin therapy, and generally are repeated weekly. Summary Vancomycin is a glycopeptide antibiotic active against most gram-positive pathogens encountered in ortho- paedic surgical practice, with the notable exception of vancomycin-resistant enterococci. Systemic therapy re- quires IV administration; the dose used depends on pa- tient size and renal function. Patients undergoing pro- longed therapy require central venous access for drug delivery as well as monitoring of drug levels, blood counts, renal function, and liver tests. Although β-lactam antibiotics are preferable for the treatment of suscepti- ble bacterial infections in nonallergic patients, vancomy- cin remains an essential agent for the treatment of methicillin-resistant staphylococcal infections encoun- tered in orthopaedic surgical practice. References 1. Wilhelm MP, Estes L: Symposium on antimicrobial agents: XII. Vancomycin. Mayo Clin Proc 1999;74:928-935. 2. Craig WA: Basic pharmacodynamics of antibacterials with clin- ical application to the use of beta-lactams, glycopeptides, and linezolid. Infect Dis Clin North Am 2003;17:479-501. 3. Murray BE: Vancomycin-resistant enterococcal infections. N Engl J Med 2000;342:710-721. 4. Recommendations for preventing the spread of vancomycin re- sistance. Recommendations of the Hospital Infection Control Practices Advisory Committee (HICPAC). MMWR Recomm Rep 1995:44:1-13. 5. Hanssen AD, Osmon DR: The use of prophylactic antimicrobial agents during and after hip arthroplasty. Clin Orthop 1999;369: 124-138. 6. Li JT, Markus PJ, Osmon DR, Estes L, Gosselin VA, Hanssen AD: Reduction of vancomycin use in orthopedic patients with a his- tory of antibiotic allergy. Mayo Clin Proc 2000;75:902-906. 7. Berbari EF, Osmon DR, Steckelberg JM: Osteomyelitis and in- fectious arthritis, in Baddour LM, Gorbach SL (eds): Therapy of Infectious Diseases. Philadelphia, PA: WB Saunders, 2003, pp 331-342. 8. Graziani AL, Lawson LA, Gibson GA, Steinberg MA, Mac- Gregor RR: Vancomycin concentrations in infected and nonin- fected human bone. Antimicrob Agents Chemother 1988;32: 1320-1322. 9. Massias L, Dubois C, de Lentdecker P, Brodaty O, Fischler M, Farinotti R: Penetration of vancomycin in uninfected sternal bone. Antimicrob Agents Chemother 1992;36:2539-2541. 10. Mader JT, Shirtliff ME, Bergquist SC, Calhoun J: Antimicrobial treatment of chronic osteomyelitis. Clin Orthop 1999;360:47-65. 11. Darley ES, MacGowan AP: Antibiotic treatment of gram- positive bone and joint infections. J Antimicrob Chemother 2004; 53:928-935. 12. Perry AC, Rouse MS, Khaliq Y, et al: Antimicrobial release ki- netics from polymethylmethacrylate in a novel continuous flow chamber. Clin Orthop 2002;403:49-53. 13. Penner MJ, Duncan CP, Masri BA: The in vitro elution charac- teristics of antibiotic-loaded CMW and Palacos-R bone cements. J Arthroplasty 1999;14:209-214. 14. Cerretani D, Giorgi G, Fornara P, et al: The in vitro elution char- acteristics of vancomycin combined with imipenem-cilastatin in acrylic bone-cements: A pharmacokinetic study. J Arthroplasty 2002;17:619-626. 15. Sahai J, Healy DP, Garris R, Berry A, Polk RE: Influence of an- tihistamine pretreatment on vancomycin-induced red-man syn- drome. J Infect Dis 1989;160:876-881. 16. Sorrell TC, Collignon PJ: A prospective study of adverse reac- tions associated with vancomycin therapy. J Antimicrob Chemother 1985;16:235-241. 17. Zimmerman AE, Katona BG, Plaisance KI: Association of van- comycin serum concentrations with outcomes in patients with gram-positive bacteremia. Pharmacotherapy 1995;15:85-91. Table 2 Dosage and Cost of Vancomycin and Other Antibacterials Antibacterial Dosage Used for Cost Calculation Cost per Day Cefazolin 1 g IVq8h $8.22 Nafcillin 2 g IVq6h $14.17 Vancomycin 1 g IV q 12 h $12.12 Linezolid 600 mg PO q 12 h 600 mg IV q 12 h $123.68 $123.09 Moxifloxacin and rifampin 400 mg PO daily and 600 mg PO BID $9.80 and 6.28: Total = $16.08 Average wholesale price (AWP) as published in the Red Book, ed 108. (Montvale, NJ: Thomson Healthcare, 2004.) Bulk purchase, generic prices used when available. Vancomycin 92 Journal of the American Academy of Orthopaedic Surgeons . typically are desir ed. In determining treatment outcome, evidence for monitoring trough concentrations is stronger than for monitoring peak concentrations. 17 Some institutions rely mainly on trough measurements