Vancomycin Use in Arthroplasty Patients

There are two key issues related to the use of vancomycin in arthroplasty patients:

1. Is the drug appropriate, and
2. Is the dose appropriate.

In arthroplasty, vancomycin is indicated for patients:

• Colonised or infected with methicillin-resistant  aureus(MRSA), or
• At increased risk of being colonised or infected with MRSA, e.g. patients undergoing a joint arthroplasty procedure that is a reoperation (return to theatre or early revision),
• Patients with immediate non-severe or delayed non-severe hypersensitivity to penicillins, use cefazolin, with or without vancomycin.
• Patients with immediate severe or delayed severe hypersensitivity to penicillins, use vancomycin as monotherapy.

As can be seen, vancomycin is not a ‘just in case’ therapy.

Historically vancomycin was dosed as 1g irrespective of the patient’s weight. However, pharmacokinetics studies have shown that there is a greater deposition of vancomycin in fat tissue compared to bone. Sharareh et al. have reported that for vancomycin “a substantial difference was noted in trabecular bone concentrations with respect to patient weight with lower body mass index (BMI) achieving greater concentrations.” Furthermore, the lipophilic nature of vancomycin has direct dosing implications in obese patients compared to those with a normal range BMI.

It is relevant to determine if there is any difference in periprosthetic joint infection (PJI) for different antibiotic therapies. Kheir and colleagues (2017) reviewed the past records of 1828 patients at a single institution who underwent primary total joint arthroplasty (TJA) and who received vancomycin prophylaxis (2008 to 2014). During the same period, 5810 patients underwent primary TJA and received cefazolin monotherapy. Adequate vancomycin dosing was defined as 15 mg/kg. All patients had vancomycin infusion initiated within two hours before incision.

One of the principal findings was that primary TJA patients receiving vancomycin had double the rate of PJI (2%) compared to patients receiving cefazolin (1%), and  94% (1726 of 1828) of patients received a fixed 1-g dose of vancomycin, of whom 64% (1105 of 1726) were underdosed.

Hence, dosing all patients with 1g of vancomycin is frequently inadequate as it is only for patients weighing 66.7kg or less. The therapeutic inappropriateness of this dosing regime is underscored by a recent report from the Australian Institute of Health and Welfare (2022), which reported that 31% of the population is obese (BMI ≥ 30).

The Australian Orthopaedic Association and South Australian Health recommend vancomycin 1.5g for patients > 80kg if the patient meets the approved indications, whilst international practice, reflected in Therapeutic Guidelines, recommends a dose of 15mg/kg. With weight-based dosing, only 12% of patients have been shown to have a vancomycin level < 15mg/L, whereas 60% of patients had a vancomycin level < 15mg/L when given 1g.

It is relevant to this discussion to appreciate that the appropriate dosing of vancomycin is best determined by using the area under the curve (AUC): minimum inhibitory concentration (MIC) ratio. This ratio combines the pharmacokinetic (time course of antimicrobial concentrations) and pharmacodynamic (antimicrobial effect of the concentration) factors. Both of these factors determine efficacy.

The AUC is determined by the peak serum level (or time at incision) and trough level (time at wound closure), whereas the pharmacodynamic parameter relates to the duration of time that the drug level is above the MIC. It is essential that vancomycin concentration levels remain above the MIC for the entire surgical procedure (until complete wound closure) so as to exert a full and effective prophylactic effect.

Dosing with 1g of vancomycin, irrespective of weight will fail the AUC/MIC standard too frequently.

Various national guidelines unambiguously argue against the routine use of vancomycin. The Australian Orthopaedic Association (AOA – 2018) has stated that:

“Vancomycin should NOT routinely be used for surgical prophylaxis except for patients with immediate hypersensitivity (eg anaphylaxis) to penicillin (where it replaces the cephalosporin) or with an increased risk of postoperative infection with methicillin-resistant Staphylococcus aureus (MRSA) (where it is added to the cephalosporin). This includes patients known to be infected or colonised pre-operatively with MRSA, or with a history of infection or colonisation with MRSA.” (Their emphasis)

International research also argues against the use of alternatives to cephalosporins such as vancomycin/clindamycin.

“ … the use of a non-cephalosporin perioperative antibiotic continues to be associated with a greater risk of TKA PJI compared to cefazolin. Strategies that increase the proportion of patients receiving cefazolin rather than non-cephalosporin alternatives must be emphasized.” In this study, 10,484 knees (90.8%) received cefazolin, while 1,066 knees (9.2%) received either vancomycin or clindamycin as preoperative prophylaxis. The rate of PJI in the cefazolin group (0.5%) was half of that seen in the vancomycin or clindamycin group. (1.0%).

A key question that may arise is whether adherence to published guidelines has any clinical outcome bearing.

Chandrananth et al. studied this issue and concluded that “Non-adherence to guidelines increased the risk of SSI in patients undergoing total knee and hip arthroplasty. Dosing adjustment recommendations of prophylaxis for patients weighing >80kg was poorly adhered to, and these patients were subsequently at higher risk of infection… In patients weighing >80kg (49.5% of surgeries), guideline-concordant dosing occurred in only 58.7% of cases.”

A major consequence of the inappropriate dosing and non-indicated use of vancomycin is the development of vancomycin-resistant enterococci (VRE) and the horizontal gene transfer (HGT) of resistant genes to other enterococci species as well as other bacterial families such as S. aureus. Due to HGT, VRE isolates of the VanA phenotype have caused disease outbreaks. Moreover, the undiscerning use of vancomycin resulting in VRE and multi-drug resistance is leading clinicians to rely on “last resort antibiotics” which are increasingly ineffective and pose a particular challenge for clinical management.

To conclude, it is clinically imprudent to use vancomycin at a sub-therapeutic level and in patients for whom there is no indication.