Prospective Cohort Study of the Tolerability of Prosthetic Joint Infection Empirical Antimicrobial Therapy

Abstract

The empirical use of vancomycin in combination with a broad-spectrum beta-lactam is currently recommended after the initial surgery of prosthetic joint infection (PJI). However, the tolerability of such high-dose intravenous regimens is poorly known. Adult patients receiving an empirical antimicrobial therapy (EAT) for a PJI were enrolled in a prospective cohort study (2011 to 2016). EAT-related adverse events (AE) were described according to the common terminology criteria for AE (CTCAE), and their determinants were assessed by logistic regression and Kaplan-Meier curve analysis. The EAT of the 333 included patients (median age, 69.8 years; interquartile range [IQR], 59.3 to 79.1 years) mostly relies on vancomycin ( = 229, 68.8%), piperacillin-tazobactam ( = 131, 39.3%), and/or third-generation cephalosporins ( = 50, 15%). Forty-two patients (12.6%) experienced an EAT-related AE. Ten (20.4%) AE were severe (CTCAE grade ≥ 3). The use of vancomycin (odds ratio [OR], 6.9; 95% confidence interval [95%CI], 2.1 to 22.9), piperacillin-tazobactam (OR, 3.7; 95%CI, 1.8 to 7.2), or the combination of both (OR, 4.1; 95%CI, 2.1 to 8.2) were the only AE predictors. Acute kidney injury (AKI) was the most common AE ( = 25; 51.0% of AE) and was also associated with the use of the vancomycin and piperacillin-tazobactam combination (OR, 6.7; 95%CI, 2.6 to 17.3). A vancomycin plasma overexposure was noted in nine (37.5%) of the vancomycin-related AKIs only. Other vancomycin-based therapies were significantly less at risk for AE and AKI. The EAT of PJI is associated with an important rate of AE, linked with the use of the vancomycin and the piperacillin-tazobactam combination. These results corroborate recent findings suggesting a synergic toxicity of these drugs in comparison to vancomycin-cefepime, which remains to be evaluated in PJI. (This study has been registered at ClinicalTrials.gov under identifier NCT03010293.).

Can metagenomic next-generation sequencing identify the pathogens responsible for culture-negative prosthetic joint infection?

“…Leukopenia, liver dysfunction, renal dysfunction, and drug eruption are the most common complications of PJI EA therapy [9], and thus, this study regularly monitored for these complications during antibiotic therapy. The results showed that the patients in the TA group experienced a lower incidence of antibiotic-related complications than those in the EA group, although no significant difference in the complication rate was found between the two groups, which might be due to the small sample size.…”

“…The current guidelines and the consensus opinion recommend the use of empirical therapy with vancomycin and broad-spectrum beta-lactams (piperacillin/tazobactam or third-generation cephalosporins) for the treatment of CN-PJI [6][7][8]. However, long-term therapy with broadspectrum antibiotics causes systemic toxicity in patients [9] and is not effective against fungi and some rare pathogens [8], which can potentially lead to treatment failure. In recent years, many studies have identified pathogens in the joint fluid or sonication fluid of PJI patients and verified these by metagenomic next-generation sequencing (mNGS).…”

The Right Time to Safely Re-Evaluate Empirical Antimicrobial Treatment of Hip or Knee Prosthetic Joint Infections

“…In addition to the benefits of early oral antibiotic administration, a shorter EAT should reduce the number of adverse effects due to broad-spectrum antibiotics. The combination of piperacillin/tazobactam plus vancomycin is becoming more and more widely criticized due to the increased risk of kidney injury compared to other broad-spectrum beta-lactams associated with vancomycin [10,11,32,33]. However, a short course does not seem to be associated with an increased risk of adverse renal outcomes [34].…”

“…Bacterial identification tools allow a faster diagnosis, but no recommendation provides guidelines on the duration of this EAT and the right time to re-evaluate it [2,3,9]. The probabilistic antibiotics often used are not harmless, and severe adverse effects can occur, such as nephrotoxicity when the vancomycin being used is associated with piperacillin/tazobactam [10,11]. The goal of the present study was to describe the growth time of bacteria involved in hip or knee PJI in order to find out when EAT can be safely re-evaluated, according to microbiological results.…”

The Different Microbial Etiology of Prosthetic Joint Infections according to Route of Acquisition and Time after Prosthesis Implantation, Including the Role of Multidrug-Resistant Organisms

“…The importance of adequate initial empirical antimicrobial therapy in the outcome of infections is well-known [10] and seems to be critical in patients with PJIs treated with debridement, antibiotics, and implant retention [11]. Vancomycin combined with a broad-spectrum beta-lactam such as piperacillin-tazobactam has been recently studied as an initial treatment [12,13] but has been associated with a high rate of adverse effects [13]. After the pathogen has been identified and antimicrobial susceptibility results are available, the most effective narrow-spectrum antibiotic regimen is selected for continuation of therapy [4,5,6,7,8,10].…”