Pharmacological Intervention for Refractory Biofilm Infection After Hemipelvic Replacement Surgery: Multidisciplinary Management of a Case of Giant Cell Tumor of Bone

Introduction

Periprosthetic joint infection (PJI) is a serious complication after prosthetic joint replacement. Among the causative pathogens, Staphylococcus epidermidis and Staphylococcus aureus are most common, present in 86.96% of cases; gram-negative pathogens and fungi can also cause PJI [1]. The infecting bacterial species are often low-virulence microorganisms, such as coagulase-negative staphylococci (CoNS), which are highly likely to form biofilms. After biofilm formation, the bacteria enter a stable growth phase [2]. Antibiotics commonly used in clinical practice have limited penetration into biofilm and reduced efficacy at the site of infection. Conventional drug susceptibility tests are also inadequate for determining the true antibiotic sensitivity of biofilm-embedded bacteria [3], frequently leading to failure of long-term antibiotic therapy [4]. PJI often damages bones and soft tissues, thereby requiring thorough debridement of the infected focus. In severe cases, prosthetic replacement may be necessary.

In the present case, after hemipelvectomy and hemipelvic tumor prosthesis replacement, the patient experienced recurrent local infection. Despite multiple debridement procedures, persistent drainage and wound secretion were observed. Although the amount of exudate decreased over time, fluid and discharge continued to appear at the wound site. Culture of the secretions revealed 2 to 3 types of CoNS and gram-negative bacilli. Recurrent prosthetic biofilm infection generally requires revision surgery, but the cost of 2-stage revision surgery is prohibitive and imposes a substantial economic burden. Through multidisciplinary collaboration, orthopedic surgeons, clinical pharmacists, and other medical staff developed a personalized treatment plan based on targeted combination antibiotic therapy. Ultimately, the infection improved and the wound healed satisfactorily.

Case Report

ANTI-INFECTION TREATMENT PROCESS:

The patient received empirical anti-infection treatment with levofloxacin and piperacillin/tazobactam sodium beginning on May 1, 2020. On May 5, 2020, routine blood examination revealed elevated C-reactive protein (44.99 mg/L) and procalcitonin (0.14 ng/mL). On May 13, 2020, the patient developed fever, with a maximum temperature of 38.5°C, as noted above. On May 17, 2020, pain, erythema, swelling, and exudate were observed at the left iliac wound. After several sutures had been removed to facilitate drainage, fluid was collected for bacterial culture and antimicrobial susceptibility testing. Methicillin-resistant S. epidermidis was isolated from the drainage fluid (Table 1) and confirmed as the pathogen responsible for the surgical incision infection. After 18 days of treatment, the surgical wound in the iliac region remained erythematous and swollen with persistent exudate, and inflammatory markers remained elevated (maximum white blood cell [WBC] count, 13.81×109/L; maximum C-reactive protein, 91.08 mg/L; maximum procalcitonin, 0.37 ng/mL; maximum temperature, 38.5°C). The WBC count decreased to 0.72×109/L on May 18, 2020.

Because of adverse reactions to the antibiotics, therapy was suspended, and symptomatic treatment was initiated. CoNS were cultured from wound secretions on the 20th and 30th postoperative days. From June 6 to July 11, 2020, the patient was treated with clindamycin. During this period, gentamicin was used for prosthesis irrigation, and fever did not recur. However, on June 13, 2020, a small number of gram-positive cocci were detected in wound secretions. Substantial drainage fluid was present after debridement, and wound healing remained poor (Figure 2). Treatment was discontinued on July 11, 2020, and debridement with drainage was performed. On July 20, 2020, imipenem/cilastatin was administered. Seven days later, small amounts of 2 types of gram-negative bacilli were detected in wound secretions. Therefore, the treatment plan was adjusted: the administration frequency was increased, and vancomycin (1.0 g every 12 h for 10 days) was combined with rifampicin capsules (300 mg orally twice daily for 23 days). Imipenem/cilastatin was discontinued between August 7 and 11, 2020. The vancomycin concentration in blood was 8.8 mg/mL, and the area under the curve/minimum inhibitory concentration ratio was 211.2, indicating poor efficacy. The vancomycin dosage was increased to 2.5 g, divided into 3 administrations. The trough concentration before the fifth administration was 17.30 μg/mL, which met the therapeutic standard. On August 10, 2020, P. aeruginosa was cultured from wound secretions. The surgical wound was erythematous and swollen, but exudate was absent. Treatment was changed to ceftazidime and fosfomycin for 5 days. On August 14, 2020, the surgical wound showed improvement, but the WBC count decreased to 1.26×109/L. Considering the possibility of bone marrow suppression, treatment was adjusted to ciprofloxacin (targeting P. aeruginosa) combined with oral rifampicin until hospital discharge on August 19, 2020. After 3 weeks of treatment, the wound healed and stitches were removed (Figure 3). Following discharge, sequential oral therapy was continued for 3 months: rifampicin 150 mg twice daily combined with levofloxacin 0.5 g once daily. In addition to empirical and etiological anti-infection treatment, 8 debridement procedures and long-term drainage were required to control infection (Figure 4), with continuous monitoring of inflammatory indicators to assess therapeutic response (Figure 5). The antimicrobial agents administered, patient clinical signs, and pathogen culture results are summarized in Figure 6.

FOLLOW-UP AND PROGNOSIS:

After 3 weeks of treatment, the patient’s wound had healed well without exudate, and she was discharged in stable condition. Levofloxacin tablets and rifampicin capsules were prescribed upon discharge for consolidation therapy, with a total treatment duration of 3 months. At the 3-month follow-up, wound healing was considered satisfactory. Eight months after discharge (April 2021), during the first outpatient reexamination, no recurrence of infection was observed; however, recurrence of the giant cell tumor of bone with pulmonary metastasis was detected. Since then, the patient has been regularly followed in the outpatient department and has received continuous denosumab therapy from May 2021 to the present (January 2025). No signs of infection have been observed during follow-up.

Discussion

SURGICAL CHALLENGES OF PELVIC GIANT CELL TUMOR OF BONE AND POSTOPERATIVE INFECTION RISK:

Giant cell tumor of bone typically arises in the epiphysis of long bones, affecting bones around the knee joint; it may cause joint deformity and disability. Pelvic involvement is extremely rare [5,6], occurring in only 1.5% to 6% of all cases [7]. When present, the acetabulum is the most commonly affected site. The preferred treatment for pelvic giant cell tumors is wide tumor resection by hemipelvectomy, combined with selective vascular embolization performed 24 h before surgery [8,9]. However, due to the complex anatomy of the periacetabular region and its proximity to critical nerves and blood vessels, surgeons often face a dilemma between achieving complete resection and preserving function. In the present case, hemipelvectomy combined with prosthesis reconstruction was performed. Factors such as the large surgical wound surface and the implantation of foreign material substantially increased the risk of infection. A previous study showed that the infection rate after pelvic tumor prosthesis replacement is relatively high, ranging from 11% to 53% [10]. Evidence also indicates that “pelvic tumors and the use of implants are significantly associated with an increased risk of postoperative infection” [11]. Based on the patient’s disease characteristics and postoperative condition, the high risk of infection may be attributed to the following factors: thin soft tissue coverage and poor blood supply in the pelvic region; the large size of the prosthesis, creating a broad surface area for biofilm formation; and limited early postoperative activity, leading to local exudate accumulation. Currently, evidence supporting these 3 theories is insufficient, and further experimental studies are needed for validation.

THERAPEUTIC DILEMMAS AND STRATEGIES IN BIOFILM-RELATED PJI:

Three weeks after surgery, our patient developed a chronic sinus tract communicating with the prosthesis, fulfilling the diagnostic criteria for PJI established by the International Consensus Meeting. Gram-positive bacteria are the predominant causative pathogens in PJI. A 10-year retrospective study conducted in French hospitals revealed that staphylococci were the most common pathogens, with CoNS present in 25.2% of cases [12]. After hip arthroplasty, the most frequent infecting pathogen is S. epidermidis, responsible for 38.10% of cases [13]. In the present case, the first pathogen detected was CoNS. These low-virulence microorganisms readily form biofilms that hinder antibiotic penetration, and routine drug susceptibility tests do not reliably reflect the true antibiotic sensitivity of biofilm-embedded bacteria. These aspects explain the ineffectiveness of the initial empirical regimen (piperacillin/tazobactam plus levofloxacin). Therefore, after prosthetic replacement, close monitoring of the patient’s clinical signs is essential. When infection is suspected, advanced diagnostic methods, such as molecular biology-based techniques, should be promptly used to accurately identify the causative microorganisms. This identification is particularly important for low-virulence, biofilm-forming species. Early initiation of targeted therapy is necessary to improve treatment outcomes.

According to previous studies, 2 classes of drugs exhibit properties necessary to effectively eliminate biofilm-producing bacteria: rifampicin [14–19] (and other rifamycins that act on staphylococci within biofilms) and fluoroquinolones [20–22], which are active against gram-negative bacilli. For empirical treatment of PJI, vancomycin has been recommended in several reports. Although the incidence of PJI caused by vancomycin-resistant enterococci is rare, vancomycin may provide the broadest antibacterial coverage [23,24]. Rifampicin has been shown to eradicate mature staphylococcal biofilms and has demonstrated efficacy in the treatment of musculoskeletal infections. Douthit and colleagues conducted an in vitro study [25] in which rifampicin and vancomycin powder solutions, applied alone or in combination to orthopedic stainless steel materials, inhibited S. aureus biofilm formation and eliminated established biofilms. Their results indicated that vancomycin and rifampicin can reliably and predictably suppress the formation of S. aureus biofilms on prosthetic materials. Additionally, rifampicin has potential applications in orthopedic trauma, where topical administration has been reported to achieve spontaneous healing of both sterile and contaminated wounds [21].

In the present case, on the 85th postoperative day, the clinical pharmacist developed a standardized strategy for biofilm infection. First, a combination of agents capable of penetrating biofilms was selected. Vancomycin (1.5 g every 12 h) was combined with rifampicin (300 mg orally twice daily). The treatment course for PJI was 15 days of vancomycin plus rifampicin for biofilm infection (July 27, 2020 to August 11, 2020), consistent with the agents, dosages, and durations recommended by guidelines and studies conducted by Nelson et al. [2,26]. The scientific rationale for this regimen is that vancomycin inhibits planktonic bacteria by disrupting the cell wall, whereas rifampicin penetrates the biofilm matrix and inhibits RNA polymerase activity. These 2 agents exert a synergistic effect, effectively reducing the number of viable bacteria within the biofilm. For drug-resistant gram-negative bacteria, imipenem/cilastatin (0.5 g every 6 h) was administered. Second, precise dose adjustment based on therapeutic drug monitoring was implemented. The dosing regimen was modified from 1.0 g every 12 h to 1 g intravenous infusion at 12: 00 a.m., 1 g at 8: 00 a.m., and 0.5 g at 4: 00 p.m. This adjustment ensured therapeutic efficacy while minimizing the risk of nephrotoxicity. The vancomycin trough concentration before the fifth dose (17.30 μg/mL) was within the target range of 15 to 20 μg/mL. Because of the uneven dosing schedule with 3 daily administrations, the exact area under the curve/minimum inhibitory concentration could not be accurately calculated. Finally, multimodal local intervention was performed. In addition to systemic antibacterial therapy, drainage and debridement were intensified. Regular debridement physically removed biofilms and enhanced local bactericidal effects.

PHARMACEUTICAL ANALYSIS AND RISK MANAGEMENT OF MYELOSUPPRESSION EVENTS:

The 2 episodes of myelosuppression observed during treatment (with the lowest WBC count of 0.72×109/L and lowest neutrophil count of 0.04×109/L) underscore the need for vigilance regarding the hematological toxicity of antibacterial agents. The first episode occurred during treatment with levofloxacin and piperacillin/tazobactam. A possible explanation is the toxic effect of these agents on bone marrow hematopoietic cells. Alternatively, the episode may have been related to drug accumulation, given that the agents were administered for 15 and 18 days, respectively, or to immune-mediated mechanisms [27]. The second episode occurred during combined treatment with ceftazidime and fosfomycin. Reports on the hematological toxicity of fosfomycin are limited. This adverse effect is rare, classified as a serious reaction with an incidence below 0.01% [28], and its mechanism remains unclear. Matusik et al. reported that bone marrow aspiration after fosfomycin administration showed disappearance of the neutrophil lineage, accompanied by a substantial increase in eosinophils, suggesting an immune-mediated allergic reaction [29]. Key considerations in pharmaceutical care include establishing a list of high-risk drugs, such as β-lactam/quinolone combinations; monitoring the complete blood cell count on a weekly basis; and prioritizing alternative regimens with a lower risk of myelosuppression.

DECISION-MAKING CONSIDERATIONS FOR NON-SURGICAL IMPLANT RETENTION TREATMENT:

According to clinical practice guidelines from the Infectious Diseases Society of America [2], for patients with PJI who can tolerate multiple surgeries or prosthetic joint re-implantation but are not candidates for single-stage debridement, 2-stage revision surgery is recommended, involving re-implantation of a new prosthesis after anti-infection therapy. A single-center retrospective cohort study of 171 patients with giant cell tumor of bone reported that 30 patients required revision due to infection [30]. However, in the present case, pharmacotherapy with implant retention was chosen because of economic constraints. This decision was based on 3 prerequisites: (1) drug susceptibility testing (using Clinical and Laboratory Standards Institute standards) that confirmed bacterial sensitivity to rifampicin (minimum inhibitory concentration ≤1 μg/mL); 2) the prosthesis demonstrated good mechanical stability without imaging evidence of loosening; and 3) the patient exhibited high compliance, completing 6 weeks of intravenous treatment followed by 3 months of oral sequential therapy. It should be emphasized that this strategy is applicable only to selected patients, such as those who can tolerate the medications. Long-term follow-up for at least 2 years is recommended to monitor the risk of infection recurrence and prosthesis failure.

Effective treatment of infection after prosthesis replacement relies on accurate diagnosis, appropriate antibiotic selection, local debridement, patient cooperation, and careful postoperative care. However, in patients with severe or recurrent infections and a prolonged disease course, prosthesis removal may still be necessary. In the present case, empirical drugs were not appropriately selected prior to biofilm formation, and conventional antibiotics were continuously administered. Some studies of empirical therapy have shown that the combination of fluoroquinolones and piperacillin-tazobactam generally exerts synergistic or additive effects, reduces the frequency of drug-resistant mutations, and provides therapeutic advantages in infections caused by non-fermenting bacteria (P. aeruginosa and Acinetobacter spp.), methicillin-resistant S. aureus, and gram-negative bacteria [31–33]. Due to the limited ability of the drugs to penetrate biofilm, antibiotic therapy was ineffective for an extended period; the prolonged infection further complicated treatment. Economic constraints also posed challenges, given that secondary revision after prosthesis removal would have imposed a substantial financial burden. Thus, clinical pharmacists formulated the treatment plan through literature consultation, close monitoring of adverse reactions, and active communication with surgeons to achieve consensus. Guideline-recommended drugs were selected, and the treatment course was appropriate. Surgeons actively performed debridement and drainage while providing ongoing encouragement to foster patient confidence, thereby gaining the patient’s trust and cooperation. Ultimately, the postoperative prosthesis infection was successfully resolved, and a favorable outcome was achieved.

LIMITATIONS:

This report has some limitations. First, the level of evidence is restricted by its single-center, single-case design. Second, genetic testing of the biofilm was not performed to clarify the drug-resistance mechanism. Finally, the case involved a young woman without comorbidities. Future prospective cohort studies are needed to verify the generalizability of this treatment strategy to broader patient populations.

Conclusions

In the present case, refractory biofilm infection after surgery for a rare pelvic giant cell tumor of bone was successfully managed through multidisciplinary collaboration. The findings suggest that vancomycin combined with rifampicin can effectively penetrate staphylococcal biofilms, but dosage must be optimized based on therapeutic drug monitoring. Pharmaceutical care plays a key role in dynamically monitoring indicators of myelosuppression and adjusting high-risk drug combinations in a timely manner, which is vital to ensure the safety of long-term antibiotic therapy.