PMC8044368_01
Clinical description of the patient #4, a 77-year-old man. He had a past history of anal cancer and congestive heart failure with arrhythmia. Right and left hip prostheses were implanted in 2013 and 2014, respectively, both following femoral head fracture. As prosthesis loosening occurred with migration of the prosthesis in the pelvis (A), a prosthetic joint infection (PJI) of the left hip was suspected. Explantation was performed in 2017 (B), revealing P. aeruginosa chronic infection. Unfortunately, the strain was resistant to ciprofloxacin, but remained susceptible to ceftazidime. Intravenous (IV) ceftazidime was administered after explantation and stopped 15 days before reimplantation. At the time of reimplantation 3 months later, a complex acetabular reconstruction with the Burch-Schneider antiprotrusio cage and allografts was performed (C), without any occurrence of loosening during the prolonged follow-up of 2 years (D). As the cultures were still positive with persistence of P. aeruginosa in culture with the same susceptibility, IV ceftazidime 2 g/8 h was prescribed again. The dose was then reduced to 1 g/12 h as chronic kidney injury occurred (creatinine clearance 30 ml/min), before performing the first therapeutic drug monitoring (TDM) 6 months after the reimplantation, after switch from IV to SC ceftazidime 1 g/12 h. The outcome was favorable with a total control of the infectious disease (i.e., without occurrence of any sign of infection) during the follow-up. Unfortunately, the patient died ~2 years after de reimplantation (727 days) following trauma and hemorrhagic shock.
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An illustrative case of our dosing approach is that of a 77-year-old man who had a chronic PJI of the hip (patient #4; Figure 1).
Example of dosage individualization based on pharmacokinetic/pharmacodynamic (PK/PD) in patient #4, treated with suppressive ceftazidime for persistent P. aeruginosa PJI. The x-axis shows the time, the y-axis represents ceftazidime plasma concentration. Of note, this is not the real time of drug therapy. The time scale has been altered to show the three dosage periods on the same plot. The blue marks on the x-axis show drug administrations. The red dots represent the patient-measured ceftazidime concentrations. The black line represents model prediction. The vertical line separates the three dosage periods: 1 g/12 h, 1 g/24 h, and 1 g on Monday and Wednesday + 2 g on Friday. On the first TDM occasion, under a dosage of 1 g/12 h, the measured ceftazidime Cmin was 20.7 mg/l, well above the target concentration of 10 mg/l (5 x MIC) for this patient. The model predicted that a dosage of 1 g/24 h would result in Cmin of 8.2 mg/l and 88% of time above the target level. The dosage was adjusted as suggested. TDM was performed a second time, 2 months later, under a dosage of 1 g/24 h. The measured ceftazidime Cmin was 7 mg/l, in good agreement with the model prediction 2 months before. The model predicted that a dosage of 1 g on Monday and Wednesday and 2 g on Friday would result in Cmin of 2.7 mg/l and 40% of time spent above the target level of 10 mg/l (5 x MIC).
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Figure 2 summarizes how his dosage regimen was changed from 1 g/12 h to a thrice weekly regimen based on TDM and PK/PD modeling.
PMC8044368_02
Clinical description of patient #5, a 75-year-old woman. She had a past history of diabetes, Parkinson's disease, and hypertension. A left knee prosthesis was implanted in 2009. In 2017, she experienced a distal femoral fracture requiring osteosynthesis and then debridement for acute infection. As a pseudarthrosis occurred, a two-stage exchange was performed. Enterobacter cloacae producing extended-spectrum beta-lactamases (ESBL) was found, and imipenem was prescribed and was stopped after the reimplantation. Unfortunately, the patient developed signs of acute infection and a new debridement revealed Pseudomonas aeruginosa and Candida albicans superinfection, with persistence of the ESBL Enterobacter cloacae. The initial therapy included IV imipenem, oral ciprofloxacin, and oral fluconazole. After 6 weeks, imipenem was replaced by IV ertapenem (1 g/12 h), and irreductible flessum persisted with mild prosthesis loosening on X-ray (A). Ciprofloxacin and fluconazole were stopped after 12 weeks and 6 months, respectively. Six months after surgery, ertapenem administered as 1 g/24 h by SC route was continued as suppressive therapy targeting the multidrug-resistant Enterobacter cloacae. Unfortunately, prosthesis loosening (B) and purulent discharge occurred (C) (the red arrow points to the fistula from which purulent discharge occurred) revealing the persistence of the ESBL Enterobacter cloacae into the joint, despite ertapenem therapy. It became resistant to ertapenem.
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A second case illustrates the importance of MIC in the dosing decision (patient #5, Figure 3). The patient had no signs of uncontrolled infection at this time but experienced a poor functional outcome with irreductible flessum and mild lucencies on X-ray (Figure 3A). Unfortunately, 7 months after this dosage adjustment, the patient showed treatment failure, with total prosthesis loosening (Figure 3B) and purulent discharge with acquired resistance of Enterobacter cloacae to ertapenem.
Example of dosage individualization based on PK/PD in patient #5, treated with suppressive ertapenem for a persistent E. cloacae PJI. The x-axis shows the time and the y-axis represents ertapenem plasma concentration. Of note, this is not the real time of drug therapy, as past therapy before TDM was much longer. The blue marks on the x-axis show drug administrations. The red dots represent the patient-measured ertapenem concentrations. The black line represents model prediction. The vertical line separates the past therapy with 1 g/24 h and predicted future therapy. The inserted table shows the predicted Cmin and PK/PD objective for three candidate dosage regimens and three possible MIC values.
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