Efficacy and Therapeutic Drug Monitoring of Continuous Beta-Lactam Infusion for Osteoarticular Infections Caused by Fluoroquinolone-Resistant Pseudomonas aeruginosa: A Prospective Cohort Study.

BACKGROUND AND OBJECTIVES: Osteoarticular infections (OIs) caused by fluoroquinolone-resistant Pseudomonas aeruginosa, including multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains, have poor outcomes. We evaluated the outcomes of an optimized strategy of continuous beta-lactam infusion (BL-CI) guided by therapeutic drug monitoring (TDM) for OIs caused by fluoroquinolone-resistant P. aeruginosa. METHODS: A prospective observational study of patients with P. aeruginosa OIs in a hospital-based BL-CI program (2016-2018) was carried out. TDM targeting free BL concentrations in plasma (fCss) of at least 3-4 × MIC was performed. We compared failure rates between patients with OIs caused by fluoroquinolone-resistant strains who were treated with BL-CI, with or without colistin, and patients with OIs caused by fluoroquinolone-susceptible strains who were treated with ciprofloxacin. RESULTS: Fifty-two patients were included in the study, 19 (36.5%) of whom had OIs caused by fluoroquinolone-resistant P. aeruginosa (13 (68.4%) MDR/XDR strains; 11 (57.9%) device-related infections). The median duration of BL-CI was 36 days; ten patients (52.6%) received BL-colistin combinations. Eighty-two samples were utilized in the TDM, and most patients were found to have a median fCss of 3-10 × MIC; 17 dose adjustments were performed and eight patients needed dose decreases, five of which were due to chronic kidney disease or acute kidney injury (AKI). BL-CI was well tolerated, with the most frequent adverse event being AKI. Failure occurred to 4 patients (21.1%), which was similar to the failure rate of patients with OIs caused by fluoroquinolone-susceptible P. aeruginosa treated with ciprofloxacin (5/30 [16.7%]) (p = 0.699). TDM was also used in the initial BL treatment of patients with OIs caused by susceptible strains before those patients were switched to treatment with ciprofloxacin alone (33 patients, 110 samples, 19 dose adjustments). CONCLUSIONS: BL-CI used with/without colistin and supported by TDM may be an alternative and effective treatment option for OIs caused by fluoroquinolone-resistant P. aeruginosa, where limited available therapeutic options exist, especially in the setting of multidrug resistance. Future research should elucidate whether this strategy can produce outcomes similar to those of patients treated for OIs caused by fluoroquinolone-susceptible strains.

Beta-lactams in continuous infusion for Gram-negative bacilli osteoarticular infections: an easy method for clinical use.

Continuous infusion (CI) of beta-lactams could optimize their pharmacokinetic/pharmacodynamic indices, especially in difficult-to-treat infections. PURPOSE: To validate an easy-to-use method to guide beta-lactams dosage in CI (formula). METHODS: A retrospective analysis was conducted of a prospectively collected cohort (n = 24 patients) with osteoarticular infections caused by Gram-negative bacilli (GNB) managed with beta-lactams in CI. Beta-lactams dose was calculated using a described formula (daily dose = 24 h × beta-lactam clearance × target "steady-state" concentration) to achieve concentrations above the MIC. We correlated the predicted concentration (Cpred = daily dose/24 h × beta-lactam clearance) with the patient's observed concentration (Cobs) measured by UPLC-MS/MS (Spearman's coefficient). RESULTS: The most frequent microorganism treated was P. aeruginosa (21 cases; 9 MDR). Beta-lactams in CI were ceftazidime (n = 14), aztreonam (7), and piperacillin/tazobactam (3), mainly used in combination (12 with colistin, 5 with ciprofloxacin) and administered without notable side effects. The plasma Cobs was higher overall than Cpred; the Spearman correlation between both concentrations was rho = 0.6 (IC 95%: 0.2-0.8) for all beta-lactams, and rho = 0.8 (IC 95%: 0.4-1) for those treated with ceftazidime. CONCLUSIONS: The formula may be useful in clinical practice for planning the initial dosage of beta-lactams in CI, while we await a systematic therapeutic drug monitoring. The use of beta-lactams in CI was safe.

Measurement of ceftazidime concentration in human plasma by ultra-performance liquid chromatography-tandem mass spectrometry. Application to critically ill patients and patients with osteoarticular infections.

Ceftazidime is an antibiotic belonging to the third generation of the cephalosporin family. It is indicated in the treatment of serious, simple or mixed bacterial infections, and its administration in continuous or intermittent infusion allows optimization of the concentration of antibiotic to keep it above the minimum inhibitory concentration. We developed and validated a chromatographic method by ultra-performance liquid chromatography-tandem mass spectrometry to measure ceftazidime concentration in human plasma. Following extraction with acetonitrile and 1,2-dichloroethane, the chromatographic separation was achieved using an Acquity ® UPLC ® BEH(TM) (2.1 × 100 mm i.d., 1.7 µm) reverse-phase C18 column, with a water-acetonitrile linear gradient containing 0.1% formic acid at a 0.4 mL/min flow rate. Ceftazidime and its internal standard (cefotaxime) were detected by electrospray ionization mass spectrometry in positive ion multiple reaction monitoring mode using mass-to-charge transitions of 547.0 → 467.9/396.1 and 456.0 → 395.8/324.1, respectively. The limit of quantification was 0.58 mg/L and linearity was observed in the range 0.58-160 mg/L. Coefficients of variation and absolute relative biases were <9.8 and 8.4%. The mean recovery for ceftazidime was 74.4 ± 8.1%. Evaluation of the matrix effect showed ion enhancement, and no carry-over was observed. The validated method could be applied to daily clinical laboratory practice to measure the concentration of ceftazidime in plasma.