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We thank Baklouti et al. (1) for commenting on our population pharmacokinetic study of dalbavancin for optimal treatment of adult patients with staphylococcal osteoarticular infections (2) and for suggesting that our model tends to underestimate the concentrations observed in a group of French patients (French group).….

Dalbavancin is gaining interest in the treatment of complex osteoarticular (OA) infections. We aimed to conduct a population pharmacokinetic analysis of dalbavancin in a prospective cohort of adult patients with OA infections caused by Gram-positive organisms and to identify optimal dosing regimens for long-term treatment. Nonlinear mixed-effects modeling was performed with Monolix. Monte Carlo simulations were performed with six dalbavancin regimens (1,500 mg at day 1; 1,000 mg at day 1 plus 500 mg at day 8; 1,500 mg at days 1 and 8; and 1,500 mg at days 1 and 8 plus 500, 1,000, or 1,500 mg at day 36) to assess the probability of target attainment (PTA) of three pharmacodynamic targets of area under the concentration-time curve for the free, unbound fraction of a drug at 24 h/MIC (fAUC(24h)/MIC) against Staphylococcus aureus (>27.1, 53.3, and 111.1). The cumulative fraction of response (CFR) was calculated against the MIC distribution of both methicillin-resistant S. aureus (MRSA) and methicillin-susceptible S. aureus (MSSA). Desirable PTAs and CFRs were ≥90%. Fifteen patients provided 120 plasma concentrations. Most (73.3%) had prosthetic joint infections. The clinical cure rate was 87%. A two-compartment model with linear elimination well described the data. No covariate was retained in the final model. Pharmacokinetic dalbavancin estimates were 0.106 liter/h for total body clearance (CL) and 36.4 liter for volume of distribution at steady state(V(ss)). The tested dosing regimens granted desirable CFRs against S. aureus at the most effective pharmacokinetic/pharmacodynamic (PK/PD) target for a period ranging 3 to 9 weeks. Giving a regimen of two 1,500-mg doses of dalbavancin 1 week apart may ensure efficacy against both MSSA and MRSA up to 5 weeks in patients with OA infections. Clinical assessment at that time may allow for considering whether an additional dose should be administered for prolonging effective treatment.

Fosfomycin is gaining interest in the treatment of complex osteoarticular infections (OI) due to multidrug-resistant (MDR) pathogens. Our aims were to conduct population pharmacokinetics of fosfomycin in a cohort of OI patients receiving 16 g daily by intermittent (II) or continuous (CI) infusion and to carry out Monte Carlo simulations for dosage optimization in the treatment of these infections. Patients underwent blood sampling on day 5 of therapy (2 to 3 serial samples). Population pharmacokinetics and Monte Carlo simulations were performed to define the probability of target attainment (PTA) of 70% T>MIC and the cumulative fraction of response (CFR) against common OI pathogens with dosages of 8, 12, 16, and 20 g/day administered by II, extended infusion (EI), or CI. Forty-eight patients were recruited. A two-compartment open model with infusion input and first-order elimination was developed. Estimated creatinine clearance (CL(CR)) was included as a covariate in the final model. Monte Carlo simulations showed that optimal PTAs and CFRs (≥90%) can be achieved in three different classes of renal function by administering a daily dosage of 2 g every 6 h (q6h) by II against Staphylococcus aureus, Escherichia coli, expanded-spectrum beta-lactamase (ESBL)-producing E. coli, and methicillin-resistant S. aureus; 8 g by CI against coagulase-negative staphylococci, K. pneumoniae, and ESBL-producing K. pneumoniae; 12 g by CI against P. aeruginosa; and 16 g by CI against KPC-producing K. pneumoniae. Our study provides a strong rationale for considering fosfomycin dosages of 8 to 16 g daily by CI in several clinical scenarios for OI patients. The feasibility of administration by CI in an elastomeric pump makes fosfomycin a candidate for OPAT programs.

Purpose (1) To evaluate the diagnostic testing performance of the synovial white blood cell (WBC) count, polymorphonuclear cell percentage, and synovial glucose, synovial protein, synovial lactate dehydrogenase, and synovial C-reactive protein levels as diagnostic markers for the diagnosis of septic arthritis after anterior cruciate ligament (ACL) reconstruction; (2) to define the ideal thresholds of the aforementioned tests, leading to the optimal sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy; and (3) to define the sensitivity of synovial fluid culture and synovial tissue sample culture, as well as determine whether previous antibiotic treatment may affect the accuracy of these tests. Methods We performed a retrospective analysis of all patients readmitted from January 2009 to September 2019 with signs suggestive of septic arthritis and undergoing a knee aspiration for synovial fluid analysis and culture. The receiver operating characteristic curve and the associated area under the curve were constructed for the aforementioned synovial markers. Sensitivity, specificity, PPV, NPV, and accuracy were calculated for the obtained optimal values. Sensitivity was also calculated for synovial fluid culture and synovial tissue sample culture, and the influence of previous antibiotic treatments on culture sensitivity was evaluated. Results Among 3,408 cases of ACL reconstruction, after the exclusion of 13 patients not meeting the inclusion criteria, 24 infected and 14 uninfected patients were reviewed and included in the analysis. The diagnosis was confirmed by the presence of 2 positive culture findings with the same isolated microorganism or at least 3 of the 4 following criteria: elevated serum C-reactive protein level and erythrocyte sedimentation rate, positive results of histologic analysis of synovial tissue, macroscopic evidence of purulence, and 1 positive culture finding. The receiver operating characteristic curve analysis showed that the most reliable marker for the diagnosis of septic arthritis after ACL reconstruction was the synovial WBC count (area under the curve, 0.89). A cutoff value of 28,100 cells/mL presented the highest accuracy (0.85), highest PPV (0.94), and highest NPV (0.76); moreover, with the threshold set at 40,000 cells/mL, postoperative infection could be diagnosed with 100% specificity. The sensitivity of synovial fluid culture was significantly lower than the sensitivity of synovial tissue sample culture (0.63 vs 0.96, P = .0045); moreover, the sensitivity further decreased if patients took antibiotics before aspiration (0.44 vs 0.73), although this decrease was not statistically significant. Conclusions The synovial WBC count is the most reliable test for the diagnosis of septic arthritis after ACL reconstruction. Although the sensitivity of synovial fluid culture is affected by previous antibiotic treatment, the synovial WBC count is not influenced and proves to be useful in the diagnosis of this uncommon complication. Level of Evidence Level II, diagnostic study.

Objectives: We aimed to develop and validate a risk score to predict severe respiratory failure (SRF) among patients hospitalized with coronavirus disease-2019 (COVID-19). Methods: We performed a multicentre cohort study among hospitalized (>24 hours) patients diagnosed with COVID-19 from 22 February to 3 April 2020, at 11 Italian hospitals. Patients were divided into derivation and validation cohorts according to random sorting of hospitals. SRF was assessed from admission to hospital discharge and was defined as: SpO2 30 breaths/min or respiratory distress. Multivariable logistic regression models were built to identify predictors of SRF, β-coefficients were used to develop a risk score. Trial Registration NCT04316949. Results: We analysed 1113 patients (644 derivation, 469 validation cohort). Mean (±SD) age was 65.7 (±15) years, 704 (63.3%) were male. SRF occurred in 189/644 (29%) and 187/469 (40%) patients in the derivation and validation cohorts, respectively. At multivariate analysis, risk factors for SRF in the derivation cohort assessed at hospitalization were age ≥70 years (OR 2.74; 95% CI 1.66–4.50), obesity (OR 4.62; 95% CI 2.78–7.70), body temperature ≥38°C (OR 1.73; 95% CI 1.30–2.29), respiratory rate ≥22 breaths/min (OR 3.75; 95% CI 2.01–7.01), lymphocytes ≤900 cells/mm3 (OR 2.69; 95% CI 1.60–4.51), creatinine ≥1 mg/dL (OR 2.38; 95% CI 1.59–3.56), C-reactive protein ≥10 mg/dL (OR 5.91; 95% CI 4.88–7.17) and lactate dehydrogenase ≥350 IU/L (OR 2.39; 95% CI 1.11–5.11). Assigning points to each variable, an individual risk score (PREDI-CO score) was obtained. Area under the receiver-operator curve was 0.89 (0.86–0.92). At a score of >3, sensitivity, specificity, and positive and negative predictive values were 71.6% (65%–79%), 89.1% (86%–92%), 74% (67%–80%) and 89% (85%–91%), respectively. PREDI-CO score showed similar prognostic ability in the validation cohort: area under the receiver-operator curve 0.85 (0.81–0.88). At a score of >3, sensitivity, specificity, and positive and negative predictive values were 80% (73%–85%), 76% (70%–81%), 69% (60%–74%) and 85% (80%–89%), respectively. Conclusion: PREDI-CO score can be useful to allocate resources and prioritize treatments during the COVID-19 pandemic.

BJECTIVES: Prolonged treatment with linezolid may cause toxicity. The purpose of this study was to define pharmacodynamic thresholds for improving safety outcomes of linezolid. METHODS: We performed a retrospective study of patients who had trough (C(min)) and peak (C(max)) plasma levels measured during prolonged linezolid treatment. Dosage adjustments were performed when C(min) ≥10 mg/L and/or AUC₂₄ ≥400 mg/L · h. Patients were divided into two subgroups according to the absence or presence of co-treatment with rifampicin (the linezolid group and the linezolid + rifampicin group, respectively). Data on demographic characteristics, disease, microbiology and haematochemical parameters were collected and outcomes in relation to drug exposure were compared between groups. RESULTS: A total of 45 patients were included. Dosage adjustments were needed in 40% versus 0% of patients in the linezolid group (n = 35) versus the linezolid + rifampicin group (n = 10), respectively. Patients in the linezolid group had either significantly higher C(min) [3.71 mg/L (1.43-6.38) versus 1.37 mg/L (0.67-2.55), P

The objective of the present retrospective observational study carried out in patients receiving a standard dosage of linezolid and undergoing routine therapeutic drug monitoring (TDM) was to assess the interindividual variability in plasma exposure, to identify the prevalence of attainment of optimal pharmacodynamics, and to define if an intensive program of TDM may be warranted in some categories of patients. Linezolid plasma concentrations (trough [ C min ] and peak [ C max ] levels) were analyzed by means of a high-performance liquid chromatography (HPLC) method, and daily drug exposure was estimated (daily area under the plasma concentration-time curve [AUC 24 ]). The final database included 280 C min and 223 C max measurements performed in 92 patients who were treated with the fixed 600-mg dose every 12 h (q12h) intravenously ( n = 58) or orally ( n = 34). A wide variability was observed (median values [interquartile range]: 3.80 mg/liter [1.75 to 7.53 mg/liter] for C min , 14.70 mg/liter [10.57 to 19.64] for C max , and 196.08 mg·h/liter [144.02 to 312.10 mg·h/liter] for estimated AUC 24 ). Linezolid C min was linearly correlated with estimated AUC 24 ( r 2 = 0.85). Optimal pharmacodynamic target attainment (defined as C min of ≥2 mg/liter and/or AUC 24 /MIC 90 ratio of >80) was obtained in about 60 to 70% of cases, but potential overexposure (defined as C min of ≥10 mg/liter and/or AUC 24 of ≥400 mg·h/liter) was documented in about 12% of cases. A significantly higher proportion of cases with potential overexposure received cotreatment with omeprazole, amiodarone, or amlodipine. Our study suggests that the application of TDM might be especially worthwhile in about 30% of cases with the intent of avoiding either the risk of dose-dependent toxicity or that of treatment failure.

The purpose of this study was to assess the clinical efficacy of high-dose levofloxacin plus rifampicin in the empirical treatment of non-tuberculous spondylodiscitis in an epidemiological context of low incidence of staphylococcal fluoroquinolone resistance. All consecutive adult patients with spondylodiscitis (January 2003 to December 2006) were empirically treated with high-dose levofloxacin (500 mg every 12 h normalised to renal function and optimised by means of therapeutic drug monitoring whenever feasible) plus rifampicin 600 mg every 24 h. Trough and peak plasma concentrations were targeted at 1-3 mg/L and 6-9 mg/L, respectively, to maximise the concentration-dependent activity of levofloxacin in bone. Follow-up was performed until 9 months after the end of therapy. Forty-eight patients were included. Eleven patients underwent a surgical approach for spine stabilisation. Among the 29 bacterial isolates, Staphylococcus aureus was the most frequent (65.5%) (all meticillin-susceptible strains). Tailored levofloxacin plasma exposure over time was ensured in most cases. Median treatment duration was 15.1 weeks. Overall response rates were: 77.1% at the intent-to-treat analysis; 84.1% among patients who completed therapy (N = 44); and 96.3% among those receiving targeted therapy against documented levofloxacin-susceptible isolates (N = 27). No patient had evidence of disease relapse at follow-up. Our findings suggest that high-dose levofloxacin regimens may be highly effective in the treatment of non-tuberculous spondylodiscitis and support its putative role in combination with rifampicin against S. aureus. © 2008 Elsevier B.V. and the International Society of Chemotherapy.