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Background: The use of piperacillin/tazobactam with vancomycin as empirical antimicrobial therapy (EAT) for prosthetic joint infection (PJI) has been associated with an increased risk of acute kidney injury (AKI), leading us to propose cefepime as an alternative since 2017 in our reference centre., Objectives: To compare microbiological efficacy and tolerance of these two EAT strategies., Methods: All adult patients with PJI empirically treated with vancomycin+cefepime (n = 89) were enrolled in a prospective observational study and matched with vancomycin+piperacillin/tazobactam-treated historical controls (n = 89) according to a propensity score including age, baseline renal function and concomitant use of other nephrotoxic agents. The two groups were compared using Kaplan-Meier curve analysis, and non-parametric tests regarding the proportion of efficacious empirical regimen and the incidence of empirical therapy-related adverse events (AE)., Results: Among 146 (82.0%) documented infections, the EAT was considered efficacious in 77 (98.7%) and 65 (98.5%) of the piperacillin/tazobactam- and cefepime-treated patients, respectively (P = 1.000). The rate of AE, particularly AKI, was significantly higher in the vancomycin+piperacillin/tazobactam group [n = 27 (30.3%) for all AE and 23 (25.8%) for AKI] compared with the vancomycin+cefepime [n = 13 (14.6%) and 6 (6.7%)] group (P = 0.019 and <0.001, respectively), leading to premature EAT discontinuation in 20 (22.5%) and 5 (5.6%) patients (P = 0.002). The two groups were not significantly different regarding their comorbidities, and AKI incidence was not related to vancomycin plasma overexposure., Conclusions: Based on the susceptibility profile of bacterial isolates from included patients, microbiological efficacy of both strategies was expected to be similar, but vancomycin + cefepime was associated with a significantly lower incidence of AKI., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Optimal treatment of prosthetic joint infection and chronic osteomyelitis consists of surgical removal of biofilm-embedded bacteria, followed by a 6-12 week course of antimicrobial therapy. However, when optimal surgery is not feasible, oral prolonged suppressive antibiotic therapy (PSAT) is recommended to prevent prosthesis loosening and/or relapse of infection. Since 2010, we have used infection salvage therapy using off-label subcutaneous (sc) injection of a β-lactam as PSAT for patients in whom oral PSAT is not possible., Methods: A single-centre prospective cohort study (2010-18) reporting treatment modalities, efficacy and safety in all patients receiving sc PSAT. NCT03403608., Results: The 10 included patients (median age 79 years) had polymicrobial (n = 5) or MDR bacterial (n = 4) prosthetic joint infection (knee, n = 4; hip, n = 3) or chronic osteomyelitis (n = 3). After initial intensive therapy, seven patients received ertapenem, three patients received ceftriaxone and one patient received ceftazidime by sc injection (one patient received 8 days of ceftriaxone before receiving ertapenem). In one patient, sc PSAT failed with recurrent signs of infection under treatment. In three patients, sc PSAT had to be discontinued due to side effects; in only one of these was the sc route implicated (skin necrosis following direct sc injection and not gravity infusion). Median treatment duration was 433 days. In six patients, sc PSAT was successful with favourable outcome at the time of writing. Interestingly, three patients with MDR bacterial carriage at baseline lost this under PSAT during follow-up., Conclusions: As salvage therapy, sc PSAT delivered by gravity infusion is a safe and interesting alternative when an optimal surgical strategy is not feasible and no oral treatment is available., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Daptomycin has been recognized as a therapeutic option for the treatment of bone and joint infection (BJI). Gene polymorphism of ABCB1, the gene encoding P-glycoprotein (P-gp), may influence daptomycin pharmacokinetics (PK)., Objectives: We aimed to examine population PK of daptomycin and its determinants, including genetic factors, in patients with BJI., Patients and Methods: We analysed data from patients who received daptomycin for BJI between 2012 and 2016 in our regional reference centre and who had measured daptomycin concentrations and P-gp genotyping. A population approach was used to analyse PK data. In covariate analysis, we examined the influence of three single nucleotide variations (SNVs) of ABCB1 (3435C > T, 2677G > T/A and 1236C > T) and that of the corresponding haplotype on daptomycin PK parameters. Simulations performed with the final model examined the influence of covariates on the probability to achieve pharmacodynamic (PD) targets., Results: Data from 81 patients were analysed. Daptomycin body CL (CLDAP) correlated with CLCR and was 23% greater in males than in females. Daptomycin central V (V1) was allometrically scaled to body weight and was 25% lower in patients with homozygous CGC ABCB1 haplotype than in patients with any other genotype. Simulations performed with the model showed that sex and P-gp haplotype may influence the PTA for high MIC values and that a dosage of 10 mg/kg/24 h would optimize efficacy., Conclusions: Daptomycin dosages higher than currently recommended should be evaluated in patients with BJI. Gender and P-gp gene polymorphism should be further examined as determinants of dosage requirements., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: Prolonged use of linezolid for bone and joint infection (BJI) is limited by its long-term toxicity. The better safety profile of tedizolid, a recently developed oxazolidinone, could offer an alternative. However, its efficacy against biofilm-embedded and intracellular Staphylococcus aureus, the two main bacterial reservoirs associated with BJI chronicity, is unknown., Methods: Using three S. aureus strains (6850 and two clinical BJI isolates), linezolid and tedizolid were compared regarding their ability: (i) to target the S. aureus intracellular reservoir in an in vitro model of osteoblast infection, using three concentrations increasing from the bone concentration reached with standard therapeutic doses (Cbone = 2.5 × MIC; Cplasm = 10 × MIC; Cmax = 40 × MIC); (ii) to eradicate mature biofilm [minimal biofilm eradication concentration (MBEC)]; and (iii) to prevent biofilm formation [biofilm MIC (bMIC) and confocal microscopy]., Results: Linezolid and tedizolid weakly reduced the intracellular inoculum of S. aureus in a strain-dependent manner despite the similar MICs for the tested strains, but improved cell viability even in the absence of an intracellular bactericidal effect. Conversely, linezolid and tedizolid were ineffective in eradicating mature biofilm formed in vitro, with MBEC >2000 and >675 mg/L, respectively. bMICs of tedizolid were 4-fold lower than those of linezolid for all strains., Conclusions: Linezolid and tedizolid alone are not optimal candidates to target bacterial phenotypes associated with chronic forms of BJI. Despite weak intracellular activity, they both reduce infection-related cytotoxicity, suggesting a role in modulating intracellular expression of staphylococcal virulence factors. Although inactive against biofilm-embedded S. aureus, both-but particularly tedizolid-are able to prevent biofilm formation., (© The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Ertapenem is a therapeutic option in patients with Gram-negative bone and joint infection (BJI). The subcutaneous (sc) route of administration is convenient in the outpatient setting and has shown favourable pharmacokinetics (PK), but available data on ertapenem are limited., Objectives: To perform population PK analysis and pharmacokinetic/pharmacodynamic (PK/PD) simulation of ertapenem administered by the intravenous (iv) or sc route to patients with BJI., Patients and Methods: This was a retrospective analysis of PK data collected in patients with BJI who received iv or sc ertapenem. Measured ertapenem concentrations were analysed with a non-parametric population approach. Then, simulations were performed based on the final model to investigate the influence of ertapenem route of administration, dosage and renal function on the probability of achieving a pharmacodynamic (PD) target, defined as the percentage of time for which free plasma concentrations of ertapenem remained above the MIC (fT>MIC) of 40%., Results: Forty-six PK profiles (13 with iv and 33 with sc ertapenem) with a total of 133 concentrations from 31 subjects were available for the analysis. A two-compartment model with linear sc absorption and linear elimination best fitted the data. Creatinine clearance was found to significantly influence ertapenem plasma clearance. Simulations showed that twice daily dosing, sc administration and renal impairment were associated with an increase in fT>MIC and target attainment., Conclusions: Our results indicate that 1 g of ertapenem administered twice daily, by the iv or sc route, may optimize ertapenem exposure and achievement of PK/PD targets in patients with BJI.

Objectives: Antifungal resistance is a significant and emerging threat. Stewardship programmes (SPs) have been proposed as an opportunity to optimize antifungal use. While examples of antifungal SP implementation have been recently described, there is yet to be an overview of interventions and their impacts on performance measures., Methods: We systematically reviewed published articles using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses check-list 2009. MEDLINE was searched using the term 'antifungal stewardship' on 15 February 2017. Eligible studies were those that described an antifungal SP and included an intervention and an evaluation of performance measures., Results: A total of 97 studies were identified and 14 were included. Only five studies reported an antifungal stewardship team composed of all the recommended members. The main intervention was the formulation of recommendations to change treatment (12 of 14). The main performance measure collected was antifungal consumption (10 of 14), followed by antifungal expenditure (7 of 14), adherence to therapeutic advice (4 of 14) and impact on mortality (4 of 14). Antifungal consumption was reduced by 11.8% to 71% and antifungal expenditure by as much as 50%. Adherence to therapeutic advice ranged from 40% to 88%, whereas antifungal SPs had no impact on mortality., Conclusions: All antifungal SPs had an impact, in particular on antifungal consumption and antifungal expenditure. Active intervention including a review of prescriptions seems to have more impact than implementation of treatment guidelines only. According to available published studies, antifungal consumption appears to be the most achievable performance measure to evaluate the impact of an antifungal SP., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: The Staphylococcus aureus intracellular reservoir is associated with bone and joint infection (BJI) chronicity. As daptomycin is increasingly prescribed in BJI, strategies for improving its reduced intracellular activity should be promoted., Objectives: Based on the known in vitro synergy of daptomycin with β-lactams, the aim of the present study was to evaluate the intracellular activity of these combinations in an ex vivo osteoblast infection model., Methods: Osteoblastic cells infected with an MRSA strain or its isogenic MSSA counterpart were incubated for 24 h with daptomycin, oxacillin or ceftaroline alone or in combination using usual intraosseous therapeutic concentrations. Intracellular bacteria were quantified by plating cell lysates. MICs for MSSA and MRSA were determined using the chequerboard method at pH 5 to mimic conditions expected within lysosomes, the foremost S. aureus intracellular location., Results: Daptomycin failed to reduce the intracellular MSSA inoculum, and was weakly active against MRSA compared with untreated cells (-27.6%; P < 10-3). Oxacillin and ceftaroline revealed significant intracellular activity, including oxacillin against MRSA-infected cells (-43.2%; P < 10-3). The daptomycin/oxacillin combination was significantly more active against intracellular MSSA and MRSA compared with daptomycin and oxacillin alone (-44.4% and -57.2%, respectively; P < 0.05). In contrast, daptomycin/ceftaroline was not more efficient than ceftaroline alone. Interestingly, oxacillin MICs for MRSA decreased in vitro from >256 to 0.023 mg/L when the pH decreased from 7 to 5, and chequerboards showed an additive effect of the daptomycin/oxacillin combination against MRSA at pH 5., Conclusions: In acidic intracellular conditions, oxacillin enhances daptomycin activity against the intraosteoblastic reservoir of S. aureus, including MRSA., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objectives: The aim of this study was to evaluate pristinamycin in the treatment of MSSA bone and joint infection (BJI)., Patients and Methods: A retrospective, single-centre cohort study (2001-11) investigated outcome in adults receiving pristinamycin for MSSA BJI and pristinamycin-related adverse events (AEs)., Results: One hundred and two MSSA BJIs were assessed in 98 patients [chronic infection, 33.3%; and orthopaedic device-related infection (ODI), 67.6%]. Surgery was performed in 77.5% of total cases, and in all but three ODIs, associated with antibiotic therapy of a median total duration of 29.2 weeks. Pristinamycin was prescribed as a part of the initial intensive treatment phase (29.4%) and/or included in final maintenance therapy (83.3%) at a dose of 47.6 (45.5-52.6) mg/kg/day for 9.3 (1.4-20.4) weeks. AEs occurred in 13.3% of patients, consisting of gastrointestinal disorder (76.9%) or allergic reaction (23.1%), leading to treatment interruption in 11 cases. AEs were related to daily dose (OR, 2.733 for each 10 additional mg/kg/day; P = 0.049). After a follow-up of 76.4 (29.6-146.9) weeks, the failure rate was 34.3%, associated with ODI (OR, 4.421; P = 0.006), particularly when the implant was retained (OR, 4.217; P = 0.007). In most patients, the pristinamycin companion drug was a fluoroquinolone (68.7%) or rifampicin (21.7%), without difference regarding outcome., Conclusions: Pristinamycin is an effective, well-tolerated alternative therapeutic option in MSSA BJI, on condition that a daily dosage of 50 mg/kg is respected., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

An open, non-comparative multicentre study was conducted at 36 sites in six countries to test the efficacy and safety of piperacillin/tazobactam in the therapy of lower respiratory tract infections. Piperacillin 4 g and tazobactam 500 mg were administered intravenously every 8 h for a minimum of five days. Two hundred and thirty patients were enrolled: 133 were evaluable for clinical efficacy and 106 for bacteriological efficacy. The clinical response was favourable in 96% of evaluable patients and the bacterial eradication rate was 93%. Nine patients (4%) had severe adverse events related to piperacillin/tazobactam and requiring discontinuation of therapy. In this study piperacillin/tazobactam was an effective and safe drug in the treatment of hospitalized patients with lower respiratory tract infection caused by sensitive organisms.

In a multicentre non-randomized open prospective study, 124 patients hospitalized in medical infectious disease or intensive care units, with severe community and hospital-acquired bacterial infections were treated with 15 mg/kg body weight amikacin in a once-daily dose given as a 30 min iv infusion, combined with other antibiotics. Infections were bacteriologically proven in 101 patients. The clinical responses showed 83.1% primary success and 83.9% definitive cure predominantly in intensive care patients with hospital-acquired infections and pneumonia. Bacteriological eradication was achieved in 67.3%. Bacteria associated with true failures and colonizations were predominantly Pseudomonas, Acinetobacter and Staphylococcus spp. The risk of nephrotoxicity may be decreased with such a regimen of amikacin, but no conclusions could be drawn with regard to ototoxicity. In summary, a once-daily dosing regimen of amikacin 15 mg/kg is practical and probably efficacious and safe in severely infected patients.