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Objectives: Ceftazidime-avibactam (CAZ-AVI)-based treatments have been associated with the emergence of resistance in KPC-producing Klebsiella pneumoniae (KPC-Kp) isolates after antimicrobial exposure. Here, we evaluated the CAZ-AVI resistance development in KPC-Kp isolated from patients treated with CAZ-AVI-based therapy., Methods: We enrolled adult patients treated with CAZ-AVI-based regimens between January 2020 and January 2021. Carbapenemase-producing isolates collected from clinical samples and rectal swabs were evaluated for CAZ-AVI resistance development after antimicrobial exposure. KPC-Kp developing CAZ-AVI resistance and parental susceptible strains were genomically characterized. Whole genome sequencing was performed by using the Illumina iSeq100 platform and genomes were analyzed for antimicrobial-resistance genes, plasmid and porins sequences., Results: We enrolled 90 patients treated with CAZ-AVI-based therapy and 62.2% (56/90) of them were colonized by KPC-producers before CAZ-AVI-based treatment and 6.6% acquired colonization during therapy. Six (6.6%) patients developed infections because of resistant KPC-Kp after CAZ-AVI exposure and 3 (3.3%) of them developed CAZ-AVI resistance in the rectum. Development of resistance among KPC in the rectum occurred after 32 (IQR, 9-35) days of therapy and after 30 (IQR, 22-40) days in clinical specimens. Genetic analysis demonstrated that the development of CAZ-AVI resistance was associated with mutated bla KPC-3 (bla KPC-31 , bla KPC-53 , bla KPC-89 , and bla KPC-130 ) and phylogenetic analysis demonstrated a close genomic relationship between KCP-Kp collected from rectum and clinical samples of the same patient., Discussion: Antimicrobial exposure induce a higher incidence of CAZ-AVI resistance development in the blood and respiratory tract than in the rectum (6.7% vs. 3.3%) of CAZ-AVI-treated patients and genome analysis showed that resistance was associated with mutated bla KPC-3 variants., (Copyright © 2023 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Nephrotoxicity and neurotoxicity are commonly associated with polymyxin treatment; however, the emergence of multidrug-resistant Gram-negative bacteria with limited therapeutic options has resulted in increased use of polymyxins., Objectives: To determine the rates of nephrotoxicity and neurotoxicity during polymyxin treatment and whether any factors influence these., Data Sources: Medline, Embase and Cochrane Library databases were searched on 2 January 2020., Study Eligibility Criteria: Studies reporting nephrotoxicity and/or neurotoxicity rates in patients with infections treated with polymyxins were included. Reviews, meta-analyses and reports not in English were excluded., Participants: Patients hospitalized with infections treated with systemic or inhaled polymyxins were included. For comparative analyses, patients treated with non-polymyxin-based regimens were also included., Methods: Meta-analyses were performed using a random-effects model; subgroup meta-analyses were conducted where data permitted using a mixed-effects model., Results: In total, 237 reports of randomized controlled trials, cohort and case-control studies were eligible for inclusion; most were single-arm observational studies. Nephrotoxic events in 35,569 patients receiving polymyxins were analysed. Overall nephrotoxicity rate was 0.282 (95% confidence interval (CI) 0.259-0.307). When excluding studies where >50% of patients received inhaled-only polymyxin treatment or nephrotoxicity assessment was by methods other than internationally recognized criteria (RIFLE, KDIGO or AKIN), the nephrotoxicity rate was 0.391 (95% CI 0.364-0.419). The odds of nephrotoxicity were greater with polymyxin therapies compared to non-polymyxin-based regimens (odds ratio 2.23 (95% CI 1.58-3.15); p < 0.001). Meta-analyses showed a significant effect of polymyxin type, dose, patient age, number of concomitant nephrotoxins and use of diuretics, glycopeptides or vasopressors on the rate of nephrotoxicity. Polymyxin therapies were not associated with a significantly different rate of neurotoxicity than non-polymyxin-based regimens (p 0.051). The overall rate of neurotoxicity during polymyxin therapy was 0.030 (95% CI 0.020-0.043)., Conclusions: Polymyxins are associated with a higher risk of nephrotoxicity than non-polymyxin-based regimens., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Individualization of antimicrobial treatment based on real-time therapeutic drug monitoring (TDM) and dosing adaptation may represent an important tool in the antimicrobial stewardship programs. Teicoplanin is a glycopeptide hydrophilic antibiotic whose pharmacokinetic behavior may consistently vary among different patient populations. Nowadays it is generally recognized that the effective trough (C min ) plasma level of tecoplanin should be of at least 10-15 mg/L for the treatment of mild infections, and of 15-30 mg/L for the treatment of deep-seated infections and/or of severe infections. The aim of this viewpoint is to provide an update for optimal use of teicoplanin TDM in different patient populations. Available literature supports TDM of C min as a helpful approach in addressing appropriate treatment with teicoplanin, with a frequency of assessment that should be guided by the severity of the infection and/or by the complexity of the pathophysiological status of the patient., Competing Interests: Declaration of Competing Interest The author participated in speaker bureau for Angelini, Basilea Pharmaceutica, Gilead, Hikma, Merck Sharp & Dohme, Nordic Pharma, Pfizer, and Sanofi Aventis, and in advisory board for Angelini, Basilea Pharmaceutica, Correvio, Gilead, Merck Sharp & Dohme, Nordic Pharma, Novartis, Pfizer, and Thermo-Fisher., (Copyright © 2020 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Invasive fungal infections (IFIs) represent a global issue and affect various patient populations. In recent years, resistant fungal isolates showing increased azole or echinocandin MICs have been reported, and their potential clinical impact has been investigated., Aims: To provide an update on the epidemiology of resistance among fungi (e.g., Candida spp., Aspergillus spp., and Cryptococcus spp.) and to offer a critical appraisal of the relevant literature regarding the impact of MICs on clinical outcome in patients with IFI., Sources: PubMed search with relevant keywords along with a personal collection of relevant publications., Content: Although antifungal resistance has been associated with a poorer response to antifungal therapy in various studies, other factors such as comorbidities, septic shock and source of infection appear to be key determinants affecting the clinical outcome of patients with IFI., Implications: Future international collaborative studies are required to tease out the relative contribution of in vitro antifungal resistance on patient outcomes, thus enabling the optimization of IFI management., (Copyright © 2020. Published by Elsevier Ltd.)

Background: Bacterial brain abscesses remain a serious central nervous system problem despite advances in neurosurgical, neuroimaging, and microbiological techniques and the availability of new antibiotics. The successful treatment of brain abscesses requires surgery, appropriate antibiotic therapy, and eradication of the primary source; nevertheless many controversial issues on the management of this serious infection remain unresolved., Controversial Issues: The aim of this GISIG (Gruppo Italiano di Studio sulle Infezioni Gravi) working group - a panel of multidisciplinary experts - was to define recommendations for some controversial issues using an evidence-based and analytical approach. The controversial issues were: (1) Which patients with bacterial brain abscesses can be managed safely using medical treatment alone? (1a) What is the efficacy in terms of outcome, tolerability, cost/efficacy, and quality of life of the different antibiotic regimens used to treat bacterial cerebral abscesses? (1b) Which antibiotics have the best pharmacokinetics and/or tissue penetration of brain and/or brain abscess? 2) What is the best surgical approach in terms of outcome in managing bacterial brain abscesses? Results are presented and discussed in detail., Methods: A systematic literature search using the MEDLINE database for the period 1988 to 2008 of randomized controlled trials and/or non-randomized studies was performed. A matrix was created to extract evidence from original studies using the CONSORT method to evaluate randomized clinical trials and the Newcastle-Ottawa Quality Assessment Scale for case-control studies, longitudinal cohorts, and retrospective studies. The GRADE method for grading quality of evidence and strength of recommendation was applied., (Copyright © 2010 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Respiratory fluoroquinolones are currently considered by several guidelines among the most effective antimicrobial agents for the treatment of acute bacterial rhinosinusitis. The aim of this study was to assess levofloxacin penetration into paranasal sinuses mucosa of 15 patients with chronic rhinosinusitis 1h (n = 4), 2 h (n = 5) and 3 h (n = 6) after a single 500 mg oral dose. Levofloxacin concentrations in plasma and tissue samples were assessed by means of HPLC. Median of mucosal concentrations were 0.96 mg l(-1) at 1 h, 2.50 mg l(-1) at 2 h, 5.84 mg l(-1) at 3 h. Average paranasal sinuses mucosa-to-plasma ratios raised from 1.46 at 1 h, to 1.81 at 2 h and to 2.56 at 3 h. These data are consistent with 500 mg oral levofloxacin ensuring appropriate therapeutic exposure in sinonasal tissue of patients with chronic rhinosinusitis, the concentrations between 1 and 3 h post-dosing being almost always higher than the MIC90 against the major bacterial pathogens responsible for upper respiratory tract infections.

In order to evaluate the pharmacokinetics of cyclosporine A comparing the traditional (CsA-SCG) with the microemulsion formulation (CsA-ME), 20 clinically stable heart-transplant patients were enrolled in the study. All patients were on a thrice-daily dosage regimen (mean single dose 1.14 +/- 0.4 mgkg(-1)body weight) of CsA-SCG. The steady-state area under the concentration-time curve during a dosage interval was calculated during three sequential periods: (1) the first after the morning oral dose of CsA-SCG; (2) the second (8 days later) after 2 hours intravenous infusion of cyclosporine; (3) the third after the CsA-ME morning oral dose (30 days after the milligram-to-milligram dose conversion). After switching from standard formulation CsA-SCG to CsA-ME, significant changes were observed in C(max)(ss)( 732 +/- 178 vs 935 +/- 250 ng ml(-1), P< 0.001) and t(max)( 2.63 +/- 1.21 vs 1.36 +/- 0.49 h, P< 0.001). The CsA-ME mean bioavailability was higher than CsA-SCG ( 75 +/- 19 vs 66 +/- 16%;P< 0.001). The main CsA pharmacokinetic parameters of both formulations in clinically stable heart-transplant patients presented evident differences from data obtained in other transplant-patient populations., (Copyright 2001 Academic Press.)

To evaluate the effects of a 6-month methotrexate (MTX) treatment period on cyclosporine A (CsA) pharmacokinetics were subsequently added in patients with rheumatoid arthritis (RA) in comparison with patients treated with CsA only, CsA was administered to 30 subjects with RA (group A) treated with MTX (10 mg week-1 i.m.) for 6 months and to 30 patients (group B) who received no MTX treatment. The mean doses +/- SD of CsA used in groups A and B were 3.2 +/- 0.5 and 3.3 +/- 0.4 mg kg-1, respectively. CsA levels were determined in whole blood by means of a fluorescence polarization immunoassay (FPIA) method with a specific monoclonal antibody. The following pharmacokinetics parameters were calculated: area under the curve from 0 to 24 h (AUC0-24), half-life of the elimination phase (T1/2 beta), total body clearance CL.F-1; V.F-1 and apparent volume of distribution (Vd beta). The mean blood concentrations and the pharmacokinetic parameters calculated in group A did not present significant statistical differences in comparison to group B. In conclusion, a 6-month MTX therapy does not produce liver function modifications to such an extent as to modify the pharmacokinetics of CsA subsequently added. Therefore, from a clinical pharmacological point of view, an MTX-CsA cotreatment appears feasible.

Since motor fluctuations in Parkinsonian patients might be, at least in part, explained by an antagonism between levodopa (LD) and its metabolite 3-O-methyldopa (3-OMD) at blood-brain-barrier (BBB), we decided to study LD and 3-OMD plasma and cerebrospinal fluid (CSF) levels in subjects undergoing lumbar puncture for diagnostic purposes. After informed consent, 70 subjects took a tablet of carbidopa-levodopa association (Sinemet or Sinemet-CR) 0.5, 1, 2, 4, 8, 12 h before blood and lumbar cerebrospinal fluid collection. LD and 3-OMD were determined by an HPLC-electrochemical method. The subjects treated with Sinemet-CR had lower LD cerebrospinal fluid concentrations along with lower LD and higher 3-OMD plasma concentrations. This pattern of LD cerebrospinal fluid concentrations may be explained by means of a transport competition between LD and 3-OMD at blood brain barrier level.

Cyclosporine (CsA) and some of its metabolites (M9, M17, M18, M21) have been determined by means of an LC-MASS method in eight psoriatic patients developing nephrotoxicity. In comparison with a control group (15 psoriatics who after the same period of time, with the same daily dose, did not develop nephrotoxicity) they showed an increase of CsA metabolites, especially M17. Because M17 blood concentrations in the nephrotoxic group tended to be higher than in the control group from the first week of treatment we suggest that M17 might be considered a marker of ongoing nephrotoxicity.

The Bayesian method (BM) can use previous information for the optimization of dosage regimen. However, Bayes' law remains true when the parameters are obtained from the infinite population. Therefore a bias might exist in the previous information and affect BM predictive performance. To overcome this shortcoming, the blood drug concentration of a patient can be used to individualize his pharmacokinetic parameters. Until now, at least two sampling strategies, i.e. steady-state and non-steady-state sampling strategies, have been developed to individualize and predict blood drug concentration. In the present study we used five sampling strategies: (1) all samples; (2) post-infusion samples; (3) during-infusion samples; (4) samples within 95% confidence interval/interquartile range of a steady-state concentration; (5) the sample of the mean/median at the mid-time-point of a steady-state to individualize and predict blood cyclosporine concentrations in haematological patients with multidrug resistance. We investigated the effects of different sampling strategies on BM and the nonlinear least squared method (NLLSM) predictive performances. The results showed that BM predictive performance was better than NLLSM. But the results did not prove that the steady-state sampling strategies were superior to the non-steady-state ones.