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Background: Ceftolozane/tazobactam (C-T) is a novel beta-lactam/beta-lactamase inhibitor combination approved for the treatment of various infections caused by difficult-to-treat Pseudomonas aeruginosa. In critically ill patients, C-T may exhibit significant pharmacokinetic variability, both between individuals and within individuals, warranting therapeutic drug monitoring for clinical purposes. We aim to develop and validate a novel and sensitive analytical method for concurrently determining C and T in human plasma microsamples (3 μL)., Methods: The method was developed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) with positive electrospray ionization and multiple reaction monitoring (MRM) detection modes, employing specific mass transitions for both drugs. Sample preparation was simple, and the chromatographic run lasted only 4 minutes. Validation was conducted according to European Medicines Agency (EMA) guidelines, encompassing specificity, sensitivity, linearity, precision, accuracy, matrix effect, extraction recovery, limit of quantification, and drug stability. The validated method was applied to measure C and T in 32 plasma samples collected from critically ill patients with multidrug-resistant, gram-negative, bacterial infections., Results: The method ensured accurate (BIAS% 2.1-9.6 for C and -2.2 to 15.2 for T) and precise intraday CV% for C: 6.7-5.5; for T: 1.3-8.9; interday CV% for C 6.0-10.8; for T 4.1-10.2) measurements of C-T over a wide concentration range (0.2-200.0 mg/L for C and 0.1-100.0 mg/L for T). Overall, the recovery at quality control concentration levels was high for both C and T (mean values: 90-91 for C and 89-92 for T). Analyte stability was satisfactory in both human plasma and extracts under various storage conditions. The clinical applicability of the assay was confirmed by the reliably quantifying C and T in clinical plasma samples., Conclusions: The developed and validated LC-MS/MS method is sensitive and suitable for monitoring C and T in human plasma microsamples., Competing Interests: M. Gatti participated in the speaker bureau for Angelini and Shionogi outside of the submitted work. F. Pea participated in the speaker's bureaus for Angelini, BeiGene, Gilead, Menarini, Merck Sharp & Dohme, Pfizer, and Sanofi Aventis and served on the advisory boards for Advanz Pharma, Angelini, BeiGene, Gilead, Merck Sharp & Dohme, and Pfizer outside of the submitted work. P. Viale has participated in speaker's bureaus for Correvio, Gilead, Merck Sharp, & Dohme, Nordic Pharma, and Pfizer and served on the advisory board for bioMérieux, Gilead, Merck Sharp, & Dohme, Nabriva, Nordic Pharma, Pfizer, Thermo-Fisher, and Venatorx outside the submitted work. The remaining authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Fosfomycin is an antibiotic recently repurposed as a potential combination treatment for difficult-to-treat Gram-negative bacterial infections. The pharmacokinetic features of fosfomycin have demonstrated that different pathophysiologic alterations may affect its exposure. Therapeutic drug monitoring may improve real-time management of fosfomycin therapy in different clinical scenarios., Objectives: To develop and validate a fast and sensitive liquid chromatography - tandem mass spectrometry method for measuring fosfomycin in human plasma microsamples (3 µL)., Methods: Analysis was preceded by a user-friendly pre-analytical single-step process performed via a rapid chromatographic run of 2.5 minutes, followed by negative electrospray ionization and detection on a high-sensitivity triple quadrupole tandem mass spectrometer operated in the multiple reaction monitoring mode. European Medicines Agency guidelines were used to validate the specificity, sensitivity, linearity, precision, accuracy, matrix effects, extraction recovery, limits of quantification, and stability of the analytical method., Results: The new assay produced accurate (BIAS%: 0.9-9.1) and precise (coefficient of variation [CV]%: 8.1-9.5) measurements of fosfomycin over a concentration range of 1-1000 mg/L. Overall, analyte recovery was consistent (mean values: 91.2%-97.2%) at all tested concentration levels. The analyte was also stable in human plasma and the final extract under various storage conditions. The clinical applicability of the assay was confirmed through quantitation of plasma samples obtained from patients., Conclusions: A sensitive liquid chromatography - tandem mass spectrometry method for measuring fosfomycin in plasma was developed and validated according to the European Medicines Agency criteria. Quantitation of fosfomycin in clinical plasma samples confirmed that the assay is suitable for therapeutic drug monitoring in clinical scenarios., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The authors present a case of a 67-year-old woman with primary biliary cirrhosis (Child-Pugh class B) who was treated with isavuconazole for invasive pulmonary and cerebral aspergillosis. Isavuconazole treatment was initiated with the standard maintenance dose of 200 mg daily. Therapeutic drug monitoring (TDM) was performed to target trough concentrations within the desired range of 1.0-5.13 mg/L., Methods: Real-time TDM and pharmacokinetic analyses were used to determine the dose adjustments. Liver transaminases (alanine aminotransferase and gamma-glutamyl transferase) were assessed to monitor hepatotoxicity., Results: The trough plasma levels gradually increased over time up to 17.8 mg/L. TDM-guided clinical pharmacological advice was helpful to initially reduce the dose, then to temporarily suspend drug administration, and finally to calculate the correct dose that allowed for long-term treatment up to day 258. No major signs and/or symptoms of drug-related toxicity occurred, apart from a transient increase in gamma-glutamyl transferases that normalized after the drop in isavuconazole trough levels within the desired range., Conclusions: TDM-guided clinical pharmacological advice was essential for the successful and safe management of isavuconazole treatment in this patient with moderate liver dysfunction., Competing Interests: P. G. Cojutti has received personal fees from Angelini and Shionogi. F. Pea has participated in speaker bureaus for Angelini, BeiGene, Gilead, InfectoPharm, Menarini, MSD, Pfizer, Sanofi-Aventis, and Shionogi and in advisory boards for Angelini, BeiGene, Gilead, MSD, Novartis, Pfizer, Sanofi-Aventis, and Shionogi, outside the submitted work. P. Viale has served as a consultant for bioMérieux, Gilead, Merck Sharp and Dohme, Nabriva, Nordic Pharma, Pfizer, Thermo-Fisher, and Venatorx and received payment for serving on the speaker's bureaus for Correvio, Gilead, Merck Sharp and Dohme, Nordic Pharma, and Pfizer, outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Limited evidence concerning optimal azole dosing regimens currently exists for antifungal prophylaxis in hemato-oncological pediatric patients., Methods: Hemato-oncological children receiving intravenous or oral isavuconazole or voriconazole for primary antifungal prophylaxis at IRCCS Azienda Ospedaliero-Universitaria of Bologna during November 2020 to October 2021 and undergoing CPA programs based on real-time therapeutic drug monitoring (TDM) were retrospectively analyzed. CPAs for isavuconazole and voriconazole and the number of dosage adjustments were collected. Normalized trough concentrations [(C min )/dose/kg] were calculated for both drugs at each TDM assessment, and the coefficient of variation was determined. The efficacy and safety of the drugs were evaluated., Results: Sixteen hemato-oncological pediatric patients received azole prophylaxis (mean age and weight: 9.1 ± 4.9 years and 32.6 ± 16.0 kg; 6 isavuconazole and 10 voriconazole). Sixty and 89 CPAs were delivered as isavuconazole and voriconazole, respectively. Dosage adjustments were needed in 3.3% of cases for isavuconazole and 53.9% of cases for voriconazole ( P < 0.001). At first TDM, achievement of the desired target during standard dosing regimens was higher for isavuconazole (83.3%) than for voriconazole (10.0%; P = 0.008). Dispersion of normalized concentrations was higher for voriconazole (CV = 139.1% vs. CV = 79.4%). Elevation of ALT and aspartate aminotransferase levels between baseline and the third month was higher in patients receiving voriconazole (median, 28 vs. 90 U/L; P = 0.038, and 19 vs. 65.5 U/L; P = 0.002)., Conclusions: Our findings suggest that there is limited variability in isavuconazole exposure in hemato-oncological pediatric patients receiving azole prophylaxis , resulting in a low need for CPA-guided dosage adjustments., Competing Interests: M. Gatti reports grants from Angelini S.p.A. outside the submitted work. F. Pea reports personal fees from Angelini, Basilea Pharmaceutica, Gilead, Hikma, MSD, Pfizer, Sanofi–Aventis, Shionogi, Thermo Fisher, and Accelerate Diagnostics outside the submitted work, has participated in speaker's bureaus for Accelerate Diagnostics, Angelini, Basilea Pharmaceutica, Gilead, Hikma, MSD, Pfizer, Sanofi-Aventis, Shionogi, Thermo Fisher, and has served as consultants for Angelini, Basilea Pharmaceutica, Gilead, MSD, Pfizer, and Shionogi outside the submitted work. P. Viale has served as a consultant for bioMérieux, Gilead, Merck Sharp & Dohme, Nabriva, Nordic Pharma, Pfizer, Thermo Fisher, and Venatorx and received payment for serving on speaker's bureaus for Correvio, Gilead, Merck Sharp & Dohme, Nordic Pharma, and Pfizer outside the submitted work. The other authors declare no potential conflicts of interest related to this study., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: The aim of this review was to perform a critical reappraisal of the real-world evidence supporting administration by prolonged infusion of novel beta-lactams for the management of multidrug-resistant Gram-negative infections., Recent Findings: Real-world evidence support the use of novel beta-lactams by prolonged infusion over intermittent infusion in terms of achieving aggressive pharmacokinetic/pharmacodynamic (PK/PD) target for either maximizing efficacy and clinical outcome or suppressing the emergence of resistance development. Continuous infusion of ceftolozane-tazobactam showed a marked superiority toward both intermittent and extended infusion (EI) in achieving a PK/PD target of 100%fT> 4 X MIC in infections caused by less-susceptible Pseudomonas aeruginosa isolates. No resistance development was found in critically ill or immunocompromised patients treated with EI ceftolozane-tazobactam compared to intermittent infusion. Prolonged infusion of ceftazidime-avibactam was negatively associated with mortality in patients affected by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae infections. Different challenging scenarios (patients showing augmented renal clearance of affected by deep-seated infections) could benefit from prolonged infusion to optimize the efficacy of novel agents., Summary: Although available data are still limited, real-world evidence regarding mainly ceftolozane-tazobactam and ceftazidime-avibactam could support the administration of novel beta-lactams by prolonged infusion in some specific scenarios in which achievement of aggressive PK/PD target is quite challenging., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

The authors present the case of a critically ill morbidly obese patient (body mass index, 51.2 kg/m) who suffered from methicillin-resistant Staphylococcus epidermidis, and Candida albicans bloodstream infections. Initial treatment with caspofungin and daptomycin was deemed inappropriate, because blood cultures remained positive for both isolates after 14 days. The clinical pharmacological consultant suggested adding fluconazole and ceftobiprole to the ongoing antimicrobial therapy, and starting a real-time therapeutic drug monitoring program of daptomycin, ceftobiprole, and fluconazole, aimed at optimizing plasma exposures. Punctual minimum inhibitory concentration knowledge on the clinical isolates allowed attainment of the desired pharmacodynamic efficacy targets. Within few days, the patient greatly improved, as blood cultures became negative, and the inflammatory markers decreased to near normal values. This is a proof-of-concept of the importance of a therapeutic drug monitoring-based multidisciplinary approach in the proper management of complex antimicrobial therapy in special populations.

Background: Under certain circumstances, clinicians treating patients with isavuconazole for invasive aspergillosis or mucormycosis may use therapeutic drug monitoring. However, the accuracy and reproducibility of the various assays used by different laboratories for the quantification of isavuconazole plasma concentrations have yet to be determined., Methods: Human plasma samples spiked with known concentrations of isavuconazole were provided to 27 European laboratories that took part in a "round-robin" test (an interlaboratory test performed independently at least 2 times; 2 rounds performed in the current study). Assay methods included liquid chromatography-tandem mass spectrometry (LC-MS/MS), LC with ultraviolet detection (LC-UV), LC with fluorescence detection (LC-FL), and bioassay. The accuracy and reproducibility compared with the known concentrations for each sample in each round were compared overall, between assays, and between laboratories., Results: Twenty-seven laboratories participated in the study (LC-MS/MS, n = 15; LC-UV; n = 9; LC-FL, n = 1; bioassay, n = 2). In round 1, for nominal concentrations of 1000, 1700, 2500, and 4000 ng/mL, the mean (SD) determined concentrations were 1007 (183), 1710 (323), 2528 (540), and 3898 (842) ng/mL, respectively. In round 2, for nominal concentrations of 1200, 1800, 2400, and 4000 ng/mL, the mean (SD) determined concentrations were 1411 (303), 2111 (409), 2789 (511), and 4723 (798) ng/mL, respectively. Over both rounds, determined concentrations were consistently within 15% of the nominal concentrations for 10 laboratories (LC-MS/MS, n = 4; LC-UV, n = 5; bioassay, n = 1) and consistently exceeded the upper 15% margin for 7 laboratories (LC-MS/MS and LC-UV, n = 3 each; LC-FL, n = 1)., Conclusions: Alignment of methodologies among laboratories may be warranted to improve the accuracy and reproducibility of therapeutic drug measurements.

Purpose of Review: This article gives an overview of the practical concept of pharmacokinetic/pharmacodynamic principles useful for clinicians in the management of skin and soft tissue infections (SSTIs)., Recent Findings: Recent studies suggest that distinguishing between bacteriostatic or bactericidal activity when choosing an antimicrobial for the treatment of severe infections could probably be clinically irrelevant. Conversely, what could help clinicians in maximizing the therapeutic efficacy of the various drugs in routine practice is taking care of some pharmacokinetic/pharmacodynamic principles. Concentration-dependent agents may exhibit more rapid bacterial killing than observed with time-dependent agents. Serum concentrations may not always adequately predict tissue exposure in patients with SSTIs, and measuring concentrations at the infection site is preferable. Hydrophilic antimicrobials showed generally lower penetration rates than the lipophilic ones and might require alternative dosing approaches in the presence of severe sepsis or septic shock. Conversely, tissue penetration of lipophilic antimicrobials is often unaffected by the pathophysiological status. Real-time therapeutic drug monitoring may be a very helpful tool for optimizing therapy of severe infections., Summary: Taking care of pharmacokinetic/pharmacodynamic principles deriving from the most recent findings may help clinicians in maximizing treatment of SSTIs with antimicrobials in every situation.

Administration by continuous infusion may represent an effective tool for the treatment of multidrug-resistant gram-negative related infections with meropenem. Currently, no data on chemical stability of generic bioequivalent versions of meropenem over time are available. Triplicate samples of 5 mg/mL solutions of a generic meropenem formulation, Hospira, were evaluated for chemical stability at increasing temperatures (25°C, 30°C, 35°C, and 40°C) by means of a high-performance liquid chromatography technique over 4 separate days. Degradation of generic meropenem was both time and temperature dependent, and the aqueous solutions were stable for up to 8 hours in the temperature range between 25°C and 35°C, and for up to 5 hours at 40°C. Continuous infusion of generic meropenem Hospira may be applied in clinical settings with ambient temperature below 35°C, provided that the 5 mg/mL aqueous solution is reconstituted at most after 6-8 hours.

Background: Several authors have documented the role of low-molecular-weight heparin injection techniques in bruising. However, few researchers have measured the influence of injection duration on the occurrence and extent of bruising., Purpose: The aim of this study was to evaluate the influence of different durations of subcutaneous heparin injection on the occurrence and extent of bruising., Methods: A quasi-experimental case-crossover study design was adopted in 2010. A consecutive series of patients admitted to 2 orthopedic units in a large (600 beds) teaching hospital located in northern Italy were eligible for enrolment. Injections were administered following a standard procedure. The manipulated variable was the duration of the injection, 10 seconds (treatment A) and 30 seconds (treatment B). The evaluation of bruise occurrence and extension performed after 48 hours and data analysis were conducted in a blinded fashion., Results: A total of 150 patients receiving their first and second subcutaneous heparin injections (300 injections) were enrolled. Eighty-seven bruises were observed out of 300 injections (29%): 57 of 150 (38%) after injections lasting 10 seconds and 30 of 150 (20%) after injections lasting 30 seconds (relative risk, 1.50; 95% confidence interval, 1.21-1.86; P = .00). Of the 87 bruises that occurred, 69 (79.3%) were small (2-5 mm) and 18 (20.6%) were large (>5 mm), with no difference in size between 10- and 30-second injections (relative risk, 0.91; 95% confidence interval, 0.39-2.12; P = .83)., Conclusions: Low-molecular-weight heparin injection should be administered over 30 seconds to decrease bruising., Clinical Implications: There is a need to reflect on the feasibility of such a practice because injecting low-molecular-weight heparin at 30 seconds requires accuracy, a steady hand, the absence of tremor, a calm environment, and the ability to administer an infinitesimally small amount of liquid (eg, 0.4 mL) per second.

Ciprofloxacin is a fluoroquinolone antibiotic effective in the treatment of lower respiratory tract infections (LRTI). The aim of this study was to assess the pharmacokinetic appropriateness of a standard switch i.v./os regimen of ciprofloxacin (200 mg i.v. bid for 3 to 5 days followed by 500 mg os bid for 7 to 10 days) frequently used in routine clinical practice in the treatment of elderly patients with mild to moderate LRTI. The pharmacokinetic study was performed on a cohort of 17 elderly inpatients. Blood samples were collected in steady state conditions at appropriate intervals. Ciprofloxacin serum concentrations were analyzed using an HPLC method and pharmacokinetic parameters were estimated using the WinNonlin software package. The pharmacokinetic data were at least partially different from those obtained by other authors in elderly patients (lower Cmax after i.v. administration and higher CL both after i.v. and oral administration). Cmax after a 1-hour 200-mg infusion were similar to those observed during the 500 mg bid peroral regimen (2.1 +/- 0.9 mg/L vs 2.6 +/- 1.0 mg/L; p = 0.054). The absolute oral bioavailability (84.1%) allowed a total body exposure 2.1-fold greater after 500 mg bid oral administration than after 200 mg bid i.v. administration (AUC(0-tau) 11.4 +/- 4.3 mg/L x h vs 5.5 +/- 1.8 mg/L x h). The results show that in malabsorption-free elderly patients a regimen of 500 mg os bid may be considered a valid therapeutic approach from the beginning of therapy for mild to moderate LRTI caused by sensitive microorganisms (MIC < 0.1 mg/L). In fact, because the peak serum level to MIC ratio (Cmax/MIC) and the area under the inhibitory serum concentration-time curve (AUIC24 = AUC24h/MIC) are actually considered major pharmacodynamic determinants for the outcome of treatment with fluoroquinolones, this regimen could guarantee both a better pharmacokinetic exposure than the 200 mg i.v. bid regimen and a cost-effective treatment of LRTI. However, because of the great pharmacokinetic interindividual variability observed a normalized dosage per kg (3 mg/kg/12h i.v. and 8 mg/kg/12h os) should be considered, especially for body weight >90 kg and, whenever possible, TDM of AUC(0-tau) or at least of Cmax should be performed to individualize therapy in this subpopulation.

After approval by the Local Ethical Committee, 60 psoriatic patients, who participated in a previous pharmacokinetic study on cyclosporin A (CsA), gave their informed consent to continue to be studied during the maintenance treatment and at withdrawal. Peak concentration (Cmax), area under the concentration-time curve (AUC), bioavailability, elimination half-life, distribution volume, and body clearance were determined at monthly check-ups, along with blood pressure, psoriasis area, severity index (PASI), and creatinine serum levels. No modifications over time of treatment were observed on kinetic parameters. At the dose of 5 mg/kg in two daily administrations, a complete remission of the disease was observed after 1 month's treatment. At withdrawal, a worsening of PASI appeared when CsA daily dose reached 2 mg/kg b.w., the mean trough levels or AUC values being, respectively, 100 and 2,200 ng/ml.hr. There was a trend for patients with hypertension and nephrotoxicity at the end of the maintenance treatment to have higher trough, Cmax, and AUC values. Furthermore, blood pressure and serum creatinine tended to correlate better with AUC and Cmax, than with trough levels.