Pharmacokinetic modeling of over-the-counter drug diphenhydramine self-administered in overdoses in Japanese patients admitted to hospital

Abstract Background Although the over-the-counter H1 receptor antagonist diphenhydramine is not a common drug of abuse, it was recently recognized as one of the substances causing acute poisoning in patients attempting suicide that led to admissions to our hospital emergency room. Case presentation Two patients [women aged 21 and 27 years (cases 1 and 2)] were emergently admitted after intentionally taking overdoses of 900 and 1200 mg diphenhydramine, respectively. The plasma diphenhydramine concentrations in case 1 were 977 and 425 ng/mL at 2.5 and 11.5 h after single oral overdose, and those in case 2 were 1320 and 475 ng/mL at 3 and 18 h after administration, respectively. We set up a simplified physiologically based pharmacokinetic (PBPK) model that was established using the reported pharmacokinetic data for a microdose of diphenhydramine. The two virtual plasma concentrations and the area under the curve (AUC) values extrapolated using the PBPK model were consistent with the observed overdose data. This finding implied linearity of pharmacokinetics over a wide dosage range for diphenhydramine. Conclusions The determined plasma concentrations of diphenhydramine of around 1000 ng/mL at ~ 3 h after orally administered overdoses in cases 1 and 2 may not have been high enough to cause hepatic impairment because levels of aspartate aminotransferase and alanine aminotransferase were normal; however, there was an increase in total bilirubin in case 1. Nonetheless, high virtual liver exposures of diphenhydramine were estimated by the current PBPK model. The present results based on drug monitoring data and pharmacokinetic predictions could serve as a useful guide when setting the duration of treatment in cases of diphenhydramine overdose.

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Physiologically Based Pharmacokinetic Model of Rifapentine and 25-Desacetyl Rifapentine Disposition in Humans

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00031-16 ◽

2016 ◽

Vol 60 (8) ◽

pp. 4860-4868

Author(s):

Todd J. Zurlinden ◽

Garrett J. Eppers ◽

Brad Reisfeld

Keyword(s):

Time Course ◽

Pbpk Model ◽

Plasma Concentrations ◽

Optimal Dose ◽

Tissue Level ◽

Pharmacokinetic Data ◽

Rat Tissues ◽

Content Type ◽

Physiologically Based Pharmacokinetic ◽

Physiologically Based

ABSTRACTRifapentine (RPT) is a rifamycin antimycobacterial and, as part of a combination therapy, is indicated for the treatment of pulmonary tuberculosis (TB) caused byMycobacterium tuberculosis. Although the results from a number of studies indicate that rifapentine has the potential to shorten treatment duration and enhance completion rates compared to other rifamycin agents utilized in antituberculosis drug regimens (i.e., regimens 1 to 4), its optimal dose and exposure in humans are unknown. To help inform such an optimization, a physiologically based pharmacokinetic (PBPK) model was developed to predict time course, tissue-specific concentrations of RPT and its active metabolite, 25-desacetyl rifapentine (dRPT), in humans after specified administration schedules for RPT. Starting with the development and verification of a PBPK model for rats, the model was extrapolated and then tested using human pharmacokinetic data. Testing and verification of the models included comparisons of predictions to experimental data in several rat tissues and time course RPT and dRPT plasma concentrations in humans from several single- and repeated-dosing studies. Finally, the model was used to predict RPT concentrations in the lung during the intensive and continuation phases of a current recommended TB treatment regimen. Based on these results, it is anticipated that the PBPK model developed in this study will be useful in evaluating dosing regimens for RPT and for characterizing tissue-level doses that could be predictors of problems related to efficacy or safety.

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Pharmacokinetics of Posaconazole Suspension in Lung Transplant Patients with and without Cystic Fibrosis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00424-16 ◽

2016 ◽

Vol 60 (6) ◽

pp. 3558-3562 ◽

Cited By ~ 11

Author(s):

Hongfei Zhang ◽

M. Hong Nguyen ◽

Cornelius J. Clancy ◽

Rujuta Joshi ◽

Wenchen Zhao ◽

...

Keyword(s):

Cystic Fibrosis ◽

Lung Transplant ◽

Fungal Infections ◽

Plasma Concentrations ◽

Treatment Strategies ◽

Area Under The Curve ◽

Therapeutic Drug ◽

Pharmacokinetic Studies ◽

Pharmacokinetic Data ◽

Average Dose

Invasive fungal infections (IFIs) are common among lung transplant recipients (LTRs). Posaconazole is an important antifungal agent for both prophylaxis and treatment of IFIs; however, detailed pharmacokinetic data are limited among LTRs, particularly those with cystic fibrosis (CF). Our objective was to conduct a pharmacokinetic study of posaconazole oral suspension among LTRs, with particular attention to patients with CF. We enrolled 20 LTRs, 7 with CF and 13 with other underlying lung diseases. Average daily doses in CF and non-CF patients were 829 and 862 mg, respectively. After ≥5 days of treatment, only 4 patients had average plasma concentrations of >0.7 μg/ml. Average steady-state plasma concentrations were 61% lower in CF patients (0.233 μg/ml) than in non-CF LTRs (0.594 μg/ml;P= 0.03). The average dose-normalized plasma area-under-the-curve (AUC) values were also lower in CF (0.007 h·μg/ml) than in non-CF LTRs (0.02 h·μg/ml;P= 0.02). The weight-normalized apparent oral clearance values were 2.51 and 0.74 liters/h/kg among CF and non-CF LTRs, respectively (P= 0.005). Despite significant interpatient variability, plasma trough concentrations were strongly correlated with posaconazole AUC across all LTRs (r2= 0.95,P< 0.0001). Taken together, our study highlights a critical need to incorporate new formulations of posaconazole into prophylaxis and treatment strategies for LTRs, particularly those with CF. Future pharmacokinetic studies of both tablet and intravenous formulations must consider LTR-specific factors and incorporate a therapeutic drug monitoring plan in this patient population.

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Optimization of Personalized Amlodipine Dosing Strategies for Children Based on Pharmacokinetic Data from Chinese Male Adults and PBPK Modeling

Children ◽

10.3390/children8110950 ◽

2021 ◽

Vol 8 (11) ◽

pp. 950

Author(s):

Xiaolu Han ◽

Xiaoxuan Hong ◽

Xianfu Li ◽

Yuxi Wang ◽

Zengming Wang ◽

...

Keyword(s):

Pbpk Model ◽

Plasma Concentrations ◽

Pbpk Modeling ◽

Pharmacokinetic Parameters ◽

Pharmacokinetic Data ◽

Optimal Dosage ◽

Continuous Administration ◽

Dosing Strategies ◽

Chinese Male ◽

Enzyme Metabolism

For children, a special population who are continuously developing, a reasonable dosing strategy is the key to clinical therapy. Accurate dose predictions can help maximize efficacy and minimize pain in pediatrics. Methods: This study collected amlodipine pharmacokinetics (PK) data from 236 Chinese male adults and established a physiological pharmacokinetic (PBPK) model for adults using GastroPlus™. A PBPK model of pediatrics is constructed based on hepatic-to-body size and enzyme metabolism, used similar to the AUC0-∞ to deduce the optimal dosage of amlodipine for children aged 1–16 years. A curve of continuous administration for 2-, 6-, 12-, 16-, and 25-year-olds and a personalized administration program for 6-year-olds were developed. Results: The results show that children could not establish uniform allometric amplification rules. The optimal doses were 0.10 mg·kg−1 for ages 2–6 years and −0.0028 × Age + 0.1148 (mg/kg) for ages 7–16 years, r = 0.9941. The trend for continuous administration was consistent among different groups. In a 6-year-old child, a maintenance dose of 2.30 mg was used to increase the initial dose by 2.00 mg and the treatment dose by 1.00 mg to maintain stable plasma concentrations. Conclusions: A PBPK model based on enzyme metabolism can accurately predict the changes in the pharmacokinetic parameters of amlodipine in pediatrics. It can be used to support the optimization of clinical treatment plans in pediatrics.

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Pharmacokinetics of a Novel Form of Biotin, Magnesium Biotinate, in Healthy Subjects (P06-027-19)

Current Developments in Nutrition ◽

10.1093/cdn/nzz031.p06-027-19 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

Author(s):

Sara Perez Ojalvo ◽

Sarah Sylla ◽

James Komorowski

Keyword(s):

Clinical Study ◽

Peak Plasma ◽

Plasma Concentrations ◽

Area Under The Curve ◽

Blood Levels ◽

Pharmacokinetic Data ◽

Open Label ◽

Post Dose ◽

Funding Sources ◽

Study Results

Abstract Objectives Biotin, also known as vitamin B7, plays an important role in the metabolization of nutrients into energy. Magnesium biotinate (MgB) is a novel biotin compound that has been shown to be 40 times more soluble than D-Biotin. Preclinical evidence has shown that MgB is well absorbed into the bloodstream and tissues, particularly the brain, over time. The following pharmacokinetic study was carried out to further explore the absorption and bioavailability of MgB. Methods In an open-label clinical study, 30 healthy female subjects (18–45 years, BMI 18.0–29.9 kg/m2) were randomized to receive a single oral capsule containing one of the following doses of MgB (n = 10 per group): 1) 10 mg MgB, 2) 40 mg MgB, 3) 100 mg MgB. Serial blood samples were collected in K2-EDTA tubes at pre-dose (within 1 hour of dose) and at 0.5, 1.0, 1.5, 3.0 and 6.0 hours post-dose. Plasma samples were analyzed for biotin by LC/MS/MS. Pharmacokinetic data were calculated for each dose group. Results Study results showed that plasma biotin levels increased at 0.5, 1.0, 1.5, 3.0 and 6.0 hours post-dose for all groups. However, the largest biotin increase was seen in the 100 mg group (Figure 1). Peak plasma concentrations were observed as follows: 84.8 ng/mL 1 hour after a 10 mg dose, 214.6 ng/mL 1.5 hours after a 40 mg dose, and 508.5 ng/mL 1.5 hours after a 100 mg dose. Area under the curve values increased with increasing biotin dose level (10 mg: 210.0 ng*h/mL; 40 mg: 605.1 ng*h/mL; 100 mg: 1652.4 ng*h/mL). No adverse effects were observed. Conclusions Results from this single-dose pharmacokinetic clinical study demonstrate that magnesium biotinate is a bioavailable form of biotin, with increasing blood levels associated with increasing dose levels. Funding Sources This study was funded by JDS Therapeutics, LLC. Supporting Tables, Images and/or Graphs

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Pharmacokinetics of Arsenic Species with Relapsed or Refractory Acute Promyelocytic Leukemia (APL) Treated with Arsenic Trioxide (ATO) in Japanese Patients.

Blood ◽

10.1182/blood.v106.11.4426.4426 ◽

2005 ◽

Vol 106 (11) ◽

pp. 4426-4426

Author(s):

Kazuyuki Shigeno ◽

Miki Kobayashi ◽

Naohi Sahara ◽

Satoki Nakamura ◽

Shinya Fujisawa ◽

...

Keyword(s):

Steady State ◽

Complete Remission ◽

Plasma Concentrations ◽

Inorganic Arsenic ◽

Japanese Patients ◽

Arsenic Species ◽

Pharmacokinetic Data ◽

Dimethylarsinic Acid ◽

Total Arsenic ◽

Excretion Rates

Abstract Background: The therapy with ATO induced high complete remission and maintained for long survival for patients with relapsed or refractory APL. While the clinical effect of ATO against APL was confirmed, its pharmacokinetics has yet to be clarified. In most reports on pharmacokinetics of ATO, the arsenic concentrations were measured as total arsenic. We investigated the pharmacokinetics of arsenic species in Japanese patients with relapsed or refractory APL treated with ATO. Patients and Methods: In the prospective study, from 12 patients with APL treated with ATO, the blood and urine for the pharmacokinetic data were collected and subsequently stored frozen until analysis. ATO (0.15 mg/kg) was intravenously administered once daily over 2 hours to until bone marrow remission to a maximum of 60 days. The plasma and urine were collected on day 1 and after 1, 2 and 4 weeks. Inorganic arsenic (AsIII and AsV) and the major metabolites monomethylarsonic acid (MAAV) and dimethylarsinic acid (DMAAV) in plasma and urine were quantified by HPLC/ICP-MS. Results: Ten of 12 patients (83%) achieved complete remission (CR). Six of ten (60%) who achieved CR were negative in the post-treatment RT-PCR test. For two patients the blood and urine were collected also during consolidation. The plasma concentrations of inorganic arsenic on day 1 reached the Cmax (mean 22.6±11.4 ng/mL) immediately after completion of administration followed by a biphasic elimination while the appearance of methylated metabolites in the blood was delayed. During the repeated administration, the plasma concentrations of inorganic arsenic reached the steady-state. The Cmax of inorganic arsenic on week 4 was similar (mean 23.2±10.2 ng/mL) but the elimination was delayed. As a result, the AUC increased about 2-fold (from mean 211.8±55.1 to 474.8±192.6 ng/mL), and the clearance declined (from 0.7±0.2 to 0.4±0.1 L/kg/h) but no marked change was observed in volume of distribution. In contrast, the MAAV and DMAAV concentrations increased in relation to increased administration frequency fold (from mean 3.1±1.6, 5.4±2.9 to 10.9±4.7, 21.4±12.3 ng/mL). The plasma concentrations of arsenobetaine, an organic arsenic compound derived from seafood, remained almost constant (about 2 mg/mL) during the study period. The urinary excretion rates of AsIII and AsV remained almost constant after week 1, suggesting that the steady-state was attained. In contrast, a tendency to increase with administration frequency was observed in the excretion rates of MAAV and DMAAV after week 4 (from mean 17.4±11.2, 19.4±8.5 to 19.6±10.0, 21.1±9.5 %). The total arsenic excretion rate remained at ~60% of dose after week 1. Conclusion: ATO is metabolized when administered intravenously to APL patients and methylated metabolites were promptly eliminated from the blood and excreted into urine after completion of administration, indicating no measurable accumulation of ATO in the blood.

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Design, Synthesis, Anticonvulsant Activity, Preclinical Study and Pharmacokinetic Performance of N-{[3-(4-chlorophenyl)-4-oxo-3, 4-dihydroquinazolin- 2-yl] methyl}, 2-[(2-isopropyl-5-methyl) 1-cyclo Hexylidene] Hydrazinecarboxamide

Central Nervous System Agents in Medicinal Chemistry ◽

10.2174/1871524919666181122124012 ◽

2019 ◽

Vol 19 (1) ◽

pp. 31-45

Author(s):

Meena K. Yadav ◽

Laxmi Tripathi

Keyword(s):

Anticonvulsant Activity ◽

Computational Study ◽

Plasma Concentrations ◽

Elimination Rate ◽

Area Under The Curve ◽

Preclinical Study ◽

In Vivo Studies ◽

Maximum Plasma ◽

Seizure Models

Background: N-{[3-(4-chlorophenyl)-4-oxo-3, 4-dihydroquinazolin-2-yl] methyl}, 2-[(2- isopropyl-5-methyl) 1-cyclohexylidene] hydrazinecarboxamide QS11 was designed by computational study. It possessed essential pharmacophoric features for anticonvulsant activity and showed good docking with iGluRs (Kainate) glutamate receptor. Methods: QSAR and ADMET screening results suggested that QS11 would possess good potency for anticonvulsant activity. QS11 was synthesised and evaluated for its anticonvulsant activity and neurotoxicity. QS11 showed protection in strychnine, thiosemicarbazide, 4-aminopyridine and scPTZ induced seizure models and MES seizure model. QS11 showed higher ED50, TD50 and PI values as compared to the standard drugs in both MES and scPTZ screen. A high safety profile (HD50/ED50 values) was noted and hypnosis, analgesia, and anaesthesia were only observed at higher doses. No considerable increase or decrease in the concentration of liver enzymes was observed. Optimized QS11 was subjected to preclinical (in-vivo) studies and the pharmacokinetic performance of the sample was investigated. The result revealed that the pharmacokinetic performance of QS11 achieved maximum plasma concentrations (Cmax) of 0.315 ± 0.011 µg/mL at Tmax of 2.0 ± 0.13 h, area under the curve (AUC0-∞) value 4.591 ± 0.163 µg/ml x h, elimination half-life (T1/2) 6.28 ± 0.71 h and elimination rate constant was found 0.110 ± 0.013 h-1. Results and Conclusion: Above evidences indicate that QS11 could serve as a lead for development of new antiepileptic drugs.

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Oral absorption and drug interaction kinetics of moxifloxacin in an animal model of weightlessness

Scientific Reports ◽

10.1038/s41598-021-82044-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Dong Liang ◽

Jing Ma ◽

Bo Wei

Keyword(s):

Oral Dose ◽

Oral Absorption ◽

Jugular Vein ◽

Plasma Concentrations ◽

Pharmacokinetic Data ◽

Simulated Weightlessness ◽

Sprague Dawley ◽

Sprague Dawley Rats ◽

Interaction Kinetics ◽

Kinetics Of

AbstractTo investigate the effect of simulated weightlessness on the pharmacokinetics of orally administered moxifloxacin and the antacid Maalox or the antidiarrheal Pepto-Bismol using a tail-suspended (TS) rat model of microgravity. Fasted control and TS, jugular-vein-cannulated, male Sprague-Dawley rats received either a single 5 mg/kg intravenous dose or a single 10 mg/kg oral dose of moxifloxacin alone or with a 0.625 mL/kg oral dose of Maalox or a 1.43 mL/kg oral dose of Pepto-Bismol. Plasma concentrations of moxifloxacin were measured by HPLC. Pharmacokinetic data were analyzed using WinNonlin. Simulated weightlessness had no effect on moxifloxacin disposition after intravenous administration but significantly decreased the extent of moxifloxacin oral absorption. The coadministration of moxifloxacin with Maalox to either control or TS rats caused significant reductions in the rate and extent of moxifloxacin absorption. In contrast, the coadministration of moxifloxacin with Pepto-Bismol to TS rats had no significant effect on either the rate or the extent of moxifloxacin absorption. These interactions showed dose staggering when oral administrations of Pepto-Bismol and moxifloxacin were separated by 60 min in control rats but not in TS rats. Dose staggering was more apparent after the coadministration of Maalox and moxifloxacin in TS rats.

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Pharmacokinetics of culture-directed antibiotics for the treatment of peritonitis in automated peritoneal dialysis: A systematic narrative review

Peritoneal Dialysis International ◽

10.1177/0896860821990528 ◽

2021 ◽

Vol 41 (3) ◽

pp. 261-272

Author(s):

Chau Wei Ling ◽

Kamal Sud ◽

Connie Van ◽

Syed Tabish Razi Zaidi ◽

Rahul P. Patel ◽

...

Keyword(s):

Peritoneal Dialysis ◽

Case Reports ◽

Plasma Concentrations ◽

Case Series ◽

Therapeutic Drug ◽

Pharmacokinetic Studies ◽

Pharmacokinetic Data ◽

Automated Peritoneal Dialysis ◽

Final Study ◽

Drug Plasma

The objectives of this study were to provide a summary of the pharmacokinetic data of some intraperitoneal (IP) antibiotics that could be used for both empirical and culture-directed therapy, as per the ISPD recommendations, and examine factors to consider when using IP antibiotics for the management of automated peritoneal dialysis (APD)-associated peritonitis. A literature search of PubMed, EMBASE, Scopus, MEDLINE and Google Scholar for articles published between 1998 and 2020 was conducted. To be eligible, articles had to describe the use of antibiotics via the IP route in adult patients ≥18 years old on APD in the context of pharmacokinetic studies or case reports/series. Articles describing the use of IP antibiotics that had been recently reviewed (cefazolin, vancomycin, gentamicin and ceftazidime) or administered for non-APD-associated peritonitis were excluded. A total of 1119 articles were identified, of which 983 abstracts were screened. Seventy-three full-text articles were assessed for eligibility. Eight records were included in the final study. Three reports had pharmacokinetic data in patients on APD without peritonitis. Each of cefepime 15 mg/kg IP, meropenem 0.5 g IP and fosfomycin 4 g IP given in single doses achieved drug plasma concentrations above the minimum inhibitory concentration for treating the susceptible organisms. The remaining five records were case series or reports in patients on APD with peritonitis. While pharmacokinetic data support intermittent cefepime 15 mg/kg IP daily, only meropenem 0.5 g IP and fosfomycin 4 g IP are likely to be effective if given in APD exchanges with dwell times of 15 h. Higher doses may be required in APD with shorter dwell times. Information on therapeutic efficacy was derived from case reports/series in individual patients and without therapeutic drug monitoring. Until more pharmacokinetic data are available on these antibiotics, it would be prudent to shift patients who develop peritonitis on APD to continuous ambulatory peritoneal dialysis, where pharmacokinetic information is more readily available.

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Physiologically Based Pharmacokinetic Modelling of Cabozantinib to Simulate Enterohepatic Recirculation, Drug–Drug Interaction with Rifampin and Liver Impairment

Pharmaceutics ◽

10.3390/pharmaceutics13060778 ◽

2021 ◽

Vol 13 (6) ◽

pp. 778

Author(s):

Bettina Gerner ◽

Oliver Scherf-Clavel

Keyword(s):

Hepatic Impairment ◽

Kinase Inhibitor ◽

Plasma Concentrations ◽

Area Under The Curve ◽

Enterohepatic Recirculation ◽

Maximum Plasma ◽

Good Precision ◽

Physiologically Based Pharmacokinetic ◽

Starting Point ◽

Physiologically Based

Cabozantinib (CAB) is a receptor tyrosine kinase inhibitor approved for the treatment of several cancer types. Enterohepatic recirculation (EHC) of the substance is assumed but has not been further investigated yet. CAB is mainly metabolized via CYP3A4 and is susceptible for drug–drug interactions (DDI). The goal of this work was to develop a physiologically based pharmacokinetic (PBPK) model to investigate EHC, to simulate DDI with Rifampin and to simulate subjects with hepatic impairment. The model was established using PK-Sim® and six human clinical studies. The inclusion of an EHC process into the model led to the most accurate description of the pharmacokinetic behavior of CAB. The model was able to predict plasma concentrations with low bias and good precision. Ninety-seven percent of all simulated plasma concentrations fell within 2-fold of the corresponding concentration observed. Maximum plasma concentration (Cmax) and area under the curve (AUC) were predicted correctly (predicted/observed ratio of 0.9–1.2 for AUC and 0.8–1.1 for Cmax). DDI with Rifampin led to a reduction in predicted AUC by 77%. Several physiological parameters were adapted to simulate hepatic impairment correctly. This is the first CAB model used to simulate DDI with Rifampin and hepatic impairment including EHC, which can serve as a starting point for further simulations with regard to special populations.

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Inappropriateness of Antibiotic Prescribing in Medical, Surgical and Intensive Care Units: Results of a Multicentre Observational Study

Life ◽

10.3390/life11060475 ◽

2021 ◽

Vol 11 (6) ◽

pp. 475

Author(s):

Margherita Macera ◽

Federica Calò ◽

Lorenzo Onorato ◽

Giovanni Di Caprio ◽

Caterina Monari ◽

...

Keyword(s):

Intensive Care ◽

Observational Study ◽

Intensive Care Units ◽

Case Report Form ◽

Antibiotic Prescribing ◽

Duration Of Treatment ◽

Campania Region ◽

Stewardship Program ◽

Surgical Units ◽

Set Up

The objectives of the present study were to provide a snapshot analysis of antibiotic appropriateness in two hospitals in Southern Italy in three specific areas, surgical, medical and intensive care, and to evaluate the risk factors associated with inappropriateness in antimicrobial prescriptions. We conducted a multicentre observational study in two hospitals in the Campania region. We collected data of all patients admitted on the day of evaluation to antibiotic therapy or prophylaxis through a case report form. The primary outcome was to assess the inappropriateness of antibiotic prescribing, related to the spectrum, dose, route of administration and duration of treatment—in particular, to assess whether there was a difference in the adequacy of the prescriptive practice in the medical, surgical and intensive sectors. Prescriptive inappropriateness was more frequently observed in surgical units (79.8% of the 104 antimicrobial prescriptions) than in medical units (53.8% of the 65 prescriptions, p = 0.0003) or in intensive care units (64.1% of the 39 prescriptions, p = 0.052). The reasons for the inappropriate antimicrobial prescriptions were similar in the three areas evaluated: antimicrobial unnecessary and antimicrobial not recommended were the most frequent reasons for inappropriateness. Not participating in an antimicrobial stewardship program (ASP) was identified as a factor associated with inappropriate antimicrobial prescriptions in medical and surgical units, but not in Intensive Care Units (ICUs). ASPs may enhance the appropriateness of antimicrobial prescriptions especially in medical and surgical units. In ICUs, specific programs able to limit empirical therapies and encourage the collection of microbiological samples may be useful to set up targeted therapies and to design antimicrobial protocols.

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