Author(s)

Irene Centeno López, Eva M Legido Perdices, Maria José Cano Cano, Salvador Benlloch Pérez, Federico Peydró Tomás, José Manuel Ventura Cerdá

Why was it done?

Acetaminophen is the most used antipyretic and analgesic drug around the world. Intentional and non-intentional acetaminophen overdose is related to acute liver failure and it is important to start the treatment during the first hours after the intake to reduce liver injury. The main treatment to prevent liver failure is n-acetilcysteine (NAC) and it is administered depending on acetaminophen plasmatic concentrations using Rumack-Matthew nomogram during the first 24 hours. Variability in sampling time and duration of NAC administration was detected when acetaminophen intake was unknown or above the first 24h. Moreover, different NAC administration protocols were used in our institution.

What was done?

An interdisciplinary team involving Hospital Pharmacy, Emergency, Gastroenterology Department and Critical Care Unit was created to establish an agreed protocol for the management of acute acetaminophen poisoning.

How was it done?

The interdisciplinary team agreed the following procedures:
– To change the traditional NAC protocol of three intravenous infusions (150 mg/kg over 1 h, 50 mg/kg over 4h and 100 mg/kg over 16h) to the SNAP protocol of two bags (100 mg/kg over 2h and 200 mg/kg over 10h) reducing duration of administrations from 21 to 12 h.
– To establish the sampling times for the determination of acetaminophen serum concentrations: the extraction will be 4h after the ingestion during the first 24h of the intake. When time is unknown or greater than 24h, two samples separated by at least 2h will be extracted to calculate acetaminophen half-life to assess the probability of liver damage (high probability when half-life (t1/2)>4h).
– Define NAC discontinuation when INR<1.3, transaminases are in normal range and acetaminophen concentration<10 mcg/ml. If one of these parameters remains altered, the last NAC perfusion must be repeated.

What has been achieved?

– Reduce the duration of NAC treatment in the Emergency and hospitalization rooms if all analytical parameters are normalised.
– Reduce the variability in the management of acetaminophen poisoning and sampling time.
– To perform a closer clinical follow up of intoxicated/over-medicated patients.

What next?

Measure the reduction of hospital admissions and safety improvement by modifying NAC administration protocol and therapeutic drug monitoring of acetaminophen.

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Author(s)

Marina Rodríguez-Marín, Paula Novo-González

Why was it done?

To optimize and improve patient treatment as well as reduce the risk of multiresistance in the case of broad-spectrum antibiotics.

What was done?

Using Monte Carlo simulation to calculate the probability of treatment success (pTA) in patients receiving meropenem, defined as the percentage of time the drug level is above the minimum inhibitory concentration (MIC). The cumulative fraction of response of the antibiotic meropenem was also measured.

How was it done?

At a hospital in the Community of Madrid, the TDMx pharmacokinetics program was employed by inputting clinical and pharmacokinetic data of patients who had received meropenem between September 15th and October 15th, 2022. The data were extracted from the SELENE electronic medical records system, and both probabilistic dosing and Bayesian dosing were performed using these data. The following information was entered: age, weight, height, antibiotic dose, dosing interval, creatinine level, MIC, and meropenem PK/PD parameter (% of time above MIC).

What has been achieved?

Twenty patients were recruited: 10 women and 10 men, with a median age of 84 years [Q1: 77, Q3: 89] years.

With a dose of 1000 mg every 4 hours, all patients, assuming a PTA of either 50% or 90%, achieved the desired probability of success.

When the PTA was set at 50%, all patients could benefit from the Monte Carlo simulation within the studied intervals. However, when the PTA was set at 90%, a dose of 2000 mg every 1 hour was required in an infusion time interval.

The majority of patients (17 out of 20) were prescribed a dose of 1000 mg every 8 hours.

Except for two patients, most of the MICs were unknown. Since this parameter influences the probability of success, the results obtained are theoretical.

What next?

1- Obtain the minimum inhibitory concentrations (MICs) for all patients using this antibiotic, with the aim of planning the program and providing recommendations.
2- Additionally, gradually implement this approach in other medications

Author(s)

Wei Wang, Hao Bai

Why was it done?

It depend on the pharmacokinetic (PK)/pharmacodynamic (PD) of vancomycin. Vancomycin can be described as a kinetic model with one compartment connected by a series of first-order kinetic rate processes. The mini programme uses two drug levels during the same dosing interval by the TDM to calculate the area under the curve (AUC) of vancomycin and integrated into patients’ condition and minimal inhibitory concentration of pathogen to provide an optimal dosing regimen of vancomycin.

What was done?

We designed and developed a mini programme support for personalised therapeutic drug monitoring (TDM) of vancomycin. This programme can be easily used in the WeChat by the mobile device.

How was it done?

The traditional vancomycin TDM strategy, which is guided by trough concentrations, has several limitations:
The recommended trough concentration range of 10-15mg/L assumes that the bacteria’s minimum inhibitory concentration (MIC) for vancomycin is ≤1mg/L. However, with the drifting of vancomycin’s MIC values over recent years, this trough concentration has not been able to effectively guide patient prognosis, as has been confirmed by many clinical studies.
There are practical difficulties: for example, the 2009 IDSA guidelines clearly specify that the trough concentration of vancomycin should be sampled half an hour before the fifth dose. However, in reality, due to misunderstandings by nursing staff or excessive workload, sampling times often deviate from this guideline.
After the trough concentration has been determined, there are no explicit measures for dose adjustment. The 2009 IDSA guidelines do not provide recommendations on how to adjust subsequent doses based on trough concentrations.
A decade later, in 2020, the IDSA released new vancomycin TDM guidelines. These guidelines suggest moving away from the trough concentration TDM strategy for vancomycin, and instead recommend using an AUC-guided strategy, determined by two-point blood concentration monitoring of vancomycin.

What has been achieved?

Vancomycin follows first-order pharmacokinetics. To monitor the AUC of vancomycin, it is necessary to measure the serum vancomycin concentration at two steady-state points, then use Monte Carlo simulations and Bayesian software to calculate the AUC and adjust the dosage. This process requires a large number of calculations. Therefore, there is an urgent need for an auxiliary decision making system in clinical practice that can facilitate personalised dosing of vancomycin.

What next?

This mini programme has run above 1 year, providing personalised medicine service of vancomycin to hundreds of patients in China, guiding the precise and rational use of antimicrobial drugs , enhancing the effectiveness of vancomycin and reducing drug toxicity in clinical practice.

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Author(s)

Iris Summer, Marina Zakhari-Betros, Alice Poier, Christine Fegerl-Stadlober

Why was it done?

There had been reports from healthcare professionals of the presence of undigested tablets in ostomy pouches and reasonable doubts of adequate drug absorption. In addition, there were recurring inquiries from clinicians about drug related problems in ostomy-patients.

What was done?

Implementation of a clinical pharmaceutical service for patients with an intestinal ostomy following their stoma-surgery. In this service, oral drug therapy of patients with either ileostomy or colostomy was assessed to determine whether possible impairment of drug liberation or absorption could lead to malabsorption of drug therapy.

How was it done?

A project was conducted, where 30 ileostomy and colostomy patients were observed. Simultaneously, a literature review concerning all orally administered drugs of this patient collective was done. During the project time, two interviews were done with the patients. The first one was lead during hospitalisation whereas the second one was conducted within 4 weeks after hospital discharge. To standardise the interviews, two different questionnaires were developed. Medical status of the patient as well as pharmacokinetic properties of the drugs administered orally were thus assessed. It was evaluated whether there are any drugs which may feature any impaired drug liberation or absorption. In case of anomalies presented, such as undigested tablets found in the pouch, a plasma level measurement of the drug was done, if reasonable. In addition, the subjective perception of the patients was also taken into account, to measure whether malabsorption of drugs is recognised or not and if patients are aware of possible impairment of absorption.

What has been achieved?

A strategy was established to help healthcare professionals assess oral drug therapy in ostomates. In addition, awareness in healthcare professionals as well as patients was raised, concerning possible impaired drug liberation because of the use of inappropriate dosage drug form. Moreover, prevention of prospective drug related complications was also achieved.

What next?

1. Modification of our electronic medical record concerning automated pharmaceutical counselling.
2. Integration of a clinical pharmaceutical service within the ostomy care service of our hospital to provide better therapeutic outcome, especially when ostomy-related problems are presented.
3. Providing patient information leaflets to improve health literacy and patient satisfaction.

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Author(s)

Alba María Fernández Varela, María Isaura Pedreira Vázquez, Sandra Koprivnik, Ana María Montero Hernández, Isaura Rodríguez Penín

Why was it done?

Therapeutic drug monitoring (TDM) allows an optimised pharmacological treatment and increases safety. Lately, we detected low interest in TDM which was confirmed from our annual activity report. An observational prospective study was carried out in a second- level hospital attending an area of 175 930 patients. The study included all inpatients prescribed a drug eligible for TDM from November 2020 to January 2021. The aim was to improve treatment individualisation of hospitalised patients through an active proposal for drug level determination of drugs susceptible for TDM at our institution: digoxin, vancomycin, antiepileptic drugs (carbamazepine, phenytoin, phenobarbital and valproic acid).

What was done?

The pharmacist encouraged therapeutic drug monitoring of susceptible treatments by an active proposal for drug level determination in the prescriptions programme.

How was it done?

Daily, a list of eligible patients was obtained. To this end, a filtering software was used. Taking into account patient’s demographics, clinical and analytical variables (creatinine clearance, the last TDM result, diagnosis) and active prescriptions (treatment initiation, interactions), the pharmacist makes a recommendation for plasma drug level determination.
Data sources: electronic prescription program, pharmacokinetic validation program and electronic medical record.

What has been achieved?

119 proposals of TDM were made in 107 patients: 79 digoxin, 31 vancomycin, 4 valproic acid, 3 carbamazepine and 2 phenytoin. 45,8% women.
74 drugs were discontinued before possible sample extraction and 5 monitorisations could not be performed due to patient death. Of the 40 remaining proposals, the physician requested monitoring of 35 drugs, which meant 87,5% acceptance rate.
It was observed that 17 levels were low or at a lower limit (a dose increase with subsequent verification of levels was proposed in 8 cases and accepted in all of them), 13 levels were in range, 4 were high or at an upper limit (in 3 of them the dose was decreased). One sample was extracted after the drug administration (vancomycin) therefore without value.

What next?

Pharmacists can contribute to treatment optimisation by being proactive. Many resources are not needed unless the burden of care was a limiting factor. The education and promotion of TDM would be interesting to improve the use of this service.

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Author(s)

María Calvo Arbeloa, Ana Isabel Idoate Grijalba, Mónica Uxue Beunza Sola, Daniel Fresán Restituto, Regina Juanbeltz Zurbano, Diana Tejada Marín , Andrea Rodriguez Esquiroz, Maite Sarobe Carricas

Why was it done?

Patients with special characteristics show a great variability in pharmacokinetic and pharmacodynamics (PK/PD) parameters, which may influence the efficacy and safety of antibiotic therapy.

What was done?

A Clinical Unit of Pharmacokinetics was implemented in the Service of Pharmacy (PS) for therapeutic drug monitoring (TDM) in patients.

How was it done?

1. Selection of drugs to be monitored: Antimicrobials (Vancomycin, amikacin, linezolid and voriconazole), Immunosuppressants (tacrolimus), Antineoplastics (methotrexate) and digoxin.
2. Installation of the Abbottbase Pharmacokinetic System (Pks®) software.
3. Creation in the Computerised Clinical History (CCH) a sheet for collecting anthropometric and pharmacological data and pharmacokinetic interpretation of the results obtained.
4. Creation in CCH of a consultation option for clinicians to request monitoring from the PS.
5. Formative session for clinicians and nurses.

What has been achieved?

To begin with the unit, we selected three drugs: vancomycin, amikacin and voriconazole. The hospital pharmacist or the clinician chose the susceptible patients.
Between December 2021 and September 2022, 171 determinations were made in 73 patients: 134 (78.36%) for vancomycin, 24 (14.06%) for amikacin and 13 (7.60%) for voriconazole. Forty-six (63.01%) patients were men and the mean age was 56.58 (17-97) years- old. Eighteen (24.66%) patients were obese. The mean creatinine level was 0.82 (0.4-2.69) mg/ml and glomerular filtration according to the Cockcroft and Gault formula was 81.16 (23.68-161.98) ml/min/m².
For vancomycin, 45 (88.24%) patients started the treatment with a standard dose of 1000 mg every 12 hours. In first determinations, 27 (52.94%) were under-therapeutic and 20 (42.55%) were overdosed. After modifying the dosage regimen, 35 (74.47%) were in range, 3 (6.38%) under-therapeutic and 13 (27.66%) supra-therapeutic.
In case of amikacin, 17 (85%) patients started with a standard dose (1000 mg every 24 hours) achieving target levels only in one case. All were under-therapeutic. After modifying the dosage regimen, we achieved the objective in all of them.
For voriconazole 3 patients were monitored. In 10 (43.5%) determinations, a change in dosage regimen was suggested due to subtherapeutic levels. All (100%) of the recommendations given by the PS were accepted.

What next?

The implementation of the unit in our hospital shows the usefulness and the need to extend pharmacokinetic monitoring to other medical services and drugs.

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Author(s)

Falko Schüllner, Martina Jeske, Martin Munz, Sabine Bischinger, Anna Reich

Why was it done?

The right handling of hazardous drugs in healthcare settings is essential to ensure occupational safety and health as the use and number of these potent drugs increase. In the last decades, protection at the workplace has become more important and several organizations analyze substances for this very reason. Although the antineoplastic drugs remain the principal focus, other drugs may also be considered hazardous because they are potent or cause irreversible effects.

What was done?

In this study drugs used in the University Hospital considered hazardous and to describe potential exposure values were evaluated in connection with exposure limits. A health risk assessment was conducted regarding protective measures related to exposure levels.

How was it done?

The National Institute for Occupational Safety and Health (NIOSH) assumes five categorizations with hazardous potential. According to their ATC-Code, substances from this categorization were listed. Findings of the European Chemicals Agency (C&L inventory), European Directorate for the Quality of Medicines & HealthCare, manufacturer’s guidance, European public assessment report, and safety data sheets were compared with categorization from the International Agency for Research on Cancer, NIOSH, Food and Drug Administration pregnancy categories, and publications from the German Berufsgenossenschaft für Gesundheit und Wohlfahrtspflege. The topic of exposure was divided into a determination of exposure limits in safety data sheets or in the “Grenzwerteverordnung” and into published information regarding exposure in healthcare settings. Monoclonal antibodies were examined separately. For risk assessment purposes, Stoffenmanager and other relevant tools were used.

What has been achieved?

717 substances were analyzed. 461 of them showed at least one probable hazardous or hazardous characteristic. It was possible to establish 177 threshold values, 124 for hazardous substances. The range of threshold values for the criterion “hazardous” was 0,015 μg/m3 – 10 mg/m3. Further research yielded a few public health publications referring to exposure values.It is hardly possible to quickly obtain information on the hazard potential of drugs, but C&L inventory has shown good results . Beside, there is a lack of data on exposure limit values, which is due to the difficulty in providing safety data sheets from manufacturers. As a result, exposure tools are not readily available for use by healthcare workers.

What next?

In an ongoing process every new drug will be evaluated towards the hazardous properties respectively associated exposure limits and communicated to the health care workers in the institution.

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Author(s)

María Mar Alañón Pardo, Alejandro Marcos de La Torre, Beatriz Proy Vega, Adrián Pérez Facila, María Luisa Moreno Perulero, Clara Notario Dongil

Why was it done?

Numerous publications have demonstrated a correlation between serum concentrations (Cs) of anti-TNF drugs and the therapeutic response and a wide interindividual variability in pharmacokinetics among patients with IBD. TDM permits dosage individualization and optimization of anti-TNF therapy.

What was done?

Pharmacokinetic monitoring (TDM) of anti-TNF therapies (infliximab/adalimumab) in inflammatory bowel disease (IBD) was implemented in our hospital by a multidisciplinary team of pharmacists, gastroenterologists and clinical analysts.

How was it done?

A computer platform was developed within the hospital electronic records system to manage consultations of gastroenterologists with the Clinical Pharmacokinetics Unit (CPU) of the Pharmacy Department. Variables in this electronic interconsultation system were: “anti-TNF drug”, “concomitant immunomodulator (IMM)”, “diagnosis”, “reason for consultation”, “date of last dose”, “date of extraction”, “weight/height”, and “observations”. Laboratory tests ordered from the Department of Clinical Analysis on the electronic request form included blood count, Cs of infliximab/adalimumab, albumin, C-reactive protein and faecal calprotectin. Quantum Blue® lateral flow immunoassay was used to quantify Cs of the anti-TNF drugs; when undetectable, the presence of anti-drug antibodies (ADAs) was investigated.
The CPU developed pharmacotherapeutic recommendations based on therapeutic algorithms, pharmacokinetic/pharmacodynamic principles and population models implemented using MW-Pharm++® software, which incorporates the principle of Bayesian estimation. For a correct interpretation of the Cs observed, adherence to anti-TNF ± IMM regimens was evaluated using electronic dispensing records and the self-administered Morisky-Green questionnaire.

What has been achieved?

Since its implementation (January 2019 – August 2020), the CPU has responded to 269 consultations on 121 patients treated with infliximab (46.3%) or adalimumab (53.7%): 70.2% were prescribed with IMM (89.4% with thiopurines); 93.4% adhered to the anti-TNF regimen and 82.4% to the IMM. Baseline anti-TNF Cs were subtherapeutic in 37.2% of patients, therapeutic in 35.5% and supratherapeutic in 27.3%. ADAs were positive in 28.6% of patients with undetectable anti-TNF Cs (n=28). A large proportion (84.8%) of consultations were related to proactive monitoring (to optimise treatment) and the remainder were reactive (after treatment failure). A very high percentage (89.9%) of the gastroenterology specialists accepted recommendations.

What next?

Extend TDM to other biological therapies and immune-mediated diseases.

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Author(s)

ANAIS AMAR, SIMON CLAUTRIER, MORGANE GIOVANELLI, REGINE CHEVRIER

Why was it done?

The phytotherapy market has continued to grow for several years. However, in oncology, concomitant use of plants with oral or injectable chemotherapies can be harmful. Plants can interact with many cytochromes (CYP), impacting on the biotransformation and kinetics of drugs. While grapefruit or St John’s wort are already recognised as interfering with many therapies, the impact of many plants remains unknown for healthcare professionals. Tools exist to evaluate their effects on drug metabolism, but the multiplication of sources delays and complicates the advice of pharmacists.

What was done?

Centralise information on plant metabolism on a single support by creating a database. Facilitate pharmacist’s expertise about interactions between plants and anticancer drugs.

How was it done?

To create the database, it was necessary to establish an exhaustive list of plants. Three sources of information have been used:
– Inventory of phytotherapy products marketed in 4 drugstores
– Census of plants consumed by patients seen in pharmaceutical consultation (PC)
– Consultation of websites specialized in phytotherapy
Then, an Excel table has been developed:
– each line corresponds to a plant
– each column corresponds respectively to 17 CYP, a transport protein (Pgp), estrogen-like (EL) and antioxidant (AO) properties of the plant.
A colour code has been defined according to the inhibitory (yellow), inductive (blue), EL (purple) and AO (red) action of the plant. If there is no interaction, the box remains blank.
Plant effects data were collected from Hedrine®, Oncolien®, MSKCC, RX list and Drugs.com websites.

What has been achieved?

Finally, 174 plants have been accounted in drugstores, 82 were identified during PC and 129 found on websites. If 10% of plants have an EL action and 16% an AO effect, approximately 30% have inductive and/or inhibitory action of at least one CYP and/or PgP. Since the tool’s creation: 91% of answers could be given immediately to patients compared to only 9% delayed (plants still unreferenced).

What next?

This database is an essential tool for answering questions from patients with anticancer drugs. It saves precious time and responsiveness during PC, but also during patient phone calls. However, critical work with divergent information between sources is to be expected. Currently, as a precaution, we don’t recommend the use of plants subject to such a contradiction.

Author(s)

Andreas von Ameln-Mayerhofer, Martin Breuling, Ina Geist

Why was it done?

In the context of antibiotic stewardship, rapid oralisation of a parenteral antibiotic is recommended in many antibiotic stewardship guidelines. Such a sequence therapy is easy to implement if both application pathways lead to comparable efficacy levels at the site of infection. However, this does not apply to all anti-infectives, in particular some beta-lactam antibiotics represent a challenge in therapy. Additionally, the information about this topic is very sparse in the literature.

What was done?

In order to achieve an improvement in antimicrobial prescriptions, we have addressed possible problems regarding oralisation of antibiotics. For this purpose, we graphically compared the simulated efficacy levels of parenteral and oral forms of beta-lactams.

How was it done?

We programmed a computer based procedure that allows a simulation of plasma levels of antibiotics upon intravenous versus oral administration. Based on the obtained data and EUCAST-based MIC-distributions for a set of bacteria, we assessed the respective putative clinical actions.

What has been achieved?

Our simulations show that some oral beta-lactams do not reach the PK/PD condition of a sufficient therapy (fT>MHK) in the approved dosage. The simulations have been used for education seminars with physicians and partly led to an improvement in oralisation procedures. Additionally, an oralisation standard has been established.

What next?

Our next step is to develop a special prescription form for oral antibiotics which will enable us to control prescription behaviour even more effectively. We plan to monitor the prescription habits for anti-infectives more closely before and after establishing the prescription form.