UHPLC-MS/MS method for the quantification of ultra-traces of irinotecan and its metabolites in red blood cells and plasma to detect caregivers' contamination.

The occupational exposure of caregivers to antineoplastic agents has been demonstrated since 1979. Since the early 1990s, numerous studies from several countries have demonstrated the contamination of care facilities by antineoplastic drugs. As it is easier to sample, most contamination measurements in workers are carried out in urine sample. The distribution and elimination half-lives of irinotecan suggest that blood can be considered as better than urine for the biomonitoring of a potential contamination of healthcare workers. We describe here the development and the validation of a UHPLC-MS/MS method to simultaneously quantify irinotecan, and two of its main metabolites, APC and SN-38, at ultra-trace levels in plasma and red blood cells (RBC). This method has been applied to blood samples collected from several healthcare services in a French comprehensive cancer center. The results demonstrate that the method is sensitive enough to identify a contamination of healthcare workers by irinotecan and SN-38 at very low concentrations. Moreover, the results show that analysis of RBC is of great interest and complementary to that of serum.

[HAS recommendations on antibiotic resistance]. / Les recommandations de la HAS sur l'antibiorésistance.

The Haute Autorité de Santé (HAS), created by the French Health Insurance Act of August 13, 2004, is an independent scientific public authority, with legal personality and financial autonomy. Involved in the fight against antibiotic resistance, the HAS provides professionals and the general public with a range of tools to encourage the adoption of best practices in the use of antibiotics.

Perception, knowledge, practices and training regarding the risk of exposure to antineoplastic drugs in three French compounding units.

INTRODUCTION: Healthcare workers are exposed to hazardous drugs such as antineoplastic drugs, which have potential carcinogenic, mutagenic and teratogenic effects. Protective measures must be taken after appropriate staff training to handle antineoplastic drugs in a safe way. The objective was to assess perception, knowledge, practices and training regarding the risk of exposure of healthcare workers in three French compounding units. METHODS: This descriptive study was based on a questionnaire made of 33 questions divided into five sections related to the handling of antineoplastic drugs: perception of the risks, knowledge of the risks, protection practices, specific training and general questions. RESULTS: Among the 39 participants, over half considered their overall risk of exposure to antineoplastic drugs not being very low. Inhalation was known to 69.2% of them as possible route of contamination. The breakroom was identified by 28.9% of them as a place of contamination. The procedure in case of accidental exposure to antineoplastic drugs was known by 69.2%, but only half could explain it. Only 38.5% said they changed their gloves every 30 min as recommended. Barely half said that they had been trained specifically for the handling of antineoplastic drugs during an initial training. Over half wished to be informed, trained and aware of the proper handling of antineoplastic drugs. CONCLUSION: Although some of these results are encouraging, specifically when compared to the other settings where antineoplastic drugs are handled, there is still room for improvement. Efforts to build an adapted and impactful training program must pursue. CLINICAL TRIAL REGISTRATION: Study CONTACT, ref. 19-504.

Four-year follow-up of surface contamination by antineoplastic drugs in a compounding unit.

OBJECTIVES: This study aimed to monitor the contamination by antineoplastic drugs on work surfaces in a compounding unit 4 years after its implementation. METHODS: This descriptive study was done in a unit performing on average 45 000 preparations per year. Surface sampling points (N=23) were monitored monthly in the frame of routine activity from the opening of an anticancer drug compounding unit. Contamination with nine antineoplastic drugs (cyclophosphamide, ifosfamide, dacarbazine, 5-fluorouracil, methotrexate, gemcitabine, cytarabine, irinotecan and doxorubicin) was assessed on wipes with a local liquid chromatography coupled with a tandem mass spectrometer analysis. The contamination rate (CR, %) was prospectively monitored every month during the entire study period. The occurrence of critical incidents was also registered. The effect of each safety measure implemented during this period was also analysed. RESULTS: Based on the 1104 samples collected between March 2016 and March 2020, the CR was 18.5%. If three different critical incidents among a vial breakage that occurred were individually considered, this CR was slightly lower than that in the literature. Eight months after opening and taking different corrective actions, the overall CR dropped from 42.39% to 11.52% (p<0.001). Contamination was limited to the area that includes the compounding room and, more precisely, the welder and the QC-Prep+ sampling points. CONCLUSIONS: From the beginning of the study and from month to month, surface contamination was limited to the nearest sampling points to the compounding unit. This 4-year monitoring study allowed us to determine the intravenous conventional antineoplastic drugs and sampling points to be focused on.

Improvement of patient care through hirudotherapy and the management of leeches from their reception to their disposal in France.

OBJECTIVE: Medicinal leech therapy - known as hirudotherapy (HT) - is an empirical medical technique that has become popular again in reconstructive surgery. However, at each step of leech management there are risks for blood contamination of the caregivers and severe infections for patients. This reduces the success of the treatment. The aim of this study was to improve the management of leeches from ordering to disposal to improve patient care. METHODS: First, a review of the literature was performed. Second, we conducted a retrospective study of patients' antibiotic prophylaxis from January 2018 to December 2019. The data we collected were patient characteristics, the specific care unit at the hospital, indication, contra-indication, posology, duration of HT, number of leeches delivered, antibiotic prophylaxis prescribed and microbial organism, if identified. Third, an interdisciplinary meeting was organised to review the entire leech circuit: ordering, maintenance, prescription, dispensing, application and disposal. RESULTS: At the end of the literature review, six articles based on practices implemented in France were selected for inclusion. These articles discussed antibiotic prophylaxis, iron supplementation, and leech storage, application and disposal. On the retrospective study performed, antibiotic prophylaxis for HT was performed for 60% (30/50) of patients, 77% (23/30) of the prescriptions followed the recommendations for antibiotic prophylaxis, and 20 patients did not receive antibiotic prophylaxis. The interdisciplinary meeting made it possible to define a collegially validated protocol, containing a computerised antibiotic prophylaxis prescription, including per os ciprofloxacin antibiotic prophylaxis, intravenous iron supplementation and biological monitoring. A leech application protocol was created, and the method of leech disposal was revised. CONCLUSION: Despite the absence of clear guidelines and heterogeneous practices, this study reveals the importance of a standard procedure including leech management practices before use, antibiotic prophylaxis and application and disposal guides. The interdisciplinary protocol allows improved patient care management and makes leech management safer for caregivers.

Knowledge and practices about safe handling regarding the risk of exposure to antineoplastic drugs for caregivers in compounding units and in operating rooms performing HIPEC/PIPAC.

INTRODUCTION: Ever since the late 1970s, occupational exposure associated with the handling of antineoplastic drugs (ADs) in the healthcare environment has been highlighted and demonstrated. Contamination was detected in both operating rooms (OR) and compounding units (CU), where healthcare workers handle and are exposed to ADs in different ways. In the OR, the risk of exposure is higher and the staff receives less training in handling ADs than in the CU. This study aimed to assess and compare knowledge and practices about the safe handling of ADs by caregivers working in these two locations, namely the CU and OR. METHODS: Two questionnaires (one each for the OR and CU) were created by two investigator pharmacists and were completed during a personal interview of 20 min. The questions were related to the following topics: training, knowledge about occupational exposure and questions related to protective practices. A scoring system was implemented to assess the knowledge and practices of each participant. RESULTS: In total, 38 caregivers working in the OR and 39 in the CU were included in our study. Significantly more CU staff had specific initial training (p < 0.001) and ongoing training (p < 0.001) in handling ADs. Concerning the knowledge score, OR caregivers had a significantly lower median score for contamination routes (p < 0.001), contamination surfaces (p < 0.001), existing procedures (p < 0.001) and total knowledge (p < 0.001) than CU caregivers. Concerning protective handling practices of ADs, the two locations had nonsignificantly different median scores (p = 0.892). CONCLUSION: This study suggests that there is still room for improvement in terms of knowledge and protection practices when handling ADs. An appropriate and tailored training program should be developed and provided to all caregivers who handle or come in contact with ADs.Clinical trial registrationStudy CONTACT, ref. 19-504.

Perception, knowledge and protective practices for surgical staff handling antineoplastic drugs during HIPEC and PIPAC.

Objectives: Two surgical techniques used for peritoneal metastasis involve a risk of exposure to antineoplastic drugs (ADs): hyperthermic intraperitoneal chemotherapy (HIPEC) and pressurized intraperitoneal aerosol chemotherapy (PIPAC). The objective of this study was to assess the differences in perception, training, and knowledge of the risks as well as in the protection practices and occupational exposures of all worker categories. Methods: This descriptive study, led in two hospitals from two distant French regions, was performed through a face-to-face interview and assessed the perception, knowledge and handling practices of ADs by a questionnaire consisting of 52 questions. Results: Fifty-one professionals participated in this survey. A total of 29.4% (n=15) professionals were afraid to handle ADs. Very few workers have been trained on handling ADs during initial training dedicated to all caregiver (5.9%; n=3). HIPEC is considered to involve a higher risk of exposure to ADs than PIPAC (81.6% (n=31) vs. 57.9% (n=22), respectively, p=0.022, agreement 65.8%). Protective equipment is considered to be less suitable for HIPEC than for PIPAC (29% (n=11) vs. 10.5% (n=4), respectively, p=0.016, agreement 81.6%). Concerning the potential AD contamination location, the participants identified a significant difference between these two practices. During HIPEC, 15.7% (n=6) of caregivers indicated that they had negative symptoms perceived in their practice vs. 2.6% (n=1) during PIPAC. Conclusions: This study shows that perception, knowledge and protection practices are different between HIPEC and PIPAC. It also shows a difference between the worker categories. In view of the difficulties in making operating room staff available, the related training programmes must have an adapted format.

Perception, knowledge, and handling practice regarding the risk of exposure to antineoplastic drugs in oncology day hospitalization units and compounding unit staff.

BACKGROUND: Antineoplastic drug exposure is a major problem in regard to caregivers' health. The aim of the present study was to assess the perception, knowledge, and handling practices of all occupation level categories of two oncology day hospitalization units and two compounding units regarding the risk of exposure to antineoplastic drugs. METHODS: This descriptive study, performed through face-to-face interviews, concurrently assessed the perception, knowledge, and handling practices of antineoplastic drugs in five different job categories in four different settings. This work was part of a larger comprehensive project examining surface and blood contamination. Different scores were assigned to evaluate responses to a questionnaire about the perception, knowledge, and handling practices of healthcare workers, a risk global score including a risk perception score, and education/knowledge and handling practices scores. RESULTS: In the survey, continuous training was associated with the global risk score (p = 0.03), particularly with the handling practices risk score (p = 0.01). Job category was also significantly associated with the global risk score (p < 0.001), particularly with the handling practices risk score (p < 0.001) and the education/knowledge score (p < 0.001). Pharmacy technicians had the highest score regarding risk perception (71.4%), indicating a higher perception of risk, and had a lower score regarding handling practices (25.0%) as well as a lower score (15.7%) regarding risk knowledge. Nurses and physicians had a high score (50%) regarding the risk of handling practices and a score of 57.1% regarding risk perception, indicating an increased perception of safety. Auxiliary caregivers had the highest global score (43.5%) and a score of 30.0% regarding handling practices. CONCLUSIONS: This study identified significant differences among healthcare workers depending on job categories in the antineoplastic drug handling practices and in the knowledge of the risks associated with occupational exposure to antineoplastic drugs. These differences were particularly important between trained and untrained participants, revealing the importance of implementing a continuous training program.

Blood contamination of the pharmaceutical staff by irinotecan and its two major metabolites inside and outside a compounding unit.

BACKGROUND: Caregivers in healthcare settings are exposed to a risk of antineoplastic drug contamination which can lead to adverse health effects. Biological monitoring is necessary to estimate the actual level of exposure of these workers. This study was conducted with the aim of assessing blood contamination levels by irinotecan and its metabolites of pharmaceutical staff operating inside and outside a compounding unit. METHODS: The study took place within the pharmaceutical unit of a French comprehensive cancer centre. Blood samples were collected from the pharmacy workers operating inside and outside the compounding unit, and analysed by UHPLC-MS/MS. Plasma and red blood cell irinotecan and its metabolites (SN-38; APC) were determined with a validated analytical method detection test. RESULTS: A total of 17/78 (21.8%) plasma and red blood cell-based assays were found to be contaminated among staff. Overall, the total number of positive assays was significantly higher for staff members working outside the compounding unit than for workers working inside it (P = 0.022), with respectively 5/42 (11.9%) and 12/36 (33.3%) positive assays. For plasma dosages, the "outside" group had a significantly higher number of positive assays (P = 0.014). For red blood cell-based assays, no significant difference was found (P = 0.309). CONCLUSIONS: This study reveals that pharmaceutical staff serving in health care settings are exposed to a risk of antineoplastic drug contamination, not only inside the compounding room but also in adjacent rooms. The results would help to raise awareness and potentially establish protective measures for caregivers working in areas close to the compounding room as well.

Specification and Evaluation of Plasticizer Migration Simulants for Human Blood Products: A Delphi Study.

Potentially toxic plasticizers are commonly added to polyvinyl chloride medical devices for transfusion in order to improve their flexibility and workability. As the plasticizers are not chemically bonded to the PVC, they can be released into labile blood products (LBPs) during storage. Ideally, LBPs would be used in laboratory studies of plasticizer migration from the medical device. However, short supply (i.e., limited stocks of human blood in collection centres) has prompted the development of specific simulants for each type of LBP in the evaluation of new transfusion devices. We performed a Delphi study with a multidisciplinary panel of 24 experts. In the first (qualitative) phase, the panel developed consensus definitions of the specification criteria to be met by each migration simulant. Next, we reviewed the literature on techniques for simulating the migration of plasticizers into LBPs. A questionnaire was elaborated and sent out to the experts, and the replies were synthesized in order to obtain a consensus. The qualitative study established specifications for each biological matrix (whole blood, red blood cell concentrate, plasma, and platelet concentrate) and defined the criteria required for a suitable LBP simulant. Ten criteria were suggested: physical and chemical characteristics, opacity, form, stability, composition, ability to mimic a particular clinical situation, ease and safety of use, a simulant-plastic interaction correlated with blood, and compatibility with analytical methods. The questionnaire data revealed a consensus on the use of natural products (such as pig's blood) to mimic the four LBPs. Opinions diverged with regard to synthetic products. However, an isotonic solution and a rheological property modifier were considered to be of value in the design of synthetic simulants. Consensus reached by the Delphi group could be used as a database for the development of simulants used to assess the migration of plasticizers from PVC bags into LBPs.

Is the blood of a surgeon performing HIPEC contaminated by irinotecan, its major metabolites and platinum compounds?

OBJECTIVES: Hyperthermic intraperitoneal chemotherapy (HIPEC) is a beneficial surgical technique for patients, but the surgeons are being exposed to cytotoxic drugs. Few biomonitoring studies were led on blood samples in the context of HIPEC. This study aimed to evaluate the surgeon's plasmatic and red blood cell (RBC) contamination by irinotecan, two of its major metabolites and platinum compounds. METHODS: HIPEC procedures performed using the coliseum techniques were observed between September 2015 and April 2018 in a French comprehensive cancer center. Irinotecan and its metabolites SN-38 and APC were dosed by UHPLC with a limit of quantification determined at 50 pg/mL. Platinum compounds were dosed by inductively coupled plasma mass spectrometry with a limit of quantification determined at 16 pg/mL. RESULTS: Despite collective and personal protective equipment, 80% of plasma samples were contaminated by irinotecan and 33% by platinum compounds out of 21. The results showed that the surgeon was contaminated after HIPEC and even after a period of HIPEC inactivity. Nineteen percent of plasmatic samples and 45% of RBC samples were contaminated by SN-38, the active metabolite of irinotecan. APC was only found in some RBC samples (33%). CONCLUSIONS: Even if this study shows blood contamination by irinotecan, two of its major metabolites (including active SN-38) and platinum compounds both in the plasma and RBC of a surgeon performing the HIPEC procedures, further studies should be performed to confirm these results. Additional studies should be carried out to further investigate the contamination in the context of HIPEC and more broadly in the hospital.

Cefepime use: A need for antimicrobial stewardship.

OBJECTIVES: Unlike other 3GCs, Cefepime is a cephalosporin that has, in animal model studies, shown a low risk of selecting resistant mutants. It also enables carbapenems to be saved in treatment of Pseudomonasaeruginosa and the CESP group (Citrobacter, Enterobacter, Serratia and Providencia, as well as the genus Klebsiellaaerogenes, Morganella and Hafnia), consequently producing cephalosporinase. We aimed to determine whether its prescription in a French teaching hospital met criteria for proper use. PATIENTS AND METHODS: We conducted a retrospective study of proper cefepime use between March 1st, 2018 and February 28th, 2019, to assess indication, antimicrobial stewardship, dosing schedule, microbiological documentation, reevaluation, and treatment duration. Prescriptions were then compared to local guidelines established from international literature. RESULTS: Out of 142 cefepime prescriptions, 97.2% were prescribed as validated according to indication. The duration of the documented treatments matched the guidelines for 56.5% of patients, dosage was adapted to the indication for 77.4% and to kidney function for 97.2%. Bacteriological documentation was performed in all cases and an antibiogram was generated in 99.2% of cases. The treatment was reassessed between 48 and 72h and between the 7th and 10th day for 44.2% and 60.9% of the prescriptions respectively. The antimicrobial stewardship team managed half of the prescriptions. Only 13.4% of prescriptions met all criteria for proper use. CONCLUSION: Notwithstanding a highly sizable majority of validated indications, a very small proportion of cefepime prescriptions met all the criteria for proper use. In the context of increased cefepime consumption, which is favored by its increased place in the latest recommendations published in 2019, proper use of cefepime prescriptions needs to be more effectively promoted.

[Reducing mid-task interruptions during medication preparation]. / Comment réduire les interruptions de tâches lors de la préparation des médicaments ?

Nurses are regularly interrupted when performing their tasks. Yet studies have shown that there is a link between the fact of being interrupted when preparing medication and the increased risk of making a mistake. Seeking to reinforce the safety of the medication preparation stage, a team in Normandy studied the benefit, for the nurse, of wearing ear plugs during this specific time.

Fastidious chemical decontamination after cyclophosphamide vial breakage in a compounding unit.

An important amount of cytotoxic drug may accumulate in the workplace following the breakage of a vial containing an anticancer drug. Thanks to the monthly monitoring of the surface contamination in our compounding unit, a strong increase of cyclophosphamide contamination was highlighted in the storage area following the breakage of the vial, despite application of the emergency procedure. This study presents an analysis of chemical decontamination in the context of massive contamination. Samples were taken on the floor and on the caster of a storage shelf where the vial broke. The residual contamination was measured with a liquid chromatography-mass spectrometry/mass spectrometry method. An admixture of 10-2 M sodium dodecyl sulfate and 70% isopropanol (SDS/IPA 8:2) was selected as the decontamination solution. High amounts of cyclophosphamide were retrieved. The initial contamination on the floor was over 20 ng/cm2. Three decontaminations with SDS/IPA were carried out at Day 61, Day 68, and Day 71. The amount of cyclophosphamide decreased to 0.45 ng/cm2 at D134. However, high values were still measured on the caster despite successive decontaminations, with a maximal value of 19.78 ng/cm2 observed at Day 106. Continuous monitoring in our unit led us to highlight the inefficiency of our emergency procedure to eliminate high cyclophosphamide contamination. The procedure involving the SDS/IPA admixture was more efficient on the floor compared to the caster, which is a different surface type and porosity. This work highlights the importance of improving the procedures of incident management using contamination monitoring and repeated decontamination procedures adapted to different contaminants and surfaces.

[A multidisciplinary collaboration for the benefit of patients]. / Une collaboration pluriprofessionnelle au bénéfice des patients.

A study focusing on therapeutic education sessions for patients with psoriasis receiving subcutaneous biotherapy was carried out in a dermatology department of a university hospital. To meet the needs identified by the research, multi-professional collaboration around a therapeutic patient education approach resulted in the creation and implementation of specific information tools and the organisation of training sessions for the nurses. A subsequent survey showed a 100% satisfaction rate among patients and nurses.

Appropriate use of antifungals: impact of an antifungal stewardship program on the clinical outcome of candidaemia in a French University Hospital.

OBJECTIVES: The objective of this study was to compare clinical outcomes of patients with candidaemia before and after implementation of an antifungal stewardship program (AFSP). METHODS: This study included all consecutive cases of candidaemia identified from January 2012 to December 2015 in a French University Hospital. Data were collected retrospectively for a period of 2 years before implementation of the AFSP, and prospectively for 2 years after. All cases were reviewed by a multidisciplinary panel of experts including infectiologists, a microbiologist and pharmacists to have a complete follow-up of patients. RESULTS: 33 and 37 patients were finally included in the first and second period, respectively. The sites of entry of the candidaemia cases studied were as follows: intraabdominal in 29 cases (41.4%), central venous catheter 21 (30.0%), other or unknown: 20 (28.6%). Infectiologist consultations increased from 36.4 to 86.5% between the two periods with a significative impact on daily blood cultures which were more frequently performed in the second period (p = 0.04), and the use of echinocandins which was more frequent in the second period (97.1% of cases vs 78.8%, p = 0.03). The 3-month mortality rate declined from 36.4% in the first period to 27.0% in the second period (p = 0.4). CONCLUSIONS: Despite the insufficient number of candidaemia cases and the presence of other unmodifiable risk factors of mortality which did not allow us to show a significant effect on the 3-month mortality, AFSP had a significant effect on daily blood cultures and echinocandin use as first-line therapy.

[Improve pharmacology training for nursing students]. / Améliorer la formation en pharmacologie des étudiants en soins infirmiers.

Often perceived as complex by nursing students, the "pharmacology and therapeutics" teaching unit provides fundamental knowledge for professional practice. In order to make students aware of the risk of errors during different stages and procedures of patient medication management, an original teaching scenario was established in Caen between l'Institut de formation soins infirmier and the university hospital. In particular, it includes a constructive look at the feedback of experience around medication error.