Use of a prospective risk analysis method to improve the safety of the cancer chemotherapy process

Objective. To perform a risk analysis of the cancer chemotherapy process, by comparing five different organizations. To quantitatively demonstrate the usefulness of centralization and information technologies, to identify residual risks that may be the target of additional actions. Study design. A reengineering of the process started in 1999 and was planned to be finished in 2006. The analysis was performed after the centralization and at the beginning of information technologies integration. Setting. Two thousand two hundred beds university hospital, with medical, surgical, haematological, gynaecological, geriatric, paediatric oncological departments. Twelve thousand cancer chemotherapies each year. Methods. According to the failure modes, effects and criticality analysis (FMECA) method, the failure modes were defined and their criticality indexes were calculated on the basis of the likelihood of occurrence, the potential severity for the patients, and the detection probability. Criticality indexes were compared and the acceptability of residual risks was evaluated. Results. The sum of criticality indexes of 27 identified failure modes was 3596 for the decentralized phase, 2682 for centralization, 2385 for electronic prescription, 2081 for electronic production control, and 1824 for bedside scanning (49% global reduction). The greatest improvements concerned the risk of errors in the production protocols (by a factor of 48), followed by readability problems during transmission (14) and product/dose errors during the production (8). Among the six criticality indexes remaining superior to 100 in the final process, two were judged to be acceptable, whereas further improvements were planned for the four others. Conclusions. Centralization to the pharmacy was associated with a strong improvement but additional developments involving information technologies also contributed to a major risk reduction. A cost-effect analysis confirmed the pertinence of all developments, as the cost per gained criticality point remained stable all over the different phase

Temporal effects of antibiotic use and hand rub consumption on the incidence of MRSA and Clostridium difficile

Objectives The aim of this study was to determine the temporal relation between the use of antibiotics and alcohol-based hand rubs (ABHRs) and the incidence of methicillin-resistant Staphylococcus aureus (MRSA) and Clostridium difficile. Methods An interventional time-series analysis was performed to evaluate the impact of two promotion campaigns on the consumption of ABHRs and to assess their effect on the incidence of non-duplicate clinical isolates of MRSA and C. difficile from February 2000 through September 2006. This analysis was combined with a transfer function model of aggregated data on antibiotic use. Results Consumption of ABHRs correlated with MRSA, but not with C. difficile. The final model demonstrated the immediate effect of the second hand hygiene promotion campaign and an additional temporal effect of fluoroquinolone (time lag, 1 month; i.e. antibiotic effect delayed for 1 month), macrolide (lag 1 and 4 months), broad-spectrum cephalosporins (lag 3, 4 and 5 months) and piperacillin/tazobactam (lag 3 months) use. The final model explained 57% of the MRSA variance over time. In contrast, the model for C. difficile showed only an effect for broad-spectrum cephalosporins (lag 1 month). Conclusions We observed an aggregate-level relation between the monthly MRSA incidence and the use of different antibiotic classes and increased consumption of ABHR after a successful hand hygiene campaign, while no association with ABHR use was detected for C. difficil

Efficacy of Two Cleaning Solutions for the Decontamination of 10 Antineoplastic Agents in the Biosafety Cabinets of a Hospital Pharmacy

Objective: This study aimed to evaluate two cleaning solutions for the chemical decontamination of antineoplastic agents on the surfaces of two biosafety cabinets routinely used for chemotherapy preparation in a hospital pharmacy. Methods: For almost 1 year (49 weeks), two different solutions were used for the weekly cleaning of two biosafety cabinets in a hospital pharmacy's centralized cytotoxic preparation unit. The solutions evaluated were a commercial solution of isopropyl alcohol (IPA) and water (70:30, vol:vol), and a detergent solution constituted by 10-2M of sodium dodecyl sulfate (SDS) with 20% IPA. Seven areas in each biosafety cabinet were wiped 14 times throughout the year, before and after the weekly cleaning process, according to a validated procedure. Samples were analyzed using a validated method of high-performance liquid chromatography coupled to mass spectrometry. The decontamination efficacy of these two solutions was tested for 10 antineoplastic agents: cytarabine, gemcitabine, methotrexate, etoposide phosphate, irinotecan, cyclophosphamide, ifosfamide, doxorubicin, epirubicin, and vincristine. Results: Overall decontamination efficacies observed were 82±6% and 49±11% for SDS solution and IPA, respectively. Higher contamination levels were distributed on areas frequently touched by the pharmacy technicians—such as sleeves and airlock handles—than on scale plates, gravimetric control hardware, and work benches. Detected contaminations of cyclophosphamide, ifosfamide, gemcitabine, and cytarabine were higher than those of the others agents. SDS solution was almost 20% more efficient than IPA on eight of the antineoplastic agents. Conclusion: Both cleaning solutions were able to reduce contamination levels in the biosafety cabinets. The efficacy of the solution containing an anionic detergent agent (SDS) was shown to be generally higher than that of IPA and, after the SDS cleaning procedure, biosafety cabinets demonstrated acceptable contamination level

Evaluation of Decontamination Efficacy of Cleaning Solutions on Stainless Steel and Glass Surfaces Contaminated by 10 Antineoplastic Agents

Objectives: The handling of antineoplastic agents results in chronic surface contamination that must be minimized and eliminated. This study was designed to assess the potential of several chemical solutions to decontaminate two types of work surfaces that were intentionally contaminated with antineoplastic drugs. Methods: A range of solutions with variable physicochemical properties such as their hydrophilic/hydrophobic balance, oxidizing power, desorption, and solubilization were tested: ultrapure water, isopropyl alcohol, acetone, sodium hypochlorite, and surfactants such as dishwashing liquid (DWL), sodium dodecyl sulfate (SDS), Tween 40, and Span 80. These solutions were tested on 10 antineoplastic drugs: cytarabine, gemcitabine, methotrexate, etoposide phosphate, irinotecan, cyclophosphamide, ifosfamide, doxorubicin, epirubicin, and vincristine. To simulate contaminated surfaces, these molecules (200ng) were deliberately spread onto two types of work surfaces: stainless steel and glass. Recovered by wiping with a specific aqueous solvent (acetonitrile/HCOOH; 20/0.1%) and an absorbent wipe (Whatman 903®), the residual contamination was quantified using high-performance liquid chromatography (HPLC) coupled to mass spectrometry. To compare all tested cleaning solutions, a performance value of effectiveness was determined from contamination residues of the 10 drugs. Results: Sodium hypochlorite showed the highest overall effectiveness with 98% contamination removed. Ultrapure water, isopropyl alcohol/water, and acetone were less effective with effectiveness values of 76.8, 80.7, and 40.4%, respectively. Ultrapure water was effective on most hydrophilic molecules (97.1% for cytarabine), while on the other hand, isopropyl alcohol/water (70/30, vol/vol) was effective on the least hydrophilic ones (85.2% for doxorubicin and 87.8% for epirubicin). Acetone had little effect, whatever the type of molecule. Among products containing surfactants, DWL was found effective (91.5%), but its formulation was unknown. Formulations with single surfactant non-ionics (tween 40 and span 80) or anionic (SDS) were also tested. Finally, solutions containing 10-2 M anionic surfactants and 20% isopropyl alcohol had the highest global effectiveness at around 90%. More precisely, their efficacy was the highest (94.8%) for the most hydrophilic compounds such as cytarabine and around 80.0% for anthracyclines. Finally, the addition of isopropyl alcohol to surfactant solutions enhanced their decontamination efficiency on the least hydrophilic molecules. Measured values from the stainless steel surface were similar to those from the glass one. Conclusion: This study demonstrates that all decontamination agents reduce antineoplastic contamination on work surfaces, but none removes it totally. Although very effective, sodium hypochlorite cannot be used routinely on stainless steel surfaces. Solutions containing anionic surfactant such as SDS, with a high efficiency/safety ratio, proved most promising in terms of surface decontaminatio

Wipe sampling procedure coupled to LC-MS/MS analysis for the simultaneous determination of 10 cytotoxic drugs on different surfaces

A simple wipe sampling procedure was developed for the surface contamination determination of ten cytotoxic drugs: cytarabine, gemcitabine, methotrexate, etoposide phosphate, cyclophosphamide, ifosfamide, irinotecan, doxorubicin, epirubicin and vincristine. Wiping was performed using Whatman filter paper on different surfaces such as stainless steel, polypropylene, polystyrol, glass, latex gloves, computer mouse and coated paperboard. Wiping and desorption procedures were investigated: The same solution containing 20% acetonitrile and 0.1% formic acid in water gave the best results. After ultrasonic desorption and then centrifugation, samples were analysed by a validated liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) in selected reaction monitoring mode. The whole analytical strategy from wipe sampling to LC-MS/MS analysis was evaluated to determine quantitative performance. The lowest limit of quantification of 10ng per wiping sample (i.e. 0.1ngcm−2) was determined for the ten investigated cytotoxic drugs. Relative standard deviation for intermediate precision was always inferior to 20%. As recovery was dependent on the tested surface for each drug, a correction factor was determined and applied for real samples. The method was then successfully applied at the cytotoxic production unit of the Geneva University Hospitals pharmacy. Figure Wipe sampling procedure for the determination of cytotoxic drug

Temporal effects of antibiotic use and Clostridium difficile infections

Objectives We tested a previously published model for the analysis of the temporal relationship between antibiotic use and the incidence of Clostridium difficile infection in a hospital with stable incidence of infection at >1 case per 1000 admissions per month. Methods The study period was from April 2004 to June 2008 and used data from Infection Control and Hospital Pharmacy. We first described the monthly variation in C. difficile infection and then constructed a multivariate transfer function model that included lag time (cases of C. difficile infection in previous months and delays between changes in antibiotic use and changes in C. difficile infection). Results The average incidence of C. difficile infection was 1.5 cases per 1000 patients per month with no significant increase over 3 years. The number of cases of C. difficile infection in 1 month was dependent on the average number of cases of C. difficile infection in the previous 2 months. The models with data from the whole hospital showed a statistically significant relationship between the number of both hospital-acquired C. difficile infections and total C. difficile infections and consumption of piperacillin/tazobactam, ciprofloxacin and cefuroxime. The association between C. difficile infection and consumption of co-amoxiclav was only significant for hospital-acquired C. difficile infection. The model for hospital-acquired C. difficile infections explained 61% of the variance in C. difficile infections. Conclusions These results provide support for antibiotic policies that minimize the use of broad-spectrum penicillins (co-amoxiclav and piperacillin/tazobactam), cephalosporins and fluoroquinolone

Risk and pharmacoeconomic analyses of the injectable medication process in the paediatric and neonatal intensive care units

Objective To analyse safety risks in injectable medications. To assess the potential impact and pharmacoeconomic aspects of safety tools. Design The injectable drug process was prospectively assessed using a failure modes, effects and criticality analysis. Criticality indexes were estimated based on their likelihood of occurrence, detection probability and potential severity. The impact of 10 safety tools on the criticality index was calculated and extrapolated to all drugs injected daily. Yearly costs for a reduction in criticality by 1 point (=1 quali) per day were estimated. Setting Paediatric and neonatal intensive care units in a University Hospital. Participants Two paediatric nurses, a neonatologist, three hospital pharmacists. Interventions Qualitative and quantitative risk assessment. Main Outcome Measures Failure modes, criticality indexes, cost-efficacy ratios. Results Thirty-one failure modes identified, with the mean of their entire criticality indexes totalling 4540. The most critical failure mode was microbial contamination. The following gains were predicted: 1292 quali (46 500 per day by extrapolation) from ready-to-use syringes, 1201 (72 060) by employing a clinical pharmacist, 996 (59 780) from double check by nurses and 984 (59 040) with computerized physician order entry. The best cost-efficacy ratios were obtained for a clinical pharmacist (1 quali = 0.54 euros), double check (1 quali = 0.71 euros) and ready-to-use syringes (1 quali = 0.72 euros). Computerized physician order entry showed the worst cost-efficacy ratio due to a very high investment costs (1 quali = 22.47 euros). Conclusion Based on our risk and pharmacoeconomic analyses, clinical pharmacy and ready-to-use syringes appear as the most promising safety tool

Simultaneous quantification of ten cytotoxic drugs by a validated LC-ESI-MS/MS method

A liquid chromatography separation with electrospray ionisation and tandem mass spectrometry detection method was developed for the simultaneous quantification of ten commonly handled cytotoxic drugs in a hospital pharmacy. These cytotoxic drugs are cytarabine, gemcitabine, methotrexate, etoposide phosphate, cyclophosphamide, ifosfamide, irinotecan, doxorubicin, epirubicin and vincristine. The chromatographic separation was carried out by RPLC in less than 21min, applying a gradient elution of water and acetonitrile in the presence of 0.1% formic acid. MS/MS was performed on a triple quadrupole in selected reaction monitoring mode. The analytical method was validated to determine the limit of quantification (LOQ) and quantitative performance: lowest LOQs were between 0.25 and 2ngmL−1 for the ten investigated cytotoxic drugs; trueness values (i.e. recovery) were between 85% and 110%, and relative standard deviations for both repeatability and intermediate precision were always inferior to 15%. The multi-compound method was successfully applied for the quality control of pharmaceutical formulations and for analyses of spiked samples on potentially contaminated surfaces. Figure Preparation of cytotoxic formulations at the Pharmacy of Geneva University Hospital

Modelling the impact of antibiotic use on antibiotic-resistant Escherichia coli using population-based data from a large hospital and its surrounding community

Objectives To determine the temporal relationship between antibiotic use and incidence of antibiotic-resistant Escherichia coli in both the inpatient and outpatient setting of a large urban area. Methods A retrospective observational time-series analysis was performed to evaluate the incidence of non-duplicate clinical isolates of E. coli resistant to ciprofloxacin, trimethoprim/sulfamethoxazole and cefepime from January 2000 through December 2007, combined with a transfer function model of aggregated data on antibiotic use in both settings obtained from the hospital's pharmacy and outpatient billing offices. Results Ciprofloxacin resistance increased from 6.0% (2000) to 15.4% (2007; P  < 0.0001) and cefepime resistance from 0.9% (2002) to 3.2% (2007; P= 0.01). Trimethoprim/sulfamethoxazole resistance remained stable (23.7%-25.8%). Total antibiotic use increased in both settings, while fluoroquinolone use increased significantly only among outpatients. A temporal effect between fluoroquinolone resistance in community E. coli isolates and outpatient use of ciprofloxacin (immediate effect and time lag 1 month) and moxifloxacin (time lag 4 months) was observed, explaining 51% of the variance over time. The incidence of cefepime resistance in E. coli was correlated with ciprofloxacin use in the inpatient (lag 1 month) and outpatient (lag 4 months) settings and with the use of ceftriaxone (lag 0 month), piperacillin/tazobactam (3 months) and cefepime (3 months) in the hospital (R2  = 51%). Conclusions These results support efforts to reduce prescribing of fluoroquinolones for control of resistant E. coli including extended-spectrum β-lactamase producers and show the added value of time-series analysis to better understand the interaction between community and hospital antibiotic prescribing and its spill-over effect on antibiotic resistanc

A Risk Analysis Method to Evaluate the Impact of a Computerized Provider Order Entry System on Patient Safety

Objectives: Quantitative evaluation of safety after the implementation of a computerized provider order entry (CPOE) system, stratification of residual risks to drive future developments. Design: Comparative risk analysis of the drug prescription process before and after the implementation of CPOE system, according to the Failure Modes, Effects and Criticality Analysis (FMECA) method. Measurements: The failure modes were defined and their criticality indices calculated on the basis of the likelihood of occurrence, potential severity for patients, and detection probability. Criticality indices of handwritten and electronic prescriptions were compared, the acceptability of residual risks was discussed. Further developments were proposed and their potential impact on the safety was estimated. Results: The sum of criticality indices of 27 identified failure modes was 3813 for the handwritten prescription, 2930 (−23%) for CPOE system, and 1658 (−57%) with 14 enhancements. The major safety improvements were observed for errors due to ambiguous, incomplete or illegible orders (−245 points), wrong dose determination (−217) and interactions (−196). Implementation of targeted pop-ups to remind treatment adaptation (−189), vital signs (−140), and automatic edition of documents needed for the dispensation (−126) were the most promising proposed improvements. Conclusion: The impact of a CPOE system on patient safety strongly depends on the implemented functions and their ergonomics. The use of risk analysis helps to quantitatively evaluate the relationship between a system and patient safety and to build a strategy for continuous quality improvement, by selecting the most appropriate improvements to the syste