Simultaneous infusion of two incompatible antibiotics: Impact of the choice of infusion device and concomitant simulated fluid volume support on the particulate load and the drug mass flow rates.

Vancomycin and piperacillin/tazobactam are known to be incompatible. The objectives of the present study were to evaluate the impact of their simultaneous infusion on mass flow rates and particulate load and identify preventive strategies. We assessed both static conditions and a reproduction of an infusion line used in a hospital's critical care unit. A high-performance liquid chromatography/UV diode array system and static and dynamic laser diffraction particle counters were used. The mass flow rates were primarily influenced by the choice of the infusion device and the presence of simulated fluid volume support. Drug incompatibility also appeared to affect vancomycin's mass flow rate, and the dynamic particulate load increased during flow rate changes - especially in the infusion set with a large common volume line and no concomitant simulated fluid volume support. Only discontinuation of the piperacillin/tazobactam infusion was associated with a higher particulate load in the infusion set with a large common volume line and no concomitant simulated fluid volume support. A low common volume line and the use of simulated fluid volume support were associated with smaller fluctuations in the mass flow rate. The clinical risk associated with a higher particulate load must now be assessed.

[Oral drugs containing alcohol: Should we be careful?] / Médicaments par voie orale contenant de l'alcool : faut-il être vigilant ?

Ethanol is an excipient with known effect whose presence is regulated because it can cause adverse effects, notably a misuse. In order to raise awareness of this risk, this study searched all oral drugs with ethanol as an excipient from the Theriaque® database. All drugs marketed in France with a unit dose ethanol intake of 0.1g or more were identified and analyzed, according to the maximum unit and daily dosage recommended by the manufacturer. This research revealed 106 pharmaceutical specialties responsible for a unit intake of ethanol of 0.1g or more among the 8532 oral drugs containing ethanol (1.2 %): 2 at a daily dose >13g and the majority (57/106; 54 %) at a daily dose <1g. These are mainly oral solutions (97/106; 91 %) of phytotherapy (45/97; 46 %). The most frequently found therapeutic class was antitussive (12/106; 11 %). The majority of drugs are over-the-counter medication (56/106; 53 %). Overall, 106 drugs on the French market can be associated with a risk of misuse and cause adverse effects in vulnerable populations such as children and pregnant women. Vigilance and appropriate monitoring is required for these drugs (especially those over-the-counter ones), and their substitution should be preferred if possible.

Strategies to prevent drug incompatibility during simultaneous multi-drug infusion in intensive care units: a literature review.

PURPOSE: Drug protocols in intensive care units may require the concomitant administration of many drugs as patients' venous accesses are often limited. A major challenge for clinicians is to limit the risk of simultaneously infusing incompatible drugs. Incompatibilities can lead to the formation of particles and inactivation of drugs, whose consequences on the body have already been indicated. Our objective was to assess current strategies to counter the risk of incompatible infusions and control the resulting clinical consequences. METHODS: This review was independently conducted by three investigators in respect of the PRISMA statement. Three online databases were consulted. Full-text articles, notes, or letters written in English or French, published or in press between the 1990s and the end of February 2020, with clinical study design, were eligible. Parameters of interest were mainly number and size of particles, and a number of observed/avoided incompatibilities. RESULTS: All in all, 382 articles were screened, 17 meeting all the acceptance criteria. The strategies outlined and assessed were filtration, the use of multi-lumen devices, the purging of infusion lines, incompatibility tables and databases, and the use of standard operating procedures. CONCLUSION: Although many strategies have been developed in recent years to address drug incompatibility risks, clinical data is still lacking. All studies with in vitro design were excluded although some current innovative strategies, like niosomes, should be considered and studied by means of clinical data in the future.

Clinical implications of intravenous drug incompatibilities in critically ill patients.

OBJECTIVE: The aim of this review is to analyse the clinical consequences of intravenous drug incompatibilities in critically ill patients, especially the incidence of organ dysfunctions and mortality. METHODS: A review of literature was conducted according to the PRISMA statement in June 2017, using Medline, ISI Web of Science and Clinicaltrials.gov. DATA EXTRACTION: Eligible studies were case reports and randomised controlled trials (RCTs) that assessed the effects of drug incompatibilities in critically ill patients on morbidity or mortality as primary or secondary outcomes, or adverse events. Two investigators independently reviewed the eligibility of the study from abstracts or manuscript data. DATA SYNTHESIS: Twelve articles met the selection criteria. The six articles reporting RCTs concern only four RCTs. RCTs were single-centre studies comparing infusion with or without filter. One of them included adult patients. The others included paediatric and neonatal intensive care unit patients. Primary endpoints were SIRS, organ failure, overall complication rate, bacteraemia, sepsis, phlebitis and length of stay. The results are mixed with one RCT reporting a reduction in SIRS, organ failure and overall complication rate, two studies in disagreement over the occurrence of sepsis and one study reporting no impact on length of hospital stay. The six articles on case reports show different drug incompatibility situations. They report pulmonary toxicity. CONCLUSION: Little data is available on this topic. Infused particles may induce organ failure, in particular pulmonary toxicity and SIRS. Further studies are needed to establish a link between the level of exposure to drug incompatibilities and clinical implication.

Cost-Effectiveness Analysis of Five Competing Strategies for the Management of Multiple Recurrent Community-Onset Clostridium difficile Infection in France.

BACKGROUND: Clostridium difficile infection (CDI) is characterized by high rates of recurrence, resulting in substantial health care costs. The aim of this study was to analyze the cost-effectiveness of treatments for the management of second recurrence of community-onset CDI in France. METHODS: We developed a decision-analytic simulation model to compare 5 treatments for the management of second recurrence of community-onset CDI: pulsed-tapered vancomycin, fidaxomicin, fecal microbiota transplantation (FMT) via colonoscopy, FMT via duodenal infusion, and FMT via enema. The model outcome was the incremental cost-effectiveness ratio (ICER), expressed as cost per quality-adjusted life year (QALY) among the 5 treatments. ICERs were interpreted using a willingness-to-pay threshold of €32,000/QALY. Uncertainty was evaluated through deterministic and probabilistic sensitivity analyses. RESULTS: Three strategies were on the efficiency frontier: pulsed-tapered vancomycin, FMT via enema, and FMT via colonoscopy, in order of increasing effectiveness. FMT via duodenal infusion and fidaxomicin were dominated (i.e. less effective and costlier) by FMT via colonoscopy and FMT via enema. FMT via enema compared with pulsed-tapered vancomycin had an ICER of €18,092/QALY. The ICER for FMT via colonoscopy versus FMT via enema was €73,653/QALY. Probabilistic sensitivity analysis with 10,000 Monte Carlo simulations showed that FMT via enema was the most cost-effective strategy in 58% of simulations and FMT via colonoscopy was favored in 19% at a willingness-to-pay threshold of €32,000/QALY. CONCLUSIONS: FMT via enema is the most cost-effective initial strategy for the management of second recurrence of community-onset CDI at a willingness-to-pay threshold of €32,000/QALY.

Compatibility of medications during multi-infusion therapy: A controlled in vitro study on a multilumen infusion device.

OBJECTIVE: Drug incompatibilities can jeopardize the safety and effectiveness of intravenous drug therapies, especially in the field of anaesthesia and intensive care. Patients receive many drugs simultaneously through limited venous accesses. This study was designed to confirm the impact of a multilumen infusion device on the occurrence of known physical drug incompatibilities. STUDY DESIGN: In vitro laboratory work. METHODS: Two infusion devices were studied: a standard single-lumen set and a multilumen infusion access device (Edelvaiss Multiline-8, Doran International). Up to six drugs were infused simultaneously: three acidic solutions of midazolam, amiodarone and dobutamine, and three alkaline solutions of furosemide, pantoprazole and amoxicillin/clavulanate. Saline, Ringer' solution and 5% dextrose were used as hydration vehicles with an infusion rate initially set at 100 mL/h and with stepwise decreases of 10 mL/h until precipitation. Two methods were used to highlight physical drug compatibility according to the European Pharmacopoeia: visual inspection of the extension set and an obscured-light sub-visible particle count test of infusions. The lowest infusion rate value for vehicle infusion to satisfy the two tests in all trials is reported for each infusion device. RESULTS: The standard set did not satisfy the test in 82% of the assessed drug combinations. The Edelvaiss Multiline-8 was able to prevent the occurrence of drug incompatibilities in 49% of the drug combinations tested. This device is therefore advantageous, especially when simultaneously infusing two or four incompatible drugs. CONCLUSIONS: Infusion device characteristics have an impact on physical drug incompatibilities. Our results confirm that the Edelvaiss Multiline-8 device prevents physical drug incompatibilities under specified conditions.

In vitro analysis of overall particulate contamination exposure during multidrug IV therapy: impact of infusion sets.

BACKGROUND: Drug incompatibilities, recognizable through precipitate, may have clinical consequences for patients, especially during multidrug IV therapies, where vancomycin and piperacillin are present. Drug concentration and infusion set influence the overall particulate contamination of pediatric infusion protocols. The use of multi-lumen infusion sets could prevent such incompatibilities. Our goal was to define and assess a new way to infuse these drugs during leukemia treatment in children. PROCEDURES: This in vitro study focused on a pediatric multidrug protocol for patients diagnosed with lymphoblastic leukemia and receiving allogeneic transplantation. Different vancomycin concentrations were tested to infuse incompatible drugs simultaneously without any particle formation (optimized multidrug protocol). A dynamic particle count test was used over 24 hr to evaluate the overall particulate contamination of our standard and optimized multidrug protocols, using both a standard and a multi-lumen infusion set. RESULTS: No visible particles were detected on a decreased vancomycin concentration compared to the standard dose. For the optimized multidrug protocol, the use of a multi-lumen infusion set reduced overall particulate contamination by 68%, compared to the standard infusion set (P = 0.002). Large-sized particles were significantly reduced when using the multi-lumen infusion set approximately 60% (P = 0.027) and 90% (P = 0.009) for particle sizes ≥10 µm and 25 µm, respectively. CONCLUSIONS: This study demonstrates that a large number of particles can be administered during parenteral multidrug infusion. The choice of drug concentration and/or the type of infusion set may reduce this. Further studies are required to evaluate adverse clinical effects.

The impact of multilumen infusion devices on the occurrence of known physical drug incompatibility: a controlled in vitro study.

BACKGROUND: Drug incompatibility is a problem, especially when managing patients in intensive care units. We designed the present study to assess the impact of multilumen infusion access devices on the occurrence of known physical drug incompatibility through a controlled in vitro study. METHODS: Three infusion devices connected to a single-lumen catheter were studied: a standard set with 2-port manifold and 1-m extension set and 2 multilumen infusion access devices: a 3-lumen extension set and a 9-lumen extension set (Edelvaiss-Multiline™; Doran International, Toussieu, France). For the 9-lumen extension set, 3 infusion access combinations were studied. Furosemide, midazolam, and saline were infused simultaneously through 3 infusion devices. Three concentrations of furosemide were tested. The infusion rate of saline (carrier) was initially set at 100 mL/h and stepwise decreased by 10 mL/h until precipitate formation. Physical incompatibility was assessed by 2 tests: visual inspection and the subvisible particle count test according to the European Pharmacopeia. The lowest saline infusion rate to prevent visible precipitate and attain an acceptable particle count (i.e., to pass "the 2 tests") was reported for each infusion set. RESULTS: The standard set revealed visible precipitate even at the highest saline flow rate (100 mL/h). The 3-lumen device prevented drug precipitation using the 2 lowest furosemide concentrations with a saline infusion rate that decreased with furosemide concentration. The 9-lumen infusion access device prevented drug precipitation whatever the furosemide concentration for 2 access combinations using saline infusion rates of between 20 and 60 mL/h but not for a third access combination, despite saline infusion rates equal to 100 mL/h. CONCLUSIONS: Infusion device characteristics appear to have an impact on the physical compatibility of the 2 drugs. Under specified conditions, the 9-lumen infusion access device prevents physical furosemide-midazolam incompatibility.