Assessing the Clinical, Economic, and Health Resource Utilization Impacts of Prefilled Syringes Versus Conventional Medication Administration Methods: Results From a Systematic Literature Review.

OBJECTIVE: The objective of this systematic review was to assess the clinical, economic, and health resource utilization outcomes associated with the use of prefilled syringes in medication administration compared with traditional preparation methods. DATA SOURCES: We conducted a systematic literature review to evaluate outcomes such as medication errors, wastage, time savings, and contamination in prefilled syringes. Our search encompassed multiple databases, including PubMed and Embase, for studies published between January 1, 2017, and November 1, 2022. STUDY SELECTION AND DATA EXTRACTION: Peer-reviewed publications meeting our inclusion criteria underwent rigorous screening, including title, abstract, and full-text article assessments, performed by two reviewers. DATA SYNTHESIS: Among reviewed articles, 24 met our eligibility criteria. Selected studies were primarily observational (46%) and conducted in Europe (46%). Our findings indicated that prefilled syringes consistently reduced medication errors (by 10%-73%), adverse events (from 1.1 to 0.275 per 100 administrations), wastage (by up to 80% of drug), and preparation time (from 4.0 to 338.0 seconds) (ranges varied by drug type, setting, and dosage). However, there was limited data on contamination. Economically, prefilled syringes reduced waste and error rates, which may translate into overall savings. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: This review highlights the value of prefilled syringes, which can streamline medication delivery, save nursing time, and reduce preventable medication errors. Moreover, prefilled syringes have the potential to minimize medication wastage, optimizing resource utilization and efficiency in health care settings. CONCLUSION AND RELEVANCE: Our findings provide new insights into clinical and economic benefits of prefilled syringe adoption. These benefits include improved medication delivery and safety, which can lead to time and cost reductions for health care departments, hospitals, and health systems. However, further real-world research on clinical and economic outcomes, especially in contamination, is needed to better understand the benefits of prefilled syringes.

Pre-ANDA strategy and Human Factors activities to de-risk pharmaceutical companies ANDA submission of drug-device combination products: case study of a formative Comparative Use Human Factors study.

BACKGROUND: This article presents a strategy that a Drug Delivery Device Developer (DDDD) has adopted to support Abbreviated New Drug Application (ANDA) submissions of drug-device combination products. As per the related FDA guidance, a threshold analysis should be compiled. If 'other differences' between the Reference Listed Drug (RLD) and the generic drug devices are identified, a Comparative Use Human Factors (CUHF) study may be requested. METHODS: The DDDD performed task analysis and physical comparison to assess the pen injector design differences. Then, a formative CUHF study with 25 participants simulating injections using both RLD and the generic pen injectors was conducted. RESULTS: After each participant completed four simulated injections, similar type and rates of use error between the RLD (0.70) and generic (0.68) pen injectors were observed. CONCLUSION: DDDDs can support pharmaceutical companies in the ANDA submission strategy of their drug-device combination product by initiating comparative task analysis and physical comparison of the device as inputs for the threshold analysis. If 'other differences' are identified, a formative CUHF study can be performed. As shown in our case study, this approach can be leveraged to support the sample size calculation and non-inferiority margin determination for a CUHF study with the final combination product.

Structural basis for the substrate specificity of a novel ß-N-acetylhexosaminidase StrH protein from Streptococcus pneumoniae R6.

The ß-N-acetylhexosaminidase (EC 3.2.1.52) from glycoside hydrolase family 20 (GH20) catalyzes the hydrolysis of the ß-N-acetylglucosamine (NAG) group from the nonreducing end of various glycoconjugates. The putative surface-exposed N-acetylhexosaminidase StrH/Spr0057 from Streptococcus pneumoniae R6 was proved to contribute to the virulence by removal of ß(1,2)-linked NAG on host defense molecules following the cleavage of sialic acid and galactose by neuraminidase and ß-galactosidase, respectively. StrH is the only reported GH20 enzyme that contains a tandem repeat of two 53% sequence-identical catalytic domains (designated as GH20-1 and GH20-2, respectively). Here, we present the 2.1 Å crystal structure of the N-terminal domain of StrH (residues Glu-175 to Lys-642) complexed with NAG. It adopts an overall structure similar to other GH20 enzymes: a (ß/α)(8) TIM barrel with the active site residing at the center of the ß-barrel convex side. The kinetic investigation using 4-nitrophenyl N-acetyl-ß-d-glucosaminide as the substrate demonstrated that GH20-1 had an enzymatic activity (k(cat)/K(m)) of one-fourth compared with GH20-2. The lower activity of GH20-1 could be attributed to the substitution of active site Cys-469 of GH20-1 to the counterpart Tyr-903 of GH20-2. A complex model of NAGß(1,2)Man at the active site of GH20-1 combined with activity assays of the corresponding site-directed mutants characterized two key residues Trp-443 and Tyr-482 at subsite +1 of GH20-1 (Trp-876 and Tyr-914 of GH20-2) that might determine the ß(1,2) substrate specificity. Taken together, these findings shed light on the mechanism of catalytic specificity toward the ß(1,2)-linked ß-N-acetylglucosides.

Structural and enzymatic characterization of the streptococcal ATP/diadenosine polyphosphate and phosphodiester hydrolase Spr1479/SapH.

Spr1479 from Streptococcus pneumoniae R6 is a 33-kDa hypothetical protein of unknown function. Here, we determined the crystal structures of its apo-form at 1.90 Å and complex forms with inorganic phosphate and AMP at 2.30 and 2.20 Å, respectively. The core structure of Spr1479 adopts a four-layer αßßα-sandwich fold, with Fe(3+) and Mn(2+) coordinated at the binuclear center of the active site (similar to metallophosphoesterases). Enzymatic assays showed that, in addition to phosphodiesterase activity for bis(p-nitrophenyl) phosphate, Spr1479 has hydrolase activity for diadenosine polyphosphate (Ap(n)A) and ATP. Residues that coordinate with the two metals are indispensable for both activities. By contrast, the streptococcus-specific residue Trp-67, which binds to phosphate in the two complex structures, is indispensable for the ATP/Ap(n)A hydrolase activity only. Moreover, the AMP-binding pocket is conserved exclusively in all streptococci. Therefore, we named the protein SapH for streptococcal ATP/Ap(n)A and phosphodiester hydrolase.

Crystal structure of the mucin-binding domain of Spr1345 from Streptococcus pneumoniae.

The surface protein Spr1345 from Streptococcus pneumoniae R6 is a 22-kDa mucin-binding protein (MucBP) involved in adherence and colonization of the human lung and respiratory tract. It is composed of a mucin-binding domain (MucBD) and a proline-rich domain (PRD) followed by an LPxTG motif, which is recognized and cleaved by sortase, resulting in a mature form of 171 residues (MF171) that is anchored to the cell wall. We found that the MucBD alone possesses comparable in vitro mucin-binding affinity to the mature form, and can be specifically enriched at the surface of human lung carcinoma A549 cells. Using single-wavelength anomalous dispersion (SAD) phasing method with the iodine signals, we solved the crystal structure of the MucBD at 2.0Å resolution, the first structure of MucBDs from pathogenic bacteria. The overall structure adopts an immunoglobulin-like fold with an elongated rod-like shape, composed of six anti-parallel ß-strands and a long loop. Structural comparison suggested that the conserved C-terminal moiety may participate in the recognition of mucins. These findings provided structural insights into host-pathogen interaction mediated by mucins, which might be useful for designing novel vaccines and antibiotic drugs against human diseases caused by pneumococci.

Formative and Validation Human Factors studies of a new disposable autoinjector for subcutaneous delivery of chronic disease therapies.

BACKGROUND: Use-related risks related to autoinjector devices have been previously identified. To minimize these problems, the identification of potential use errors is a critical task during device development. METHODS: This article presents iterative human factor studies, which aim to assess user interaction with the tested push-on-skin BD Intevia™ 1 mL Disposable Autoinjector, across a wide range of indications, and a broad user population. RESULTS: Through the different human factor studies, use errors were recorded when the participants completed the critical tasks, but their occurrence continuously decreased. First, the incidence of use errors was reduced when the participants read the IFU. In addition, the IFU updates and design change implemented contributed to improve the usability performance. During the validation study, some use errors were still observed, mainly during the first uses. Nevertheless, providing a training to the participants almost fully eliminated the remaining use errors. CONCLUSION: Thus, these results demonstrated that this new autoinjector can be safely and efficiently used for its intended uses and under the expected use conditions by all tested user groups.

New adhesin functions of surface-exposed pneumococcal proteins.

BACKGROUND: Streptococcus pneumoniae is a widely distributed commensal Gram-positive bacteria of the upper respiratory tract. Pneumococcal colonization can progress to invasive disease, and thus become lethal, reason why antibiotics and vaccines are designed to limit the dramatic effects of the bacteria in such cases. As a consequence, pneumococcus has developed efficient antibiotic resistance, and the use of vaccines covering a limited number of serotypes such as Pneumovax and Prevnar results in the expansion of non-covered serotypes. Pneumococcal surface proteins represent challenging candidates for the development of new therapeutic targets against the bacteria. Despite the number of described virulence factors, we believe that the majority of them remain to be characterized. This is the reason why pneumococcus invasion processes are still largely unknown. RESULTS: Availability of genome sequences facilitated the identification of pneumococcal surface proteins bearing characteristic motifs such as choline-binding proteins (Cbp) and peptidoglycan binding (LPXTG) proteins. We designed a medium throughput approach to systematically test for interactions between these pneumococcal surface proteins and host proteins (extracellular matrix proteins, circulating proteins or immunity related proteins). We cloned, expressed and purified 28 pneumococcal surface proteins. Interactions were tested in a solid phase assay, which led to the identification of 23 protein-protein interactions among which 20 are new. CONCLUSIONS: We conclude that whether peptidoglycan binding proteins do not appear to be major adhesins, most of the choline-binding proteins interact with host proteins (elastin and C reactive proteins are the major Cbp partners). These newly identified interactions open the way to a better understanding of host-pneumococcal interactions.

User experience for manual injection of 2 mL viscous solutions is enhanced by a new prefillable syringe with a staked 8 mm ultra-thin wall needle.

OBJECTIVES: User experience was compared between a new pre-fillable 2.25 mL glass syringe equipped with an ultra-thin-wall (UTW) 8 mm staked needle and a marketed BD Neopak™ syringe equipped with a special-thin-wall (STW) 12.7 mm staked needle. METHODS: Participants simulated subcutaneous injections with both syringes alone (formative Human Factors study) and in combination with a needlestick-prevention device (validation Human Factors study). RESULTS: Usability results of both studies showed higher success rates for delivering the full dose of 2 mL viscous solution (30 cP) with the 8mmUTW syringe than with the 12.7mmSTW one (63% vs. 42% in the formative study). The use of the 8mmUTW syringe demonstrated also better ease of use and acceptance results and 72% of formative study participants preferred this new syringe over the current one when delivering the viscous solution. Using a shorter needle also showed a benefit in decreasing the injection-related anxiety. Besides, in the case of a non-recommended injection technique, the calculated risk of accidental intramuscular injection is reduced by 2 to 13 times with the 8mmUTW syringe. CONCLUSION: Altogether, the results obtained demonstrated an improvement of the user experience with this new syringe compared to the current one in the manual delivery of 2 mL viscous solutions.

Structure of the choline-binding domain of Spr1274 in Streptococcus pneumoniae.

Spr1274 is a putative choline-binding protein that is bound to the cell wall of Streptococcus pneumoniae through noncovalent interactions with the choline moieties of teichoic and lipoteichoic acids. Its function is still unknown. The crystal structure of the choline-binding domain of Spr1274 (residues 44-129) was solved at 2.38 A resolution with three molecules in the asymmetric unit. It may provide a structural basis for functional analysis of choline-binding proteins.

Streptococcus pneumoniae choline-binding protein E interaction with plasminogen/plasmin stimulates migration across the extracellular matrix.

The virulence mechanisms leading Streptococcus pneumoniae to convert from nasopharyngeal colonization to a tissue-invasive phenotype are still largely unknown. Proliferation of infection requires penetration of the extracellular matrix, which occurs by recruitment of host proteases to the bacterial cell surface. We present evidence supporting the role of choline-binding protein E (CBPE) (a member of the surface-exposed choline-binding protein family) as an important receptor for human plasminogen, the precursor of plasmin. The results of ligand overlay blot analyses, solid-phase binding assays, and surface plasmon resonance experiments support the idea of an interaction between CBPE and plasminogen. We have shown that the phosphorylcholine esterase (Pce) domain of CBPE interacts with the plasminogen kringle domains. Analysis of the crystal structure of the Pce domain, followed by site-directed mutagenesis, allowed the identification of the plasminogen-binding region composed in part by lysine residues, some of which map in a linear fashion on the surface of the Pce domain. The biological relevance of the CBPE-plasminogen interaction is supported by the fact that, compared to the wild-type strain, a mutant of pneumococcus with the cbpE gene deleted (i) displays a reduced level of plasminogen binding and plasmin activation and (ii) shows reduced ability to cross the extracellular matrix in an in vitro model. These results support the idea of a physiological role for the CBPE-plasminogen interaction in pneumococcal dissemination into human tissue.

Two mosquito LRR proteins function as complement control factors in the TEP1-mediated killing of Plasmodium.

Plasmodium development within Anopheles mosquitoes is a vulnerable step in the parasite transmission cycle, and targeting this step represents a promising strategy for malaria control. The thioester-containing complement-like protein TEP1 and two leucine-rich repeat (LRR) proteins, LRIM1 and APL1, have been identified as major mosquito factors that regulate parasite loads. Here, we show that LRIM1 and APL1 are required for binding of TEP1 to parasites. RNAi silencing of the LRR-encoding genes results in deposition of TEP1 on Anopheles tissues, thereby depleting TEP1 from circulation in the hemolymph and impeding its binding to Plasmodium. LRIM1 and APL1 not only stabilize circulating TEP1, they also stabilize each other prior to their interaction with TEP1. Our results indicate that three major antiparasitic factors in mosquitoes jointly function as a complement-like system in parasite killing, and they reveal a role for LRR proteins as complement control factors.

Boosting NF-kappaB-dependent basal immunity of Anopheles gambiae aborts development of Plasmodium berghei.

Anopheles gambiae, the major vector for the protozoan malaria parasite Plasmodium falciparum, mounts powerful antiparasitic responses that cause marked parasite loss during midgut invasion. Here, we showed that these antiparasitic defenses were composed of pre- and postinvasion phases and that the preinvasion phase was predominantly regulated by Rel1 and Rel2 members of the NF-kappaB transcription factors. Concurrent silencing of Rel1 and Rel2 decreased the basal expression of the major antiparasitic genes TEP1 and LRIM1 and abolished resistance of Anopheles to the rodent malaria parasite P. berghei. Conversely, depletion of a negative regulator of Rel1, Cactus, prior to infection, enhanced the basal expression of TEP1 and of other immune factors and completely prevented parasite development. Our findings uncover the crucial role of the preinvasion defense in the elimination of parasites, which is at least in part based on circulating blood molecules.