Finding value in novel antibiotics: How can infectious diseases adopt incremental cost-effectiveness to improve new antibiotic utilization?

Research and development of innovative antimicrobials is paramount to addressing the antimicrobial resistance threat. Although antimicrobial discovery and development has increased, difficulties have emerged in the pharmaceutical industry after market approval. In this minireview, we summarize clinical trial data on recently approved antibiotics, calculate incremental cost-effectiveness ratio (ICER) values, and explore ways to adapt ICER calculations to the limitations of antimicrobial clinical trial design. We provide a systematic review and analysis of randomized, controlled studies of antibiotics approved from 2014 - 2022 and extracted the relevant clinical data. Adapted-ICER (aICER) calculations were conducted using the primary condition-specific outcome that was reported in each study (percent mortality or percent cure rate). The literature search identified 18 studies for the 8 total antibiotics which met inclusion criteria and contained data required for aICER calculation. aICER values ranged from -$17,374 to $4,966 per percent mortality and -$43,931 to $2,529 per percent cure rate. With regards to mortality, ceftolozane/tazobactam and imipenem/cilastatin/relebactam proved cost efficacious, with aICER values of $4,965 per percent mortality and $1,955 per percent mortality respectively. Finding value in novel antibiotic agents is imperative to further justifying their development, and aICER values are the most common method of determining value in healthcare. The current outcomes of clinical trials are difficult to translate to aICER, which most effectively use Quality-Adjusted Life Years (QALY) as the quality standard in other fields such as oncology. Future antimicrobial trials should consider introducing methods of assessing measures of health gain such as QALY to better translate the value of novel antimicrobials in healthcare.

The economic burden of difficult intravenous access in the emergency department from a United States' provider perspective.

Background: Peripheral intravenous catheter placement is one of the most common invasive procedures that nurses will perform, especially in emergency departments. Aims: This early analysis aimed to quantify the economic burden associated with intravenous therapy in patients presenting in emergency departments with difficult intravenous access, receiving traditional peripheral intravenous catheters. This may inform the opportunity for improvement for investment in nursing tools and services regarding difficult venous access burden reduction. Methods: Model parameter data were obtained from published literature where possible via a targeted literature review for the terms including relative variations of 'Difficult Venous Access', 'burden', and 'costs', or elicited from expert clinical opinion. A simple decision tree model was developed in Microsoft® Excel 2016. Results included number of insertion attempts, number of patients requiring escalation, catheter failures due to complications, healthcare professional (e.g. nurse) time, and total costs (including/excluding health care professional time). Sensitivity analyses were performed. Results: The model considers 64,000 individuals presenting in the emergency department annually, of which 75% (48,000) require a peripheral intravenous catheter; of these 22% (10,560) are estimated to have difficult venous access. The total cost burden of difficult venous access is estimated to be $890,095 per year/$84.29 per patient with difficult venous access, including the cost of clinician time. Key total cost drivers include the population size treated in the emergency department annually, the proportion of midlines placed by a specialist IV (intravenous access) nurse and the percentage of patients with difficult venous access. Conclusion: This is the first formal analysis estimating the significant economic burden of difficult venous access in emergency departments via peripheral intravenous catheter placement, a task frequently performed by nurses. Further studies are needed to evaluate nursing-centric strategies for reducing this burden. Additionally, adoption of a concise definition is needed, as is routine use of reliable assessment tools so that future cost analyses can be better contextualised.

Diagnostic testing and antibiotic utilization among inpatients evaluated for coronavirus disease 2019 (COVID-19) pneumonia.

We evaluated diagnostic test and antibiotic utilization among 252 patients from 11 US hospitals who were evaluated for coronavirus disease 2019 (COVID-19) pneumonia during the severe acute respiratory coronavirus virus 2 (SARS-CoV-2) omicron variant pandemic wave. In our cohort, antibiotic use remained high (62%) among SARS-CoV-2-positive patients and even higher among those who underwent procalcitonin testing (68%).

Differential Screening for Nonviral Sexually Transmitted Infections by Type of Vaginitis Testing.

BACKGROUND: Data are lacking on adherence to Centers for Disease Control and Prevention testing guidelines among insured US women presenting with vaginal health complaints; thus, we quantified vaginitis testing frequency and assessed the co-testing rate for causes of vaginitis and Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG). METHODS: This was a retrospective analysis of deidentified data from a medical database. Information from women aged 18 to 50 years was obtained from the Truven MarketScan Commercial Database (2012-2017) using Current Procedural Terminology ( CPT ) codes; χ2 testing was applied to determine co-testing differences for CT/NG based on vaginitis test type. Odds ratios were calculated to determine the association with CT/NG screening across vaginitis testing categories. RESULTS: Approximately 48% of 1,359,289 women received a vaginitis diagnosis that involved a laboratory-based test. Of these women, only 34% were co-tested for CT/NG. CT/NG co-testing was highest for those with nucleic acid amplification testing for vaginitis and lowest for those with no vaginitis testing CPT code (71% vs. 23%, respectively; P < 0.0001). CONCLUSIONS: The vaginitis nucleic acid amplification test, indicated by CPT code, was associated with statistically significantly higher CT/NG testing rates. Molecular diagnostics may support vaginitis testing in settings that have limited opportunities for microscopy and clinical examinations and offer greater opportunity to offer comprehensive women's health care that includes testing for chlamydia and/or gonorrhea infections.

The impact of coronavirus disease 2019 (COVID-19) on the antimicrobial stewardship pharmacist workforce: A multicenter survey.

Objective: The coronavirus disease 2019 (COVID-19) pandemic has required healthcare systems and hospitals to rapidly modify standard practice, including antimicrobial stewardship services. Our study examines the impact of COVID-19 on the antimicrobial stewardship pharmacist. Design: A survey was distributed nationally to all healthcare improvement company members. Participants: Pharmacist participants were mostly leaders of antimicrobial stewardship programs distributed evenly across the United States and representing urban, suburban, and rural health-system practice sites. Results: Participants reported relative increases in time spent completing tasks related to medication access and preauthorization (300%; P = .018) and administrative meeting time (34%; P = .067) during the COVID-19 pandemic compared to before the pandemic. Time spent rounding, making interventions, performing pharmacokinetic services, and medication reconciliation decreased. Conclusion: A shift away from clinical activities may negatively affect the utilization of antimicrobials.

Comparison of antigen- and RT-PCR-based testing strategies for detection of SARS-CoV-2 in two high-exposure settings.

Surveillance testing for infectious disease is an important tool to combat disease transmission at the population level. During the SARS-CoV-2 pandemic, RT-PCR tests have been considered the gold standard due to their high sensitivity and specificity. However, RT-PCR tests for SARS-CoV-2 have been shown to return positive results when performed to individuals who are past the infectious stage of the disease. Meanwhile, antigen-based tests are often treated as a less accurate substitute for RT-PCR, however, new evidence suggests they may better reflect infectiousness. Consequently, the two test types may each be most optimally deployed in different settings. Here, we present an epidemiological model with surveillance testing and coordinated isolation in two congregate living settings (a nursing home and a university dormitory system) that considers test metrics with respect to viral culture, a proxy for infectiousness. Simulations show that antigen-based surveillance testing coupled with isolation greatly reduces disease burden and carries a lower economic cost than RT-PCR-based strategies. Antigen and RT-PCR tests perform different functions toward the goal of reducing infectious disease burden and should be used accordingly.

Association of Penicillin or Cephalosporin Allergy Documentation and Antibiotic Use in Hospitalized Patients with Pneumonia.

BACKGROUND: Treatment guidelines for pneumonia recommend beta-lactam antibiotic-based therapy. Although reported penicillin allergy is common, more than 90% of patients with reported penicillin allergy are not allergic. OBJECTIVE: We evaluated the association of a documented penicillin and/or cephalosporin (P/C) allergy to antibiotic use for the treatment of inpatient pneumonia. METHODS: This was a national cross-sectional study conducted among Vizient, Inc., network hospitals that voluntarily contributed data. Among hospitalized patients with pneumonia, we examined the relation of a documented P/C allergy in the electronic health record to prevalence of first-line beta-lactam antibiotic administration and alternative antibiotics using multivariable log-binomial regression with generalized estimating equations. RESULTS: Of 2,276 inpatients receiving antibiotics for pneumonia at 95 U.S. hospitals, 450 (20%) had a documented P/C allergy. Compared with pneumonia patients without a documented P/C allergy, patients with a documented P/C allergy had reduced prevalence of first-line beta-lactam antibiotic use (adjusted prevalence ratio [aPR] 0.79; 95% confidence interval [95% CI] 0.69-0.89]). Patients with high-risk P/C reactions (n = 91) had even lower prevalence of first-line beta-lactam antibiotic use (aPR 0.47; 95% CI 0.35-0.64). Alternative antibiotics associated with a higher use in pneumonia patients with a documented P/C allergy included carbapenems (aPR 1.61; 95% CI 1.22-2.13) and fluoroquinolones (aPR 1.52; 95% CI 1.21-1.91). CONCLUSIONS: Inpatients with documented P/C allergy and pneumonia were less likely to receive recommended beta-lactams and more likely to receive carbapenems and fluoroquinolones. Inpatient allergy assessment may improve optimal antibiotic therapy for the 20% of inpatients with pneumonia and a documented P/C allergy.

Multicompartment Theranostic Nanoemulsions Stabilized by a Triphilic Semifluorinated Block Copolymer.

The presence of a perfluorocarbon block in a multiblock polymer has been shown to be an additional driving force toward nanoparticle assembly. In the preparation of nanoemulsions, this perfluorocarbon block also provides enhanced particle stability. Herein, the synthesis of a new triphilic, semifluorinated copolymer, M2F8H18, is introduced. This ABC type block copolymer can be used to formulate extremely stable nanoemulsions, assembled around a lipophilic droplet, with lifetimes of one year or more. The central oil droplet can stably solubilize high concentrations of hydrophobic drugs, making this system an ideal drug delivery vehicle. The incorporation of the perfluorocarbon block modulates drug release from the lipophilic core via the surrounding fluorous shell. Fluorous imaging agents incorporated into the fluorous shell prolong drug release even further as well as provide potent 19F-MRI contrast ability. In vitro studies show that these nanoemulsions efficiently inhibit cancer cell growth, thus providing a theranostic drug delivery system.

Sequential unfolding of the hemolysin two-partner secretion domain from Proteus mirabilis.

Protein secretion is a major contributor to Gram-negative bacterial virulence. Type Vb or two-partner secretion (TPS) pathways utilize a membrane bound ß-barrel B component (TpsB) to translocate large and predominantly virulent exoproteins (TpsA) through a nucleotide independent mechanism. We focused our studies on a truncated TpsA member termed hemolysin A (HpmA265), a structurally and functionally characterized TPS domain from Proteus mirabilis. Contrary to the expectation that the TPS domain of HpmA265 would denature in a single cooperative transition, we found that the unfolding follows a sequential model with three distinct transitions linking four states. The solvent inaccessible core of HpmA265 can be divided into two different regions. The C-proximal region contains nonpolar residues and forms a prototypical hydrophobic core as found in globular proteins. The N-proximal region of the solvent inaccessible core, however, contains polar residues. To understand the contributions of the hydrophobic and polar interiors to overall TPS domain stability, we conducted unfolding studies on HpmA265 and site-specific mutants of HpmA265. By correlating the effect of individual site-specific mutations with the sequential unfolding results we were able to divide the HpmA265 TPS domain into polar core, nonpolar core, and C-terminal subdomains. Moreover, the unfolding studies provide quantitative evidence that the folding free energy for the polar core subdomain is more favorable than for the nonpolar core and C-terminal subdomains. This study implicates the hydrogen bonds shared among these conserved internal residues as a primary means for stabilizing the N-proximal polar core subdomain.