Cohort study of patients with advanced cancer: outcomes associated with duration of antibiotic therapy for non-ventilator hospital-acquired pneumonia.

In this single-center observational study of 118 older adults with advanced cancer who developed non-ventilator hospital-acquired pneumonia, prolonged antibiotic durations (8-14 and ≥15 vs ≤7 d) were not associated with reduced adjusted odds of 90-day all-cause readmission or death. These data may inform antimicrobial stewardship efforts in palliative care settings.

Antibiotic therapy is associated with adverse drug events among older adults with advanced cancer: A cohort study.

BACKGROUND: Older adults with advanced cancer are exposed to antibiotics but estimates of adverse drug events associated with antibiotic therapy are lacking. AIM: Evaluate the association of antibiotic therapy with adverse drug events in older adults with advanced cancer. DESIGN: Cohort study where the exposure was the ratio of days of therapy of an oral or intravenous antibiotic per patient-day and the outcome was an adverse drug event, defined as cardiotoxicity, hepatotoxicity, nephrotoxicity, Clostridioides difficile infection, or new detection of a multidrug-resistant organism. SETTING/PARTICIPANTS: Patients aged ⩾65 years with solid tumors from a tertiary care center who received palliative chemotherapy (n = 914). RESULTS: Mean age was 75 ± 6.6 years, and 52% were female. Common tumors were lung (31%, n = 284) and gastrointestinal (26%, n = 234). Mean time from first course of palliative chemotherapy to index admission was 128 days. Five-hundred thirty (58%) patients were exposed to antibiotics during the index admission; of these, 27% (n = 143) met standardized criteria for infection. Patients were commonly exposed to cephalosporins (33%, n = 298) and vancomycin (30%, n = 276). Among patients exposed to antibiotics, 35% (n = 183/530) developed an adverse drug event. In multivariable testing, antibiotic therapy was associated with development of an adverse drug event (>0 to <1 vs 0 days of therapy/patient-day: adjusted odds ratio [aOR] = 1.9; 95% confidence interval [CI], 1.2-2.8; ⩾1 vs 0 days of therapy/patient-day: aOR = 2.1, 95% CI, 1.4-3.0). CONCLUSION: Antibiotic therapy was independently associated with adverse drug events in hospitalized older adults with advanced cancer. These findings may inform antibiotic decision-making among palliative care providers.

Prevalence and treatment of postobstructive pneumonia among older adults with advanced cancer.

Among 124 older adults with advanced cancer who were hospitalized with pneumonia, 7.3% met criteria for postobstructive pneumonia. There were no differences in antibiotic duration, antibiotic spectrum, 30-day and 90-day readmissions, or mortality between those with and without postobstructive pneumonia. Bacteria were identified in 5 patients with postobstructive pneumonia.

National Cohort Study of Homebound Persons Living With Dementia: Antibiotic Prescribing Trends and Opportunities for Antibiotic Stewardship.

Background: Over 7 million older Americans are homebound. Managing infections in homebound persons presents unique challenges that are magnified among persons living with dementia (PLWD). This work sought to characterize antibiotic use in a national cohort of PLWD who received home-based primary care (HBPC) through the Veterans Health Administration. Methods: Administrative data identified veterans aged ≥65 years with ≥2 physician home visits in a year between 2014 and 2018 and a dementia diagnosis 3 years before through 1 year after their initial HBPC visit. Antibiotics prescribed orally, intravenously, intramuscularly, or by enema within 3 days of an HBPC visit were assessed from the initial HBPC visit to death or December 31, 2018. Prescription fills and days of therapy (DOT) per 1000 days of home care (DOHC) were calculated. Results: Among 39 861 PLWD, the median age (interquartile range [IQR]) was 85 (78-90) years, and 15.0% were Black. Overall, 16 956 (42.5%) PLWD received 45 122 prescription fills. The antibiotic use rate was 20.7 DOT per 1000 DOHC. Telephone visits and advanced practice provider visits were associated with 30.9% and 42.0% of fills, respectively. Sixty-seven percent of fills were associated with diagnoses for conditions where antibiotics are not indicated. Quinolones were the most prescribed class (24.3% of fills). The overall median length of therapy (IQR) was 7 (7-10) days. Antibiotic use rates varied across regions. Within regions, the median annual antibiotic use rate decreased from 2014 to 2018. Conclusions: Antibiotic prescriptions were prevalent in HBPC. The scope, appropriateness, and harms of antibiotic use in homebound PLWD need further investigation.

Comparison of traditional instruction versus nontraditional learning to improve trainee knowledge of urine culture practices in catheterized patients.

We surveyed trainees about their urine culture practices and assessed the impact of an educational intervention delivered electronically and in-person. Trainee scores improved across all levels of training and across all questions on the post-intervention survey, but there was no difference in scores by mode of education (P=0.91).

Prolonged Retrobulbar Local Anesthesia of the Cornea Does Not Cause Keratopathy in Mice.

Purpose: Prolonged local anesthesia (PLA) of the cornea is currently assumed to cause neurotrophic keratitis and is strongly discouraged. We investigate whether PLA of the cornea per se causes neurotrophic keratitis. Methods: PLA of the cornea was induced in 12 female albino BALB/c mice by retrobulbar injection of a polymeric prodrug (PGS-TTX) where the site 1 sodium channel blocker tetrodotoxin (TTX) was slowly released from the polymer polyglycerol sebacate. The duration and depth of corneal anesthesia was monitored by the Cochet-Bonnet esthesiometer. Corneal injury from PLA was assessed by slit lamp examination with 2% sodium fluorescein dye, histology, corneal nerve density by immunohistochemistry with anti-ß III tubulin antibody and confocal microscopy, and corneal neurotrophin levels (substance P and neurokinin A) by an enzyme-linked immunosorbent assay. PLA was also induced by topical amitriptyline (80 mM), used as a positive control for local anesthetic-induced corneal injury. Frequent ocular lubrication was provided. Results: Retrobulbar PGS-TTX resulted in complete corneal anesthesia lasting 50.1 ± 3.6 hours and mean time to complete resolution of block of 55.1 ± 3.6 hours with no keratopathy provided lubrication was provided. Topical 80 mM amitriptyline induced complete corneal anesthesia for 24 hours and developed keratopathy. There was no difference in the histology, levels of corneal neurotrophins, and corneal nerve density between the retrobulbar PGS-TTX group and normal cornea. Conclusions: In the absence of topical toxicity or corneal exposure, PLA of the cornea per se does not cause keratitis. Translational Relevance: PLA of the cornea could be highly beneficial in acute and chronic painful corneal conditions.

Delivery of local anaesthetics by a self-assembled supramolecular system mimicking their interactions with a sodium channel.

Site-1 sodium channel blockers (S1SCBs) act as potent local anaesthetics, but they can cause severe systemic toxicity. Delivery systems can be used to reduce the toxicity, but the hydrophilicity of S1SCBs makes their encapsulation challenging. Here, we report a self-assembling delivery system for S1SCBs whose design is inspired by the specific interactions of S1SCBs with two peptide sequences on the sodium channel. Specifically, the peptides were modified with hydrophobic domains so that they could assemble into nanofibres that facilitated specific binding with the S1SCBs tetrodotoxin, saxitoxin and dicarbamoyl saxitoxin. Injection of S1SCB-carrying nanofibres at the sciatic nerves of rats led to prolonged nerve blockade and to reduced systemic toxicity, with benign local-tissue reaction. The strategy of mimicking a molecular binding site via supramolecular interactions may be applicable more broadly to the design of drug delivery systems for receptor-mediated drugs.

Enhancement of the Mechanical and Drug-Releasing Properties of Poloxamer 407 Hydrogels with Casein.

PURPOSE: Topical therapy of local disease (e.g. skin) is advantageous over oral therapy since there is less systemic drug distribution (so fewer side-effects), no first-pass effect, etc. However, patient compliance with topical therapy can be poor as it may require many applications a day and can last months. Here we propose a topical controlled release formulation with thermoresponsive gelation at body temperature and improved adhesiveness, making it easier to remain in contact with the body. METHODS: The formulation contains two excipients, poloxamer 407 (P407) and casein. Casein can modify the properties of the hydrogel through molecular entanglement. In addition, tissue reaction and drug release profile were evaluated. RESULTS: Changes in casein concentration affected adhesive strength, viscosity, mechanical properties and drug release, presumably by hydrophobic interactions between casein and P407. Two different concentrations of P407 were tested with two different concentrations of casein. Formulations containing 5% and 10% casein released 80% of model drug in 48 h, while formulations without casein released the same fraction in around 24 h hours. Formulations with 10% casein had almost twice the adhesive strength of those without casein. CONCLUSIONS: Addition of casein modified the mechanical properties and drug release rate of the hydrogel. There was no inflammation or injury after brief exposure in vivo.

Clinical implications of SARS-CoV-2 cycle threshold values in solid organ transplant recipients.

Detection of SARS-CoV-2 viral RNA by RT-PCR assays is the primary diagnostic test for COVID-19. Cycle threshold (CT ) values generated by some of these assays provide inversely proportional proxy measurements of viral load. The clinical implications of CT values are incompletely characterized, particularly in solid organ transplant (SOT) recipients. We conducted a retrospective chart review of 25 adult SOT recipients admitted to the Yale New Haven Health System between March 1 and May 15, 2020, analyzing 50 test results to investigate the clinical implications of SARS-CoV-2 CT values in this population. Initial CT values from upper respiratory tract samples were significantly higher in patients on tacrolimus, but were not associated with admission severity nor highest clinical acuity. Viral RNA was detected up to 38 days from symptom onset with a gradual increase in CT values over time. In five patients with serial testing, CT values <35.0 were detected >21 days after symptom onset in 4/5 and ≥27 days in 2/5, demonstrating prolonged RNA detection. These data describe SARS-CoV-2 viral dynamics in SOT patients and suggest that CT values may not be useful to predict COVID-19 severity in SOT patients. SARS-CoV-2 CT values may be more useful in informing infection prevention measures.

Education needed to improve antimicrobial use during end-of-life care of older adults with advanced cancer: A cross-sectional survey.

BACKGROUND: Antimicrobial use during end-of-life care of older adults with advanced cancer is prevalent. Factors influencing the decision to prescribe antimicrobials during end-of-life care are not well defined. AIM: To evaluate factors influencing medicine subspecialists to prescribe intravenous and oral antimicrobials during end-of-life care of older adults with advanced cancer to guide an educational intervention. DESIGN: 18-item single-center cross-sectional survey. SETTING/PARTICIPANTS: Inpatient medicine subspecialists in 2018. RESULTS: Of 186 subspecialists surveyed, 67 (36%) responded. Most considered withholding antimicrobials at the time of clinical deterioration during hospitalization (n = 54/67, 81%), viewed the initiation of additional intravenous antimicrobials as escalation of care (n = 44/67, 66%), and believed decision-making should involve patients or surrogates and providers (n = 64/67, 96%). Fifty-one percent (n = 30/59) of respondents who conducted advance care planning did not discuss antimicrobials. Barriers to discussing end-of-life antimicrobials included the potential to overwhelm patients or families, challenges of withdrawing antimicrobials, and insufficient training. CONCLUSIONS: Although the initiation of additional intravenous antimicrobials was viewed as escalation of care, antimicrobials were not routinely discussed during advance care planning. Educational interventions that promote recognition of antimicrobial-associated adverse events, incorporate antimicrobial use into advance care plans, and offer communication simulation training around the role of antimicrobials during end-of-life care are warranted.

Adverse Events and Healthcare Utilization Associated With Outpatient Parenteral Antimicrobial Therapy Among Older Versus Younger Adults.

Among older (n = 204) versus younger (n = 253) adults, there was no difference in adverse events (adjusted odds ratio [aOR] = 0.98; 95% confidence interval [CI] = 0.6-1.6) or healthcare utilization (incidence rate ratio = 1.09; 95% CI = 0.9-1.3) within 30 days after discontinuing outpatient parenteral antimicrobial therapy. Vancomycin (aOR = 1.92) and oxacillin (aOR = 3.12) were independently associated with adverse events.

Inconsistent Addiction Treatment for Patients Undergoing Cardiac Surgery for Injection Drug Use-associated Infective Endocarditis.

INTRODUCTION: Cases of surgical injection drug use-associated infective endocarditis (IDU-IE) are on the rise, amid the US opioid epidemic. We aimed to describe nature of perioperative addiction treatment for these patients. METHODS: This is a retrospective review of 56 surgical IDU-IE from 2011 to 2016 at a tertiary care center. Data collected included substances used, documented psychosocial consultations (social work or psychiatry), medications for addiction and evidence of enrollment in a drug rehabilitation program after discharge.Among patients with active drug use (ADU), we compared the 24-month survival of those who received comprehensive addiction treatment, defined as both psychosocial consultation and medications for opioid use disorder to that of those who received partial or no treatment. RESULTS: Out of 56 patients, 42 (75%, n = 56) received a psychosocial consultation, 23 (41.1%, n = 56) received medications for opioid use disorder and 15 (26.8% n = 56) attended a drug rehabilitation program.Forty-two patients had ADU. Among those, 20 (47.6%, n = 42) received comprehensive addiction treatment, while 28 (52.4%, n = 42) received partial or no treatment, and 10 (23.8%, n = 42) attended drug rehabilitation. Most patients with ADU who attended drug rehabilitation (9, 90%) had received comprehensive addiction treatment. All patients with ADU who received comprehensive addiction treatment were alive after 24-months, while 7 patients (25%, n = 28) who received partial or no treatment were not. CONCLUSION: Addiction treatment was inconsistent for surgical IDU-IE patients. Comprehensive addiction treatment predicted drug rehabilitation attendance, and was protective against 24-month mortality. Implementing protocols for comprehensive perioperative addiction treatment in IDU-IE patients is of the utmost importance.

Repurposing antimicrobial stewardship tools in the electronic medical record for the management of COVID-19 patients.

During the COVID-19 pandemic, the antimicrobial stewardship module in our electronic medical record was reconfigured for the management of COVID-19 patients. This change allowed our subspecialist providers to review charts quickly to optimize potential therapy and management during the patient surge.

Light-triggered release of conventional local anesthetics from a macromolecular prodrug for on-demand local anesthesia.

An on-demand anesthetic that would only take effect when needed and where the intensity of anesthesia could be easily adjustable according to patients' needs would be highly desirable. Here, we design and synthesize a macromolecular prodrug (P407-CM-T) in which the local anesthetic tetracaine (T) is attached to the polymer poloxamer 407 (P407) via a photo-cleavable coumarin linkage (CM). P407-CM-T solution is an injectable liquid at room temperature and gels near body temperature. The macromolecular prodrug has no anesthetic effect itself unless irradiated with a low-power blue light emitting diode (LED), resulting in local anesthesia. By adjusting the intensity and duration of irradiation, the anesthetic effect can be modulated. Local anesthesia can be repeatedly triggered.

Functionalized Multiarmed Polycaprolactones as Biocompatible Tissue Adhesives.

Existing tissue adhesives have a trade-off between adhesive strength and biocompatibility. Here, we report a series of biocompatible multiarmed polycaprolactones (PCL) as tissue adhesives that can be released from a hot glue gun and the length of each arm was kept at ∼2-3 kg mol-1 in all the polymers. The adhesion properties were dependent on the number of functionalized (N-hydroxysuccinimide ester (NHS), aldehyde (CHO), and isocyanate (NCO)) arms of the multiarmed polymers. The more arms, the higher the adhesion strength. For example, the adhesion strength in binding cut rat skin increased from 2.3 N cm-2 for 2PCL-NHS to 11.2 N cm-2 for 8-PCL-NHS. CHO- and NCO-modified 8PCL also had suitable adhesive properties. All the multiarmed polymers had minimal cytotoxicity in vitro and good biocompatibility in vivo, suggesting their potential as promising alternative surgical adhesives.

Increased Length of Stay Associated With Antibiotic Use in Older Adults With Advanced Cancer Transitioned to Comfort Measures.

BACKGROUND: Antibiotic use may increase hospital length of stay (LOS) among older patients with advanced cancer who are transitioned to comfort measures. METHODS: We studied a cohort of patients with advanced cancer aged ≥65 years who were transitioned to comfort measures during admission from July 1, 2014, through November 30, 2016. We evaluated the association between antibiotic exposure and LOS using a Poisson regression model adjusted for age, gender, cancer type, comorbidities, infection, and intensive care unit admission. RESULTS: Among 461 patients with advanced cancer, median age was 74 years (range: 65-99), 49.0% (n = 226) were female, and 20.6% (n = 95) had liquid tumors. Overall, 82.9% (n = 382) received ≥1 antibiotic and 64.6% (n = 298) had ≥1 infection diagnosis during hospitalization. Infection diagnoses commonly included sepsis (35%, n = 161/461), pneumonia (25%, n = 117/461), and urinary tract infection (14%, n = 66/461). Among those receiving antibiotics, the most common choices included vancomycin (79%, n = 300/382), cephalosporins (63%, n = 241/382), and penicillins (45%, n = 172/382). In a multivariable Poisson regression model, LOS was 34% longer (count ratio = 1.34, [95% confidence interval: 1.20-1.51]) among those exposed versus unexposed to antibiotics. CONCLUSIONS: Antibiotic use among patients with advanced cancer who are transitioned to comfort measures is associated with longer LOS. These data illustrate the importance of tradeoffs associated with antibiotic use, such as unintended increased LOS, when striving for goal-concordant care near the end of life.

Prolonged Duration Topical Corneal Anesthesia With the Cationic Lidocaine Derivative QX-314.

PURPOSE: Topical corneal local anesthetics are short acting and may impair corneal healing. In this study we compared corneal anesthesia and toxicity of topically applied N-ethyl lidocaine (QX-314) versus the conventional local anesthetic, proparacaine (PPC). METHODS: Various concentrations of QX-314 and 15 mM (0.5%) PPC were topically applied to rat corneas. Corneal anesthesia was assessed with a Cochet-Bonnet esthesiometer at predetermined time points. PC12 cells were exposed to the same solutions to assess cytotoxicity. Repeated topical corneal administration in rats was then used to assess for histologic evidence of toxicity. Finally, we created uniform corneal epithelial defects in rats and assessed the effect of repeated administration of these compounds on the defect healing rate. RESULTS: QX-314 (15 mM) and PPC (15 mM) caused similar total duration (114 ± 17 and 87 ± 16 minutes, respectively; P = 0.06) of anesthesia. The depth of anesthesia was similar between these low-dose groups at 15 minutes after application (1.8 ± 0.3- and 2.0 ± 0.8-cm filament lengths). QX-314 (100 mM) provided more prolonged corneal anesthesia (174 ± 13 minutes; P < 0.0001), with improved depth at 15 minutes (0.7 ± 0.3-cm filament length; P = 0.007). All tested concentrations of QX-314 demonstrated similar or less toxicity than 0.5% PPC. CONCLUSIONS: Topical administration of QX-314 is effective for corneal anesthesia and demonstrates no histologic signs of local toxicity in a rodent model. In higher concentrations, QX-314 provides more than twofold the duration of anesthetic effect than does 0.5% PPC. TRANSLATIONAL RELEVANCE: Our study reveals a clinically relevant compound providing prolonged duration topical corneal anesthesia.

Clinical Practice Guideline for the Management of Asymptomatic Bacteriuria: 2019 Update by the Infectious Diseases Society of America.

Asymptomatic bacteriuria (ASB) is a common finding in many populations, including healthy women and persons with underlying urologic abnormalities. The 2005 guideline from the Infectious Diseases Society of America recommended that ASB should be screened for and treated only in pregnant women or in an individual prior to undergoing invasive urologic procedures. Treatment was not recommended for healthy women; older women or men; or persons with diabetes, indwelling catheters, or spinal cord injury. The guideline did not address children and some adult populations, including patients with neutropenia, solid organ transplants, and nonurologic surgery. In the years since the publication of the guideline, further information relevant to ASB has become available. In addition, antimicrobial treatment of ASB has been recognized as an important contributor to inappropriate antimicrobial use, which promotes emergence of antimicrobial resistance. The current guideline updates the recommendations of the 2005 guideline, includes new recommendations for populations not previously addressed, and, where relevant, addresses the interpretation of nonlocalizing clinical symptoms in populations with a high prevalence of ASB.