Broad Spectrum Research Articles

Enhancing Stability and Investigating Target Attainment of Benzylpenicillin in Outpatient Parenteral Antimicrobial Therapy: Insights from In Vitro and In Vivo Evaluations.

Background/Objective: Narrow-spectrum beta-lactam antibiotics such as benzylpenicillin and flucloxacillin are increasingly used in outpatient parenteral antimicrobial therapy (OPAT) programs to mitigate the adverse effects associated with broad-spectrum antibiotics. These beta-lactams require continuous administration via portable infusion devices during OPAT. However, the use of benzylpenicillin in OPAT requires special consideration because of its limited stability at elevated temperatures. Methods: We tested the benzylpenicillin stability, pH, and degradation of products in elastomeric pumps at different concentrations in saline and in buffered solution containing sodium citrate during a prolonged storage and at high temperatures (seven days at 2-8 °C followed by 24 h at 37 °C). Additionally, drug concentrations during intermittent bolus infusion and during OPAT were determined in five patients. The concentrations and degradation products of benzylpenicillin were measured using liquid chromatography mass spectrometry (LC-MS/MS). Results: Unbuffered benzylpenicillin solutions that were already degraded during refrigerator storage and analyte concentration were not measurable after 8 days. The stability of the buffered solutions was acceptable at all three of the tested concentrations (97.6 ± 1.3%, 96.3 ± 0.8%, and 94.9 ± 1.1% for 10 Mio IU, 20 Mio IU, and 40 Mio IU of benzylpenicillin). The stability was influenced by benzylpenicillin concentration, and several breakdown products were identified. Benzylpenicillin concentrations were measured in five patients during OPAT and ranged from 7.2 to 60 mg/L. Conclusions: Benzylpenicillin buffered with sodium citrate is a safe and convenient option for use in continuous infusions during OPAT and should be favored over broad-spectrum antibiotics. Therapeutic drug monitoring data indicate sufficient to high plasma levels when patients received benzylpenicillin as continuous infusions.

Psychiatric disorders associated with fluoroquinolones: a pharmacovigilance analysis of the FDA adverse event reporting system database.

Fluoroquinolones are broad-spectrum antibiotics with significant antimicrobial activity. Despite their therapeutic benefits, they are associated with a range of adverse drug reactions (ADRs), particularly those affecting the central nervous system (CNS). This study aimed to analyze the psychiatric ADRs linked to fluoroquinolones using data from the FDA Adverse Event Reporting System (FAERS) database. A retrospective pharmacovigilance study was conducted using FAERS data from Q1 2004 to Q4 2023. The data processing phase involved the FDA-recommended deduplication method, and ADRs were classified according to Medical Dictionary for Regulatory Activities (MedDRA). Disproportionality analysis was performed using the reporting odds ratio (ROR), and statistical significance was assessed using the Chi-square test or Fisher's exact test. The study identified 84,777 reports associated with fluoroquinolones, with 359,480 Preferred Terms-annotated entries, 27,816 of these reports were psychiatric ADRs. Mood disorders were the most frequently reported, including anxiety, depression, and delirium, with some reports escalating to suicidal ideation and behaviors. The Standardized MedDRA Query classification system was used to categorize these ADRs into Depression, Suicide/self-injury, Psychosis and psychotic disorders, and Non-infectious encephalopathy/delirium. Ciprofloxacin was most frequently linked to depression and suicidal ideation, while moxifloxacin showed a robust correlation with delirium. The risk of psychiatric ADRs varied by age group, with affective disorders more prevalent in adults under 65 and psychosis and delirium in those over 65. Fluoroquinolones are associated with a range of psychiatric ADRs, with notable differences between the drugs in the class. The study highlights the need for caution in prescribing fluoroquinolones, particularly for patients with pre-existing mental health conditions or those in higher risk age groups. The findings also underscore the importance of considering age-specific preventive strategies when administering these antibiotics.

Impact of discontinuing routine fluoroquinolone prophylaxis in neutropenic allogeneic haematopoietic stem cell transplant recipients: an observational study.

Uncertainty exists as to the role of fluoroquinolone (FQ) prophylaxis for patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT) in the era of rising antibiotic resistance. We aimed to evaluate rates of bloodstream infections (BSI), resistance patterns and outcomes of patients after discontinuing routine FQ prophylaxis administration. All adult recipients of first HSCT from 2017 to 2020 were retrospectively included and classified according to time of HSCT as FQ group (HSCT January 2017-December 2018) or no FQ group (January 2019-December 2020). The primary outcome was Gram-negative (GN) BSI from day -7 to 30 days post-HSCT. The independent association between the study period and BSI was assessed using survival analysis, and adjusting for confounders. We included 254 patients, 130 (51%) and 124 (49%) in the FQ and no FQ groups, respectively. Compared to the FQ group, no FQ had significantly more GN BSI (21% versus 33%, P = 0.027) and the median time to first GN BSI was significantly shorter [4 (IQR 1-8) days versus 6 (1-10) days, P = 0.009]. Following adjustment, FQ prophylaxis remained associated with lower hazard for GN BSI (hazard ratio 0.57, 95% CI 0.34-0.93). Eighty-two GN BSI episodes had FQ susceptibility testing. More GN BSI episodes were FQ resistant in the FQ group (68.9% versus 41.6%, P = 0.021). No significant difference was found for 30-day mortality, time to first febrile neutropenia and time to first broad-spectrum antibiotics between the groups (P was not significant). FQ prophylaxis is associated with fewer GN BSI in the early post-HSCT period even in high FQ resistance settings, with FQ resistance rates reaching >60% following prophylaxis.

A tale of two old drugs tetracycline and salicylic acid with new perspectives—Coordination chemistry of their Co(II) and Ni(II) complexes, redox activity of Cu(II) complex, and molecular interactions

Extensive use of the broad-spectrum tetracycline antibiotics (TCs) has resulted their wide spread in the environment and drive new microecological balances, including the infamous antibiotic resistance. TCs require metal ions for their antibiotic activity and resistance via interactions with ribosome and tetracycline repressor TetR, respectively, at specific metal-binding sites. Moreover, the Lewis-acidic metal center(s) in metallo-TCs can interact with Lewis-basic moieties of many bioactive secondary metabolites, which in turn may alter their associated chemical equilibria and biological activities. Thus, it is ultimately important to reveal detailed coordination chemistry of metallo-TC complexes. Herein, we report (a) conclusive specific Co2+, Ni2+, and Cu2+-binding of TC revealed by paramagnetic 1H NMR, showing different conformations of the coordination and different metal-binding sites in solution and solid state, (b) significant metal-mediated activity of Cu-TC toward catechol oxidation with different mechanisms by air and H2O2 (i.e., mono- and di-nuclear pathways, respectively), (c) interactions of metallo-TCs with bioactive salicylic acid and its precursor benzoic acid, and (d) noticeable change of TC antibiotic activity by metal and salicylic acid. The results imply that TCs may play broad and versatile roles in maintaining certain equilibria in microecological environments in addition to their well-established antibiotic activity. We hope the results may foster further exploration of previously unknown metal-mediated activities of metallo-TC complexes and other metalloantibiotics.

Chronic Disseminated Candidiasis among Pediatric Cancer Patients: The Hidden Threat

Abstract Background Chronic disseminated Candidiasis (CDC) is a severe invasive fungal infection observed during neutrophil recovery in patients with acute leukemia treated with intensive chemotherapy. Clinical manifestations include persistent fever under broad-spectrum antibiotics and abdominal discomfort. HSC is characterized by the presence of nodular lesions in the liver, spleen, and other organs (lungs, kidneys, and skin) on radiological imaging. Methods The retrospective study was conducted from 2013 - 2022 including all pediatric hematological patients diagnosed with chronic disseminated candidiasis admitted and treated in Children’s Cancer Hospital Egypt (CCHE). Data included primary diagnosis, clinical presentation, microbiological, radiological, and treatment data. Results Three hundred fifty (350) pediatric cancer patients were diagnosed with candidemia. The median age was four years (4 months- 18 years). Chronic dissemination candidiasis (CDC) was reported in 30(9%) of our patients. The most affected organs were Liver (19 patients), spleen (13), renal (13), cautelous (13), brain (2) and retina (2). Candida tropicalis was the most common isolated spp. from blood/tissue culture (24 patients) followed by C. parapsilosis (3 patients). The primary diagnosis in patients with CDC was ALL (24 Patients) while (4 patients) has AML. CDC was developed on top of antifungal prophylaxis in 7 patients (24%): liposomal-amho B (3 patients), Micafungin (3 patients) and voriconazole (1 patient). Candida tropicalis was the most common isolated spp. from blood/tissue culture (80%). Steroid as treatment for CDC immune reconstitution syndrome done in around 50% of patients (Persistent fever with neutrophil recovery, absent progressive clinical/radiological findings). PET-CT was done in 10 patients with positive uptake in all cases, was helpful in resuming intensive chemotherapy in six patients despite persistent lesions in CT and was used to stop antifungal treatment despite positive radiological lesions in CT in three patients. The first line of treatment was echinocandin (53%) and liposomal ampho-B (46%) with overall mortality among CDC patients were 30%. Conclusion CDC is still a hidden threat among pediatric patients with still high mortality rate. Antifungal stewardship through screening and Rapid diagnosis using non-culture diagnostics are needed. PET scan is a helpful tool for diagnosis and response assessment and can add to treatment decision. Figure 1. Chronic Disseminated Candidiasis among Pediatric Cancer patients.

High Mortality Rates and Antimicrobial Resistance in Children with Invasive Bacterial Infections in a Tertiary Care Facility in West Africa

Abstract Background Childhood data on infection mortality and antimicrobial resistance in Sub-Saharan Africa are emerging but remain limited. The University of Maryland Center for Vaccine Development (CVD) and CVD-Mali have been conducting a prospective observational study at L’Hopital Gabriel Toure (HGT), a referral hospital in Bamako, Mali, since 2002 to identify causes of invasive bacterial infections (IBI) in children. These data have been used to initiate vaccination programs to decrease the burden of Haemophilus influenzae type b and Streptococcus pneumoniae. Additional demographic and antimicrobial susceptibility data have been collected since 2021, allowing for more detailed resistance and mortality analyses. Methods All children presenting to HGT are screened. Children ages 0-15 years with temperature of at least 39 degrees Celsius and/or suspicion of IBI are eligible. Eligible children have blood cultures collected with additional site-specific cultures when focal infection is suspected. Cultures are performed using the Bactec system; when positive, Gram staining, sub-culturing, and antimicrobial susceptibility testing (by disk diffusion using standard methods) are performed. Organisms thought to be contaminants are excluded. American type culture collection strains are utilized for quality control. Results Between 1/14/2021 and 9/14/2023, 28703 patients were screened. 2156 patients were included. 212 patients (10%) had 235 pathogens isolated. Gram positive organisms were most frequently isolated (N=112), followed by Gram negative Enterobacterales (N=81), non-Enterobacterales Gram negatives (N=36), and yeast (N=6). Staphylococcus aureus was the most frequently isolated Gram positive organism (59 bloodstream isolates, 2 joint isolates, 2 subcutaneous isolates) followed by S.pneumoniae (10 bloodstream isolates, 17 cerebrospinal fluid isolates, 1 joint isolate) and Enterococcus species (16 bloodstream isolates). Klebsiella pneumoniae (28 bloodstream isolates, 2 cerebrospinal fluid isolates) and Escherichia coli (18 bloodstream isolates, 3 cerebrospinal fluid isolates, 2 subcutaneous isolates) were the most frequently isolated Gram negative Enterobacterales, with Pseudomonas species most common among non-Enterobacterales Gram negative organisms (16 bloodstream isolates, 1 cerebrospinal fluid isolate). Mortality rates in both culture-positive and culture-negative patients were high (52% and 28%, respectively), with greater than 50% of deaths occurring within 48 hours in both groups. 88% of Gram negative Enterobacterales were ceftriaxone resistant or intermediate, with 56% ciprofloxacin resistant or intermediate; 55% of isolates were resistant or intermediate to both. 71% of isolates were gentamicin resistant. Imipenem resistance remained low, with 91% of isolates retaining sensitivity. 24% of S. aureus isolates were oxacillin resistant and 34% of isolates were resistant or intermediate to trimethoprim/sulfamethoxazole. 100% of S. aureus isolates tested (14/60) retained sensitivity to clindamycin. Only 54% of pneumococcal isolates had positive oxacillin screens, implying frequent penicillin resistance, and only 60% of enterococcal species were ampicillin sensitive, although 92% retained vancomycin sensitivity. Conclusion We found higher mortality rates in our study than in similar studies; the contribution of issues such as limited access to advanced supportive care and delay in presentation is an area for further study. The high frequency of multidrug-resistant organisms is alarming, suggesting an urgent need to investigate underlying contributing factors, increase access to affordable broad-spectrum antibiotics, and create robust antimicrobial stewardship programs.

Procalcitonin Level Monitoring in Antibiotic De-Escalation and Stewardship Program for Patients with Cancer and Febrile Neutropenia

Objective: Serial procalcitonin (PCT) monitoring has been adopted to supplement clinical judgement and help guide antibiotic therapy as part of antimicrobial stewardship programs. PCT levels peak 24 to 48 h after infection onset and decline with infection resolution. We explored the role of PCT as an infection biomarker for guiding antibiotic therapy in cancer patients hospitalized for febrile neutropenia. Design: Prospective randomized study. Methods: Patients were enrolled between October 2021 and August 2023 and received empiric intravenous broad-spectrum antibiotics (IVBSA) for at least 48 h. PCT was measured at baseline and 48–72 h after IVBSA initiation. PCT drop 48–72 h after IVBSA initiation was defined as a reduction of 30% from baseline or a PCT level < 0.25 ng/mL. De-escalation was defined as a switch from IVBSA to oral or simplified once-daily IV therapy. Results: Of the 89 patients with available PCT levels, 53 (60%) had a PCT drop, most of whom (79%) underwent IVBSA de-escalation. Compared with patients without a PCT drop, patients with a PCT drop had a higher de-escalation rate at 72 h (71% vs. 45%; p = 0.003) and a shorter median antibiotic duration (55 h vs. 98 h; p = 0.004). Patients with bacteremia had a significantly higher median PCT level than those without bacteremia (2.35 ng/mL vs. 0.370 ng/mL, p = 0.013). Conclusions: In patients with cancer and febrile neutropenia, a PCT drop was associated with earlier therapy de-escalation and shorter antibiotic duration. PCT monitoring may be useful in antimicrobial stewardship initiatives in this patient population. Clinical trials identifier: NCT04983901.

"Explosive" CaCO3 microcapsules driven by EDTA combined with a "signal booster" semiconductor Zn0.995Ce0.005O SERS substrate for ultra-sensitive SERS detection of chloramphenicol

BackgroundChloramphenicol (CAP) is a broad-spectrum antibiotic, and its continuous use in human medicine, livestock has resulted disturbances in ecosystem stability. The complex background and low concentration of CAP in aquatic environments present significant scientific challenges for its sensitive detection. Currently detection techniques such as high-performance liquid chromatography (HPLC) and gas chromatography-mass spectrometry (GC-MS) are hindered by their complex procedures and high costs. Surface-enhanced Raman spectroscopy (SERS), due to its unique ability for fingerprint recognition, has emerged as a powerful tool for analysis and detection. However, it is often limited by the low kurtosis expression of the target. ResultThe water-soluble explosive polyethylenimide grafted calcium carbonate (PEI@CaCO3) microcapsule was utilized to encapsulate the signal probe Ag@4-NTP and combine it with a semiconductor SERS substrate Zn0.995Ce0.005O, enabling ultra-sensitive detection of CAP through a signal attenuation strategy. Moreover, magnetic molecularly imprinted polymers (MMIP) and nucleic acid aptamers were employed as capture probes for achieving rapid and direct magnetic separation, followed by layer-by-layer assembly to construct the sensor probe. In the presence of CAP, the aptamers and rMMIPs selectively recognized the target, forming a PEI@CaCO3@Ag@4-NTP@Apt@CAP@rMMIPs "sandwich" structure (Microcapsule@Apt@rMMIPs). After multiple magnetic separations, the "igniter" EDTA solution was added, causing the CaCO3 capsules to rapidly "explode" and release a significant amount of Ag@4-NTP. This was then applied to the "signal booster" semiconductor SERS substrate. Under optimal conditions, this method exhibited a detection range of 1.0 × 10−5 M to 1.0 × 10−15 M, with a detection limit of 6.84 × 10−16 M. SignificantThe unite of magnetic MIP and nucleic acid aptamer to form a “sandwich” structure, in combination with a semiconductor SERS substrate, not only enhances the sensor's sensitivity but also offers significant economic advantages. Moreover, this innovative technology holds great promise for accurate and highly sensitive detection of pollutants in complex environments.

Antibiotic spectrum coverage scoring as a potential metric for evaluating the antimicrobial stewardship team activity: a single-center study.

Days of antibiotic spectrum coverage (days of ASC: DASC) is a metric for antibiotic usage calculated by ASC scores for spectrum and addresses limitations of days of therapy (DOT), which does not include spectrum. This study aims to investigate whether ASC-related metrics offer different aspects compared to aggregated DOT for all antibiotics (DOTtotal) and to assess their correlation in evaluating the impact of antimicrobial stewardship team (AST) programs. Retrospective. A single center within an 845-bed hospital. Trends in DOTtotal, DASC, and the DASC/DOT ratio, representing the average spectrum coverage per therapy day, were analyzed pre- and post-AST programs (April 2018) from January 2015 to December 2023, using interrupted time series analysis. Independent of the DASC/DOT, we also advocated ASC-stratified DOT (ASDOT), which facilitates comprehensive evaluation of DOT across ASC scores of <6, 6-10, and >10, representing narrow-, intermediate-, and broad-spectrum antibiotics. Among inpatients, AST programs significantly moderated the increasing trends of these metrics. Specifically, although the rates of increase in DOTtotal and DASC were slowed or plateaued, the DASC/DOT ratio decreased (P < 0.001). ASDOT metrics revealed a decrease and subsequent plateau in DOTtotal for the broad- and intermediate-spectrum antibiotics, with an increase observed for the narrow-spectrum antibiotics (P < 0.001 for each). DASC did not provide additional insights in the outpatient's population. The study demonstrates that ASC-related metrics may yield different and useful conclusions about the effectiveness of AST programs for inpatients.

Antibiotic Appropriateness for Urinary Tract Infections in Children.

We examined local prescribing patterns across the entire treatment course for children treated for uncomplicated urinary tract infection (UTI) to determine opportunities for antibiotic stewardship initiatives. We conducted a retrospective review of emergency department and inpatient encounters for febrile and afebrile UTI in a children's hospital from 2021 to 2022. An antibiotic spectrum ranking was established, and providers' choices were assessed for appropriateness on the basis of the individuals' urine culture (UCx). Groups were stratified by fever presence and compared using χ2, Fisher's exact, and Mann-Whitney U tests. Of 172 encounters (83% emergency department), 99 (58%) had a positive UCx. Eighty (80%) grew Escherichia coli, with 67 (84%) being susceptible to cefazolin (minimum inhibitory concentration ≤16 mg/L). There were 229 antibiotic regimens and 39 (17%) were appropriate. Inappropriate antibiotic choices included unnecessary use of broad-spectrum antibiotics and misdiagnosed UTI. Grouping by encounter, at least 1 dose of a third cephalosporin was given in 51% of encounters, and 80% of these received it unnecessarily because of UTI misdiagnosis or suitability of a narrower-spectrum antibiotic. The median prescribed antibiotic duration was 7 days (interquartile range 7-10). Of 73 encounters with UCx growing mixed flora or a nonuropathogen, only 29 (40%) had antibiotics discontinued. Confirmed UTI was associated with fever and nitrite positivity. Our study revealed high prevalence of inappropriate antibiotics, particularly unnecessary prescribing of third cephalosporin, prescriptions not supported by laboratory data, and prolonged treatment courses. Our results identify factors that can be used to support UTI treatment pathways and ensure antibiotic stewardship.

Discovery of highly potent triazole derivatives with broad-spectrum antifungal activity based on Iodiconazole

The widespread use of broad-spectrum antibiotics, the growing number of immunocompromised individuals, and the emergence of drug-resistant strains have resulted in the increasing incidence and mortality of invasive fungal infections. Azole drugs are the primary treatment for invasive fungal infections, and Iodiconazole is a potent azole drug with strong antifungal activity, but its stability is poor. In order to improve stability, a series of triazole compounds containing ethynyl group were designed and synthesized. Most of the compounds showed strong inhibitory activity against pathogenic fungi, among which compound 20l showed excellent inhibitory activity against pathogenic fungi and drug-resistant fungi. Importantly, and the stability of 20l (T1/2 = 30.2 min) was obviously improved compared with Iodiconazole (T1/2 = 4.39 min). In addition, the preferred compound 20l can prevent fungal phase transition and the formation of fungal biofilm, and show satisfactory fungicidal activity. In addition, the compound 20l was almost non-toxic to mammalian HUVEC cell and 293T cell. In vivo pharmacokinetic studies showed that 20l had acceptable pharmacokinetic properties. These results strongly demonstrate that compound 20l was worth further investigation as a potential antifungal inhibitor.

Umbilical Amniotic Tissue Graft as an Alternative Approach for Eyelid Reconstruction After Necrotizing Fasciitis Debridement

A 54-year-old female with myelodysplastic syndrome on chemotherapy presented with 10 days of periocular erythema and edema worsening on oral antibiotics. Computed Tomography scan showed periorbital soft tissue swelling without postseptal extension or abscess. Intravenous broad-spectrum antibiotics were administered. However, she developed necrosis of the upper eyelid requiring aggressive debridement. Nine days after debridement, the defect measuring 5.5 × 3 cm was covered using an umbilical amniotic tissue graft (AmnioGuard, BioTissue, Miami, FL). At postoperative week 4, 5-fluorouracil was injected to prevent the shortening of anterior lamella. At postoperative week 20, the graft had dissolved and been replaced by regenerated skin. Final eyelid exam demonstrated normal eyelid elevation and minimal lagophthalmos. Herein, we present a case of umbilical amniotic membrane as a substrate graft to support the healing of the eyelid defect by secondary intention.

Empiric gram-negative antibiotics usage among critically ill patients across 13 ICUs of Nepal: A retrospective cohort study

Background This study aims to investigate the associations between patient characteristics and the receipt of empiric broad-spectrum gram-negative antimicrobials among adult patients admitted to ICUs in Nepal. Methods A retrospective cohort study was conducted in 13 ICUs in Nepal between January 1st, 2020, and December 31st, 2022. Empiric antibiotic use was defined as receiving gram-negative antibiotics within the first two days of ICU admission without evidence of infection from culture. Patient characteristics between patients receiving narrow-spectrum antibiotics and broad-spectrum gram-negative antibiotics were compared. Continuous variables were compared using mean and standard deviation, with mean differences and 95% confidence intervals calculated. Categorical variables were compared using the chi-square test. A multi-level multivariable regression model assessed the relationship between selected variables and broad-spectrum antibiotic usage, treating admitting ICU as a random factor. Results Among 12,349 eligible patients, 8720 (70.6%) received Empiric gram-negative antibiotics. Of those, 3240 (37.15%) received empiric narrow-spectrum gram-negative antibiotics, and 5480 (62.8%) received Empiric broad-spectrum gram-negative antibiotics. Patients receiving broad-spectrum gram-negative antibiotics were older (57.4 vs 53.8 yrs); had higher mean heart rates (97.3 vs 89.5 bpm), respiratory rates (24 vs 21.9), a fraction of inspired oxygen ( 50% vs 40%), blood sugar levels (163.4 vs 153.9 mg/dl), total leucocyte counts (12,685 vs 10,647 cells/cu mm) and serum creatinine (2.06 vs 1.03 umol/l) compared to narrow spectrum antibiotics. Similarly, patients receiving broad-spectrum gram-negative antibiotics had lower systolic blood pressure (122.6 vs 126.5 mm Hg), partial pressure of oxygen (96.7 vs 105.3), and pH ( 7.33 vs 7.36) compared to narrow-spectrum antibiotics. On multivariable regression; patients with readmission, cardiac support, and mechanical ventilation were more likely to receive broad-spectrum antibiotics. Conclusion The rate of empiric broad-spectrum gram-negative antibiotics usage in intensive care units is significantly high and associated with features of increased severity of illness.

Excitation and manipulation of super cavity solitons in multi-stable passive Kerr resonators

We report on the theoretical analysis as well as the numerical simulations about the nonlinear dynamics of cavity solitons in a passive Kerr resonator operating in the multistable regime under the condition of a sufficiently strong pump. In this regime, the adjacent tilted cavity resonances might overlap, thus leading to the co-existence of combinatory states of temporal cavity solitons and the extended modulation instability patterns. The cavity in the regime of multistablity may sustain distinct families of cavity solitons, vividly termed as super cavity solitons with much higher intensity and broader spectra if compared with those in the conventional bi-stable regime. The description of such complex cavity dynamics in the multstable regime requires either the infinite-dimensional Ikeda map, or the derived mean-field coupled Lugiato-Lefever equations by involving multiple contributing cavity resonances. With the latter model, we revealed the existence of different orders of super cavity solitons, whose stationary solutions were obtained by using the Newton-Raphson algorithm. Along this line, with the continuation calculation, we have plotted the Hopf / saddle-node bifurcation curves, thus identifying the existing map of the stable and breathing (super) cavity solitons. With this defined parameter space, we have proposed an efficient method to excite and switch the super cavity solitons by adding an appropriate intensity (or phase) perturbation on the pump. Such deterministic cavity soliton manipulation technique is demonstrated to underpin the multi-level coding, which may enable the large capacity all-optical buffering based on the passive fiber ring cavities.

Broad-Spectrum Engineered Multivalent Nanobodies Against SARS-CoV-1/2.

SARS-CoV-2 Omicron sublineages escape most preclinical/clinical neutralizing antibodies in development, suggesting that previously employed antibody screening strategies are not well suited to counteract the rapid mutation of SARS-CoV-2. Therefore, there is an urgent need to screen better broad-spectrum neutralizing antibody. In this study, a comprehensive approach to design broad-spectrum inhibitors against both SARS-CoV-1 and SARS-CoV-2 by leveraging the structural diversity of nanobodies is proposed. This includes the de novo design of a fully human nanobody library and the camel immunization-based nanobody library, both targeting conserved epitopes, as well as the development of multivalent nanobodies that bind nonoverlapping epitopes. The results show that trivale B11-E8-F3, three nanobodies joinedtandemly in trivalent form, have the broadest spectrum and efficient neutralization activity, which spans from SARS-CoV-1 to SARS-CoV-2 variants. It is also demonstrated that B11-E8-F3 has a very prominent preventive and some therapeutic effect in animal models of three authentic viruses. Therefore, B11-E8-F3 has an outstanding advantage in preventing SARS-CoV-1/SARS-CoV-2 infections, especially in immunocompromised populations or elderly people with high-risk comorbidities.

Early changes in the gut microbiome among HIV-infected Individuals in Uganda initiating daily TMP/SMX.

Daily cotrimoxazole (TMP/SXT) prophylaxis is part of the HIV treatment package for all new HIV-infected individuals in Uganda. Although this treatment has shown reduced morbidity and mortality in HIV, it remains controversial due to its contribution to developing antibiotic-resistant bacteria. Moreover, the effects of daily use of a broad-spectrum antibiotic on the gut microbiome remain unknown. To study the early effects, we analysed shotgun metagenome sequence data from stool samples of five newly HIV-infected individuals initiating TMP/SXT prophylaxis longitudinally for the first 30 days of treatment. Using shotgun metagenomics sequencing, we generated both taxonomic and functional profiles from each patient and compared gut microbial changes Pre-TMP/SXT and post-TMP/SXT on Day 5, Day 14, and Day 30. Daily TMP/SXT prophylaxis resulted in a shift characterised by an enrichment of Prevetollea and Ruminococcus genera members and the depletion of Lactococcus and Bacteroides genera members. Furthermore, these microbial shifts were associated with changes in the functional profile revealed by a differential abundance of pathways of amino acid metabolism, carbohydrate metabolism, and nucleotide biosynthesis linked to members of the Bacteroidaceae and Enterobacteriaceae families. TMP/SXT daily prophylaxis in HIV-infected individuals is associated with dramatic changes in microbial composition and functional profiles; however, other factors such as Age, Gender, HIV clinical stage, and ART regiment are at play. Further investigation is needed to examine the implication of these shifts on clinical management and outcomes among HIV patients.

7964 Manipulation of the Gut Microbiome Using Antibiotics Is Associated With Sex-Specific Reductions in Systemic Testosterone Levels in Rats

Abstract Disclosure: G. Parodi: None. G. Leite: None. W. Morales: None. S.R. Weitsman: None. G.M. Barlow: None. M. Sanchez: None. M. Pimentel: None. M. Villanueva-Millan: None. M. Pimentel: None. R. Mathur: None. The gut microbiome has impacts on metabolic endocrine and reproductive functions. It is known that specific bacteria can impact host metabolism by synthesizing, secreting, and/or metabolizing sex-related hormones. However, the impacts of gut bacterial biosynthesis and/or metabolism of steroids on host metabolism and reproduction have not been fully addressed. In this study we challenged the gut microbiome of wild-type male and female rats with broad-spectrum antibiotics and examined the effects on circulating testosterone levels. Methods: Male (M) and female (F) Sprague-Dawley rats (8 weeks old) were housed with phytoestrogen-free bedding and received a phytoestrogen-free diet with water from glass bottles. Rats were given a combination of vancomycin (0.5g/L), ampicillin (1g/L), neomycin (1g/L), and metronidazole (1g/L) in their water for 8 days, and then returned to normal drinking water for another 13 days. Control rats were given normal water throughout the study. Serum and stool samples were collected before the start of antibiotics (baseline), on day 8 of antibiotics (AbxD8), and at 13 days post-removal of antibiotics (PAbxD13). Stool total DNA was extracted with the MagAttract PowerSoil DNA KF kit and quantified on a Qubit. Circulating testosterone levels were analyzed on a Luminex platform. Paired-ANOVA test was used to determine changes in testosterone levels in each group over time. Results: A total of 31 rats (M=16, F=15) received antibiotics, and 28 (M=14, F=14) were controls. Antibiotic exposure resulted in significant decreases in total stool DNA quantity in both male and female exposed rats relative to controls on AbxD8 (P&amp;lt;0.0001), which returned to baseline levels by PAbxD13. Antibiotic exposed male rats had a continuous decrease in testosterone levels throughout the timepoints collected (baseline: 5.78±2.74 ng/mL, AbxD8: 3.11±2.46 ng/mL, PAbxD13: 2.55±1.80 ng/mL, P=0.0027), however, in control male rats, circulating testosterone levels remained stable throughout the timepoints analyzed (baseline: 3.81±1.73 ng/mL, AbxD8: 3.72±1.12 ng/mL, PAbxD13: 3.92±3.38 ng/mL, P=0.49). There was no effect on circulating testosterone levels in female rats, with both groups, control and exposed, following the same cyclical pattern throughout the timepoints analyzed. Conclusions: Antibiotic depletion of the gut microbiome is associated with changes in systemic levels of testosterone in rats. These changes are sex-specific, and only detected in males. These results suggest a potential involvement of the gut microbiome in testosterone metabolism that is sex-specific. Presentation: 6/1/2024

Resistance Pattern of Acinetobacter baumannii in Hospitalized Patients

Background: One of the most prevalent bacteria in nosocomial infections is Acinetobacter baumannii. Misuse of antibiotics has resulted in an increase in A. baumannii multidrug-resistant (MDR) strain resistance. To assess the resistant gene pattern of MDR A. baumannii, empirical antibiotic therapy is required. In order to do this, the current study used a genotypic diagnostic technique to assess the resistance gene pattern of MDR A. baumannii that was collected from hospitalized patients. A. baumannii has resistance mechanisms against broad-spectrum antibiotics, including β-lactamases, efflux pumps, and aminoglycosides, altering targets, permeability shifts, and enzyme modifications. Efforts have been made to target plant-derived compounds and a combination of antibiotics and phytocompounds to circumvent resistance mechanisms. Many studies have been conducted on plant extract-synthesised nanoparticles. Additionally, we projected contemporary techniques to investigate insights into the mechanisms of action of antibiotics, such as multi-omics analysis. The data implied that A. baumannii putative antibiotic pathways would result in a different approach to treating A. baumannii infections. One of these resilient pathogens is A. baumannii, which is becoming more common in hospitals, resistant to treatment, and linked to higher death rates. Notwithstanding its clinical importance, little is known about this pathogen's behavior outside of hospitals. Additionally, unknown are its virulence factors. Consequently, our goal in this review is to provide light on the most recent findings about the ecological niches, microbiological characteristics, and antibiotic resistance profiles of A. baumannii. According to recent research, this bacterium is found in an increasing number of environmental niches, such as soils, treatment plants, and rivers.

8227 Complex Case of Myxedema Coma Complicated by Cardiac Arrest in a Geriatric Patient with Multiple Comorbidities

Abstract Disclosure: M. Parvez: None. L. Makahleh: None. S. Nagpal: None. A. Kavarthapu: None. V. Vedantam: None. Introduction: This case report details a rare instance of cardiac arrest in a patient with myxedema coma, a severe form of hypothyroidism. It highlights the diagnostic and therapeutic challenges in managing such complex endocrine emergencies. Case Presentation: A 70-year-old female with a history of hypothyroidism, type 2 diabetes, atrial fibrillation, pacemaker implantation, and COPD presented with a 3 day history of progressive lethargy and weakness. EMS found her with critically low blood glucose level of 20. History and Examination revealed non-compliance with thyroid medication and myxedematous features including moon-like facies, periorbital edema, generalized edema, elevated JVP, and cold extremities with sluggish capillary refill. In the ER, she was hypotensive, labs showed a significantly elevated TSH level of 30.55 (0.45-4.5), free T3 level of 1.2 (2.3-4.2), free T4 level of 1.12 (0.93-1.70), high lactate, metabolic acidosis, renal impairment, and liver enzyme elevation. These findings, coupled with the clinical presentation, led to the diagnosis of myxedema coma. The patient's critical state was further complicated by distributive shock, shock liver and oliguric AKI. Management included sodium bicarbonate infusion for severe acidosis, IV hydrocortisone, IV levothyroxine, and broad-spectrum antibiotics. Amiodarone was discontinued due to its potential contribution to acute liver injury and hypothyroidism. Despite interventions, she developed acute respiratory failure, requiring intubation and norepinephrine for low mean arterial pressure. Her renal function improved with pressor support, and her lactic acidosis resolved. She recovered quickly and was subsequently extubated. After stabilization, she was switched to oral levothyroxine and discharged. Shortly after discharge, she returned again with generalized weakness, confusion, and dysuria. ER evaluation revealed lethargy, hypotension, hypoglycemia, severe metabolic acidosis, and a UTI. She tested positive for Influenza. While in the ER, she had cardiac arrest, presenting with agonal breathing and PEA. CPR was initiated, achieving ROSC after two rounds and one dose of epinephrine. She was treated again with IV levothyroxine, and IV antibiotics. She recovered well and was discharged to rehab facility with re-education on compliance. Conclusion: This case exemplifies the complexity and challenges in managing a geriatric patient with multiple comorbidities, particularly in the context of myxedema coma. The intricate interplay of endocrine, cardiovascular, respiratory, and infectious complications necessitated a multifaceted and dynamic therapeutic approach. This case underscores the importance of compliance, vigilant monitoring, prompt recognition of complicating factors, and the need for a coordinated multidisciplinary approach in managing similar cases. Presentation: 6/2/2024

7964 Manipulation of the Gut Microbiome Using Antibiotics Is Associated With Sex-Specific Reductions in Systemic Testosterone Levels in Rats

Abstract Disclosure: G. Parodi: None. G. Leite: None. W. Morales: None. S.R. Weitsman: None. G.M. Barlow: None. M. Sanchez: None. M. Pimentel: None. M. Villanueva-Millan: None. M. Pimentel: None. R. Mathur: None. The gut microbiome has impacts on metabolic endocrine and reproductive functions. It is known that specific bacteria can impact host metabolism by synthesizing, secreting, and/or metabolizing sex-related hormones. However, the impacts of gut bacterial biosynthesis and/or metabolism of steroids on host metabolism and reproduction have not been fully addressed. In this study we challenged the gut microbiome of wild-type male and female rats with broad-spectrum antibiotics and examined the effects on circulating testosterone levels. Methods: Male (M) and female (F) Sprague-Dawley rats (8 weeks old) were housed with phytoestrogen-free bedding and received a phytoestrogen-free diet with water from glass bottles. Rats were given a combination of vancomycin (0.5g/L), ampicillin (1g/L), neomycin (1g/L), and metronidazole (1g/L) in their water for 8 days, and then returned to normal drinking water for another 13 days. Control rats were given normal water throughout the study. Serum and stool samples were collected before the start of antibiotics (baseline), on day 8 of antibiotics (AbxD8), and at 13 days post-removal of antibiotics (PAbxD13). Stool total DNA was extracted with the MagAttract PowerSoil DNA KF kit and quantified on a Qubit. Circulating testosterone levels were analyzed on a Luminex platform. Paired-ANOVA test was used to determine changes in testosterone levels in each group over time. Results: A total of 31 rats (M=16, F=15) received antibiotics, and 28 (M=14, F=14) were controls. Antibiotic exposure resulted in significant decreases in total stool DNA quantity in both male and female exposed rats relative to controls on AbxD8 (P&amp;lt;0.0001), which returned to baseline levels by PAbxD13. Antibiotic exposed male rats had a continuous decrease in testosterone levels throughout the timepoints collected (baseline: 5.78±2.74 ng/mL, AbxD8: 3.11±2.46 ng/mL, PAbxD13: 2.55±1.80 ng/mL, P=0.0027), however, in control male rats, circulating testosterone levels remained stable throughout the timepoints analyzed (baseline: 3.81±1.73 ng/mL, AbxD8: 3.72±1.12 ng/mL, PAbxD13: 3.92±3.38 ng/mL, P=0.49). There was no effect on circulating testosterone levels in female rats, with both groups, control and exposed, following the same cyclical pattern throughout the timepoints analyzed. Conclusions: Antibiotic depletion of the gut microbiome is associated with changes in systemic levels of testosterone in rats. These changes are sex-specific, and only detected in males. These results suggest a potential involvement of the gut microbiome in testosterone metabolism that is sex-specific. Presentation: 6/1/2024