Search

Objective To characterize the referral patterns and characteristics of men presenting for infertility evaluation using data obtained from the Andrology Research Consortium. Design Standardized male infertility questionnaire. Setting Male infertility centers. Patient(s) Men presenting for fertility evaluation. Intervention(s) Not applicable. Main Outcome Measure(s) Demographic, infertility history, and referral data. Result(s) The questionnaires were completed by 4,287 men, with a mean male age of 40 years ± 7.4 years and female partners age of 37 years ± 4.9 years. Most were Caucasian (54%) with other races being less commonly represented (Asian 18.6%, and African American 5.5%). The majority (59.7%) were referred by a reproductive gynecologist, 19.4% were referred by their primary care physician, 4.2% were self-referred, and 621 (14.5%) were referred by “other.” Before the male infertility investigation, 12.1% of couples had undergone intrauterine insemination, and 4.9% of couples had undergone in vitro fertilization (up to six cycles). Among the male participants, 0.9% reported using finasteride (5α-reductase inhibitor) at a dose used for androgenic alopecia, and 1.6% reported exogenous testosterone use. Conclusion(s) This broad North American patient survey shows that reproductive gynecologists are the de facto gateway for most male infertility referrals, with most men being assessed in the male infertility service being referred by reproductive endocrinologists. Some of the couples with apparent male factor infertility are treated with assisted reproductive technologies before a male factor investigation. The survey also identified potentially reversible causes for the male infertility including lifestyle factors such as testosterone and 5α-reductase inhibitor use.

Infectious complications are a major cause of morbidity and mortality in patients undergoing solid organ or stem cell transplantation. Over the past years, advances in immunology and molecular biology have greatly contributed to a better understanding of the pathogenesis of opportunistic infections in the immunocompromised host. The lifelong immunosuppression required by the transplant recipients together with the limitations of the current anti-infective agents makes strategies able to stimulate immune response attractive aids to conventional treatment options. Among the immunotherapeutic strategies studied in transplant recipients aiming to enhance the adaptive immune response are the adoptive transfer of T lymphocytes and the use of cytokines such as granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF), or interferon-gamma (IFN-γ). While some encouraging results in in vitro and in vivo studies exist, currently available clinical evidence on the use of these approaches is limited to allow firm recommendations.

This paper reviews recent advances in three selected areas of pediatric invasive candidiasis: epidemiology, diagnosis, and treatment. Although the epidemiological trends of pediatric invasive candidiasis illustrate a declining incidence, this infection still carries a heavy burden of mortality and morbidity that warrants a high index of clinical suspicion, the need for rapid diagnostic systems, and the early initiation of antifungal therapy. The development of non-culture-based technologies, such as the T2Candida system and (1→3)-β-d-glucan detection assay, offers the potential for early laboratory detection of candidemia and CNS candidiasis, respectively. Among the complications of disseminated candidiasis in infants and children, hematogenous disseminated Candida meningoencephalitis (HCME) is an important cause of neurological morbidity. Detection of (1→3)-β-d-glucan in cerebrospinal fluid serves as an early diagnostic indicator and an important biomarker of therapeutic response. The recently reported pharmacokinetic data of liposomal amphotericin B in children demonstrate dose⁻exposure relationships similar to those in adults. The recently completed randomized clinical trial of micafungin versus deoxycholate amphotericin B in the treatment of neonatal candidemia provides further safety data for an echinocandin in this clinical setting.

Contains fulltext : 205145.pdf (Publisher’s version ) (Open Access) Since its introduction in the 1990s, liposomal amphotericin B (LAmB) continues to be an important agent for the treatment of invasive fungal diseases caused by a wide variety of yeasts and molds. This liposomal formulation was developed to improve the tolerability of intravenous amphotericin B, while optimizing its clinical efficacy. Since then, numerous clinical studies have been conducted, collecting a comprehensive body of evidence on its efficacy, safety, and tolerability in the preclinical and clinical setting. Nevertheless, insights into the pharmacokinetics and pharmacodynamics of LAmB continue to evolve and can be utilized to develop strategies that optimize efficacy while maintaining the compound's safety. In this article, we review the clinical pharmacokinetics, pharmacodynamics, safety, and efficacy of LAmB in a wide variety of patient populations and in different indications, and provide an assessment of areas with a need for further clinical research.

Contains fulltext : 205184.pdf (Publisher’s version ) (Open Access) The improved safety profile and antifungal efficacy of liposomal amphotericin B (LAmB) compared to conventional amphotericin B deoxycholate (DAmB) is due to several factors including, its chemical composition, rigorous manufacturing standards, and ability to target and transit through the fungal cell wall. Numerous preclinical studies have shown that LAmB administered intravenously distributes to tissues frequently infected by fungi at levels above the minimum inhibitory concentration (MIC) for many fungi. These concentrations can be maintained from one day to a few weeks, depending upon the tissue. Tissue accumulation is dose-dependent with drug clearance occurring most rapidly from the brain and slowest from the liver and spleen. LAmB localizes in lung epithelial lining fluid, within liver and splenic macrophages and in kidney distal tubules. LAmB has been used successfully in therapeutic and prophylactic animal models to treat many different fungal pathogens, significantly increasing survival and reducing tissue fungal burden.

BackgroundMucormycosis is a difficult to diagnose rare disease with high morbidity and mortality. Diagnosis is often delayed, and disease tends to progress rapidly. Urgent surgical and medical intervention is lifesaving. Guidance on the complex multidisciplinary management has potential to improve prognosis, but approaches differ between health care settings.MethodsFrom January 2018, authors from 33 countries in all United Nations regions analysed the published evidence on mucormycosis management and provided consensus recommendations addressing differences between the regions of the world as part of the “One World One Guideline” initiative of the European Confederation of Medical Mycology (ECMM). The author group based in 17 time zones, relied on electronic media including video tutorial on methodology, and central document repository with several daily updates.FindingsSigns and symptoms of mucormycosis depend on organ patterns and underlying conditions. Diagnostic management does not differ greatly between world regions. Upon suspicion of mucormycosis appropriate imaging is strongly recommended to document extent of disease and is followed by strongly recommended surgical intervention. First-line treatment with high-dose liposomal amphotericin B is strongly recommended, while intravenous isavuconazole and intravenous or delayed release tablet posaconazole are recommended with moderate strength. Both triazoles are strongly recommended salvage treatments. Amphotericin B deoxycholate is recommended against, because of substantial toxicity, but may be the only option in resource limited settings.InterpretationManagement of mucormycosis depends on recognising disease patterns and on early diagnosis. Limited availability of contemporary treatments burdens patients in low and middle income settings. Areas of uncertainty were identified and future research directions specified.

Infections of the central nervous system (ICNS) contribute significantly to morbidity and mortality in patients receiving solid organ and stem cell transplants. The risk for ICNS is influenced by multiple factors, including the organ transplanted, type and degree of immunosuppression, post-transplant adverse events, as well as donor characteristics. These infections may be classified by anatomic location – intracranial, spinal, and paraspinal – as well as by time of onset. The early post-transplant period is generally defined as the first month after transplantation. Because the major effects of exogenous immunosuppression are not yet apparent, the causes of ICNS in this time period are those derived from either the donor or recipient and infectious complications of the transplant and hospitalization. In the period 1 to 6 months after transplantation, also known as the intermediate time period, the composition of the pathogens changes. Opportunistic infections prevail; however, there is geographic variation given the inter-institution variation in immunosuppressive and antimicrobial prophylaxis strategies. During the late time period, generally defined as more than 6 months after transplantation, most patients with good graft function receive stable and reduced levels of immunosuppression while continuing on some form of antimicrobial prophylaxis. The pathogens that cause CNS infection tend to more closely resemble the community-acquired pathogens responsible for these infections in immunocompetent hosts.

Author(s): Arrieta, Antonio C; Sung, Lillian; Bradley, John S; Zwaan, C Michel; Gates, Davis; Waskin, Hetty; Carmelitano, Patricia; Groll, Andreas H; Lehrnbecher, Thomas; Mangin, Eric; Joshi, Amita; Kartsonis, Nicholas A; Walsh, Thomas J; Paschke, Amanda | Abstract: BACKGROUND:Posaconazole (POS) is a potent triazole antifungal agent approved in adults for treatment and prophylaxis of invasive fungal infections (IFIs). The objectives of this study were to evaluate the pharmacokinetics (PK), safety, and tolerability of POS oral suspension in pediatric subjects with neutropenia. METHODS:This was a prospective, multicenter, sequential dose-escalation study. Enrolled subjects were divided into 3 age groups: AG1, 7 to l18 years; AG2, 2 to l7 years; and AG3, 3 months to l2 years. AG1 and AG2 were divided into 3 dosage cohorts: DC1, 12 mg/kg/day divided twice daily (BID); DC2, 18 mg/kg/day BID; and DC3, 18 mg/kg/day divided thrice daily (TID). AG3 was also divided into DC1 and DC2; however, no subjects were enrolled in DC2. Subjects received 7-28 days of POS oral suspension. PK samples were collected at predefined time points. The POS PK target was predefined as ~90% of subjects with Cavg (AUC /dosing interval) between 500 and 2500 ng/mL, with an anticipated mean steady state Cavg exposure of ~1200 ng/mL. RESULTS:The percentage of subjects meeting the PK target was l90% across all age groups and dosage cohorts (range: 31% to 80%). The percentage of subjects that achieved the Cavg target of 500 to 2500 ng/mL on Day 7 ranged from 31% to 80%, with the lowest proportion in subjects 2 to l7 years receiving 12 mg/kg/day BID (AG2/DC1) and the highest proportion in subjects 7 to l18 years receiving 18 mg/kg/day TID (AG1/DC3). At all three dose levels (12 mg/kg/day BID, 18 mg/kg/day BID and 18 mg/kg/day TID), subjects in AG1 (7 to l18 years old) had higher mean PK exposures at steady state than those in AG2. High variability in exposures was observed in all groups. POS oral suspension was generally well tolerated and most of the reported adverse events were related to the subjects' underlying diseases. CONCLUSION:The POS PK target of 90% of subjects with Cavg between 500 and 2500 ng/mL was not achieved in any of the age groups across the different dosage cohorts. New formulations of the molecule with a greater potential to achieve the established PK target are currently under investigation. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT01716234.

Infections are major complications in pediatric patients undergoing hematopoietic stem cell or solid organ transplantation. They also represent the most significant barrier to short- and long-term survival of the transplanted allograft. The achievements and advances during the past 30 years have resulted in remarkably improved outcome for pediatric patients undergoing transplantation. These advances in pediatric infectious disease supportive care have contributed substantially to the patients’ well-being and improved survival, alike. The immune defects and the possible etiologic agents for infection vary with the time elapsed since transplantation, a formal timetable for infectious complications after hematopoietic stem cell and solid organ transplantation forms the bases for an organized approach to assess a relevant differential diagnosis, treatment and management plan for these complex and severely immunosuppressed young transplant recipients. In this chapter a comprehensive review on epidemiology, clinical manifestations, and strategies for managing infectious diseases in pediatric transplant recipients is provided.

A focused multivector ultraviolet (FMUV) light system was used in a parallel process with manual chemical disinfection during operating room (OR) turnovers to assess the impact on cleaning time. The average time to disinfect an OR using only chemical wipes and mops was 19.0 minutes (n = 68); for the FMUV process, the average time was 18.8 minutes (n = 61). The mean cleaning times were equivalent within a 7% margin (P.17), and total turnover time was not significantly affected.

INTRODUCTION The presence of Candida species in the blood is known as candidemia and may constitute a medical emergency for patients with cancer. Despite advances in diagnosis and treatment of this fungal infection, mortality remains unacceptably high. Areas covered: This paper reviews recent advances in molecular diagnostics to detect species of Candida as well as novel antifungal agents that have been developed to address candidiasis. We also review prophylaxis strategies to prevent candidiasis in high-risk cancer patients. Expert commentary: We draw from our own experiences treating candidemia in the cancer patient and review novel diagnostic strategies involving molecular resonance and mass spectroscopy. We also explore novel chemoprophylaxis and treatment options, including new drugs such as rezafungin and SCY-078. We also look ahead, to examine how this condition will be managed in the years ahead.

Supplemental Digital Content is available in the text., Background: Amphotericin B deoxycholate (AmB-D) is standard of care treatment for neonatal invasive candidiasis (IC). Micafungin (MCA) has broad-spectrum fungicidal activity against Candida spp. We compared the efficacy and safety of intravenous MCA with intravenous AmB-D and assessed the pharmacokinetics of MCA in infants >2–120 days of age with proven IC in a phase 3, randomized, double-blind, multicenter, parallel-group, noninferiority study (NCT00815516). Methods: Infants were randomized 2:1 to MCA (10 mg/kg/d) or AmB-D (1 mg/kg/d) for ≥21 days. Primary efficacy endpoint was fungal-free survival (FFS) 1 week after last study drug dose. MCA population pharmacokinetics included simulated area under the curve (AUC) at steady state and maximum plasma concentration after 2-hour infusion. AUC pharmacodynamic target exposure was 170 µg·h/mL. Results: Thirty infants received MCA (n = 20) or AmB-D (n = 10). The trial was terminated early because of slow recruitment. FFS was observed in 12 of 20 [60%; 95% confidence interval (CI): 36%–81%] MCA-group infants and in 7 of 10 (70%; 95% CI: 35%–93%) AmB-D-group infants. The most common treatment-emergent adverse events were anemia [MCA: n = 9 (45%); AmB-D: n = 3 (30%)] and thrombocytopenia [n = 2 (10%) and n = 3 (30%), respectively]. Model-derived mean AUC at steady state for MCA was 399.3 ± 163.9 µg·h/mL (95% prediction interval: 190.3–742.3 µg/mL); steady state and maximum plasma concentration after 2-hour infusion was 31.1 ± 10.5 µg/mL (95% prediction interval: 17.0–49.7 µg/mL). MCA exposures were above the AUC pharmacodynamic target exposure. Conclusions: Within the study limitations, infants with IC treated with MCA achieved similar FFS compared with AmB-D. Both agents were safe and well tolerated.

Mucormycosis is a life threatening, rapidly progressing infection associated with high mortality.…

Invasive mycoses present a global challenge with expansion into new hosts, emergence of new pathogens, and development of multidrug resistance. In parallel, new antifungal agents and advanced laboratory diagnostic systems are being developed. In response to these evolving challenges, the European Confederation of Medical Mycology (ECMM) is committed to providing international expertise, guidance, and leadership with the key objectives of improving diagnosis, treatment, outcome, and survival of persons with invasive fungal diseases. Representing 25 affiliated National Medical Mycology Societies, the ECMM has developed several major ways to achieving these critical objectives: (a) tasking specific medical mycology working groups; (b) founding the ECMM Academy and Fellow program (FECMM); (c) expanding the goals of ECMM beyond the European region; (d) implementing the ECMM Excellence Centre Initiative in Europe; and (e) the ECMM Global Guidelines and Neglected Orphan Disease Guidance Initiatives focusing on mucormycosis, rare mould diseases, rare yeast diseases, and endemic mycoses. We believe that these important initiatives and other strategies of the ECMM will advance the field of medical mycology and improve the outcome of patients with invasive mycoses worldwide. ispartof: MYCOSES vol:61 issue:11 pages:885-894 ispartof: location:Germany status: published

Eravacycline (7-fluoro-9-pyrrolidinoacetamido-6-demethyl-6-deoxytetracycline or TP-434) is a novel, fully synthetic broad-spectrum fluorocycline with potent activity against Gram-positive bacteria, anaerobes, and multidrug-resistant Enterobacteriaceae. We characterized the plasma pharmacokinetics of eravacycline and conducted a comprehensive analysis of the eravacycline tissue distribution in rabbits after multiple-day dosing. For single-dose pharmacokinetic analysis, eravacycline was administered to New Zealand White (NZW) rabbits at 1, 2, 4, 8, and 10 mg/kg of body weight intravenously (i.v.) once a day (QD) (n = 20). For multidose pharmacokinetic analysis, eravacycline was administered at 0.5, 1, 2, and 4 mg/kg i.v. QD (n = 20) for 6 days. Eravacycline concentrations in plasma and tissues were analyzed by a liquid chromatography-tandem mass spectrometry assay. Mean areas under the concentration-time curves (AUCs) following a single eravacycline dose ranged from 5.39 μg · h/ml to 183.53 μg · h/ml. Within the multidose study, mean AUCs ranged from 2.53 μg · h/ml to 29.89 μg · h/ml. AUCs correlated linearly within the dosage range (r = 0.97; P = 0.0001). In the cardiopulmonary system, the concentrations were the highest in the lung, followed by the heart > pulmonary alveolar macrophages > bronchoalveolar lavage fluid; for the intra-abdominal system, the concentrations were the highest in bile, followed by the liver > gallbladder > spleen > pancreas; for the renal system, the concentrations were the highest in urine, followed by those in the renal cortex > renal medulla; for the musculoskeletal tissues, the concentrations were the highest in muscle psoas, followed by those in the bone marrow > adipose tissue; for the central nervous system, the concentrations were the highest in cerebrum, followed by those in the aqueous humor > cerebrospinal fluid > choroid > vitreous. The prostate and seminal vesicles demonstrated relatively high mean concentrations. The plasma pharmacokinetic profile of 0.5 to 4 mg/kg in NZW rabbits yields an exposure comparable to that in humans (1 or 2 mg/kg every 12 h) and demonstrates target tissue concentrations in most sites.

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the effects of testosterone compared to placebo or other medical treatments in men with sexual dysfunction.

Candida osteomyelitis is a debilitating disease that is difficult to diagnose and treat. As there are no animal models or prospective studies for this uncommon infection, little is known about the pathogenesis, diagnosis, or treatment. We therefore sought to establish an animal model for the study of the pathophysiology, diagnostic modalities, and therapeutic interventions of Candida osteomyelitis. We developed a modified version of the Norden rabbit model of tibial osteomyelitis, in which the right tibia was inoculated intraoperatively with different inocula of C. albicans or normal saline as control. On days 7, 14, and 21 after inoculation, the animals underwent bone radiography, 18-fluoro-2-deoxy-D-glucose positron emission tomography combined with computed tomography (PET/CT) scan, and blood sampling for blood cultures, blood counts, erythrocyte sedimentation rate, and Candida mannan antigen serum levels. On day 21, animals were euthanized, and infected tibias harvested for culture and histology. Among eight evaluable animals inoculated with 1 × 106 to 1 × 107 cfu, histology and bone cultures established the presence of Candida osteomyelitis in seven, with a host response of neutrophils, mononuclear cells, multinucleate giant cells, fibrosis, and necrosis. Infected animals demonstrated radiological signs of osteomyelitis with significantly increased tracer uptake in 18FDG-PET/CT scans (P < .01) and elevated serum mannan levels (P < .01). All blood cultures were negative. Indices of inflammation were only slightly increased. In conclusion, we report successful establishment of a new animal model of Candida albicans osteomyelitis that may be applicable to advancing our understanding of the pathophysiology, diagnostic modalities, and treatment of this debilitating infection.

Clinical use of voriconazole, posaconazole, and itraconazole revealed the need for therapeutic drug monitoring (TDM) of plasma concentrations of these antifungal agents. This need for TDM was not evident from clinical trials. In order to establish whether this requirement also applies to isavuconazole, we examined the plasma concentrations of 283 samples from patients receiving isavuconazole in clinical practice and compared the values with those from clinical trials. The concentration distributions from real-world use and clinical trials were nearly identical (>1 μg/ml in 90% of patients). These findings suggest that routine TDM may not be necessary for isavuconazole in most instances.

Background: Neonatal candidiasis causes significant morbidity and mortality in high risk infants. The micafungin dosage regimen of 10 mg/kg established for the treatment of neonatal candidiasis is based on a laboratory animal model of neonatal hematogenous Candida meningoencephalitis and pharmacokinetic (PK)–pharmacodynamic (PD) bridging studies. However, little is known about the how these PK–PD data translate clinically. Methods: Micafungin plasma concentrations from infants were used to construct a population PK model using Pmetrics software. Bayesian posterior estimates for infants with invasive candidiasis were used to evaluate the relationship between drug exposure and mycologic response using logistic regression. Results: Sixty-four infants 3–119 days of age were included, of which 29 (45%) infants had invasive candidiasis. A 2-compartment PK model fits the data well. Allometric scaling was applied to clearance and volume normalized to the mean population weight (kg). The mean (standard deviation) estimates for clearance and volume in the central compartment were 0.07 (0.05) L/h/1.8 kg and 0.61 (0.53) L/1.8 kg, respectively. No relationship between average daily area under concentration–time curve or average daily area under concentration–time curve:minimum inhibitory concentration ratio and mycologic response was demonstrated (P > 0.05). Although not statistically significant, mycologic response was numerically higher when area under concentration–time curves were at or above the PD target. Conclusions: While a significant exposure–response relationship was not found, PK–PD experiments support higher exposures of micafungin in infants with invasive candidiasis. More patients would clarify this relationship; however, low incidence deters the feasibility of these studies.

Purpose Results of an assessment of the chemical stability of isoniazid injection in 0.9% sodium chloride injection and 5% dextrose injection are reported. Methods Triplicate solutions of isoniazid (0.5 and 6.0 mg/mL) in the 2 diluents were prepared in ethylene and propylene copolymer i.v. containers and stored under light protection at room temperature (20–25 °C) or under refrigeration (2–8 °C). Standard aliquots were removed from each solution at time points up to 72 hours and analyzed via high-performance liquid chromatography (HPLC). Stability was defined as retention of >90% of the initial isoniazid concentration; pH, osmolality, and visual appearance were assessed. Results Isoniazid 0.5- and 6.0-mg/mL solutions in 0.9% sodium chloride injection were stable for up to 72 hours at room temperature or under refrigeration. HPLC analysis of isoniazid 0.5-mg/mL solutions in 5% dextrose injection revealed a decrease to less than 90% of the initial concentration at 8 hours at room temperature and at 30 hours under refrigeration. Isoniazid 6.0-mg/mL solutions in 5% dextrose injection were stable for 24 hours at room temperature and for 48 hours under refrigeration. The pH, osmolality, and visual appearance of the solutions were not affected. Conclusion Isoniazid solutions of 0.5 and 6.0 mg/mL in 0.9% sodium chloride injection were stable under light protection for up to 72 hours when stored at room temperature or under refrigeration. Isoniazid injection was less stable in 5% dextrose injection, especially at a concentration of 0.5 mg/mL at room temperature.

BACKGROUND: Bacteremia caused by extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae (ESBL-E) is associated with inadequate empirical therapy and substantial mortality in neutropenic patients. Strategies are needed to identify neutropenic patients at high risk of these infections. METHODS: From April 2014 to September 2016, we collected perianal swabs, both at admission and weekly thereafter, from patients undergoing hematopoietic stem cell transplantation (HSCT). Patients received prophylactic levofloxacin while neutropenic. Swabs were plated onto selective agar, colonies were identified and underwent antimicrobial susceptibility testing, and phenotypic ESBL testing and polymerase chain reaction for β-lactamase genes were performed on ceftriaxone-resistant Enterobacteriaceae. We then determined the prevalence of pre-transplant ESBL-E colonization and risk of ESBL-E bacteremia. Colonizing and bloodstream isolates from patients with ESBL-E bacteremia underwent multilocus sequence typing and pulsed-field gel electrophoresis. RESULTS: We analyzed 312 patients, including 212 allogeneic and 100 autologous HSCT recipients. Ten percent (31/312) of patients had pre-transplant ESBL-E colonization. Susceptibility rates of colonizing ESBL-E were: levofloxacin, 25%; cefepime, 9%; piperacillin-tazobactam, 84%; and meropenem, 97%. Of 31 patients colonized with ESBL-E pre-transplant, 10 (32%) developed ESBL-E bacteremia during their transplant admission, compared to 1 (0.4%) of 281 patients not colonized with ESBL-E (P < .001). All bloodstream ESBL-E were levofloxacin-resistant and colonizing and bloodstream isolates from individual patients had identical genotypic profiles. CONCLUSIONS: HSCT recipients who are colonized with levofloxacin-resistant ESBL-E pre-transplant and receive levofloxacin prophylaxis have high rates of bacteremia from their colonizing strain during neutropenia. Assessing for ESBL-E colonization in neutropenic patients could lead to optimization of empirical antibacterial therapy.

Ventilator-associated bacterial pneumonia (VABP) is a difficult therapeutic problem. Considerable controversy exists regarding the optimal chemotherapy for this entity. The recent guidelines of the Infectious Diseases Society of America and the American Thoracic Society recommend a 7-day therapeutic course for VABP based on the balance of no negative impact on all-cause mortality, less resistance emergence, and fewer antibiotic treatment days, counterbalanced with a higher relapse rate for patients whose pathogen is a nonfermenter. The bacterial burden causing an infection has a substantial impact on treatment outcome and resistance selection. We describe the baseline bronchoalveolar lavage (BAL) fluid burden of organisms in suspected VABP patients screened for inclusion in a clinical trial. We measured the urea concentrations in plasma and BAL fluid to provide an index of the dilution of the bacterial and drug concentrations in the lung epithelial lining fluid introduced by the BAL procedure. We were then able to calculate the true bacterial burden as the diluted colony count times the dilution factor. The median dilution factor was 28.7, with the interquartile range (IQR) being 11.9 to 53.2. Median dilution factor-corrected colony counts were 6.18 log

Micafungin (MFG) demonstrates potent activity against biofilms of Candida albicans and Candida parapsilosis, the most frequent opportunistic fungal pathogens. Little is known about its immunopharmacologic effect on antibiofilm activity of phagocytic cells following exposure to Candida biofilms. In this study, we investigated the effects of MFG on human neutrophil-mediated damage of C. albicans and C. parapsilosis biofilms by XTT [2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide] and the potential mechanisms underlying the immunomodulatory MFG activities on cultured monocyte-derived THP-1 cells in response to these biofilms by reverse transcription-PCR and sandwich and multiplex enzyme-linked immunosorbent assay. Preexposure of C. albicans to subinhibitory MFG concentrations significantly enhanced neutrophil-mediated biofilm damage, an effect that appears to be species specific since a comparable effect was not observed with drug-pretreated C. parapsilosis biofilms. Human THP-1 cells responded to both Candida biofilms through Toll-like receptor 2 (TLR2) and TLR4 upregulation, modest TLR6 involvement, and enhanced NLRP3 activation, whereas the signal was relayed to the nucleus via NF-κB p65 activation. MFG caused 2- to 3-fold lower TLR2 and TLR4 mRNA levels than those caused by either organism. C. albicans biofilms induced a robust proinflammatory response, whereas C. parapsilosis biofilms either alone or in the presence of MFG caused increased interleukin-1β (IL-1β) production, but small amounts of IL-8, IL-23, and tumor necrosis factor alpha. In conclusion, MFG may condition THP-1 cells toward an inflammatory response through TLR2/TLR4 recruitment. Inflammatory signals observed with C. albicans biofilms are considerably reduced upon exposure of THP-1 cells to C. parapsilosis biofilms, possibly enhancing fungal survival and increasing biofilm pathogenicity.

Discovering new drugs for treatment of invasive fungal infections is an enduring challenge. There are only three major classes of antifungal agents, and no new class has been introduced into clinical practice in more than a decade. However, recent advances in our understanding of the fungal life cycle, functional genomics, proteomics, and gene mapping have enabled the identification of new drug targets to treat these potentially deadly infections. In this paper, we examine amino acid transport mechanisms and metabolism as potential drug targets to treat invasive fungal infections, including pathogenic yeasts, such as species of Candida and Cryptococcus, as well as molds, such as Aspergillus fumigatus. We also explore the mechanisms by which amino acids may be exploited to identify novel drug targets and review potential hurdles to bringing this approach into clinical practice.

Background Disseminated fusariosis in patients with hematological malignancies is a frequently fatal and emerging invasive mycosis. Fusarium spp. are often resistant to safely achievable concentrations of mould active triazoles and amphotericin B. We aimed to determine the efficacy of isavuconazonium sulfate (ISA) alone or in combination with micafungin (MICA) in a murine model of disseminated fusariosis caused by Fusarium solani. Methods Groups of five 5-week-old Swiss Webster female mice, 20–22 g, were rendered neutropenic by intraperitoneal (IP) injection of cyclophosphamide at 200 mg/kg on day −2 and 150 mg/kg on day +3. Mice were infected with 5 × 10E5 CFU F. solani intravenously (IV) via the lateral tail vein on day 0. To prevent bacterial infection, ceftazidime was administered 50 mg/kg/day IP. Therapy began 18 h post-challenge for 6 days. MICA was given at dosages of 10, 5, 2.5 and 1.25 mg/kg IP Q12h combined with ISA 14 mg/kg/day IP. Six groups of mice received ISA orogastrically (OG) Q8h, Q12h and Q24h at 224 mg/kg alone or combined with MICA at 10 mg/kg Q12h IP. Kaplan–Meier survival analysis was performed. Results ISA at 14 mg/kg Q12h combined with 10 mg/kg MICA doses resulted in improved survival but with no significant reduction of residual fungal burden compared with monotherapy or other ISA/MICA dose combinations. Improved survival with dose-escalated oral monotherapy was observed at ISA 224 mg/kg Q12h (50% survival) and Q8h OG (60%) compared with other monotherapy or combination, or untreated groups (18–20%). The residual fungal burden in kidney between monotherapy and combination therapy groups was 5.81 10Log (untreated), 4.03 10Log (ISA 224 mg/kg, OG Q12h), 5.19 10Log (ISA 224 mg/kg Q12h + MICA 10 mg/kg, Q12h), 4.67 10Log (ISA 224 mg/kg, Q24h), and 4.82 10Log (ISA 224 mg/kg Q24h + MICA 10 mg/kg, Q12h). Conclusion High doses of isavuconazole (exceeding currently approved human dosages) in combination with micafungin improved survival in experimental murine disseminated fusariosis. Given the excellent safety profile of ISA, exploration of higher dosages that are necessary to achieve this antifungal effect is warranted for successful management of disseminated fusariosis. Disclosures All authors: No reported disclosures.

Background Community-acquired pneumonia (CAP) and hospital-acquired pneumonia (HAP) are the leading causes of death from infection in developed countries. Mannose-binding lectin (MBL) is a C-type serum lectin that plays a central role in the innate pulmonary host defenses against respiratory pathogens. We hypothesized that MBL polymorphisms may increase the risk of developing Legionella pneumonia. Therefore, the aim of this study was to evaluate the role of MBL polymorphisms in susceptibility to CAP and HAP caused by Legionella spp. Methods A total of 96 BAL and blood samples collected for routine microbiological analysis from Lithuanian patients presenting with CAP and HAP, were used for this study. MBL polymorphisms in the 54 codon (54 G/G, 54 G/A, and 54 A/A) were detected by BanIRFLP. Legionella spp. were detected by nested PCR. Results Polymorphisms in the 54 codon of MBL were determined in 96 patients. Among 96 patients with CAP and HAP, the most commonly observed 54 codon MBL variant was 54 G/G (69.8%, n = 67), followed by 54 G/A (21.9%, n = 21), and 54 A/A (8.3%, n = 8). By using nested PCR, Legionella pneumonia was detected among 15.6% (n = 15) of patients diagnosed with CAP and HAP. Legionella spp. were detected among 7 patients with MBL 54 codon G/G variant (10.4%), while 3 patients with MBL 54 G/A (14.3%), and 5 patients with MBL 54 codon A/A variant (62.5%). During this study Legionella spp. were detected more frequently (P < 0.05) among patients with the A/A variant of the 54 codon vs. those with other variants of MBL 54 codon. There were no significant differences found among those with Legionella infection and G/A (14.3%) or G/G (10.4%) variants of MBL gene 54 codon. Conclusion MBL gene 54 codon variant A/A polymorphisms may play an important role in increased susceptibility to lower respiratory infectionscaused by Legionella spp. Disclosures All authors: No reported disclosures.

Background Pneumocystis jirovecii pneumonia is an uncommon and life-threatening disease that can occur following hematopoietic stem cell transplantation (HSCT). Trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis greatly reduces the incidence of PJP. We aim to determine what factors contribute to the development of PJP following HSCT where TMP-SMX prophylaxis is widely used. Methods We performed a single-center, retrospective case series of HSCT recipients from January 1, 2012 to December 31, 2018. Subjects had clinical symptoms and radiographic evidence for PJP along with at least one positive Pneumocystis test obtained from bronchoalveolar lavage (BAL) including direct fluorescence antibody (DFA), quantitative polymerase chain reaction (qPCR), cytology, and pathology. Results 1111 subjects underwent HSCT; of whom, 25 (2.2%) met inclusion criteria and were treated for PJP. 6 were autologous and 19 were allogeneic HSCT recipients (1.23% and 3.05% of total autologous and allogeneic HSCT, respectively). All allogeneic HSCT recipients received in-vivo T-cell depletion. Median duration from autologous and allogeneic HSCT to PJP diagnosis were 138 days (range 20 to 348) and 346 days (range 41 to 771), respectively. PJP qPCR was positive in all samples tested (n = 20, range < 84 to 14900). DFA was positive in 6 (28%). Death from pneumonia occurred in 2 subjects; 11 (44%) required ICU stay, and 7 (27%) required intubation. At diagnosis, 3 subjects had relapse of underlying disease and 10 were on immunosuppression. 12 were on PJP prophylaxis (autologous HSCT n = 3), the most common of which was atovaquone (n = 5); only 2 subjects were on TMP-SMX. Cytomegalovirus (CMV) viremia was detected in 9 subjects (36%) prior to PJP diagnosis; 4 had pulmonary CMV coinfection. In total, 17 subjects (68%) had one of the above risk factors for PJP. Median total lymphocyte count and % lymphocytes were 5.1 × 103 cells/μL (range 1.4 to 38.5 × 103 cells/μL) and 9.6% (range 1.1 to 29.5%), respectively. Conclusion PJP is an uncommon (2.2% of the study population) complication of HSCT while receiving PJP prophylaxis and in the absence of disease relapse, CMV reactivation, or ongoing immunosuppression. Presentation is often delayed in this population; a high degree of clinical suspicion should prompt diagnostic evaluation using a combination of laboratory tests on BAL fluid. Disclosures All authors: No reported disclosures.

Background Prolonged admissions for acute bacterial skin and skin structure infections (ABSSSI) present an opportunity to improve efficiency and quality of care. A primary reason for admission for ABSSSI is to receive intravenous (IV) antibiotics, where multiple guidelines support shifting care to outpatient settings for appropriate patients. A hospital pathway for ABSSSI that leverages long-acting IV antibiotic therapy, such as dalbavancin, may reduce the length of stay (LOS). The ENHANCE ABSSSI trial (NCT03233438) sought to quantify LOS vs. that of usual care after implementing a new ABSSSI pathway. Methods A single-center, pre- vs. post-period pragmatic trial at Weill-Cornell Medical Center assessed usual care for consecutively enrolled ABSSSI patients during an observational period (pre-period). A new ABSSSI pathway was implemented in the post-period, which included (1) identification of eligible admitted ABSSSI patients and (2) treatment with dalbavancin. Those with life-threatening infections, requiring multiple antibiotics/intensive care, or with unstable comorbidities were excluded. Outcomes were assessed over a 44-day follow-up period. Results Of 48 and 43 patients enrolled in pre- and post-periods (Figure 1), mean infection-related LOS was reduced in the post-period (3.2 days vs. 4.8 days; P = 0.003; Figure 2 and 3). Similar results were found in an adjusted LOS analysis. Work productivity and activity impairment outcomes significantly improved in the post-period, apart from absenteeism, while quality of life was similar between periods (Figure 4). Complete response to treatment was similar between periods: 50% (pre-period) and 57% (post-period). A greater proportion of total adverse events (AEs) occurred in the post-period (n = 20; 48%) vs. pre-period (n = 3; 6%) with most AEs being mild in severity and not related to antibiotic use; few AEs were serious (7% [n = 3] post-period vs. 2% [n = 1] pre-period). The most common AEs were unrelated infection in the pre-period and fever in the post-period. Conclusion After implementing the ENHANCE ABSSSI pathway among eligible patients, LOS was significantly reduced by almost 2 days, with potential improvements in work productivity and the ability to complete daily activities. Disclosures All authors: No reported disclosures.

Measurement of intratesticular sex steroid concentrations in men informs both the development of male hormonal contraceptives and the understanding of male infertility. Given the challenges of using invasive techniques to measure testicular hormone physiology, our group has used a minimally-invasive fine-needle aspiration technique to measure intratesticular hormones in normal healthy men. Herein, we present a post-hoc analysis of the safety and efficacy of testicular fine-needle aspiration (FNA) completed as part of six clinical trials. From 2001 through 2011, a total of 404 procedures were conducted among 163 research volunteers, 85.9% of which were successful in obtaining sufficient fluid for the measurement of intratesticular steroid concentrations. Pain was the most common side effect, with 36.8% of procedures associated with moderate procedural pain and 4.7% with severe procedural pain. Postprocedural pain was uncommon and abated within a few days. Mild local bruising occurred with 14.9% of procedures. Two serious adverse events (0.5%) required surgical intervention. The risk of an adverse event was not associated with age, body mass index, testicular size, or the volume of fluid aspirated. Testicular FNA to obtain fluid for measurement of intratesticular steroid concentrations frequently causes mild to moderate procedural pain, but serious adverse events occur rarely. Testicular FNA has been instrumental for defining human intratesticular hormone physiology and is a minimally-invasive, safe, effective method for obtaining fluid for research on testicular physiology and pathology.

Biofilm-related infections have become an increasingly important clinical problem. Many of these infections occur in patients with multiple comorbidities or with impaired immunity. Echinocandins (caspofungin, micafungin, and anidulafungin) exert their fungicidal activity by inhibition of the synthesis of the (1→3)-β-d-glucan. They are active among in vitro and in vivo model systems against a number of Candida species and filamentous fungi in their planktonic and biofilm phenotype. Their superior activity against biofilms poses them in an advantageous position among the antifungal armamentarium. However, additional studies are warranted to expand our knowledge on the role of echinocandins against biofilm-related infections.

Candida biofilm-associated infections of central venous catheters are a challenging therapeutic problem. Recent in vitro and in vivo studies of the structure, formation, pathogenesis, and treatment establish a rationale for new approaches to management of these tenacious infections.

Background Human rhinoviruses (HRVs) are common causes of upper respiratory tract infection (URTI) in hematologic malignancy (HM) patients. Predictors of lower respiratory tract infection (LRTI) including the impact of HRV species and types are poorly understood. Objectives This study aims to describe the clinical and molecular epidemiology of HRV infections among HM patients. Study design From April 2012–March 2013, HRV-positive respiratory specimens from symptomatic HM patients were molecularly characterized by analysis of partial viral protein 1 (VP1) or VP4 gene sequence. HRV LRTI risk-factors and outcomes were analyzed using multivariable logistic regression. Results One hundred and ten HM patients presented with HRV URTI (n = 78) and HRV LRTI (n = 32). Hypoalbuminemia (OR 3.0; 95% CI, 1.0–9.2; p = 0.05) was independently associated with LRTI, but other clinical and laboratory markers of host immunity did not differ between patients with URTI versus LRTI. Detection of bacterial co-pathogens was common in LRTI cases (25%). Among 92 typeable respiratory specimens, there were 58 (64%) HRV-As, 12 (13%) HRV-Bs, and 21 (23%) HRV-Cs, and one Enterovirus 68. LRTI rates among HRV-A (29%), HRV-B (17%), and HRV-C (29%) were similar. HRV-A infections occurred year-round while HRV-B and HRV-C infections clustered in the late fall and winter. Conclusions HRVs are associated with LRTI in HM patients. Illness severity is not attributable to specific HRV species or types. The frequent detection of bacterial co-pathogens in HRV LRTIs further substantiates the hypothesis that HRVs predispose to bacterial superinfection of the lower airways, similar to that of other community-acquired respiratory viruses.

Few studies have evaluated the role of antibacterial prophylaxis during neutropenia in patients with multiple myeloma undergoing autologous hematopoietic stem cell transplantation (HSCT). At our center, levofloxacin prophylaxis was initiated in June 2006 in patients with myeloma who were undergoing autologous HSCT. We compared the incidence of bloodstream infection (BSI) and fever and neutropenia (FN) within 30 days of transplantation before (January 2003 to May 2006) and after (June 2006 to April 2010) the initiation of levofloxacin prophylaxis in patients undergoing autologous HSCT for myeloma. We also compared rates of BSI and FN during the same time periods in autologous HSCT recipients with lymphoma who did not receive antibacterial prophylaxis during either time period. After the initiation of levofloxacin prophylaxis, the BSI rate decreased from 41.2% (49 of 119) to 14.7% (23 of 156) and the rate of FN decreased from 91.6% to 60.9% in patients with myeloma (P < .001, for each). In contrast, rates of BSI (43.1% versus 47.3%; P = .50) and FN (98.8% versus 97.1%; P = .63) did not change in patients with lymphoma. Levofloxacin prophylaxis was independently associated with decreased odds of BSI (odds ratio, .27; 95% confidence interval, .14 to .51; P < .001) and FN (odds ratio, .18; 95% confidence interval, .09 to .36; P < .001) in multivariate analysis. Patients with myeloma had a nonsignificant increase in the risk of BSI due to levofloxacin-resistant Enterobacteriaceae (5% versus 1%, P = .08) and Clostridium difficile infection (7% versus 3%, P = .12) after the initiation of levofloxacin prophylaxis but did not have higher rates of BSI due to other resistant bacteria. Levofloxacin prophylaxis is associated with decreased risk of BSI and FN in patients with myeloma undergoing autologous HSCT.

BACKGROUND Candidemia causes significant morbidity and mortality among children. Removal of a central venous catheter (CVC) is often recommended for adults with candidemia to reduce persistent and metastatic infection. Pediatric-specific data on the impact of CVC retention are limited. METHODS A retrospective cohort study of inpatients

Testicular germ cell cancer is one of the most curable cancers. Most patients are treated during their reproductive years, making infertility a significant quality of life issue after successful treatment. This focused review evaluates the factors that contribute to infertility and specific fertility risks with the various testicular cancer treatments. Timing of patient discussions and current fertility treatments are reviewed.

Galactomannan and (1→3)-β-D-glucan are useful biomarkers of invasive pulmonary aspergillosis (IPA). However, the effects of immunosuppression on levels of galactomannan or (1→3)-β-D-glucan in IPA are not well understood or quantified. We therefore studied the simultaneous levels of galactomannan and (1→3)-β-D-glucan in two rabbit models of experimental IPA: (1) AraC-induced neutropenia in untreated (UC-AraC) and liposomal amphotericin B-treated (LAMB-AraC) rabbits; and (2) nonneutropenic cyclosporine-methylprednisolone immunosuppression in untreated (UC-CsA+M) and LAMB-treated (LAMB-CsA+M) rabbits. Simultaneous levels of galactomannan and (1→3)-β-D-glucan were determined in bronchoalveolar lavage (BAL) fluid and serial serum specimens and correlated with pulmonary host response. Serum galactomannan index (GMI) and (1→3)-β-D-glucan concentration-time-curves were higher in UC-AraC vs. UC-CsA+M (Mann-Whitney U-test, P < .05). Serum galactomannan and (1→3)-β-D-glucan in treatment groups demonstrated therapeutic responses with similarly lower levels in comparison to UC (P < .01) in both models. Host differences did not affect BAL fluid GMI or (1→3)-β-D-glucan but did affect galactomannan and (1→3)-β-D-glucan levels in serum. The higher serum GMI and (1→3)-β-D-glucan concentration-time-curves in UC-AraC correlated with extensive pulmonary infiltration by angioinvasive hyphae and minimal inflammation, while the lower concentration-time-curves in UC-CsA+M were associated with shorter and fewer hyphae in lung tissue and an intensive neutrophil response to Aspergillus hyphae. Thus, serum levels of galactomannan and (1→3)-β-D-glucan in IPA depended upon immunosuppression, which also affected severity of infection and hyphal morphology, while BAL fluid galactomannan and (1→3)-β-D-glucan were sensitive biomarkers not affected by host response.

Background: Trimethoprim-sulfamethoxazole (TMP-SMX) is an antimicrobial drug combination commonly prescribed in children and adults. The study objectives were to validate and apply an HPLC–MS/MS method to quantify TMP-SMX in dried plasma spots (DPS) and dried urine spots (DUS), and perform a comparability analysis with liquid matrices. Results: For TMP the validated range was 100–50,000 ng/ml for DPS and 500–250,000 ng/ml for DUS; for SMX, the validated range was 1000–500,000 ng/ml for both DPS and DUS. Good agreement was noted between DPS/DUS and liquid plasma and urine samples for TMP, while only modest agreement was observed for SMX in both matrices. Conclusion: A precise, accurate and reproducible method was developed to quantify TMP-SMX in DPS and DUS samples.