Are Nutraceuticals Effective in COVID-19 and Post-COVID Prevention and Treatment?

The beginning of the end or the end of the beginning? After two years mastered by coronavirus disease 19 (COVID-19) pandemic, we are now witnessing a turnaround. The reduction of severe cases and deaths from COVID-19 led to increasing importance of a new disease called post-COVID syndrome. The term post-COVID is used to indicate permanency of symptoms in patients who have recovered from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Immune, antiviral, antimicrobial therapies, as well as ozone therapy have been used to treat COVID-19 disease. Vaccines have then become available and administered worldwide to prevent the insurgence of the disease. However, the pandemic is not over yet at all given the emergence of new omicron variants. New therapeutic strategies are urgently needed. In this view, great interest was found in nutraceutical products, including vitamins (C, D, and E), minerals (zinc), melatonin, probiotics, flavonoids (quercetin), and curcumin. This review summarizes the role of nutraceuticals in the prevention and/or treatment of COVID-19 disease and post-COVID syndrome.

Pharmacokinetics, Tissue Distribution, and Efficacy of VIO-001 (Meropenem/Piperacillin/Tazobactam) for Treatment of Methicillin-Resistant Staphylococcus aureus Bacteremia in Immunocompetent Rabbits with Chronic Indwelling Vascular Catheters.

Methicillin-resistant Staphylococcus aureus (MRSA) infections of surgically implanted subcutaneous vascular catheters (SISVCs) cause serious morbidity in patients with chronic illnesses. Previous in vitro and murine models demonstrated the synergistic interaction of equimolar concentrations of meropenem/piperacillin/tazobactam (MPT) (VIO-001) against MRSA infection. We investigated the pharmacokinetics (PK) and efficacy of VIO-001 for the treatment of MRSA bacteremia in immunocompetent rabbits with SISVCs. In PK studies, we determined that optimal dosing to achieve a time above 4× MIC (T>4×MIC) of a duration of 3 to 3.30 h required a 1-h infusion with every-4-h (Q4h) dosing. Study groups in efficacy experiments consisted of MPT combinations of 100/150/100 mg/kg of body weight (MPT100), 200/300/200 mg/kg (MPT200), and 400/600/400 mg/kg (MPT400); vancomycin (VAN) at 15 mg/kg; and untreated controls (UC). The inoculum of MRSA isolate USA300-TCH1516 (1 × 103 organisms) was administered via the SISCV on day 1 and locked for 24 h. The 8-day therapy started at 24 h postinoculation. There was a significant reduction of MRSA in blood cultures from the SISVCs in all treatment groups, with full clearance on day 4, versus UCs (P < 0.05). Consistent with the clearance of SISVC-related infection, full eradication of MRSA was achieved in lungs, heart, liver, spleen, and kidneys at the end of the study versus UC (P < 0.01). These results strongly correlated with time-kill data, where MPT in the range of 4/6/4 µg/ml to 32/48/32 µg/ml demonstrated a significant 6-log decrease in the bacterial burden versus UC (P < 0.01). In summary, VIO-001 demonstrated a favorable PK/pharmacodynamic (PD) profile and activity against SISCV MRSA infection, bacteremia, and disseminated infection. This rabbit model provides a new system for understanding new antimicrobial agents against MRSA SISVC-related infection, and these data provide a basis for future clinical investigation.

Efficacy and Pharmacokinetics of Fosmanogepix (APX001) in the Treatment of Candida Endophthalmitis and Hematogenous Meningoencephalitis in Nonneutropenic Rabbits.

Candida endophthalmitis is a serious sight-threatening complication of candidemia that may occur before or during antifungal therapy. Hematogenous Candida meningoencephalitis (HCME) is also a serious manifestation of disseminated candidiasis in premature infants, immunosuppressed children, and immunocompromised adults. We evaluated the antifungal efficacy and pharmacokinetics of the prodrug fosmanogepix (APX001) in a rabbit model of endophthalmitis/HCME. Manogepix (APX001A), the active moiety of prodrug fosmanogepix, inhibits the fungal enzyme Gwt1 and is highly active in vitro and in vivo against Candida spp., Aspergillus spp., and other fungal pathogens. Plasma pharmacokinetics of manogepix after oral administration of fosmanogepix on day 6 at 25, 50, and 100 mg/kg resulted in maximum concentration of drug in plasma (Cmax) of 3.96 ± 0.41, 4.14 ± 1.1, and 11.5 ± 1.1 µg/ml, respectively, and area under the concentration-time curve from 0 to 12 h (AUC0-12) of 15.8 ± 3.1, 30.8 ± 5.0, 95.9 ± 14 µg·h/ml, respectively. Manogepix penetrated the aqueous humor, vitreous, and choroid with liquid-to-plasma ratios ranging from 0.19 to 0.52, 0.09 to 0.12, and 0.02 to 0.04, respectively. These concentrations correlated with a significant decrease in Candida albicans burden in vitreous (>101 to 103 log CFU/g) and choroid (>101 to 103 log CFU/g) (P ≤ 0.05 and P ≤ 0.001, respectively). The aqueous humor had no detectable C. albicans in treatment and control groups. The tissue/plasma concentration ratios of manogepix in meninges, cerebrum, cerebellum, and spinal cord were approximately 1:1, which correlated with a >102 to 104 decline of C. albicans in tissue versus control (P ≤ 0.05). Serum and cerebrospinal fluid (CSF) (1→3)-ß-d-glucan levels demonstrated significant declines in response to fosmanogepix treatment. These findings provide an experimental foundation for fosmanogepix in treatment of Candida endophthalmitis and HCME and derisk the clinical trials of candidemia and invasive candidiasis.

Antifungal efficacy of isavuconazole and liposomal amphotericin B in a rabbit model of Exserohilum rostratum meningoencephalitis: A preclinical paradigm for management of CNS phaeohyphomycosis.

Treatment options for Exserohilum rostratum meningoencephalitis and other causes of phaeohyphomycosis of the central nervous system (CNS) are limited, while mortality and morbidity remain high. We therefore evaluated isavuconazole, a new antifungal triazole in comparison to liposomal amphotericin B (LAMB), in vitro and in the rabbit model of Exserohilum rostratum meningoencephalitis. We hypothesized that isavuconazole alone or in combination with LAMB or micafungin may be alternative options for treatment of CNS phaeohyphomycosis. We therefore investigated the in vitro antifungal activity of isavuconazole alone or in combination with amphotericin B deoxycholate (DAMB) or micafungin and efficacy of treatment with isavuconazole and LAMB in a rabbit model of experimental E. rostratum meningoencephalitis. Combination checkerboard plates were used to determine the minimum inhibitory concentrations, minimal lethal concentrations, fractional inhibitory concentration indices, and Bliss surface analysis of isavuconazole and amphotericin B deoxycholate (DAMB), either alone or in combination. As there were no in vitro synergistic or antagonistic interactions for either combination of antifungal agents against the E. rostratum isolates, in vivo studies were conducted with isavuconazole and LAMB as monotherapies. Rabbits were divided in following groups: treated with isavuconazole at 60 mg/kg/d (ISAV60), LAMB at 5.0 (LAMB5), 7.5 (LAMB7.5), and 10 mg/kg/d (LAMB10), and untreated controls (UC). In ISAV60-, LAMB5-, LAMB7.5-, and LAMB10-treated rabbits, significant reductions of fungal burden of E. rostratum in cerebral, cerebellar, and spinal cord tissues (P < 0.01) were demonstrated in comparison to those of UC. These antifungal effects correlated with significant reduction of CSF (1→3)-ß-D-glucan levels vs UC (P < 0.05). These data establish new translational insights into treatment of CNS phaeohyphomycosis.

Efficacy of Amphotericin B in Corneal Preservation Media After Extended Frozen Storage.

PURPOSE: To investigate the antimycotic activity of amphotericin B deoxycholate that has been previously frozen for 28 days before supplementation of Optisol-GS. METHODS: Triplicate Optisol-GS samples were inoculated with 10 colony-forming units (CFU) of Candida albicans. Each set of triplicate cultures was supplemented with 2.5 µg/mL of amphotericin B that was either freshly resuspended and never frozen, frozen overnight at -20°C and thawed, or frozen at -20°C for 4 weeks and thawed. The cultures were stored at 4°C, with aliquots taken at 0, 6, 24, and 72 hours for quantification. The efficacy of each preparation of amphotericin B in reducing C. albicans growth was assessed at these time points. RESULTS: Six hours after antifungal supplementation, there was a 1.33 log10 CFU reduction with freshly resuspended amphotericin B, compared with a 1.31 log10 reduction with amphotericin B that was frozen overnight (P = 0.20) and a 1.18 log10 reduction with amphotericin B that was frozen for 4 weeks (P = 0.05). After 72 hours, there was a 2.72 log10 CFU reduction with freshly resuspended amphotericin B, a 2.64 log10 CFU reduction with amphotericin B that was frozen overnight (P = 0.45), and a 2.18 log10 CFU reduction with amphotericin B that was frozen for 4 weeks (P = 0.05). CONCLUSIONS: Previously frozen amphotericin B remains highly effective against C. albicans. Optisol-GS supplemented with 2.5 µg/mL amphotericin B that was frozen for 4 weeks at -20°C resulted in >90% CFU reduction by 6 hours and >99% reduction by 72 hours.

Pharmacokinetics and Efficacy of Ceftazidime-Avibactam in the Treatment of Experimental Pneumonia Caused by Klebsiella pneumoniae Carbapenemase-Producing K. pneumoniae in Persistently Neutropenic Rabbits.

Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) is an emerging global public health threat that causes life-threatening pneumonia and bacteremia. Ceftazidime-avibactam (CZA) represents a promising advance for the treatment of serious infections caused by KPC-Kp We investigated the pharmacokinetics and efficacy of ceftazidime-avibactam in the treatment of experimental KPC-Kp pneumonia in persistently neutropenic rabbits. For single-dose and multidose (administration every 8 h) pharmacokinetics, rabbits received ceftazidime-avibactam intravenous infusions at 60/15, 90/22.5, and 120/30 mg/kg of body weight. Ceftazidime mean area under the concentration-time curves (AUCs) ranged from 287 to 608 µg·h/ml for a single dose and from 300 to 781 µg·h/ml for multiple doses. Avibactam AUCs ranged from 21 to 48 µg·h/ml for a single dose and from 26 to 48 µg·h/ml for multiple doses. KPC-Kp pneumonia was established by direct endotracheal inoculation. Treatments consisted of ceftazidime-avibactam at 120/30 mg/kg every 6 h, a polymyxin B (PMB) loading dose of 2.5 mg/kg followed by 1.5 mg/kg every 12 h q12h, or no treatment (untreated controls [UC]). There were significant reductions in the residual bacterial burden, lung weights, and pulmonary hemorrhage scores in CZA- and PMB-treated rabbits for a 7-day or a 14-day (P ≤ 0.01) course in comparison with those in the UC. These results corresponded to significant decreases in the bacterial burden in bronchoalveolar lavage fluid after a 7-day or a 14-day treatment (P ≤ 0.01). The outcomes demonstrated an improved response at 14 days versus that at 7 days. There was significantly prolonged survival in rabbits treated with CZA for 14 days in comparison with that in the PMB-treated or UC rabbits (P ≤ 0.05). This study demonstrates that ceftazidime-avibactam displays linear dose-proportional exposures simulating those seen from human plasma pharmacokinetic profiles, is active for the treatment of experimental KPC-Kp pneumonia in persistently neutropenic rabbits, and provides an experimental foundation for the treatment of severely immunocompromised patients with this life-threatening infection.

Exposure-Response Analysis of Micafungin in Neonatal Candidiasis: Pooled Analysis of Two Clinical Trials.

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.

Colonization With Levofloxacin-resistant Extended-spectrum ß-Lactamase-producing Enterobacteriaceae and Risk of Bacteremia in Hematopoietic Stem Cell Transplant Recipients.

Background: Bacteremia caused by extended-spectrum ß-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 ß-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.

Special considerations for the diagnosis and treatment of invasive pulmonary aspergillosis.

INTRODUCTION: The diagnosis and treatment of invasive pulmonary aspergillosis (IPA) are ongoing challenges in clinical practice. While important advances have recently been made, including enhanced diagnostic modalities as well as novel therapeutic and prophylactic options, more effective options are urgently needed as the population of immunocompromised patients continues to expand. Areas covered: In this paper, we review novel approaches to diagnosis of IPA, including multiplex PCR, Matrix Assisted Laser Desorption/Ionization-Time of Flight Mass Spectrometry and provide a detailed review of the extended-spectrum triazole isavuconazole, which was approved in 2015 to treat IPA. Expert commentary: We explore burgeoning approaches to diagnosis, including the lateral flow assay, volatile organic compounds, and artificial olfactory technology, as well as novel antifungal agents to treat IPA such as SCY-078 and F901318.

Drug development challenges and strategies to address emerging and resistant fungal pathogens.

INTRODUCTION: Invasive fungal infections represent an expanding threat to public health. The recent emergence of Candida auris, which is often resistant to existing antifungal agents and is associated with a high mortality rate, underscores the urgent need for novel drug development strategies. Areas covered: In this paper, we examine both challenges and opportunities associated with antifungal drug development and explore potential avenues to accelerate the development pipeline, including data sharing, surrogate endpoints, and the role of historical controls in clinical trials. Expert commentary: We review important lessons learned from the study of other rare diseases, including mitochondrial storage diseases and certain forms of cancer that may inform strategies to develop new antifungal agents while highlighting promising new compounds such as SCY-078 for the treatment of invasive fungal infections.

In vitro combination therapy with isavuconazole against Candida spp.

Combination therapy may be an alternative therapeutic approach for difficult-to-treat Candida infections with the aim of increasing efficacy of antifungal therapy. Whether isavuconazole, an extended-spectrum triazole, possesses synergistic activity in combination therapy with echinocandins or polyenes for the treatment of invasive candidiasis has not been studied. We used Bliss independence drug interaction analysis and time-kill assays to examine the in vitro interactions of isavuconazole with amphotericin B or micafungin, an echinocandin, against strains of Candida albicans, Candida parapsilosis, Candida glabrata, Candida tropicalis, and Candida krusei. The Bliss independence-based drug interactions modeling showed that the combination of isavuconazole and micafungin resulted in synergistic interactions against C. albicans, C. parapsilosis, and C. krusei. The degree of synergy ranged from 1.8% to 16.7% (mean %ΔΕ value) with the highest synergy occurring against C. albicans (⊙SYN% = 8.8%-110%). Time-kill assays showed that the isavuconazole-micafungin combination demonstrated concentration-depended synergy against C. albicans and C. parapsilosis. The combined interaction by Bliss analysis between isavuconazole and amphotericin B was indifferent for C. albicans, C. parapsilosis, and C. tropicalis while for C. glabrata was antagonistic (-2% to -6%) and C. krusei synergistic (3.4% to 7%). The combination of isavuconazole-amphotericin B by time-kill assay was antagonistic against C. krusei and C. glabrata. Collectively, our findings demonstrate that combinations of isavuconazole and micafungin are synergistic against Candida spp., while those of isavuconazole and amphotericin B are indifferent in vitro.

The Role of Echinocandins in Candida Biofilm-Related Vascular Catheter Infections: In Vitro and In Vivo Model Systems.

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.

Role of Echinocandins in Fungal Biofilm-Related Disease: Vascular Catheter-Related Infections, Immunomodulation, and Mucosal Surfaces.

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)-ß-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.

Breakthrough candidaemia caused by phenotypically susceptible Candida spp. in patients with haematological malignancies does not correlate with established interpretive breakpoints.

In a study of 27,864 patients with haematological malignancies, 40 patients with candidaemia were identified, among whom 21 developed candidaemia while receiving systemic antifungal therapy [breakthrough candidaemia (BTC)]. Demographic, clinical, microbiological and molecular features of these episodes were analysed. Compared with 19 patients with de novo candidaemia, patients with BTC were more likely to have neutropenia (81% vs. 63%), longer median duration of neutropenia (27 days vs. 15 days), hypogammaglobulinaemia (62% vs. 37%) and central venous catheters (CVCs) (86% vs. 68%). The median duration of prior antifungal exposure was 46 days (range 3-108 days). Among the 18 available Candida spp. isolates, 15 (83%) were phenotypically susceptible to the antifungal agent that the patient was receiving. Emergence of resistance was the mechanism leading to BTC in three cases of patients receiving echinocandins. Other possible mechanisms of BTC were (i) elevated (≥2) minimum lethal concentration/minimum inhibitory concentration (MLC/MIC) ratio (reduced ability for a fungicidal agent to kill a fungal pathogen) in all patients receiving amphotericin B and (ii) elevated MLC/MIC ratios in all Candida parapsilosis isolates with MICs≤1 µg/mL to echinocandins. DNA sequencing of the hotspot 1 region of the fks1 and fks2 genes in seven different isolates of C. parapsilosis group demonstrated P660A in Fks1 but no polymorphisms in fks2. In conclusion, mechanisms for BTC in the setting of prolonged neutropenia may be host-based (hypogammaglobulinaemia and CVC) and pathogen-based. CLSI interpretive breakpoints do not reliably predict BTC in patients with haematological malignancies and warrant further investigation.

Erectile dysfunction is not independently associated with cardiovascular death: data from the vitamins and lifestyle (VITAL) study.

INTRODUCTION: Erectile dysfunction (ED) is a significant problem among aging men. ED is independently associated with cardiovascular (CV) events (angina, myocardial infarction, and stroke). AIM: We sought to determine if ED was associated with CV death. MAIN OUTCOME MEASURES: Risk of CV death in men with ED. METHODS: Exactly 31,296 men in Washington aged 50-76 completed a questionnaire in 2000-2002 on supplements, diet, exercise, personal health, and ED. ED was determined by one question: "Have you experienced impotence in the last year?" We excluded patients with a history of coronary artery disease or stroke. Participants linked yearly through 2008 to the Washington State Death Certificate System. CV death was defined by death certificates listing CV-related deaths (International Classification of Diseases 10th Revision [ICD-10] codes: I00-I15, I20-I52, and I60-I99). We performed multivariate Cox proportional hazard regression adjusting for age, marital status, race, education, self-rating of health, body mass index (BMI), antihypertensive/lipid-lowering drug use, diabetes, family history of CV disease, smoking, and exercise. RESULTS: About 7,762 men had ED and there were 486 CV deaths over 7.8-year average follow-up. The typical man who suffered CV death was older, single, reporting poor health, taking antihypertensives, higher BMI, a smoker, a diabetic, and had a family history of CV disease. When adjusting for age, marital status, and education only, men with ED had a 23% increased risk of CV death (hazard ratio [HR] 1.23, 95% confidence interval [CI] 1.01, 1.49). With further adjustment for known risk factors for CV disease (diabetes, treatment for hypertension or hyperlipidemia, family history of myocardial infarction/stroke, BMI, and exercise), ED no longer predicted CV death (HR 0.93, 95% CI 0.76, 1.15). CONCLUSIONS: In this community-based cohort, ED was not independently associated with an elevated risk of CV death. These data do not contradict prior data associating ED and CV events but rather suggest that ED may be a manifestation of other known risk factors for CV disease.

Pathogenesis of mucormycosis.

Mucormycosis is a life-threatening infection that occurs in patients who are immunocompromised because of diabetic ketoacidosis, neutropenia, organ transplantation, and/or increased serum levels of available iron. Because of the increasing prevalence of diabetes mellitus, cancer, and organ transplantation, the number of patients at risk for this deadly infection is increasing. Despite aggressive therapy, which includes disfiguring surgical debridement and frequently adjunctive toxic antifungal therapy, the overall mortality rate is high. New strategies to prevent and treat mucormycosis are urgently needed. Understanding the pathogenesis of mucormycosis and the host response to invading hyphae ultimately will provide targets for novel therapeutic interventions. In this supplement, we review the current knowledge about the virulence traits used by the most common etiologic agent of mucormycosis, Rhizopus oryzae. Because patients with elevated serum levels of available iron are uniquely susceptible to mucormycosis and these infections are highly angioinvasive, emphasis is placed on the ability of the organism to acquire iron from the host and on its interactions with endothelial cells lining blood vessels. Several promising therapeutic strategies in preclinical stages are identified.

Physical compatibility of magnesium sulfate and sodium bicarbonate in a pharmacy-compounded hemofiltration solution.

PURPOSE: The physical compatibility of magnesium sulfate and sodium bicarbonate in a pharmacy-compounded hemofiltration solution was assessed. METHODS: Two bicarbonate-buffered hemofiltration solutions (low- and high-magnesium formulations) were compounded in triplicate. The concentrations of magnesium (15 meq/L) and sodium bicarbonate (50 meq/L) in the high-magnesium formulation were chosen to be somewhat below the concentrations reported as being incompatible in a popular reference. The six hemofiltration bags were stored at 22-25 degrees C without protection from light for 48 hours. Physical compatibility was assessed by visual inspection and microscopy. The pH of the solutions was assayed 3-4 and 52-53 hours after compounding. Electrolyte and glucose concentrations of the solutions were assayed at 3-4 and 50-51 hours after preparation. RESULTS: No particulate matter was observed by visual or microscopic inspection in the compounded hemofiltration solutions at 48 hours. The mean +/- S.D. pH values of the low-magnesium solutions were 8.01 +/- 0.02 and 8.04 +/- 0.02 at 3-4 and 52-53 hours after compounding, respectively. The mean +/- S.D. pH values of the high-magnesium solutions were 7.96 +/- 0.02 and 7.98 +/- 0.01 at 3-4 and 52-53 hours after compounding, respectively. The electrolyte and glucose concentrations in the low- and high-magnesium solutions were similar 3-4 and 50-51 hours after preparation. CONCLUSION: Magnesium sulfate 1.5 meq/L and sodium bicarbonate 50 meq/L were physically compatible in a pharmacy-compounded hemofiltration solution for 48 hours when stored at 22-25 degrees C without protection from light.

Continuous-infusion beta-lactam antibiotics during continuous venovenous hemofiltration for the treatment of resistant gram-negative bacteria.

OBJECTIVE: To describe the rationale, principles, and dosage calculations for continuous-infusion beta-lactam antibiotics to treat multidrug-resistant bacteria in patients undergoing continuous venovenous hemofiltration (CVVH). DATA SOURCES: A MEDLINE search (1968-November 2008) of the English-language literature was performed using the terms continuous infusion and Pseudomonas or Acinetobacter; hemofiltration or CVVH or hemodiafiltration or CVVHDF or continuous renal replacement therapy or pharmacokinetics; and terms describing different beta-lactam antibiotics. STUDY SELECTION AND DATA EXTRACTION: In vitro, in vivo, and human studies were evaluated that used continuous-infusion beta-lactam antibiotics to treat Pseudomonas aeruginosa and Acinetobacter baumannii infections. Studies were reviewed that described the pharmacokinetics of beta-lactam antibiotics during CVVH as well as other modalities of continuous renal replacement therapy. DATA SYNTHESIS: Continuous infusion of beta-lactam antibiotics, maintaining drug concentrations 4-5 times higher than the minimum inhibitory concentration, is a promising approach for managing infections caused by P. aeruginosa and A. baumannii. Safe yet effective continuous infusion therapy is made difficult by the occurrence of acute renal failure and the need for renal replacement therapy. Case series and pharmacokinetic properties indicate that several beta-lactam antimicrobials that have been studied for continuous infusion, such as cefepime, ceftazidime, piperacillin, ticarcillin, clavulanic acid, and tazobactam, are significantly cleared by hemofiltration. Methodology and formulas are provided that allow practitioners to calculate dosage regimens and reach target drug concentrations for continuous beta-lactam antibiotic infusions during CVVH based on a literature review, pharmacokinetic principles, and our experience at the National Institutes of Health Clinical Center. CONCLUSIONS: Continuous infusion of beta-lactam antibiotics may be a useful treatment strategy for multidrug-resistant gram-negative infections in the intensive care unit. Well-established pharmacokinetic and pharmacodynamic principles can be used to safely reach and maintain steady-state target concentrations of beta-lactam antibiotics in critical illness complicated by acute renal failure requiring CVVH.

Safety and outcomes of open-label deferasirox iron chelation therapy for mucormycosis.

We sought to describe the safety profile of open-label, adjunctive deferasirox iron chelation therapy in eight patients with biopsy-proven mucormycosis. Deferasirox was administered for an average of 14 days (range, 7 to 21) at 5 to 20 mg/kg of body weight/day. The only adverse effects attributable to deferasirox were rashes in two patients. Deferasirox treatment was not associated with changes in renal or liver function, complete blood count, or transplant immunosuppressive levels. Thus, deferasirox appears safe as an adjunctive therapy for mucormycosis.

Infections caused by Scedosporium spp.

Scedosporium spp. are increasingly recognized as causes of resistant life-threatening infections in immunocompromised patients. Scedosporium spp. also cause a wide spectrum of conditions, including mycetoma, saprobic involvement and colonization of the airways, sinopulmonary infections, extrapulmonary localized infections, and disseminated infections. Invasive scedosporium infections are also associated with central nervous infection following near-drowning accidents. The most common sites of infection are the lungs, sinuses, bones, joints, eyes, and brain. Scedosporium apiospermum and Scedosporium prolificans are the two principal medically important species of this genus. Pseudallescheria boydii, the teleomorph of S. apiospermum, is recognized by the presence of cleistothecia. Recent advances in molecular taxonomy have advanced the understanding of the genus Scedosporium and have demonstrated a wider range of species than heretofore recognized. Studies of the pathogenesis of and immune response to Scedosporium spp. underscore the importance of innate host defenses in protection against these organisms. Microbiological diagnosis of Scedosporium spp. currently depends upon culture and morphological characterization. Molecular tools for clinical microbiological detection of Scedosporium spp. are currently investigational. Infections caused by S. apiospermum and P. boydii in patients and animals may respond to antifungal triazoles. By comparison, infections caused by S. prolificans seldom respond to medical therapy alone. Surgery and reversal of immunosuppression may be the only effective therapeutic options for infections caused by S. prolificans.