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Antimicrobial Agents and Chemotherapy Feb 2021The objectives of this study were to characterize the role of the , , and genes in fosfomycin resistance in and evaluate the use of sodium phosphonoformate (PPF) in...
The objectives of this study were to characterize the role of the , , and genes in fosfomycin resistance in and evaluate the use of sodium phosphonoformate (PPF) in combination with fosfomycin. Seven clinical isolates of and the reference strain (ATCC 700721) were used, and their genomes were sequenced. Δ, Δ, and Δ mutants were constructed from two isolates and ATCC 700721. Fosfomycin susceptibility testing was done by the gradient strip method. Synergy between fosfomycin and PPF was studied by checkerboard assay and analyzed using SynergyFinder. Spontaneous fosfomycin mutant frequencies at 64 and 512 mg/liter, activity using growth curves with fosfomycin gradient concentrations (0 to 256mg/liter), and time-kill assays at 64 and 307 mg/liter were evaluated with and without PPF (0.623 mM). The MICs of fosfomycin against the clinical isolates ranged from 16 to ≥1,024 mg/liter. The addition of 0.623 mM PPF reduced fosfomycin MIC between 2- and 8-fold. Deletion of led to a 32-fold decrease. Synergistic activities were observed with the combination of fosfomycin and PPF (most synergistic area at 0.623 mM). The lowest fosfomycin-resistant mutant frequencies were found in Δ mutants, with decreases in frequency from 1.69 × 10 to 1.60 × 10 for 64 mg/liter of fosfomycin. In the final growth monitoring and time-kill assays, fosfomycin showed a bactericidal effect only with the deletion of and not with the addition of PPF. We conclude that gene inactivation leads to a decrease in fosfomycin resistance in The pharmacological approach using PPF did not achieve enough activity, and the effect decreased with the presence of fosfomycin-resistant mutations.
Topics: Anti-Bacterial Agents; Foscarnet; Fosfomycin; Klebsiella pneumoniae; Microbial Sensitivity Tests; beta-Lactamases
PubMed: 33361305
DOI: 10.1128/AAC.01911-20 -
Retinal Cases & Brief Reports Nov 2022To describe a patient with recurrent acute retinal necrosis (ARN), her treatment, and propose a possible pathophysiologic mechanism.
PURPOSE
To describe a patient with recurrent acute retinal necrosis (ARN), her treatment, and propose a possible pathophysiologic mechanism.
METHOD
Case report.
RESULTS
A 4-year-old girl presented elsewhere with bilateral ARN, was treated, but developed a retinal detachment in the left eye that failed vitrectomy surgery. She was referred 10 years later with recurrent ARN. The infection was difficult to get under control, but eventually responded to intravenous acyclovir and foscarnet. She was given laser photocoagulation. She was placed on oral valacyclovir prophylaxis and was disease-free for 10 years at which point she decided to go to South America on vacation and stop her valacyclovir. Within a few days she developed a recurrence of ARN and flew back for treatment. She had discrete areas of retinal necrosis, vasculitis, and the laser photocoagulation lesions seemed to be ringed by a retinal change suggestive of retinitis. She responded to antiviral treatment, but developed a retinal detachment that was successfully treated. Her visual acuity was 20/20 six years later, and she was using antiviral prophylaxis.
CONCLUSION
Recurrent ARN can respond to aggressive treatment. Chorioretinal scars, such as from photocoagulation, may be potential sites of viral invasion during recurrences. Antiviral prophylaxis may be indicated for at-risk patients.
Topics: Female; Humans; Child, Preschool; Retinal Necrosis Syndrome, Acute; Valacyclovir; Foscarnet; Retinal Detachment; Acyclovir; Antiviral Agents
PubMed: 33346624
DOI: 10.1097/ICB.0000000000001107 -
Virologie (Montrouge, France) Oct 2020Herpes simplex virus (HSV) infections remain an important cause of morbidity among immunocompromised patients, such as transplant recipients and human immunodeficiency...
Herpes simplex virus (HSV) infections remain an important cause of morbidity among immunocompromised patients, such as transplant recipients and human immunodeficiency virus [HIV]-infected individuals. Only few antiviral drugs are available to treat HSV infections: (val)acyclovir, foscarnet, and cidofovir. Prophylactic and curative antiviral treatments administered during prolonged periods among patients with altered T-cell immunity may lead to the emergence of HSV resistance to antivirals, contributing to a challenging therapeutic management of viral infection. The persistence of herpetic lesions after 10 days of well-conducted antiviral therapy is suggestive of viral resistance. Resistance to antivirals can be detected using genotypic methods (identifications of antiviral resistance-associated mutations by sequencing genes encoding viral proteins involved in the mechanism of action of antivirals) or phenotypic methods (measure of antiviral drug concentration inhibiting 50% of viral replication in cell culture). The prevalence of HSV resistance to acyclovir is below 1% in immunocompetent individuals, except those with herpetic keratitis for whom prevalence can reach 7%, and varies from 3.5% to 11% in immunocompromised patients. Adverse effects and the absence of eradication of viral latent infection constitute other limits to the use of antiviral drugs. New antiviral compounds undergoing clinical trials and novel potential viral targets seem very promising to enlarge the panel of efficient compounds to treat HSV infections.
Topics: Acyclovir; Antiviral Agents; Foscarnet; Herpes Simplex; Humans; Simplexvirus
PubMed: 33111706
DOI: 10.1684/vir.2020.0864 -
Oncology Research and Treatment 2020We report on patients who developed severe acyclovir-resistant (ACVr) herpes simplex virus 1 (HSV-1) stomatitis after allogeneic hematopoietic cell transplantation (HCT).
INTRODUCTION
We report on patients who developed severe acyclovir-resistant (ACVr) herpes simplex virus 1 (HSV-1) stomatitis after allogeneic hematopoietic cell transplantation (HCT).
PATIENTS
HCT patients suffering from HSV-1 stomatitis without response after 1 week of high-dose acyclovir (ACV) were tested for ACV resistance. Patients with proven ACV resistance were treated either topically with cidofovir solution and gel or with topical foscavir cream or with intravenous foscavir.
RESULTS
Among 214 consecutive HCT patients, 6 developed severe ACVr HSV-1 stomatitis (WHO grade III n = 1, WHO grade IV n = 5). All 6 patients suffered from relapse of acute myeloid leukemia (AML) after HCT. ACVr stomatitis was treated topically with first-line (n = 4) or second-line (n = 2) cidofovir. Topical foscavir cream was applied as first-line (n = 1) or second-line (n = 1) therapy. Intravenous foscavir was used in 3 patients (first-line therapy, n = 1; second-line therapy, n = 2). Complete remission was reached by topical cidofovir (n = 3), topical foscavir (n = 1), and intravenous foscavir (n = 1), respectively. Five of the 6 patients died due to progression of leukemia. Only 1 patient survived.
CONCLUSIONS
ACVr HSV-1 stomatitis is a severe complication in AML patients relapsing after HCT. It reflects the seriously impaired general condition of these patients. This analysis shows that topical treatment with cidofovir or foscavir might be a sufficient first-line therapy approach in ACVr HSV-1 stomatitis. It might serve as a less toxic alternative to intravenous foscavir.
Topics: Acyclovir; Administration, Topical; Adult; Aged; Antiviral Agents; Cidofovir; Drug Resistance, Viral; Female; Foscarnet; Hematopoietic Stem Cell Transplantation; Herpes Simplex; Herpesvirus 1, Human; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Stomatitis; Treatment Outcome
PubMed: 33070144
DOI: 10.1159/000510988 -
Transplantation and Cellular Therapy Jan 2021The high incidence of human herpesvirus-6 (HHV-6) reactivation, potentially interfering with engraftment after umbilical cord blood (UCB) hematopoietic cell...
The high incidence of human herpesvirus-6 (HHV-6) reactivation, potentially interfering with engraftment after umbilical cord blood (UCB) hematopoietic cell transplantation (HCT), remains a major challenge. To potentially address this problem, we evaluated the effect of prophylactic foscarnet administered twice daily beginning on day +7 and continuing through engraftment in 25 patients. To determine the impact of foscarnet on HHV-6, engraftment, and other transplantation outcomes, we compared results in 61 identically treated patients with hematologic malignancies. Treatment and control groups underwent reduced-intensity conditioning UCB HCT with a conditioning regimen of fludarabine, cyclophosphamide, and total body irradiation 200 cGy with or without antithymocyte globulin (ATG), using sirolimus plus mycophenolate mofetil immune suppression. The treatment and control groups were similar in terms of age, disease risk, use of ATG, Hematopoietic Cell Transplantation Comorbidity Index, and graft CD34 cell dose; however, foscarnet-treated patients were less likely to receive a double UCB graft and to be treated more recently (2016 to 2018). The cumulative incidence of HHV-6 reactivation by day +100 was 63% for all patients (95% confidence interval [CI], 51% to 75%) and was not significantly different between the 2 groups. HHV-6 reactivation occurred at a median of 34 days in the foscarnet group and 25.5 days in the control group. The incidence of neutrophil engraftment at day 42 was higher in the foscarnet group compared with the control group (96%; [95% CI, 83% to 100%] versus 75% [95% CI, 64% to 85%]; P< .01). The cumulative incidence of platelet engraftment by 6 months was 92% (95% CI, 69% to 100%) for the foscarnet group versus 75% (95% CI, 60% to 90%) for the control group (P= .08), and multivariate analysis identified the use of foscarnet as an independent predictor of better platelet engraftment. No patients died as a result of graft failure in recipients of foscarnet, whereas 5 patients died from graft failure in the control group. Six-month overall survival (OS) and nonrelapse mortality (NRM) were better in the foscarnet group (96% versus 72% [P= .02] and 4% versus 18% [P= .07], respectively). Even though foscarnet prophylaxis did not prevent HHV-6 viremia, we observed a delay in time to HHV-6 reactivation, a trend toward differences in engraftment, NRM, and OS compared with historical controls.
Topics: Cord Blood Stem Cell Transplantation; Foscarnet; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Herpesvirus 6, Human; Humans
PubMed: 33053448
DOI: 10.1016/j.bbmt.2020.10.008 -
[Rinsho Ketsueki] the Japanese Journal... 2020Human herpesvirus (HHV)-6B encephalitis has been increasingly recognized as an important central nervous system (CNS) complication after allogeneic hematopoietic stem... (Review)
Review
Human herpesvirus (HHV)-6B encephalitis has been increasingly recognized as an important central nervous system (CNS) complication after allogeneic hematopoietic stem cell transplantation. In this review, the best way to diagnose and treat this devastating complication is described. Diagnostic pitfalls: HHV-6B encephalitis should be diagnosed based on the presence of CNS symptoms, positive results for HHV-6 DNA in the cerebrospinal fluid (CSF), and exclusion of other causes of CNS symptoms. There are potential pitfalls when diagnosing HHV-6B encephalitis. Moreover, false-positive detection of HHV-6 DNA in the CSF can occur. Pleocytosis is observed in few patients, and CSF protein levels are often normal. Limbic encephalitis findings are not commonly detected through a brain MRI at the time of development. Prevention: Neither routine monitoring nor routine prophylactic antiviral therapy is recommended to prevent the development of HHV-6B encephalitis. Treatment: Empiric therapy should be started immediately after HHV-6B encephalitis is suspected. The Guideline Committee of the JSHCT recommends full-dose foscarnet (180 mg/kg/day) for the treatment of HHV-6B encephalitis. Therapeutic effect of anti-HHV6 therapy is assessed based on CNS symptoms and HHV-6 DNA in the CSF, which should be evaluated 1-2 weeks after initiating treatment. Even in patients exhibiting good therapeutic effects, antiviral treatment should be continued for at least 3 weeks.
Topics: Encephalitis, Viral; Foscarnet; Hematopoietic Stem Cell Transplantation; Herpesvirus 6, Human; Humans; Roseolovirus Infections; Transplantation, Homologous
PubMed: 32908059
DOI: 10.11406/rinketsu.61.945 -
Bioorganic Chemistry Nov 2020A series of alkylphosphocholines with foscarnet moiety was synthesized. The structure of these zwitterionic amphiphiles was modified in both polar and non-polar parts of...
A series of alkylphosphocholines with foscarnet moiety was synthesized. The structure of these zwitterionic amphiphiles was modified in both polar and non-polar parts of surfactant molecule. Investigations of physicochemical properties are represented by the determination of critical micelle concentration, the surface tension value at the cmc and the surface area per surfactant head group utilising surface tension measurements. Hydrodynamic diameter of surfactant micelles was determined using the dynamic light scattering technique. Alkylphosphocholines exhibit significant cytotoxic, anticandidal (Candida albicans) and antiamoebal (Acanthamoeba spp. T4 genotype) activity. The relationship between the structure, physicochemical properties and biological activity of the tested compounds revealed that lipophilicity has a significant influence on biological activity of the investigated surfactants. More lipophilic alkylphosphocholines with octadecyl chains show cytotoxic activity against cancer cells which is higher than that of the compounds with shorter alkyl chains. The opposite situation was observed in case of anticandidal and antiamoebal activity of these surfactants. The most active compounds were found to have pentadecyl chains. The foscarnet analogue of miltefosine C15-PFA-C showed the highest anticandidal activity. The minimum value of anticandidal activity of this compound is 1,4 μM thus representing the highest anticandidal activity found within the group of alkylphosphocholines.
Topics: 3T3 Cells; Acanthamoeba; Amebicides; Animals; Antifungal Agents; Antineoplastic Agents; Candida albicans; Cell Proliferation; Cells, Cultured; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Foscarnet; Humans; Hydrodynamics; Mice; Micelles; Microbial Sensitivity Tests; Molecular Structure; Parasitic Sensitivity Tests; Phosphorylcholine; Structure-Activity Relationship; Surface Tension
PubMed: 32892068
DOI: 10.1016/j.bioorg.2020.104224 -
Accounts of Chemical Research Oct 2020Chemically modified oligonucleotides are being developed as a new class of medicines for curing conditions that previously remained untreatable. Three primary classes of...
Chemically modified oligonucleotides are being developed as a new class of medicines for curing conditions that previously remained untreatable. Three primary classes of therapeutic oligonucleotides are single-stranded antisense oligonucleotides (ASOs), double stranded small interfering RNAs (siRNAs), and oligonucleotides that induce exon skipping. Recently, ASOs, siRNAs, and exon skipping oligonucleotides have been approved for patients with unmet medical needs, and many other candidates are being tested in late stage clinical trials. In coming years, therapeutic oligonucleotides may match the promise of small molecules and antibodies. Interestingly, in the 1980s when we developed chemical methods for synthesizing oligonucleotides, no one would have imagined that these highly charged macromolecules could become future medicines. Indeed, the anionic nature and poor metabolic stability of the natural phosphodiester backbone provided a major challenge for the use of oligonucleotides as therapeutic drugs. Thus, chemical modifications of oligonucleotides were essential in order to improve their pharmacokinetic properties. Keeping this view in mind, my laboratory has developed a series of novel oligonucleotides where one or both nonbridging oxygens in the phosphodiester backbone are replaced with an atom or molecule that introduces molecular properties that enhance biological activity. We followed two complementary approaches. One was the use of phosphoramidites that could act directly as synthons for the solid phase synthesis of oligonucleotide analogues. This approach sometimes was not feasible due to instability of various synthons toward the reagents used during synthesis of oligonucleotides. Therefore, using a complementary approach, we developed phosphoramidite synthons that can be incorporated into oligonucleotides with minimum changes in the solid phase DNA synthesis protocols but contain a handle for generating appropriate analogues postsynthetically.This Account summarizes our efforts toward preparing these types of analogues over the past three decades and discusses synthesis and properties of backbone modified oligonucleotides that originated from the Caruthers' laboratory. For example, by replacing one of the internucleotide oxygens with an acetate group, we obtained so-called phosphonoacetate oligonucleotides that were stable to nucleases and, when delivered as esters, entered into cells unaided. Alternatively oligonucleotides bearing borane phosphonate linkages were found to be RNase H active and compatible with the endogenous RNA induced silencing complex (RISC). Oligonucleotides containing an alkyne group directly linked to phosphorus in the backbone were prepared as well and used to attach molecules such as amino acids and peptides.
Topics: Boranes; DNA; Foscarnet; Oligonucleotides; Organophosphonates; Organophosphorus Compounds; Phosphines; Phosphonoacetic Acid; Phosphorus
PubMed: 32885957
DOI: 10.1021/acs.accounts.0c00078 -
International Journal of Hematology Dec 2020Many drugs are used for unapproved indications in Japan for post hematopoietic stem cell transplant (HCT) complications. To investigate unapproved or off-label drug...
Many drugs are used for unapproved indications in Japan for post hematopoietic stem cell transplant (HCT) complications. To investigate unapproved or off-label drug usage for graft-versus-host disease (GVHD) and virus infections after allogeneic HCT, we analyzed the data of Japanese HCT registry. Between 2006 and 2017, 39,941 adults and children received HCT for a variety of disease and their transplant data were captured in the registry. Among them, 14,687 and 8914 patients receiving treatment for acute and/or chronic GVHD, 24,828 patients with cytomegalovirus (CMV) infection or receiving therapies for CMV, and 4943 who received treatment for other viral infections were included in the analyses of off-label or unapproved drugs. For GVHD, mycophenolate mofetil was the most frequently used off-label drug, followed by beclomethasone, infliximab, and etanercept. For viral infections other than CMV, foscarnet was the most frequently used off-label drug. Cidofovir, which is not approved for use in Japan, was mainly used for adenovirus infection. This study demonstrated that numerous off-label and unapproved drugs have been used as key drugs for GVHD and post-transplant viral infection, and the real world date in the transplant registry may serve as an important asset to regulatory purposes.
Topics: Acute Disease; Adult; Beclomethasone; Chronic Disease; Cidofovir; Cytomegalovirus Infections; Etanercept; Female; Foscarnet; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Infliximab; Japan; Male; Middle Aged; Mycophenolic Acid; Off-Label Use; Postoperative Complications; Registries; Transplantation, Homologous; Virus Diseases
PubMed: 32875487
DOI: 10.1007/s12185-020-02972-0 -
Ocular Immunology and Inflammation Jan 2022To report the detection of retinitis in the second eye of a patient with viral acute retinal necrosis (ARN), before the appearance of clinical change, using swept-source...
PURPOSE
To report the detection of retinitis in the second eye of a patient with viral acute retinal necrosis (ARN), before the appearance of clinical change, using swept-source optical coherence tomography.
RESULTS
A 63 year-old male developed right-sided varicella-zoster virus (VZV) ARN, confirmed with aqueous sampling. High-dose intravenous aciclovir caused renal impairment and was suspended for two-days. One day later, left eye macular SS-OCT revealed focal retinal thickening and disruption of retinal architecture without clinically detectable retinitis. The patient was asymptomatic. Aqueous sampling was VZV PCR positive. He received bilateral foscarnet injections and renal adjusted dose of aciclovir. The left OCT signs improved with full restoration of retinal layers.
CONCLUSIONS
We report for the first time the use of OCT to detect pre-clinical second eye retinitis during ARN. Prompt diagnosis and combined systemic and intensive local antiviral therapy resulted in a favourable structural and functional outcome.
Topics: Eye Infections, Viral; Foscarnet; Herpesvirus 3, Human; Humans; Male; Middle Aged; Retinal Necrosis Syndrome, Acute; Tomography, Optical Coherence
PubMed: 32815746
DOI: 10.1080/09273948.2020.1783324