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Medicine Feb 2017The case reported the rapid remission of disease recurrence achieved adding foscarnet, a DNA polymerase inhibitor that interacts with fibroblast growth factor 2, to low...
RATIONALE
The case reported the rapid remission of disease recurrence achieved adding foscarnet, a DNA polymerase inhibitor that interacts with fibroblast growth factor 2, to low molecular weight heparin and sunitinib for the first time in a patient with an anaplastic thyroid cancer (ATC).
PATIENT CONCERNS
A 65-year-old woman with a multinodular goiter referred for a rapid enlargement of a nodule. Histological examination revealed an ATC with a little area of papillary thyroid cancer (PTC). The patient was resistant to selective single-target treatment.
DIAGNOSES
Immunophenotyping and gene analyses found a significant increase in FGF2 and FGFR1 expression in the primary ATC area (FGF2 = 38.2 ± 6.2% in ATC vs 34.6 ± 6.0% in the differentiated area of PTC, P < 0.05; FGFR1: 41.7 ± 6.0% in ATC vs 34.4 ± 4.2% in PTC, P < 0.001) and in metastatic neck lymph nodes (P < 0.001 vs normal control tissues). Unlike conventional imaging, F-FDG PET/CT with PERCIST 1.0 criteria promptly and quantitatively detected disease recurrence and remission before and after multitarget therapy, combining anatomic, metabolic, and functional data.
INTERVENTIONS
Foscarnet was administered given the positivity for FGF2, FGFR1 and FGFR4 in ATC. Low molecular wight heparin and Sunitinib were coadministere to limiti metastatic progression and on neck tumor masse, respectively.
OUTCOMES
The rationale for the clinical response to this innovative multitarget association with foscarnet is based on the histological and genetic finding that fibroblast growth factors and their receptor super-family are up-regulated in the primary anaplastic thyroid tumor and in the metastatic lymph node of our patient.
LESSONS
We propose that fibroblast growth factors and their receptor super-family play a key role as potential therapeutic targets in anaplastic thyroid cancer and the positive relevance of this suggestion for patient care, especially for an individualized management.
Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Antiviral Agents; Female; Fluorodeoxyglucose F18; Foscarnet; Humans; Positron Emission Tomography Computed Tomography; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms
PubMed: 28178124
DOI: 10.1097/MD.0000000000005621 -
Mikrobiyoloji Bulteni Apr 2023Encephalitis is the inflammation of the brain parenchyma accompanied by mental or behavioral neurological dysfunction, sensory or motor deficits, speech or movement...
Encephalitis is the inflammation of the brain parenchyma accompanied by mental or behavioral neurological dysfunction, sensory or motor deficits, speech or movement disorders, and seizure. Encephalitis is an acute, life-threatening emergency that requires prompt recognition and a systematic approach for appropriate management. Human herpes virus (HHV-7) is one of the causative agents of encephalitis. In this report, a three years and six months old girl admitted to the hospital with the complaints of fever, cough, gushing vomiting, and altered consciousness, with fever, neck stiffness and blurred consciousness in her physical examination, and positive HHV-7 DNA polymerase chain reaction (PCR) in the cerebrospinal fluid (CSF) was presented. The CSF biochemistry of the patient was normal, and lymphocytic pleocytosis was detected in the CSF. Electroencephalography of the case revealed a cerebral dysfunction and hyperexcitability due to background activity abnormalities, and a cytotoxic transient lesion of the splenium in cranial magnetic resonance imaging. A 14-day foscarnet treatment was given to the patient after she progressed under empirical acyclovir treatment and HHV-7 was found to be the causative agent in the CSF. The patient was cured with the treatment and was followed up on an outpatient basis without any sequelae. In general, HHV-7 is estimated to be a common cause of pediatric acute encephalitis cases. It has been observed in the literature that almost all of the HHV-7-associated encephalitis cases occur after the age of six years, suggesting that HHV-7 causes neurological disease in children as a late infection. This case was three years and six months old and it was thought that she had encephalitis during primary infection. With this case report, we contributed to the literature by presenting a case of encephalitis in an immunocompetent pediatric patient with a transient splenial lesion associated with HHV-7, which progressed with empirical acyclovir treatment and responded to foscarnet treatment.
Topics: Humans; Child; Female; Infant; Antiviral Agents; Foscarnet; Herpesvirus 7, Human; Acyclovir; Encephalitis
PubMed: 37067214
DOI: 10.5578/mb.20239925 -
The Journal of Antimicrobial... Sep 2016The objectives of this study were to elucidate the genetic context of a novel plasmid-mediated fosA variant, fosA6, conferring fosfomycin resistance and to characterize...
OBJECTIVES
The objectives of this study were to elucidate the genetic context of a novel plasmid-mediated fosA variant, fosA6, conferring fosfomycin resistance and to characterize the kinetic properties of FosA6.
METHODS
The genome of fosfomycin-resistant Escherichia coli strain YD786 was sequenced. Homologues of FosA6 were identified through BLAST searches. FosA6 and FosA(ST258) were purified and characterized using a steady-state kinetic approach. Inhibition of FosA activity was examined with sodium phosphonoformate.
RESULTS
Plasmid-encoded glutathione-S-transferase (GST) FosA6 conferring high-level fosfomycin resistance was identified in a CTX-M-2-producing E. coli clinical strain at a US hospital. fosA6 was carried on a self-conjugative, 69 kb IncFII plasmid. The ΔlysR-fosA6-ΔyjiR_1 fragment, located between IS10R and ΔIS26, was nearly identical to those on the chromosomes of some Klebsiella pneumoniae strains (MGH78578, PMK1 and KPPR1). FosA6 shared >99% identity with chromosomally encoded FosA(PMK1) in K. pneumoniae of various STs and 98% identity with FosA(ST258), which is commonly found in K. pneumoniae clonal complex (CC) 258 including ST258. FosA6 and FosA(ST258) demonstrated robust GST activities that were comparable to each other. Sodium phosphonoformate, a GST inhibitor, reduced the fosfomycin MICs by 6- to 24-fold for K. pneumoniae and E. coli strains carrying fosA genes on the chromosomes and plasmids, respectively.
CONCLUSIONS
fosA6, probably captured from the chromosome of K. pneumoniae, conferred high-level fosfomycin resistance in E. coli. FosA6 functioned as a GST and inactivated fosfomycin efficiently. K. pneumoniae may serve as a reservoir of fosfomycin resistance for E. coli.
Topics: Aged; Anti-Bacterial Agents; DNA, Bacterial; Drug Resistance, Bacterial; Enzyme Inhibitors; Escherichia coli; Escherichia coli Infections; Escherichia coli Proteins; Female; Foscarnet; Fosfomycin; Genome, Bacterial; Glutathione Transferase; Humans; Kinetics; Microbial Sensitivity Tests; Plasmids; Sequence Analysis, DNA; Urine; beta-Lactamases
PubMed: 27261267
DOI: 10.1093/jac/dkw177 -
Romanian Journal of Ophthalmology 2021To report a case of acute retinal necrosis (ARN) and to emphasize special aspects of the management. Factors that must be considered. We present the case of an...
To report a case of acute retinal necrosis (ARN) and to emphasize special aspects of the management. Factors that must be considered. We present the case of an 83-year-old woman examined for acute vision loss in her left eye (LE). Background: diabetes, pseudophakic in her LE; subluxated intraocular lens (IOL) and advanced pseudoexfoliative glaucoma in her right eye (RE). The visual acuity (VA) was hand movements in both eyes. Funduscopic examination revealed vitritis, temporal area of retinal necrosis with peripapillary choroiditis spots and macular haemorrhages in her LE and OCT showed a cystic macular edema. A positive polymerase chain reaction (PCR) test for Varicella Zoster Virus (VZV) in aqueous humor of her LE was found. She underwent intravenous Acyclovir 10 mg per kg every 8 hours. She received two doses of adjunctive intravitreal Foscarnet (2.4 mg/ 0.1 mL) in the first 3 days of treatment (2 days between doses). After 3 days of treatment, she started with intravenous prednisone 60 mg per day. The VA of her LE was 0,8 and the retinal necrosis activity was stationary. In fundoscopic examination, vitritis and retinal hemorrhages have disappeared. At that moment there were no foci of chorioretinitis or macular edema although retinal ischemia persisted at the inferior nasal level. The role of adjunctive intravitreal antiviral therapy in combination with systemic treatment revealed promising results. Corticosteroids can be used topically and orally to decrease the severe inflammatory response associated with ARN. Early treatment is crucial to optimize visual and anatomic outcomes.
Topics: Acyclovir; Aged, 80 and over; Eye Infections, Viral; Female; Foscarnet; Herpesvirus 3, Human; Humans; Retinal Necrosis Syndrome, Acute
PubMed: 35036649
DOI: 10.22336/rjo.2021.53 -
Antimicrobial Agents and Chemotherapy Dec 2017FosA proteins confer fosfomycin resistance to Gram-negative pathogens via glutathione-mediated modification of the antibiotic. In this study, we assessed whether...
FosA proteins confer fosfomycin resistance to Gram-negative pathogens via glutathione-mediated modification of the antibiotic. In this study, we assessed whether inhibition of FosA by sodium phosphonoformate (PPF) (foscarnet), a clinically approved antiviral agent, would reverse fosfomycin resistance in representative Gram-negative pathogens. The inhibitory activity of PPF against purified recombinant FosA from (FosA3), (FosA), (FosA), and (FosA) was determined by steady-state kinetic measurements. The antibacterial activity of PPF against FosA in clinical strains of these species was evaluated by susceptibility testing and time-kill assays. PPF increased the Michaelis constant ( ) for fosfomycin in a dose-dependent manner, without affecting the maximum rate () of the reaction, for all four FosA enzymes tested, indicating a competitive mechanism of inhibition. Inhibitory constant ( ) values were 22.6, 35.8, 24.4, and 56.3 μM for FosA, FosA, FosA, and FosA3, respectively. Addition of clinically achievable concentrations of PPF (∼667 μM) reduced the fosfomycin MICs by ≥4-fold among 52% of the , , and clinical strains tested and led to a bacteriostatic or bactericidal effect in time-kill assays among representative strains. PPF inhibits FosA activity across Gram-negative species and can potentiate fosfomycin activity against the majority of strains with chromosomally encoded These data suggest that PPF may be repurposed as an adjuvant for fosfomycin to treat infections caused by some FosA-producing, multidrug-resistant, Gram-negative pathogens.
Topics: Anti-Bacterial Agents; Antiviral Agents; Drug Repositioning; Drug Resistance, Multiple, Bacterial; Drug Synergism; Drug Therapy, Combination; Enterobacter cloacae; Escherichia coli; Escherichia coli Proteins; Foscarnet; Fosfomycin; Kinetics; Klebsiella pneumoniae; Microbial Sensitivity Tests; Protein Isoforms; Pseudomonas aeruginosa; Recombinant Proteins
PubMed: 28993329
DOI: 10.1128/AAC.01424-17 -
PLoS Pathogens May 2018Late gene transcription in herpesviruses is dependent on viral DNA replication in cis but the mechanistic basis for this linkage remains unknown. DNA replication results...
Late gene transcription in herpesviruses is dependent on viral DNA replication in cis but the mechanistic basis for this linkage remains unknown. DNA replication results in demethylated DNA, topological changes, removal of proteins and recruitment of proteins to promoters. One or more of these effects of DNA replication may facilitate late gene transcription. Using 5-azacytidine to promote demethylation of DNA, we demonstrate that late gene transcription cannot be rescued by DNA demethylation. Late gene transcription precedes significant increases in DNA copy number, indicating that increased template numbers also do not contribute to the linkage between replication and late gene transcription. By using serial, timed blockade of DNA replication and measurement of late gene mRNA accumulation, we demonstrate that late gene transcription requires ongoing DNA replication. Consistent with these findings, blocking DNA replication led to dissolution of DNA replication complexes which also contain RNA polymerase II and BGLF4, an EBV protein required for transcription of several late genes. These data indicate that ongoing DNA replication maintains integrity of a replication-transcription complex which is required for recruitment and retention of factors necessary for late gene transcription.
Topics: Azacitidine; DNA Demethylation; DNA Replication; DNA-Directed DNA Polymerase; Enzyme Inhibitors; Gammaherpesvirinae; Gene Expression Regulation, Viral; Genes, Immediate-Early; Kinetics; Nucleic Acid Synthesis Inhibitors; Phosphonoacetic Acid; Promoter Regions, Genetic; Transcription, Genetic; Virus Replication
PubMed: 29813138
DOI: 10.1371/journal.ppat.1007070 -
Clinical NephrologyFoscarnet (trisodium phosphonoformate hexahydrate) is standard treatment for ganciclovir-resistant cytomegalovirus (CMV) infections. In the kidney, foscarnet-induced...
INTRODUCTION
Foscarnet (trisodium phosphonoformate hexahydrate) is standard treatment for ganciclovir-resistant cytomegalovirus (CMV) infections. In the kidney, foscarnet-induced injury may be attributed to reversible tubulointerstitial lesions, but foscarnet crystals have also been observed within glomerular capillaries, suggesting that foscarnet can lead to glomerular lesions such as crescentic glomerulonephritis. We present biopsy and autopsy findings of foscarnet induced nephropathy in a transplanted kidney, with a particular emphasis on the histopathology and electron micrographic peculiarities of drug crystal deposits.
CASE PRESENTATION
A 72-year-old Caucasian male patient with a deceased donor kidney was treated with several foscarnet applications due to ganciclovir-resistant CMV infection. Transplant kidney biopsy revealed massive glomerular crystalline precipitates, resulting in crescentic glomerulonephritis and tubular damage. The last foscarnet application was complicated with several infections and kidney graft failure. Autopsy revealed multi-organ damage due to foscarnet crystal precipitations associated with systemic CMV and fungal infection. On autopsy of kidney specimens, we succeeded in preserving the rectangular flat plate-like foscarnet crystals in stacks detected by transmission electron microscopy (TEM) after 100% alcohol fixation. The chemical composition of the crystals was confirmed by attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy.
CONCLUSION
Transplant kidney biopsy remains the gold standard in distinguishing between foscarnet crystalline glomerular and/or tubulointerstitial lesions, and various forms of rejection and other causes of impaired renal function in transplant kidney.
Topics: Aged; Allografts; Antiviral Agents; Foscarnet; Ganciclovir; Humans; Kidney; Kidney Transplantation; Male; Nephritis, Interstitial
PubMed: 34643504
DOI: 10.5414/CNP96S23 -
Antimicrobial Agents and Chemotherapy Mar 2020Herein, we phenotypically and enzymatically characterize the theoretical mutation Q579I in helix K and the already described clinical mutation K805Q in helix P of...
Herein, we phenotypically and enzymatically characterize the theoretical mutation Q579I in helix K and the already described clinical mutation K805Q in helix P of cytomegalovirus DNA polymerase for susceptibility to foscarnet. Q579I and K805Q recombinant viruses were hypersusceptible to foscarnet (respective mean 50% effective concentrations [EC] of 0.12- and 0.19-fold that of the wild type). Three-dimensional modeling analysis suggested that both mutations favor the closed conformation of the enzyme to which foscarnet binds with a higher affinity.
Topics: Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; DNA, Viral; DNA-Directed DNA Polymerase; Drug Resistance, Viral; Foscarnet; Humans; Models, Molecular; Mutation
PubMed: 32015044
DOI: 10.1128/AAC.01910-19 -
BMJ Case Reports Dec 2021The early engraftment phase of allogeneic haematopoietic stem cell transplantation can be associated with a number of oromucosal infective complications. While the...
The early engraftment phase of allogeneic haematopoietic stem cell transplantation can be associated with a number of oromucosal infective complications. While the routine use of prophylactic acyclovir has reduced the incidence of herpes simplex virus (HSV) reactivation, there is an increasing prevalence of acyclovir resistance within this cohort of patients. The authors present a case of acyclovir-resistant HSV reactivation in a 26-year-old woman 7 days post T-deplete sibling allograft on a background of combined cyclophosphamide and total body irradiation myeloablative conditioning, successfully treated with foscarnet and cidofovir therapy and discuss the differential diagnoses for early/late engraftment oral disease.
Topics: Acyclovir; Adult; Antiviral Agents; Female; Foscarnet; Hematopoietic Stem Cell Transplantation; Herpes Simplex; Humans
PubMed: 34969809
DOI: 10.1136/bcr-2021-247109 -
Biochemistry Feb 2016We examined the impact of two clinically approved anti-herpes drugs, acyclovir and Forscarnet (phosphonoformate), on the exonuclease activity of the herpes simplex...
Effects of Acyclovir, Foscarnet, and Ribonucleotides on Herpes Simplex Virus-1 DNA Polymerase: Mechanistic Insights and a Novel Mechanism for Preventing Stable Incorporation of Ribonucleotides into DNA.
We examined the impact of two clinically approved anti-herpes drugs, acyclovir and Forscarnet (phosphonoformate), on the exonuclease activity of the herpes simplex virus-1 DNA polymerase, UL30. Acyclovir triphosphate and Foscarnet, along with the closely related phosphonoacetic acid, did not affect exonuclease activity on single-stranded DNA. Furthermore, blocking the polymerase active site due to either binding of Foscarnet or phosphonoacetic acid to the E-DNA complex or polymerization of acyclovir onto the DNA also had a minimal effect on exonuclease activity. The inability of the exonuclease to excise acyclovir from the primer 3'-terminus results from the altered sugar structure directly impeding phosphodiester bond hydrolysis as opposed to inhibiting binding, unwinding of the DNA by the exonuclease, or transfer of the DNA from the polymerase to the exonuclease. Removing the 3'-hydroxyl or the 2'-carbon from the nucleotide at the 3'-terminus of the primer strongly inhibited exonuclease activity, although addition of a 2'-hydroxyl did not affect exonuclease activity. The biological consequences of these results are twofold. First, the ability of acyclovir and Foscarnet to block dNTP polymerization without impacting exonuclease activity raises the possibility that their effects on herpes replication may involve both direct inhibition of dNTP polymerization and exonuclease-mediated destruction of herpes DNA. Second, the ability of the exonuclease to rapidly remove a ribonucleotide at the primer 3'-terminus in combination with the polymerase not efficiently adding dNTPs onto this primer provides a novel mechanism by which the herpes replication machinery can prevent incorporation of ribonucleotides into newly synthesized DNA.
Topics: Acyclovir; Antiviral Agents; Catalytic Domain; DNA, Single-Stranded; DNA-Directed DNA Polymerase; Exodeoxyribonucleases; Foscarnet; Herpesvirus 1, Human; Hydrolysis; Kinetics; Models, Molecular; Molecular Structure; Nucleic Acid Synthesis Inhibitors; Recombinant Proteins; Ribonucleotides; Substrate Specificity; Viral Proteins
PubMed: 26836009
DOI: 10.1021/acs.biochem.6b00065