-
Transplantation Proceedings Mar 2024Cytomegalovirus (CMV) infections are common opportunistic infections in solid organ transplants (SOT) with increased health care resource USE and costs. Costs are...
BACKGROUND
Cytomegalovirus (CMV) infections are common opportunistic infections in solid organ transplants (SOT) with increased health care resource USE and costs. Costs are further increased with ganciclovir-resistance (GR). This study aimed to evaluate the real-world impact of conversion to oral step-down therapy on duration of foscarnet and hospital length of stay (LOS) for treatment of GR-CMV infections in SOT.
METHODS
This study included adult recipients of kidney or lung transplants who received foscarnet for genotypically documented GR-CMV while admitted at the University of Wisconsin Hospital from October 1, 2015, to January 31, 2022. Patients in the oral step-down group were converted from standard of care (SOC; foscarnet) to maribavir or letermovir; patients in the historical control group were treated with SOC.
RESULTS
Twenty-six patients met the inclusion criteria: 5 in the intervention group and 21 in the SOC group. The median viral load at foscarnet initiation was 11,435 IU/mL. Patients who received oral step-down conversion had shorter mean foscarnet duration than those who received SOC (7 ± 4 vs 37 ± 25 days, P = .017). Mean hospital LOS in the oral step-down group (16 ± 3 days) was shorter than the SOC group (33 ± 21 days; P < .001). In the SOC group, 9 patients lost their graft, and 9 patients died; 2 deaths were attributed to CMV. There were 2 deaths in the oral step-down group, neither of which was attributed to CMV.
CONCLUSION AND RELEVANCE
In this real-world case series of patients receiving treatment for GR-CMV infection, oral step-down conversion decreased foscarnet therapy duration and hospital LOS. Future studies are needed to evaluate better the effect of oral step-down in treating GR-CMV infection on treatment duration and cost-savings.
Topics: Adult; Humans; Cytomegalovirus; Foscarnet; Antiviral Agents; Ganciclovir; Cytomegalovirus Infections; Organ Transplantation; Transplant Recipients
PubMed: 38355369
DOI: 10.1016/j.transproceed.2024.01.052 -
Biochemistry Dec 2023CRISPR gene editing and control systems continue to emerge and inspire novel research and clinical applications. Advances in CRISPR performance such as optimizing the...
CRISPR gene editing and control systems continue to emerge and inspire novel research and clinical applications. Advances in CRISPR performance such as optimizing the duration of activity in cells, tissues, and organisms, as well as limiting off-target activities, have been extremely important for expanding the utility of CRISPR-based systems. By investigating the effects of various chemical modifications in guide RNAs (gRNAs) at defined positions and combinations, we find that 2'--methyl-3'-phosphonoacetate (MP) modifications can be substantially more effective than 2'--methyl-3'-phosphorothioate (MS) modifications at the 3' ends of single-guide RNAs (sgRNAs) to promote high editing yields, in some instances showing an order of magnitude higher editing yield in human cells. MP-modified 3' ends are especially effective at promoting the activity of guide RNAs cotransfected with Cas messenger RNA (mRNA), as the gRNA must persist in cells until the Cas protein is expressed. We demonstrate such an MP enhancement for sgRNAs cotransfected with a BE4 mRNA for cytidine base editing and also demonstrate that MP at the 3' ends of prime editing guide RNAs (pegRNAs) cotransfected with PE2 mRNA can promote maximal prime editing yields. In the presence of serum, sgRNAs with MP-modified 3' ends showed marked improvements in editing efficiency over sgRNAs with MS-modified 3' ends codelivered with Cas9 mRNA and showed more modest improvements at enhancing the activity of transfected ribonucleoprotein (RNP) complexes. Our results suggest that MP should be considered as a performance-enhancing modification for the 3' ends of synthetic gRNAs, especially in situations where the guide RNAs may be susceptible to exonuclease-mediated degradation.
Topics: Humans; CRISPR-Cas Systems; RNA, Guide, CRISPR-Cas Systems; Phosphonoacetic Acid; Gene Editing; RNA, Messenger
PubMed: 35436085
DOI: 10.1021/acs.biochem.1c00768 -
Chemical & Pharmaceutical Bulletin Jan 2024The spectrum of P-NMR is fundamentally simpler than that of H-NMR; consequently identifying the target signal(s) for quantitation is simpler using quantitative P-NMR...
The spectrum of P-NMR is fundamentally simpler than that of H-NMR; consequently identifying the target signal(s) for quantitation is simpler using quantitative P-NMR (P-qNMR) than using quantitative H-NMR (H-qNMR), which has been already established as an absolute determination method. We have previously reported a P-qNMR method for the absolute determination of cyclophosphamide hydrate and sofosbuvir as water-soluble and water-insoluble organophosphorus compounds, respectively. This study introduces the purity determination of brigatinib (BR), an organophosphorus compound with limited water solubility, using P-qNMR at multiple laboratories. Phosphonoacetic acid (PAA) and 1,4-BTMSB-d were selected as the reference standards (RSs) for P-qNMR and H-qNMR, respectively. The qNMR solvents were chosen based on the solubilities of BR and the RSs for qNMR. CDOH was selected as the solvent for P-qNMR measurements to prevent the influence of deuterium exchange caused by the presence of exchangeable intramolecular protons of BR and PAA on the quantitative values, while CDOD was the solvent of choice for the H-qNMR measurements to prevent the influence of water signals and the exchangeable intramolecular protons of BR and PAA. The mean purity of BR determined by P-qNMR was 97.94 ± 0.69%, which was in agreement with that determined by H-qNMR (97.26 ± 0.71%), thus indicating the feasibility of purity determination of BR by P-qNMR. Therefore, the findings of this study may provide an effective method that is simpler than conventional H-qNMR for the determination of organophosphorus compounds.
Topics: Protons; Organophosphorus Compounds; Reference Standards; Water; Solvents
PubMed: 37899177
DOI: 10.1248/cpb.c23-00635 -
European Journal of Ophthalmology Sep 2023To report a case of cytomegalovirus (CMV) retinitis improved by treatment with ganciclovir in a patient with ganciclovir-resistant CMV infection associated with Good...
PURPOSE
To report a case of cytomegalovirus (CMV) retinitis improved by treatment with ganciclovir in a patient with ganciclovir-resistant CMV infection associated with Good syndrome.
STUDY DESIGN
Case report.
RESULT
A 52-year-old gentleman with Good syndrome presented with visual disturbance in his right eye. He had a history of receiving intravitreal ganciclovir treatment with CMV retinitis a year ago. During treatment for CMV colitis three months ago, in systemic blood, UL97 mutation was identified and improved after changing treatment from ganciclovir to foscarnet. CMV retinitis recurred, and intravitreal ganciclovir injection was performed but there was no improvement. Therefore, the treatment was changed to foscarnet, but retinal infiltration progressed. Accordingly, it was changed to ganciclovir again and as a result, the progression of retinitis could be stopped.
CONCLUSIONS
Even in the case of CMV retinitis, which has been genetically confirmed to be ganciclovir resistance in systemic blood, ganciclovir treatment can be considered if other anti-CMV agents are not effective.
Topics: Humans; Male; Middle Aged; Cytomegalovirus Retinitis; Ganciclovir; Antiviral Agents; Foscarnet; Treatment Outcome
PubMed: 36314436
DOI: 10.1177/11206721221136316 -
Leukemia & Lymphoma Jun 2024Cytomegalovirus (CMV) reactivation increases treatment-related mortality (TRM) after allogeneic hematopoietic cell transplantation (allo-HCT). We analyzed 141 adult... (Comparative Study)
Comparative Study
Cytomegalovirus (CMV) reactivation increases treatment-related mortality (TRM) after allogeneic hematopoietic cell transplantation (allo-HCT). We analyzed 141 adult acute leukemia (AL) patients suffered allo-HCT between 2017 and 2021, who developed CMV viremia post-HCT and treated with valganciclovir or foscarnet, to evaluate effectiveness and safety of both drugs. Viremia clearance rates (14 and 21 d post treatment) and toxicities were similar in two groups. However, valganciclovir was associated with a lower cumulative incidence of CMV recurrence within 180 days (16.7% vs. 35.7%, =0.029) post CMV clearance. Finally, 2-year TRM was lower in valganciclovir group (9.7% ± 0.2% 26.2% ± 0.3%, = 0.026), result a superior 2-year overall survival (OS; 88.1% ± 5.2% 64.4% ± 5.5%, = 0.005) and leukemia-free survival (LFS; 82.0% ± 5.9% 58.9% ± 5.6%, = 0.009). Valganciclovir might decrease CMV viremia recurrence and led to better long-term outcome than foscarnet in adult AL patients developed CMV viremia post-HCT. Considering the inherent biases of retrospective study, well-designed trials are warranted to validate our conclusion.
Topics: Humans; Hematopoietic Stem Cell Transplantation; Cytomegalovirus Infections; Valganciclovir; Male; Female; Viremia; Adult; Antiviral Agents; Foscarnet; Middle Aged; Transplantation, Homologous; Cytomegalovirus; Retrospective Studies; Young Adult; Aged; Leukemia, Myeloid, Acute; Treatment Outcome; Leukemia
PubMed: 38475670
DOI: 10.1080/10428194.2024.2321322 -
Drug Metabolism and Pharmacokinetics Apr 2024Meropenem (MEPM) is used for the treatment of serious infectious diseases solely as. INJECTABLE: Therefore, the development of an oral formulation would expand its...
Meropenem (MEPM) is used for the treatment of serious infectious diseases solely as. INJECTABLE: Therefore, the development of an oral formulation would expand its clinical utility. To this end, an exact understanding of the absorption characteristics of MEPM is essential. In this study, MEPM absorption in the rat small intestine was investigated using an in situ loop technique and an in vitro diffusion chamber method. The disappearance ratios of MEPM (0.1 mM) were in the order of ileum > duodenum > jejunum. The extensive MEPM disappearance in the ileum was significantly reduced in the presence of foscarnet, a Na-dependent phosphate transporter (NaPi-T) substrate, whereas glycylsarcosine, thiamine, taurocholic acid, and biapenem had no effects. The mucosal-to-serosal (M-to-S) permeation of MEPM across the rat ileal segments was very small under normal experimental conditions. However, on addition of 1α,25-dihydroxyvitamin D (1,25(OH)D) to the experimental medium, the M-to-S permeation of MEPM markedly increased, showing a more than 7-fold greater apparent permeation coefficient. The present results suggest that MEPM is preferentially absorbed in the rat ileum, sharing with foscarnet, and that 1,25(OH)D potentially activates the absorption of MEPM there. A likely candidate for involvement in MEPM absorption was NaPi-T or a related transporter.
Topics: Rats; Animals; Foscarnet; Meropenem; Phosphate Transport Proteins; Ileum; Intestinal Absorption; Vitamin D
PubMed: 38367298
DOI: 10.1016/j.dmpk.2024.100997 -
Clinical Infectious Diseases : An... Apr 2024We evaluated Ibalizumab (IBA)-containing standardized optimized salvage regimen (with or without a 4-week foscarnet induction) in individuals harboring...
We evaluated Ibalizumab (IBA)-containing standardized optimized salvage regimen (with or without a 4-week foscarnet induction) in individuals harboring multidrug-resistant human immunodeficiency virus type 2 (HIV-2). Nine were included; 2 achieved virological suppression after foscarnet induction with a sustained suppression at Week 24 after IBA initiation, and an additional individual at Week 24 after Ibalizumab initiation.
Topics: Humans; Foscarnet; HIV-2; Anti-HIV Agents; Salvage Therapy; HIV Infections; Antibodies, Monoclonal
PubMed: 38630945
DOI: 10.1093/cid/ciad695 -
The Pediatric Infectious Disease Journal May 2024Cytomegalovirus (CMV) infection following allogeneic hematopoietic cell transplantation has considerable morbidity and mortality, and foscarnet is a treatment option...
Retrospective Evaluation of Cystatin C as a Measure of Renal Function in Pediatric Hematopoietic Stem Cell Transplant Patients Receiving Foscarnet for Cytomegalovirus Reactivation.
BACKGROUND
Cytomegalovirus (CMV) infection following allogeneic hematopoietic cell transplantation has considerable morbidity and mortality, and foscarnet is a treatment option that requires renal dose adjustment. Serum creatinine (SCr)-based estimated glomerular filtration rate (eGFR) equations are used to estimate renal function for patients receiving foscarnet, but cystatin C (cysC) has been shown as a possible alternative. Data examining cysC-based eGFR in this population is sparse. Our primary objective was to evaluate outcomes of patients treated with foscarnet dosed utilizing cysC-based eGFR versus SCr-based eGFR.
METHODS
We analyzed patients on the transplantation and cellular therapies service at Memorial Sloan Kettering Kids from January 2011 to September 2021 who received allogeneic hematopoietic cell transplantation and ≥14 days of foscarnet for CMV infection. Patients with cysC-based eGFR were compared to a historical cohort of patients who only had SCr-based eGFR. Outcomes included time to CMV clearance, death or change in anti-CMV therapy. Cumulative incidence curves and cause-specific hazards model were used for analysis.
RESULTS
In 61 analyzed patients, no differences were found between the cohorts in cumulative incidence of change in anti-CMV therapy ( P = 0.17) or death ( P = 0.69). After adjustment for multiple confounders, patients in the SCr cohort seemed to have a higher chance of CMV clearance compared with the cysC cohort, but the difference was not statistically significant (hazard ratio = 2.42, P = 0.089). Patients who received corticosteroids appeared to have lower incidence of CMV clearance ( P = 0.056).
CONCLUSIONS
We did not find differences in outcomes when dosing foscarnet using cysC versus SCr for treatment of CMV infection.
Topics: Humans; Child; Foscarnet; Cytomegalovirus; Cystatin C; Retrospective Studies; Cytomegalovirus Infections; Hematopoietic Stem Cell Transplantation; Kidney; Antiviral Agents
PubMed: 38190640
DOI: 10.1097/INF.0000000000004238 -
International Journal of STD & AIDS Apr 2024Herpes simplex virus (HSV) is the leading cause of genital ulcers worldwide. In rare cases, mostly among immunocompromised hosts, HSV infections can present as...
Herpes simplex virus (HSV) is the leading cause of genital ulcers worldwide. In rare cases, mostly among immunocompromised hosts, HSV infections can present as hypertrophic pseudotumoral forms simulating malignancies or often mistaken as other viral infections, usually resistant to conventional antiviral therapy and often requiring alternative therapeutic approaches. A high level of clinical suspicion is needed. We present a case of woman living with HIV with pseudotumoral vulvar herpes refractory to oral acyclovir, successfully treated with systemic foscarnet and topical imiquimod.
Topics: Female; Humans; Herpes Genitalis; Antiviral Agents; Acyclovir; Foscarnet; HIV Infections
PubMed: 38031871
DOI: 10.1177/09564624231218759 -
Journal of Infection in Developing... Jan 2024Human herpesvirus 6B (HHV-6B) encephalitis is common in immunosuppressed patients and presents a diagnostic challenge for physicians. Metagenomic next-generation...
Metagenomic Next-Generation Sequencing (mNGS) of cerebrospinal fluid for diagnosis of human herpesvirus 6B encephalitis following transplantation for severe aplastic anemia.
INTRODUCTION
Human herpesvirus 6B (HHV-6B) encephalitis is common in immunosuppressed patients and presents a diagnostic challenge for physicians. Metagenomic next-generation sequencing (mNGS) may facilitate early diagnosis of HHV-6B encephalitis. Herein, we described a case of HHV-6B encephalitis following transplantation for severe aplastic anemia (SAA) diagnosed by mNGS.
CASE SUMMARY
A 31-year-old male underwent myeloablative haploid hematopoietic stem cell transplantation for the treatment of SAA. On day + 21 after transplantation, the patient developed symptoms such as sudden epilepsy, drowsiness, memory dislocation, and memory loss. HHV-6B encephalitis was confirmed based on cranial MRI and mNGS of cerebrospinal fluid. Following antiviral therapy with sodium foscarnet, the symptoms improved and HHV-6B was negative by mNGS. There were no serious sequelae. Currently, the patient is in good health and is still under follow-up.
CONCLUSIONS
A case of HHV-6B encephalitis after SAA transplantation was diagnosed by mNGS of cerebrospinal fluid in time and was effectively treated with sodium foscarnet.
Topics: Male; Humans; Adult; Foscarnet; Herpesvirus 6, Human; Anemia, Aplastic; Encephalitis, Viral; Roseolovirus Infections; Hematopoietic Stem Cell Transplantation; Encephalitis; High-Throughput Nucleotide Sequencing; Sodium
PubMed: 38377081
DOI: 10.3855/jidc.18152