Advances in pharmacotherapies for cytomegalovirus infection: what is the current state of play?

INTRODUCTION: Cytomegalovirus (CMV) remains a serious opportunistic infection in hematopoietic cell transplant (HCT) and solid-organ transplant (SOT) recipients. Traditional anti-CMV drugs are limited by toxicities and the development of resistance. Letermovir and maribavir are newly approved antivirals for the prevention and treatment of CMV. AREAS COVERED: Prior reviews have discussed use of letermovir for prevention of CMV after HCT and maribavir for resistant or refractory (R/R) CMV post HCT or SOT. Subsequent data have expanded their use including letermovir for primary CMV prophylaxis in high-risk renal transplant recipients and new recommendations for extending prophylaxis through day + 200 in certain HCT patients. Data on the use of maribavir for first asymptomatic CMV infection post-HCT has also been published. This review compares the pharmacology of anti-CMV agents and discusses the updated literature of these new drugs in the prevention and treatment of CMV. EXPERT OPINION: Letermovir and maribavir are much needed tools that spare toxicities of ganciclovir, foscarnet, and cidofovir. High cost is a challenge preventing their integration into clinical practice in resource-limited countries. Transplant centers need to exercise restraint in overuse to avoid resistance, particularly in the setting of high viral loads.

Modeling Invasive Aspergillosis Risk for the Application of Prophylaxis Strategies.

The epidemiology of invasive aspergillosis (IA) is evolving. To define the patient groups who will most likely benefit from primary or secondary Aspergillus prophylaxis, particularly those whose medical conditions and IA risk change over time, it is helpful to depict patient populations and their risk periods in a temporal visual model. The Sankey approach provides a dynamic figure to understand the risk of IA for various patient populations. While the figure depicted within this article is static, an internet-based version could provide pop-up highlights of any given flow's origin and destination nodes. A future version could highlight links to publications that support the color-coded incidence rates or other actionable items, such as bundles of applicable pharmacologic or non-pharmacologic interventions. The figure, as part of the upcoming Infectious Diseases Society of America's aspergillosis clinical practice guidelines, can guide decision-making in clinical settings.

False-Positive Human Immunodeficiency Virus Nucleic Acid Amplification Test After Chimeric Antigen Receptor T-Cell Therapy With Ciltacabtagene Autoleucel.

Chimeric antigen receptor (CAR) T-cell therapy has emerged as a novel therapeutic option for hematologic malignancies. Human immunodeficiency virus (HIV) nucleic acid amplification tests (NAATs) amplifying 5' long terminal repeat and gag genes cross-react with lentiviral vector-based CAR T-cell products. Cross-reactivity between CAR T-cell products and HIV NAATs may lead to false-positive test results.

Polymerase chain reaction in the diagnosis of invasive aspergillosis: approaches for appropriate use.

Detection of aspergillus by PCR is a helpful tool for early diagnosis. The test has excellent sensitivity and specificity with a high negative predictive value. Well-accepted, standardized method for DNA extraction for PCR testing is to be adopted for all commercial assays and conclusive validation data are awaited in varied clinical settings. This perspective offers guidance for utilizing PCR testing while awaiting such data. Quantification by PCR, species-specific identification assays and detection of resistance genetic markers are of future promise. Herein, we summarize the available data on aspergillus PCR and describe its potential utility through a clinical case scenario-based approach.

Infectious complications after second allogeneic hematopoietic cell transplant in adult patients with hematological malignancies.

We conducted a retrospective review of the infectious complications and outcomes over a 2-year follow-up period of adult patients who received a second allogeneic hematopoietic cell transplant (2nd allo-HCT) during a five-year period at two cancer centers in Michigan. Sixty patients, of whom 44 (73%) had acute leukemia or myelodysplastic syndrome, were studied. The majority (n = 37,62%) received a 2nd allo-HCT because of relapsed leukemia. Infection episodes after the 2nd allo-HCT totaled 112. Bacteria were identified in 76 episodes, the majority of which occurred pre-engraftment. The most common infecting organisms were Enterococcus species and Clostridioides difficile. Viral infections, predominantly cytomegalovirus, accounted for 59 infection episodes and occurred mostly in pre-engraftment and early post-engraftment periods. There were 16 proven/probable fungal infections, of which 9 were invasive aspergillosis or candidiasis. Mortality was 45% (n = 27) at one year and 65% (n = 39) at 2 years after transplant, and 16 deaths (41%) were due to infection. Of those 16 infection deaths, 8 were bacterial, 4 fungal, 2 both bacterial and fungal, and 2 viral. Failure to engraft neutrophils or platelets was significantly associated with decreased survival, p < 0.0001 and p < 0.001, respectively. Infections are common after a 2nd allo-HCT and are associated with a high mortality rate.

Efficacy and safety of Isavuconazole for the treatment of invasive Aspergillus infection - an update of the literature.

INTRODUCTION: Invasive aspergillosis is associated with high morbidity and mortality in immunocompromised patients. It is now increasingly reported in critically ill patients, including those with respiratory viral infections, such as influenza and COVID-19. Antifungal management is challenging due to diagnostic delay, adverse drug reactions, drug-drug interactions, narrow therapeutic window, and the emergence of resistance. Isavuconazole is the most recent FDA approved azole for the treatment of invasive aspergillosis, with data continuing to accumulate. AREAS COVERED: The authors review the safety and efficacy of isavuconazole in the management of invasive aspergillosis based on the currently available evidence. The authors also report on the structure, mechanism of action, pharmacokinetic properties, in vitro and in vivo studies as well as clinical safety and efficacy reports of isavuconazole since its FDA approval. EXPERT OPINION: Isavuconazole is non-inferior to voriconazole and is a safe, effective, and better tolerated option for the treatment of invasive aspergillosis. It offers several advantages over other antifungal agents, including having a better adverse event profile with respect to hepatotoxicity, neuro-visual toxicity, QTc prolongation, as well as a stable pharmacokinetic profile obviating the need for therapeutic drug monitoring. Further studies are needed to evaluate its performance in prophylaxis against invasive aspergillosis as well as in the treatment of aspergillosis in critically ill patients without underlying cancer or transplant.

Azole resistance in Aspergillus species: promising therapeutic options.

INTRODUCTION: Azoles are the first-line antifungal agents used for the treatment of Aspergillus infection. There is an increasing concern for azole resistance all over the world mainly from agricultural fungicide use. Choosing safe and effective antifungal regimens has become a challenge. AREAS COVERED: Here, the authors review the epidemiology, mechanisms, and detection of azole resistance along with management options for azole-resistant Aspergillus infection, including new antifungal agents under development. EXPERT OPINION: Routine global epidemiological surveillance is required to understand azole resistance prevalence. Azole-resistant Aspergillus infections are associated with high mortality. No good therapeutic options are currently available. High index of suspicion of resistance is required if a patient is not responding to 4-7 days of azole therapy, particularly in the areas of resistance. Susceptibility testing for Aspergillus is not routinely available in many parts of the world, which makes it difficult to diagnose azole resistance in Aspergillus infection. There are several new antifungal classes with novel mechanisms of action; clinical trials are ongoing.

Favorable outcome of COVID-19 among African American (AA) renal transplant recipients in Detroit.

Transplant recipients are vulnerable to infections, including COVID-19, given their comorbidities and chronic immunosuppression. In this study, all hospitalized renal transplant recipients (RTR) with a positive nasal swab for Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV2) seen consecutively between 03/01/2020 and 05/01/2020 at the Detroit Medical Center were included. Data on demographics, clinical presentation, laboratory findings, management, and outcomes were collected. Twenty-five patients were included, all African American (AA) and deceased-donor transplant recipients. The most common presenting symptom was dyspnea, followed by fever, cough and diarrhea. Multifocal opacities on initial chest x-ray were seen in 52% patients and 44% of patients had a presenting oxygen saturation of less than or equal to 94%. Four patients (16%) required transfer to the intensive care unit, one required intubation and one expired. COVID-19-infected RTR in this cohort had low mortality of 4% (n = 1). Despite multiple comorbidities and chronic immunosuppression, our cohort of African American RTR had favorable outcomes compared to other reports on COVID-19 in RTR.

Evaluation of Susceptibility and Innate Immune Response in C57BL/6 and BALB/c Mice During Candida albicans Endophthalmitis.

Purpose: Candida remains the leading cause of fungal endophthalmitis. However, the pathobiology and innate immune responses in this disease are not well characterized. Here, we developed two murine models of candida endophthalmitis and evaluated their disease susceptibility and differential immune response. Methods: Endophthalmitis was induced in C57BL/6 (B6) and BALB/c mice by intravitreal injection of Candida albicans (CA). Disease progression was monitored by slit-lamp examination and clinical scoring, followed by retinal function assessment using electroretinography (ERG). Enucleated eyes were used to estimate fungal burden and retinal tissue damage by hematoxylin and eosin and TUNEL staining. The level of inflammatory mediators were determined by quantitative Polymerase Chain Reaction (qPCR) and enzyme-linked immunosorbent assay, whereas neutrophil infiltration was assessed by flow cytometry and immunostaining. Results: Intravitreal injection of CA at 6500 colony-forming units resulted in sustained (non-resolving) ocular inflammation in both B6 and BALB/c mice as evidenced by increased levels of inflammatory cytokines (tumor necrosis factor-α, interleukin-1ß, and interleukin-6) and chemokine (CXCL2/MIP-2). In both mouse strains, fungal burden peaked at 24 to 48 hours post-infection (hpi) and decreased by 72 to 96 hpi. CA-infected eyes exhibited increased polymorphonuclear neutrophils (PMN) infiltration and retinal tissue damage. Overall retinal function declined rapidly, with a significant reduction in ERG response at 12 hpi and near-total loss by 24 hpi. Differential analyses revealed increased pathology in BALB/c versus B6 mice. Conclusions: C. albicans was able to cause endophthalmitis in mice. Although BALB/c mice were found to be more susceptible to CA endophthalmitis, both BALB/c and B6 models could be used to study fungal endophthalmitis and test therapeutic modalities.

Preventing Varicella-Zoster: Advances With the Recombinant Zoster Vaccine.

Prevention strategies against varicella zoster infection include chemoprophylaxis with acyclovir and live attenuated zoster vaccine. However, resistance to acyclovir has been problematic, and safety concerns have limited the use of the live attenuated vaccine in immunosuppressed patients. Recombinant zoster vaccine, made available in 2017 for the immunocompetent host, has been evaluated for safety, immunogenicity, and efficacy in several immunocompromised settings as well. The present review compares the live attenuated vaccine and the recombinant zoster vaccine and highlights data on the use of recombinant zoster vaccine in different immunocompromised states. Robust data are available for the safety, immunogenicity, and efficacy of the recombinant vaccine in the autologous stem cell population, particularly among patients with multiple myeloma. The vaccine appears safe and immunogenic in populations including those with cancer (solid tumors and hematologic malignancies), HIV-infected patients, and renal transplant recipients. Efficacy and safety data in other populations are awaited before use of the recombinant vaccine can be more widespread. It is anticipated that an increased use of the recombinant zoster vaccine, particularly in immunosuppressed patients, would lead to a decreased use of acyclovir prophylaxis.

Baseline Chest Computed Tomography as Standard of Care in High-Risk Hematology Patients.

Baseline chest computed tomography (BCT) in high-risk hematology patients allows for the early diagnosis of invasive pulmonary aspergillosis (IPA). The distribution of BCT implementation in hematology departments and impact on outcome is unknown. A web-based questionnaire was designed. International scientific bodies were invited. The estimated numbers of annually treated hematology patients, chest imaging timepoints and techniques, IPA rates, and follow-up imaging were assessed. In total, 142 physicians from 43 countries participated. The specialties included infectious diseases (n = 69; 49%), hematology (n = 68; 48%), and others (n = 41; 29%). BCT was performed in 57% (n = 54) of 92 hospitals. Upon the diagnosis of malignancy or admission, 48% and 24% performed BCT, respectively, and X-ray was performed in 48% and 69%, respectively. BCT was more often used in hematopoietic cell transplantation and in relapsed acute leukemia. European centers performed BCT in 59% and non-European centers in 53%. Median estimated IPA rate was 8% and did not differ between BCT (9%; IQR 5-15%) and non-BCT centers (7%; IQR 5-10%) (p = 0.69). Follow-up computed tomography (CT) for IPA was performed in 98% (n = 90) of centers. In high-risk hematology patients, baseline CT is becoming a standard-of-care. Chest X-ray, while inferior, is still widely used. Randomized, controlled trials are needed to investigate the impact of BCT on patient outcome.

Orolabial Lymphogranuloma Venereum, Michigan, USA.

Orolabial lymphogranuloma venereum was diagnosed for a man in Michigan, USA, who had sex with men, some infected with HIV. High index of suspicion for lymphogranuloma venereum led to accurate diagnosis, successful therapy, and description of an L2b variant with a unique genetic mutation.

Pathobiology of Aspergillus Fumigatus Endophthalmitis in Immunocompetent and Immunocompromised Mice.

Despite Aspergillus being the leading cause of exogenous fungal endophthalmitis following traumatic injury to the eye, its pathogenesis is not fully understood. In the current study, we developed a murine model of Aspergillus fumigatus (AF) endophthalmitis and investigated the disease pathobiology. Endophthalmitis was induced by intravitreal injection of Aspergillus spores in immunocompetent and immunocompromised (neutropenic) C57BL/6 mice, and disease severity was assessed by eye exam, fungal burden estimation, and histological examination. Our data showed that AF infection caused a time-dependent increase in corneal haze, opacity, and hypopyon beginning at two days post-infection (DPI). The fungal burden in infected eyes of immunocompetent mice peaked at 2 DPI and declined over 9 DPI. AF-infected neuroretina exhibited induction of innate immune response via upregulation of Toll-like receptors (TLRs) and inflammatory mediators (TNFα, IL-1ß, and IL6), and increased polymorphonuclear neutrophil (PMN) infiltration. Histological analysis revealed heavy cellular infiltrates in the vitreous cavity as well as disruption of normal retinal architecture and increased retinal cell death. Neutropenic mice exhibited severe disease pathology with the prolonged fungal burden and increased inflammatory mediators. Our study described the first immunocompetent murine model of exogenous AF endophthalmitis and demonstrated an important role of neutrophils in innate defense against fungal endophthalmitis.

Infectious Complications After Umbilical Cord Blood Transplantation for Hematological Malignancy.

BACKGROUND: Umbilical cord blood transplant (UCBT) is used for patients who do not have a matched donor, but engraftment often takes longer than with a standard allogeneic transplant, likely increasing the risk for infection. We characterized specific infections and outcomes in adults undergoing UCBT at our 2 centers. METHODS: All adults who underwent UCBT between January 1, 2006 and December 31, 2015 were included. Infectious episodes from 6 months before to 2 years after UCBT were reviewed. RESULTS: Fifty-seven patients underwent UCBT; 47 had neutrophil engraftment. A total of 179 infectious episodes occurred in 55 patients, 73 (41%) within 30 days post-UCBT. Viruses caused 85 (47%) infections. Cytomegalovirus caused 32 infectious episodes and was most common from day 30 to 100. Human herpesvirus 6 occurred in 28 episodes, was most common within 30 days, and caused 1 death. Bacteria were responsible for 82 (46%) infections, most commonly bacteremias due to Staphylococcus spp, Enterococcus spp, and Enterobacteriaceae. Of 11 invasive fungal infections, 9 were aspergillosis, 4 of which were fatal. Overall mortality was 56% in the first year. Thirteen deaths were from infection; 11 occurred in the first 100 days and 7 in the first 30 days post-UCBT. Of 10 patients who never engrafted, 9 died, 6 from infection, within 100 days post-UCBT. CONCLUSIONS: Infectious complications were common after UCBT, especially in the first 30 days. Deaths from viral infections were fewer than expected. Delayed engraftment and nonengraftment continue to convey increased risk for fatal bacterial and fungal infections post-UCBT.

Isavuconazole for Treatment of Experimental Fungal Endophthalmitis Caused by Aspergillus fumigatus.

Fungal endophthalmitis remains a significant cause of vision impairment and blindness. Moreover, the prognosis is poor, in part due to delay in diagnosis and to limited availability of effective antifungal agents with good ocular penetration. Thus, it is imperative to evaluate the therapeutic efficacy in fungal endophthalmitis of newer antifungal agents. In this study, we assessed the efficacy of isavuconazole in treating Aspergillus fumigatus endophthalmitis in an exogenous mouse model of the disease. Briefly, endophthalmitis was induced by intravitreal (IVT) injection of A. fumigatus spores into immunocompetent C57BL/6 (B6) mouse eyes. Mice were randomized into five groups that received isavuconazole via (i) oral gavage, (ii) IVT injections, (iii) intravenous injection, (iv) IVT injection followed by oral gavage, and (v) IVT injection followed by intravenous injection. Our data showed that isavuconazole treatment via all routes reduced fungal burden in A. fumigatus-infected eyes. This coincided with the preservation of retinal structural integrity (histology analysis) and retinal function (electroretinography [ERG] analysis), resulting in significantly improved disease outcome. Furthermore, isavuconazole treatment reduced the levels of inflammatory cytokines (tumor necrosis factor α [TNF-α], interleukin 1ß [IL-1ß], and IL-6) and cellular infiltration in the eyes. Notably, oral administration of isavuconazole was as effective in ameliorating endophthalmitis as intravitreal injection of the drug. Collectively, our study demonstrates that isavuconazole is effective in treating A. fumigatus endophthalmitis in mice, indicating its potential use in human ocular infections.

Infectious Complications of Cryoablation and Microwave Ablation in Metastatic Solid Tumors.

Cryoablation and microwave ablation are commonly used techniques to reduce tumor burden in unresectable neoplasms. This retrospective study demonstrated low risk for infectious complications (1.4%) following these invasive procedures. Abscess formation was the most common infection around the ablation sites. All infections were successfully treated with imaging-guided drainage and antibiotics.Infect Control Hosp Epidemiol 2018;39:723-726.