Impact of an antimicrobial stewardship programme on antibiotic utilization and resistance burden in patients with acute leukaemia: an 11-year longitudinal cohort study using interrupted time-series analysis.

BACKGROUND: Antimicrobial resistance (AMR), driven by inappropriate and overuse of antibiotics, poses a significant threat, especially to patients with acute leukaemia. OBJECTIVES: To evaluate the impact of antimicrobial stewardship programmes (ASPs) on antibiotic use and analyse temporal changes in bloodstream infections (BSI) caused by AMR organisms. METHODS: We performed a retrospective, interventional, longitudinal cohort study spanning an 11-year period. ASPs included optimizing antibiotic use, enhancing tracking and reporting systems and delineating leadership and accountability. A segmented regression model of interrupted time series was used to evaluate the trend of antibiotic consumption and BSI with AMR organisms after the interventions. RESULTS: A total of 3296 BSI episodes with 454 419 days of therapy (DOT) from 7754 patients were obtained. ASPs were significantly associated with an immediate reduction [-70.03 DOT/1000 patient-days (PD), P = 0.036] and a decreasing trend (-11.65 DOT/1000 PD per quarter, P < 0.001) in overall antibiotic use. The increasing incidence of BSI with AMR before ASP intervention was notably curbed and revealed a decreasing trend (slope change: -0.06 BSI/1000 PD per quarter, P = 0.002). The decreasing trend was more significant for Enterobacterales: ciprofloxacin-resistant and ESBL-producing isolates showed a slope change of -0.06 BSI/1000 PD and -0.08 BSI/1000 PD per quarter, respectively (all P < 0.05). However, Pseudomonas aeruginosa BSI increased. CONCLUSIONS: Multidimensional ASPs effectively reduced both the immediate and trends in overall antibiotic usage even in patients with acute leukaemia. Additionally, there was a notable decrease in the incidence of BSI caused by AMR organisms, particularly among Enterobacterales.

Impact of the coronavirus disease 2019 pandemic on the incidence of other infectious diseases in the hematology hospital in Korea.

BACKGROUND/AIMS: Since the coronavirus disease 2019 (COVID-19) outbreak, hospitals have implemented infection control measures to minimize the spread of the virus within facilities. This study aimed to investigate the impact of COVID-19 on the incidence of healthcare-associated infections (HCAIs) and common respiratory virus (cRV) infections in hematology units. METHODS: This retrospective study included all patients hospitalized in Catholic Hematology Hospital between 2019 and 2020. Patients infected with vancomycin-resistant Enterococci (VRE), carbapenemase-producing Enterobacterales (CPE), Clostridium difficile infection (CDI), and cRV were analyzed. The incidence rate ratio (IRR) methods and interrupted time series analyses were performed to compare the incidence rates before and after the pandemic. RESULTS: The incidence rates of CPE and VRE did not differ between the two periods. However, the incidence of CDI increased significantly (IRR: 1.41 [p = 0.002]) after the COVID-19 pandemic. The incidence of cRV infection decreased by 76% after the COVID-19 outbreak (IRR: 0.240 [p < 0.001]). The incidence of adenovirus, parainfluenza virus, and rhinovirus infection significantly decreased in the COVID-19 period (IRRs: 0.087 [p = 0.003], 0.031 [p < 0.001], and 0.149 [p < 0.001], respectively). CONCLUSION: The implementation of COVID-19 infection control measures reduced the incidence of cRV infection. However, CDI increased significantly and incidence rates of CPE and VRE remained unchanged in hematological patients after the pandemic. Infection control measures suitable for each type of HCAI, such as stringent hand washing for CDI and enough isolation capacities, should be implemented and maintained in future pandemics, especially in immunocompromised patients.

2,4,6-Triphenyl-1-hexene, an Anti-Melanogenic Compound from Marine-Derived Bacillus sp. APmarine135.

Although melanin protects against ultraviolet radiation, its overproduction causes freckles and senile lentigines. Recently, various biological effects of metabolites derived from marine microorganisms have been highlighted due to their potential for biological and pharmacological applications. In this study, we discovered the anti-melanogenic effect of Bacillus sp. APmarine135 and verified the skin-whitening effect. Fractions of APmarine135 showed the melanin synthesis inhibition effect in B16 melanoma cells, and 2,4,6-triphenyl-1-hexene was identified as an active compound. The melanogenic capacity of 2,4,6-triphenyl-1-hexene (1) was investigated by assessing the intracellular melanin content in B16 cells. Treatment with 5 ppm of 2,4,6-triphenyl-1-hexene (1) for 72 h suppressed the α-melanocyte-stimulating hormone (α-MSH)-induced intracellular melanin increase to the same level as in the untreated control group. Additionally, 2,4,6-triphenyl-1-hexene (1) treatment suppressed the activity of tyrosinase, the rate-limiting enzyme for melanogenesis. Moreover, 2,4,6-triphenyl-1-hexene (1) treatment downregulated tyrosinase, Tyrp-1, and Tyrp-2 expression by inhibiting the microphthalmia-associated transcription factor (MITF). Furthermore, 2,4,6-triphenyl-1-hexene (1) treatment decreased the melanin content in the three-dimensional (3D) human-pigmented epidermis model MelanoDerm and exerted skin-whitening effects. Mechanistically, 2,4,6-triphenyl-1-hexene (1) exerted anti-melanogenic effects by suppressing tyrosinase, Tyrp-1, and Tyrp-2 expression and activities via inhibition of the MITF. Collectively, these findings suggest that 2,4,6-triphenyl-1-hexene (1) is a promising anti-melanogenic agent in the cosmetic industry.

Co-Occurrence of Gram-Negative Rods in Patients with Hematologic Malignancy and Sinopulmonary Mucormycosis.

Both Mucorales and Gram-negative rods (GNRs) commonly infect patients with hematological malignancies (HM); however, their co-occurrence is understudied. Therefore, we retrospectively reviewed the records of 63 patients with HM and proven or probable sinopulmonary mucormycosis at MD Anderson Cancer Center (Houston, Texas) from 2000-2020. Seventeen out of sixty-three reviewed patients (27.0%) had sinopulmonary co-occurrence of GNRs (most commonly Pseudomonas aeruginosa and Stenotrophomonas maltophilia) within 30 days of a positive Mucorales culture or histology demonstrating Mucorales species. Eight of seventeen co-isolations of Mucorales and GNRs were found in same-day samples. All 15 patients with GNR co-occurrence and reported antimicrobial data had received anti-Pseudomonal agents within 14 days prior to diagnosis of mucormycosis and 5/15 (33.3%) had received anti-Stenotrophomonal agents. Demographic and clinical characteristics of patients with and without GNR co-occurrence were comparable. Forty-two-day all-cause mortality was high (34.9%) and comparable in patients with (41.2%) and without (32.6%) GNR detection (p = 0.53). In summary, over a quarter of heavily immunosuppressed patients with sinopulmonary mucormycosis harbored GNRs in their respiratory tract. Although no impact on survival outcomes was seen in a background of high mortality in our relatively underpowered study, pathogenesis studies are needed to understand the mutualistic interplay of GNR and Mucorales and their influence on host responses.

Mucoadhesive chitosan microcapsules for controlled gastrointestinal delivery and oral bioavailability enhancement of low molecular weight peptides.

A bioactive compound, collagen peptide (CP), is widely used for biological activities such as anti-photoaging and antioxidant effects, with increased oral bioavailability because of its low molecular weight and high hydrophilicity. However, controlling release time and increasing retention time in the digestive tract for a more convenient oral administration is still a challenge. We developed CP-loaded chitosan (CS) microcapsules via strong and rapid ionic gelation using a highly negative phytic acid (PA) crosslinker. The platform enhanced the oral bioavailability of CP with controlled gastrointestinal delivery by utilizing the mucoadhesiveness and tight junction-opening properties of CS. CS and CP concentrations varied from 1.5 to 3.5% and 0-30%, respectively, for optimal and stable microcapsule synthesis. The physicochemical properties, in vitro release profile with intestinal permeability, in vivo oral bioavailability, in vivo biodistribution, anti-photoaging effect, and antioxidant effect of optimized CS microcapsules were analyzed to investigate the impact of controlling parameters. The structure of CS microcapsules was tuned by PA diffused gradient ionic cross-linking degree, resulting in a controlled CP release region in the gastrointestinal tract. The optimized microcapsules increased Cmax, AUC, and tmax by 1.5-, 3.4-, and 8.0-fold, respectively. Furthermore, CP in microcapsules showed anti-photoaging effects by downregulating matrix metalloproteinases-1 via antioxidant effects. According to our knowledge, this is the first study to microencapsulate CP for oral bioavailability enhancement. The peptide delivery method employed is simple, economical, and can be applied to customize bioactive compound administration.

Clinical Implementation of ß-Tubulin Gene-Based Aspergillus Polymerase Chain Reaction for Enhanced Aspergillus Diagnosis in Patients with Hematologic Diseases: A Prospective Observational Study.

The ß-tubulin (benA) gene is a promising target for the identification of Aspergillus species. Assessment of the clinical implementation and performance of benA gene-based Aspergillus polymerase chain reaction (PCR) remains warranted. In this study, we assessed the analytical performance of the BenA probe PCR in comparison with the Aspergenius kit. We prospectively collected bronchoalveolar lavage (BAL) fluid via diagnostic bronchoscopy from adult patients with hematologic diseases. BenA gene-based multiplex real-time PCR and sequential melting temperature analysis were performed to detect the azole resistance of Aspergillus fumigatus. In total, 76 BAL fluids in 75 patients suspicious of invasive pulmonary aspergillosis (IPA) were collected. Before the application of PCR, the prevalence of proven and probable IPA was 32.9%. However, after implementing the benA gene-based PCR, 15.8% (12 out of 76) of potential IPA cases were reclassified as probable IPA. The analytical performance of the BenA probe PCR in BAL samples was comparable to that of the Aspergenius kit. The diagnostic performance was as follows: sensitivity, 52.0%; specificity, 64.7%; positive predictive value, 41.9%; negative predictive value, 73.3%; positive likelihood ratio, 1.473; and negative likelihood ratio, 0.741. Moreover, benA gene-based Aspergillus PCR discriminated all major sections of Aspergillus, including cryptic species such as Aspergillus tubingensis. Sequential melting temperature analysis successfully detected 2 isolates (15.4%) of A. fumigatus carrying resistant mutations. BenA gene-based Aspergillus PCR with melting temperature analysis enhances diagnostic accuracy and detects not only cryptic species but also resistant mutations of A. fumigatus. It shows promise for clinical applications in the diagnosis of IPA.

Cytomegalovirus Infection after Allogeneic Hematopoietic Cell Transplantation under 100-Day Letermovir Prophylaxis: A Real-World 1-Year Follow-Up Study.

The prevention and management of cytomegalovirus (CMV) reactivation is important to improve the outcomes of allogeneic hematopoietic cell transplantation (allo-HCT) recipients. The aim of this study was to analyze real-world data regarding the incidence and characteristics of CMV infections until 1 year after allo-HCT under 100-day letermovir prophylaxis. A single-center retrospective study was conducted between November 2020 and October 2021. During the study period, 358 patients underwent allo-HCT, 306 of whom received letermovir prophylaxis. Cumulative incidence of clinically significant CMV infection (CS-CMVi) was 11.4%, 31.7%, and 36.9% at 14 weeks, 24 weeks, and 1 year post-HCT, respectively. Through multivariate analysis, the risk of CS-CMVi increased with graft-versus-host disease (GVHD) ≥ grade 2 (adjusted odds ratio 3.640 [2.036-6.510]; p < 0.001). One-year non-relapse mortality was significantly higher in letermovir breakthrough CS-CMVi patients than those with subclinical CMV reactivation who continued receiving letermovir (p = 0.002). There were 18 (15.9%) refractory CMV infection cases in this study population. In summary, letermovir prophylaxis is effective at preventing CS-CMVi until day 100, which increased after the cessation of letermovir. GVHD is still a significant risk factor in the era of letermovir prophylaxis. Further research is needed to establish individualized management strategies, especially in patients with significant GVHD or letermovir breakthrough CS-CMVi.

Epidemiology, treatment patterns, and disease burden of cytomegalovirus in hematopoietic cell transplant recipients in selected countries outside of Europe and North America: A systematic review.

BACKGROUND: Cytomegalovirus (CMV) disease impacts morbidity and mortality in hematopoietic cell transplant (HCT) recipients. This systematic review summarized data on the epidemiology, management, and burden of CMV post-HCT outside of Europe and North America. METHODS: The MEDLINE, Embase, and Cochrane databases were searched for observational studies and treatment guidelines in HCT recipients across 15 selected countries from Asia-Pacific, Latin America, and Middle East (search period: 1 January 2011-17 September 2021). Outcomes included incidence of CMV infection/disease, recurrence, risk factors, CMV-related mortality, treatments, refractory, resistant CMV, and burden. RESULTS: Of 2708 references identified, 68 were eligible (67 studies and one guideline; 45/67 studies specific to adult allogeneic HCT recipients). The rates of CMV infection and disease within 1 year of allogeneic HCT were 24.9%-61.2% (23 studies) and 2.9%-15.7% (10 studies), respectively. Recurrence occurred in 19.8%-37.9% of cases (11 studies). Up to 10% of HCT recipients died of CMV-related causes. In all countries, first-line treatment for CMV infection/disease involved intravenous ganciclovir or valganciclovir. Conventional treatments were associated with serious adverse events such as myelosuppression (10.0%) or neutropenia only (30.0%, 39.8%) and nephrotoxicity (11.0%) (three studies), frequently leading to treatment discontinuation (up to 13.6%). Refractory CMV was reported in 2.9%, 13.0%, and 28.9% of treated patients (three studies) with resistant CMV diagnosed in 0%-10% of recipients (five studies). Patient-reported outcomes and economic data were scarce. CONCLUSION: The incidence of CMV infection and disease post-HCT is high outside of North America and Europe. CMV resistance and toxicity highlight a major unmet need with current conventional treatments.

Genetic Variants Associated with Drug Resistance of Cytomegalovirus in Hematopoietic Cell Transplantation Recipients.

Cytomegalovirus (CMV) infection is a serious complication in hematopoietic cell transplantation (HCT) recipients. Drug-resistant strains make it more challenging to treat CMV infection. This study aimed to identify variants associated with CMV drug resistance in HCT recipients and assess their clinical significance. A total of 123 patients with refractory CMV DNAemia out of 2271 HCT patients at the Catholic Hematology Hospital between April 2016 and November 2021 were analyzed, which accounted for 8.6% of the 1428 patients who received pre-emptive therapy. Real-time PCR was used to monitor CMV infection. Direct sequencing was performed to identify drug-resistant variants in UL97 and UL54. Resistance variants were found in 10 (8.1%) patients, and variants of uncertain significance (VUS) were found in 48 (39.0%) patients. Patients with resistance variants had a significantly higher peak CMV viral load than those without (p = 0.015). Patients with any variants had a higher risk of severe graft-versus-host disease and lower one-year survival rates than those without (p = 0.003 and p = 0.044, respectively). Interestingly, the presence of variants reduced the rate of CMV clearance, particularly in patients who did not modify their initial antiviral regimen. However, it had no apparent impact on individuals whose antiviral regimens were changed due to refractoriness. This study highlights the importance of identifying genetic variants associated with CMV drug resistance in HCT recipients for providing appropriate antiviral treatment and predicting patient outcomes.

Kaempferol tetrasaccharides restore skin atrophy via PDK1 inhibition in human skin cells and tissues: Bench and clinical studies.

Skin aging is a major risk factor for the dermal diseases, and interventions to attenuate cellular senescence are expected to reduce the risk for age-related diseases involving skin atrophy. However, blocking cell death or extending proliferation causally results in side effects and an increased cancer risk. For identification of a safer approach, we focused on PDK1 inhibition, which could revert cellular senescence and reduce senescence factors in skin in vitro, in a human skin equivalent model and in an exploratory, placebo-controlled, interventional trial. Natural phytochemical kaempferol tetrasaccharides resulted in a significant reduction in cellular senescence, and an increase in collagen fiber was observed in the skin cell and human skin equivalent. Clinical enhancement in skin appearance was noted in multiple participants, and an immunohistochemical study revealed improvement in the histological appearance of skin tissue and extracellular matrix. This change was associated with relative improvement in histological markers of senescence and clinical appearance of the aged skin and an increase in collagen fiber, an essential factor for preventing skin atrophy and consistency of the basement membrane. These results indicate that PDK1 inhibition is a potentially effective antiaging intervention, suggesting a diagnostic role and preventive actions of PDK1 in senescence-associated skin atrophy.

Intra-host diversity of drug-resistant cytomegalovirus: A case report of cytomegalovirus infection after allogeneic hematopoietic cell transplantation.

Cytomegalovirus (CMV) is a major infectious agent causing severe complications in allogeneic hematopoietic cell transplantation (HCT) recipients, thereby warranting the need for aggressive preemptive or targeted antiviral therapy. However, prolonged or repeated use of antiviral agents, such as ganciclovir (GCV), foscarnet (FOS), and cidofovir (CDV), can result in drug-resistant CMV infection, posing challenges to successful outcomes. Here, we report a case of a patient with acute myeloid leukemia and drug-resistant CMV infection who presented with persistent CMV DNAemia, colitis, pneumonia, and encephalitis. An intra-host diversity of UL97 and UL54 mutations were detected through the genotypic resistance testing conducted on two blood samples (D+199 and D+224) and a cerebrospinal fluid (CSF) specimen (D+260) collected from the patient. UL97 L595W/L595F and L595W mutations were detected in the blood and CSF samples, respectively, that conferred GCV resistance. UL54 F412L mutation detected in all three samples conferred GCV/CDV resistance. However, the V787L mutation of UL54, conferring GCV/FOS resistance, was observed only in the D+224 blood sample. Despite combination therapy with FOS and high dose GCV and adjunctive therapy with leflunomide, the patient died from CMV infection and multiple organ failure on D+279. Further data on resistant mutations and intra-host diversity of CMV should be accumulated to elucidate the antiviral resistance and related outcomes.

Advances in prophylaxis and treatment of invasive fungal infections: perspectives on hematologic diseases.

Invasive fungal infections (IFIs) are common causes of mortality and morbidity in patients with hematologic diseases. Delayed initiation of antifungal treatment is related to mortality. Aspergillus sp. is the leading cause of IFI followed by Candida sp. Diagnosis is often challenging owing to variable conditions related to underlying diseases. Clinical suspect and prompt management is important. Imaging, biopsy, and non-culture-based tests must be considered together. New diagnostic procedures have been improved, including antigen-based assays and molecular detection of fungal DNA. Among hematologic diseases, patients with acute myeloid leukemia, myelodysplastic syndrome, recipients of hematopoietic stem cell transplantation are at high risk for IFIs. Antifungal prophylaxis is recommended for these high-risk patients. There are continuous attempts to achieve ideal management of IFIs. Scoring system for quality control has been developed with important recommendations of current guidelines. Higher adherence to guidelines is related to decreased mortality in IFIs.

Pneumonia due to Schizophyllum commune in a Patient with Acute Myeloid Leukemia: Case Report and Literature Review.

Schizophyllum commune is a mold in phylum Basidiomycota and is an uncommon human pathogen. Sinusitis and allergic bronchopulmonary mycosis are the two major diseases caused by S. commune. Although there have been several reports of invasive fungal diseases, most of them were invasive sinusitis. We present a case of invasive fungal pneumonia due to S. commune, developed in a patient with acute myeloid leukemia presenting neutropenic fever. The diagnosis was made by characteristic macroscopic and microscopic findings of fungal isolate and was confirmed via sequencing of internal transcribed spacer region. The patient was improved after 8 weeks of antifungal therapy based on the susceptibility result. We propose that S. commune should be considered as an emerging pathogen of invasive fungal pneumonia when a patient is under immunocompromised state. We also reviewed global literatures focused on the invasive fungal diseases caused by S. commune.

Infections of Venetoclax-Based Chemotherapy in Acute Myeloid Leukemia: Rationale for Proper Antimicrobial Prophylaxis.

Although venetoclax (VEN)-based combination chemotherapy in patients with acute myeloid leukemia (AML) results in prolonged and profound neutropenia, data regarding infectious complications and antimicrobial prophylaxis are lacking. We investigated the infectious complications in 122 adult patients with AML under the same standard of care for prevention. The prophylaxis protocol was fluconazole 400 mg/d without antibacterial agents. The incidence of proven or probable invasive fungal infections (IFIs) was 6.6/100 cycles, and 22 patients (18.0%) were diagnosed (median, second cycle; interquartile range, 1-2). All IFIs were caused by Aspergillus and significantly influenced the overall mortality (odds ratio (OR), 2.737; 95% confidence interval (CI), 1.051-7.128; p = 0.034). In the multivariate analysis, secondary or therapy-related AML was an independent risk factor for IFIs (OR, 3.859; 95% CI, 1.344-11.048, p = 0.012). A total of 39 bloodstream infection (BSIs) episodes occurred in 35 patients (28.7%), with an incidence of 12.7/100 cycles. High-dose steroid administration within 90 days was associated with the occurrence of BSIs (OR, 7.474; 95% CI; 1.661-3.631, p = 0.008), although BSIs themselves did not have an impact on the outcomes. Our findings suggest evidence for the need for mold-active antifungal agents as antifungal prophylaxis, rather than fluconazole, especially in patients with secondary or therapy-related AML.

Characteristics and risk factors for mortality of invasive non-Aspergillus mould infections in patients with haematologic diseases: A single-centre 7-year cohort study.

Since mould-active azole prophylaxis has become a standard approach for patients with high-risk haematologic diseases, the epidemiology of invasive fungal infections (IFIs) has shifted towards non-Aspergillus moulds. It was aimed to identify the epidemiology and characteristics of non-Aspergillus invasive mould infections (NAIMIs). Proven/probable NAIMIs developed in patients with haematologic diseases were reviewed from January 2011 to August 2018 at Catholic Hematology hospital, Seoul, Korea. There were 689 patients with proven/probable invasive mould infections; of them, 46 (47 isolates) were diagnosed with NAIMIs. Fungi of the Mucorales order (n = 27, 57.4%) were the most common causative fungi, followed by Fusarium (n = 9, 19.1%). Thirty-four patients (73.9%) had neutropenia upon diagnosis of NAIMIs, and 13 (28.3%) were allogeneic stem cell transplantation recipients. The most common site of NAIMIs was the lung (n = 27, 58.7%), followed by disseminated infections (n = 8, 17.4%). There were 23.9% (n = 11) breakthrough IFIs, and 73.9% (n = 34) had co-existing bacterial or viral infections. The overall mortality at 6 and 12 weeks was 30.4% and 39.1%, respectively. Breakthrough IFIs (adjusted hazards ratio [aHR] = 1.99, 95% CI: 1.3-4.41, P = .031) and surgical treatment (aHR = 0.09, 95% CI: 0.02-0.45, P = .003) were independently associated with 6-week overall mortality. NAIMIs were not rare and occur as a complex form of infection often accompanied by breakthrough/mixed/concurrent IFIs and bacterial or viral infections. More active diagnostic efforts for NAIMIs are needed.

Evaluation of posaconazole plasma concentrations achieved with the delayed-release tablets in Korean high-risk patients with haematologic malignancy.

BACKGROUND: Posaconazole (PCZ) is a triazole approved for prophylaxis of invasive fungal infections. OBJECTIVES: Herein, the impact of clinical variables on PCZ plasma concentrations (PPCs) attained with PCZ delayed-release tablet (DRT) was investigated and compared with a historical cohort treated with PCZ oral suspension (OS). PATIENTS/METHODS: Steady-state PCZ PPCs in 513 patients with haematologic malignancy treated with PCZ-DRT were assessed and impact of variables were analysed. Also, a comparison with matched historical cohort treated with PCZ-OS was made. RESULTS: The median PPC in the PCZ-DRT group was 1,308.9 ng/mL (range: 29.8-10 455.9). Use of proton pump inhibitor (1181 vs 1344 ng/mL, P = .0337) in the AML/myelodysplastic syndrome remission induction group, diarrhoea (867 vs 1543 ng/mL, P = .0325) and gastrointestinal graft-versus-host disease (870 vs 1713 ng/mL, P = .0178) in the HSCT group were associated with lower PPCs. There was lack of evidence that hepatotoxicity was related with PCZ-DRT. Higher prevalence of UGT1A4*3 allele (33.0%) was noted compared to allele frequency in Koreans in those with PPCs < 500 mg/mL. The median PPC in the PCZ-DRT group was significantly higher than that in the PCZ-OS group (1308.9 vs 713.0 ng/mL, P < .0001). Significantly less patients had PPCs < 700 ng/mL in the PCZ-DRT group compared to the PCZ-OS group (18.7% vs 48.0%, P < .0001). CONCLUSIONS: Our study demonstrates that PCZ-DRT has enhanced absorption and bioavailability than PCZ-OS in real-world clinical settings. In addition, specific factors associated with lower PPCs should prompt consideration of therapeutic drug monitoring in patients treated with PCZ-DRT.

Reactivation and dynamics of cytomegalovirus and Epstein-Barr virus after rabbit antithymocyte globulin and cyclosporine for aplastic anemia.

OBJECTIVES: This study aimed to identify the natural course of cytomegalovirus (CMV)/Epstein-Barr virus (EBV) after rabbit antithymocyte globulin and cyclosporine (rATG-CsA) for aplastic anemia (AA). METHODS: In 113 prospectively observed AA patients treated with rATG-CsA, the CMV/EBV cohort was classified into two groups by baseline viremic status: no viremia (CMV-G1, n = 112; EBV-G1, n = 98) and the presence of viremia (CMV-G2, n = 1; EBV-G2, n = 13). RESULTS: In CMV-G1, the mean CMV load increased up to 3 months but was completely resolved from 6 months. The mean EBV load of EBV-G1 showed a peak at 1 month and then gradually decreased over time but remained detectable throughout the observation period. EBV-G2 showed fluctuating EBV dynamics. With reactivation rates of 38.4% in CMV-G1 and 62.2% in EBV-G1, a longer time to rATG-CsA from diagnosis and a lower absolute lymphocyte count at 1 month from rATG-CsA were significantly associated with CMV and EBV reactivation, respectively. The mean peak CMV and EBV loads of patients with CMV-related (3.5%) and EBV-related (0.9%) diseases were evidently higher than those of the remaining patients without CMV and EBV diseases in the respective cohort. CONCLUSION: Considering frequent reactivation and distinct courses of CMV/EBV, virologic surveillance is recommended after rATG-CsA for AA.

Cytomegalovirus Infections after Hematopoietic Stem Cell Transplantation: Current Status and Future Immunotherapy.

Cytomegalovirus (CMV) infection after hematopoietic stem cell transplantation (HSCT) is one of the critical infectious complications related to host immune recovery. The spectrum of CMV infection is quite extensive, from asymptomatic CMV reactivation presenting mainly as CMV DNAemia to fatal CMV diseases involving gut, liver, lungs, or brain. In addition to organ involvement, CMV reactivation can exert indirect effects such as immunosuppression or graft failure that may result in the development of concurrent infectious complications. Currently, preemptive therapy, which is based on PCR-based monitoring of CMV from blood, is a mainstay enabling improvement in CMV-related outcomes. During the past decades, new antiviral drugs, clinical trials for prophylaxis in high-risk groups, and vaccines for preventing CMV infection have been introduced. In addition, data for immunologic monitoring and adoptive immunotherapy have also been accumulated. Here, we review the current status and recent updates in this field, with future perspectives including immunotherapy in HSCT recipients.

Clinical Characteristics and Antimicrobial Susceptibility Trends in Citrobacter Bacteremia: An 11-Year Single-Center Experience.

BACKGROUND: Recently, Citrobacter freundii bacteremia outbreak in a neonatal intensive care unit has attracted public attention in Korea. However, Citrobacter bacteremia is uncommon and usually occurs in patients with underlying diseases such as malignancy and hepatobiliary diseases. Increase in resistance and emerging of multidrug resistance among Citrobacter species have gradually been reported. The aim of this study was to investigate the clinical characteristics and outcome of C. freundii and non-freundii bacteremia and antimicrobial susceptibility trends. MATERIALS AND METHODS: We reviewed the medical records of patients with Citrobacter bacteremia at St. Mary's Hospital, from 2007 to 2017. RESULTS: A total of 43 patients with a median age of 72 (24-93) years was identified and 90.7% of them had comorbidities. Twenty-nine (67.4%) patients had C. freundii bacteremia while 14 had non-freundii bacteremia (six of C. braakii, five of C. koseri, two of C. amalonaticus and one of C. youngae). A total of 26 (51.2%) patients had community-acquired infection and intra-abdominal infection including hepatobiliary tract was the most common portal of entry (24/43, 55.8%). Moreover, hepatobiliary tract was the leading primary site of nosocomial infection (9/17, 52.9%). Polymicrobial bacteremia was observed in 21 (48.8%) patients. The percentages of Citrobacter species susceptible to ampicillin, amikacin, aztreonam, cefazolin, cefoxitin, cefotaxime, cefepime, piperacillin-tazobactam, ciprofloxacin, and imipenem were 9.5%, 97.6%, 73.8%, 9.5%, 14.3%, 71.4%, 92.9%, 83.3%, 83.3% and 100%, respectively. The resistance rate did not increase during the study period. Of 39 patients treated with antibiotics, 36 (92.3%) received appropriate empirical antibiotics. Overall mortality was 18.6%. High Charlson comorbidity index and Pitt bacteremia score were significant risk factors for death in univariate analysis and showed trends in the multivariate analysis. No significant difference in clinical features and antimicrobial susceptibility rate was observed between C. freundii and non-freundii bacteremia. CONCLUSION: Citrobacter bacteremia was predominant in the elderly with comorbidities, while no pediatric case was observed. Hepatobiliary tract is the leading primary focus of bacteremia both in community-acquired and nosocomial infection. The rate of susceptibility to antibiotics has not changed in the last 11 years.