A retrospective study of intravenous pentamidine for PCP prophylaxis in adult patients with hematological malignancies - its utility during respiratory virus pandemics.

BACKGROUND: In Haematology, prophylaxis for Pneumocystis jirovecii pneumonia (PCP) is recommended for patients undergoing hematopoietic stem cell transplantation and in selected categories of intensive chemotherapy for hematological malignancies. Trimethoprim-sulfamethoxazole (TMP-SMX) is the recommended first-line agent, but its use is not straightforward. Inhaled pentamidine is the recommended second-line agent but aerosolized medications were discouraged during respiratory virus outbreaks, especially during the COVID-19 pandemic, in view of potential contamination risks. Intravenous (IV) pentamidine is a potential alternative agent. AIM: We evaluated the effectiveness and tolerability of IV pentamidine use for PCP prophylaxis in adult allogeneic HSCT recipients and patients with hematological malignancies during COVID-19. FINDINGS: A total of 202 unique patients who received 239 courses of IV pentamidine, with a median of 3 doses received (1-29). The largest group of the patients (49.5%) who received IV pentamidine were undergoing or had received a hematopoietic stem cell transplant. The commonest reason for not using TMP-SMX prophylaxis was cytopenia (34.7%). We have no patients who had breakthrough PCP infection while on IV pentamidine. None of the patients develop an infusion reaction or suffer adverse effects from IV pentamidine Conclusion: Pentamidine administered IV monthly is safe and effective.

Immune monitoring of prevalent kidney transplant recipients using Torque Teno Virus: Protocol for a single-centre prospective cohort study.

INTRODUCTION: Kidney transplant recipients (KTRs) suffer from immunosuppression-related adverse events (iRAEs), such as infections and malignancy from chronic immunosuppression, but are also at risk of graft loss from rejection with underimmunosuppression. Biomarkers that predict both iRAEs and rejection while allowing individualisation of immunosuppression exposure are lacking. Although plasma viral DNA levels of torque teno virus (TTV), a widely prevalent, non-pathogenic virus, have been shown to predict both iRAE and rejection in newly transplanted KTRs within the first year after transplant, its role for prevalent KTRs on stable immunosuppression is less clear.This study aims to determine the prognostic value of TTV levels for severe infections (defined as infections requiring hospitalisation) in prevalent KTRs on stable immunosuppression for at least 3 months and compare it against that of other commonly available biomarkers. The study also aims to explore the relationship between TTV levels and factors affecting the 'net state of immunosuppression' as well as other clinical outcomes. METHODS AND ANALYSIS: This is a single-centre, prospective, observational cohort study of 172 KTRs on stable immunosuppression for more than 3 months. TTV levels will be measured using the TTV R-GENE kit upon recruitment when study subjects are admitted and when kidney allograft biopsies are performed. Subjects will be monitored for iRAEs and rejection for at least 12 months. The relationship between TTV load and clinical outcomes such as severe infections will be analysed and compared against that from other common biomarkers and previously published predictive scores. ETHICS AND DISSEMINATION: The study was approved by the SingHealth Centralised Institutional Review Board (2023/2170). The results will be presented at conferences and submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT05836636.

Comparative Activities of Novel Therapeutic Agents against Molecularly Characterized Clinical Carbapenem-Resistant Enterobacterales Isolates.

Limited treatment options exist for the treatment of carbapenem-resistant Enterobacterales (CRE) bacteria. Fortunately, there are several recently approved antibiotics indicated for CRE infections. Here, we examine the in vitro activity of various novel agents (eravacycline, plazomicin, ceftazidime-avibactam, imipenem-relebactam, and meropenem-vaborbactam) and comparators (tigecycline, amikacin, levofloxacin, fosfomycin, polymyxin B) against 365 well-characterized CRE clinical isolates with various genotypes. Nonduplicate isolates collected from the largest public health hospital in Singapore between 2007 and 2020 were subjected to antimicrobial susceptibility testing (broth microdilution or antibiotic gradient test strips). Susceptibilities were defined using Clinical and Laboratory Standards Institute (CLSI) or Food and Drug Administration (FDA) interpretative criteria. Sequence types and resistance mechanisms were characterized using short-read whole-genome sequencing. Overall, tigecycline and plazomicin exhibited the highest susceptibility rates (89.6% and 80.8%, respectively). However, the tigecycline susceptibility breakpoint utilized here may be outdated in view of prevailing pharmacokinetic-pharmacodynamic (PK/PD) data. Susceptibility varied by carbapenemase genotype; the ß-lactam/ß-lactamase inhibitor combinations were equally active (92.3 to 99.2% susceptible) against KPC producers, but only ceftazidime-avibactam retained high susceptibility (98.7%) against OXA-48-like producers. Against metallo-ß-lactamase producers, only plazomicin exhibited moderate activity (77.0% susceptible). Aminoglycoside activity was also influenced by carbapenemase genotypes. This work provides an insight into the comparative activity and presumptive utility of novel agents in this geographic region. IMPORTANCE This study determined the susceptibilities of carbapenem-resistant Enterobacterales isolates to various novel antimicrobial agents (ceftazidime-avibactam, imipenem-relebactam, meropenem-vaborbactam, eravacycline, and plazomicin). Whole-genome sequencing was performed for all strains. Our study findings provide insights into the comparative activities of novel agents in this geographic region. Plazomicin and ceftazidime-avibactam exhibited the lowest nonsusceptibility rates and may be considered promising agents in the management of carbapenem-resistant Enterobacterales infections. We note also that antibiotic activity is influenced by genotypes and that understanding the geographic region's molecular epidemiology could aid in the definition of the presumptive utility of novel agents and contribute to antibiotic decision-making.

An outpatient model of care for COVID-19 infected kidney transplant patients - The hospital-at-home.

BACKGROUND: The COVID-19 pandemic is protracted and episodic surges from viral variants continue to place significant strain on healthcare systems. COVID-19 vaccines, antiviral therapy and monoclonal antibodies have significantly reduced COVID-19 associated morbidity and mortality. Concurrently, telemedicine has gained acceptance as a model of care and a tool for remote monitoring. These advances allow us to safely transit our inpatient-based care for COVID-19 infected kidney transplant recipients (KTRs) to a hospital-at-home (HaH) model of care. METHODS: KTRs with PCR-proven COVID-19 infection were triaged by teleconsult and laboratory tests. Suitable patients were enrolled into the HaH. Remote monitoring via teleconsults were conducted daily until patients were de-isolated based on a time-based criterion. Monoclonal antibodies were administered in a dedicated clinic where indicated. RESULTS: Eighty-one KTRs with COVID-19 were enrolled into the HaH between February and June 2022, 70 (86.4%) completed HaH recovery without complications. Eleven (13.6%) patients required inpatient hospitalization for medical issues (n = 8) and weekend monoclonal antibody infusion (n = 3). Patients requiring inpatient hospitalization had longer transplant vintage (15 years vs. 10 years, p = .03), anaemia (haemoglobin 11.6 g/dL vs. 13.1 g/dL, p = .01), lower eGFR (39.8 vs. 62.9 mL/min/1.73 m2 , p < .05) and lower RBD levels (<50 AU/mL vs. 1435 AU/mL, p = .02). HaH saved 753 inpatient patient-days with no deaths observed. Hospital admission rates from the HaH programme was 13.6%. Patients who required inpatient care had direct access admission without utilization of emergency department resources. CONCLUSION: Selected KTRs with COVID-19 infection can be safely managed in a HaH programme; alleviating strain on inpatient and emergency healthcare resources.

Favorable outcomes of COVID-19 in vaccinated hematopoietic stem cell transplant recipients: A single-center experience.

INTRODUCTION: A high incidence of mortality and severe COVID-19 infection was reported in hematopoietic stem cell transplant (HSCT) recipients during the early phases of the COVID-19 pandemic; however, outcomes with subsequent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, such as the omicron variant, have yet to be reported. Additionally, rollout of COVID-19 vaccinations in subsequent pandemic waves may modify COVID-19 disease severity and mortality in this immunocompromised population. We describe COVID-19 outcomes among a highly vaccinated population of HSCT recipients at a single center during successive waves of community transmission arising from the SARS-CoV-2 delta and omicron variants. METHODS: We retrospectively reviewed medical records of all HSCT recipients at our institution who tested positive for SARS-CoV-2 from May 2021 to May 2022. Descriptive statistics were reported; the chi-square test was utilized to identify factors associated with 90-day all-cause mortality and severity of COVID-19 infection. RESULTS: Over the 1-year study period, 77 HSCT recipients at our center contracted COVID-19 (43 allogenic; 34 autologous). Twenty-six (33.8%) patients were infected with the SARS-CoV-2 delta variant, while 51 (66.2%) had the SARS-CoV-2 omicron variant. Thirty-nine (50.6%) patients required hospitalization. More than 80% had received prior COVID-19 vaccination (57.1% with two doses, 27.3% with three doses). The majority (90.9%) had mild disease; only one (1.3%) patient required mechanical ventilation. Active hematological disease at time of COVID-19 infection was associated with increased odds of mortality [odds ratio (OR) = 6.90, 95% confidence interval (CI) = 1.20-40]. The 90-day all-cause mortality was 7.8% (six patients). Infection with the omicron variant (vs. delta) was associated with less severe illness (OR = 0.05, 95% CI = 0.01-0.47) and decreased odds of mortality (OR = 0.08, 95% CI = 0.01-0.76). Being on immunosuppression (OR = 5.10, 95% CI = 1.10-23.60) and being unvaccinated at disease onset (OR = 14.76, 95% CI = 2.89-75.4) were associated with greater severity of COVID-19 infection. CONCLUSION: We observed favorable outcomes with COVID-19 infection in a cohort of vaccinated HSCT patients. The SARS-CoV-2 omicron variant was associated with both less severe illness and decreased odds of mortality. As COVID-19 moves toward endemicity, early access to treatment and encouraging vaccination uptake is crucial in mitigating the challenge of COVID-19 management among HSCT recipients. Surveillance and assessment of clinical outcomes with new SARS-CoV-2 variants also remains important in this immunocompromised population.

inPhocus: Current State and Challenges of Phage Research in Singapore.

Bacteriophages and phage-derived proteins are a promising class of antibacterial agents that experience a growing worldwide interest. To map ongoing phage research in Singapore and neighboring countries, Lee Kong Chian School of Medicine, Nanyang Technological University Singapore (NTU) and Yong Loo Lin School of Medicine, National University of Singapore (NUS) recently co-organized a virtual symposium on Bacteriophage and Bacteriophage-Derived Technologies, which was attended by more than 80 participants. Topics were discussed relating to phage life cycles, diversity, the roles of phages in biofilms and the human gut microbiome, engineered phage lysins to combat polymicrobial infections in wounds, and the challenges and prospects of clinical phage therapy. This perspective summarizes major points discussed during the symposium and new perceptions that emerged after the panel discussion.

Current state of antimicrobial stewardship in organ transplantation in Singapore.

BACKGROUND: Antibiotic stewardship programs (ASPs) are well established in the public hospitals in Singapore, but they are not mandatory for transplant programs. Given the positive impact of ASPs in non-organ transplant patients (improved use of broad-spectrum antibiotics, reduced length of stay, and lower healthcare costs), stewardship principles are likely to benefit transplant recipients. METHODS: We reviewed the progress made in ASPs in the Asia Pacific region as well as the progress of our ASP over the last decade since it was established. We also described how stewardship strategies have evolved for the purposes of our transplant program. RESULTS: Currently, pressing stewardship issues for our transplant program include high antibiotic consumption, as well as the burden, morbidity, and mortality associated with drug-resistant bacterial infections. Transplanting the model of stewardship onto a transplant program ignores the intricacies of transplant patients; the bespoke form of stewardship, "handshake stewardship", is more appropriate. CONCLUSION: To advance the cause of ASP in the transplant unit in Singapore, stakeholder buy-in is key; empowering transplant physicians to be stewardship-focused would be more sustainable in the long run. In addition, expanding our diagnostic armamentarium, optimizing existing therapeutics and multi-disciplinary team involvement (including stakeholders from microbiology, and infection prevention teams) are vital.

Antibiotic stewardship program (ASP) in palliative care: antibiotics, to give or not to give.

Antimicrobial therapy in terminally ill patients remains controversial as goals of care tend to be focused on optimizing comfort. International guidelines recommend for antibiotic stewardship program (ASP) involvement in antibiotic decisions in palliative patients. The primary objective was to evaluate the clinical impact of ASP interventions made to stop broad-spectrum intravenous antibiotics in terminally ill patients. This was a retrospective chart review of 459 terminally ill patients in Singapore General Hospital audited by ASP between December 2010 and December 2018. Antibiotic duration, time-to-terminal discharge for end-of-life care, time-to-mortality, and mortality rates of patients with antibiotics ceased or continued upon ASP recommendations were compared. A total of 283 and 176 antibiotic courses were ceased and continued post-intervention, respectively. The intervention acceptance rate was 61.7%. The 7-day mortality rate (47.3% vs 61.9%, p = 0.003) was lower in the ceased group, while 30-day mortality rate (76.0% vs 81.2%, p = 0.203) and time-to-mortality post-intervention (3 [0-24] vs 2 [0-27] days, p = 0.066) did not differ between the ceased and continued groups. After excluding the 57 patients who had antibiotics continued until death within 48 h of intervention, only time-to-mortality post-intervention was statistically significantly shorter in the ceased group (3 [0-24] vs 4 [0-27], p < 0.001). Of the 131 terminally discharged patients, antibiotic duration (4 [0-17] vs 6.5 [1-14] days, p = 0.001) and time-to-terminal discharge post-intervention (6 [0-74] vs 10.5 [3-63] days, p = 0.001) were shorter in the ceased group. Antibiotic cessation in terminally ill patients was safe, and was associated with a significantly shorter time-to-terminal discharge.

Hospital Pharmacists and Antimicrobial Stewardship: A Qualitative Analysis.

Antimicrobial stewardship programmes (ASPs) in hospitals are predominantly led by specific ASP physicians and pharmacists. Limited studies have been conducted to appreciate non-ASP-trained hospital pharmacists' perspectives on their roles in antimicrobial stewardship. Focus group discussions (FGDs) were conducted with 74 pharmacists, purposively sampled from the 3 largest acute-care public hospitals in Singapore, to explore facilitators and barriers faced by them in antimicrobial stewardship. Applied thematic analysis was conducted and codes were categorised using the social-ecological model (SEM). At the intrapersonal level, pharmacists identified themselves as reviewers for drug safety before dispensing, confining to a restricted advisory role due to lack of clinical knowledge, experience, and empowerment to contribute actively to physicians' prescribing decisions. At the interpersonal level, pharmacists expressed difficulties conveying their opinions and recommendations on antibiotic therapy to physicians despite frequent communications, but they assumed critical roles as educators for patients and their caregivers on proper antibiotic use. At the organisational level, in-house antibiotic guidelines supported pharmacists' antibiotic interventions and recommendations. At the community level, pharmacists were motivated to improve low public awareness and knowledge on antibiotic use and antimicrobial resistance. These findings provide important insights into the gaps to be addressed in order to harness the untapped potential of hospital pharmacists and fully engage them in antimicrobial stewardship.

Dengue virus infection among renal transplant recipients in Singapore: a 15-year single-centre retrospective review.

INTRODUCTION: Dengue is a mosquito-borne viral infection endemic in Singapore. Its impact in renal transplantation is limited to small case series. We aimed to characterise the clinical presentation and outcomes of dengue infection among renal transplant recipients in Singapore. METHODS: We conducted a 15-year retrospective review of dengue in renal transplant patients treated at Singapore General Hospital between January 2005 and October 2019. The diagnosis of dengue was made if there were a compatible clinical syndrome and a positive dengue diagnostic assay (Dengue NS1 antigen, IgM or RT-PCR). RESULTS: 31 patients were diagnosed with dengue, 18 (58.1%) were deceased donor recipients. The median age was 52 (IQR 40-61) years; 16 (51.6%) were females. The median time to diagnosis was 99 (IQR 18-169) months from transplant. The most common clinical symptoms were fever (87.1%), myalgia (41.9%), gastrointestinal symptoms (38.7%) and headache (25.8%). 19 (61.3%) patients had dengue without warning signs, 9 (29.0%) had dengue with warning signs, 3 (9.7%) had severe dengue and 30 (96.8%) were hospitalized. 17 (54.8%) patients had graft dysfunction, 16 (94.1%) of whom had recovery of graft function. 1 (3.2%) patient required dialysis and subsequently died. There were two cases of donor-derived infections (DDIs) with favourable outcomes. CONCLUSION: Our experience with dengue in renal transplant recipients is concordant with published data. Although graft dysfunction is common, it is often transient with favourable outcomes. Outpatient management may be considered for mild infections. Although dengue DDIs are uncommon, more stringent donor screening may be considered in endemic regions.

Aortic endograft infection secondary to Burkholderia pseudomallei: A case report and review of the literature.

Aortic graft infection is a rare complication after endovascular aneurysm repair that is usually caused by gram-positive organisms such as Staphylococcus spp or gram-negative organisms such as Enterobacteriaceae or Salmonella spp. We have presented a unique case of a patient with acute graft infection secondary to Burkholderia pseudomallei. Because treatment of B. pseudomallei infections is challenging owing to its inherent resistance to multiple antibiotics, we have proposed an approach for managing similar cases in the future. Lifestyle advice on avoiding soil exposure in the postoperative period after endovascular aneurysm repair might be an important preventative measure in endemic regions.

Waitlisted Transplant Candidates' Attitudes and Concerns Toward Transplantation During COVID-19.

BACKGROUND In solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) recipients, coronavirus disease 2019 (COVID-19) can contribute to a severe clinical course and an increased risk of death. Thus, patients awaiting a SOT or HSCT face the dilemma of choosing between a life-saving treatment that presents a significant threat of COVID-19 and the risk of waitlist dropout, progression of disease, or mortality. The lack of established literature on COVID-19 complicates the issue as patients, particularly those with inadequate health literacy, may not have the resources needed to navigate these decisions. MATERIAL AND METHODS We conducted a standardized phone survey of patients awaiting SOT or HSCT to assess the prevalence of inadequate health literacy and attitudes toward transplant during the COVID-19 pandemic. RESULTS Seventy-one patients completed the survey, with a response rate of 84.5%. Regardless of health literacy, most waitlisted candidates recognized that the current pandemic is a serious situation affecting their care and that COVID-19 poses a significant risk to their health. Despite the increased risks, most patients reported they would choose immediate transplantation if there was no foreseeable end to the pandemic, and especially if the medical urgency did not permit further delay. There were no differences in responses across the patient waitlist groups for heart, kidney, liver, and stem cell transplant. CONCLUSIONS These findings can help transplant centers decide how transplantation services should proceed during this pandemic and can be used to educate patients and guide discussions about informed consent for transplant during the COVID-19 pandemic.

Performance of Population Pharmacokinetic Models in Predicting Polymyxin B Exposures.

Polymyxin B is the last line of defense in treating multidrug-resistant gram-negative bacterial infections. Dosing of polymyxin B is currently based on total body weight, and a substantial intersubject variability has been reported. We evaluated the performance of different population pharmacokinetic models to predict polymyxin B exposures observed in individual patients. In a prospective observational study, standard dosing (mean 2.5 mg/kg daily) was administered in 13 adult patients. Serial blood samples were obtained at steady state, and plasma polymyxin B concentrations were determined by a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method. The best-fit estimates of clearance and daily doses were used to derive the observed area under the curve (AUC) in concentration-time profiles. For comparison, 5 different population pharmacokinetic models of polymyxin B were conditioned using patient-specific dosing and demographic (if applicable) variables to predict polymyxin B AUC of the same patient. The predictive performance of the models was assessed by the coefficient of correlation, bias, and precision. The correlations between observed and predicted AUC in all 5 models examined were poor (r2 < 0.2). Nonetheless, the models were reasonable in capturing AUC variability in the patient population. Therapeutic drug monitoring currently remains the only viable approach to individualized dosing.

An unusual case of Scedosporium apiospermum fungaemia in an immunocompetent patient with a left ventricular assist device and an implantable cardiac device.

Left ventricular assist device (LVAD)-related infections are a leading cause of morbidity and mortality, with fungal infections being particularly difficult to manage. We report a case of an immunocompetent 39-year-old male with an LVAD and an implantable cardiac device (ICD) who developed fatal Scedosporium apiospermum fungaemia. To the best of our knowledge, this is the first reported case of LVAD-related S. apiospermum fungaemia.

Antimicrobial stewardship programme: a vital resource for hospitals during the global outbreak of coronavirus disease 2019 (COVID-19).

Healthcare resources are being diverted for the containment and control of coronavirus disease 2019 (COVID-19). During this outbreak, it is cautioned that antibiotic misuse may be increased, especially for respiratory tract infections. With stewardship interventions, the duration of antibiotic therapy and length of stay of hospitalized patients can be reduced significantly. Antibiotic stewardship programmes should continually engage and educate prescribers to mitigate antibiotic misuse during the COVID-19 pandemic.

Practical Considerations for Solid Organ Transplantation During the COVID-19 Global Outbreak: The Experience from Singapore.

The current coronavirus disease 2019 (COVID-19) pandemic has not only caused global social disruptions but has also put tremendous strain on healthcare systems worldwide. With all attention and significant effort diverted to containing and managing the COVID-19 outbreak (and understandably so), essential medical services such as transplant services are likely to be affected. Closure of transplant programs in an outbreak caused by a highly transmissible novel pathogen may be inevitable owing to patient safety. Yet program closure is not without harm; patients on the transplant waitlist may die before the program reopens. By adopting a tiered approach based on outbreak disease alert levels, and having hospital guidelines based on the best available evidence, life-saving transplants can still be safely performed. We performed a lung transplant and a liver transplant successfully during the COVID-19 era. We present our guidelines and experience on managing the transplant service as well as the selection and management of donors and recipients. We also discuss clinical dilemmas in the management COVID-19 in the posttransplant recipient.