Presentation, management, and outcomes of norovirus in adult and pediatric solid organ and hematopoietic stem cell transplant recipients: A multicenter, retrospective study.

BACKGROUND: Norovirus (NoV) can cause chronic relapsing and remitting diarrhea in immunocompromised patients.  Few multicenter studies have described the clinical course, outcomes, and complications of chronic NoV in transplant recipients. METHODS: A multicenter retrospective study of adult and pediatric SOT and HSCT recipients diagnosed with NoV between November 1, 2017, and February 28, 2021. Data were obtained from electronic medical records (EMR) and entered into a central REDCap database. Descriptive statistics were calculated. RESULTS: A total of 280 NoV+ patients were identified across eight sites. The majority were adults (74.1%) and SOT recipients (91.4%). Initial diagnosis of NoV occurred a median of 36 months post-Tx (IQR [15.0, 90.0]). Most NoV cases had >3 diarrheal episodes daily (66.0%), nausea and vomiting (60.1%). Duration of diarrhea varied greatly (median = 10 days, mean = 85.9 days, range (1, 2100)). 71.3% were hospitalized. Adjustment of immunosuppression, including reduction and discontinuation of mToR inhibitor, CNI, and/or MMF, was the most common management intervention for NoV. Other therapies resulted only in temporary improvement. Four patients died within 30 days and three others died by 180 days postdiagnosis. Clinically significant renal dysfunction was observed in 12.5% by 30 days and 21.4% by 180 days post-NoV diagnosis. CONCLUSION: In HSCT and SOT patients, NoV frequently resulted in severe symptoms, prolonged diarrhea (30% persistent with diarrhea for >30 days), and clinically significant renal dysfunction (up to 21% of patients). Utilized therapies did not reliably result in the resolution of infection demonstrating the need for more effective treatment.

Pharmacodynamic Analysis of Daptomycin-treated Enterococcal Bacteremia: It Is Time to Change the Breakpoint.

BACKGROUND: Currently, there is debate over whether the daptomycin susceptibility breakpoint for enterococci (ie, minimum inhibitory concentration [MIC] ≤4 mg/L) is appropriate. In bacteremia, observational data support prescription of high doses (>8 mg/kg). However, pharmacodynamic targets associated with positive patient outcomes are undefined. METHODS: Data were pooled from observational studies that assessed outcomes in daptomycin-treated enterococcal bacteremia. Patients who received an additional antienterococcal antibiotic and/or a ß-lactam antibiotic at any time during treatment were excluded. Daptomycin exposures were calculated using a published population pharmacokinetic model. The free drug area under the concentration-time curve to MIC ratio (fAUC/MIC) threshold predictive of survival at 30 days was identified by classification and regression tree analysis and confirmed with multivariable logistic regression. Monte Carlo simulations determined the probability of target attainment (PTA) at clinically relevant MICs. RESULTS: Of 114 patients who received daptomycin monotherapy, 67 (58.8%) were alive at 30 days. A fAUC/MIC >27.43 was associated with survival in low-acuity (n = 77) patients (68.9 vs 37.5%, P = .006), which remained significant after adjusting for infection source and immunosuppression (P = .026). The PTA for a 6-mg/kg/day (every 24 hours) dose was 1.5%-5.5% when the MIC was 4 mg/L (ie, daptomycin-susceptible) and 91.0%-97.9% when the MIC was 1 mg/L. CONCLUSIONS: For enterococcal bacteremia, a daptomycin fAUC/MIC >27.43 was associated with 30-day survival among low-acuity patients. As pharmacodynamics for the approved dose are optimized only when MIC ≤1 mg/L, these data continue to stress the importance of reevaluation of the susceptibility breakpoint.

Norovirus in health care and implications for the immunocompromised host.

PURPOSE OF REVIEW: The majority of norovirus outbreaks in the United States occur in healthcare facilities. With the growing population of immunocompromised hosts who are in frequent contact with healthcare facilities, norovirus is not only a threat to hospitals and nursing homes but also to these individuals. This review summarizes the impact of norovirus infection on healthcare facilities and immunocompromised hosts. RECENT FINDINGS: The natural history of norovirus infection in immunocompromised individuals remains poorly understood. Although host immune responses play a critical role in reducing duration of viral shedding and viral load in norovirus-infected individuals, why some immunocompromised patients spontaneously recover while others develop a chronic and protracted course of illness remains unclear. Norovirus outbreaks occur in healthcare facilities because the virus is highly contagious, resistant to disinfection and efficiently transmitted. The use of real-time metagenomic next-generation sequencing and phylogenetic analyses has provided valuable information on transmission patterns in complex hospital-associated norovirus outbreaks. The development of human intestinal enteroid cultures enables the determination of effectiveness of disinfectants against human noroviruses, circumventing the validity questions with surrogate virus models due to differences in susceptibility to inactivation and disinfectants. SUMMARY: Metagenomics next-generation sequencing can enhance our understanding of norovirus transmission and lead to more timely mitigation strategies to curb norovirus outbreaks in healthcare facilities. With new in-vitro cultivation methods for human noroviruses, candidate vaccines and effective antivirals could be available in the near future.

Live vaccines after pediatric solid organ transplant: Proceedings of a consensus meeting, 2018.

Growing evidence suggests receipt of live-attenuated viral vaccines after solid organ transplant (SOT) has occurred and is safe and needed due to lapses in herd immunity. A 2-day consortium of experts in infectious diseases, transplantation, vaccinology, and immunology was held with the objective to review evidence and create expert recommendations for clinicians when considering live viral vaccines post-SOT. For consideration of VV and MMR post-transplant, evidence exists only for kidney and liver transplant recipients. For MMR vaccine post-SOT, consider vaccination during outbreak or travel to endemic risk areas. Patients who have received antiproliferative agents (eg. mycophenolate mofetil), T cell-depleting agents, or rituximab; or have persistently elevated EBV viral loads, or are in a state of functional tolerance, should be vaccinated with caution and have a more in-depth evaluation to define benefit of vaccination and net state of immune suppression prior to considering vaccination. MMR and/or VV (not combined MMRV) is considered to be safe in patients who are clinically well, are greater than 1 year after liver or kidney transplant and 2 months after acute rejection episode, can be closely monitored, and meet specific criteria of "low-level" immune suppression as defined in the document.

A Systematic Review of Safety and Immunogenicity of Influenza Vaccination Strategies in Solid Organ Transplant Recipients.

Immunogenicity from seasonal inactivated influenza vaccine (IIV) remains suboptimal in solid organ transplant recipients (SOTRs). We conducted a systematic review that compared the safety and immunogenicity of nonstandard influenza vaccination strategies with single-dose IIV in SOTRs. Booster doses and possibly high-dose (HD) influenza vaccination strategies seem to hold promise for improving vaccination immunogenicity in SOTRs. Administration of intradermal and MF59-adjuvanted trivalent IIV (IIV3) did not improve vaccine immunogenicity compared with single-dose intramuscular IIV. Alternative vaccine strategies were generally well tolerated; SOTRs who received HD, intradermal or adjuvanted IIV3 had a higher frequency of infection site reactions, while systemic adverse events were more frequent in SOTRs who received HD IIV3. Allograft rejection rates were similar in both groups. SOTRs should continue to receive standard-dose IIV annually in accordance with current recommendations, pending future studies to determine the optimal timing, frequency, and dosage of IIV using the booster-dose strategy.

Letermovir successfully used for secondary prophylaxis in a heart transplant recipient with ganciclovir-resistant cytomegalovirus syndrome (UL97 mutation).

Letermovir was approved by the Food and Drug Administration (FDA) in November 2017 for use in adult cytomegalovirus (CMV)-seropositive allogeneic stem cell transplant (SCT) recipients for primary prophylaxis of CMV infection and disease. We report off-label use of letermovir for secondary prophylaxis of genotype-confirmed ganciclovir-resistant cytomegalovirus (CMV) syndrome (UL 97 mutation [C603W]) in a heart transplant recipient initially treated with intravenous cidofovir followed by foscarnet, both discontinued due to unacceptable toxicities.

Clinical presentation and outcomes of norovirus infection in intestinal allograft compared to native intestine.

BACKGROUND: No data are available on clinical manifestations and course of norovirus gastroenteritis (NVE) in intestinal allograft (from intestinal and multivisceral transplant recipients, ITR) compared to native intestine (from other allograft recipients, nITR). METHODS: This was a retrospective study of solid organ transplant recipients with NVE at two centers from January 1, 2010 to April 1, 2014. Chi-square, t-test, linear and logistic regression analyses were done to compare NVE in ITR vs nITR patients. RESULTS: The ITR (45 patients) were compared to nITR (107 patients). ITR were younger (odds ratio [OR]=0.90; P<.0001), less likely to receive anti-lymphocyte induction therapy (OR=0.15; P<.0001), and had shorter time from transplant to NVE (OR=0.99; P=.008). On presentation ITR had less frequent nausea (OR=0.11; P<.0001) or vomiting (OR=0.36; P=.01), higher white blood cell count (OR=1.09; P=.001), and higher glomerular filtration rate (OR=1.02; P<.0001). ITR were less likely to receive anti-motility agents (OR=9.6; P<.0001). ITR were more likely to stay longer on intravenous (IV) fluids (OR=1.18; P<.0001); have recurrent NVE (OR=4.25; P<.0001); have longer hospital stay (OR=1.07; P<.0001); develop acute rejection (OR=5.1; P=.006); and have lower overall survival (OR=0.28; P=.006). CONCLUSIONS: Compared to nITR, the ITR with NVE were significantly younger, had less nausea and vomiting at presentation, received less anti-motility agents, required more IV fluids, and had longer hospital stay. A trend was seen for lower survival with NVE in ITR.

Predictors of persistent diarrhea in norovirus enteritis after solid organ transplantation.

Solid organ transplant (SOT) recipients may develop protracted diarrheal illness from norovirus. We performed a retrospective chart review between January 2010 and April 2014 to identify predictors of persistent diarrhea in transplant recipients with norovirus enteritis. A total of 152 SOT recipients with mean age of 31.5 years (SD 23.1) were included: 43.4% male, 34.2% pediatric patients. Allograft types were abdominal 136 (89.5%) (kidney [39.5%], liver-small bowel [23%], other [27%]) and thoracic 16 (10.5%). The median time to diagnosis of first norovirus enteritis episode from date of transplantation was 1.7 (0.3-5.3) years. At time of presentation, diarrhea was present in 141 (93%). Thirty percent had persistent diarrhea at 2 weeks. Hospitalization was required for treatment in 121 (80%) of episodes with the mean length of stay of 10±15.2 days. Most (91%) infections were due to norovirus genogroup II, and gastrointestinal coinfections were seen in 23 (19%) norovirus enteritis episodes. Nausea at time of diagnosis (P=.002) and cytomegalovirus (CMV) infection in the preceding 90 days (P=.036) were identified as independent risk factors for persistent diarrhea using univariate and multivariable logistic regression. Our study shows that nausea on presentation and prior CMV infection were associated with persistent diarrhea in patients with norovirus enteritis.

Epidemiology of invasive fungal infections in lung transplant recipients on long-term azole antifungal prophylaxis.

Lung transplant recipients (LTR) at our institution receive prolonged and mostly lifelong azole antifungal (AF) prophylaxis. The impact of this prophylactic strategy on the epidemiology and outcome of invasive fungal infections (IFI) is unknown. This was a single-center, retrospective cohort study. We reviewed the medical records of all adult LTR from January 2002 to December 2011. Overall, 16.5% (15 of 91) of patients who underwent lung transplantation during this time period developed IFI. Nineteen IFI episodes were identified (eight proven, 11 probable), 89% (17 of 19) of which developed during AF prophylaxis. LTR with idiopathic pulmonary fibrosis were more likely to develop IFI (HR: 4.29; 95% CI: 1.15-15.91; p = 0.03). A higher hazard of mortality was observed among those who developed IFI, although this was not statistically significant (hazard ratio [HR]: 1.71; 95% confidence interval [CI] [0.58-4.05]; p = 0.27). Aspergillus fumigatus was the most common cause of IFI (45%), with pulmonary parenchyma being the most common site of infection. None of our patients developed disseminated invasive aspergillosis, cryptococcal or endemic fungal infections. IFI continue to occur in LTR, and the eradication of IFI appears to be challenging even with prolonged prophylaxis. Azole resistance is uncommon despite prolonged AF exposure.

Impact of Respiratory Viral Panel Results on Piperacillin-Tazobactam Use in a Medical Intensive Care Unit: A Single-Center Retrospective Study.

PURPOSE: In critically ill patients with acute respiratory infection, antibiotic stewardship can be challenging given the acuity and complexities of such patients, and the associated high mortality. This study determined the impact of respiratory viral panel (RVP) testing on piperacillin-tazobactam (PT) use in patients admitted to a medical intensive care unit (MICU). METHODS: This retrospective chart review used data from adults admitted to a MICU between January 1, 2017, and January 31, 2018, and with findings from at least one RVP available. FINDINGS: RVP testing was performed on samples from 90 patients admitted to the MICU. RVP was positive in 41% (37/90) of patients, and 53.3% (48/90) received PT during their MICU stay. PT was discontinued in 25.5% (23/90) of patients, 16.2% (6/37) with a positive RVP and 32.1% (17/53) with a negative RVP. Overall mortality was significantly lower in the positive RVP group versus the negative RVP group (odds ratio = 0.28; P = 0.001). In a multivariate Cox proportional hazards model (adjusted for acute kidney injury and culture positivity), the risk for PT discontinuation was significantly less in patients with a positive RVP compared to those with a negative RVP (primary outcome). Overall mortality rate and median length of stay were significantly lower in patients with a positive RVP compared to those in patients with a negative RVP (secondary outcomes). The 30-day hospital readmission rate and the risk for AKI were not significantly different between those with positive versus negative RVP. IMPLICATIONS: Reasons for these observations are currently unclear, but deserve further exploration in future studies. It is hypothesized that the treating providers were concerned about the presence of concurrent bacterial infections along with the diagnosed viral infections given that the patients were critically ill. This suggests that RVP results did not impact PT-prescribing practices in the MICU, and thus that the routine use of RVP solely for guiding antimicrobial-stewardship practices may not be effective.

The gut microbiota in transplant patients.

Solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) recipients are at increased risk for developing infections due to underlying immunosuppression. Antibiotic use, and in HSCT recipients, the use of preparative regimens prior to transplantation can deplete gut commensal bacteria, resulting in intestinal dysbiosis. Emerging evidence in transplant patients, particularly HSCT, suggest that disturbances in gut microbiota populations are associated with a number of adverse outcomes. Here, we review the outcomes of HSCT and SOT recipients with gut microbiota imbalance or dysbiosis, explore the nascent field of gut microbiome therapeutic approaches including fecal microbiota transplantation and the use of precision probiotics in HSCT and SOT recipients.

Pharmacodynamics of daptomycin in combination with other antibiotics for the treatment of enterococcal bacteraemia.

Daptomycin is commonly prescribed in combination with other antibiotics for treatment of enterococcal bacteraemia. Whilst a free drug area under the concentration-time curve to minimum inhibitory concentration (fAUC/MIC) ratio >27.4 is associated with 30-day survival with daptomycin monotherapy, it is unknown whether receipt of other antibiotics affects this threshold. Data were pooled from seven published trials assessing outcomes in daptomycin-treated enterococcal bacteraemia, including patients receiving daptomycin (≥72 h) and any ß-lactam, intravenous aminoglycoside, linezolid, tigecycline and/or vancomycin. Exposures were calculated using a published population pharmacokinetic model based on creatinine clearance, 90% protein binding and daptomycin Etest MIC. The fAUC/MIC threshold predictive of 30-day survival was determined by classification and regression tree analysis. Following pooling of data, 240 adults were included; 137 (57.1%) were alive at 30 days. A majority of patients were immunosuppressed (65.8%) and received a ß-lactam (94.6%). Examining the threshold in low-acuity patients (n = 135) to control for co-morbidities, these patients were more likely to survive when fAUC/MIC >12.3 was achieved (63.2% vs. 20.0%; P = 0.015). The difference remained significant in a multivariable logistic regression model that controlled for infection source and immunosuppression (P = 0.017). This threshold is 2-fold lower than that observed with daptomycin monotherapy. Probabilities of threshold attainment using a 10 mg/kg/day dose were 100% for isolates with MICs ≤ 2 mg/L and 95.2% for a 12 mg/kg/day dose for MICs of 4 mg/L. These data support the use of high-dose daptomycin in combination with another antibiotic for treatment of enterococcal bacteraemia.

A Comprehensive Review of Immunization Practices in Solid Organ Transplant and Hematopoietic Stem Cell Transplant Recipients.

BACKGROUND: Vaccine-preventable diseases, especially influenza, varicella, herpes zoster, and invasive pneumococcal infections, continue to lead to significant morbidity and mortality in solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) recipients. METHODS: We highlight guideline recommendations for the use of key vaccines in SOT and HSCT recipients and to review the latest evidence and developments in the field. RESULTS: Physicians should vaccinate individuals with end-stage organ disease, as vaccine seroresponse rates are higher pretransplantation. Most live attenuated vaccines continue to be contraindicated post-transplantation, but there are emerging safety profile and efficacy data to support the use of specific live attenuated vaccines, such as measles, mumps, and rubella in pediatric liver or kidney transplant recipients who are on low-level maintenance immunosuppression and without recent history of allograft rejection. An inactivated subunit varicella zoster virus vaccine is currently awaiting US Food and Drug Administration approval. While we await the safety profile and efficacy data of this subunit vaccine in transplant recipients, it will likely benefit immunocompromised individuals, including transplant recipients, because the live attenuated herpes zoster vaccine is currently contraindicated in transplant recipients and transplantation candidates receiving immunosuppression. CONCLUSIONS: There is currently no evidence that vaccines lead to allograft rejection in SOT recipients. Household contacts of SOT and HSCT recipients should be vaccinated per the Advisory Committee on Immunization Practices schedule and recommendations. IMPLICATIONS: Immunizations remain underutilized in transplantation patients. Although efficacy of vaccines in SOT and HSCT may be suboptimal, partial protection is preferred over no protection.

Vancomycin-resistant Enterococcal Bloodstream Infections in Hematopoietic Stem Cell Transplant Recipients and Patients with Hematologic Malignancies: Impact of Daptomycin MICs of 3 to 4 mg/L.

PURPOSE: Case reports of treatment failure with standard-dose daptomycin (6 mg/kg) have recently surfaced in vancomycin-resistant Enterococcus (VRE) bloodstream infection (BSI) episodes with daptomycin MICs of 3 to 4 mg/L. The clinical implications of daptomycin MICs of 3 to 4 mg/L in VRE BSIs have not been elucidated. METHODS: We performed a single institutional retrospective analysis of adult stem cell transplant recipients and patients with hematologic malignancies diagnosed with VRE BSI from 2006 to 2014 and compared outcomes between those with daptomycin MICs of 3 to 4 mg/L those with 2 mg/L, as determined by Etest. FINDINGS: Forty-two daptomycin-treated VRE BSI episodes, all due to Enterococcus faecium were identified; 19 episodes with daptomycin MICs of 3 to 4 mg/L and 23 episodes with a daptomycin MIC of 2 mg/L. Patients in the higher daptomycin MIC group were more likely to be male, to be stem cell transplant recipients, and to have received high-dose daptomycin treatment (>6 mg/kg). In unadjusted analyses, microbiological failure in the daptomycin MICs 3 to 4 mg/L versus 2 mg/L groups (odds ratio = 1.79, 95% CI, 0.52-6.11; P = 0.35), the median duration of bacteremia (4 days in daptomycin MICs 3-4 mg/L vs 3 days in daptomycin MIC 2 mg/L; P = 0.18) and all-cause 30-day mortality (21% in daptomycin MICs 3-4 mg/L vs 35% in daptomycin MIC 2 mg/L group; P = 0.49) were not different. In adjusted analyses, the association between higher Pitt bacteremia scores and all-cause 30-day mortality was statistically significant (P = 0.0006), whereas the association between daptomycin MICs of 3 to 4 mg/L and all-cause 30-day mortality approached statistical significance (P = 0.06). IMPLICATIONS: Duration of bacteremia and microbiological failure rates did not differ by daptomycin MICs in VRE BSI episodes in our patients, composed of adult stem cell transplant recipients and patients with hematologic malignancies. There was a nonsignificant trend in multivariable analysis suggesting that all-cause 30-day mortality was lower in patients whose VRE bloodstream isolates were with daptomycin MICs of 3 to 4 mg/L.

Increasing Rates of Fluoroquinolone Resistance in Escherichia coli Isolated From the Blood and Urine of Patients with Hematologic Malignancies and Stem Cell Transplant Recipients.

Fluoroquinolone (FQ) antibiotics have been shown to reduce mortality and the number of febrile episodes when used as prophylaxis during neutropenia. Prior studies suggest that prophylaxis may result in increasing rates of FQ resistance. Fluoroquinolone non-susceptibility trends in Escherichia coli isolated from blood and urine cultures were evaluated over a 16-year period during which prophylaxis was initiated in patients with hematologic malignancies and stem cell transplants. Non-susceptibility rates increased after the introduction of prophylaxis, with yearly non-susceptibility rates rising from 30%-33% to 40%-88% in blood isolates. The high rates of non-susceptibility now observed raise concerns about the continued efficacy of FQ prophylaxis. This concern exists particularly in those patients undergoing stem cell transplants where the total FQ non-susceptibility rates over the study period were 82.3%. Further evaluation of the effect of FQ prophylaxis on antibiotic resistance and its efficacy in the setting of increased rates of resistance is warranted.

Diagnostic and management strategies for donor-derived infections.

Donor-derived infections continue to occur in spite of standard organ donor screening. These infections can be challenging to diagnose and manage for a treating physician. This article reviews the process of organ donor evaluation, limitations of current screening strategies, approach to recipient evaluation in suspected donor-derived infections, and diagnostic and management strategies of selected donor-derived infections.