Donor-derived carbapenem-resistant gram-negative bacterial infections in solid organ transplant recipients: Active surveillance enhances recipient safety.

Donor-derived infections (DDIs) caused by carbapenem-resistant gram-negative bacteria (CR-GNB) in solid organ transplant recipients are potentially life-threatening. In this prospective study, we evaluated the incidence, factors associated with transmission, and the outcome of recipients with unexpected CR-GNB DDIs after the implementation of our local active surveillance system (LASS). LASS provides for early detection of unexpected donor CR-GNB infections, prophylaxis of recipients at high risk, and early diagnosis and treatment of DDIs. Whole genome sequencing confirmed DDI. Among 791 recipients, 38 (4.8%) were at high risk of unexpected CR-GNB DDI: 25 for carbapenem-resistant Enterobacterales (CRE) and 13 for carbapenem-resistant Acinetobacter baumannii (CRAB). Transmission did not occur in 27 (71%) cases, whereas DDIs occurred in 9 of 25 of CRE and 2 of 13 of CRAB cases. Incidence of CR-GNB DDI was 1.4%. Recipients of organs with CR-GNB-positive preservation fluid and liver recipients from a donor with CRE infection were at the highest risk of DDI. There was no difference in length of hospital stay or survival in patients with and without CR-GNB DDI. Our LASS contains transmission and mitigates the negative impacts of CR-GNB DDI. Under well-defined conditions, organs from donors with CR-GNB may be considered after a thorough evaluation of the risk/benefit profile.

Skin and soft tissue infections in solid organ transplants.

PURPOSE OF REVIEW: Skin and soft tissue infections (SSTI) in solid organ transplant (SOT) recipients may be a great challenge for clinicians caring for SOT due to the involvement of both common and opportunistic pathogens associated with a blunted immune response. The purpose of this review is to outline current literature and describe open issues on the management of SSTI in this special population. RECENT FINDINGS: Clinical presentation in SOT recipients can manifest as isolated skin lesions after primary inoculation or be the sign of a disseminated infection. Tissue samples for microscopy and histopathology are crucial to making an accurate diagnosis given the nonspecific and heterogeneous appearance of skin lesions. Multidisciplinary teams are required for a comprehensive diagnosis and management. SUMMARY: SSTI are frequent contributors to morbidity and mortality in SOT. Specific research focused on the clinical presentation, risk factors and management in this special population is needed.

Cytokine storm and severe hepatitis in pregnancy due to herpes simplex virus 2.

CASE PRESENTATION: A pregnant woman developed hepatitis due to a herpes simplex virus 2 primary infection with a severe systemic inflammatory response. Treatment with acyclovir and human immunoglobulin was given and both mother and baby survived. PURPOSE: We provide the first description of the inflammatory response associated with herpetic hepatitis in pregnancy.

Current management of SARS-CoV-2 infection in solid organ transplant recipients: Experience derived from an ESGICH-ESOT survey.

OBJECTIVE: Solid organ transplant (SOT) recipients have a poorer SARS-CoV-2 vaccine response and higher risk for COVID-19-associated complications. However, there is no consensus on the current management of COVID-19 and data on persistent COVID-19 rates in SOT recipients are lacking. METHODS: An electronic survey concerning the management of COVID-19 in SOT recipients was distributed among all members of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Study Group for Infections in Compromised Hosts (ESGICH) and of the European Society for Organ Transplantation (ESOT). Four major sections were covered: prevention, early COVID-19, late COVID-19, and persistent COVID-19. We developed a structured questionnaire including eight multiple-choice questions with branching logic in case of positive answers and three open-ended questions related to clinical practice. Questions were asked separately for lung and non-lung transplantation. RESULTS: Thirty-two physicians from 24 different centers participated. Most answers (n = 30) were provided by European physicians. Thirty of 32 (93.75%) physicians managed non-lung transplant recipients and 12 of 32 (33.3%) lung transplant recipients. There was a huge variability in practice regarding the treatment of COVID-19, and particularly noticeable when considering lung and non-lung transplant recipients. Main discordances included the use of nirmatrelvir alone or in combination therapy for early COVID-19, the use of immunomodulatory drugs other than steroids for late COVID-19, and the need for treating asymptomatic viral shedding in persistent COVID-19. There was more similarity in terms of prophylaxis recommendations. CONCLUSION: Despite a low number of respondents, this survey shows that there are many differences on how experts manage SARS-CoV-2 infections in SOT recipients.

Donor-derived mold infections in lung transplant recipients: The importance of active surveillance.

Unexpected donor-derived fungal infections represent a rare but potentially fatal complication in lung transplant (Tx) recipients. Timely communication of the results of donor cultures and prompt treatment of recipients are crucial to mitigate the consequences of donor-derived transmissions. In this prospective cohort study, all consecutive patients who underwent lung transplantation from 2015 to 2022 were included. In December 2015, a Local Active Surveillance System has been implemented to provide biovigilance of donor culture results and optimize recipients' management. The aim of this study is to investigate the incidence of unexpected, mold-positive cultures among lung donors and the rate of transmission to recipients. Furthermore, management strategies and outcome of recipients with mold transmission are described. In case of isolation of the same mold in donor and recipient cultures, when possible, transmission was confirmed by dendrogram analysis. During the study period, 82 lung Tx were performed from 80 donors. The prevalence of donors with "unexpected" mold isolation from the respiratory tract was 3.75% (3/80). Isolated molds were Aspergillus niger, Rhizopus oryzae, and Aspergillus flavus. Transmissions occurred in all the three cases (100%) with a mean time of 5 days from lung Tx but none of the recipients developed invasive mold disease. Our Local Active Surveillance System allowed prompt recognition of lung donors unexpected mold colonization. Even though transmission occurred, introduction of early targeted antifungal therapy prevented potential catastrophic consequence of mold donor-derived infection in the immediate post-Tx period.

Recent advances in cytomegalovirus infection management in solid organ transplant recipients.

PURPOSE OF REVIEW: Human cytomegalovirus (CMV) continues to be the most important infectious complication following solid organ transplantation (SOT). RECENT FINDINGS: Universal prophylaxis and preemptive therapy are the most adopted strategies for prevention of CMV disease globally. Prophylaxis with valganciclovir is the most widely used approach to CMV prevention, however leukopenia and late onset CMV disease after discontinuation of prophylaxis requires new strategies to prevent this complication. The use of assays detecting CMV-specific T cell-mediated immunity may individualize the duration of antiviral prophylaxis after transplantation. Letermovir has been recently approved for prophylaxis in kidney transplant recipients. CMV-RNAemia used together with CMV-DNAemia in the viral surveillance of CMV infection provides accurate information on viral load kinetics, mostly in patients receiving letermovir prophylaxis/therapy. The development of refractory and resistant CMV infection remains a major challenge and a new treatment with maribavir is currently available. In the present paper we will review the most recent advances in prevention and treatment of CMV diseases in SOT recipients. SUMMARY: Recent findings, summarized in the present paper, may be useful to optimize prevention and treatment of CMV infection in SOT.

Prevention and treatment of recurrent cellulitis.

PURPOSE OF REVIEW: Recurrent cellulitis is a challenging clinical condition affecting up to 47% of patients after the first episode, especially those with predisposing risk factors. The purpose of this review is to describe the state of the art of literature evidence and to highlight recent developments in its management. RECENT FINDINGS: Recurrent cellulitis can occur after successful treatment of cellulitis. Conditions that commonly increase the risk of cellulitis include local and systemic modifiable and nonmodifiable factors. A rigorous approach to the management of risk factors and treatment of acute infection is important as the risk of recurrence rises with repeated episodes. Risk factors, if present, need to be targeted in association with antibiotic prophylaxis. Penicillin V is the preferred antibiotic for prevention but other antibiotics and new drugs can be considered in cases of ß-lactam allergy, intolerance, or failure. SUMMARY: Recurrent cellulitis is associated with short term and long-term morbidity as well as significant healthcare costs. Management of underlying predisposing conditions is crucial to prevent recurrence in addition with evaluation of pharmacological measures, but specialized and multidisciplinary skills are needed. More efforts are needed to prevent and treat this underestimated problem.

Donor-derived infections in solid organ transplant recipients.

PURPOSE OF REVIEW: The potential for transmission of donor-derived infections (DDIs) is impossible to eliminate, but a thoughtful and systematic approach to donor evaluation can mitigate the risk. Prevention is a key issue and clinicians must maintain a high index of suspicion and remain vigilant in staying up to date on emerging infections. COVID-19 and Monkeypox have represented a new challenge for infectious disease screening and recommendations have been evolving, as knowledge in the field has grown. Additional considerations for pretransplant deceased donor screening include testing for neglected and endemic infectious diseases such as strongyloidiasis and HTLV 1/2. Molecular diagnostic tests have improved awareness on pathogenicity of mollicutes and fungi in the setting of DDIs. The aim of this review is to provide an update on the most recent literature on DDI with a special focus on these emerging hot topics. RECENT FINDINGS: Donor screening for uncommon pathogens must be guided by knowledge of changing epidemiology of infectious disease and availability of new diagnostic methods. SUMMARY: Appropriate screening, early recognition, timely reporting, close monitoring, and appropriate management are essential to help reducing the risk of emerging DDIs.

COVID-19 positive donor for solid organ transplantation.

The COVID-19 pandemic has significantly changed organ donation and transplantation worldwide. Since the beginning of the pandemic, the uncertainty regarding the potential route of transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has created tremendous pressures on transplantation communities, and international organisations have advised against using organs from deceased donors who have tested positive for SARS-CoV-2. The possibility of SARS-CoV-2 transmission through organ donation has only been reported for lung transplantation; hence, based on current experience, transplantation of non-lung organs from donors with active SARS-CoV-2 infection has been considered possible and safe, at least over short-term follow-up. As the evolving outbreak of SARS-CoV-2 continues, alongside the presence of vaccines and new treatment options, clinicians should consider transplanting organs from deceased donors with active SARS-CoV-2 infection to recipients with limited opportunities for transplantation and those with specific natural or vaccine-induced immunity. This article proffers an expert opinion on the use of organs from deceased donors with resolved or active SARS-CoV-2 infection in the absence of more definitive data and standardised acceptance patterns.

Clinical evidence supporting cefiderol for serious Acinetobacter baumannii infections.

PURPOSE OF REVIEW: Nosocomial infections caused by Acinetobacter baumannii currently represent a serious challenge for clinicians because treatment options are limited and frequently associated with significant toxicity. Cefiderocol is a first-in-class siderophore cephalosporin that has a proven efficacy for the treatment of multidrug-resistant Gram-negative infections, including carbapenem-resistant A. baumannii. The aim of this review is to evaluate the current evidence for the role of cefiderocol in the management of A. baumannii infections. RECENT FINDINGS: In this review, we briefly summarize the available data on the efficacy (from randomized controlled trials) and on effectiveness and cure rates (from observational studies), pertaining to the use of cefiderocol for treatment of serious A. baumannii infections. SUMMARY: Cefiderocol represents a promising and safe antibiotic option for treating patients with carbapenem-resistant A. baumannii infections. Due to conflicting mortality data from available experience, well-designed future randomized controlled trials and real-life studies are needed.

Cytomegalovirus Management in Solid Organ Transplant Recipients: A Pre-COVID-19 Survey From the Working Group of the European Society for Organ Transplantation.

Infections are leading causes of morbidity/mortality following solid organ transplantation (SOT) and cytomegalovirus (CMV) is among the most frequent pathogens, causing a considerable threat to SOT recipients. A survey was conducted 19 July-31 October 2019 to capture clinical practices about CMV in SOT recipients (e.g., how practices aligned with guidelines, how adequately treatments met patients' needs, and respondents' expectations for future developments). Transplant professionals completed a ∼30-minute online questionnaire: 224 responses were included, representing 160 hospitals and 197 SOT programs (41 countries; 167[83%] European programs). Findings revealed a heterogenous approach to CMV diagnosis and management and, sometimes, significant divergence from international guidelines. Valganciclovir prophylaxis (of variable duration) was administered by 201/224 (90%) respondents in D+/R- SOT and by 40% in R+ cases, with pre-emptive strategies generally reserved for R+ cases: DNA thresholds to initiate treatment ranged across 10-10,000 copies/ml. Ganciclovir-resistant CMV strains were still perceived as major challenges, and tailored treatment was one of the most important unmet needs for CMV management. These findings may help to design studies to evaluate safety and efficacy of new strategies to prevent CMV disease in SOT recipients, and target specific educational activities to harmonize CMV management in this challenging population.

Perioperative antibiotic stewardship in the organ transplant setting.

BACKGROUND: Solid organ transplant (SOT) recipients can benefit from traditional antimicrobial stewardship (AMS) activities directed to improve judicious perioperative prescribing and management, but evidence is lacking. The aim of this expert opinion review is to provide an update on the current landscape of application of AMS practices for optimization of perioperative prophylaxis (PP). METHODS: We reviewed the available literature on early postoperative infectious complications in SOT and PP management, on modified perioperative approaches in case of infection or colonization in recipients and donors and on AMS in transplantation PP. RESULTS: SOT recipients are at high risk for early postoperative infectious complications due to the complexity of surgical procedures, severity of end stage organ disease, net state of immunosuppression in the posttransplant period and to the high risk for multidrug resistant organism. Moreover, SOT may be exposed to preservation fluid infections and expected or unexpected donor-derived infections. We summarize main factors to take into account when prescribing transplant PP. CONCLUSION: Creating personalized PP to avoid unwanted consequences of antimicrobials while improving outcomes is an emerging and critical aspect in SOT setting. Further studies are needed to offer best PP tailored to SOT type and to evaluate interventions efficacy and safety.

Liver transplantation from active COVID-19 donors: Is it ethically justifiable?

The debate on the opportunity to use organs from donors testing positive for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in recipients with naïve resolved or active COVID-19 is ongoing. We aim to present the ethical analyses underlying the decision to perform liver transplantation (LT) in selected patients with resolved or active COVID-19 in Italy. We used Jonsen, Siegler, and Winslade's Four-Boxes casuistic method, addressing the four topics considered as constitutive of the essential structure of single clinical cases for their ethical analysis (medical indications, patient preferences, quality of life, and contextual features) to enable decision-making on a case-by-case basis. Based on these topics, we elucidate the meaning and balance among the principles of biomedical ethics. Clinical ethics judgment based on the relation between the risk of acquiring SARS-CoV-2 along with its potentially negative effects and the expected benefits of transplant lead to consider LT as clinically appropriate. Shared decision-making allows the integration of clinical options with the patient's subjective preferences and considerations, enabling a valid informed consent specifically tailored to the patients' individual circumstances. The inclusion of carefully selected SARS-CoV-2 positive donors represents an opportunity to offer lifesaving LT to patients who might otherwise have limited opportunities to receive one. COVID-19 positive donor livers are fairly allocated among equals, and respect for fundamental rights of the individual and the broader community in a context of healthcare rationing is guaranteed.The ethical analysis of the decision to perform LT in selected patients shows that the decision is ethically justifiable.

Cytomegalovirus in the transplant setting: Where are we now and what happens next? A report from the International CMV Symposium 2021.

The CMV Symposium in September 2021 was an international conference dedicated to cytomegalovirus (CMV) infection after solid organ or hematopoietic stem cell transplantation. This review provides an overview of the presentations given by the expert faculty, supplemented with educational clinical cases. Topics discussed include CMV epidemiology and diagnosis, the burden of CMV infection and disease, CMV-specific immunity and management of CMV in transplant settings. Major advances in the prevention and treatment of CMV in the past decade and increased understanding of CMV immunity have led to improved patient outcomes. In the future, management algorithms may be individualized based on the transplant recipient's immune profile, which will mark the start of a new era for patients with CMV.

Ceftazidime-Avibactam Use for Klebsiella pneumoniae Carbapenemase-Producing K. pneumoniae Infections: A Retrospective Observational Multicenter Study.

BACKGROUND: A growing body of observational evidence supports the value of ceftazidime-avibactam (CAZ-AVI) in managing infections caused by carbapenem-resistant Enterobacteriaceae. METHODS: We retrospectively analyzed observational data on use and outcomes of CAZ-AVI therapy for infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-Kp) strains. Multivariate regression analysis was used to identify variables independently associated with 30-day mortality. Results were adjusted for propensity score for receipt of CAZ-AVI combination regimens versus CAZ-AVI monotherapy. RESULTS: The cohort comprised 577 adults with bloodstream infections (n = 391) or nonbacteremic infections involving mainly the urinary tract, lower respiratory tract, and intra-abdominal structures. All received treatment with CAZ-AVI alone (n = 165) or with ≥1 other active antimicrobials (n = 412). The all-cause mortality rate 30 days after infection onset was 25% (146/577). There was no significant difference in mortality between patients managed with CAZ-AVI alone and those treated with combination regimens (26.1% vs 25.0%, P = .79). In multivariate analysis, mortality was positively associated with presence at infection onset of septic shock (P = .002), neutropenia (P < .001), or an INCREMENT score ≥8 (P = .01); with lower respiratory tract infection (LRTI) (P = .04); and with CAZ-AVI dose adjustment for renal function (P = .01). Mortality was negatively associated with CAZ-AVI administration by prolonged infusion (P = .006). All associations remained significant after propensity score adjustment. CONCLUSIONS: CAZ-AVI is an important option for treating serious KPC-Kp infections, even when used alone. Further study is needed to explore the drug's seemingly more limited efficacy in LRTIs and potential survival benefits of prolonging CAZ-AVI infusions to ≥3 hours.

Imported SARS-CoV-2 Variant P.1 in Traveler Returning from Brazil to Italy.

We report an imported case of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant P.1 detected in an asymptomatic traveler who arrived in Italy on an indirect flight from Brazil. This case shows the risk for introduction of SARS-CoV-2 variants from indirect flights and the need for continued SARS-CoV-2 surveillance.

Liver transplantation from active COVID-19 donors: A lifesaving opportunity worth grasping?

COVID-19 pandemic dramatically impacted transplantation landscape. Scientific societies recommend against the use of donors with active SARS-CoV-2 infection. Italian Transplant Authority recommended to test recipients/donors for SARS-CoV-2-RNA immediately before liver transplant (LT) and, starting from November 2020, grafts from deceased donors with active SARS-CoV-2 infection were allowed to be considered for urgent-need transplant candidates with active/resolved COVID-19. We present the results of the first 10 LTs with active COVID-19 donors within an Italian multicenter series. Only two recipients had a positive molecular test at LT and one of them remained positive up to 21 days post-LT. None of the other eight recipients was found to be SARS-CoV-2 positive during follow-up. IgG against SARS-CoV-2 at LT were positive in 80% (8/10) of recipients, and 71% (5/7) showed neutralizing antibodies, expression of protective immunity related to recent COVID-19. In addition, testing for SARS-CoV-2 RNA on donors' liver biopsy at transplantation was negative in 100% (9/9), suggesting a very low risk of transmission with LT. Immunosuppression regimen remained unchanged, according to standard protocol. Despite the small number of cases, these data suggest that transplanting livers from donors with active COVID-19 in informed candidates with SARS-CoV-2 immunity, might contribute to safely increase the donor pool.

EASL position paper on the use of COVID-19 vaccines in patients with chronic liver diseases, hepatobiliary cancer and liver transplant recipients.

According to a recent World Health Organization estimate, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, which originated in China in 2019, has spread globally, infecting nearly 100 million people worldwide by January 2021. Patients with chronic liver diseases (CLD), particularly cirrhosis, hepatobiliary malignancies, candidates for liver transplantation, and immunosuppressed individuals after liver transplantation appear to be at increased risk of infections in general, which in turn translates into increased mortality. This is also the case for SARS-CoV-2 infection, where patients with cirrhosis, in particular, are at high risk of a severe COVID-19 course. Therefore, vaccination against various pathogens including SARS-CoV-2, administered as early as possible in patients with CLD, is an important protective measure. However, due to impaired immune responses in these patients, the immediate and long-term protective response through immunisation may be incomplete. The current SARS-CoV-2 pandemic has led to the exceptionally fast development of several vaccine candidates. A small number of these SARS-CoV-2 vaccine candidates have already undergone phase III, placebo-controlled, clinical trials in healthy individuals with proof of short-term safety, immunogenicity and efficacy. However, although regulatory agencies in the US and Europe have already approved some of these vaccines for clinical use, information on immunogenicity, duration of protection and long-term safety in patients with CLD, cirrhosis, hepatobiliary cancer and liver transplant recipients has yet to be generated. This review summarises the data on vaccine safety, immunogenicity, and efficacy in this patient population in general and discusses the implications of this knowledge on the introduction of the new SARS-CoV-2 vaccines.

Propensity Score and Desirability of Outcome Ranking Analysis of Ertapenem for Treatment of Nonsevere Bacteremic Urinary Tract Infections Due to Extended-Spectrum-Beta-Lactamase-Producing Enterobacterales in Kidney Transplant Recipients.

There are scarce data on the efficacy of ertapenem in the treatment of bacteremia due to extended-spectrum-beta-lactamase (ESBL)-producing Enterobacterales (ESBL-E) in kidney transplant (KT) recipients. We evaluated the association between treatment with ertapenem or meropenem and clinical cure in KT recipients with nonsevere bacteremic urinary tract infections (B-UTI) caused by ESBL-E. We performed a registered, retrospective, international (29 centers in 14 countries) cohort study (INCREMENT-SOT, NCT02852902). The association between targeted therapy with ertapenem versus meropenem and clinical cure at day 14 (the principal outcome) was studied by logistic regression. Propensity score matching and desirability of outcome ranking (DOOR) analyses were also performed. A total of 201 patients were included; only 1 patient (treated with meropenem) in the cohort died. Clinical cure at day 14 was reached in 45/100 (45%) and 51/101 (50.5%) of patients treated with ertapenem and meropenem, respectively (adjusted OR 1.29; 95% CI 0.51 to 3.22; P = 0.76); the propensity score-matched cohort included 55 pairs (adjusted OR for clinical cure at day 14, 1.18; 95% CI 0.43 to 3.29; P = 0.74). In this cohort, the proportion of cases treated with ertapenem with better DOOR than with meropenem was 49.7% (95% CI, 40.4 to 59.1%) when hospital stay was considered. It ranged from 59 to 67% in different scenarios of a modified (weights-based) DOOR sensitivity analysis when potential ecological advantage or cost was considered in addition to outcome. In conclusion, targeted therapy with ertapenem appears as effective as meropenem to treat nonsevere B-UTI due to ESBL-E in KT recipients and may have some advantages.

International survey of human herpes virus 8 screening and management in solid organ transplantation.

BACKGROUND: HHV-8/Kaposi Sarcoma herpesvirus has been associated with a broad spectrum of diseases in solid organ transplant (SOT) recipients. Primary donor-derived infection can be associated with severe and rapidly fatal non-neoplastic disease, and diagnosis is made with high HHV-8 DNAemia. METHODS: We carried out an international survey to investigate the current approach to HHV-8 screening, and management in SOT since a protocol has not been established by international guidelines. RESULTS: A total of 51 transplant centers from 15 countries filled out the survey. HHV-8-associated diseases in SOT have been diagnosed during the previous 5 years in 67% of centers. Pretransplant serological screening is performed in 17 centers (33%), and posttransplant HHV-8 nucleic acid testing (NAT) monitoring is performed in 21 centers (41%). Performing HHV-8 NAT monitoring and serological screening were found associated with having diagnosed in the previous 5 years a non-malignant HHV-8-associated disease. CONCLUSIONS: Serological pretransplant screening of donors and recipients and post-transplant HHV-8 NAT monitoring recommendations should be standardized. Even though serological assays are not optimal, they could contribute to increasing knowledge on epidemiology and management of HHV-8-associated diseases after SOT.