Tobramycin Systemic Absorption in Lung Transplant Recipients Treated With Inhaled Tobramycin: A Cohort Study.

Inhaled tobramycin treatment has been associated with nephrotoxicity in some case reports, but limited data are available about serum levels and its possible systemic absorption in lung transplant recipients (LTR). We conducted a single-center, observational and retrospective study of all adult (>18 years old) LTR treated with inhaled tobramycin for at least 3 days between June 2019 and February 2022. Trough serum levels were collected and >2 µg/mL was considered a high drug level. The primary outcome assessed the presence of detectable trough levels, while the secondary outcome focused on the occurrence of acute kidney injury (AKI) in individuals with detectable trough levels. Thirty-four patients, with a median age of 60 years, were enrolled. The primary indications for treatment were donor bronchial aspirate bacterial isolation (18 patients) and tracheobronchitis (15 patients). In total, 28 patients (82%) exhibited detectable serum levels, with 9 (26%) presenting high levels (>2 µg/mL). Furthermore, 9 patients (26%) developed acute kidney injury during the treatment course. Median trough tobramycin levels were significantly elevated in invasively mechanically ventilated patients compared to non-ventilated individuals (2.5 µg/mL vs. 0.48 µg/mL) (p < 0.001). Inhaled tobramycin administration in LTRs, particularly in those requiring invasive mechanical ventilation, may result in substantial systemic absorption.

Transplantation of organs from SARS-CoV-2-positive donors: Preliminary experience from Spain.

BACKGROUND: The utilization of non-lung organs from deceased donors with a positive polymerase chain reaction (PCR) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at the time of donation can be lifesaving, although the safety of this policy must be assessed. METHODS: This is a nationwide, prospective study, reporting the experience on the utilization of non-lung organs from SARS-CoV-2-positive donors between December 15, 2020 and May 31, 2022 in Spain. RESULTS: A total of 69 patients received a solid organ transplant (41 kidney, 18 liver, 8 heart, and 2 combined liver-kidney) obtained from 32 donors with a positive SARS-CoV-2 PCR at the time of donation (four of them with a cycle threshold value <30). All recipients tested negative for SARS-CoV-2 and were free of coronavirus disease 2019 (COVID-19) symptoms prior to transplantation. Nasopharyngeal swab turned positive for SARS-CoV-2 PCR in 4 (5.8%) recipients at 3, 8, 11, and 20 days after transplantation, though evidence did not support a donor-derived COVID-19. Four kidney recipients lost their grafts and two patients died: one heart recipient due to cardiogenic shock and one combined liver-kidney recipient due to lung hypertension and right heart failure. Graft losses and patient deaths were deemed unrelated to the donor SARS-CoV-2 status by the treating teams. No other adverse reactions were reported. CONCLUSIONS: This preliminary experience supports the safety of the use of organs other than lungs from SARS-CoV-2 PCR-positive donors, in alignment with previous series. However, the impact of SARS-CoV-2 infection upon organ quality should be established in future research.

Immunoguided Discontinuation of Prophylaxis for Cytomegalovirus Disease in Kidney Transplant Recipients Treated With Antithymocyte Globulin: A Randomized Clinical Trial.

BACKGROUND: Antiviral prophylaxis is recommended in cytomegalovirus (CMV)-seropositive kidney transplant (KT) recipients receiving antithymocyte globulin (ATG) as induction. An alternative strategy of premature discontinuation of prophylaxis after CMV-specific cell-mediated immunity (CMV-CMI) recovery (immunoguided prevention) has not been studied. Our aim was to determine whether it is effective and safe to discontinue prophylaxis when CMV-CMI is detected and to continue with preemptive therapy. METHODS: In this open-label, noninferiority clinical trial, patients were randomized 1:1 to follow an immunoguided strategy, receiving prophylaxis until CMV-CMI recovery or to receive fixed-duration prophylaxis until day 90. After prophylaxis, preemptive therapy (valganciclovir 900 mg twice daily) was indicated in both arms until month 6. The primary and secondary outcomes were incidence of CMV disease and replication, respectively, within the first 12 months. Desirability of outcome ranking (DOOR) assessed 2 deleterious events (CMV disease/replication and neutropenia). RESULTS: A total of 150 CMV-seropositive KT recipients were randomly assigned. There was no difference in the incidence of CMV disease (0% vs 2.7%; P = .149) and replication (17.1% vs 13.5%; log-rank test, P = .422) between both arms. Incidence of neutropenia was lower in the immunoguided arm (9.2% vs 37.8%; odds ratio, 6.0; P < .001). A total of 66.1% of patients in the immunoguided arm showed a better DOOR, indicating a greater likelihood of a better outcome. CONCLUSIONS: Prophylaxis can be prematurely discontinued in CMV-seropositive KT patients receiving ATG when CMV-CMI is recovered since no significant increase in the incidence of CMV replication or disease is observed. CLINICAL TRIALS REGISTRATION: NCT03123627.

Ceftazidime-Avibactam plus Aztreonam for the Treatment of Infections by VIM-Type-Producing Gram-Negative Bacteria.

This is a retrospective single-center study of 24 patients who received ceftazidime-avibactam plus aztreonam (CZA/ATM) for the treatment of VIM-type-producing Gram-negative bacillus (GNB) infections. The bacteria isolated were Enterobacterales in 22 patients and Pseudomonas aeruginosa in 2. Sixteen out of 19 isolates showed synergistic activity. Two patients presented clinical failure at day 14, and the 30-day mortality was 17% (4/24). CZA/ATM could be considered an alternative therapy for VIM-type-producing GNB infections.

Impact of ceftazidime/avibactam versus best available therapy on mortality from infections caused by carbapenemase-producing Enterobacterales (CAVICOR study).

BACKGROUND: Infections caused by carbapenemase-producing Enterobacterales (CPE) are not well represented in pivotal trials with ceftazidime/avibactam. The best strategy for the treatment of these infections is unknown. METHODS: We conducted a multicentre retrospective observational study of patients who received ≥48 h of ceftazidime/avibactam or best available therapy (BAT) for documented CPE infections. The primary outcome was 30 day crude mortality. Secondary outcomes were 21 day clinical response and microbiological response. A multivariate logistic regression model was used to identify factors predictive of 30 day crude mortality. A propensity score to receive treatment with ceftazidime/avibactam was used as a covariate in the analysis. RESULTS: The cohort included 339 patients with CPE infections. Ceftazidime/avibactam treatment was used in 189 (55.8%) patients and 150 (44.2%) received BAT at a median of 2 days after diagnosis of infection. In multivariate analysis, ceftazidime/avibactam treatment was associated with survival (OR 0.41, 95% CI 0.20-0.80; P = 0.01), whereas INCREMENT-CPE scores of >7 points (OR 2.57, 95% CI 1.18-1.5.58; P = 0.01) and SOFA score (OR 1.20, 95% CI 1.08-1.34; P = 0.001) were associated with higher mortality. In patients with INCREMENT-CPE scores of >7 points, ceftazidime/avibactam treatment was associated with lower mortality compared with BAT (16/73, 21.9% versus 23/49, 46.9%; P = 0.004). Ceftazidime/avibactam was also an independent factor of 21 day clinical response (OR 2.43, 95% CI 1.16-5.12; P = 0.02) and microbiological eradication (OR 0.40, 95% CI 0.18-0.85; P = 0.02). CONCLUSIONS: Ceftazidime/avibactam is an effective alternative for the treatment of CPE infections, especially in patients with INCREMENT-CPE scores of >7 points. A randomized controlled trial should confirm these findings.

CMV-Specific Cell-Mediated Immunity Predicts a High Level of CMV Replication After Prophylaxis Withdrawal in Lung Transplant Recipients.

Monitoring cytomegalovirus (CMV)-specific cell-mediated immunity (CMI) is useful in predicting late-onset CMV infection after solid organ transplantation, but few data have been reported after lung transplantation (LT). CMV CMI against 2 CMV antigens (IE-1, pp65) was evaluated in 60 seropositive LT at 6-month prophylaxis withdrawal. LT with late-onset CMV infection showed significantly lower (IE-1)CMV CMI than patients without (P = .045), and was more evident in patients developing high viral loads (P = .010). (IE-1)CMV CMI independently predicted high first late-onset viral replication (odds ratio, 4.358; 95% confidence interval, 1.043-18.215). CMV-specific CMI may be useful in CMV preventive strategies after LT.

COVID-19 in lung transplant recipients: A multicenter study.

This study describes the clinical presentation, treatment, and outcomes of SARS-CoV-2 infection in lung transplant recipients (LTRs). This is a multicenter, retrospective study of all adult LTRs with confirmed SARS-CoV-2 infection from March 4 until April 28, 2020 in six Spanish reference hospitals for lung transplantation. Clinical and radiological data, treatment characteristics, and outcomes were reviewed. Forty-four cases were identified in that period. The median time from transplantation was 4.2 (interquartile range: 1.11-7.3) years. Chest radiography showed acute parenchymal abnormalities in 32 (73%) cases. Hydroxychloroquine was prescribed in 41 (93%), lopinavir/ritonavir (LPV/r) in 14 (32%), and tocilizumab in 19 (43%) patients. There was a strong interaction between tacrolimus and LPV/r in all cases. Thirty-seven (84%) patients required some degree of respiratory support and/or oxygen therapy, and 13 (30%) were admitted to intermediate or intensive critical care units. Seventeen (39%) patients had died and 20 (45%) had been discharged at the time of the last follow-up. Deceased patients had a worse respiratory status and chest X-ray on admission and presented with higher D-dimer, interleukin-6, and lactate dehydrogenase levels. In this multicenter LTR cohort, SARS-CoV-2 presented with high mortality. Additionally, the severity of disease on presentation predicted subsequent mortality.

Nebulized Micafungin Treatment for Scopulariopsis/Microascus Tracheobronchitis in Lung Transplant Recipients.

Scopulariopsis/Microascus isolates cause infections with high mortality in lung transplant recipients. Treatment is challenging due to antimicrobial resistance. We describe two cases of Scopulariopsis/Microascus tracheobronchitis in lung transplant recipients successfully treated with nebulized micafungin. This antifungal was well tolerated and achieved high concentrations in epithelial lining fluid up to 14 h after nebulization without significant plasma concentrations. Nebulized micafungin may be a safe and effective option for the treatment of fungal tracheobronchitis.

A new pleosporalean fungus isolated from superficial to deep human clinical specimens.

Human infections by pleosporalean fungi (class Dothideomycetes, phylum Ascomycota) are rarely reported. Because their identification is challenging using morphological characterization, several phylogenetic markers must be sequenced for an accurate identification and taxonomical placement of the isolates. Three isolates of clinical origin were phenotypically characterized, but due to the absence of relevant morphological traits, D1-D2 domains of the 28S nrRNA gene (LSU), the internal transcribed spacer region (ITS) of the nrRNA, and fragments of the RNA polymerase II subunit 2 (rpb2) and translation elongation factor 1-alpha (tef1) genes were sequenced to allow a phylogenetic analysis that would solve their phylogenetic placement. That analysis revealed that these isolates did not match any previously known pleosporalean genera, and they are proposed here as the new fungal genus, Gambiomyces. Unfortunately, the isolates remained sterile, which, consequently, made the morphological description of the reproductive structures impossible. Future studies should try to understand the behaviour of this fungus in nature as well as its characteristics as an opportunistic fungal pathogen. Molecular identification is becoming an essential tool for proper identification of Dothideomycetes of clinical origin. LAY ABSTRACT: We describe a new pleosporalen pathogenic fungus, Gambiomyces profunda, found in superficial to deep samples from a human patient. Because all strains remained sterile, the fungus was finally identified following a phylogenetic analysis by using four different molecular markers.

Recommendations for screening, monitoring, prevention, and prophylaxis of infections in adult and pediatric patients receiving CAR T-cell therapy: a position paper.

Chimeric antigen receptor (CAR) T-cell therapy is one of the most promising emerging treatments for B-cell malignancies. Recently, two CAR T-cell products (axicabtagene ciloleucel and tisagenlecleucel) have been approved for patients with aggressive B-cell lymphoma and acute lymphoblastic leukemia; many other CAR-T constructs are in research for both hematological and non-hematological diseases. Most of the patients receiving CAR-T therapy will develop fever at some point after infusion, mainly due to cytokine release syndrome (CRS). The onset of CRS is often indistinguishable from an infection, which makes management of these patients challenging. In addition to the lymphodepleting chemotherapy and CAR T cells, the treatment of complications with corticosteroids and/or tocilizumab increases the risk of infection in these patients. Data regarding incidence, risk factors and prevention of infections in patients receiving CAR-T cell therapy are scarce. To assist in patient care, a multidisciplinary team from hospitals designated by the Spanish Ministry of Health to perform CAR-T therapy prepared these recommendations. We reviewed the literature on the incidence, risk factors, and management of infections in adult and pediatric patients receiving CAR-T cell treatment. Recommendations cover different areas: monitoring and treatment of hypogammaglobulinemia, prevention, prophylaxis, and management of bacterial, viral, and fungal infections as well as vaccination prior and after CAR-T cell therapy.

Low seroprevalence of SARS-CoV-2 antibodies in a liver transplant cohort.

Solid organ transplant recipients might be at greater risk for acquisition and mortality because of SARS-CoV-2. There are no data regarding SARS-CoV-2 seroprevalence among liver transplant (LT) recipients, and whether it is different from that of the general population or other immunosuppressed groups. We evaluated the prevalence of IgG SARS-CoV-2 antibodies among LT recipients to estimate the frequency of asymptomatic SARS-CoV-2 infection using serological assays in our outpatient clinic. We conducted a cross-sectional analysis from 10 May to 26 October 2020 of all adult (>18 years) LT recipients that underwent a routine laboratory test for the outpatient clinic follow-up at the Hospital Universitari Vall d'Hebron (Barcelona) in which we included serological testing for SARS-CoV-2. Nine out of 294 LT recipients (3.1%) tested positive for anti-SARS-CoV-2 IgG antibodies. Five of them (55.5%) had suffered clinically symptomatic SARS-CoV-2 infection confirmed by RT-PCR, four (44.4%) had presented compatible symptoms but without microbiological confirmation and only one patient (1/9, 11.1%) tested positive without any previous symptom. SARS-CoV-2 seroprevalence among LT recipients in an area highly affected by the pandemic is lower than in the general population in the same area. These results render the possibility of asymptomatic infection in LT recipients very unlikely.

Routine Bile Culture From Liver Donors as Screening of Donor-Transmitted Infections in Liver Transplantation.

Bacterial infections are an important threat in the early post-liver transplantation period. Donor-transmitted infections, although rare, can have high mortality. The utility of routine culture from the donor bile duct as screening of donor-transmitted infection has not been evaluated. We performed a retrospective study of 200 consecutive liver transplants between 2010 and 2015. Demographic, clinical, and microbiological data were collected from the recipients' medical records. Clinical data included pretransplantation, perioperative, and posttransplantation information (until 30 days after the procedure). The 3-month patient survival and/or retransplantation were recorded. A total of 157 samples from the donor bile duct were collected and cultured. Only 8 were positive. The microorganisms isolated were as follows: Klebsiella pneumoniae, n = 2; Escherichia coli, n = 1; Enterobacter cloacae, n = 1; Streptococcus anginosus, n = 1; Streptococcus sp., n = 1; multiple gram-negative bacilli, n = 1; and polymicrobial, n = 1. All of the microorganisms were susceptible to the antibiotic prophylaxis administered. During the first month after transplantation, 81 recipients developed 131 infections. Only 1 of these recipients had a donor with a positive bile culture, and none of the infections were due to the microorganism isolated in the donor's bile. The 3-month overall survival was 89.5%, and there were no differences between recipients with positive donor bile cultures and those with negative donor bile cultures (87.5% versus 89.26%; P > 0.99). Routine testing of donor bile cultures does not predict recipients' infection or survival after liver transplantation and should not be recommended.

Effects of the extracorporeal membrane oxygenation circuit on plasma levels of ceftolozane.

INTRODUCTION: New antibiotics with bactericidal activity against multi-drug-resistant bacteria are increasingly used in the intensive care units. Here, we aimed to evaluate the influence of the extracorporeal membrane oxygenation on plasma levels of ceftolozane. CASE REPORT: A 34-year-old female was admitted to the intensive care unit after bilateral lung transplantation, complicated by primary graft dysfunction and cardiogenic shock needing venoarterial extracorporeal membrane oxygenation. Ceftolozane/tazobactam was started. Plasma ceftolozane levels were monitored on the first and third days of antibiotic treatment. A non-compartment pharmacokinetic analysis was performed and the extraction rate through the oxygenator was calculated. DISCUSSION: The extracorporeal circuit of extracorporeal membrane oxygenation may alter the pharmacokinetics of antibiotics, to varying degrees due to drug sequestration and increased distribution volume. In this case, the extracorporeal membrane oxygenation circuit had little impact on the ceftolozane plasma concentration. CONCLUSION: Plasma levels of ceftolozane are stable in the extracorporeal membrane oxygenation circuit, suggesting that adjustment of standard doses of ceftolozane in patients with extracorporeal membrane oxygenation support may not be needed.

Community-acquired Respiratory Viruses Are a Risk Factor for Chronic Lung Allograft Dysfunction.

BACKGROUND: The relationship between community-acquired respiratory viruses (CARVs) and chronic lung allograft dysfunction (CLAD) in lung transplant recipients is still controversial. METHODS: We performed a prospective cohort study (2009-2014) in all consecutive adult patients (≥18 years) undergoing lung transplantation in the Hospital Universitari Vall d'Hebron (Barcelona, Spain). We systematically collected nasopharyngeal swabs from asymptomatic patients during seasonal changes, from patients with upper respiratory tract infectious disease, lower respiratory tract infectious disease (LRTID), or acute rejection. Nasopharyngeal swabs were analyzed by multiplex polymerase chain reaction. Primary outcome was to evaluate the potential association of CARVs and development of CLAD. Time-dependent Cox regression models were performed to identify the independent risk factors for CLAD. RESULTS: Overall, 98 patients (67 bilateral lung transplant recipients; 63.3% male; mean age, 49.9 years) were included. Mean postoperative follow-up was 3.4 years (interquartile range [IQR], 2.5-4.0 years). Thirty-eight lung transplant recipients (38.8%) developed CLAD, in a median time of 20.4 months (IQR, 12-30.4 months). In time-controlled multivariate analysis, CARV-LRTID (hazard ratio [HR], 3.00 [95% confidence interval {CI}, 1.52-5.91]; P = .002), acute rejection (HR, 2.97 [95% CI, 1.51-5.83]; P = .002), and cytomegalovirus pneumonitis (HR, 3.76 [95% CI, 1.23-11.49]; P = .02) were independent risk factors associated with developing CLAD. CONCLUSIONS: Lung transplant recipients with CARVs in the lower respiratory tract are at increased risk to develop CLAD.

Prognostic factors in 264 adults with invasive Scedosporium spp. and Lomentospora prolificans infection reported in the literature and FungiScope®.

Invasive Scedosporium spp. and Lomentospora prolificans infections are an emerging threat in immunocompromised and occasionally in healthy hosts. Scedosporium spp. is intrinsically resistant to most, L. prolificans to all the antifungal drugs currently approved, raising concerns about appropriate treatment decisions. High mortality rates of up to 90% underline the need for comprehensive diagnostic workup and even more for new, effective antifungal drugs to improve patient outcome. For a comprehensive analysis, we identified cases of severe Scedosporium spp. and L. prolificans infections from the literature diagnosed in 2000 or later and the FungiScope® registry. For 208 Scedosporium spp. infections solid organ transplantation (n = 58, 27.9%) and for 56 L. prolificans infection underlying malignancy (n = 28, 50.0%) were the most prevalent risk factors. L. prolificans infections frequently presented as fungemia (n = 26, 46.4% versus n = 12, 5.8% for Scedosporium spp.). Malignancy, fungemia, CNS and lung involvement predicted worse outcome for scedosporiosis and lomentosporiosis. Patients treated with voriconazole had a better overall outcome in both groups compared to treatment with amphotericin B formulations. This review discusses the epidemiology, prognostic factors, pathogen susceptibility to approved and investigational antifungals, and treatment strategies of severe infections caused by Scedosporium spp. and L. prolificans.

Lung transplantation in two cystic fibrosis patients infected with previously pandrug-resistant Burkholderia cepacia complex treated with ceftazidime-avibactam.

We describe two cystic fibrosis patients infected with pandrug-resistant Burkholderia cepacia complex, with the exception of ceftazidime-avibactam, who received prophylaxis with this antibiotic during lung transplantation. Although both patients had a post-operative relapse of respiratory infection, one with positive blood cultures, ceftazidime-avibactam treatment yielded a favourable outcome. 12 months after transplantation, one patient presented an excellent clinical outcome. However, the other patient died 10 months later due to severe B. cepacia sinusitis with intracranial invasion.

Phaeohyphomycosis caused by Medicopsis romeroi in solid organ transplant recipients: Report of two cases and comprehensive review of the literature.

Medicopsis romeroi is a melanized coelomycetous fungus, mainly found in tropical and subtropical regions and an uncommon cause of infection in solid organ transplant (SOT) recipients. We describe two cases of SOT recipients diagnosed with phaeohyphomycosis due to M romeroi and provide a comprehensive literature review. These infections should be considered in patients native to tropical countries with a localized skin and soft tissue infection. Sequencing is needed for accurate identification of uncommon melanized fungi. Surgical treatment is recommended to cure the infection and co-adjunctive oral antifungals should be considered.

Clinical Characteristics and Outcome of Lung Transplant Recipients with Respiratory Isolation of Corynebacterium spp.

Although chronic respiratory disease and immunosuppression are risk factors for Corynebacterium species respiratory infection, data are scarce regarding this disease in lung transplantation. Our aim was to describe the clinical characteristics and outcomes of lung transplant recipients (LTR) with respiratory isolation of Corynebacterium spp. This was a retrospective observational study performed at a referral center in Barcelona, Spain (2014 to 2016). We included all LTR in whom Corynebacterium spp. were isolated in at least one good-quality lower respiratory tract specimen. Overall, 24 of 527 (4.6%) LTR at risk during the study period were included. The main epidemiological, clinical, and microbiological data were analyzed. The most frequently isolated species were C. striatum (11/24), C. pseudodiphtheriticum (3/24), and C. amycolatum (3/24). All 19 (76%) patients who underwent bronchoscopy showed abnormalities, mainly mucosal plaques at the bronchial suture and purulent secretions. Clinical cure was achieved in 8/12 (67%) patients who fulfilled the CDC definition of lower respiratory tract infection (LRTI). To assess the clinical relevance of Corynebacterium spp., only patients with monomicrobial isolation (n = 18) were evaluated. LRTI was diagnosed in 9, and a nonsignificant association was found with a significant number of Corynebacterium sp. CFU/ml (7/9 LRTI versus 2/9 non-LRTI, P = 0.057). Persistent infection was associated with metallic bronchial stent implantation (4/4 versus 2/14, P = 0.005). The isolation of Corynebacterium spp. in respiratory specimens of lung transplant recipients may herald a respiratory tract infection or bronchial suture damage. Bronchial stent implantation is a risk factor for the persistence of Corynebacterium species infection.

Ceftolozane/tazobactam for the treatment of XDR Pseudomonas aeruginosa infections.

PURPOSE: The aim of this study was to evaluate the effectiveness of ceftolozane/tazobactam (C/T) for treating extensively drug-resistant Pseudomonas aeruginosa (XDR-PA) infections, and to analyze whether high C/T dosing (2 g ceftolozane and 1 g tazobactam every 8 h) and infection source control have an impact on outcome. METHODS: Retrospective study of all consecutive patients treated with C/T for XDR-PA infection at a tertiary referral hospital (November 2015-July 2017). Main clinical and microbiological variables were analyzed. RESULTS: Thirty-eight patients were included. Median age was 59.5 years and Charlson Comorbidity Index was 3.5. Fourteen (36.8%) patients had respiratory tract infection, six (15.8%) soft tissue, and six (15.8%) urinary tract infection. Twenty-three (60.5%) received high-dose C/T and in 24 (63.2%) C/T was combined with other antibiotics. At completion of treatment, 33 (86.8%) patients showed clinical response. At 90 days of follow-up, 26 (68.4%) achieved clinical cure, and 12 (31.6%) had clinical failure because of persistent infection in one patient, death attributable to the XDR-PA infection in four, and clinical recurrence in seven. All-cause mortality was 5 (13.2%). Lower C/T MIC and adequate infection source control were the only variables significantly associated with clinical cure. CONCLUSIONS: C/T should be considered for treating XDR-PA infections, with infection source control being an important factor to avoid failure and resistance.