Improved diagnostic testing (DT) of infections may optimize outcomes for solid organ transplant recipients (SOTR), but a comprehensive analysis is lacking.

We conducted a systematic literature review across multiple databases, including EMBASE and MEDLINE(R), of studies published between 1 January 2012-11 June 2022, to examine the evidence behind DT in SOTR. Eligibility criteria included the use of conventional diagnostic methods (culture, biomarkers, directed-polymerase chain reaction [PCR]) or advanced molecular diagnostics (broad-range PCR, metagenomics) to diagnose infections in hospitalized SOTR. Bias was assessed using tools such as the Cochrane Handbook and PRISMA 2020.

Of 2362 studies, 72 were eligible and evaluated heterogeneous SOT populations, infections, biospecimens, DT, and outcomes. All studies exhibited bias, mainly in reporting quality. Median study sample size was 102 (range, 11-1307). Culture was the most common DT studied (N = 45 studies, 62.5%), with positive results in a median of 27.7% (range, 0%-88.3%). Biomarkers, PCR, and metagenomics were evaluated in 7, 19, and 3 studies, respectively; only 6 reported sensitivity, specificity, and positive/negative predictive values. Directed-PCR performed well for targeted pathogens, but only 1 study evaluated broad-range PCR. Metagenomics approaches detected numerous organisms but required clinical adjudication, with too few studies (N = 3) to draw conclusions. Turnaround time was shorter for PCR/metagenomics than conventional diagnostic methods (N = 4 studies, 5.6%). Only 6 studies reported the impact of DT on outcomes like antimicrobial use and length of stay.

We identified considerable evidence gaps in infection-related DT among SOT, particularly molecular DT, highlighting the need for further research.

Invasive fungal infections are associated with high morbidity in solid organ transplant recipients. Risk factor modification may help with preventative efforts. The objective of this study was to identify risk factors for the development of fungal infections within the first year following solid organ transplant.

We searched for eligible articles through February 3, 2023. Studies published after January 1, 2001, that pertained to risk factors for development of invasive fungal infections in solid organ transplant were reviewed for inclusion. Of 3087 articles screened, 58 were included. Meta-analysis was conducted using a random-effects model to evaluate individual risk factors for the primary outcome of any invasive fungal infections and invasive candidiasis or invasive aspergillosis (when possible) within 1 y posttransplant.

We found 3 variables with a high certainty of evidence and strong associations (relative effect estimate ≥ 2) to any early invasive fungal infections across all solid organ transplant groups: reoperation (odds ratio [OR], 2.92; confidence interval [CI], 1.79-4.75), posttransplant renal replacement therapy (OR, 2.91; CI, 1.87-4.51), and cytomegalovirus disease (OR, 2.97; CI, 1.78-4.94). Both posttransplant renal replacement therapy (OR, 3.36; CI, 1.78-6.34) and posttransplant cytomegalovirus disease (OR, 2.81; CI, 1.47-5.36) increased the odds of early posttransplant invasive aspergillosis. No individual variables could be pooled across groups for invasive candidiasis.

Several common risk factors exist for the development of any invasive fungal infections in solid organ transplant recipients. Additional risk factors for invasive candidiasis and aspergillosis may be unique to the pathogen, transplanted organ, or both.

Pediatric living-donor liver transplantation (LDLT) candidates often receive long-term antibiotic treatment. Micafungin has been used as an antifungal agent after LDLT, but the adequate dose after pediatric LDLT was unknown. Here, we report micafungin blood concentrations after pediatric LDLT and discuss its safety and adequate dosing.

Pediatric patients with data on micafungin concentrations after LDLT were identified. Those with surgical complications were excluded. All patients received standard tacrolimus-based immunosuppression. A micafungin dose of 1 mg/kg was administered once daily for 10 days starting on postoperative day (POD) 1. The trough and peak micafungin blood concentrations were evaluated on PODs 1, 4, 7, and 10. Beta D glucan levels and liver function tests were assessed to determine micafungin effectiveness and safety.

Ten patients were enrolled, with a median age of 1.2 years. The median graft vs body weight ratio was 2.7%. The primary diseases were biliary atresia (n = 7), Alagille syndrome (n = 2), and progressive familial intrahepatic cholestasis type 2 (n = 1). Mean peak micafungin levels were 4.47, 6.27, 5.47, and 5.47 µg/mL on PODs 1, 4, 7, and 10, respectively. Mean trough levels were 2.03, 1.88, and 2.66 µg/mL on PODs 4, 7, and 10, respectively. The micafungin half-lives were 13.7, 14.7, and 14.0 hours on PODs 4, 7, and 10, respectively. Beta D glucan levels were 4.4 pg/mL and 3.7 pg/mL before and after transplantation, respectively, indicating no significant difference (P = .3). No clinical fungal infections were observed.

Micafungin administration is safe and effective after pediatric LDLT.

Invasive fungal infections (IFIs) remain one of the most common infectious complications after organ transplantation, and liver transplant recipients (LTRs) have the highest mortality rate. However, risk factors associated with IFIs have only been evaluated in small single-center studies. We performed a meta-analysis by conducting a comprehensive search using Ovid MEDLINE, Ovid Embase, Cochrane database of systematic reviews, and Cochrane central register of controlled trials. All case-control and cohort studies evaluating risk factors for IFIs in adult LTRs were screened. Utilizing a random-effects model, a multivariate analysis was completed, and 28 studies were eligible for meta-analysis. Rates of IFIs ranged from 1.4% to 32.7%. Previous antibiotic use (OR 9.3; 95% CI 3.2-27.0) and bacterial infection (OR 4.3; 95% CI 2.1-8.6) were risk factors of invasive candidiasis. Yet for invasive aspergillosis, posttransplant renal replacement therapy (OR 9.2; 95% CI 4.2-20.4), reoperation (OR 8.0; 95% CI 2.9-21.7), and cytomegalovirus infection (OR 6.2; 95% CI 2.0-19.3) were risk factors. The top independent risk factors for IFIs during studies from 2010 to 2019 were previous fungal colonization (OR 9.19; 95% CI 4.92-17.16), reoperation (OR 5.45; 95% CI 2.93-10.15), and previous bacterial infections (OR 3.81; 95% CI 2.13-6.83). These risk factors may be targeted by antifungal prophylaxis in LTRs.

Invasive pulmonary aspergillosis (IPA) after liver transplantation (LT) is most often fatal. We analyzed the outcomes of IPA in a single center.

We reviewed, retrospectively, the medical records of recipients of living donor LT (LDLT) or deceased donor LT (DDLT) performed between 1995 and 2019 at our institute. We analyzed the incidence of IPA and assessed the treatment courses of patients treated successfully and those not treatment successfully.

Among 326 recipients, IPA was diagnosed in 6 (1.8%). The incidence of IPA was significantly higher in patients with acute liver failure (ALF, 9.8%) than in those without ALF (0.4%), after DDLT (8.8%) than after LDLT (1.0%), and in recipients who received preoperative steroid pulse therapy (16.0%) than in those who did not (0.7%). Complete cure of IPA was achieved in the most recent three patients, by administering voriconazole immediately after the diagnosis of IPA and performing lung resection, while the IPA lesion was single and localized.

Patients with risk factors for IPA must be monitored closely. Our three successfully treated cases demonstrate that initiating immediate voriconazole treatment and making a calculated decision about lung resection can contribute to a favorable outcome.

In liver transplant (LT) recipients, Pneumocystis jirovecii pneumonia (PJP) is most frequently reported before 1992 when immunosuppressive regimens were more intense. It is uncertain whether universal PJP prophylaxis is still applicable in the contemporary LT setting. We aimed to examine the incidence of PJP in LT recipients followed at our institution where routine prophylaxis has never been practiced and to define the prophylaxis strategies currently employed among LT units in Spain. All LT performed from 1990 to October 2019 were retrospectively reviewed and Spanish LT units were queried via email to specify their current prophylaxis strategy. During the study period, 662 LT procedures were carried out on 610 patients. Five cases of PJP were identified, with only one occurring within the first 6 months. The cumulative incidence and incidence rate were 0.82% and 0.99 cases per 1000 person transplant years. All LT units responded, the majority of which provide prophylaxis (80%). Duration of prophylaxis, however, varied significantly. The low incidence of PJP in our unprophylaxed cohort, with most cases occurring beyond the usual recommended period of prophylaxis, questions a one-size-fits-all approach to PJP prophylaxis. A significant heterogeneity in prophylaxis strategies exists among Spanish LT centres.

Although invasive fungal infections (IFIs) contribute to substantial morbidity and mortality in liver transplant recipients, only a few randomized studies analyzed the results of antifungal prophylaxis with echinocandins. The aim of this open-label, non-inferiority study was to evaluate the efficacy and safety of micafungin in the prophylaxis of IFIs in living-donor liver transplantation recipients (LDLTRs), with fluconazole as the comparator.

LDLTRs (N = 172) from five centers were randomized 1:1 to receive intravenous micafungin 100 mg/day or fluconazole 100~200 mg/day (intravenous or oral). A non-inferiority of micafungin was tested against fluconazole.

The per-protocol set included 144 patients without major clinical trial protocol violations: 69 from the micafungin group and 75 from the fluconazole group. Mean age of the study patients was 54.2 years and mean model for end-stage liver disease (MELD) score amounted to 16.5. Clinical success rates in the micafungin and fluconazole groups were 95.65% and 96.10%, respectively (difference: - 0.45%; 90% confidence interval [CI]: - 6.93%, 5.59%), which demonstrated micafungin's non-inferiority (the lower bound for the 90% CI exceeded - 10%). The study groups did not differ significantly in terms of the secondary efficacy endpoints: absence of IFIs at the end of the prophylaxis and the end of the study, time to proven IFI, fungal-free survival, and adverse reactions. A total of 17 drug-related adverse events were observed in both groups; none of them was serious and all resolved.

Micafungin can be used as an alternative to fluconazole in the prevention of IFIs in LDLTRs.

NCT01974375.

Invasive pulmonary aspergillosis (IPA) patients with non-hematological malignancy are far less than with hematological malignancy patients. We encountered a very rare case of IPA in which type 1 diabetes was the only conceivable risk factor. Further, according to the diagnostic categories of the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) criteria for IPA, the frequency of proven diagnosis is very low. Here we report a proven IPA, which rapidly developed when the patient with type 1 diabetes was being treated for diabetic ketoacidosis, which was successfully treated with the combination therapy of voriconazole (VRCZ) and micafungin (MCFG), based on early diagnosis using bronchoscopy.

Invasive fungal infections (IFIs) postliver transplantation are a frequent cause of morbidity and mortality; however, studies reporting on these infections in the paediatric population are scarce. To investigate the incidence and risk factors of IFIs in paediatric liver transplant recipients during the early posttransplantation period (≤3 months). Data were collected for all paediatric liver transplant recipients registered in a national transplantation center from 2004 to 2014. Using a stepwise logistic regression to identify independent risk factors for IFIs, a predictive model was formulated. Ten IFIs were identified in 81 liver transplant recipients (12.3%) all occurring during the first month posttransplantation. Candida species were responsible for nine cases (90%), of which four were non-albicans Candida (44%). Significant risk factors were identified; recipient of multiple blood product transfusions during transplantation, prolonged use of indwelling intravenous catheter, prolonged IV antibiotic treatment, surgical complications, pulse steroid treatment and living donor liver transplantation. The predictive model used two clinical parameters to define high-risk patients: a living donor transplantation and duration of IV antibiotic treatment (area under the ROC curve 0.918). IFIs are a significant complication occurring in the first month posttransplantation. Future studies are required to assess efficacy of targeted antifungal prophylaxis in high risk patients.

The European Society for Clinical Microbiology and Infectious Diseases, the European Confederation of Medical Mycology and the European Respiratory Society Joint Clinical Guidelines focus on diagnosis and management of aspergillosis. Of the numerous recommendations, a few are summarized here. Chest computed tomography as well as bronchoscopy with bronchoalveolar lavage (BAL) in patients with suspicion of pulmonary invasive aspergillosis (IA) are strongly recommended. For diagnosis, direct microscopy, preferably using optical brighteners, histopathology and culture are strongly recommended. Serum and BAL galactomannan measures are recommended as markers for the diagnosis of IA. PCR should be considered in conjunction with other diagnostic tests. Pathogen identification to species complex level is strongly recommended for all clinically relevant Aspergillus isolates; antifungal susceptibility testing should be performed in patients with invasive disease in regions with resistance found in contemporary surveillance programmes. Isavuconazole and voriconazole are the preferred agents for first-line treatment of pulmonary IA, whereas liposomal amphotericin B is moderately supported. Combinations of antifungals as primary treatment options are not recommended. Therapeutic drug monitoring is strongly recommended for patients receiving posaconazole suspension or any form of voriconazole for IA treatment, and in refractory disease, where a personalized approach considering reversal of predisposing factors, switching drug class and surgical intervention is also strongly recommended. Primary prophylaxis with posaconazole is strongly recommended in patients with acute myelogenous leukaemia or myelodysplastic syndrome receiving induction chemotherapy. Secondary prophylaxis is strongly recommended in high-risk patients. We strongly recommend treatment duration based on clinical improvement, degree of immunosuppression and response on imaging.

Invasive fungal infection (IFI) is associated with high mortality after living donor liver transplant (LDLT). The aim of this study was to identify the risk factors for post-LDLT IFI for early diagnosis and improvement of antifungal treatment outcome.

Risk analysis data were available for all 153 patients who underwent LDLT between January 2005 and April 2012.

During the follow-up period (1,553 ± 73 days, range 20-2,946 days), 15 patients (9.8%) developed IFI classified as "proven" (n = 8) and "probable" (n = 7) with fungal pathogens including Candida spp. (n = 10), Aspergillus spp. (n = 4), and Trichosporon (n = 2). Of these patients, 7 patients with IFI died despite treatment. The 1-, 3-, and 5-year survival rates were lower in patients with IFI than those without IFI (66.7/59.3/44.4 vs. 90.4/85.7/81.8%, respectively; p = 0.0026). Multivariate analysis identified model for end-stage liver disease score of ≥26 (OR 16.0, p = 0.0012) and post-transplant acute kidney injury (RIFLE criteria I- or F-class; OR 4.87, p = 0.047) as independent risk factors for IFI.

Preoperative recipients' status and postoperative kidney dysfunction can affect an occurrence of post-transplant IFI. These risk factors would be taken into consideration for designation of proper antifungal therapy.

With the improvements in immunosuppressive agents and graft survival, infections such as mycoses have become major complications after solid organ transplantation (SOT).

Our group has continuously updated an epidemiological database of visceral mycoses (VM) among autopsy cases in Japan since 1989. Data on infectious agents and clinical information were complied using similar procedures.

Among the all autopsied cases studied, 356 undergone SOT. Of these, 214 (60.1%) suffered from one or more types of infections, including 51 (14.3%) with VM. Thus, the incidence of VM was higher in SOT recipients than in non-transplanted cases (P < 0.0001). Aspergillus spp. (Asp) was the most predominant agent and Candida spp. was second. Specifically, among SOT recipients, Asp was the most predominant in liver and lung transplant recipients. Among the 217 autopsied liver transplants cases, the incidence of VM was highest in those with fulminant hepatitis (FH, P = 0.01). The incidence of cytomegalovirus infection tended to be higher in cases with mycosis (P = 0.06). Multivariate logistic regression analysis identified FH (odds ratio, 3.61, 95% confidence interval 1.34-9.75; P = 0.03) as an independent risk factor for mycosis in liver transplant recipients.

This epidemiological analysis of autopsied cases provides a strong incentive to intensify efforts to diagnose and treat post-SOT infectious diseases.

Prolonged OR, re-transplantation, and high-volume intraoperative transfusion have been associated with increased risk for IC in adult LT recipients. Antifungal prophylaxis is recommended for adult patients with these risk factors. There are limited data on the incidence of and risk factors for IC in pediatric LT recipients. A retrospective cohort study of all pediatric LT patients at the CHOP between 2000 and 2012 and the CHP between 2004 and 2012 was performed to define the incidence of IC within 30 days of LT. A 3:1 matched case-control study with incidence density sampling was performed. Conditional logistic regression analyses were used to explore risk factors associated with IC. Among 397 recipients, the incidence of IC was 2.5%. Bivariate analyses showed that ICU admission prior to transplant, OR > 10 h, intraoperative volume infusion of >300 mL/kg, and broad-spectrum antibiotics were significantly associated with IC. In a multivariate model, only ICU admission remained significantly associated with IC. Antifungal prophylaxis was not significantly protective against IC. The low incidence of IC and lack of an identified protective effect from antifungal prophylaxis suggest that prophylaxis in pediatric LT recipients should not be routinely recommended to prevent IC events in the first 30 days post-transplant.

Antifungal resistance of Candida species is a clinical problem in the management of diseases caused by these pathogens. In this study we identified from a collection of 423 clinical samples taken from Tunisian hospitals two clinical Candida species (Candida albicans JEY355 and Candida tropicalis JEY162) with decreased susceptibility to azoles and polyenes. For JEY355, the fluconazole (FLC) MIC was 8 μg/ml. Azole resistance in C. albicans JEY355 was mainly caused by overexpression of a multidrug efflux pump of the major facilitator superfamily, Mdr1. The regulator of Mdr1, MRR1, contained a yet-unknown gain-of-function mutation (V877F) causing MDR1 overexpression. The C. tropicalis JEY162 isolate demonstrated cross-resistance between FLC (MIC > 128 μg/ml), voriconazole (MIC > 16 μg/ml), and amphotericin B (MIC > 32 μg/ml). Sterol analysis using gas chromatography-mass spectrometry revealed that ergosterol was undetectable in JEY162 and that it accumulated 14α-methyl fecosterol, thus indicating a perturbation in the function of at least two main ergosterol biosynthesis proteins (Erg11 and Erg3). Sequence analyses of C. tropicalis ERG11 (CtERG11) and CtERG3 from JEY162 revealed a deletion of 132 nucleotides and a single amino acid substitution (S258F), respectively. These two alleles were demonstrated to be nonfunctional and thus are consistent with previous studies showing that ERG11 mutants can only survive in combination with other ERG3 mutations. CtERG3 and CtERG11 wild-type alleles were replaced by the defective genes in a wild-type C. tropicalis strain, resulting in a drug resistance phenotype identical to that of JEY162. This genetic evidence demonstrated that CtERG3 and CtERG11 mutations participated in drug resistance. During reconstitution of the drug resistance in C. tropicalis, a strain was obtained harboring only defective Cterg11 allele and containing as a major sterol the toxic metabolite 14α-methyl-ergosta-8,24(28)-dien-3α,6β-diol, suggesting that ERG3 was still functional. This strain therefore challenged the current belief that ERG11 mutations cannot be viable unless accompanied by compensatory mutations. In conclusion, this study, in addition to identifying a novel MRR1 mutation in C. albicans, constitutes the first report on a clinical C. tropicalis with defective activity of sterol 14α-demethylase and sterol Δ(5,6)-desaturase leading to azole-polyene cross-resistance.

From a collection of yeast isolates isolated from patients in Tunisian hospitals between September 2006 and July 2010, the yeast strain JEY63 (CBS 12513), isolated from a 50-year-old male that suffered from oral thrush, could not be identified to the species level using conventional methods used in clinical laboratories. These methods include matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS), germ tube formation, and the use of CHROMagar Candida and metabolic galleries. Sequence analysis of the nuclear rRNA (18S rRNA, 5.8S rRNA, and 26S rRNA) and internal transcribed spacer regions (ITS1 and ITS2) indicated that the ribosomal DNA sequences of this species were not yet reported. Multiple gene phylogenic analyses suggested that this isolate clustered at the base of the Dipodascaceae (Saccharomycetales, Saccharomycetes, and Ascomycota). JEY63 was named Candida tunisiensis sp. nov. according to several phenotypic criteria and its geographical origin. C. tunisiensis was able to grow at 42°C and does not form chlamydospores and hyphae but could grow as yeast and pseudohyphal forms. C. tunisiensis exhibited most probably a haploid genome with an estimated size of 10 Mb on at least three chromosomes. Using European Committee for Antimicrobial Susceptibility Testing (EUCAST) and Clinical and Laboratory Standards Institute (CLSI) Candida albicans susceptibility breakpoints as a reference, C. tunisiensis was resistant to fluconazole (MIC = 8 μg/ml), voriconazole (MIC = 0.5 μg/ml), itraconazole (MIC = 16 μg/ml), and amphotericin B (MIC = 4 μg/ml) but still susceptible to posaconazole (MIC = 0.008 μg/ml) and caspofungin (MIC = 0.5 μg/ml). In conclusion, MALDI-TOF MS permitted the early selection of an unusual isolate, which was still unreported in molecular databases but could not be unambiguously classified based on phylogenetic approaches.