Combination antifungal therapy for breakthrough invasive mould disease in patients with haematological malignancies: when management reasoning eclipses evidence-based medicine.

Timely diagnosis and treatment of invasive mould disease is challenging in severely immunocompromised patients, particularly for patients who develop breakthrough infections while on antifungal prophylaxis. Currently, there are no high-quality data on how to best diagnose and treat these infections. Many essential decisions affecting the management of breakthrough mould disease are made before a definitive diagnosis is established. In this scenario, sound management reasoning often favours the use of combination antifungal therapy, especially when antifungal resistance, suspicion of undetected sites of infection or pharmacokinetic/pharmacodynamic limitations at the site of infection are likely. In these scenarios, pre-emptive use of antifungal combination therapy with frequent re-evaluation with an aim of de-escalation could be justified for many high-risk patients.

Serum bactericidal titres for monitoring antimicrobial therapy: current status and potential role in the management of multidrug-resistant Gram-negative infections.

BACKGROUND: Serum bactericidal titres (SBTs) were widely used in the 1970s and 1980s to monitor antimicrobial therapy but are now seldom recommended. It is the only laboratory test that integrates drug pharmacodynamics, host pharmacokinetics and synergistic or antagonistic interactions of antimicrobial combinations into a single index of antimicrobial activity. We hypothesized that SBTs could play a renewed role in monitoring antibiotic treatment of multidrug-resistant Gram-negative infections. However, the last critical appraisal of the test was published over 30 years ago. OBJECTIVES: This narrative review provides an updated assessment of the SBT test and its methodological limitations. We performed a diagnostic meta-analysis to estimate the value of SBTs for predicting clinical failure or death during antibiotic treatment. SOURCES: A comprehensive literature search of PubMed including all English publications was performed in December 2019 using the Medical Subject Headings (MeSH search terms "serum", "bactericidal", "inhibitory", "titre", "monitoring", "anti-infective agents" "antimicrobial therapy" and "therapeutic drug monitoring"). CONTENT: Although standardized methods for performing SBTs were approved in 1999, the test remains labour intensive, and results may not be available until 72 hr. However, the use of non-culture-based endpoints (i.e. spectrophotometric or fluorescent) may shorten test time to 24 hr. Despite considerable heterogeneity in published studies, a meta-analysis of 11 evaluable studies published from 1974 to 2007 indicated a critical SBT result (peak SBT ≤1:8 or trough ≤1:2) is associated with a diagnostic odds ratio for clinical failure during antibiotic treatment of 12.27 (95% confidence interval 5.28-28.54) and a 5.32 (95% 1.32-21.42) odds of death. IMPLICATIONS: SBTs have prognostic value for identifying patients at high risk for antibiotic treatment failure, but the slow turnaround time of the current test limits its clinical utility. Standardization of a more rapid SBT testing method is needed.

Diagnosis and management of Aspergillus diseases: executive summary of the 2017 ESCMID-ECMM-ERS guideline.

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.

Treatment duration for Escherichia coli bloodstream infection and outcomes: retrospective single-centre study.

OBJECTIVES: To investigate the impact of treatment duration on mortality and on relapse in patients with Escherichia coli bloodstream infection (BSI). METHODS: Retrospective single-centre study of patients diagnosed with E. coli BSI at our centre over a 4-year period. EXCLUSION CRITERIA: age <18 years, clinical data not available, polymicrobial BSI, failure to receive in vitro active therapy, and death while receiving antibiotic therapy. Exposure variable was treatment duration dichotomized into short (≤10 days) and long (>10 days) therapy. Primary end point was all-cause mortality within 90 days after index BSI. Secondary end point was relapse, defined as repeat isolation of E. coli from blood cultures within 90 days after index BSI, in patients with documented clinical cure and completion of therapy for the initial episode. RESULTS: Of the 856 analysed patients: 426 received short and 430 received long therapy. All-cause mortality at day 90 occurred in 47 patients; on multivariate analysis, short therapy was not associated with a higher risk of mortality, also after adjusting the model for the propensity score of receiving short therapy. Relapse occurred in 42 patients. Independent risk factors for relapse using death as competing risk were immunosuppression (subhazard ratio 4.67, p < 0.001), and end-stage liver disease (subhazard ratio 2.58, p 0.013). The propensity-weighted estimation of the average treatment effect for relapse reduction with long therapy (>10 days) was -1.6% (p 0.26) in the total population, and -7.1% (p 0.18) in immunocompromised patients. CONCLUSIONS: We could not identify shorter treatment duration as a risk factor for mortality and for relapse in patients with E. coli BSI.

A prospective international Aspergillus terreus survey: an EFISG, ISHAM and ECMM joint study.

OBJECTIVES: A prospective international multicentre surveillance study was conducted to investigate the prevalence and amphotericin B susceptibility of Aspergillus terreus species complex infections. METHODS: A total of 370 cases from 21 countries were evaluated. RESULTS: The overall prevalence of A. terreus species complex among the investigated patients with mould-positive cultures was 5.2% (370/7116). Amphotericin B MICs ranged from 0.125 to 32 mg/L, (median 8 mg/L). CONCLUSIONS: Aspergillus terreus species complex infections cause a wide spectrum of aspergillosis and the majority of cryptic species display high amphotericin B MICs.

Characterization of antibody response in neuroinvasive infection caused by Toscana virus.

OBJECTIVES: Among sandfly-borne pathogens, Toscana virus (TOSV) is a prominent cause of summer meningitis in Mediterranean Europe. Here, we assessed the kinetics of anti-TOSV antibodies over time in 41 patients diagnosed with TOSV meningitis or meningoencephalitis in northeastern Italy. METHODS: Acute and follow-up serum samples were collected up to 20 months after diagnosis of TOSV infection and tested for the presence of specific antibody using immunoenzymatic and indirect immunofluorescence assays. In addition, maturation of anti-TOSV IgG over time was evaluated as well as production of neutralizing antibodies. RESULTS: Specific IgM and IgG response was present at diagnosis in 100% of patients; TOSV-specific IgM and IgG were detected in patients' sera up to 6 and 20 months after diagnosis, respectively. The avidity index (AI) increased over the first month after infection in 100% of patients and most cases exceeded 60% by Day 30 post infection. The AI subsequently plateaued then declined at 20 months after diagnosis. Finally, neutralization assay to TOSV was performed in 217 sera collected from 41 patients; 69.6% of tested samples resulted in reactive and moderate levels of neutralizing antibodies observed during all phases of infection despite high titres of total anti-TOSV IgG. CONCLUSIONS: Specific antibody response develops rapidly and is long-lasting for neuroinvasive TOSV infection. Serodiagnosis of neuroinvasive TOSV requires simultaneous detection of specific IgM and IgG. Moderate levels of neutralizing antibodies were maintained over the study period, while the protective role of antibodies lacking neutralizing activity is unclear and requires further evaluation.

Antifungal prophylaxis in liver transplant recipients: one size does not fit all.

BACKGROUND: Targeted antifungal prophylaxis against Candida species or against Candida species and Aspergillus species, according to individual patient risk factors (RFs), is recommended by experts. However, recent studies have reported fluconazole is as effective as broader spectrum antifungals for preventing invasive fungal infection (IFI) after liver transplantation (LT). METHODS: We performed a retrospective cohort study of all adult patients who underwent LT at our 1420-bed tertiary teaching hospital, from June 2010 to December 2014, to assess the rate and etiology of IFI within 100 days after LT, to investigate the compliance with targeted prophylaxis, and to analyze risk factors for developing IFI. RESULTS: In total, 303 patients underwent LT. Patients were classified as having low (no RFs), intermediate (1 RF for invasive candidiasis [IC]), and high risk (1 RF for invasive aspergillosis [IA] or ≥2 RFs for IC) for IFI in 20%, 30%, and 50% of cases, respectively. A total of 139 patients received antifungal prophylaxis: 98 with a mold-active drug and 41 with fluconazole. Overall adherence to targeted prophylaxis was 53%. Nineteen patients (6.3%) developed IFI: 7 IC and 12 IA. Multivariate Cox regression analysis, adjusted for median model for end-stage liver disease score at LT, stratification risk group, and adherence to targeted prophylaxis, showed that graft dysfunction, renal replacement therapy, and prophylaxis with fluconazole were independent risk factors for IFI. Seven of the 9 patients who received fluconazole prophylaxis and developed IFI were classified as having high risk for IFI, and 6 developed IA. CONCLUSION: Recommended stratification is accurate for predicting patients at very high risk for IFI, who should receive prophylaxis with a mold-active drug.

Initial use of combination treatment does not impact survival of 106 patients with haematologic malignancies and mucormycosis: a propensity score analysis.

In view of the poor outcomes associated with mucormycosis in patients with haematologic malignancies (HM) and haematopoietic cell transplant recipients, antifungal combinations are frequently used, yet the value of such strategy remains unclear. We reviewed the records of HM patients treated for mucormycosis from 1994 to 2014. The primary outcome was 6-week mortality after treatment initiation. Of the 106 patients identified, 44% received monotherapy and 56% received combination treatment as initial therapy. Six-week mortality was associated with disseminated mucormycosis (p 0.018), active malignancy (p <0.01), higher Acute Physiology and Chronic Health Evaluation (APACHE) II scores (p <0.001), neutropenia (p 0.049), lymphopenia (p 0.0003) and intensive care unit (ICU) admission at diagnosis (p 0.0001). Survivors were more likely to have localized mucormycosis (p <0.01) and to receive hyperbaric oxygen therapy (p 0.02). There were no differences in mortality between monotherapy and combination treatment groups (43% vs. 41%; p 0.85). In multivariate analysis, lymphopenia (odds ratio (OR), 5.5; 95% confidence interval (CI), 1.9-15.9; p 0.002) and ICU admission at diagnosis (OR, 8.2; 95% CI, 2.3-29.2; p 0.001) were associated with increased mortality. Localized mucormycosis was associated with better outcome (OR, 0.06; 95% CI, 0.01-0.6; p 0.019). Initial combination treatment had no impact on mortality, even after propensity score adjustment (OR, 0.8; 95% CI, 0.3-2.4; p 0.69). A weighted mortality risk score was then calculated for each patient based on the factors independently associated with mortality and baseline APACHE II score. In the low-risk group (n = 49), 13% of monotherapy versus 15% of combination therapy patients died within 6 weeks (p >0.99). In the high-risk group (n = 57), 71% of monotherapy versus 61% of combination therapy patients died within 6 weeks (p 0.42). With the current status of mucormycosis diagnosis, there was no difference in mortality in HM patients, whether they received monotherapy or combination treatment as initial therapy. Earlier diagnosis and immune reconstitution are unmet needs to affect outcomes.

Impact of a hospital-wide multifaceted programme for reducing carbapenem-resistant Enterobacteriaceae infections in a large teaching hospital in northern Italy.

We performed a quasi-experimental study of a multifaceted infection control programme for reducing carbapenem-resistant Enterobacteriaceae (CRE) transmission and bloodstream infections (BSIs) in a 1420-bed university-affiliated teaching hospital during 2010-2014, with 30 months of follow-up. The programme consisted of the following: (a) rectal swab cultures were performed in all patients admitted to high-risk units (intensive-care units, transplantation, and haematology) to screen for CRE carriage, or for any room-mates of CRE-positive patients in other units; (b) cohorting of carriers, managed with strict contact precautions; (c) intensification of education, cleaning and hand-washing programmes; and (d) promotion of an antibiotic stewardship programme carbapenem-sparing regimen. The 30-month incidence rates of CRE-positive rectal cultures and BSIs were analysed with Poisson regression. Following the intervention, the incidence rate of CRE BSI (risk reduction 0.96, 95% CI 0.92-0.99, p 0.03) and CRE colonization (risk reduction 0.96, 95% CI 0.95-0.97, p <0.0001) significantly decreased over a period of 30 months. After accounting for changes in monthly census and percentage of externally acquired cases (positive at ≤72 h), the average institutional monthly rate of compliance with CRE screening procedures was the only independent variable associated with a declining monthly incidence of CRE colonization (p 0.002). The monthly incidence of CRE carriage was predictive of BSI (p 0.01). Targeted screening and cohorting of CRE carriers and infections, combined with cleaning, education, and antimicrobial stewardship measures, significantly decreased the institutional incidence of CRE BSI and colonization, despite endemically high CRE carriage rates in the region.

Risk factors for carbapenem-resistant Klebsiella pneumoniae bloodstream infection among rectal carriers: a prospective observational multicentre study.

Knowledge of carbapenem-resistant Klebsiella pneumoniae (CR-KP) colonization is important to prevent nosocomial spread but also to start prompt adequate antibiotic therapy in patients with suspicion of infection. However, few studies have examined the incidence and risk factors for CR-KP bloodstream infection (BSI) among rectal carriers. To identify risk factors for CR-KP BSI among carriers, we performed a multicentre prospective matched case-control study of all adult CR-KP rectal carriers hospitalized in five tertiary teaching hospitals in Italy over a 2-year period. Carriers who developed CR-KP BSI were compared with those who did not develop subsequent BSI. Overall, 143 CR-KP BSIs were compared with 572 controls without a documented infection during their hospitalization. Multivariate analysis revealed that admission to the Intensive Care Unit (ICU) (OR, 1.65; 95% CI, 1.05-2.59; p 0.03), abdominal invasive procedure (OR, 1.87; 95% CI, 1.16-3.04; p 0.01), chemotherapy/radiation therapy (OR, 3.07; 95% CI, 1.78-5.29; p <0.0001), and number of additional colonization sites (OR, 3.37 per site; 95% CI, 2.56-4.43; p <0.0001) were independent risk factors for CR-KP BSI development among CR-KP rectal carriers. A CR-KP BSI risk score ranging from 0 to 28 was developed based on these four independent variables. At a cut-off of ≥2 the model exhibited a sensitivity, specificity, positive predictive value and negative predictive value of 93%, 42%, 29% and 93%, respectively. Colonization at multiple sites with CR-KP was the strongest predictor of BSI development in our large cohort of CR-KP rectal carriers.

Voriconazole-associated zygomycosis: a significant consequence of evolving antifungal prophylaxis and immunosuppression practices?

Mucormycosis (zygomycosis) is an uncommon infection that afflicts severely immunocompromised patients and those with poorly controlled diabetes mellitus. A recent increase in the incidence of mucormycosis at many transplant centres has been linked to the introduction and widespread use of voriconazole prophylaxis in these high-risk populations. However, it is not known if this association reflects a true epidemiological link or represents a marker of changing immunosuppression occurring in parallel with the evolution of transplant practices and immunosuppression strategies.

Decreased TLR4 gene expression in leukemic leukocyte populations.

Toll-like receptor 4 (TLR4) is one member of a class of pattern recognition receptors that play a significant role in the physiologic innate immune response. As leukemia is a disease state that may be associated with a compromised immune system, it was hypothesized that depressed TLR4 function resulting from decreased gene expression might be related to the development and further sustained presence of a leukemic clone of cells. This study thus analyzed gene expression of TLR4 in groups of lymphocytic leukemia cases, myeloid leukemia cases, cases of myeloid leukemia in remission, and normal controls by real-time quantitative reverse transcription-PCR (qRT-PCR). It was observed that TLR4 gene expression was indeed decreased to a statistically significant degree (P<0.05) in both the lymphocytic leukemic subset and myeloid leukemic subset when compared to normal controls. Thus, further study is warranted into determining whether this decreased TLR4 expression contributes to the pathogenesis of leukemic clone development through an associated depressed immune surveillance as well as whether TLR4 agonists might serve to effectively strengthen the response of the immune system in battling leukemic burden.

Azoles and antidepressants: a mini-review of the tolerability of co-administration.

Depression is a common condition in chronically ill immunosuppressed patients on long-term antifungal therapy with azoles. As both azoles and more recent antifungals are metabolised by the P450 enzymatic system in the liver, here we review the potential of clinically meaningful interactions between antidepressants and azoles. Selective serotonin reuptake inhibitors are safer compared to tricycle antidepressants when co-administered with azoles. More pharmacovigilance is needed.

Immunocompromised hosts: immunopharmacology of modern antifungals.

In addition to their in vitro inhibitory and fungicidal effects, modern antifungal agents interact in vivo with host immune functions involved in defense against fungal pathogens. The nature of such interactions is diverse and depends on the drug, the immunological status of the host, and the fungal pathogen. Given the prominent role of the host's immune response in controlling invasive fungal infection, immunomodulation by antifungal drugs may prove to be clinically significant. Elucidation of the immunopharmacology of these drugs may aid in designing therapeutic regimens for specific clinical scenarios associated with defined immunological dysfunction.

Does pre-exposure of Aspergillus fumigatus to voriconazole or posaconazole in vitro affect its virulence and the in vivo activity of subsequent posaconazole or voriconazole, respectively? A study in a fly model of aspergillosis.

OBJECTIVES: Voriconazole and posaconazole are effective as both prophylaxis and treatment for invasive aspergillosis (IA) in immunocompromised patients. Hence, it is important to determine whether Aspergillus pre-exposure to voriconazole or posaconazole diminishes subsequent posaconazole or voriconazole activity, respectively. METHODS: We used Aspergillus fumigatus (AF) 293 conidia with or without prior exposure to voriconazole or posaconazole [three serial passages on plates containing regular yeast extract-glucose (YAG) media, YAG+0.0625 mg/L voriconazole or YAG+0.025 mg/L posaconazole]. Toll-deficient Drosophila melanogaster flies were infected by injection, and 8 day survival was monitored. Following infection, flies were fed either regular food, food containing 1000 mg/L voriconazole (posaconazole-exposed conidia) or 1000 mg/L posaconazole (voriconazole-exposed conidia). Voriconazole and posaconazole concentrations in flies were confirmed by HPLC. RESULTS: AF inoculation resulted in 71% mortality 8 days post-infection (median survival 4 days). Prior conidial exposure to voriconazole or posaconazole did not affect mortality (73%, P = 0.8 for voriconazole pre-exposed and 76%, P = 0.49 for posaconazole pre-exposed). Voriconazole treatment post-infection had a protective effect, reducing mortality to 42% (P = 0.0002), while prior conidial exposure to posaconazole did not alter the protective effect of voriconazole (34% 8 day mortality, P = 0.35). Likewise, posaconazole treatment post-infection reduced mortality to 36%, while prior conidial exposure to voriconazole did not alter the protective effect of posaconazole (39% mortality, P = 0.92). Median fly homogenate concentrations of voriconazole and posaconazole were 0.44 and 2.05 mg/L, respectively. CONCLUSIONS: Prior exposure of AF to voriconazole or posaconazole did not affect the virulence of AF nor the subsequent activity of the alternate triazole in a Drosophila model of IA.

Fungal endophthalmitis in a tertiary care cancer center: a review of 23 cases.

Few data exist on the etiology, presentation, prognosis, and management of fungal endophthalmitis (FE) in cancer patients. FE cases were identified by reviewing the ophthalmology reports and microbiology cultures of patients at The University of Texas M. D. Anderson Cancer Center. We retrospectively reviewed the medical records and obtained information related to malignancy, fungal infection and its management, visual outcome, and mortality. We compared FE caused by Candida spp. (CE) to FE caused by molds (ME). Of the 102 cancer patients with a fungal infection for whom an ophthalmology consult was requested, 23 met the criteria for definite (N = 6) or probable (N = 17) FE (8 with CE, 15 with ME). All of the patients with ME had hematologic malignancies, whereas half of the patients with CE had solid tumor (P = .008). Only patients with CE had a history of surgery within 30 days of FE diagnosis (38%, P = .03). Fungal pneumonia [17 (74%)] and disseminated infection [14, (61%)] were common. The most common presenting symptoms were decreased vision [16 (70%)] and ocular pain [14 (61%)]. All treated patients received systemic antifungals (combination therapy in 72% of the cases). Seven patients (30%) underwent vitrectomy. Only one patient received intraocular injection of amphotericin B along with systemic antifungals. Four-week mortality was high [13 (57%)], especially in ME (73%, P = .04). Among the eight surviving patients where visual acuity could be assessed, visual outcome improved or remained stable in five (63%). FE in cancer patients occurs in the setting of severe, frequently disseminated opportunistic mycoses, is caused predominantly by hyalohyphomycetes, and is a marker for high 4-week mortality.

Zygomycetes hyphae trigger an early, robust proinflammatory response in human polymorphonuclear neutrophils through toll-like receptor 2 induction but display relative resistance to oxidative damage.

Human polymorphonuclear neutrophils (HPMNs) displayed attenuated hyphal damage associated with impaired O(2)(-) release following exposure to Rhizopus oryzae versus that with Aspergillus fumigatus. Exposure of HPMNs to R. oryzae hyphae resulted in upregulation in Toll-like receptor 2 mRNA and a robust proinflammatory gene expression with rapid (1-h) induction of NF-kappaB pathway-related genes.

Aspergillus nidulans is frequently resistant to amphotericin B.

The high failure rate of amphotericin B-based therapy in patients with Aspergillus nidulans infections may not be entirely a result of host factors as suggested previously. Innate resistance of A. nidulans to polyenes may contribute to the poor response in patients.

Cellular and molecular alterations in spinal cord injury patients with pressure ulcers: a preliminary report.

The study was designed to investigate the changes, both numerically and functionally, of the molecules critical to wound healing in spinal cord injury (SCI) patients. Spinal cord injury patients who demonstrated delayed healing of their pressure ulcers were used as study subjects. Age-matched healthy individuals served as controls. Adhesion molecule expression of the peripheral blood leukocytes, including lymphocytes and granulocytes, was measured by flow cytometric analysis. Binding capacity of the lymphocytes was evaluated using human umbilical cord vein endothelial cells (HUVECs) as the binding matrix. Samples from pressure ulcers of the patients were immunostained to define fibronectin, kalinin, beta4 integrin, alpha2beta1, alpha3beta1, alpha5beta1, and CD138 expression. Compared to healthy controls, there was decreased expression of CD11a, CD11b, CD18, CD49b, CD49c, CD49d, CD54, and CD8 in patients' lymphocyte populations and CD11a, CD18, CD49c, CD49d, and CD8 in patients' granulocyte populations. The binding capacity, expressed as percentage binding of the lymphocytes to the HUVEC matrix, was greatly diminished in the patients. There was markedly diminished immunohistochemical staining of fibronectin in pressure ulcers. These findings showed that delayed healing of pressure ulcers in SCI patients can be attributed to reduced adhesion molecule expression, impaired cell-cell interaction, and lack of extracellular matrix structural and functional protein.