Refractory Invasive Aspergillosis Research Articles

Consensus guidelines for the diagnosis and management of invasive aspergillosis, 2021.

Invasive aspergillosis (IA) in haematology/oncology patients presents as primary infection or breakthrough infection, which can become refractory to antifungal treatment and has a high associated mortality. Other emerging patient risk groups include patients in the intensive care setting with severe respiratory viral infections, including COVID-19. These guidelines present key diagnostic and treatment recommendations in light of advances in knowledge since the previous guidelines in 2014. Culture and histological-based methods remain central to the diagnosis of IA. There is increasing evidence for the utility of non-culture methods employing fungal biomarkers in pre-emptive screening for infection, as well as for IA diagnosis when used in combination. Although azole resistance appears to be uncommon in Australia, susceptibility testing of clinical Aspergillus fumigatus complex isolates is recommended. Voriconazole remains the preferred first-line antifungal agent for treating primary IA, including for extrapulmonary disease. Recommendations for paediatric treatment broadly follow those for adults. For breakthrough and refractory IA, a change in class of antifungal agent is strongly recommended, and agents under clinical trial may need to be considered. Newer immunological-based imaging modalities warrant further study, while surveillance for IA and antifungal resistance remain essential to informing the relevance of current treatment recommendations.

Azole resistance and cyp51A mutation screening in Aspergillus fumigatus in Mexico.

Fungicide exposure in the environment has driven the emergence of azole-resistant Aspergillus fumigatus worldwide. A screening test allows identification of resistant isolates. We screened clinical samples for azole-resistant Aspergillus through azole-containing agar plates and identified mutations in the cyp51A gene of A. fumigatus. Aspergillus isolates from clinical samples collected in a tertiary care centre from 2014 to 2017 were screened for azole resistance. Samples were subcultured in azole-containing agar plates. Isolates with a positive screening test were subject to DNA extraction, DNA amplification and sequencing of the cyp51A gene (coding and promoter regions). Clinical data were obtained from medical records. We screened 43 Aspergillus isolates from 39 patients for azole resistance. Three isolates from three patients grew on azole-containing agar plates: two A. fumigatus and one Aspergillus flavus. PCR analysis and cyp51A sequencing identified the TR34/L98H mutation in both A. fumigatus isolates. The prevalence of cyp51A mutations among A. fumigatus was 8.3% (2/24). Both patients with TR34/L98H mutants were azole naive and presented with invasive aspergillosis; one had multiple myeloma and the other was a liver retransplant recipient. They suffered progressive disease and failed voriconazole therapy. To the best of our knowledge, this is the first report of azole-resistant A. fumigatus with the TR34/L98H mutation in two azole-naive patients with refractory invasive aspergillosis in Mexico.

Optimization of polyene-azole combination therapy against aspergillosis using an in vitro pharmacokinetic-pharmacodynamic model.

Although amphotericin B-azole combination therapy has traditionally been questioned due to potential antagonistic interactions, it is often used successfully to treat refractory invasive aspergillosis. So far, pharmacodynamic (PD) interactions have been assessed with conventional in vitro tests, which do not mimic human serum concentrations and animal models using limited doses. We therefore simulated the human serum concentration profiles of amphotericin B and voriconazole in an in vitro dialysis/diffusion closed pharmacokinetic-pharmacodynamic (PK-PD) model and studied the pharmacodynamic interactions against an azole-resistant and an azole-susceptible Aspergillus fumigatus isolate, using Bliss independence and canonical mixture response surface analyses. Amphotericin B dosing regimens with the drug administered every 24 h (q24h) were combined with voriconazole q12h dosing regimens. In vitro PK-PD combination data were then combined with human PK data by using Monte Carlo analysis. The target attainment rate and the serum concentration/MIC ratio were calculated for isolates with different MICs. Synergy (20 to 31%) was observed at low amphotericin B-high voriconazole exposures, whereas antagonism (-6 to -16%) was found at high amphotericin B-low voriconazole exposures for both isolates. Combination therapy resulted in 17 to 48% higher target attainment rates than those of monotherapy regimens for isolates with voriconazole/amphotericin B MICs of 1 to 4 mg/liter. Optimal activity was found for combination regimens with a 1.1 total minimum concentration of drug in serum (tCmin)/MIC ratio for voriconazole and a 0.5 total maximum concentration of drug in serum (tCmax)/MIC ratio for amphotericin B, whereas the equally effective monotherapy regimens required a voriconazole tCmin/MIC ratio of 1.8 and an amphotericin B tCmax/MIC ratio of 2.8. Amphotericin B-voriconazole combination regimens were more effective than monotherapy regimens. Therapeutic drug monitoring can be employed to optimize antifungal combination therapy with low-dose (≤0.6 mg/kg) amphotericin B-based combination regimens against resistant isolates for minimal toxicity.

Treatment options in Invasive Aspergillosis.

Aspergillus species are septated molds that cause a wide spectrum of clinical syndromes. Among these, invasive aspergillosis (IA) causes very high morbidity and mortality among the most severely immunosuppressed, especially those with profound qualitative or quantitative neutropenia. Empirical, pre-emptive, and targeted approaches have been attempted to blunt establishment of infection with variable success. The preferred treatment of primary IA is voriconazole, which has been found to be superior to amphotericin B. Azoles interfere with the synthesis of ergosterol found in the fungal cell membrane, whereas polyenes—such as amphotericin B—interfere with ergosterol function. An echinocandin that disrupts fungal cell wall synthesis—caspofungin—and itraconazole have been approved for salvage therapy of IA. Lipid amphotericin B formulations are used in those intolerant to amphotericin B deoxycholate. Posaconazole is used for prophylaxis in high-risk groups such as those with acute myelogenous leukemia, myelodysplastic syndrome, and stem cell transplant recipients with graft versus host disease to reduce the incidence of invasive fungal infections (IFI) such as IA. Combining mold-active azoles or a lipid amphotericin B formulation with an echinocandin may have a role in refractory IA. Immunomodulatory properties of antifungals, growth factors, cytokines, and immune cell infusions may enhance host ability to facilitate adjunctive control of infection, but an uncontrolled, exuberant inflammatory response can also cause significant pathology. Surgical resection may be a last resort when angioinvasion of critical structures places a patient at high risk for bleeding, thrombosis, or embolic phenomena, despite medical therapy. Nevertheless, immune reconstitution with myeloid lineage recovery is the key to successful outcomes.

Refractory invasive aspergillosis controlled with posaconazole and pulmonary surgery in a patient with chronic granulomatous disease: case report

Invasive aspergillosis is an important cause of morbidity and mortality in immunocompromised patients. Among primary immunodefiencies, chronic granulomatous disease (CGD) has the highest prevalence of invasive fungal diseases. Voriconazole is recommended for the primary treatment of invasive aspergillosis in most patients. In patients whose aspergillosis is refractory to voriconazole, therapeutic options include changing class of antifungal, for example using an amphotericin B formulation, an echinocandin, combination therapy, or further use of azoles. Posaconazole is a triazole derivative which is effective in Aspergillosis prophylaxis and treatment. Rarely, surgical therapy may be needed in some patients. Lesions those are contiguous with the great vessels or the pericardium, single cavitary lesion that cause hemoptysis, lesions invading the chest wall, aspergillosis that involves the skin and the bone are the indications for surgical therapy.Chronic granulomatous disease (CGD) is an inherited immundeficiency caused by defects in the phagocyte nicotinamide adenine dinucleotidephosphate (NADPH) oxidase complex which is mainstay of killing microorganisms. CGD is characterized by recurrent life-threatening bacterial and fungal infections and by abnormally exuberant inflammatory responses leading to granuloma formation, such as granulomatous enteritis, genitourinary obstruction, and wound dehiscence. The diagnosis is made by neutrophil function testing and the genotyping.Herein, we present a case with CGD who had invasive pulmonary aspergillosis refractory to voriconazole and liposomal amphotericine B combination therapy that was controlled with posaconazole treatment and pulmonary surgery.

Caspofungin plus posaconazole as salvage therapy of invasive fungal infections in immunocompromised patients

Invasive aspergillosis (IA) is a major cause of mortality in immunocompromised patients. Substantial improvements of treatment have been achieved by the introduction of new antifungal agents including azoles (e.g. posaconazole) and echinocandins (e.g. caspofungin). However, mortality associated with treatment-refractory aspergillosis remains high. Preliminary data suggest that the combination of azoles and echinocandins may increase activity against refractory IA. The objective of the present study was to evaluate efficiency and safety of caspofungin plus posaconazole for salvage therapy in immunocompromised patients. In this monocentric, retrospective study, 31 hospitalised haematopoietic stem cell transplant recipients with IA refractory to primary treatment were treated with a combination therapy of caspofungin 50 mg a day and posaconazole 200 mg four times per day. Efficacy was assessed by signs, symptoms and the degree of pulmonary infiltrate regression. A favourable response was seen in the majority of patients (77%). In two patients (6%), clinical improvement, but no decline in pulmonary infiltrates, was observed. Five patients (16%) did not respond to combination therapy with a fatal outcome in four of them. Combination therapy was well tolerated. No patient discontinued treatment due to toxicity. This study indicates that the combination of caspofungin and posaconazole may provide an effective and tolerable therapy of IA in immunocompromised patients refractory to primary treatment.

Micafungin – Overview of Efficacy in Pediatric Patients

Background and aim: Invasive fungal infections are a major source of morbidity and mortality in immunocompromized children; however, information on new antifungal therapies in children is limited. We evaluated the efficacy and pharmacokinetics (PK) of micafungin, a novel antifungal agent, by reviewing pediatric data from micafungin clinical trials. Methods: A retrospective review of pediatric data from clinical trials was performed. Results: A total 296 children received micafungin (MICA) for invasive candidiasis (IC), refractory IC, refractory invasive aspergillosis (IA), prophylaxis in hematopoietic stem cell transplantation (HSCT) patients, or to assess PK. Most patients age <1 year were premature (38/66), whereas most children age >1 year were HSCT recipients or malignancy patients (181/230). Median maximum daily dose for patients <1, 1 to 4, 5 to 8, 9 to 12 and 13 to 15 years were 2.0, 1.5, 1.5, 1.9 and 1.5mg/kg, respectively. Treatment success rates are shown in the table. MICA showed linear PK, with a higher clearance in neonates than in older children and adults.

Immunomodulation Therapy for Invasive Aspergillosis: Discussion on Myeloid Growth Factors, Recombinant Cytokines, and Antifungal Drug Immune Modulation

Understanding fungal pathogenesis and host-pathogen immune interaction at various stages of infection is critical to examine strategies for bolstering antifungal immune defenses. Recombinant myeloid growth factors, especially granulocyte-macrophage colony-stimulating factor and the protagonist T helper (Th) 1 cytokine, interferon-γ, are most frequently used in patients with refractory invasive aspergillosis. These cytokines are given alone or in combination and have also been used together in neutropenic patients receiving donor granulocyte transfusions. Recently, a number of investigators have presented provoking data regarding auxiliary effect of conventional antifungal drugs on hosts' immune response and pathogen's susceptibility for antifungal immune defenses. Antifungal immunotherapy and its ameliorative role in treatment for Aspergillus disease will need clinical trials that 1) consider well-characterized fungal disease; 2) illustrate underlying immune defect(s) (such as Th1 vs Th2, vs Th17 and functional status of natural killer and effector scavenger cells); 3) include a more specific patient population; 4) include standardized antifungal drug therapy; and importantly 5) consider its impact on hosts' immune response and changes in pathogen's susceptibility and virulence. At present, immunotherapy is reserved for patients with life-threatening invasive fungal disease in whom conventional antifungal drug therapy has failed, or for patients with advanced fungal disease and with factors associated with high probability of failure of conventional therapy alone.

Clinical Outcome of Aspergillus-Specific Cytotoxic T Lymphocytes for Refractory Invasive Aspergillosis in Patients with Hematological Malignancies.

Invasive aspergillosis has high mortality in patients with hematological malignancies after chemotherapy or allogeneic stem cell transplantation (SCT) due to usually low response rate to current antifungal agents and relatively poor tolerance to the toxicities of the antifungal medicines. In this pilot clinical study, we explore to manage the patients with refractory invasive aspergillosis with aspergillus-specific cytotoxic T lymphocytes (aspergillus CTL). Ten patients who were either no longer response to antifungal medicines or have to stop antifungal agents due to severe toxicities were included in this clinical study. Diagnosis are ALL (2 cases), AML (5 cases), and CML (3 cases). The median age was 37 (10 to 62) years old. Seven of them received allogeneic SCT (unrelated 3 cases, haploidentical 3 cases, identical sibling 1 case), and 3 patients were after chemotherapy. Aspergillus CTLs were either donor origin (5 cases) or patient origin (5 cases) if original donor was not available. Patients received 1 to 3 infusions of aspergillus CTLs. The median CTLs infused were 3.61 (0.28–40.00) x 105/kg. No infusion-related reactions were noted. No pre-existed graft-versus-host disease deteriorated. With aspergillus CTL therapy, one of them (10%) achieved complete response, 6 patients (60%) improved significantly, 1 case was stable, and 2 patients became worse. Our preliminary data has shown that aspergillus-specific cytotoxic T lymphocyte is a safe and promising mean to manage refractory invasive aspergillosis in patients with hematological malignancies.

Caspofungin as salvage monotherapy for invasive aspergillosis in patients with haematological malignancies or following allogeneic stem cell transplantation: efficacy and concomitant cyclosporin A

Caspofungin (CAS) has shown efficacy as salvage monotherapy for invasive aspergillosis (IA) in two open label non-comparative trials. The association between hepatotoxicity and concomitant use of CAS and cyclosporin A (CsA) has not been fully elucidated. We report results on CAS efficacy in the first cohort from outside Europe and USA and the interaction between CAS and CsA. We retrospectively reviewed the charts of all patients with haematological malignancies or postallogeneic haematopoietic stem cell transplant (HSCT) who received >/=1 dose of CAS as salvage monotherapy for IA as part of the Australian Special Access Scheme (4/2001-8/2002). Outcomes were assessed at the end of CAS therapy. Favourable response (FR) was defined as >50% clinical and radiological improvement. Risk factors for elevation of liver transaminases (LTs) were examined using multivariate models. 54 patients were included in the analysis with 47 neutropenic at study entry. Proven or probable IA occurred in 11 and refractory IA in 28. An FR occurred in 26 (48.1%) and predictors for a poor response to CAS were allogeneic HSCT, graft vs. host disease and treatment with CAS for <14 days. Concomitant CAS and CsA for >7 days was an independent risk factor for laboratory hepatoxicity. The CAS efficacy results from the Australian cohort confirm those of previous studies. Close monitoring of LTs is necessary on concomitant CAS and CsA but clinically relevant hepatotoxicity is rare.

Concentration-Dependent Synergy and Antagonism within a Triple Antifungal Drug Combination againstAspergillusSpecies: Analysis by a New Response Surface Model

Triple antifungal combinations are used against refractory invasive aspergillosis without an adequate understanding of their pharmacodynamic interactions. We initially studied the in vitro triple combination of voriconazole, amphotericin B, and caspofungin against Aspergillus fumigatus, A. flavus, and A. terreus by a spectrophotometric microdilution broth method after 48 h of incubation. We then analyzed these results with a recently described nonlinear mixture response surface E(max)-based model modified to assess pharmacodynamic interactions at various growth levels. The new model allows flexibility in all four parameters of the E(max) model and is able to describe complex pharmacodynamic interactions. Concentration-dependent pharmacodynamic interactions were found within the triple antifungal combination. At the 50% growth level, synergy (median interaction indices of 0.43 to 0.82) was observed at low concentrations of voriconazole (<0.03 mg/liter) and amphotericin B (</=0.20 mg/liter) and at intermediate concentrations of caspofungin (0.95 to 14.88 mg/liter), whereas antagonism (median interaction indices of 1.17 to 1.80) was found at higher concentrations of voriconazole and amphotericin B. Ternary plot and interaction surface analysis further revealed the complexity of these concentration-dependent interactions. With increasing concentrations of amphotericin B, the synergistic interactions of voriconazole-caspofungin double combination decreased while the antagonistic interactions increased. A similar effect was observed when voriconazole was added to the double combination of amphotericin B and caspofungin. In conclusion, the new nonlinear mixture-amount response surface modeling of the triple antifungal combination demonstrated a net antagonism or synergy against Aspergillus species depending upon drug concentrations and species.

Voriconazole Treatment for Subacute Invasive and Chronic Pulmonary Aspergillosis

Backround Voriconazole is a novel triazole antifungal with a broad spectrum including Aspergillus species. We conducted an open, noncomparative multicenter study to evaluate the efficacy and safety of voriconazole in subacute invasive and chronic pulmonary aspergillosis (CPA). Methods Patients without profound neutropenia and a proven or probable diagnosis of subacute invasive aspergillosis (IA) or CPA received voriconazole 200 mg twice daily for a period of 4-24 weeks as primary or salvage therapy. Dose escalation was allowed if efficacy was suboptimal, and toleration and safety were satisfactory. Response was assessed by clinical, radiological and mycological changes. A complete or partial response in subacute IA and improved or stable in CPA were assessed as favorable responses. Results Of 39 patients treated, 36 were assessable. The majority of patients had subacute IA (n = 21), proven in all 11 extra-pulmonary and in 23/25 (92%) of the pulmonary cases. Voriconazole was given as primary therapy in 22 (61%). All patients receiving salvage therapy (n = 14) had refractory IA, having failed itraconazole or amphotericin B (AmB) or both. Overall, a complete or partial response was seen in 9/21(43%) of subacute IA and improved or stable in 12/15 (80%) of those with CPA. Adverse events, mainly liver function test abnormalities, skin reactions, and visual disturbances were mild and transient, leading to early discontinuation of treatment in 5 cases. Conclusions In patients with subacute IA and CPA, voriconazole was efficacious as salvage or primary therapy.

New strategy for fungal infections

An alarming increase in the number of invasive fungal infections has been observed. This is due to more aggres-sive bone marrow ablative regimens as well as to intensive use of corticosteroids and other immunosuppressants in numerous disorders. Principally amongst seriously ill non-cancer patientsCandida has become a very prominent isolate. The attributable mortality from candidemia ranges from about 40% in patients with candidemia alone to over 90% for those who have acute tissue invasion with or without fungemia. Secondary bloodstream infections, which evolve from infectious foci such as wounds, carry a higher mortality than do primary, catheter-related infections. Many patients die within the first 48 hours after establishing the diagnosis. If applicable, a return of the granulocytes is an important prognostic feature, just as timely commencement of antifungal agents. Until recently fluconazole and amphotericin B were seen as a first line options for the treatment of disseminated candidosis. However, whereas more than 15 years ago, 80% infections by yeasts were due toC. albicans, in the 1990’s non-albicans species have now become responsible for at least half of them, presumably related to the intensive prophylactic use of fluconazole. Development of the lipid formulations, with their improved therapeutic index raised hope for the future, but evidence on their general efficacy is still rather limited. Moreover, the results published on the treatment of non-albicans species have been rather disappointing up until now. On the other hand, the high expectations on the activity of the new candins againstCandida species, including those resistant to the azoles and polyenes, appear justified. These compounds have a mechanism of action totally different from the traditional antifungals. Data on an improved outcome of candidemia if a central venous catheter is removed promptly are conflicting. To avoid untimely death, most specialists nowadays prescribe systemic empirical antifungal therapy to immunocompromised patients who fail to respond to adequate broad spectrum antibacterial treatment or show any sign of an invasive fungal infection. Given its broad spectrum of activity, amphotericin B at a dose of 1 mg/kg per day is still the drug of choice for such purposes; the lipid preparation should be reserved for patients who can not tolerate the conventional formulation. Fluconazole can be an option for cases with a low risk of invasive mould infections but its lack of activity againstAspergillus species is a major drawback. The other traditional antifungal agent registered for used for the treatment of invasive aspergillosis is itraconazole. A randomized study in neutropenic patients comparing itraconazole with amphotericin B hinted at equivalence but did not reach a statistical endpoint. Unfavorable drug interactions has led to failure in many a patient. The new azoles, voriconazole and posaconazole possess an expanded spectrum of activity. Voriconazole, which now has been filed for approval in many countries, was shown to be clearly superior to amphotericin B in the first-line treatment of invasive pulmonary aspergillosis. It also offers promise for the treatment of some hitherto notoriously difficult-to-treat infections by rare organisms such asScedosporium andFusarium species. A phase II trial assessing the activity of caspofungin in the treatment of refractory invasive aspergillosis provided results that warrant a further evaluation of its potency for rescue purposes and in an empirical setting, where both moulds and yeasts can be encountered.

Caspofungin acetate: an antifungal agent.

The pharmacology, bioavailability and pharmacokinetics, clinical efficacy, and adverse effects of caspofungin acetate are reviewed. Caspofungin acetate is an echinocandin with fungicidal activity against a wide range of pathogens, including Candida spp., Aspergillus spp., and Histoplasma spp. It is active against fluconazole-resistant and fluconazole-susceptible strains of Candida albicans. Caspofungin acetate irreversibly inhibits the enzyme 1,3-beta-D-glucan synthase, preventing the formation of glucan polymers and disrupting the integrity of the fungal cell wall. Caspofungin acetate has an elimination half-life of 9-10 hours and is suitable for once-daily regimens. Data from animal and human studies demonstrate that the drug is 80-96% protein bound. Less than 3% of the dose is eliminated unchanged in the urine, and the proposed route of elimination is hepatic. In a trial of 128 patients with Candida esophagitis, clinical response rates were higher with caspofungin acetate 50 or 70 mg/day (85%) than with amphotericin B 0.5 mg/kg/day (67%). Most enrolled patients had HIV infection, and almost half had CD4+ lymphocyte counts of less than 50 cells/microL in another study, 56 immunocompromised patients with aspergillosis were treated with one 70-mg dose of caspofungin acetate, then 50 mg once a day. All patients had refractory invasive aspergillosis or were intolerant of amphotericin B, liposomal amphotericin B, or azole therapy. In patients who received at least one dose of caspofungin acetate, a favorable response was reported in 41%. In 128 patients who received either caspofungin acetate or amphotericin B, fewer caspofungin acetate recipients (1.4%) had elevated serum creatinine levels and discontinued therapy because of adverse effects (4%) than amphotericin B recipients (15% and 22%, respectively). The manufacturer's recommended dose for infections caused by Candida or Aspergillus spp. has not been determined. Caspofungin acetate appears to be fungicidal, with a wide spectrum of antifungal activity and a good safety profile. The lack of adequate efficacy and safety data in humans makes a recommendation to add this drug to the formulary premature. Pending advanced clinical trials and cost information, caspofungin acetate may be a reasonable addition to the formulary, particularly in hospitals with large immunocompromised patient populations.