Failure Of Antifungal Treatment Research Articles

Dynamic surface-enhanced Raman spectroscopy-based metabolic profiling: A novel pathway to overcoming antifungal resistance

Antifungal resistance is the leading cause of antifungal treatment failure in invasive candidiasis. Metabolic rewiring could become a new insight to account for antifungal resistance as to find innovative clinical therapies. Here, we show that dynamic surface-enhanced Raman spectroscopy is a promising tool to identify the metabolic differences between fluconazole-resistant and fluconazole-sensitive Candida albicans through the signatures of biochemical components and complemented with machine learning algorithms and two-dimensional correlation spectroscopy, an underlying resistance mechanism, that is, the change of purine metabolites induced the resistance of Candida albicans has been clarified yet never reported anywhere. We hope the integrated methodology introduced in this work could be beneficial for the interpretation of cellular regulation, propelling the development of targeted antifungal therapies and diagnostic tools for more efficient management of severe antifungal resistance.

The Metabolism of Susceptibility: Clearing the FoG Between Tolerance and Resistance in Candida albicans.

Failure of antifungal treatment is alarmingly common in patients infected with Candida albicans isolates that test as susceptible in vitro. This means that clinical susceptibility tests have limited predictive value for treatment success. To guide the improvement of patient outcomes, we must understand the effects of environmental and metabolic states on drug responses. Lab conditions often deviate from host environments, and current susceptibility testing standards ignore slow-growing, tolerant phenotypes; both factors may contribute to antifungal treatment failure. Metabolomic studies reveal that strain background, nutrient availability, and drug exposure influence the metabolic state of C. albicans cells; similarly, the metabolic state influences drug susceptibility. Identifying tolerant strains in the clinic may improve patient outcomes. Studies that analyze the effects of essential but limited nutrients have the potential to improve the avoidance of persistent candidiasis and to reduce the frequency of antifungal treatment failures. Here, we highlight literature that explores the effect of drug exposure and antifungal drug resistance status on the C. albicans metabolome. Similar analyses need to be carried out relative to antifungal drug tolerance. Additionally, we focus on the biological relevance of four essential small molecules-iron, zinc, phosphate, and sphingolipids-to antifungal tolerance and resistance.

P474 The value of PCR-based azole resistance detection in invasive aspergillosis: A prospective multicenter study

Poster session 1, September 21, 2022, 12:30 PM - 1:30 PMObjectivesPrompt detection of azole-resistant Aspergillus fumigatus will result in the timely start of active treatment and may improve the survival of invasive aspergillosis (IA). The use of a multiplex polymerase chain reaction (PCR) targeting Aspergillus species and fumigatus DNA as well as the two most prevalent azole resistance- associated mutations (RAMs) in the cyp51A gen (TR34/L98H and TR46/Y121F/T289A) could shorten the time to detect azole-resistant IA.MethodsIn a prospective study in 12 Dutch and Belgian centers, we evaluated the clinical value of the multiplex AsperGenius®PCR in hematology patients with a pulmonary infiltrate undergoing bronchoalveolar lavage (BALf) sampling. The primary endpoint was antifungal treatment failure in the 6 weeks after antifungal treatment initiation in the patients in which azole-resistant IA was detected. Treatment failure was defined as death or a switch to an antifungal agent from another class after at least 5 days of first-line therapy. Patients with a mixed azole-susceptible/resistant infection were excluded from this analysis to ascertain that the infection was indeed caused by the resistant strain.ResultsOf 323 patients enrolled, sufficient BALf for PCR testing remained in 299. Probable fungal disease was diagnosed in 95 (34%), Aspergillus cultured in 24 (8%), Aspergillus DNA detected in 118 (39%), and A. fumigatus DNA in 88 (29%) patients. The resistance PCR was conclusive in 54/88 (61%) and RAMs were detected in 8 (15%), Table 1. All 8 had probable IA but 2 had a mixed infection and were excluded. In the 6 remaining patients, treatment failure was observed in one. Compared with the GM negative patients and despite antifungal therapy, a positive GM test was associated with a 13% higher 6-week overall mortality (P = .01), Table 2. Surprisingly, the 6-week mortality in the 65 patients who had a positive Aspergillus PCR but a negative GM and culture was not increased compared to those with a negative PCR (PCR + 14% vs. PCR- 16% mortality, P = .68).ConclusionsIn patients with an underlying hematological disease and a pulmonary infiltrate, the detection of Aspergillus DNA by PCR on BALf was not associated with increased mortality. The exact place of the Aspergillus PCR in the EORTC-MSGERC invasive fungal infection criteria is therefore uncertain. In 15% of the patients in whom A. fumigatus DNA was present, azole RAMs were detected by PCR. In only 1/6 probable cases of IA with RAMs detected, antifungal treatment failure was observed. Basing the choice of antifungal therapy on the result of a cyp51a resistance PCR may help to reduce the impact of azole resistance on mortality.

Emerging antifungal treatment failure of dermatophytosis in Europe: take care or it may become endemic.

Dermatophytosis is a world-wide distributed common infection. Antifungal drug resistance in dermatophytosis used to be rare, but unfortunately the current Indian epidemic of atypical widespread recalcitrant and terbinafine-resistant dermatophytosis is spreading and has sporadically been reported in Europe. To explore the occurrence of clinical and mycological proven antifungal drug resistance in dermatophytes in Europe. A standardized questionnaire was distributed through the EADV Task Force of Mycology network to dermatologists in Europe. Representatives from 20 countries completed the questionnaires of which 17 (85 %) had observed clinical and/or mycological confirmed antifungal resistance, two countries published cases of antifungal resistance and one country had no known cases. This pilot study confirms that both clinical and mycological antifungal resistance exist in Europe.

Clinical and Radiographic Features of Cryptococcal Neoformans Meningitis-associated Immune Reconstitution Inflammatory Syndrome

Cryptococcal meningitis is the most common intracranial infectious fungal disease. After a period of antifungal treatment, as the number of cells in the cerebrospinal fluid decreases, the biochemical indexes improve and the number of cryptococcus reduces, the patient’s condition suddenly worsen. Most of the symptoms are severe headache, raised intracranial pressure, together with impaired clinical nerve function. These presentations are often mistaken for a failure of antifungal treatment. In fact it’s an encephalitis syndrome which is unrecognized by most clinicians: Immune reconstitution inflammatory syndrome (IRIS). To increase awareness we retrospectively analyzed clinical data of 100 cases of cryptococcal neoformans meningitis, among which 26 patients develop CM-IRIS. All patients have been divided into three groups: Group 1, patients who were not treated with glucocorticoid and didn’t experienced IRIS; Group 2, patients who were not treated with glucocorticoid although developed CM-IRIS; Group 3, patients started treatment with glucocorticoid for two weeks with new onset CM-IRIS. Compared with the group treated with glucocorticoid, treatment without glucocorticoid was subjected to a higher risk of incident IRIS. The difference was statistically significant (P < 0.05). Imaging findings demonstrated diseased area of the white matter area, and it looked like commonly in the supratentorial region. Moreover, if it appears in the infratentorial region then must be combined with supratentorial region.

Contribution of a Simple Bioassay in Effective Therapeutic Drug Monitoring of Posaconazole and Voriconazole.

With the constantly growing incidence of invasive fungal infections, any failure of antifungal treatment is worrying. Azole antifungals present high variability of their plasma trough concentrations (Cmin), justifying their therapeutic drug monitoring (TDM). The authors aimed to develop a simple bioassay to determine the in vitro growth inhibition diameter (ID) and to correlate this ID with Cmin in patients treated with voriconazole or posaconazole. The bioassay determined the ID for Candida parapsilosis using a disk diffusion method. Calibration curves were built for posaconazole and voriconazole in water and in 45% plasma. ID was determined in plasma from patients currently undergoing TDM for posaconazole (n = 73) or voriconazole (n = 90). In water or plasma spiked with antifungals and patient samples, cubic regression between ID and Cmin gave coefficient of determination values of 0.997, 0.999, and 0.819, respectively, for posaconazole and 0.996, 0.990 and 0.925, respectively, for voriconazole (P < 0.001 for each curve). Calibration curves with or without plasma did not differ. For voriconazole, Cmin of 1 and 4.7 mg/L corresponded to 54% and 90% of maximal ID, respectively. For posaconazole, Cmin of 0.5, 0.7, and 1 mg/L corresponded to 26%, 40%, and 53% of maximal ID, respectively. Bioassay could be useful to better characterize the antifungal therapeutic range and brings additional information to the interpretation of TDM in patients for whom Cmin alone is insufficient to adjust the antifungal dosage.

The contribution of a simple bioassay in effective therapeutic drug monitoring of Posaconazole and Voriconazole

The contribution of a simple bioassay in effective therapeutic drug monitoring of Posaconazole and Voriconazole

Granulocyte Macrophage Colony-Stimulating Factor in 66 Patients with Myeloid or Lymphoid Neoplasms and Recipients of Hematopoietic Stem Cell Transplantation with Invasive Fungal Disease

Background/Aims: Adding granulocyte macrophage colony-stimulating factor (GM-CSF) may improve the response to antifungal therapy in immunosuppressed patients with invasive fungal disease (IFD). Methods: We retrospectively assessed 66 patients in whom GM-CSF was given during antifungal therapy. Results: Severe neutropenia (77%) and refractory/relapsed cancer (65%) were common in the group. Prior to GM-CSF therapy, 15% of patients received high-dose corticosteroids for a median of 30 ± 16 days [median cumulative dose (c.d.) 1,184 ± 1,019 mg], and 9 received steroids during GM-CSF therapy for a median of 16 ± 12 days (median c.d. 230 ± 1,314 mg). Mild toxic effects were noted in 9% of patients; there were no cases of cardiopulmonary toxicity. All-cause deaths were observed in 68% of patients and 48% died of progressive IFD. High-dose corticosteroids prior to GM-CSF (OR 24; 95% CI 2.21–264.9; p ≤ 0.009), GM-CSF started in the intensive care unit (OR 10; 95% CI 1.66–63.8; p ≤ 0.01), concurrent granulocyte transfusions (OR 5; 95% CI 1.27–16.8; p ≤ 0.02) and proven/probable IFD (OR 4; 95% CI 1–16.2; p ≤ 0.05) predicted antifungal treatment failure. Conclusions: GM-CSF adjuvant therapy was tolerated without serous toxicity and antifungal treatment failure remained a challenge in patients treated with high-dose systemic corticosteroids.

Practical considerations on current guidelines for the management of non‐neutropenic adult patients with candidaemia

Recent guideline recommendations on the management of candidaemia provide valuable treatment guidance for routine clinical practice, but need to be interpreted in the light of the actual situation of the patient and the local epidemiology of fungal infections. Echinocandins emerge as the generally preferred primary treatment. Treatment should be initiated immediately after notification of a Candida-positive blood culture in all patients. Ambiguous issues include the definition of optimum duration of treatment, the indication and time point to step down to oral azoles, catheter management, and the appropriate approach in critically ill patients at high risk for candidaemia in the absence of definitive proof of infection. Patients with clinical suspicion of antifungal treatment failure need prompt workup for adequacy of treatment, focal sources of sustained infection and potential superinfection.

Determination of antifungal susceptibility patterns among the clinical isolates of Candida species

Context:Candida species are opportunistic yeasts that cause infections ranging from simple dermatosis to potentially life-threatening fungemia. The emergence of resistance to antifungal drugs has been increased in the past two decades.Aim:the present study we determined to find out the susceptibility profiles of clinical isolates of Candida species against four antifungal drugs, including amphotericin B, ketoconazole, fluconazole and itraconazole.Materials and Methods:Antifungal susceptibility testing of the yeasts was done in accordance with the proposed guidelines for antifungal disk diffusion susceptibility testing of yeasts based on the CLSI document M44-A.Results:A total of 206 yeast isolates were assessed. Among the evaluated Candida species, the highest rates of resistance to ketoconazole were seen in Candida glabrata (16.6%) and Candida albicans (3.2%). Susceptibility and intermediate response to fluconazole were seen in 96.6% and 3.4% of the Candida isolates, respectively. A total of 19 (9.2%) yeast isolates showed petite phenomenon including 11 C. glabrata, 3 C. albicans, 2 Candida dubliniensis and one isolate of each Candida krusei and Candida parapsilosis.Conclusion:The high number of petite mutation in the isolated yeasts should be seriously considered since it may be one of the reasons of antifungal treatment failure.

Persistence of Candida albicans Candidemia in Non-Neutropenic Surgical Patients: Management of a Representative Patient in the Absence of Second-Line Treatment Guidelines

Primary treatment failure and mortality in non-neutropenic patients with candidemia is high according to clinical trial experience. Current guidelines are mainly useful only for first line treatment strategies.We describe treatment failure and persistent protracted Candida albicans candidemia without clinically evident ocular involvement nor catheter recolonization in a malnourished non-neutropenic surgical patient with peritonitis. Primary antifungal treatment failure with fluconazole and secondary treatment failure with caspofungin occurred in the absence of evident Candida seeding the eye, valvular endocardium, or the intravascular catheter. Switch to liposomal amphotericin B was followed by clinical and microbiological cure.In patients with multiple risk factors for the acquisition of candidemia and life-threatening clinical conditions, the possibility of primary/secondary failure of new potent antifungal regimens may be initially neglected.Additional multicenter controlled clinical data are needed to guide the timing and choice of secondary antifungal treatment regimens in non-neutropenic candidemia patients.

Papillomatose confluente et réticulée de Gougerot et Carteaud : étude rétrospective de neuf cas

Confluent and reticulate papillomatosis of Gougerot and Carteaud is a rare entity and a subject of controversy in terms of nosology. It has occasionally been regarded as a peculiar variant of acanthosis nigricans, pityriasis versicolor or amyloidosis. To discuss confluent and reticulate papillomatosis and its diagnostic criteria as a distinct entity. Retrospective study from 1994 to 2005 based on photographic files from 2 dermatology wards at the Saint Louis Hospital, Paris. Files containing a precise clinical description of the rash and at least one mycological element were included. Nine cases were included (6 females, 3 males). These patients showed clinical features comprising elementary lesion, distribution and topography corresponding to the classical description; histology was also consistent with confluent and reticulate papillomatosis, with no signs of amylosis and negative fungal samples or failure of antifungal treatment. One patient was presenting associated acanthosis nigricans. Doxycycline was efficacious in 4 cases in which it was evaluated. Confluent and reticulate papillomatosis is a definite entity and is not a superficial fungal disease. It must be distinguished from pityriasis versicolor as well as acanthosis nigricans and cutaneous amyloidosis. The therapeutic efficacy of oral cyclines (doxycycline or minocycline) appears to be an important distinguishing feature that can serve as a diagnostic criterion.