Role of Antifungal Susceptibility Testing in Non-Aspergillus Invasive Mold Infections

Abstract

No clinical breakpoints are available to delineate antifungal drug efficacy in non-Aspergillus invasive mold infections (NAIMIs). In this analysis of 39 NAIMI episodes, the MIC of the first-line antifungal drug was the most important predictor of therapeutic response. For amphotericin B, an MIC of <0.5 g/ml was significantly associated with better 6-week outcomes.M olds other than Aspergillus spp. account for an increasing proportion of invasive fungal infections in the expanding population of immunosuppressed patients (1). Mucorales, Fusarium spp., and Scedosporium spp. are the most frequently seen nonAspergillus mold pathogens and are associated with a high mortality rate, while Paecilomyces spp. and Scopulariopsis spp. are emerging opportunistic pathogens (1-5). Antifungal agents often have variable activity against these organisms, many of which are notoriously resistant to multiple antifungal drug classes. The utility of in vitro susceptibility testing in this setting is controversial, as clinical breakpoints are lacking and the correlation between drug MICs and outcomes has, to our knowledge, never been demonstrated. The aim of this study was to investigate factors influencing the outcome of non-Aspergillus invasive mold infections (NAIMIs) with a focus on the association between MICs and response to therapy.Retrospective analysis of patient medical records where a nonAspergillus mold was isolated from a clinical specimen between 2009 and 2013 at Duke University (Durham, NC, USA) led to the identification of 39 proven or probable NAIMI cases, according to European Organization for Research and Treatment of Cancer and Mycoses Study Group (EORTC-MSG) definitions (6). Antifungal susceptibility testing (amphotericin B, voriconazole, posaconazole, micafungin) of these samples was performed according to the Clinical and Laboratory Standards Institute (CLSI) M38-A2 procedure (7). The odds ratio (OR) and 95% confidence interval (CI) for predictors of the 6-week response were reported. Fisher's exact test was used for the comparison of categorical variables. This study was approved by the institutional review board of Duke University.Data regarding underlying conditions, fungal species, first-line antifungal drugs, MICs, surgical procedures, and outcomes of all 39 cases are listed in Table S1 in the supplemental material. Twenty-two patients (56%) had hematological malignancies, 13 patients (33%) were solid-organ transplant recipients, and 3 patients (8%) had diabetes mellitus as the only risk factor for mucormycosis (Table 1). The remaining patient underwent allogeneic bone marrow transplantation for pansclerotic morphea. Mucorales and Fusarium spp. accounted for 49% and 31% of cases, respectively. Scedosporium apiospermum, Scedosporium prolificans, Purpureocillium lilacinum (formerly Paecilomyces lilacinus), Paecilomyces variotii, and Scopulariopsis spp. were isolated in the remaining cases. Mortality at week 4 was 46%, and response to therapy, defined as a complete or partial recovery at week 6 according to EORT...

Rare fungal infectious agents: a lurking enemy

“…There seems to be some correlation between the degree of susceptibility of Mucorales isolates to amphotericin B and outcomes. In a small study by Lamoth et al ., an MIC of not more than 0.5 μg/mL was significantly associated with better 6-week outcomes 131 . Liposomal amphotericin B is the drug of choice for first-line treatment.…”

Therapeutic Challenges of Non- Aspergillus Invasive Mold Infections in Immunosuppressed Patients

“…The fact that NAIMIs are uncommon diseases and that the outcome depends on multiple factors (Table 1) with a key role of nonpharmacologic parameters (e.g., stage of the fungal infection at time of diagnosis, activity of underlying disease, comorbidities, and recovery of immunosuppression) renders this assessment particularly difficult. Indeed, studies attempting to correlate MICs and outcome in opportunistic mold infections, including NAIMIs, in high-risk hematology patients are scarce (9,(12)(13)(14). Differences between in vitro artificial AST conditions and the complexity of in vivo infections are illustrated in Fig.…”

“…For amphotericin B, MICs are distributed in a narrower range, with values rarely exceeding 4 g/ml (16). One small retrospective study suggested that amphotericin B MICs of Յ0.5 g/ml were associated with a better response to therapy (9). Most importantly, prompt initiation of amphotericin B therapy is crucial for outcome, with a rate of mortality that was twice higher among patients for which therapy was delayed (Ն6 days from diagnosis) (61).…”

Characteristics and risk factors for mortality of invasive non‐Aspergillus mould infections in patients with haematologic diseases: A single‐centre 7‐year cohort study

“…Clinically, it is difficult to distinguish NAIMIs from invasive aspergillosis (IA), and NAIMIs often have a progressive and aggressive course . NAIMIs should be distinguished from IA primarily because many of these non‐ Aspergillus moulds are not susceptible to or are intrinsically resistant to azoles, including voriconazole . This may lead to treatment failure and increased mortality.…”

“…10 NAIMIs should be distinguished from IA primarily because many of these non-Aspergillus moulds are not susceptible to or are intrinsically resistant to azoles, including voriconazole. [13][14][15] This may lead to treatment failure and increased mortality. However, data for the epidemiology of NAIMIs are limited, owing to its rarity and the lack of microbiological confirmation.…”