Rare Mold Infections Caused by Mucorales, Lomentospora Prolificans and Fusarium, San Diego: The Role of Antifungal Combination Therapy

Abstract

Non-Aspergillus invasive mold infections (IMIs) are associated with devastating morbidity and mortality rates, and are increasingly diagnosed in immunocompromised hosts. The objective of this study was to describe the epidemiology and outcomes of non-Aspergillus IMIs at our university hospital in San Diego, California, United States. We performed a retrospective chart review of medical records of all patients with cultures growing non-Aspergillus molds at the Microbiology Laboratory in the Center for Academic Laboratory Medicine, Department of Pathology, University of California San Diego (UCSD) Health between mid-2014 and mid-2017 (3 year period). A total of 23 cases of non-Aspergillus IMIs were identified, including 10 cases of mucormycosis, 8 cases of lomentosporiosis, and 5 cases of fusariosis. Antifungal susceptibility testing was performed in 14 isolates and 10/11 Fusarium and Lomentospora isolates had MICs >16 μg/mL for voriconazole and/orposaconazole. Overall 180-day mortality was significantly lower among those who received combination antifungal therapy than among those who received single agent therapy [3/13 (23%) vs. 9/10 (90%); p=0.003]. In conclusion, Lomentospora prolificans (35% of non-Aspergillus IMIs), and Fusarium spp. (22%) accounted for high proportions of non-Aspergillus IMIs during the time period. Non-Aspergillus IMIs were detected in patients with various underlying diseases and associated with high mortality rates, which was significantly lower in those who received antifungal combination therapy.

1. Background

Despite recent advances in diagnosis and treatment, invasive mold infections (IMIs) are an important cause of morbidity and mortality globally, particularly in immunocompromised individuals [1]. The incidence of invasive aspergillosis (IA), the most common IMI, is 10–20 cases per 1 million population overall, with an incidence of 0.2–0.6% in the intensive care unit (ICU), 0.5–3.9% after hematopoietic stem cell transplant (HSCT), and 0.1–2.4% after solid organ transplant (SOT) [2]. Reported mortality rates from IA range from 30% to 60% at 12 weeks in patients with an underlying hematologic malignancy, HSCT, SOT or solid tumor and 41% at 12 months in SOT patients [1,2,3]. Prophylaxis against IA with newer triazoles such as posaconazole and voriconazole, particularly with induction chemotherapy for acute myeloid leukemia (AML) and in patients with graft versus host disease (GVHD), is now widely recommended and has helped decrease the morbidity and mortality from IA and increase overall survival [4–6].

However, the selective pressure of antifungal prophylaxis may be contributing to the emergence of less common IMIs [7]. Mucormycosis, the second most common IMI, is caused by widely prevalent fungi found in decaying organic matter and accounts for 8% of invasive fungal infections after HSCT [3] and 2% after SOT [8], with an incidence rate of 1.7 cases per 1 million population and mortality rates averaging 54%. Other filamentous fungi such as Scedosporium spp, Lomentospora spp, and Fusarium spp are also emerging opportunistic pathogens in immunocompromised individuals with incidence rates 3–8 times lower than the Mucorales. Scedosporium and Lomentospora spp are commonly found in soil and polluted waters and account for 1.6% of infections after HSCT and 0.9% of IFIs after SOT [8]. Fusarium spp are major plant pathogens and account for 3.2% of IFIs after HSCT, and 0.5% of IFIs after SOT [8]. All can cause serious, invasive infections and are associated with mortality rates between 30% and 77% for Scedosporium and Lomentospora infections [8]. Invasive fusariosis has also been associated with very high mortality rates of 79% at 90 days in patients with underlying hematologic malignancies and 87% in HSCT recipients [9] when treated with deoxycholate amphotericin B. Survival rates for invasive fusariosis have increased since the introduction of lipid formulation of amphotericin B (53% survival) and voriconazole (60% survival) [9].

The goal of this study was to investigate the risk factors, clinical manifestations, treatment modalities, and outcomes in patients with rare IMIs at our institution in San Diego, California.

2. Methods

All patients who had a non-Aspergillus mold isolated in any sample/material in the Microbiology Laboratory at University of California San Diego (UCSD) Health (San Diego, CA, USA) between July 1, 2014 and July 1, 2017 were included in the study. We then performed a retrospective chart review of medical records of all of these potential cases with non-Aspergillus mold isolates to determine if the positive cultures represented true invasive infection or colonization. Isolates were determined to represent colonization if there was either a lack of compatible findings of invasive disease on imaging, the treating physicians documented that the isolates represented colonization rather than true infection, and/or no antifungal therapy was initiated in response to these positive microbiologic findings. Conversely, isolates were determined to represent true infection if there were compatible findings on imaging and clinical findings consistent with invasive infection, and the treating physicians determined that the microbiologic findings represented true infection and antifungal therapy was initiated. Only cases in adult patients over the age of 18 were included in the analysis. Cases were classified according to revised EORTC/MSG criteria, which have been established for classifying proven IMIs in all types of cases, and probable and possible IMIs only in the subset of individuals with underlying hematologic malignancies or who received a SOT. Cases without proven infection and without underlying hematological malignancies and who were not recipients of solid organ transplantation were classified as “not classifiable”. Clinical data were compiled using the web-based registry FungiScope™ [1].

In vitro susceptibilities were determined in a total of 14 strains by a broth microdilution technique following the guidelines of the Clinical and Laboratory Standards Institute (CLSI) M38A document. Antifungal susceptibility testing was performed at the University of Texas San Antonio, Pathology, Fungus Testing Laboratory, San Antonio, Texas in 2014 and at the Associated Regional and University Pathologists, Inc. (ARUP) Laboratories, Salt Lake City, Utah, United States (2015–2017). Results were read after 48h. All azoles were tested in concentrations ranging from 0.016 to 16 μg/ml, all echinocandins and amphotericinB were tested in concentrations ranging from 0.0625 to 8 μg/ml, while terbinafine was tested in concentrations from 0.0625 to 2 μg/ml.

Statistical analyses were performed using SPSS 23 (SPSS Inc., Chicago, IL, USA). Proportions were compared using Fishers Exact test for 2 groups, and Chi-squared testing for 3 groups. A two-sided P-value of less than 0.05 was considered statistically significant. The Human Research Protections Program at the University of California, San Diego approved the study protocol and all study-related procedures (Project #171104).

3. Results

A total of 62 adult cases with non-Aspergillus mold isolates were identified over the 3-year study period, of which 23 cases had sufficient clinical data available and were determined to represent invasive infection (60% of cases with Mucor isolates, 40% of cases with Rhizopus isolates, 57% of cases with Lomentospora prolificans isolates, and 18% of cases with Fusarium isolates).

We focused our analysis on the 23 cases of invasive non-Aspergillus IMI (Table 1 and Table 2), including the 10 (43%) caused by Mucorales spp (6 by Mucor and 4 by Rhizopus; case 7 had later also detection of Trichosporon asahii; 8 proven cases, 2 probable cases), 8 (35%) by Lomentospora prolificans (case 16 had also detection of Scedosporium apiospermum in a later sputum culture, case 18 had later also detection of Mucor sp; 6 proven cases, 1 probable case and 1 not classifiable), and 5 (22%) by Fusarium spp (4 proven cases and 1 probable case). Overall, 35% of infections (8/23) occurred in patients with underlying hematologic malignancy or after SOT, while 26% (6/23) occurred in burn patients, 17% (4/23) in patients with diabetes mellitus, and 13% (3/23) after trauma or in patients in the ICU.

Table 1:

Demographic Characteristics, Underlying Diseases and Survival.

	Mucormycosis (n=10)	Lomentosporios is (n=8)	Fusariosis (n=5)
Female Sex	4	5	2
Age (median, range)	47 (18–81)	53 (18–69)	45 (23–63)
Underlying Diseases/Main Risk Factors
Hematological Malignancies	3	2	1
Burn	3	-	3
Uncontrolled Diabetes	3	1	-
Lung Transplant/Cystic Fibrosis	-	2	-
ICU/Polytrauma	1	2	-
Liver Disease	-	-	1
Chronic Granulomatous Disease	-	1	-
Source of Isolate
Blood Culture	-	2	-
Lung / BALF	3	2	-
Deep Soft Tissue / Biopsies	2	1	3
Eye	-	3	-
Sinuses	5	-	1
Peritoneal Fluid	-	-	1
Survival day 180	4	4	3

ICU, intensive care unit; BALF, bronchoalveolar lavage fluid

Table 2:

Cases of non-Aspergillus Invasive Mold infections (IMI): Underlying Diseases, IMI Characteristics, Treatment and Outcome.

Cas e num ber	Primar y Underl ying Diseas e	Antifun gals within 14 Days before Diagno sis = Day 0 (Duratio n in Days)	Source of Isolate	IMI Classifi cation	Antifun gal Treatme nt (Day of Initiatio n)	Surgery	Outcome (final assessment)	Surv ival day 180
Mucormycosis
1	Trauma ICU	LipAmp hB (Day -8 – Day 0), Micafun gin (Day -10 – Day -3), Flucona zole (Day -15 – Day - 11)	Soft Tissue, Biopsies from: stomach , omentu m, abdomin al wall, Colon/S plenic flexion	Proven	LipAmp hB (Day -8) & Posacon azole (Day 4; combina tion)	Stomac h, sleeve resectio n, Colon/S plenic flexion resectio n	Progression/un controlled disease (day 13)	No
2	Acute Myeloid Leuke mia	LipAmp hB & Posacon azole (combin ation; Day -7 – Day 0)	Sinuses, Intraope rative Tissue (2×)	Proven	LipAmp hB (Day -7) & Posacon azole (Day -7) & Micafun gin (Day 2; combina tion)	Debride ment	Complete response (day 330)	Yes
3	Uncont rolled Diabete s mellitus	LipAmp hB & Micafun gin (combin ation; Day -3 – Day 0)	Sinuses	Proven	LipAmp hB (Day -3) & Posacon azole (Day 6; combina tion)	-	Partial response (day 56)	Yes
4	Burn	LipAmp hB (Day -10 – Day -7), Micafun gin (Day -10 – Day 0)	Soft Tissue	Proven	LipAmp hB & Posacon azole (Day 0; combina tion)	Debride ment	Complete response (day 42)	Yes
5	Uncont rolled Diabete s mellitus (ICU)	Flucona zole (Day -4 – Day 0)	BALF, Sputum, Lung Tissue	Proven	Micafun gin (Day -2)	-	Progression/un controlled disease (day 2)	No
6	Uncont rolled Diabete s mellitus	-	Sinuses, Hard palate biopsy	Proven	LipAmp hB & Posacon azole (Day 0; combina tion)	Debride ment	Progression/un controlled disease (day 22)	No
7	Acute Lymph atic Leuke mia	Posacon azole (Day -44 – Day 0)	BALF	Probable	LipAmp hB (Day 0)	-	Progression/un controlled disease (day 15)	No
8	Burn	Voricon azole (Day -30 – Day 0)	Sinuses (6×)	Proven	LipAmp hB (Day 0)	Debride ment	Progression/un controlled disease (day 26)	No
9	Acute Lymph atic Leuke mia	Posacon azole (Day -17 – Day 0)	BALF	Probable	LipAmp hB (Day 0)	-	Progression/un controlled disease (day 17)	No
10	Burn	Voricon azole (Day -3 – Day 10), Flucona zole (Day -12 – Day 0)	Sinuses (5×)	Proven	LipAmp hB (Day 0) & Posacon azole (Day 10; combina tion)	Debride ment	Complete response (day 104)	Yes
Lomentosporiosis
11	Uncont rolled Diabete s Mellitus	NA	Eye	Proven	Voricon azole systemic & intravitre al (Day 0)	Right Eye Enuclea tion	Progression/un controlled disease (day 3)	No
12	Chronic Cardio- vascula r Diseas e (ICU)	Flucona zole (Day -4 – Day - 2)	Eye (2×)	Proven	Voricon azole (Day -1) & Terbinafi ne (Day 0; combina tion) +/− Micafun gin (Day 2 – Day 9)	Left Eye Enuclea tion	Partial Response (day 75)	Yes
13	Non Hodgki n Lymph oma	Micafun gin (Day -11 – Day 0), Flucona zole (Day -11 – Day - 9)	Blood Culture (2×)	Proven	Micafun gin (Day -11), LipAmp hB (Day 5)	-	Progression/un controlled disease (day 6)	No
14	Multiple Myelo ma	Lip AmphB intravitre al (Day - 5)	Eye (twice)	Proven	Lip AmphB systemic and intravitre al (Day 0)	Left Eye Vitrecto my	Progression/un controlled disease (day 7)	No
15	Lung Transpl ant Recipie nt (4 years ago); Cystic Fibrosi s	Posacon azole (Day -31 – Day 0)	BALF	Probable	Voricon azole & Micafun gin & Terbinafi ne (Day 2; combina tion)	-	Stable disease (day 84)	Yes
16	Cystic Fibrosi s	NA	Sputum 2×	Not classifia ble	Voricon azole & Micafun gin (Day 0; combina tion)	-	Stable disease (day 84)	Yes
17	Chronic granulo - matous disease	Micafun gin (Day -12 – Day -8), Flucona zole (Day -31 – Day 0)	Blood culture	Proven	Voricon azole (Day 0) & Terbinafi ne (Day 2; combina tion)	-	Complete response (day 42)	Yes
18	Major Surger y (ICU)	Micafun gin & LipAmp hB (Day -15 – Day 0; combina tion)	Deep soft tissue (7×)	Proven	Voricon azole & LipAmp hB (Day 0; combina tion), then Posacon azole & Terbinafi ne (Day 21; combina tion)	Debride ment	Stable Disease (day 115)	No
Fusariosis
19	Chronic lympho cytic leukemi a	NA	Sinuses (5×)	Proven	Voricon azole (Day 0) & Terbinafi ne (Day 4; combina tion)	Debride ment of sinuses	Stable disease (day 230)	Yes
20	Burn	Micafun gin (Day -3 – Day 0), Flucona zole (Day -12 – Day - 5)	Skin/soft tissue (2×)	Proven	LipAmp hB (Day -3) & Voricon azole (Day 0; combina tion)	Debride ment	Complete response (day 42)	Yes
21	Alcohol ic liver disease	Micafun gin (Day -20 – Day 0), Flucona zole (Day -6 - Day - 3)	Peritone al fluid	Proven	LipAmp hB (Day 0)	-	Progression/un controlled disease (day 2)	No
22	Burn	Flucona zole (Day -16 – Day 0)	Skin/soft tissue (2×)	Proven	LipAmp hB (Day 0)	Debride ment	Stable disease (day 54)	No
23	Burn	NA	Skin/soft tissue (8×) Sterile fluid (×)	Proven	Voricon azole (Day 0)	Debride ment	Complete response (day 183)	Yes

Abbreviations: BALF, bronchoalveolar lavage fluid; ICU, intensive care unit; LipAmphB, liposomal Amphotericin B

Table 1 shows demographic characteristics, underlying diseases, source of isolates and survival for each group of IMI. No significant difference was observed in underlying diseases between the three groups (p=0.142), while significant differences were observed regarding the source of the fungal isolate (p=0.017), with Mucorales being more frequently isolated from sinuses and Lomentospora prolificans being more frequently isolated from eyes.

Table 2 shows patient and disease characteristics as well as treatment and outcome for all 23 cases. Overall 180-day mortality was 52% (12/23), and significantly lower among those who received combination antifungal therapy than among those who received single agent therapy [3/13 (23%) mortality among those with combination therapy vs. 9/10 (90%) mortality among those with single agent therapy; p=0.003].

Out of 10 cases of mucormycosis (4 caused by Rhizopus spp. and 6 by Mucor spp.), 6 died within 30 days of detection of Mucorales; all 4 survivors received combination therapy with liposomal amphotericin B and posaconazole, while only 2/6 non-survivors received combination therapy (p=0.076).

Table 3 shows results of antifungal susceptibility testing and minimum inhibitory concentrations (MIC). Antifungal susceptibility testing revealed that 10/11 Lomentospora prolificans and Fusarium spp isolates had MICs >16 μg/mL against voriconazole and/or posaconazole. Among cases with Lomentospora prolificans infections, all four survivors received combination therapy with either voriconazole plus terbinafine (n=3) or voriconazole plus micafungin (n=1), while 1/4 non-survivors received also combination therapy (p=0.143). In patients with invasive fusariosis, treatment with voriconazole alone or in combination showed a trend to being associated with survival (3/3 survived, while both patients who did not receive voriconazole did not survive; p=0.100).

Table 3.

Results of Antifungal Susceptibility Testing (performed in 14/23 isolates). Minimum inhibitory concentrations (MIC) displayed.

Case number	Isolate	AF Before Isolation	MIC (mg/L)
2	Rhizopus sp.	LipAmphB & Posaconazole (combination)	LipAmphB: 1 Itraconazole: 1 Posaconazole: 0.5 Voriconazole: 8
3	Rhizopus sp.	LipAmphB, Micafungin (combination)	LipAmphB: 2 Itraconazole: 2 Posaconazole: 1 Voriconazole: >16
10	Mucor sp.	Voriconazole, Fluconazole	LipAmphB: 0.5 Itraconazole: >16 Voriconazole: >16
11	Lomentospora prolificans	NA	LipAmphB: >8 Itraconazole: >16 Posaconazole: >16 Voriconazole: >16 Anidulafungin: 4 Caspofungin: >8 Micafungin: >8
12	Lomentospora prolificans	Fluconazole	Posaconazole: >16 Anidulafungin: 1
14	Lomentospora prolificans	Lip AmphB systemic and intravitreal	Posaconazole: >16 Terbinafine: >2
15	Lomentospora prolificans	Posaconazole	LipAmphB: >8 Itraconazole: >16 Posaconazole: >16 Voriconazole: >16 Anidulafungin: >8 Caspofungin: >8 Micafungin: 1
16	Lomentospora prolificans	NA	Itraconazole: >16 Posaconazole: 1 Anidulafungin: 2 Caspofungin: 1 Micafungin: 0.25
17	Lomentospora prolificans	Micafungin, Fluconazole	LipAmphB: >8 Posaconazole: >16 Voriconazole: >16 Anidulafungin: <0.0625 Caspofungin: <0.0625 Micafungin: <0.0625 Terbinafine: 2
18	Lomentospora prolificans	Micafungin & LipAmphB (combination)	Posaconazole: >16 Anidulafungin: >8 Caspofungin: >8 Micafungin: >8
19	Fusarium solanii	NA	LipAmphB: 2 Posaconazole: >16 Voriconazole: 16 Caspofungin: >8 Isavuconazole: >16 Terbinafine: 0.25
20	Fusarium sp.	Micafungin, Fluconazole	LipAmphB: 2 Itraconazole: >16 Posaconazole: >16 Voriconazole: >16
21	Fusarium sp.	Micafungin, Fluconazole	LipAmphB: 2 Itraconazole: >16 Voriconazole: >16
22	Fusarium sp.	Fluconazole	LipAmphB: >8 Itraconazole: >16 Voriconazole: >16

Abbreviations: AF, antifungals; LipAmphB, liposomal Amphotericin B; NA, not applicable

4. Discussion

Invasive infection due to non-Aspergillus molds is an important cause of morbidity and mortality, particularly in immunocompromised individuals. In this study, infections occurred in patients with a variety of underlying diseases and diverse sites, with mucormycosis most likely isolated from the sinuses, Lomentospora prolificans from the eye, and Fusarium from soft tissue. Thus, invasive infection from these molds can occur in individuals without classically-defined immunocompromising drugs and conditions, (e.g., HSCT or SOT), and can occur in a variety of sites. Clinicians should be observant for signs of these infections in the right clinical context. Overall, non-Aspergillus IMIs were associated with high mortality rates, particularly in cases with single agent antifungal therapy (9/10 died, 90%), while mortality was significantly lower in those who received combination antifungal therapy (2/13 died, 23%).

High mortality rates from non-Aspergillus molds were noted in this study, similar to previous studies [3, 8, 9]. Mortality at 180 days ranged from 40% with invasive fusariosis, 50% with Lomentospora infection, and 60% with mucormycosis. There was an association between survival and the use of combination therapy, driven in particular by patients with mucormycosis and Lomentospora infections, with a trend towards improved survival in both. Of the 10 patients with mucormycosis, 6 received combination therapy with liposomal amphotericin B plus posaconazole, with one patient receiving treatment with micafungin as well. Of those who received combination therapy, 4/6 survived, with none surviving in those that received monotherapy. The European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and the European Conference on Infections in Leukemia (ECIL-6) guidelines recommend liposomal amphotericin B as first-line therapy (AII and BII recommendations, respectively) for the management of invasive mucormycosis [10], although posaconazole has shown good efficacy for salvage treatment of mucormycosis [11].

There is some data supporting combination therapy for the treatment of infections from mucormycosis. In-vitro studies with combination of amphotericin B and posaconazole has demonstrated synergy against Rhizopus isolates [12]. Combination therapy with amphotericin B and posaconazole in animal models has yielded mixed results. In one study investigating combination therapy with amphotericin B plus posaconazole versus monotherapy with amphotericin B in diabetic ketoacidotic or neutropenic mice with disseminated mucormycosis, combination therapy did not result in improved survival [13]. However, in another study in immunosuppressed mice, amphotericin B plus posaconazole improved survival and reduced fungal tissue burden compared to monotherapy with either drug in mice with disseminated mucormycosis [14].

In terms of clinical data, a retrospective study of diabetic patients with rhino-orbital or rhino-orbital-cerebral mucormycosis showed that combination therapy with amphotericin B and caspofungin was associated with greater 30-day survival compared to monotherapy with amphotericin B (100% versus 45%), although the sample size was small [15]. Another retrospective study examined combination therapy with amphotericin B and posaconazole to treat invasive mucormycosis in 32 patients with hematologic malignancy or aplastic anemia [16]. Most patients initially received monotherapy with amphotericin B, with posaconazole added as salvage therapy due to lack of response with amphotericin B alone. At 3 months, those patients who received both antifungal agents did not have worse survival, although posaconazole was used as salvage rather than combination therapy [16]. Another large retrospective study of 106 patients with underlying hematologic malignancy or HSCT recipients with mucormycosis investigated outcomes between patients treated with monotherapy and combination therapy at a single medical center from 1994 to 2014. This study did not find an overall mortality benefit between those treated with monotherapy and combination therapy at 6-weeks (43% versus 41%, respectively), although those receiving combination therapy with amphotericin B plus posaconazole had a higher rate of survival compared to those receiving monotherapy (24/32 survived versus 27/47, respectively) [17]. Thus, combination therapy with liposomal amphotericin B with posaconazole may be more efficacious than monotherapy with amphotericin B, although further investigation is warranted.

In line with previous studies, high MICs against most antifungals were observed for Lomentospora prolificans isolates, with some isolates displaying lower MICs for echinocandins and one isolate displaying a low MIC for posaconazole. Of the 8 patients with Lomentospora infections, 5 received combination therapy with voriconazole plus at least one other agent (in 4/5 patients the combination included voriconazole and terbinafine). Of those receiving combination therapy 80% (4/5) survived, while no patients who received monotherapy survived. Combination treatment (primarily broad spectrum azole plus terbinafine) is also the recommended treatment (BII recommendation) for the treatment of Lomentospora prolificans infections by the ESCMID and the European Confederation of Medical Mycology (ECMM) [18]. This recommendation is mostly based on case reports demonstrating clinical efficacy with combination voriconazole and terbinafine, while data from large scale studies to support this approach is lacking given the rareness of these infections.

Notably, the majority of Fusarium isolates were resistant to both first-line and salvage therapy. Of the 5 patients with Fusarium infection, 4 had antifungal susceptibility testing; of these, all 4 had an MIC ≥16 to voriconazole, and of those tested against posaconazole (2/4), both had a MIC >16 mg/L. In other studies the MIC of voriconazole and posaconazole against Fusarium ranged from 1.0 – 16.0 mg/L and 0.25 – 32 mg/L [19], respectively. Nevertheless, studies have shown the benefit of voriconazole-based treatment regimens for survival of invasive fusariosis [9], and a similar trend was also observed in our study (all patients with voriconazole based treatment regimens survived, while both patients who did not receive voriconazole did not survive). However, this difference may also be explained by the fact that all survivors received surgery, which plays a major adjuvant role in the treatment of these infections, particularly when high MICs are noted, as in this study.

This non-randomized study does have several limitations and our main finding that combination therapy was strongly associated with a better outcome should therefore be interpreted with caution. This is a retrospective cohort study done at a single medical institution in San Diego, so these findings may not be representative of other patient populations. Still, the patients in this study had a wide variety of predisposing factors increasing their risk for IMI, resulting in a diverse cohort. In addition, the sample size was low, although this is a natural limitation of studies looking at rare diseases such as those documented here. This study was mostly descriptive in character and underpowered to assess for clear associations, such as antifungal treatment and survival, for example. Finally, none of the cases received isavuconazole, which has recently been shown to be a promising therapeutic option for non-Aspergillus IMIs and also IMIs caused by more than one fungal species [20]. Nevertheless, this study adds to the current body of literature investigating rare IMIs.

5. Conclusions

In conclusion, this study describes non-Aspergillus IMIs in patients with various underlying diseases that resulted in high mortality rates. Notably, of these IMIs Lomentospora prolificans (35%) and Fusarium spp. (22%) were emerging pathogens, with the vast majority of isolates resistant to both voriconazole and posaconazole, the two agents preferred for the treatment of these infections. Overall, mortality rates were significantly lower in patients who received antifungal combination therapy. Further investigation is needed to determine the optimal treatment for these infections, including if combination antifungal therapy offers a survival benefit over monotherapy.

Highlights.

• Retrospective analysis of patients diagnosed with non-Aspergillus invasive mold infections at the University of California San Diego Medical Center, San Diego, California, United States.

• IMIs occurred in patients with a variety of underlying diseases and diverse sites, not just those with classically-defined immunocompromising drugs and conditions

• Most Fusarium and Lomentospora isolates had MICs >16 μg/mL for voriconazole and/or posaconazole

• Overall 180-day mortality was significantly lower among those who received combination antifungal therapy [3/13 (23%)] than among those who received single agent therapy [9/10 (90%); p=0.003]