Skip to main content
Download PDF

Compare the efficacy of antifungal agents as primary therapy for invasive aspergillosis: a network meta-analysis

BMC Infectious Diseases volume 24, Article number: 581 (2024) Cite this article

Abstract

Background

Several antifungal agents are available for primary therapy in patients with invasive aspergillosis (IA). Although a few studies have compared the effectiveness of different antifungal agents in treating IA, there has yet to be a definitive agreement on the best choice. Herein, we perform a network meta-analysis comparing the efficacy of different antifungal agents in IA.

Methods

We searched PubMed, Embase, and the Cochrane Central Register of Controlled Clinical Trials databases to find studies (both randomized controlled trials [RCTs] and observational) that reported on treatment outcomes with antifungal agents for patients with IA. The study quality was assessed using the revised tool for risk of bias and the Newcastle Ottawa scale, respectively. We performed a network meta-analysis (NMA) to summarize the evidence on antifungal agents’ efficacy (favourable response and mortality).

Results

We found 12 studies (2428 patients) investigating 11 antifungal agents in the primary therapy of IA. There were 5 RCTs and 7 observational studies. When treated with monotherapy, isavuconazole was associated with the best probability of favourable response (SUCRA, 77.9%; mean rank, 3.2) and the best reduction mortality against IA (SUCRA, 69.1%; mean rank, 4.1), followed by voriconazole and posaconazole. When treated with combination therapy, Liposomal amphotericin B plus caspofungin was the therapy associated with the best probability of favourable response (SUCRA, 84.1%; mean rank, 2.6) and the best reduction mortality (SUCRA, 88.2%; mean rank, 2.2) against IA.

Conclusion

These findings suggest that isavuconazole, voriconazole, and posaconazole may be the best antifungal agents as the primary therapy for IA. Liposomal amphotericin B plus caspofungin could be an alternative option.

Peer Review reports

Introduction

Invasive aspergillosis (IA) is a severe infection with high morbidity and mortality, primarily affecting immunocompromised individuals, including transplant recipients, advanced HIV patients, and those with primary immunodeficiency or hematologic malignancies [1, 2]. Recent studies suggest a susceptibility to IA in individuals with severe viral respiratory infections like influenza and COVID-19 [3, 4]. With over 200,000 cases annually worldwide [5], IA previously had an 80% mortality rate in immunocompromised individuals [6], but with triazoles as primary therapy, this has decreased to less than 30% [7].

Voriconazole and isavuconazole are the top recommended antifungal agents for primary therapy according to international guidelines [8, 9], with posaconazole showing non-inferiority to voriconazole in a recent randomized clinical trial (RCT) for all-cause mortality [10]. Echinocandins, though static against aspergillus, are considered for primary and salvage therapy in combination with other antifungals due to low toxicity [11,12,13,14,15], but RCTs evaluating monotherapy with echinocandins are lacking. Lipid formulations of amphotericin B are less toxic than amphotericin B deoxycholate but show less efficacy than voriconazole [16]. Azole resistance among aspergillus is a growing concern, with prevalence ranging from 3–30% [17, 18]. Considering these challenges and the high mortality of IA, combination therapies like liposomal amphotericin B plus echinocandins may offer enhanced survival rates as primary therapy [13, 15].

Thus, the best choice of antifungal agents for primary therapy in patients with IA remains unclear. Network meta-analysis (NMA) provides the relative effectiveness of various interventions. We conducted a NMA to evaluate the relative efficacy of different treatments in IA.

Methods

Protocol and registration

This NMA was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses for Network Meta-analysis (PRISMA-NMA) reporting guideline [19]. This protocol has been registered at PROSPERO under registration number CRD42023436758.

Literature search

We searched the Pubmed, EMBASE, and the Cochrane Central Register of Controlled Clinical Trials to collect all published evidence from RCTs and observational studies from inception to 01 July 2023 that assessed primary therapy in patients with IA. The detailed search strategy is presented in the supplemental eTable 1 in the Supplement. The reference lists from all included studies were also screened to identify potentially relevant evidence.

Study inclusion and exclusion criteria

The inclusion criteria were (a) RCTs comparing different antifungal agents or placebo in patients with IA; (b) RCTs with reported available data that measured response rate and/or mortality rate; (c) observational studies providing the outcomes with at least two different antifungal agents; (d) published in only English language. The exclusion criteria were (a) abstracts, comments, editorials, case reports, and reviews; (b) studies using a single antifungal agent without a control arm or with different dose; (c) studies including patients with allergic bronchopulmonary aspergillosis or chronic pulmonary aspergillosis.

Data extraction

From each relevant study, two authors (L.-B.X. and L.W.) independently extracted the following data: authors’ names, year of publication, number of patients, age, use, and dosage of drugs. Extracted outcomes included favourable therapy response and mortality of different antifungal agents used. Any differences in the data extraction process were resolved by discussion.

Quality assessment

Two authors (H.Z. and X.G.) independently participated in the quality assessment, and disagreements were resolved by discussion. The quality of the evidence was assessed using the revised tool for risk of bias (ROB2) and the Newcastle-Ottawa scale (NOS)in RCTs and observational studies, respectively [20, 21].

Outcome measure

The outcomes including favourable response and mortality were to compare the efficacy of antifungal agents in treating IA. Favourable response was defined based on the criteria used by the authors, which included complete response, partial response, or stable disease.

Statistical analysis

We compared different antifungal agents through network meta-analyses performed under a frequentist framework using a random-effects model. The analysis utilized the network and mvmeta packages in Stata (StateCorp, USA) [22]. We assessed the results of each study using the relative risk (RR) with 95% confidence intervals (CIs). If the 95% CI of an RR did not include 1, it indicated a significant association. We utilized forest plots and league tables to present the network meta-analysis findings. Additionally, we ranked each agent individually for each outcome using the surface under the cumulative ranking curve (SUCRA) [23]. A higher SUCRA value indicates a better rank. To ensure reliability and validity, we addressed inconsistencies and heterogeneity in the comparative studies of various treatments when assessing the networks [24]. The overall and loop inconsistencies were evaluated [22, 25]. We used the restricted maximum likelihood method to assess heterogeneity. A τ2 value less than 0.1 indicated a very low level of heterogeneity, and a τ2 value from 0.1 to 0.5 indicated a reasonable level; a τ2 value greater than 0.5 indicated a high heterogeneity [26]. We also used a funnel plot to describe small-study effects and tested each plot with the Egger’s test. A 2-sided P-value less than 0.05 is statistically significant.

Results

Characteristics of the studies

The flowchart of study selection for this NMA is shown in Fig. 1. In total, 5 RCTs and 7 observational studies with 2428 patients were included [10, 13,14,15, 27,28,29,30,31,32,33,34], including 11 groups: amphotericin B colloidal dispersion, amphotericin B deoxycholate, liposomal amphotericin B, amphotericin B lipid complex, voriconazole, posaconazole, caspofungin, isavuconazole, liposomal amphotericin B plus caspofungin, voriconazole plus caspofungin, voriconazole plus anidulafungin. The basic characteristics of the included studies are summarized in Table 1. The quality of included studies is shown in supplemental eTable 2 and eFigure 2. ROB2 scored 1, 2, and 3, respectively, mean low risk, some concerns, and high risk.

Table 1 Basic Characteristics of Included Studies
Full size table

Network geometry and synthesis of results

The network geometry for each outcome is shown in Fig. 2: favourable response rates included 11 groups, 12 studies, and 2043 patients; mortality rates included 11 groups, 12 studies, and 2074 patients. Indirect and mixed-treatment comparisons are shown as forest plots (eFigure 2 in the Supplement).

The SUCRA value and rank of each agent for each outcome are shown in Table 2. Regarding response rate, combination therapy of liposomal amphotericin B plus caspofungin was the approach with the highest ranking (SUCRA, 84.1%; mean rank, 2.6), followed by isavuconazole (SUCRA, 77.9%; mean rank, 3.2), voriconazole (SUCRA, 59.1%; mean rank, 5.1), voriconazole plus caspofungin (SUCRA, 58.7%; mean rank, 5.1), posaconazole (SUCRA, 56.5%; mean rank, 5.3). Amphotericin B deoxycholate ranked the lowest (SUCRA, 17.7%; mean rank, 9.2). Compared to voriconazole, liposomal amphotericin B plus caspofungin show a trend improving favourable response (RR, 1.84; 95% CI, 0.47–7.21), but the difference is not significant. Isavuconazole (RR, 1.41; 95% CI, 0.69–2.87), posaconazole (RR, 0.99; 95% CI, 0.45–2.21), voriconazole plus caspofungin (RR, 1.01; 95% CI, 0.34–2.95) didn’t show a significant difference compared with voriconazole (Table 3).

Table 2 SUCRA Values and Mean Rank for All Outcomes
Full size table
Table 3 League Tables of All Outcomes
Full size table

Regarding mortality rate, the approach that ranked highest with the lower mortality rate was liposomal amphotericin B plus caspofungin (SUCRA, 88.2%; mean rank, 2.2), followed by voriconazole plus anidulafungin (SUCRA, 79.1%; mean rank, 3.1), isavuconazole (SUCRA, 69.1%; mean rank, 4.1), voriconazole plus caspofungin (SUCRA, 66.9%; mean rank, 4.3), voriconazole (SUCRA, 57.7%; mean rank, 5.2), posaconazole (SUCRA, 48.4%; mean rank, 6.2). Caspofungin ranked the lowest (SUCRA, 12.9%; mean rank, 9.7). Compared to voriconazole, liposomal amphotericin B plus caspofungin also showed a trend in reducing mortality (RR, 0.19; 95% CI, 0.01–3.80), but the difference is not significant. Voriconazole plus anidulafungin (RR, 0.75; 95% CI, 0.48–1.16), voriconazole plus caspofungin (RR, 0.87; 95% CI, 0.31–2.42), isavuconazole (RR, 0.87; 95% CI, 0.59–1.29), posaconazole (RR, 1.11; 95% CI, 0.73–1.69) didn’t show a significant difference compared with voriconazole (Table 3).

Funnel plot and publication bias

Heterogeneity and inconsistency are shown in Table 4. Heterogeneity was low for mortality; heterogeneity was reasonable for the response. Loop inconsistency for liposomal amphotericin B, voriconazole, and caspofungin was not found for response and mortality (eFigure 3). As shown in Fig. 3, it did not suggest any publication bias in the comparison-adjusted funnel plots.

Table 4 Tests for Inconsistency, Heterogeneity, and Small-Study Effects
Full size table

Discussion

In the present NMA, we combined direct and indirect evidence to compare primary therapies for patients with IA. Our result may provide vital information for these patients’ clinical decision-making for antifungal therapy. We derived some principal findings from our analysis: combination antifungal agents of liposomal amphotericin B and caspofungin may be the best choice for primary therapy of IA, and voriconazole plus echinocandins also could be considered. Isavuconazole and voriconazole are the top choices for primary therapy, intravenous or oral posaconazole can be considered an alternative agent. Isavuconazole and voriconazole are recommended for IA as primary treatment for solid-organ and hematopoietic stem cell transplant patients according to the international guidelines [8, 9]. Overall, isavuconazole, voriconazole, posaconazole, liposomal amphotericin B plus caspofungin and voriconazole plus echinocandins are recommended as the most reasonable options for the primary therapy of IA.

In the current NMA, liposomal amphotericin B plus caspofungin demonstrated the highest response rate and lowest mortality rate. However, it should be noted that the evidence supporting this finding is based on a pilot study with a limited sample size [14]. The study showed that the combination therapy group exhibited significantly more favourable responses (partial or complete) than the liposomal amphotericin B monotherapy group (10/15 vs. 4/15). Moreover, at week 12, survival rate was higher in the combination therapy group (100%) than in the amphotericin B monotherapy group (80%). A larger randomized controlled trial is necessary to confirm these findings. Therefore, liposomal amphotericin B plus caspofungin is not recommended as a primary therapy according to international guidelines [8, 9].

Our NMA concluded that combination antifungal therapy of voriconazole and an echinocandin don’t show more efficacy than monotherapy with voriconazole, isavuconazole, or posaconazole. A large RCT had assessed the safety and efficacy of 6 weeks of voriconazole with or without anidulafungin for the treatment of IA in patients with hematologic malignancies and/or hematopoietic cell transplantation, mortality rates at 6 weeks were 19.3% (26/135) for combination therapy and 27.5% (39/142) for monotherapy (difference, -8.2%, 95% CI, -19.0 to 1.5; P = 0.087) [13]. Another observational study compared the primary therapy of 40 solid organ transplant patients who received voriconazole and caspofungin with a historical control group of 47 patients who were given liposomal amphotericin B. Overall survival at 90 days was 67.5% (27/40) in the cases and 51% (24/47) in the control group (HR 0.57, 95% CI: 0.29–1.1, P = 0.11) [15]. Overall, due to limited evidence of the effectiveness of combination therapy, it is essential for clinicians to carefully evaluate the potential risks and benefits of administering two drugs. This evaluation should consider individual factors such as potential toxicities, the severity of the disease, and the level of immunosuppression, as well as practical considerations, including cost and the feasibility of intravenous therapy.

Based on the Global Comparative Aspergillus Study results [16, 32], primary therapy with voriconazole showed better responses and improved survival and resulted in fewer severe side effects than the standard approach with amphotericin B in patients with IA. Voriconazole is the preferred antifungal agent recommended by international guidelines [8, 9]. Our NMA found that isavuconazole and posaconazole are equally effective in treating IA as voriconazole. However, while isavuconazole is recommended as the preferred antifungal agent by international guidelines, posaconazole is not. Because published in 2016, the SECURE trial showed isavuconazole was non-inferior to voriconazole for the primary therapy of suspected invasive mold disease [33]. Before the latest vision guidelines were updated, no RCT had compared the efficacy of posaconazole and voriconazole. Now, posaconazole injection and delayed-release tablets are FDA approved for the treatment of IA in patients ≥ 13 years because a RCT comparing posaconazole vs. voriconazole for the therapy of IA in 575 patients, all-cause mortality at day 42 was lower in the posaconazole group (15% vs. 21%, p < 0.0001) in the intention to treat analysis [10]. For primary therapy of IA, we recommend voriconazole, isavuconazole, and posaconazole, if resistant Aspergillus isolates are not suspected. When patients cannot tolerate voriconazole and avoid its toxicity, Posaconazole and isavuconazole are the preferred alternatives [35]. It is noted that the absorption of an oral suspension of posaconazole is less reliable than the delayed-release tablets, and patients with higher serum posaconazole levels have higher favourable response rates than those with lower drug levels [36]. We don’t recommend oral suspension of posaconazole for primary therapy in patients with IA if posaconazole injection and delayed-release tablets are available.

Our NMA included 4 formulations of amphotericin B, liposomal amphotericin B, amphotericin B colloidal dispersion, and amphotericin B lipid complex were ranked higher than amphotericin B deoxycholate at response and mortality in our analysis. And amphotericin B deoxycholate was ranked lowest at response and near lowest at mortality among all the 11 antifungal agents. Amphotericin B deoxycholate should not be considered in the primary therapy of IA. The other 3 formulations of amphotericin B have similar efficacy, but they all have less effect than voriconazole, posaconazole, and isavuconazole. The echinocandins, including caspofungin and anidulafungin, are encompassed within our analysis. Though the FDA has approved caspofungin for treating IA in patients who cannot tolerate or are refractory to standard therapy [37], monotherapy with caspofungin was ranked lowest at mortality in the rank analysis.

Though we couldn’t analyze antifungal agent toxicity due to limited data, clinical practice demands considering drug toxicity alongside efficacy. Amphotericin B deoxycholate often triggers severe nephrotoxicity due to vasoconstrictive and tubulo-toxic effects [27,28,29,30, 38,39,40]. Lipid formulations mitigate, but don’t eliminate, nephrotoxicity [41, 42]. Two hypotheses suggest: absence of deoxycholate in liposomal preparations reduces tubular toxicity, and liposomes may preferentially target fungal sites, sparing kidney cells [38, 40]. Concurrent administration of nephrotoxic agents, baseline chronic kidney disease, and dose-dependent factors heighten nephrotoxicity risk for both formulations [43,44,45]. Additionally, amphotericin B can also disrupt electrolyte and acid-base balance, necessitating electrolyte supplement for management [38]. Triazoles pose lower nephrotoxicity concerns than amphotericin B, with commonly reported gastrointestinal and hepatic function abnormalities [10, 16, 33]. Each azole carries unique toxicity profiles; Voriconazole is linked with vision changes, neurologic toxicity, skin toxicity, periostitis, cardiac toxicity, alopecia, and nail changes. Isavuconazole shares similar toxicity with voriconazole but at a lower rate. Posaconazole has a more favorable toxicity profile, particularly regarding cardiac toxicity and vision changes [10, 33, 46]. . Echinocandins are generally well tolerated, with less frequent serious toxicity than other systemic antifungal agents [46]. Additionally, route of administration is crucial; with the minimum 12-week therapy duration, both amphotericin B and echinocandins are exclusively administered intravenously, potentially leading to prolonged hospital stays and increased costs.

Finally, while our NMA revealed triazoles’ favorable efficacy for antifungal therapy, the mortality rate of invasive aspergillosis persists at up to 20% [10, 33]. Despite the severity of invasive fungal infections, research funding in this field has been perennially lacking, leading to inadequate diagnostic and therapeutic options. However, hope is on the horizon with the emergence of new antifungal agents, such as rezafungin, ibrexafungerp, olorofim, and fosmanogepix, which are advancing to advanced trial stages or gaining approval from regulatory bodies, following a prolonged period of near emptiness in the drug pipeline [47, 48].

Limitations

Our study has some limitations. The first limitation is the lack of enough head-to-head RCTs in IA. To overcome this limitation, we included non-randomized trials in our NMA. Due to constraints in available data, we employed a naive data synthesis method instead of the more robust statistical methodologies recommended by the guideline [49]. The insufficiencies in the study design and inconsistent conduct and reporting of the included studies have significantly influenced the outcomes of our analysis. Second, the different durations of treatment and follow-up times are also significant factors contributing to heterogeneity. Third, the definitions for the response have some different criteria among the included studies in our NAM, which could influence our statistical result. Fourth, more than 60% of the studies included less than 100 patients per group, which could lead to bias due to small study effects. Fifth, the characteristics of patients and treatments were heterogeneous among the various RCTs and observational studies. Due to insufficient data, we could not perform more detailed subgroup analyses, such as those for different underlying diseases. We also could not conduct a more detailed analysis considering the dosage form and dose of agents. As a result, the evidence gathered from this NMA should be approached with caution when making shared decisions. Nonetheless, our research offers valuable insights that could help shape future practice-changing prospective trials.

Conclusions

This network meta-analysis assessed the efficacy of various antifungal agents as primary treatment in patients with IA. Our findings suggest that voriconazole, posaconazole, and isavuconazole may be the best options for patients with IA, liposomal amphotericin B plus caspofungin may also be a reasonable option.

Fig. 1
figure 1

PRISMA Flowchart

Full size image
Fig. 2
figure 2

Network Geometry of All Outcomes. Network plot for response (panel A) and mortality (panel B) of antifungal agents for primary therapy of invasive aspergillosis. When study for direct comparisons exist, this is shown by connections between nodes. The size of the node represents the number of studies with a particular drug. The thickness of lines connecting nodes represents the number of trials for that comparison. AmB, amphotericin B deoxycholate; L-AmB, liposomal amphotericin B; ABCD, amphotericin B colloidal dispersion; ABLC, amphotericin B lipid complex; VOCZ, voriconazole; POCZ, posaconazole; CAFG, caspofungin; ISCZ, isavuconazole; ANFG, anidulafungin

Full size image
Fig. 3
figure 3

Funnel Plots of all outcomes. Funnel Plots of response (A) and mortality (B). In the comparison-adjusted funnel plot, the horizontal axis shows the difference of each i-study estimate YiXY from the summary effect for the respective comparison (YiXY-µXY) while the vertical axis presents the measure of dispersion of YiXY, namely the standard error of the effect size. The red line shows the null hypothesis. Each point represents a direct comparison; different colors correspond to different comparisons. The dashed black line represents the 95% confidence interval. The horizontal line represents the regression line; the regression line demonstrates that no asymmetry is present. AmB, amphotericin B deoxycholate; L-AmB, liposomal amphotericin B; ABCD, amphotericin B colloidal dispersion; ABLC, amphotericin B lipid complex; VOCZ, voriconazole; POCZ, posaconazole; CAFG, caspofungin; ISCZ, isavuconazole; ANFG, anidulafungin

Full size image

Data availability

The data of this study can be obtained from the corresponding author according to reasonable requirements.

References

  1. Segal BH, Aspergillosis. N Engl J Med. 2009;360(18):1870–84. 10.1056/NEJMra0808853 From NLM.

    Article  CAS  PubMed  Google Scholar 

  2. Camargo JF, Husain S. Immune correlates of protection in human invasive aspergillosis. Clin Infect Dis. 2014;59(4):569–77. https://doi.org/10.1093/cid/ciu337. From NLM.

    Article  CAS  PubMed  Google Scholar 

  3. Shi C, Shan Q, Xia J, Wang L, Wang L, Qiu L, Xie Y, Lin N, Wang L. Incidence, risk factors and mortality of invasive pulmonary aspergillosis in patients with influenza: a systematic review and meta-analysis. Mycoses. 2022;65(2):152–63. https://doi.org/10.1111/myc.13410. From NLM.

    Article  PubMed  Google Scholar 

  4. Feys S, Almyroudi MP, Braspenning R, Lagrou K, Spriet I, Dimopoulos G, Wauters JA. Visual and Comprehensive Review on COVID-19-Associated Pulmonary Aspergillosis (CAPA). J Fungi (Basel) 2021, 7 (12). DOI: 10.3390/jof7121067 From NLM.

  5. Bongomin F, Gago S, Oladele RO, Denning DW. Global and Multi-National Prevalence of Fungal Diseases-Estimate Precision. J Fungi (Basel) 2017, 3 (4). DOI: 10.3390/jof3040057 From NLM.

  6. Marr KA, Carter RA, Crippa F, Wald A, Corey L. Epidemiology and outcome of mould infections in hematopoietic stem cell transplant recipients. Clin Infect Dis. 2002;34(7):909–17. 10.1086/339202 From NLM.

    Article  PubMed  Google Scholar 

  7. Neofytos D, Horn D, Anaissie E, Steinbach W, Olyaei A, Fishman J, Pfaller M, Chang C, Webster K, Marr K. Epidemiology and outcome of invasive fungal infection in adult hematopoietic stem cell transplant recipients: analysis of Multicenter prospective antifungal therapy (PATH) Alliance registry. Clin Infect Dis. 2009;48(3):265–73. https://doi.org/10.1086/595846. From NLM.

    Article  CAS  PubMed  Google Scholar 

  8. Tissot F, Agrawal S, Pagano L, Petrikkos G, Groll AH, Skiada A, Lass-Flörl C, Calandra T, Viscoli C, Herbrecht R. ECIL-6 guidelines for the treatment of invasive candidiasis, aspergillosis and mucormycosis in leukemia and hematopoietic stem cell transplant patients. Haematologica. 2017;102(3):433–44. https://doi.org/10.3324/haematol.2016.152900. From NLM.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Husain S, Camargo JF. Invasive aspergillosis in solid-organ transplant recipients: guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transpl. 2019;33(9):e13544. https://doi.org/10.1111/ctr.13544. From NLM.

    Article  Google Scholar 

  10. Maertens JA, Rahav G, Lee DG, Ponce-de-León A, Ramírez Sánchez IC, Klimko N, Sonet A, Haider S, Diego Vélez J, Raad I, et al. Posaconazole versus Voriconazole for primary treatment of invasive aspergillosis: a phase 3, randomised, controlled, non-inferiority trial. Lancet (London England). 2021;397(10273):499–509. https://doi.org/10.1016/S0140-6736(21)00219-1. Journal article.

    Article  CAS  PubMed  Google Scholar 

  11. Hanadate T, Wakasugi M, Sogabe K, Kobayashi T, Horita H, Kawamura I, Hori Y, Matsui K, Hoshino Y, Sou M. Evaluation of the safety and efficacy of micafungin in Japanese patients with deep mycosis: a post-marketing survey report. J Infect Chemother. 2011;17(5):622–32. https://doi.org/10.1007/s10156-011-0219-0. From NLM.

    Article  CAS  PubMed  Google Scholar 

  12. Maertens J, Raad I, Petrikkos G, Boogaerts M, Selleslag D, Petersen FB, Sable CA, Kartsonis NA, Ngai A, Taylor A, et al. Efficacy and safety of caspofungin for treatment of invasive aspergillosis in patients refractory to or intolerant of conventional antifungal therapy. Clin Infect Dis. 2004;39(11):1563–71. https://doi.org/10.1086/423381. From NLM.

    Article  CAS  PubMed  Google Scholar 

  13. Marr KA, Schlamm HT, Herbrecht R, Rottinghaus ST, Bow EJ, Cornely OA, Heinz WJ, Jagannatha S, Koh LP, Kontoyiannis DP, et al. Combination antifungal therapy for invasive aspergillosis: a randomized trial. Ann Intern Med. 2015;162(2):81–9. https://doi.org/10.7326/M13-2508. Journal article.

    Article  PubMed  Google Scholar 

  14. Caillot D, Thiébaut A, Herbrecht R, de Botton S, Pigneux A, Bernard F, Larché J, Monchecourt F, Alfandari S, Mahi L. Liposomal amphotericin B in combination with caspofungin for invasive aspergillosis in patients with hematologic malignancies: a randomized pilot study (Combistrat trial). Cancer. 2007;110(12):2740–6. https://doi.org/10.1002/cncr.23109. From NLM.

    Article  CAS  PubMed  Google Scholar 

  15. Singh N, Limaye AP, Forrest G, Safdar N, Muñoz P, Pursell K, Houston S, Rosso F, Montoya JG, Patton P, et al. Combination of voriconazole and caspofungin as primary therapy for invasive aspergillosis in solid organ transplant recipients: a prospective, multicenter, observational study. Transplantation. 2006;81(3):320–6. https://doi.org/10.1097/01.tp.0000202421.94822.f7. From NLM.

    Article  CAS  PubMed  Google Scholar 

  16. Herbrecht R, Denning DW, Patterson TF, Bennett JE, Greene RE, Oestmann JW, Kern WV, Marr KA, Ribaud P, Lortholary O, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med. 2002;347(6):408–15. https://doi.org/10.1056/NEJMoa020191. Journal article.

    Article  CAS  PubMed  Google Scholar 

  17. van der Linden JW, Arendrup MC, Warris A, Lagrou K, Pelloux H, Hauser PM, Chryssanthou E, Mellado E, Kidd SE, Tortorano AM, et al. Prospective multicenter international surveillance of azole resistance in aspergillus fumigatus. Emerg Infect Dis. 2015;21(6):1041–4. https://doi.org/10.3201/eid2106.140717.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Steinmann J, Hamprecht A, Vehreschild MJ, Cornely OA, Buchheidt D, Spiess B, Koldehoff M, Buer J, Meis JF, Rath PM. Emergence of azole-resistant invasive aspergillosis in HSCT recipients in Germany. J Antimicrob Chemother. 2015;70(5):1522–6. https://doi.org/10.1093/jac/dku566.

    Article  CAS  PubMed  Google Scholar 

  19. Hutton B, Salanti G, Caldwell DM, Chaimani A, Schmid CH, Cameron C, Ioannidis JP, Straus S, Thorlund K, Jansen JP, et al. The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations. Ann Intern Med. 2015;162(11):777–84. https://doi.org/10.7326/m14-2385. From NLM.

    Article  PubMed  Google Scholar 

  20. Wells G, O’Connell SB, Peterson D, Welch J, Losos V, Tugwell M. P. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. 2013. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp.

  21. Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, Cates CJ, Cheng HY, Corbett MS, Eldridge SM, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366:l4898. https://doi.org/10.1136/bmj.l4898. From NLM.

    Article  PubMed  Google Scholar 

  22. White IR. Network Meta-analysis. Stata J. 2015;15(4):951–85. https://doi.org/10.1177/1536867X1501500403. (acccessed 2023/06/22).

    Article  Google Scholar 

  23. Salanti G, Ades AE, Ioannidis JP. Graphical methods and numerical summaries for presenting results from multiple-treatment meta-analysis: an overview and tutorial. J Clin Epidemiol. 2011;64(2):163–71. https://doi.org/10.1016/j.jclinepi.2010.03.016. From NLM.

    Article  PubMed  Google Scholar 

  24. Higgins JP, Jackson D, Barrett JK, Lu G, Ades AE, White IR. Consistency and inconsistency in network meta-analysis: concepts and models for multi-arm studies. Res Synth Methods. 2012;3(2):98–110. https://doi.org/10.1002/jrsm.1044. From NLM.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Shim S, Yoon BH, Shin IS, Bae JM. Network meta-analysis: application and practice using Stata. Epidemiol Health. 2017;39:e2017047. https://doi.org/10.4178/epih.e2017047. From NLM.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Turner RM, Davey J, Clarke MJ, Thompson SG, Higgins JP. Predicting the extent of heterogeneity in meta-analysis, using empirical data from the Cochrane database of systematic reviews. Int J Epidemiol. 2012;41(3):818–27. https://doi.org/10.1093/ije/dys041. From NLM.

    Article  PubMed  PubMed Central  Google Scholar 

  27. White MH, Anaissie EJ, Kusne S, Wingard JR, Hiemenz JW, Cantor A, Gurwith M, Du Mond C, Mamelok RD, Bowden RA. Amphotericin B colloidal dispersion vs. amphotericin B as therapy for invasive aspergillosis. Clin Infect Dis. 1997;24(4):635–42. From NLM.

    CAS  PubMed  Google Scholar 

  28. Leenders AC, Daenen S, Jansen RL, Hop WC, Lowenberg B, Wijermans PW, Cornelissen J, Herbrecht R, van der Lelie H, Hoogsteden HC, et al. Liposomal amphotericin B compared with amphotericin B deoxycholate in the treatment of documented and suspected neutropenia-associated invasive fungal infections. Br J Haematol. 1998;103(1):205–12. https://doi.org/10.1046/j.1365-2141.1998.00944.x. Journal article.

    Article  CAS  PubMed  Google Scholar 

  29. Bowden R, Chandrasekar P, White MH, Li X, Pietrelli L, Gurwith M, van Burik JA, Laverdiere M, Safrin S, Wingard JR. A double-blind, randomized, controlled trial of amphotericin B colloidal dispersion versus amphotericin B for treatment of invasive aspergillosis in immunocompromised patients. Clin Infect Dis. 2002;35(4):359–66. https://doi.org/10.1086/341401. From NLM.

    Article  CAS  PubMed  Google Scholar 

  30. Hachem RY, Boktour MR, Hanna HA, Husni RN, Torres HA, Afif C, Kontoyiannis DP, Raad II. Amphotericin B lipid complex versus liposomal amphotericin B monotherapy for invasive aspergillosis in patients with hematologic malignancy. Cancer. 2008;112(6):1282–7. https://doi.org/10.1002/cncr.23311. From NLM.

    Article  CAS  PubMed  Google Scholar 

  31. Pagano L, Caira M, Candoni A, Offidani M, Martino B, Specchia G, Pastore D, Stanzani M, Cattaneo C, Fanci R, et al. Invasive aspergillosis in patients with acute myeloid leukemia: a SEIFEM-2008 registry study. Haematologica. 2010;95(4):644–50. https://doi.org/10.3324/haematol.2009.012054. From NLM.

    Article  PubMed  Google Scholar 

  32. Herbrecht R, Patterson TF, Slavin MA, Marchetti O, Maertens J, Johnson EM, Schlamm HT, Donnelly JP, Pappas PG. Application of the 2008 definitions for invasive fungal diseases to the trial comparing voriconazole versus amphotericin B for therapy of invasive aspergillosis: a collaborative study of the Mycoses Study Group (MSG 05) and the European Organization for Research and Treatment of Cancer Infectious Diseases Group. Clin Infect Dis. 2015;60(5):713–20. https://doi.org/10.1093/cid/ciu911.

    Article  CAS  PubMed  Google Scholar 

  33. Maertens JA, Raad II, Marr KA, Patterson TF, Kontoyiannis DP, Cornely OA, Bow EJ, Rahav G, Neofytos D, Aoun M, et al. Isavuconazole versus Voriconazole for primary treatment of invasive mould disease caused by aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial. Lancet. 2016;387(10020):760–9. https://doi.org/10.1016/s0140-6736(15)01159-9. From NLM.

    Article  CAS  PubMed  Google Scholar 

  34. Cheng MP, Orejas JL, Arbona-Haddad E, Bold TD, Solomon IH, Chen K, Pandit A, Kusztos AE, Cummins KC, Liakos A, et al. Use of triazoles for the treatment of invasive aspergillosis: a three-year cohort analysis. Mycoses. 2020;63(1):58–64. https://doi.org/10.1111/myc.13013. From NLM.

    Article  PubMed  Google Scholar 

  35. Batista MV, Ussetti MP, Jiang Y, Neofytos D, Cortez AC, Feriani D, Schmidt-Filho J, França-Silva ILA, Raad I, Hachem R. Comparing the real-world use of Isavuconazole to other anti-fungal therapy for invasive fungal infections in patients with and without underlying disparities: a Multi-center Retrospective Study. J Fungi (Basel). 2023;9(2). https://doi.org/10.3390/jof9020166. From NLM.

  36. Jung DS, Tverdek FP, Kontoyiannis DP. Switching from posaconazole suspension to tablets increases serum drug levels in leukemia patients without clinically relevant hepatotoxicity. Antimicrob Agents Chemother. 2014;58(11):6993–5. https://doi.org/10.1128/aac.04035-14. From NLM.

    Article  PubMed  PubMed Central  Google Scholar 

  37. McCormack PL, Perry CM. Caspofungin: a review of its use in the treatment of fungal infections. Drugs. 2005;65(14):2049–68. https://doi.org/10.2165/00003495-200565140-00009. From NLM.

    Article  CAS  PubMed  Google Scholar 

  38. Zager RA, Bredl CR, Schimpf BA. Direct amphotericin B-mediated tubular toxicity: assessments of selected cytoprotective agents. Kidney Int. 1992;41(6):1588–94. https://doi.org/10.1038/ki.1992.229. From NLM.

    Article  CAS  PubMed  Google Scholar 

  39. Cavassin FB, Baú-Carneiro JL, Vilas-Boas RR, Queiroz-Telles F. Sixty years of amphotericin B: an overview of the Main Antifungal Agent used to treat invasive fungal infections. Infect Dis Ther. 2021;10(1):115–47. https://doi.org/10.1007/s40121-020-00382-7. From NLM.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Brüggemann RJ, Jensen GM, Lass-Flörl C. Liposomal amphotericin B-the past. J Antimicrob Chemother. 2022;77(Suppl2):ii3–10. https://doi.org/10.1093/jac/dkac351. From NLM.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Mistro S, Maciel Ide M, de Menezes RG, Maia ZP, Schooley RT, Badaró R. Does lipid emulsion reduce amphotericin B nephrotoxicity? A systematic review and meta-analysis. Clin Infect Dis. 2012;54(12):1774–7. https://doi.org/10.1093/cid/cis290. From NLM.

    Article  CAS  PubMed  Google Scholar 

  42. Botero Aguirre JP, Restrepo Hamid AM. Amphotericin B deoxycholate versus liposomal amphotericin B: effects on kidney function. Cochrane Database Syst Rev 2015, 2015 (11), Cd010481. https://doi.org/10.1002/14651858.CD010481.pub2 From NLM.

  43. Walsh TJ, Finberg RW, Arndt C, Hiemenz J, Schwartz C, Bodensteiner D, Pappas P, Seibel N, Greenberg RN, Dummer S, et al. Liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. National Institute of Allergy and Infectious diseases mycoses Study Group. N Engl J Med. 1999;340(10):764–71. https://doi.org/10.1056/nejm199903113401004.

    Article  CAS  PubMed  Google Scholar 

  44. Fisher MA, Talbot GH, Maislin G, McKeon BP, Tynan KP, Strom BL. Risk factors for amphotericin B-associated nephrotoxicity. Am J Med. 1989;87(5):547–52. https://doi.org/10.1016/s0002-9343(89)80612-6. From NLM.

    Article  CAS  PubMed  Google Scholar 

  45. Takazono T, Tashiro M, Ota Y, Obata Y, Wakamura T, Miyazaki T, Nishino T, Izumikawa K. Factor analysis of acute kidney injury in patients administered liposomal amphotericin B in a real-world clinical setting in Japan. Sci Rep. 2020;10(1):15033. https://doi.org/10.1038/s41598-020-72135-y. From NLM.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Johnson MD. Antifungals in clinical use and the Pipeline. Infect Dis Clin North Am. 2021;35(2):341–71. https://doi.org/10.1016/j.idc.2021.03.005. From NLM.

    Article  PubMed  Google Scholar 

  47. Hoenigl M, Sprute R, Egger M, Arastehfar A, Cornely OA, Krause R, Lass-Flörl C, Prattes J, Spec A, Thompson GR, et al. The Antifungal Pipeline: Fosmanogepix, Ibrexafungerp, Olorofim, Opelconazole, and Rezafungin. Drugs. 2021;81(15):1703–29. https://doi.org/10.1007/s40265-021-01611-0. 3rdFrom NLM.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Hoenigl M, Arastehfar A, Arendrup MC, Brüggemann R, Carvalho A, Chiller T, Chen S, Egger M, Feys S, Gangneux JP, et al. Novel antifungals and treatment approaches to tackle resistance and improve outcomes of invasive fungal disease. Clin Microbiol Rev. 2024;e0007423. https://doi.org/10.1128/cmr.00074-23. From NLM.

  49. Efthimiou O, Mavridis D, Debray TP, Samara M, Belger M, Siontis GC, Leucht S, Salanti G. Combining randomized and non-randomized evidence in network meta-analysis. Stat Med. 2017;36(8):1210–26. https://doi.org/10.1002/sim.7223. From NLM.

    Article  PubMed  Google Scholar 

Download references

Funding

No Funding.

Author information

Authors and Affiliations

  1. Department of Respiratory Medicine, Chengdu BOE hospital, Chengdu, Sichuan Province, 610000, China

    Ao Liu, Liubo Xiong, Lian Wang, Han Zhuang, Xiao Gan, Mengying Zou & Xiaoming Wang

Authors
  1. Ao Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Liubo Xiong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lian Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Han Zhuang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiao Gan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mengying Zou
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xiaoming Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Ao Liu and Xiaoming Wang designed the study and supervised the overall project; Liubo Xiong and Lian Wang participated in collecting data; Han Zhuang and Xiao Gan participated in data collecting and analysis; Ao Liu and Mengying Zou provided the statistical analysis and wrote the manuscript.

Corresponding author

Correspondence to Ao Liu.

Ethics declarations

Ethics approval and consent to participate

This is a systematic review and meta-analysis, ethics approval and consent to participate are not applicable.

Consent for publication

Not applicable. The manuscript does not include the participant’s identification image or other personal or clinical details.

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Material 1

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, A., Xiong, L., Wang, L. et al. Compare the efficacy of antifungal agents as primary therapy for invasive aspergillosis: a network meta-analysis. BMC Infect Dis 24, 581 (2024). https://doi.org/10.1186/s12879-024-09477-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12879-024-09477-9

Keywords

BMC Infectious Diseases

ISSN: 1471-2334

Contact us