Liposomal amphotericin for secondary prophylaxis: A systematic review and meta-analysis

Abstract

Introduction

This systematic review and meta-analysis aimed to determine the safety of liposomal amphotericin B (L-AMB) compared to other antifungal agents for secondary prophylaxis.

Method

We conducted a comprehensive search across international databases and reference lists of articles to compile all relevant published evidence evaluating the efficacy and safety of L-AMB versus other antifungals (NLAMB) for secondary prophylaxis against invasive fungal infections. Pooled estimates were calculated after data transformation to evaluate mortality, breakthrough infections, and the frequency of adverse effects, including hypokalemia and nephrotoxicity. Comparisons of breakthrough fungal infection and mortality between the L-AMB and NLAMB groups were performed.

Result

We identified 10 studies. The cumulative frequency of patients using L-AMB was 148, compared to 341 patients in the NLAMB group. The mortality rates in the L-AMB and NLAMB groups were 10% and 0%, respectively. However, based on the odds ratio, the mortality in the L-AMB group was lower than that in the NLAMB group. No significant difference was observed in breakthrough invasive fungal infections between the L-AMB and NLAMB groups. The frequencies of nephropathy and hypokalemia in the L-AMB group were 36% and 18%, respectively.

Conclusion

Our findings indicate a lower incidence of mortality in the L-AMB group compared to the NLAMB group. No statistically significant difference was observed in the incidence of breakthrough infection between the two groups. L-AMB administration is associated with nephropathy and hypokalemia. However, the refusal to continue treatment due to adverse effects is not significantly high.

Keywords

Liposomal amphotericin B secondary prophylaxis invasive fungal infection IFIs

Introduction

Invasive fungal infections (IFIs) pose a significant threat to individuals, with high morbidity and mortality rates.¹ Immunocompromised hosts, such as myeloproliferative and leukemia patients, along with transplant recipients, constitute high-risk populations for IFIs.^2,3 The predominant fungal pathogens include Aspergillus spp., Candida spp., Cryptococcus neoformans, Mucorales (e.g. Rhizopus spp.), hyalohyphomycetes (e.g. Fusarium and Scedosporium spp.), or phaeohyphomycetes (e.g. Alternaria spp. and Cladophialophora bantiana).⁴ Additionally, susceptible hosts often experience recurrent episodes of fungal infections, necessitating long-term suppressive treatment with antifungal agents to ensure complete resolution.^1,5

While broad-spectrum oral triazoles are commonly employed as secondary prophylaxis for most patients with a history of IFIs, some individuals cannot tolerate them due to factors such as intolerance, hepatic dysfunction, significant drug interactions, non-adherence, or cost,^6,7 along with occasional drug shortages. Consequently, secondary broad-spectrum parenteral salvage prophylaxis, such as liposomal amphotericin B (L-AMB), may be considered in complex situations. Moreover, the emergence of triazole-resistant Aspergillus fumigatus, particularly in recent years,^8–10 has led to the reconsideration of L-AMB as a potential candidate for the treatment and prophylaxis of IFIs. L-AMB, a lipid formulation approved for IFI treatment in many countries worldwide, is of particular interest.¹¹

Despite the long half-life of L-AMB suggesting the effectiveness of intermittent dosing in antifungal treatment,¹² its advantages and the exact intermittent dosing strategy in the secondary prophylactic setting remain unclear.^13,14

To address these gaps in knowledge, we conducted a systematic review and meta-analysis to evaluate the efficacy and safety of L-AMB compared with NLAMB as secondary antifungal prophylaxis against IFIs.

Materials and methods

Eligibility criteria

The included studies were articles available for review, excluding reviews and case reports, with the intention of investigating the efficacy and safety of L-AMB and NLAMB for secondary prophylaxis in patients at any stage of immunosuppression that could lead to IFIs, with no time limit (up to July 2022).

Literature selection

A literature review was conducted on Google Scholar, Scopus, and PubMed (Medline) from their inception until July 2022.

Search strategy

The search strategy employed the keywords “amphotericin B” AND “prophylaxis.” The search was limited to studies performed in humans, and the reference lists of all included studies were reviewed to identify relevant evidence.

Quality assessment

The risk of bias for each study was independently assessed by a reviewer using the revised Cochrane Risk of Bias Tool (RoB 2.0). Disagreements were resolved through consensus with another reviewer.

Pooled Estimates: Pooled estimates of the prevalence of break-in non-Ampho were obtained through meta-analysis under the random-effects model (DerSimonian & Laird, 1986).

Heterogeneity Assessment: The heterogeneity of prevalence estimates between studies was determined by the Q statistic (Cochran, 1954) and further quantified by the I2 Index (Higgins & Thompson, 2002; Higgins et al., 2003).

Statistical analysis

A random-effects model was employed for the meta-analysis to account for the heterogeneous target populations in the recruited studies. Graphical representation of the meta-analysis was conducted using forest plots. Given numerous zero rates of L-AMB, a Freeman-Tukey double arcsine transformation (Freeman, M. F., and Tukey, J. W. 1950) was used to include studies with zero cases of L-AMB. Pooled estimates for stabilizing variance were calculated after transformation. Publication bias was tested using Egger's Regression Test, which is considered a more accurate measure of asymmetry for plots with fewer than 25 studies. Heterogeneity was evaluated by the I2 statistic. Meta-analysis was performed using the “Metaprop” command in STATA 17 software.

Results

Included studies and main characteristics

Figure 1 illustrates the flowchart of the procedure for selecting relevant studies. After systematic searches of three databases and excluding duplicates, 4458 studies were identified. Following the screening process, 10 studies were considered for meta-analysis, focusing on data from patients receiving L-AMB for secondary prophylaxis of IFI, including epidemiology, management, outcomes, and adverse effects (Table 1).

Table 1.

Data from the patients included in metaanalysis.

Number	Author	Year	Type	Dose	Duration	Follow-up	Disease	Number. L-AMB	Number.non L-AMB	Age	Male	Nephropathy	Hypokalemia	Break.A¹	Break.nA²	Mortality.A¹	Mortality .nA²	Readmission AEs	Discontinue treatment
1 ¹⁵	Pepeler, MS	2018	Retrospective	1 mg/kg/d	_	145 D	Allo-HSCT	35	23	29.5	41	_	_	10	8	_	_	_	_
2 ¹⁶	Azık, F	2015	Retrospective	3 mg/kg/d	298.8	66.8 ± 38.2	HS-CT	5	5	12.3	40%	3	1	0	0	0	0	_	3
3 ¹⁷	Allinson, K	2008	Prospctive cohort	1 mg/kg/d	30	152D	HS-CT	11	0	14	4	11	_	3		2		_	1
4 ¹⁸	Ginocchio, F	2012	Retrospective	10 mg/kg/w	119	D 60	Immunocompromised children	7	0	8.5y	5	0	3	1		0		0	1
5 ¹⁹	Liu, M	2014	Retrospective	0.5–1 mg/kg/d	_	180D	HSCT	10	154	38	84	_	_	1	20	_	_	_	_
6 ¹⁴	Cahuayme-Zuniga, L	2012	Retrospective	5 to 10 mg/kg/W		_	Allo HS-CT	14	0	55y	9	5	2	5		1		_	3
7 ²⁰	Krüger, WH	2004	Retrospective	2.4 mg/kg/d	19	_	HS-CT	43	0	37y	25	2	0	_		12		0	0
8 ²¹	Nosari, A	2007	Retrospective	3 mg/kg/day	_	405D	Acute leukemia	7	0	49.5y	7	2	_	0		0		_	2
9 ²²	Sevilla, J	2000	Cohort	1.5 mg/kg/day	_	_	Hematological malignancy	6	3	39y	_	_	_	0	0	0	0	_	_
10 ²³	Corneyl., OA	2008	Retrospective	1–3.8 mg/kg/d	_	_	AML	10	156	53y	97	_	_	1	26	0	2	_	_

1 = Amphotericin; 2 = None-Amphotericin.

Meta-analysis of breakthrough infection: A meta-analysis of breakthrough infection during L-AMB administration included data from 148 patients from 10 studies. A fixed-effects model was employed due to insignificant heterogeneity (I2 = 6.09%, df = 8, p = 0.38) among the nine studies (Figure 2). Similarly, a meta-analysis of breakthrough infection during NLAMB involved data from 341 individuals from 10 studies, utilizing a fixed-effect model due to low heterogeneity (I2 = 43.2%, df = 4, p = 0.13) among five studies (Figure 3).

Dosing

Seven reports examined patients receiving L-AMB daily,^{15–17,19–22} while two studies had patients receiving L-AMB weekly,^14,18 and one study involved L-AMB administered three times a week.¹²

Breakthrough

Breakthrough Infections: Breakthrough IFIs were observed in five studies,^{12,14,15,17,19} with the common pathogen being Aspergillus. The pooled estimate of breakthrough prevalence was 15% (95% CI: 0.07–0.24) in the L-AMB group (Figure 2) and 13% in the NLAMB group (95% CI: 0.07–0.21) (Figure 3). Despite a lack of homogeneity between studies (p < 0.001), there was no significant difference in the incidence of breakthrough IFIs between the L-AMB and NLAMB groups (OR, 0.7 [95% CI: 0.29–1.72], p = 0.96, I2 = 0.0%) (Figure 4).

Mortality due to IFI

IFIs-related mortality was foun5d in five studies,^{14,15,17,19,20} with the pooled estimate in the L-AMB group at 10% (95% CI: 0.04–0.18) (Figure 5) and 0% in the NLAMB group (95% CI: 0.00–0.00) (Figure 6). Mortality in the L-AMB group was lower than that in the NLAMB group (OR, 2.94 [95% CI: 0.13–65.33], p = 0.00, I2 = 100%) (Figure 7).

Safety outcomes

Nephrotoxicity was observed in five studies,^{12,14,16,20,21} with a pooled estimate of 36% (95% CI: 0.03–0.77) (Figure 8). Hypokalemia was noted in three studies,^14,16,18 with a pooled estimate of 12% (95% CI: 0.00–0.42) (Figure 9). Treatment discontinuation due to adverse effects occurred in six studies, with a pooled estimate of 15% (95% CI: 0.01–0.39) (Figure 10).

Discussion

This systematic review and meta-analysis offer a comprehensive overview of the efficacy and safety of L-AMB as secondary prophylaxis in IFIs. IFIs pose a significant threat to immunocompromised patients, necessitating antifungal prophylaxis to mitigate associated morbidity and mortality. Notably, our findings indicate lower mortality in the L-AMB group compared to the non-L-AMB group, though no significant difference was observed in breakthrough IFIs incidence.

The investigation of intermittent or extended interval dosing of L-AMB for prophylaxis has revealed promising regimens, such as daily, weekly, or a single-dose approach, particularly in high-risk populations. These populations include hematopoietic stem cell or solid organ transplant recipients, malignancies undergoing intensive chemotherapy, and immunosuppressed patients.²⁴

Nephrotoxicity, a known concern with amphotericin, was observed at a lower rate with L-AMB in our study. Previous meta-analyses have supported this, emphasizing the reduced risk of nephrotoxicity associated with L-AMB compared to amphotericin B deoxycholate or lipid emulsions. Despite the risk of hypokalemia, L-AMB demonstrated a lower incidence compared to historical reports.²⁵

Breakthrough IFIs, a significant issue in patients on systemic antifungals, did not show a statistically significant difference between the L-AMB and non-L-AMB groups. Mortality, while lower in the non-L-AMB group based on the pooled test, demonstrated lower odds ratios in the L-AMB group. This discrepancy may be attributed to variations in study reporting, with some studies not providing mortality data for the non-L-AMB group.^14,17,18,20

The mechanism by which amphotericin induces nephrotoxicity involves tubular injury and renal vasoconstriction, potentially mediated through increased membrane permeability.^26,27 Interestingly, L-AMB consistently exhibits a lower rate of nephrotoxicity in animal models.²⁸

Comparisons with other antifungal agents, such as echinocandins or triazoles, revealed mixed results in terms of treatment success and mortality.²⁹ However, amphotericin B demonstrated a higher frequency of treatment discontinuation due to adverse effects, emphasizing the importance of careful consideration of side effect profiles.³⁰

Limitations of this study include the small number of trials and patients, potentially impacting the precision of treatment efficacy estimates. Additionally, the restriction of searches to English databases may lead to the omission of relevant articles.

Conclusion

In conclusion, while the administration of L-AMB for secondary prevention is associated with reduced mortality, it is important to note an increased incidence of renal side effects, including hypokalemia and renal failure.

Footnotes

Acknowledgments

The authors would like to thank the Clinical Research Development Unit (CRDU) of Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran for their help and support in conducting this clinical trial.

Author contributions

FH and IAD had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis; concept and design: IAD; acquisition, analysis, or interpretation of data: FH; drafting of the manuscript: FJG, FH; critical revision of the manuscript for important intellectual content: IAD, LL, SS, FJG; statistical analysis: MF; supervision: IAD.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Ilad Alavi Darazam

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