A retrospective clinical comparison between antifungal treatment with liposomal amphotericin B (AmBisome) and conventional amphotericin B in transplant recipients

Invasive fungal infections are an important cause of morbidity and mortality in immunosuppressed bone marrow and solid organ transplant recipients. Treatment with amphotericin B, the drug of choice for these infections, is however often limited by toxicity. Ten transplant patients receiving a liposomal amphotericin B formulation (AmBisome) were compared to ten retrospective control patients given conventional amphotericin B. Each group included bone marrow (8), kidney (1), and liver transplant (1) recipients. Conventional amphotericin B treatment was instituted due to nine Candida infections, and one Aspergillus fumigatus infection. In the AmBisome group treatment was instituted due to eight Candida infections, one infection caused by Saccharomyces cerevisiae and in one case as prophylactic treatment. In the amphotericin B group, maximal daily doses ranged from 0.1 to 0.65 mg kg-1 and cumulative doses were 21-836 mg kg-1 and were given over 3-32 days. In the AmBisome group, maximal daily doses ranged from 0.9 to 2.3 mg kg-1 and cumulative doses ranged from 225 to 3525 mg kg-1 over 8-28 days. All patients in the amphotericin B group experienced severe toxicity, especially nephrotoxicity which in four cases caused withdrawal of the drug. In contrast, the only adverse reaction in the AmBisome group was cholestasis in one patient. Only three out of ten patients in the amphotericin B group responded to treatment, seven patients died and six patients still had evidence of invasive fungal infection at autopsy. In contrast, eight out of nine patients in the AmBisome group responded to treatment, and the patient that received prophylaxis had a successful course.     

Comparison of nephrotoxicity associated to different lipid formulations of amphotericin B: a real‐life study

Amphotericin B (AmB) use is limited by the occurrence of kidney toxicity. Here, we evaluated the incidence and impact of nephrotoxicity in a large series of patients receiving therapy with amphotericin B deoxycholate (d‐AmB), liposomal AmB (L‐AmB), or AmB lipid complex (ABLC), in a clinical practice scenario. In a retrospective cohort study, patients treated with different AmB formulations between 2003 and 2012 were evaluated. Medical records and laboratory data were reviewed. Nephrotoxicity was determined according to modified RIFLE criteria. Predictors of nephrotoxicity and mortality were determined and treatment groups were compared. About 431 patients were studied (d‐AmB, n = 236; L‐AmB, n = 105; ABLC, n = 90). Frequency of severe nephrotoxicity (RIFLE ‘Failure’) was 11.5%, 2.4% and 7.2% for d‐AmB, L‐AmB and ABLC, respectively (P = 0.046). Use of L‐AmB was found to be an independent protective factor (OR: 0.18; 95% CI: 0.03–0.64; P = 0.006) for severe nephrotoxicity, considering d‐AmB as a reference. L‐AmB was also a protective factor for mortality (OR: 0.56; 95% CI: 0.32–0.99; P = 0.046). In addition, in‐hospital overall mortality was associated with cancer, previous dialysis, evolution to dialysis, and stay in the intensive care unit. Patients treated with ABLC showed similar frequency of severe kidney toxicity than those treated with d‐AmB. L‐AmB was associated with better outcomes than other formulations, including severe nephrotoxicity and overall mortality.     

Role of plasma lipids and lipoproteins in predicting amphotericin B-induced nephrotoxicity in pediatric oncology patients

Purpose: The objective of this study was to determine if total plasma and lipoprotein cholesterol (C) and triglyceride (TG) concentrations could predict the degree of nephrotoxicity caused by the antifungal agent amphotericin B (AmpB); and to use the average amount of potassium supplementation received daily as a indicator of nephrotoxicity in pediatric oncology patients. Patients and methods: Plasma samples from 18 patients (ages<17 years) who were receiving AmpB due to suspected or confirmed fungal infection at British Columbia Children’s Hospital were analyzed for lipid concentrations. The high density lipoprotein (HDL) fractions were separated by precipitation; total (TOT) plasma and fraction C and TG concentrations were measured by enzymatic colorimetric assays; and low density lipoprotein (LDL) C levels were determined by Friedewald’s formula. Changes in serum creatinine levels from baseline and amounts of potassium supplementation were used as indicators of nephrotoxicity; both were obtained from patients’ medical charts. Pearson correlation coefficients (r) were determined and considered significant if P<0.05. Results: The total cumulative AmpB dose, adjusted for weight, does not seem to predict AmpB-induced nephrotoxicity. Positive but relatively weak correlations were found between total potassium supplementation and LDL C (r=0.489, P<0.02); and TOT C (r=0.551, P<0.01). In addition, a positive but relatively weak correlation between the average amount of potassium supplementation per day above baseline and HDL C (r=0.407; P<0.02) was observed. Conclusion: Differences in total plasma and LDL cholesterol concentrations may be used as predictors of AmpB-induced nephrotoxicity in pediatric oncology patients.     

Continuous infusion of amphotericin B deoxycholate: an innovative,low‐cost strategy in antifungal treatment

The combination of amphotericin B and sodium deoxycholate is the formulation most used in clinical practice. The development of new agents such as amphotericin with lipid formulations, caspofungin, voriconazole and other azolic derivatives, promoted alternatives to amphotericin B deoxycholate. However, because of the high cost of these new drugs, their use is difficult in a scenario of limited resources. A few strategies have been devised to make the use of amphotericin B deoxycholate less toxic. In this review, we seek to describe the accumulated knowledge about this molecule, with focus on its use in continuous infusion, which appears to be an alternative to reduce toxicity, while maintaining its clinical efficacy.     

Pancreatic toxicity after liposomal amphotericin B

Though liposomal amphotericin B has been available in Germany since 1992, efficacy and safety of this formulation of amphotericin B are still not well-documented in children. As far as gastrointestinal side-effects are concerned, an elevated alkaline phosphatase and elevated transaminases have been reported. In our department, liposomal amphotericin B had been used since 1994 to treat patients with proven or suspected fungal infections in a daily dose of 1-3 mg kg-1. Additionally, patients with high-dose chemotherapy and autologous stem cell support received liposomal amphotericin B prophylactically in a dose of 1 mg kg(-1) three times per week. We performed a retrospective analysis of all 31 patients who had received liposomal amphotericin B by 1999. In five patients, an isolated transient elevation of the serum lipase level during, or shortly after, the therapy with liposomal amphotericin B was detected. Three of these patients showed clinical signs of pancreatitis, with one patient displaying slightly elevated transaminases. So far, elevated levels of serum lipase have not been described as a possible side-effect of a liposomal amphotericin B therapy. The pathogenesis of this elevation is unclear. As possible reasons, an enzyme induction due to fat overload or a toxic damage of the pancreatic tissue by the liposomes or amphotericin B itself are discussed.     

伊曲康唑与两性霉素B治疗恶性实体瘤化疗后真菌感染的临床对照研究

目的:比较伊曲康唑与两性霉素B治疗恶性实体瘤化疗后真菌感染的疗效和毒副作用。方法:30例恶性实体瘤化疗后真菌感染患者,包括自体造血干细胞移植13例,常规强化治疗17例。按时间先后分为两组,1996年6月~2003年11月真菌感染15例患者均用两性霉素B治疗,2003年12月~2005年10月真菌感染15例患者均用伊曲康唑治疗。观察并评价两药疗效和毒副作用。结果:伊曲康唑和两性霉素B治疗恶性实体瘤中性粒细胞减少真菌感染疗效分别为86.8%和93.4%,两组比较无统计学意义(P=0.482);两性霉素B组出现发热、寒战33.3%、低血钾39.6%,伊曲康唑组均未出现以上不良反应,两组对比有统计学意义(P<0.05)。结论:两药治疗真菌感染疗效相似,但伊曲康唑的毒副作用轻。     

Selective potentiation of platinum drug cytotoxicity in cisplatin-sensitive and-resistant human ovarian carcinoma cell lines by amphotericin B

Resistance to the clinically used platinum-based drugs cisplatin and carboplatin represents a major limitation to their clinical effectiveness. Using cisplatin-sensitive and-resistant human ovarian carcinoma cell lines previously characterized in terms of their major underlying mechanisms of resistance, we attempted to potentiate the cytotoxic effects of cisplatin and carboplatin using the clinically used antifungal agent amphotericin B (AmB). Using nontoxic concentrations of AmB (up to 15 g/ml) and continuous exposure to cisplatin, a concentration-dependent selective potentiation (maximum of 3.2-fold) of cisplatin cytotoxicity was observed in two cisplatin-resistant cell lines (41 McisR6, acquired resistant, and HX/62, intrinsically resistant). In both these cisplatin-resistant cell lines, previous studies have shown resistance to be due primarily to reduced platinum uptake. Notably, no significant potentiation was observed in the parent 41M cell line, in the intrinsically resistant SKOV-3 cell line (where reduced drug accumulation plays only a partial role in determining resistance) or in a pair of cell lines (CH1 and its acquired-resistant variant CH1cisR6) where reduced drug uptake does not play any role in determining resistance. The potentiating effect of AmB was lower with carboplatin and not significant in all cell lines. Platinum uptake following a 2-h exposure of cells to cisplatin was enhanced 3.5-fold in 41McisR6 cells (producing platinum levels similar to those obtained in the parental line) and 1.7-fold in 41M cells by the concomitant exposure to AmB. These data indicate that the potentiation of cisplatin (and carboplatin) cytotoxicity by AmB is not due to a generalized membrane disruption, as effects were observed only in resistant lines where reduced drug transport was apparent. Moreover, AmB did not increase the cytotoxicity of JM216 [bis-acetatoammine(cyclohexylamine)dichloroplatinum (II)], a recently developed, more lipophilic orally active platinum drug, in the 41M/41McisR6 lines. JM216 has previously been shown to circumvent acquired cisplatin resistance due to decreased drug uptake. In vivo, however, using the HX/62 xenograft, AmB (at its maximum tolerated dose of 20 mg/kg; q7d×4 schedule) did not enhance the antitumour effect of carboplatin (at its maximum tolerated dose of 80 mg/kg; q7d×4 schedule).This study was supported by grants to the Institute of Cancer Research from the Cancer Research Campaign and the Medical Research Council, the Johnson Matthey Technology Centre and Bristol Myers Squibb Oncology     

Liposomal amphotericin B treatment in a 9-month-old liver recipient

A 9-month-old boy with a suggested candidemia was treated with liposomal amphotericin B (AmBisome, Vestar) after a liver transplant due to an inherited glycogenosis (Pompe's disease). This is believed to be the youngest patient in which this new therapeutic agent has been utilized.     

Amphotericin B lipid complex versus liposomal amphotericin B monotherapy for invasive aspergillosis in patients with hematologic malignancy

BACKGROUND: Invasive aspergillosis (IA) is a major cause of morbidity and mortality in patients with hematologic malignancy (HM). There are 2 lipid formulations of amphotericin B (AMB) currently in widespread use: AMB lipid complex (ABLC) and liposomal AMB (L-AMB). There are limited data comparing the efficacy and safety of these 2 agents in the treatment of IA in patients with cancer. METHODS: The authors retrospectively studied 381 consecutive patients with HM who had proven or probable IA (according to European Organization for Research and Treatment of Cancer/Mycosis Study Group of the National Institute of Allergy and Infectious Diseases criteria) between June 1993 and December 2005. Of these patients, 158 received primary antifungal therapy with either L-AMB (n=106) or ABLC (n=52). The number of salvage antifungal regimens given were 51 L-AMB regimens and 30 ABLC regimens. It should be noted that the population described in this report was not typical of the hematologic cancer population with IA because of the advanced stage and the severity of the underlying diseases. RESULTS: Risk factors for IA, such as underlying malignancy, neutropenia, steroid use, admission to an intensive care unit, and the presence of graft-versus-host disease, were comparable among the study drug group in the primary or salvage setting. Likewise, comparable distribution of types of Aspergillus species and the presence of disseminated IA were observed. Response to primary or salvage therapy was equally poor in both drug study groups regardless of treatment modality (range, 7.7-15.8% response). In the primary therapy group, ABLC was associated with significantly higher nephrotoxicity than L-AMB (P<.001). CONCLUSIONS: Among patients with HM, primary therapy and salvage therapy for IA with either ABLC or L-AMB as single agent were associated equally with poor outcome. L-AMB appeared to be less nephrotoxic in the primary therapy setting.     

Optimization of bioassay method for the quantitative microbiological determination of amphotericin B

The aim of this study was to find the optimal bioassay parameters for the quantitative analysis of an amphotericin B nasal spray solution as the bioassay conditions recommended by the Ph. Eur. 6. were less sensitive and were only applicable for the measurement of a narrow concentration range, which makes the method unsuitable in case of a stability test. We evaluated five commonly used assay media with Candida albicans and Saccharomyces cerevisiae as test organisms. Our results showed that Mueller Hinton Agar supplemented with 2% glucose and 0.5 μg ml⁻¹ methylene blue inoculated with C. albicans gave the best bioassay circumstance as a wide concentration range (1.54–60.0 μg ml⁻¹ amphotericin B) could be measured and the inhibition zone borders were distinct and easy to read.     

Interactions between amphotericin B and nitroimidazoles against Candida albicans

Summary. This work proved that nitroimidazole antiprotozoal agents, such as metronidazole, ornidazole, secnidazole and tinidazole, in concentrations of up to 64 μg ml^-1 did not present any antifungal activity against 17 strains of Candida albicans. The combination of each drug with amphotericin B showed the occurrence of variable interactions according to the studied strain. Promising results were observed based on synergistic and additive interactions of the polyene with the metronidazole; the inhibitory and lethal activities of the drugs were potentiated against all strains in concentrations reachable in vivo.
Zusammenfassung. In der vorliegenden Studie konnte gezeigt werden, daß die Nitroimidazol-Antiparasitika Metronidazol, Ornidazol, Secnidazol und Tinidazol in Konzentrationen bis zu 64 μg ml^-1 allein keine antimyzetische Aktivität gegen 17 C. albicans -Stämme aufwiesen. Die Anwendung dieser Agenzien gemeinsam mit Amphotericin B zeigte unterschiedliche Wirkungen auf die untersuchten Stämme. Erfolgversprechende Ergebnisse wurden als synergistische und additive Effekte bei der Kombination der einzelnen Nitroimidazole mit Amphotericin B beobachtet. Konzentrationen, die in vivo anwendbar sind, potenzierten die inhibitorischen und letalen Aktivitäten der Agenzien gegen alle untersuchten C. albicans -Stämme.     

In vitro antifungal activity of Indian liposomal amphotericin B against clinical isolates of emerging species of yeast and moulds,and its comparison with amphotericin B deoxycholate,voriconazole, itraconazole and fluconazole

Fungisome^TM is a liposomal preparation of amphotericin B (AMB), already marketed in India. However, its antifungal activity has not been evaluated against a wide range of fungal pathogens. The study was planned to elucidate the in vitro antifungal activity of Fungisome^TM against wide range of fungi and compare it with AMB deoxycholate (AMB‐d), voriconazole (VOR), itraconazole (ITR) and fluconazole (FLU). Minimum inhibitory concentrations (MICs) of the drugs were determined for 262 clinical fungal isolates, including yeast, dimorphic and filamentous fungi, by broth microdilution method approved by Clinical and Laboratory Standards Institute, USA (yeast, M27‐A3; filamentous fungi, M38‐A2). The MIC_90s of Fungisome^TM were 0.125, 0.5 and 0.25 mg l^?1 against yeast, filamentous and dimorphic fungi respectively. In comparison, MIC_90s of AMB‐d, FLU, ITR and VOR were 1, 1 and 1 mg l^?1 (AMB‐d), 4, 64 and 64 mg l^?1 (FLU), 1, 16 and 16 mg l^?1 (ITR) and 0.5, 4 and 16 mg l^?1 (VOR) against yeast, filamentous and dimorphic fungi respectively. The MIC of Fungisome^TM was two to 16‐fold lower than AMB‐d. These results reveal an efficient in vitro activity of Fungisome^TM.     

Cyanotic Raynaud's phenomenon with conventional but not with liposomal amphotericin B: three case reports

Summary. Despite its common adverse effects intravenous (i.v.) amphotericin B is an indispensable antifungal drug in childhood oncology. We report here on three cases of painful cyanotic Raynaud's phenomenon after i.v. administration or inhalation of amphotericin B. A liposomal i.v. preparation of amphotericin B was well tolerated by the infants. Spasms of peripheral vessels mediated by thromboxane A2 could be responsible for the Raynaud's phenomenon. Hence, inhibitors of prostaglandin synthesis are suggested for therapy.
Zusammenfassung. Trotz seiner bekannten Nebenwirkungen bei intravenöser Applikation ist Amphotericin B ein unverzichtbares Therapieelement in der Behandlung schwerer Mykosen in der Kinderonkologie. Wir berichten über drei Fälle von schmerzhaftem, zynotischem Raynaud-Phänomen in zeitlichem Zusammenhang mit intravenöser und inhalativer Verabreichung von konventionellem Amphotericin B. Die intravenöse Gabe von liposomalem Amphotericin B wurde ohne Nebenwirkungen toleriert. Thromboxan A2-vermittelte Gefäßspasmen dürften verantwortlich sein für das Raynaud-Phänomen. Eine logische Therapieoption wäre demzufolge die Verabreichung von Inhibitoren der Prosta-glandinsynthese.     

Evaluation of the inhibitory effect of amphotericin B on the apical growth of F. solani using the BioCell-Tracer system

The BioCell-Tracer (BCT) system is an automatic microscopic method used for measuring the growth rate of a single fungal hyphae, which has not yet been applied to study Fusarium spp. Considering the large resistance of Fusarium species to the available chemotherapy and that hyphae is the morphological fungal form most often seen in vivo, in this work, Amphotericin B MIC and MFC values for a Fusarium solani strain were obtained by the conventional assay method testing conidia and also by the BCT monitoring system. Both MIC and MFC values of AMB against F. solani determined by broth dilution method resulted in 4.0 microg ml(-1). By the BCT system, their values were 1.0 microg ml(-1), with an inhibition rate of 99.5% (Exp-GR) and 100.0% (Post-GR), showing that when testing hyphae directly, MIC and MFC were determined at two lower dilutions than the MIC and MFC values obtained with conidia. Using the BCT system, 4.0, 2.0 and 1.0 microg ml(-1) of AMB concentrations inhibited hyphae growth in 50 min whereas 0.5 microg ml(-1) of AMB needed 100 min to start hyphae growth inhibition. These findings lead us to conclude that antifungal susceptibility varies between conidia and hyphae. For this strain of Fusarium solani, hyphae were more susceptible to AMB than conidia.     

Comparison of high-performance liquid chromatography and bioassay of amphotericin B in serum

Summary. For the determination of amphotericin B in serum a high-performance liquid chromatography (HPLC) method using simple protein precipitation and an isocratic mobile phase as well as a plate diffusion bioassay are described. Using 5-fluorocytosine-resistant strain of Candida albicans and peptone in medium as an antagonist of 5-fluorocytosine allows simple measurement of amphotericin B both in the absence and in the presence of 5-fluorocytosine. The correlation coefficient ( r ) between bioassay and HPLC runs is 0.88. Generally, the biological determination gives slightly higher values of amphotericin B than the HPLC method. Both methods are useful for amphotericin B drug monitoring.
Zusammenfassung. Es werden für die Bestimmung von Amphotericin B im Serum eine HPLC-Methode, die eine einfache Proteinfällung und eine isokratische mobile Phase verwendet, und ein Bioassay mittels eines Plattendiffusionstests beschrieben. Die Verwendung eines 5-Fluorcytosin-resistenten Stammes von Candida albicans und Pepton im Medium erlauben die Bestimmung von Amphotericin B sowohl in Abwesenheit als auch in Anwesenheit von 5-Fluorcytosin in einfacher Weise. Die Korrelation zwischen Bioassay und der HPLC-Methode beträgt r = 0.88. Im allgemeinen ergibt die biologische Methode etwas höhere Werte im Vergleich zur HPLC-Bestimmung. Beide Methoden sind für die Bestimmung von Amphotericin-B-Serumspiegeln brauchbar.     

Brief report: practicability and safety of amphotericin B deoxycholate as continuous infusion in neutropenic patients with hematological malignancies

Fungal infections are a major cause of morbidity and mortality in patients with hematological malignancies. Candida and Aspergillus species are the most important opportunistic fungal pathogens in this patient population. Amphotericin B is the treatment of choice, but its administration is often hampered by severe side-effects, which may be reduced by continuous infusion of this drug. We describe 17 consecutive patients with hematological malignancies, suffering from fever of unknown origin with possible fungal infections, treated with amphotericin B as continuous infusion compared with a control group of 10 patients treated with conventional rapid infusion of amphotericin B over 2 - 6 h. No acute side-effects or severe nephrotoxicity were observed during continuous infusion of amphotericin B. Target doses were reached faster in patients with continuous infusion of amphotericin B than in patients with rapid infusion. We conclude that continuous infusion of amphotericin B is safe in neutropenic patients with hematological malignancies.     

Fatal trichosporonosis is not related to tolerance to amphotericin B

A case of disseminated trichosporonosis in a 45-year-old female suffering from acute lymphocytic leukaemia is reported. The patient died of that mycosis despite of therapy with amphotericin B for which the pathogen had been proven susceptible in vitro.     

Potentiation of cisplatin and carboplatin cytotoxicity by amphotericin B in different human ovarian carcinoma and malignant peritoneal mesothelioma cells

An in vitro study of the combined cytotoxicity of either cisplatin (CDDP) or carboplatin and amphotericin B (AmB) was undertaken on a set of different ovarian carcinoma (IGROVI, IGROVI-C10, OAW42) and peritoneal malignant mesothelioma (CFB-CARP1) cell lines and ascitic cells freshly obtained from ovarian cancer patients so as to investigate the possibility of overcoming their resistance to platinum compounds. Growth-inhibition curves obtained 6 days after a 2-h period of exposure to the drugs showed that AmB at 5–10 mg/l allowed a 5- to 10-fold decrease in the 50% growth-inhibitory concentrations (IC₅₀) of CDDP and carboplatin on either sensitive or resistant cells. Intracellular platinum assays with IGROVI cells showed that AmB acted by increasing dramatically the platinum uptake at a proportion that accounted for the increase in cytotoxicity. In the subline IGROVI-C10, a 10-fold resistant subline of IGROVI, AmB at 10 mg/l allowed recovery to the level of sensitivity seen in the parental cell line in the absence of AmB but not to the level observed in the presence of AmB. Acquisition of resistance mechanisms that are independent of the regulation of platinum uptake might be involved in this cell line. Thus, AmB might act by increasing the intracellular concentration of platinum without modifying the resistance mechanism involved downstream. However, in our models an increase in the intracellular level of platinum was always sufficient for the recovery of chemosensivity in vitro. We also show that the phosphodiesterase inhibiting methylxanthines act synergistically with AmB. The latter drugs are weakly toxic and could also attenuate the nephrotoxicity of AmB. Received: 11 August 1996 / Accepted: 7 March 1997