Assessing the antifungal activity, pharmacokinetics, and tissue distribution of amphotericin B following the administration of Abelcet® and AmBisome® in combination with caspofungin to rats infected with Aspergillus fumigatus

Sivak, Olena; Rosland, Michael; Risovic, Verica; Bartlett, Karen H.

doi:10.1002/jps.20801

Cited by 17 publications

(17 citation statements)

References 38 publications

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“…Similar to the findings of these studies, interpatient variability was high, likely due to the unique distribution and elimination of the liposomal carriers, which also make plasma data of the parent difficult to interpret (6). Finally, in line with preclinical data (47), the data presented in this study clearly demonstrate that the pharmacokinetics of amphotericin B following administration of liposomal amphotericin B was not altered by the concomitant administration of caspofungin, and vice versa, and that the pharmacokinetics of caspofungin was not influenced by liposomal amphotericin B. Notable limitations of our study include the slow subject recruitment, the missed recruitment target, and the fact that half of the patients were enrolled in one center.…”

Section: Discussionsupporting

confidence: 74%

Randomized Comparison of Safety and Pharmacokinetics of Caspofungin, Liposomal Amphotericin B, and the Combination of Both in Allogeneic Hematopoietic Stem Cell Recipients

Groll

Silling

Young³

et al. 2010

Antimicrob Agents Chemother

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The combination of liposomal amphotericin B (LAMB) and caspofungin (CAS) holds promise to improve the outcome of opportunistic invasive mycoses with poor prognosis. Little is known, however, about the safety and pharmacokinetics of the combination in patients at high risk for these infections. The safety and pharmacokinetics of the combination of LAMB and CAS were investigated in a risk-stratified, randomized, multicenter phase II clinical trial in 55 adult allogeneic hematopoietic stem cell recipients (aHSCT) with granulocytopenia and refractory fever. The patients received either CAS (50 mg/day; day 1, 70 mg), LAMB (3 mg/kg of body weight/day), or the combination of both (CASLAMB) until defervescence and granulocyte recovery. Safety, development of invasive fungal infections, and survival were assessed through day 14 after the end of therapy. Pharmacokinetic sampling and analysis were performed on days 1 and 4. All three regimens were well tolerated. Premature study drug discontinuations due to grade III/IV adverse events occurred in 1/18, 2/20, and 0/17 patients randomized to CAS, LAMB, and CASLAMB, respectively. Adverse events not leading to study drug discontinuation were frequent but similar across cohorts, except for a higher frequency of hypokalemia with CASLAMB (P < 0.05). Drug exposures were similar for patients receiving combination therapy and those randomized to monotherapy. There was no apparent difference in the occurrence of proven/probable invasive fungal infections and survival through day 14 after the end of therapy. CASLAMB combination therapy in immunocompromised aHSCT patients was as safe as monotherapy with CAS or LAMB and had similar plasma pharmacokinetics, lending support to further investigations of the combination in the management of patients with invasive opportunistic mycoses.Invasive opportunistic fungal infections are an important cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation. Depending on the presence of well-characterized risk factors, rates of infection by opportunistic fungal pathogens are between 10 and 25%. The case fatality rates vary between 35 and 50% for invasive candidiasis and 65 and 90% for invasive aspergillosis and infections by other filamentous fungi (8, 15).The existence of antifungal agents with different molecular targets is providing new opportunities to improve the efficacy of antifungal chemotherapy through combination therapy. Potential target populations include profoundly immunocompromised patients with prolonged granulocytopenia or following allogeneic hematopoietic stem cell transplantation, patients with fulminant or refractory infections, or those with infections in compartments that are difficult to treat and infections by fungal pathogens with decreased microbiological susceptibility (23,31,39,48,49,50).Based on its favorable microbiologic and pharmacokinetic properties (16), well-documented efficacy against Candida and Aspergillus infections, and excellent safety (24,28,32,45), the echinocandin lipop...

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Section: Discussionsupporting

confidence: 74%

Randomized Comparison of Safety and Pharmacokinetics of Caspofungin, Liposomal Amphotericin B, and the Combination of Both in Allogeneic Hematopoietic Stem Cell Recipients

Groll

Silling

Young³

et al. 2010

Antimicrob Agents Chemother

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“…However, in a rat model of disseminated A. fumigatus infection, Wasan et al reported additive effects for the concomitant administration of liposomal amphotericin B (5 mg/kg) plus caspofungin (3 mg/kg) (58). In this disseminated study, the investigators showed that the combination significantly decreased CFU (by 98%) compared to untreated controls, while liposomal amphotericin B or caspofungin alone decreased the CFU by 69% and 80%, respectively, compared to the untreated controls.…”

Section: Discussionmentioning

confidence: 79%

“…In our previous work using the same immunosuppressed murine pulmonary aspergillosis model that was used in this study (39), we determined that doses of 3 to 15 mg/kg of liposomal amphotericin B produced 100% survival, although the optimum treatment was achieved with 15 mg/kg, reducing the lung fungal burden by 100-fold and causing no significant nephrotoxicity in the mice. For the echinocandins, we used doses similar to those used by other investigators who evaluated combination treatments for disseminated aspergillosis (58).…”

Section: Discussionmentioning

confidence: 99%

Liposomal Amphotericin B and Echinocandins as Monotherapy or Sequential or Concomitant Therapy in Murine Disseminated and Pulmonary Aspergillus fumigatus Infections

Olson

George

Constable

et al. 2010

Antimicrob Agents Chemother

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Monotherapy and combination therapy were compared using optimal doses of liposomal amphotericin B, micafungin, or caspofungin in Aspergillus fumigatus pulmonary and disseminated infections. Mice were challenged intravenously (2.8 ؋ 10 4 to 5.7 ؋ 10 4 conidia) or intranasally (5.8 ؋ 10 7 conidia) with A. fumigatus. Drugs (5, 10, or 15 mg/kg of body weight) were given for 3 or 6 days as single, concomitant, or sequential therapy (i.e., days 1 to 3 and then days 4 to 6). Mice were monitored for survival, and tissues were assayed for fungal burden and drug concentrations. Treatments starting 24 h postchallenge significantly prolonged survival in disseminated aspergillosis (P < 0.002), but only liposomal amphotericin B treatments or treatments beginning with liposomal amphotericin B increased survival to 100% in the pulmonary aspergillosis model. Fungi in kidneys and spleens (disseminated) and lungs (pulmonary) were significantly decreased (P < 0.04) by liposomal amphotericin B, liposomal amphotericin B plus echinocandin, or liposomal amphotericin B prior to echinocandin. In the disseminated infection, liposomal amphotericin B and micafungin (10 or 15 mg/kg) had similar kidney drug levels, while in the spleen, 5 and 15 mg/kg liposomal amphotericin B gave higher drug levels than micafungin (P < 0.02). In the pulmonary infection, drug levels in lungs and spleen with 5-mg/kg dosing were significantly higher with liposomal amphotericin B than with caspofungin (P < 0.002). In summary, treatment of A. fumigatus infections with liposomal amphotericin B plus echinocandin or liposomal amphotericin B prior to echinocandin was as effective as liposomal amphotericin B alone, and a greater decrease in the fungal burden with liposomal amphotericin B supports using liposomal amphotericin B prior to echinocandin.

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“…Although for the disseminated and pulmonary murine infections, administering LAmpB along with MCF or CAS, was reported to be neither antagonistic or additive nor synergistic although improved survival or decrease in fungal load also considered. However, Wasan et al [33] observed additive effects in a rat model (infected with A. fumigatus) when it was exposed LAmpB (5 mg/kg) plus CAS (3 mg/kg), parallely. In this study, the researchers reported that the combination appreciably reduced colony forming unit (CFU) (by 98%), while LAmpB or CAS monotherapy reduced 69% and 80% CFU, respectively, in comparison with untreated controls.…”

Section: Monotherapy/combination Therapy Of Echinocandins and Their Cmentioning

confidence: 99%

Echinocandins Versus Dated Antifungals in Combination Against Opportunistic Mycotic Infections

Narwal¹,

Balhara²,

Chaudhary³

et al. 2017

Asian J Pharm Clin Res

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Scientific and clinical reports globally demonstrated that the opportunistic mycotic infections are at major risk to the human fitness. In the past few decades, the development of resistance in microbes to existing antifungals has emphasized on the search of new antimycotic drugs. As a matter of fact, "echinocandins" are new categories of broad-spectrum antifungal enlighten a hope in this direction. Echinocandins are bulky lipopeptides that inhibit the production of β-[1,3]-glucan "a major constituent of fungal cell wall" which ultimately leads to the death of fungal pathogens. In vitro as well as in vivo published reports have demonstrated that the echinocandins exhibit fungicidal activity against most Candida spp., while fungistatic against Aspergillus spp. and exclusively found to be more effective when tested in combination with polyenes/azoles. The present article is expert views on the recent and historical literature available on the antifungal therapies with accessing their impact on the human health. Emphasis is given to the utility of the echinocandins a potental antifungal agent by discussing recent examples of clinical and laboratory studies including the use of improved proteomics approaches to know a bit more about the interaction of human host and fungal pathogens.

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Assessing the antifungal activity, pharmacokinetics, and tissue distribution of amphotericin B following the administration of Abelcet® and AmBisome® in combination with caspofungin to rats infected with Aspergillus fumigatus

Cited by 17 publications

References 38 publications

Randomized Comparison of Safety and Pharmacokinetics of Caspofungin, Liposomal Amphotericin B, and the Combination of Both in Allogeneic Hematopoietic Stem Cell Recipients

Randomized Comparison of Safety and Pharmacokinetics of Caspofungin, Liposomal Amphotericin B, and the Combination of Both in Allogeneic Hematopoietic Stem Cell Recipients

Liposomal Amphotericin B and Echinocandins as Monotherapy or Sequential or Concomitant Therapy in Murine Disseminated and Pulmonary Aspergillus fumigatus Infections

Echinocandins Versus Dated Antifungals in Combination Against Opportunistic Mycotic Infections

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