Differences in Efficacy and Cytokine Profiles following Echinocandin or Liposomal Amphotericin B Monotherapy or Combination Therapy for Murine Pulmonary or Systemic Aspergillus flavus Infections

ABSTRACTGiven the recent increase in aspergillosis caused by species other thanAspergillus fumigatus, micafungin, caspofungin, and liposomal amphotericin B (L-AmBi) were investigated as monotherapy or combination therapy for murine systemic or pulmonaryAspergillus flavusinfection. Treatment for 3 or 6 days was begun at 24 h (intravenous [i.v.], 2.8 × 104conidia) or 2 h (intranasal, 4.1 × 106to 6.75 × 106conidia) postchallenge as follows: 5 or 10 mg/kg L-AmBi, 10 mg/kg caspofungin, 15 mg/kg micafungin, L-AmBi plus echinocandin, L-AmBi on days 1 to 3 and echinocandin on days 4 to 6, or echinocandin on days 1 to 3 and L-AmBi on days 4 to 6. Mice were monitored for survival, fungal burden, serum or tissue cytokines, and lung histopathology. In the systemic infection, micafungin or caspofungin was more effective than L-AmBi in prolonging survival (P< 0.05), and L-AmBi was associated with significantly elevated serum levels of interleukin-6 (IL-6), macrophage inflammatory protein 1α (MIP-1α), and IL-12 (P< 0.05). In contrast, L-AmBi was significantly more effective than the echinocandins in reducing fungal growth in most tissues (P< 0.05). Concomitant therapies produced significantly enhanced survival, reduction in fungal burden, and low levels of proinflammatory cytokines, while antagonism was seen with some sequential regimens. In comparison, in the pulmonary infection, L-AmBi was significantly better (P< 0.05) than caspofungin or the combination of L-AmBi and caspofungin in prolonging survival and reducing lung fungal burden. Caspofungin stimulated high lung levels of IL-1α, tumor necrosis factor alpha (TNF-α), and IL-6, with extensive tissue damage. In summary, systemicA flavusinfection was treated effectively with L-AmBi plus micafungin or caspofungin provided that the drugs were administered concomitantly and not sequentially, while pulmonaryA. flavusinfection responded well to L-AmBi but not to caspofungin.

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Posaconazole Mono- or Combination Therapy for Treatment of Murine Zygomycosis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01124-08 ◽

2008 ◽

Vol 53 (2) ◽

pp. 772-775 ◽

Cited By ~ 62

Author(s):

Ashraf S. Ibrahim ◽

Teclegiorgis Gebremariam ◽

Julie A. Schwartz ◽

John E. Edwards ◽

Brad Spellberg

Keyword(s):

Combination Therapy ◽

Amphotericin B ◽

Liposomal Amphotericin ◽

Rhizopus Oryzae ◽

Liposomal Amphotericin B ◽

Fungal Burden ◽

Better Than

ABSTRACT We compared the efficacy of combination posaconazole-liposomal amphotericin B (LAmB) therapy to monotherapy with either drug in diabetic ketoacidotic or neutropenic mice with disseminated zygomycosis caused by Rhizopus oryzae. Combination therapy was no better than LAmB alone, and posaconazole monotherapy did not improve survival or reduce fungal burden versus placebo.

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Combination Therapy of Murine Mucormycosis or Aspergillosis with Iron Chelation, Polyenes, and Echinocandins

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01577-10 ◽

2011 ◽

Vol 55 (4) ◽

pp. 1768-1770 ◽

Cited By ~ 40

Author(s):

Ashraf S. Ibrahim ◽

Teclegiorgis Gebremariam ◽

Guanpingsheng Luo ◽

Yue Fu ◽

Samuel W. French ◽

...

Keyword(s):

Combination Therapy ◽

Triple Therapy ◽

Amphotericin B ◽

Liposomal Amphotericin ◽

Iron Chelation ◽

Liposomal Amphotericin B ◽

Fungal Burden

ABSTRACTLiposomal amphotericin B (LAmB) combined wither either micafungin or deferasirox was synergistic in previous murine studies with mucormycosis or aspergillosis. We hypothesized that triple therapy using LAmB, micafungin, and deferasirox could further improve outcomes of mucormycosis or aspergillosis. Triple therapy improved survival and reduced tissue fungal burden of mice with mucormycosis and to a lesser extent with aspergillosis. Continued investigation into the use of triple therapy against mucormycosis and aspergillosis is warranted.

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Assessing the Efficacy and Safety of Liposomal Amphotericin B and Miltefosine in Combination for Treatment of Post Kala-Azar Dermal Leishmaniasis

The Journal of Infectious Diseases ◽

10.1093/infdis/jiz486 ◽

2019 ◽

Vol 221 (4) ◽

pp. 608-617 ◽

Cited By ~ 2

Author(s):

V Ramesh ◽

Keerti Kaumudee Dixit ◽

Neha Sharma ◽

Ruchi Singh ◽

Poonam Salotra

Keyword(s):

Combination Therapy ◽

Amphotericin B ◽

Liposomal Amphotericin ◽

Quantitative Polymerase Chain Reaction ◽

Treatment Options ◽

Parasite Load ◽

Liposomal Amphotericin B ◽

Rapid Decline ◽

Kala Azar

Abstract Background No satisfactory canonical treatment is available for post-kala-azar dermal leishmaniasis (PKDL), clinical sequela of visceral leishmaniasis. Confined treatment options and substantial increase in relapse rate after miltefosine (MIL) treatment warrant the need to adapt resilient combination therapies. In this study, we assessed the safety and efficacy of combination therapy using liposomal amphotericin B (LAmB) and MIL for treating PKDL. Methods Thirty-two PKDL patients, confirmed by microscopy or quantitative polymerase chain reaction (qPCR), were included in the study. An equal number of cases (n = 16) were put on MIL monotherapy (100 mg/day for 90 days) or MIL and LAmB combination for 45 days (3 injections of LAmB, 5 mg/kg body weight, and 100 mg/day MIL). Parasite load in slit aspirate was monitored using qPCR. Results Patients treated with combination therapy demonstrated a rapid decline in parasite load and achieved 100% cure, with no reports of relapse. Those treated with MIL monotherapy attained clinical cure with a gradual decrease in parasite load; however, 25% relapsed within 18 months of follow-up. Conclusions Liposomal amphotericin B and MIL combination for treating PKDL is efficacious and safe, with high tolerability. Furthermore, this study established the utility of minimally invasive slit aspirate method for monitoring of parasite load and assessment of cure in PKDL.

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Combination therapy with caspofungin and liposomal amphotericin B for invasive aspergillosis

The Pediatric Infectious Disease Journal ◽

10.1097/01.inf.0000073060.20277.29 ◽

2003 ◽

Vol 22 (7) ◽

pp. 653-656 ◽

Cited By ~ 13

Author(s):

ZIJU ELANJIKAL ◽

JAN SÖRENSEN ◽

HELGA SCHMIDT ◽

WOLFGANG DUPUIS ◽

KATHRIN TINTELNOT ◽

...

Keyword(s):

Combination Therapy ◽

Invasive Aspergillosis ◽

Amphotericin B ◽

Liposomal Amphotericin ◽

Liposomal Amphotericin B

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1577. Particle Characterization of Nebulized Liposomal Amphotericin B and Its Use in the Treatment of Murine Pulmonary Aspergillosis

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz360.1441 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S576-S576

Author(s):

Janam J Dave ◽

Adilene Sandoval ◽

Jon Olson ◽

Jill Adler-Moore

Keyword(s):

Amphotericin B ◽

Liposomal Amphotericin ◽

In Vivo Studies ◽

Liposomal Amphotericin B ◽

Drug Penetration ◽

Particle Characterization ◽

Pulmonary Aspergillosis ◽

Fungal Burden

Abstract Background Immunocompromised patients are very susceptible to pulmonary aspergillosis causing 50% mortality with present treatments, indicating a need for improved therapy. To address this, we standardized a nebulization method for effectively delivering liposomal amphotericin B (AmBisome®, AmBi) into lungs of Aspergillus fumigatus-infected mice. Methods AmBi particle characterization was done with a Cascade particle impactor and a Schuco S5000 nebulizer containing 1.33 mg/mL AmBi. For in vivo studies, AmBi was nebulized (neb) into a 12 compartment chamber (one mouse/compartment), following immunosuppression with 28 mg/kg triamcinolone IP (d-3, -1, +1). Mice were challenged d0 with 9 x 106A. fumigatus (ATCC#13073) and 4 hours post-challenge, divided into 5 groups (n = 12/gp): 5 days of 20 min/day neb AmBi (Gp1), 5 days of 10 min/day neb AmBi (Gp2), 20 min/day neb AmBi days 0, 1, 3, 5, 7 (Gp 3), 5 days of intravenous(IV) AmBi 7.5 mg/kg/day (Gp4) and IV PBS (Gp5). Seven mice/gp were monitored for survival to d21 and lungs, livers, kidneys, spleens (5 mice/gp) analyzed for mean amphotericin B µg/g and CFU/g. Results 87% of neb AmBi particles were between 0.43 mm to 3.3 mm allowing for drug penetration into 1°, 2° and terminal bronchi, bronchioles, and alveoli. This resulted in very good protection, with 20 min daily neb treatments (Gp1) giving 100% survival and 10 min daily neb treatments producing 71% survival (Gp2). There were no survivors in the PBS gp (P < 0.02 vs. Gp1 and Gp2). Every other day neb AmBi or daily IV AmBi was less effective (43% survival). In addition, neb AmBi for 20 min (Gp1) yielded significantly lower fungal burden in lungs vs. all other AmBi treatments (P < 0.02). While drug was detected in lungs of mice given 20 min of neb AmBi (2.6 µg/g), there was no drug detected in livers, kidneys or spleens of any mice given neb AmBi. In comparison, with IV AmBi, drug was detected in the lungs (7 µg/g), livers (204 µg/g), kidneys (38 µg/g), and spleens (114 µg/g). Conclusion Daily AmBi nebulization was an effective and potentially less nephrotoxic treatment for murine pulmonary aspergillosis since it achieved significantly lower tissue fungal burden and much better survival vs. daily IV AmBi, without delivering drug to the kidneys. Disclosures All authors: No reported disclosures.

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In Vivo Efficacy of Liposomal Amphotericin B against Wild-Type and Azole-Resistant Aspergillus fumigatus Isolates in Two Different Immunosuppression Models of Invasive Aspergillosis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02479-16 ◽

2017 ◽

Vol 61 (6) ◽

Cited By ~ 3

Author(s):

Seyedmojtaba Seyedmousavi ◽

Johan W. Mouton ◽

Willem J. G. Melchers ◽

Paul E. Verweij

Keyword(s):

Invasive Aspergillosis ◽

Aspergillus Fumigatus ◽

Amphotericin B ◽

Liposomal Amphotericin ◽

Treated Group ◽

Liposomal Amphotericin B ◽

Wild Type ◽

Resistance Mutations ◽

Content Type

ABSTRACT Using an immunocompetent murine model of invasive aspergillosis (IA), we previously reported that the efficacy of liposomal amphotericin B (L-AmB) (Ambisome) is not hampered by the presence of azole resistance mutations in Aspergillus fumigatus (S. Seyedmousavi, W. J. G. Melchers, J. W. Mouton, and P. E. Verweij, Antimicrob Agents Chemother 57:1866–1871, 2013, https://doi.org/10.1128/AAC.02226-12 ). We here investigated the role of immune suppression, i.e., neutropenia and steroid treatment, in L-AmB efficacy in mice infected with wild-type (WT) A. fumigatus and with azole-resistant A. fumigatus harboring a TR34/L98H mutation in the cyp-51A gene. Survival of treated animals at day 14 in both immunosuppressed models was significantly better than that of nontreated controls. A dose-response relationship was observed that was independent of the azole-resistant mechanism and the immunosuppression method used. In the neutropenic model, 100% survival was reached at an L-AmB dose of 16 mg/kg of body weight for the WT strain and the TR34/L98H isolate. In the steroid-treated group, 90.9% survival and 100% survival were achieved for the WT isolate and the TR34/L98H isolate with an L-AmB dose of 16 mg/kg, respectively. The 50% effective dose (ED50) was 1.40 mg/kg (95% confidence interval [CI], 0.66 to 3.00 mg/kg) for the WT isolate and 1.92 mg/kg (95% CI, 0.60 to 6.17 mg/kg) for the TR34/L98H isolate in the neutropenic model and was 2.40 mg/kg (95% CI, 1.93 to 2.97 mg/kg) for the WT isolate and 2.56 mg/kg (95% CI, 1.43 to 4.56 mg/kg) for the TR34/L98H isolate in the steroid-treated group. Overall, there were no significant differences between the two different immunosuppressed conditions in the efficacy of L-AmB against the wild-type and azole-resistant isolates (P > 0.9). However, the required L-AmB exposure was significantly higher than that seen in the immunocompetent model.

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In VitroCombination of Isavuconazole with Micafungin or Amphotericin B Deoxycholate against Medically Important Molds

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.03261-14 ◽

2014 ◽

Vol 58 (11) ◽

pp. 6934-6937 ◽

Cited By ~ 25

Author(s):

Aspasia Katragkou ◽

Matthew McCarthy ◽

Joseph Meletiadis ◽

Vidmantas Petraitis ◽

Patriss W. Moradi ◽

...

Keyword(s):

Combination Therapy ◽

Invasive Aspergillosis ◽

Amphotericin B ◽

Aspergillus Flavus ◽

Aspergillus Terreus ◽

Synergistic Activity ◽

Content Type ◽

Amphotericin B Deoxycholate ◽

Combination Studies

ABSTRACTWhether isavuconazole, an extended-spectrum triazole, possesses synergistic activity in combination therapy with echinocandins or amphotericin B for the treatment of invasive molds infections has not been studied. Ourin vitrocombination studies showed that isavuconazole and micafungin are synergistically active againstAspergillus fumigatus,Aspergillus flavus,Aspergillus terreus, andCunninghamella bertholletiae. These results suggest that isavuconazole, in combination with micafungin, may have a role in the treatment of invasive aspergillosis and warrants further investigation.

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Caspofungin at Catheter Lock Concentrations Eradicates Mature Biofilms of Candida lusitaniae and Candida guilliermondii

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.03117-14 ◽

2014 ◽

Vol 58 (8) ◽

pp. 4953-4956 ◽

Cited By ~ 10

Author(s):

Maria Simitsopoulou ◽

Daniela Kyrpitzi ◽

Aristea Velegraki ◽

Thomas J. Walsh ◽

Emmanuel Roilides

Keyword(s):

Amphotericin B ◽

Liposomal Amphotericin ◽

Candida Guilliermondii ◽

Liposomal Amphotericin B ◽

Antibiofilm Activity ◽

Test Species ◽

Content Type ◽

Lock Therapy ◽

Catheter Lock ◽

Candida Lusitaniae

ABSTRACTThe antibiofilm activities of caspofungin, anidulafungin, micafungin, and liposomal amphotericin B were studied againstCandida lusitaniae,Candida guilliermondii, and aCandida albicanscontrol strain. While anidulafungin and micafungin (0.007 to 2,048 mg/liter) showed reduced activity against biofilms of both test species, caspofungin displayed concentration-dependent antibiofilm activity, reaching complete and persistent eradication at concentrations achievable during lock therapy (512 to 2,048 mg/liter,P< 0.05). Although liposomal amphotericin B strongly inhibited mature biofilms, it possessed lower antibiofilm activity than caspofungin (P< 0.05).

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