Efficacy of cilofungin alone and in combination with amphotericin B in a murine model of disseminated aspergillosis

Denning, David W.; Stevens, David A.

doi:10.1128/aac.35.7.1329

Cited by 73 publications

(60 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For the quantification of CFU burdens, to ensure that death was considered as a worse outcome than survival with any amount of burden, a log value of 5 was assigned to data points missing due to death from infection (28). This value has been determined to be the approximate number of CFU in the organ just prior to death (16,23).High-inoculum model. The first deaths occurred on day 3 and continued through day 9.…”

mentioning

confidence: 99%

“…All surviving mice were then euthanatized by CO 2 asphyxia, and the number of CFU of A. fumigatus in the brain and kidneys was determined by quantitative plating of organ homogenates (16,23); the dilution procedures eliminated drug carryover.…”

mentioning

confidence: 99%

“…Systemic model. Murine models of systemic aspergillosis were established in 6-week-old female CD-1 mice (average weight, 24.2 g) by intravenous injection of 8 ϫ 10 6 (high inoculum) or 3.6 ϫ 10 6 (low inoculum) conidia of Aspergillus fumigatus isolate 10AF (16,23). Therapy began 1 day after infection, with groups of 10 or 11 mice receiving either no treatment, 0.8 mg of conventional AMB per kg of body weight (a dose just below toxicity in this model), or 0.8, 4, or 8 mg of ABCD, AmBi, or ABLC per kg.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Comparative Efficacies of Four Amphotericin B Formulations—Fungizone, Amphotec (Amphocil), AmBisome, and Abelcet—against Systemic Murine Aspergillosis

Clemons

Stevens

2004

Antimicrob Agents Chemother

View full text Add to dashboard Cite

We compared various amphotericin B formulations (no treatment or 0.8 mg of Fungizone [conventional deoxycholate amphotericin B] per kg of body weight, or 0.8, 4, or 8 mg of Amphocil, AmBisome, or Abelcet per kg of body weight) for treatment of systemic murine aspergillosis. In two studies, all formulations prolonged survival, with the results for AmBisome nearly equivalent to those for Fungizone; Amphocil and Abelcet were less effective or equivalent depending on the severity of infection. No survivors were cured in both kidneys and brain, but each formulation showed efficacy, especially in the kidneys. Although higher doses could be given, no lipid-based formulation showed consistent superiority over Fungizone or over each other.In spite of present therapeutic options, the mortality rate from invasive aspergillosis is high (13)(14)(15). Despite the introduction of newer agents into the therapy of aspergillosis, conventional deoxycholate-formulated amphotericin B (AMB; Fungizone) remains a principal therapeutic and comparator in clinical trials. However, its well-described toxicities can limit its usefulness (19).The following lipid-carried formulations of AMB have reduced toxicities (20,24,30): Amphotec (Amphocil [ABCD]; Intermune, Inc., Burlingame, Calif.), a discoidal complex of cholesteryl sulfate and AMB (21, 22); AmBisome (AmBi; Gilead Sciences, Foster City, Calif.), a true unilamellar liposome (1, 33); and Abelcet (ABLC; Enzon, Fairfield, N.J.), a ribbon form of dimyristoyl phosphatidyl choline and dimyristoyl phosphatidyl glycerol with AMB (27, 35). Each formulation has been reported to have efficacy against aspergillosis equal to or better than that of conventional AMB (3,4,18,25,29,32). However, no studies comparing the four formulations against aspergillosis have been done. Systemic model. Murine models of systemic aspergillosis were established in 6-week-old female CD-1 mice (average weight, 24.2 g) by intravenous injection of 8 ϫ 10 6 (high inoculum) or 3.6 ϫ 10 6 (low inoculum) conidia of Aspergillus fumigatus isolate 10AF (16, 23). Therapy began 1 day after infection, with groups of 10 or 11 mice receiving either no treatment, 0.8 mg of conventional AMB per kg of body weight (a dose just below toxicity in this model), or 0.8, 4, or 8 mg of ABCD, AmBi, or ABLC per kg. All dosages were based on an equivalent number of milligrams of AMB per kilogram of body weight. Four doses were administered intravenously every other day, as AMB has a long half-life in all four preparations (4, 21, 30, 33).Deaths were tallied through 9 days of infection. All surviving mice were then euthanatized by CO 2 asphyxia, and the number of CFU of A. fumigatus in the brain and kidneys was determined by quantitative plating of organ homogenates (16, 23); the dilution procedures eliminated drug carryover.Statistics. Evaluation of survival was done by using a logrank test and a comparison of the number of CFU by a MannWhitney U test. For the quantification of CFU burdens, to ensure that death was considered as a worse outcome t...

show abstract

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Comparative Efficacies of Four Amphotericin B Formulations—Fungizone, Amphotec (Amphocil), AmBisome, and Abelcet—against Systemic Murine Aspergillosis

Clemons

Stevens

2004

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…Immunocompetent mice can be infected by the i.v. route, but they tend to clear the infection from lung, liver and spleen, and often from the brains, and die with high fungal concentrations in their kidneys [11]. Intracerebral injection of conidia in non-immunosuppressed mice either resulted in 100% lethality in the Wrst 2 days or survival of more than 50% of the animals, depending on the size of the inoculum that could not be more Wnely titrated [3].…”

Section: Discussionmentioning

confidence: 99%

A model of cerebral aspergillosis in non-immunosuppressed nursing rats

2007

View full text Add to dashboard Cite

Central nervous system aspergillosis is an often fatal complication of invasive Aspergillus infection. Relevant disease models are needed to study the pathophysiology of cerebral aspergillosis and to develop novel therapeutic approaches. This study presents a model of central nervous system aspergillosis that mimics important aspects of human disease. Eleven-day-old non-immunosuppressed male Wistar rats were infected by an intracisternal injection of 10 l of a conidial suspension of Aspergillus fumigatus. An inoculum of 7.18 log 10 colony-forming units (CFU) consistently produced cerebral infection and resulted in death of all animals (n = 25) within 3-10 days. Median survival time was 3 days. Histomorphologically, all animals developed intracerebral abscesses (2-26 per brain) containing abundant fungal hyphae and neutrophils. Fungal culture of cortical homogenates yielded maximal growth on day 3 after infection (5.4 log 10 CFU/g, n = 15) that declined over time. Galactomannan concentrations in cortical homogenates, assessed as an index for hyphal burden, peaked on days 3-5. Fungal infection spread to peripheral organs in 83% of animals. Fungal burden in lung, liver, spleen and kidney was two orders of magnitude lower than in the brain. The successful establishment of a model of cerebral aspergillosis in a non-immunosuppressed host provides the opportunity to investigate mechanisms of disease and to develop novel treatment regimens for this commonly fatal infection.

show abstract

“…These agents have fungicidal, narrow-spectrum activity against Candida and Aspergillus spp. (1,5,6), and L-671,329 has also been shown to have activity against Pneumocystis cannii (9, 10). They both have the potential for improved efficacy and tolerance over existing therapy.…”

mentioning

confidence: 99%

Pharmacokinetics of L-671,329 in rhesus monkeys and DBA/2 mice

Sundelof

Hajdu

Cleare

et al. 1992

Antimicrob Agents Chemother

View full text Add to dashboard Cite

The time course of plasma drug levels and urinary recovery for two lipopeptide antifungal antibiotics, L-671,329 and cilofungin, were measured in male rhesus monkeys (Macaca mulatta) and in female DBA/2 mice. The antibiotics were administered intravenously at 10 mg/kg of body weight in phosphate-buffered saline-26% polyethylene glycol for the rhesus monkeys and in 5% dimethyl sulfoxide for the mice. Plasma and urine drug concentrations were determined by high-pressure liquid chromatography and/or a microbiological assay versus AspergiUlus niger, and pharmacokinetic parameters were determined for both species. In each of the two rhesus crossover tests as well as in the mouse studies, the pharmacokinetics of the two compounds were similar; however, a marked difference was evident between species. The half-lives of L-671,329 and cilofungin in plasma were 39 and 34 min in the mice and averaged 1.8 and 2 h in the rhesus monkeys, respectively. In mice and rhesus monkeys, urinary recovery was <4% for both compounds.In the search for new therapeutic agents, animal models of disease states have been an indispensable tool for the prediction of efficacy in humans. For any number of reasons, a therapeutic advantage of one agent over another demonstrated in an animal model may not translate analogously to humans. Thus, it behooves an investigator to be critical of the models he relies on and to develop additional experimental procedures to confirm his predictions. It is customary in our laboratory, for example, to explore any species-specific pharmacokinetic properties of a compound of interest. A comparison in rodents versus primates provides some of the additional parameters necessary for projecting success or failure in humans.In this study, species-specific pharmacokinetics of two recently reported, structurally similar ( Fig. la and b) lipopeptide antifungal antibiotics, L-671,329 and cilofungin (LY-121019, L-646,991), are presented. These agents have fungicidal, narrow-spectrum activity against Candida and Aspergillus spp. (1,5,6), and L-671,329 has also been shown to have activity against Pneumocystis cannii (9, 10). They both have the potential for improved efficacy and tolerance over existing therapy. MATERUILS AND METHODSMice. Female DBA/2 mice weighing 20 + 2 g were used in these studies. The mice were housed and fed in accordance with National Institutes of Health guidelines (2).Rhesus monkeys. Two male rhesus monkeys (Macaca mulatta) weighing 4.8 kg were used in these studies. They were also housed and fed in accordance with National Institutes of Health guidelines (2).Drugs. L-671,329 and cilofungin were prepared in our laboratory by published methods (4, 11). They were diluted in 5% dimethyl sulfoxide to 1.0 mg/ml or phosphate-buffered saline-26% polyethylene glycol (molecular weight, 300) to 10 mg/ml. Samples were kept on ice at 0°C and administered the same day.HPLC conditions. Conditions for high-pressure liquid chromatography (HPLC) areas were linear from 200 to 0.5 ,ug/ml (limit of detection based on a ...

show abstract

Efficacy of cilofungin alone and in combination with amphotericin B in a murine model of disseminated aspergillosis

Cited by 73 publications

References 15 publications

Comparative Efficacies of Four Amphotericin B Formulations—Fungizone, Amphotec (Amphocil), AmBisome, and Abelcet—against Systemic Murine Aspergillosis

Comparative Efficacies of Four Amphotericin B Formulations—Fungizone, Amphotec (Amphocil), AmBisome, and Abelcet—against Systemic Murine Aspergillosis

A model of cerebral aspergillosis in non-immunosuppressed nursing rats

Pharmacokinetics of L-671,329 in rhesus monkeys and DBA/2 mice

Contact Info

Product

Resources

About