Skip to main page content

• HOME
• Current Issue
• Archive
• Alerts
• About ASM
• Contact us
• Tech Support
• Journals.ASM.org

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by van de Sande, W. W. J. Articles by Bakker-Woudenberg, I. A. J. M. Search for Related Content PubMed PubMed Citation Articles by van de Sande, W. W. J. Articles by Bakker-Woudenberg, I. A. J. M.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, April 2008, p. 1345-1350, Vol. 52, No. 4
0066-4804/08/$08.00+0     doi:10.1128/AAC.00536-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Caspofungin Prolongs Survival of Transiently Neutropenic Rats with Advanced-Stage Invasive Pulmonary Aspergillosis

Wendy W. J. van de Sande,^1* Wim van Vianen,¹ Marian T. ten Kate,¹ Jolanda Vissers,¹ John Laurijsens,¹ Mehri Tavakol,¹ Bart J. A. Rijnders,^1,2 Ron A. A. Mathot,³ and Irma A. J. M. Bakker-Woudenberg¹

Erasmus MC, University Medical Center Rotterdam, Department of Medical Microbiology & Infectious Diseases, 's-Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands,¹ Erasmus MC, University Medical Center Rotterdam, Department of Internal Medicine, Section Infectious Diseases, 's-Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands,² Erasmus MC, University Medical Center Rotterdam, Department of Hospital Pharmacy, Clinical Pharmacology Unit, 's-Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands³

Received 23 April 2007/ Returned for modification 9 July 2007/ Accepted 4 January 2008

Top ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
A high-dose-step-down strategy for caspofungin treatment was evaluated in an experimental model of advanced-stage invasive pulmonary aspergillosis. The therapeutic efficacy of caspofungin in relation to the severity of invasive pulmonary infection caused by Aspergillus fumigatus in transiently neutropenic rats was investigated by using rat survival and the decrease in the fungal burden as the parameters of efficacy. When treatment was started at either 16 h or 24 h after fungal inoculation, caspofungin administered intraperitoneally at 4 mg/kg of body weight/day for 10 days was highly effective (100% and 93% rat survival, respectively). However, only 27% rat survival was obtained when treatment was started at 72 h, when the rats had advanced-stage infection. Increasing the dose from 4 to 10 mg/kg/day could compensate for the decrease in efficacy and resulted in 67% rat survival. The high dose of 10 mg/kg/day for 10 days did not appear to be necessary since a high-dose-step-down dosing schedule with 10 mg/kg/day for 3 days followed by 4 mg/kg/day for 7 days was equally effective. At 10 days after the end of treatment with 10 mg/kg/day caspofungin, the level of neither A. fumigatus DNA nor A. fumigatus galactomannan in the infected left lung was significantly decreased. In contrast, A. fumigatus galactomannan concentrations in serum were significantly decreased. The levels of creatinine, blood urea nitrogen, alanine aminotransferase, and asparate aminotransferase were not elevated during treatment. Caspofungin is effective for the treatment of invasive pulmonary aspergillosis in transiently neutropenic rats and is even effective in rats with advanced-stage infection. In this model, the administration of high-dose-step-down treatment was as effective as treatment with high doses for the whole treatment period.

Top ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Invasive pulmonary aspergillosis is a life-threatening fungal infection observed in severely immunocompromised patients. Antifungal treatment has changed as a result of the introduction of broader-spectrum azoles and the echinocandins. In contrast to amphotericin B and the azoles, the echinocandins, of which caspofungin is the first approved member, do not act on the cell membrane but act on the cell wall (11, 12). The echinocandins inhibit the synthesis of 1,3-β-D-glucan, an essential molecule which provides osmotic stability to fungi and is essential in growth and division (11, 12). As 1,3-β-D-glucan is not found in mammalian cells, inhibition of the synthesis of this molecule in fungi is highly specific, resulting in high degrees of tolerability of the echinocandins (11), which explains why, until now, no serious side effects of caspofungin treatment have been published and the drug seems to have an excellent safety profile (4). Caspofungin has been demonstrated to be effective as salvage therapy in patients with documented invasive aspergillosis and as empirical therapy in patients with persistent fever and neutropenia (10, 18). Although caspofungin seems to have a favorable therapeutic effect in neutropenic patients with invasive aspergillosis, animal studies remain necessary to evaluate the full efficacy of this drug. Our earlier study already showed the therapeutic efficacy of caspofungin in a clinically relevant Aspergillus fumigatus infection model with transiently neutropenic rats (17). Treatment was started at 16 h after inoculation, when fungal hyphal growth was established. Caspofungin was administered at 4 mg/kg of body weight/day for 10 days, and the treatment resulted in 100% rat survival, whereas only 27% of the rats survived after treatment with amphotericin B at 1 mg/kg/day, which was the maximum tolerated dose (17). The present study investigated the therapeutic efficacy of caspofungin in relation to the severity of fungal infection. In the clinical situation, we are also often faced with patients with extensive fungal lesions and high fungal burdens. In this study, the efficacy of caspofungin was determined in transiently neutropenic rats with early-stage invasive pulmonary aspergillosis and was compared with that in neutropenic rats with advanced-stage invasive pulmonary aspergillosis. Furthermore, the efficacy of therapy with high doses of caspofungin throughout the entire treatment was compared to the efficacy of high-dose-step-down therapy.

Top ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Aspergillus fumigatus isolate. In our infection model, a clinical strain of A. fumigatus originally isolated from a hemato-oncological patient with invasive pulmonary aspergillosis was used in all experiments. To maintain its virulence, the strain was regularly passed through neutropenic rats and maintained on Sabouraud agar slants. For this strain, the MIC of caspofungin was determined according to the criteria of the CLSI in a previous study and appeared to be 8 mg/liter (17). The minimal effective concentration for this strain was 0.05 mg/liter and was determined by Etest (AB Biodisk, Goes, The Netherlands), according to the manufacturer's instructions.

Infection model of invasive pulmonary aspergillosis and antifungal treatment. The rat model of aerogenic left-sided invasive pulmonary aspergillosis in neutropenic rats was used, as described previously (2, 3), and has slightly been modified by van Vianen et al. (17). In short, neutropenia was induced by the intraperitoneal administration of 75 mg/kg cyclophosphamide (Endoxan; Baxter, Utrecht, The Netherlands) 5 days before fungal inoculation, followed by administration of a dose of 60 mg/kg 1 day before inoculation and 50, 40, and 30 mg/kg on days 3, 7, and 11 after fungal inoculation, respectively. Fungal infection was established by intubation of the left main bronchus while the rats were under general anesthesia. A cannula was passed through the tube, and the left lung was inoculated with 6 x 10⁴ conidia in 20 µl phosphate-buffered saline. Treatment with caspofungin (Cancidas; Merck & Company, Rahway, NJ) was started at either 16 h, 24 h, or 72 h after fungal inoculation. As determined by histological examination, hyphal growth was established at these time points. Caspofungin was diluted in saline and was administered intraperitoneally once daily for 10 days. The treatment regimens included 4 or 10 mg/kg/day.

The experimental protocols adhered to the rules specified in the Dutch Animal Experimentation Act (1977) and the Guidelines on the Protection of Experimental Animals published by the Council of the EC (7a). The present protocols were approved by the Institutional Animal Care and Use Committee of the Erasmus MC Rotterdam.

Parameters for therapeutic efficacy. To determine therapeutic efficacy, several parameters were monitored. The main parameter was the survival of the infected rats, which were monitored daily during therapy and for the 10-day period after the termination of therapy. The decrease in the fungal burden in the infected left lung was also measured on days 1, 3, and 6 after fungal inoculation for the untreated control rats and on days 6, 9, 13, and 23 for the treated rats. This was done by the quantitative detection of both A. fumigatus DNA and A. fumigatus galactomannan (GM). GM is a fungal cell wall polysaccharide that Aspergillus spp. can release during growth. The GM concentrations in serum were also assessed. At the indicated time intervals, the rats were euthanized while they were under CO₂ anesthesia. Blood was obtained by puncture of the orbital plexus. The left lung was then dissected and stored at –80°C until analysis.

The quantitative detection of A. fumigatus DNA in the left lung by a TaqMan PCR and calculation of conidial equivalents (CEs) were performed as described by Bowman et al. (5) Normalization for DNA was done by adding a universal control to each sample before DNA extraction. This control consisted of a seal herpesvirus (phocid herpesvirus type 1) and provided a means of testing the precision and the reproducibility of the assays, as has been prescribed for other quantitative TaqMan assays (16). When the threshold cycle value of the internal control exceeded the mean value ± 2 standard deviations, it was assumed that inhibition or loss of the sample had occurred either during DNA isolation or during PCR. In such cases, the DNA isolation and TaqMan analysis were repeated until the value for the internal control was within the normal range.

The GM concentrations in both serum and left lung were determined by use of the commercial Platelia Aspergillus system of Bio-Rad (Marnes-la-Coquette, France). To obtain quantitative results, this system was modified in our laboratory as described before (3).

Organs dissected from all deceased animals were cultured to exclude bacterial superinfections.

Pharmacokinetics of antifungal agents. The pharmacokinetics of caspofungin were determined after the administration of multiple doses to uninfected neutropenic rats. For rats receiving three doses of 10 mg/kg/day, serial blood samples were taken at 5 min and 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, and 24 h after administration of the third dose by retro-orbital puncture while the animals were under CO₂ anesthesia. For rats receiving three doses of 10 mg/kg/day followed by seven doses of 4 mg/kg/day, serial blood samples were taken at the same time points described above after administration of the 10th dose. Plasma samples were obtained from three rats at each time point, and the concentration of caspofungin was assessed by a standard large plate agar diffusion assay, as described before (17). The area under the plasma concentration-versus-time curve (AUC) over 24 h (AUC₂₄) was calculated by using the log-linear trapezoidal rule.

Toxic side effects of caspofungin. To determine whether the caspofungin doses had toxic side effects on the kidneys or the liver, renal and hepatic functions were monitored. This was done by sampling blood on day 6 and day 13 after the start of caspofungin treatment. The creatinine (CREAT) and blood urea nitrogen (BUN) levels in these serum samples were determined to assess renal function, while the alanine aminotransferase (ALAT) and aspartate aminotransferase (ASAT) levels in these serum samples were measured to assess hepatic function. The same parameters were determined for a healthy control group, consisting of 35 rats, to calculate the normal values for this rat strain. Mild toxicity was defined when the levels for either one of these parameters was more than three times the upper limit of normal (three times the 95 percentile boundary for the healthy control group), and severe toxicity was defined as levels greater than five times the upper limit of normal.

Statistical analysis. Kaplan-Meier survival curves were generated, and the differences in rat survival rates were assessed by the log rank test. The normalities of the ALAT, ASAT, BUN, and CREAT levels were determined by use of the Shapiro-Wilk test.

Top ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Effect of antifungal treatment on rat survival. During the treatment period of 10 days, rats were persistently neutropenic (granulocyte counts, <0.1 x 10⁹/liter), and in the 10-day period after the termination of treatment, neutrophil numbers gradually rose. As shown in Fig. 1, all untreated control rats died between day 5 and day 9 after fungal inoculation. Treatment with caspofungin at 4 mg/kg/day for 10 days, which was started 16 h after fungal infection, the time at which hyphal growth in the left lung was established, resulted in therapeutic efficacy, with 100% of the rats surviving. The delay of treatment until 24 h after fungal infection resulted in a slight but not significant reduction in the therapeutic effect (P = 0.3918), with 93% of the rats surviving. When treatment was further delayed until 72 h after infection, when the rats had advanced-stage invasive pulmonary aspergillosis, caspofungin was still effective compared to no treatment (P < 0.0001). However, a rat survival rate of only 27% was obtained, and the therapeutic effect was significantly less when treatment was started 72 h after fungal inoculation than when treatment was started 24 h or 16 h after fungal inoculation (P < 0.0001 for both comparisons). To evaluate if a higher dose of caspofungin would compensate for the limited therapeutic effect related to the late start of treatment, a dose of 10 mg/kg/day was administered for 10 days. We observed that an increase in the caspofungin daily dose from 4 mg/kg to 10 mg/kg resulted in a significant increase in therapeutic effect (P = 0.0159), with the rat survival rate being 67%. Finally, to investigate whether the relatively high dose of 10 mg/kg/day was needed throughout the entire treatment period, we investigated whether a similar efficacy could be achieved with a high-dose-step-down schedule. As shown in Fig. 1, the efficacy of a high dose of caspofungin of 10 mg/kg/day for only 3 days followed by 4 mg/kg/day for 7 days did not differ from that of the 10-mg/kg/day continuous schedule for 10 days (P = 0.9147).

View larger version (30K): [in this window] [in a new window]

FIG. 1. Therapeutic efficacy of caspofungin (CAS) administered intraperitoneally in transiently neutropenic rats with invasive pulmonary aspergillosis. Caspofungin was administered intraperitoneally and consisted of 10 days of treatment at 4 mg/kg/day (10*4), 10 days of treatment at 10 mg/kg/day (10*10), or 3 days of treatment at 10 mg/kg/day followed by 7 days of treatment at 4 mg/kg/day (3*10 + 7*4). Treatment once daily was started either 16 h, 24 h, or 72 h after fungal inoculation and continued for 10 days. Statistical significance was determined with the log rank test.

Apparently, a high dose of caspofungin was essential only during the first 3 days of treatment. The AUC₂₄ of caspofungin determined after the third dose in rats receiving three doses of 10 mg/kg/day caspofungin appeared to be 549.3 µg·h/ml. The AUC₂₄ of caspofungin determined after the 10th dose in rats receiving three doses of 10 mg/kg/day followed by 7 doses of 4 mg/kg/day was 114 µg·h/ml.

Toxic side effects of dosing schemes. In order to investigate whether an increase in the dosage of caspofungin was well tolerated by the rats, we determined the renal and hepatic functions of the treated animals. Serum CREAT, BUN, ALAT, and ASAT levels were determined. As shown in Table 1, none of the caspofungin dosage schemes applied resulted in alarmingly high levels of the parameter for either function, even in the severely ill infected neutropenic animals. Although the kidney and liver functions were unimpaired, it was observed that animals receiving the relatively high dose of caspofungin of 10 mg/kg/day became lethargic, had respiratory distress, and felt cold within the first minutes after administration. These effects were found in both the infected group and the noninfected control group. The rats recovered within 1 or 2 h. The effects were the strongest after the first dose but became less intense after each subsequent dose.

View this table: [in this window] [in a new window]

TABLE 1. Renal and hepatic functions after administration of the different caspofungin dosing schemes started 72 h after fungal inoculationa

Effect of antifungal treatment on fungal burden in rats. The CE counts in the infected left lungs and the GM concentrations in the infected left lungs and the sera of the surviving rats are presented in Fig. 2 and 3. As shown in Fig. 2A and B, in the untreated infected rats, the mean log CE counts and the mean log GM concentrations increased over time in the first days after fungal infection. However, the fungal burden in terms of the DNA or the GM concentration did not decrease during caspofungin therapy when it was started 72 h after fungal infection. Even in rats treated with caspofungin dosage schedules that resulted in a significant rat survival rate of 67%, the fungal burden in the left lung still remained high. Figure 3 shows that in untreated infected control rats, the mean log GM concentration in serum increased over time, from undetectable on day 1 to 0.98 ng/ml on day 6. In the caspofungin-treated animals, the GM levels further increased, with peak levels on day 9 (6 days after the start of treatment). From that time, the GM levels in the surviving animals decreased.

View larger version (37K): [in this window] [in a new window]

FIG. 2. Number of CEs (A) and concentration of GM (B) in the infected left lung of surviving transiently neutropenic rats with invasive pulmonary aspergillosis treated with caspofungin (CAS). Caspofungin treatment was started 72 h after fungal inoculation and consisted of 10 days of treatment at 4 mg/kg/day (10*4), 3 days of treatment at 10 mg/kg/day followed by 7 days of treatment at 4 mg/kg/day (3*10 + 7*4), or 10 days of treatment at 10 mg/kg/day (10*10). The numbers above the bars indicate the numbers of surviving rats in groups of six rats at each time interval. The error bars represent standard deviations.

View larger version (18K): [in this window] [in a new window]

FIG. 3. Concentration of GM in the serum of surviving transiently neutropenic rats with invasive pulmonary aspergillosis treated with caspofungin (CAS). Caspofungin treatment was started 72 h after fungal inoculation and consisted of 10 days of treatment at 4 mg/kg/day (10*4), 3 days of treatment at 10 mg/kg/day followed by 7 days of treatment at 4 mg/kg/day (3*10 + 7*4), or 10 days of treatment at 10 mg/kg/day (10*10). The numbers indicated above the bars indicate the numbers of surviving rats in groups of six rats at each time interval. The error bars represent standard deviations. In performing the calculations, any sample with a value below the limit of detection was assigned the highest possible value below the limit of detection (GM concentration, 1 ng/ml; log GM concentration, 0 ng/ml).

Top ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
The findings from previous experimental studies on the treatment of invasive aspergillosis in animals have been shown to be of merit in the treatment of this disease in humans (1, 5, 13, 17). However, the effect of the drug in relation to the severity of Aspergillus infection has not yet been evaluated. Also, data on the potential benefit of treatment with a higher dose are needed. We previously showed that in a transiently neutropenic rat model of invasive pulmonary aspergillosis, a therapeutic caspofungin dose of 4 mg/kg/day resulted in 100% rat survival when treatment was started early at 16 h after fungal inoculation, the time at which hyphal growth in the left lung is established. Treatment with 1 mg/kg/day amphotericin B resulted in a survival rate of only 27% on day 21. With the 4-mg/kg/day dose of caspofungin, the GM concentrations in serum decreased to undetectable levels after 11 days postinfection. In the current study we investigated whether caspofungin was also effective against advanced-stage invasive pulmonary aspergillosis, which may be a clinically more relevant end point because the diagnosis of invasive pulmonary aspergillosis is often made at a late stage of disease. To this aim, antifungal treatment of the rats was delayed from 16 h to 24 h or 72 h after fungal inoculation. Although the efficacy of caspofungin treatment decreased with the increase in the severity of infection, this decrease in efficacy could partly be compensated for by increasing the dose of caspofungin from 4 to 10 mg/kg/day. A regimen of caspofungin in which the caspofungin dose was increased during only the first 3 days of treatment was essential to increase the therapeutic efficacy.

A relatively high AUC₂₄ (549.3 µg·h/ml) was observed after 3 days of treatment with the high dose of 10 mg/kg/day caspofungin. The AUC₂₄ value of 114 µg·h/ml obtained after the last dose of 4 mg/kg/day at day 10 of the high-dose-step-down schedule was comparable to the AUC₂₄ value of 91.8 µg·h/ml obtained after a single 4-mg/kg/day dose, as published before (17). At 1 h after administration of the last dose of 4 mg/kg/day on day 10 of the high-dose-step-down schedule, the concentration in plasma was twofold higher than that achieved with a single 4-mg/kg/day dose (17); at 12 h after administration, the levels in plasma were similar. The AUCs presented here were determined in neutropenic noninfected animals, which could result in an underestimation of the real AUC, as demonstrated by Groll et al. for anidulafungin, another member of the echinocandin class (9). It should be noted that the AUC₂₄ value obtained after the administration of 10 mg/kg/day caspofungin was not proportionally increased, based on the increase in the dosage, compared to the AUC₂₄ value obtained after the administration of 4 mg/kg/day. This cannot be easily explained.

The benefit of a relatively high AUC₂₄ in the first phase of the therapy was also observed in humans by Stone et al. (15). They showed that a loading dose on day 1 generates a higher drug concentration in plasma during the initial days of therapy; without this dose the mean concentration during the first days of therapy is below the target concentration (15). This could explain why the high-dose-step-down regimen was more efficacious.

The increase in the efficacy of higher doses of caspofungin in severely infected rats was observed only in terms of rat survival and the lower concentrations of GM in serum. At the same time the decrease in the fungal burden in the lung in terms of the amount of DNA or GM in the left lung was not observed. Both GM, a constituent of the fungal cell wall (8), and DNA are present as viable as well as nonviable fungal masses that have not yet been cleared by the host. In this respect, the amount of GM measured in serum may be more informative than the data from the site of infection, as the detection of GM in serum may reflect the presence of an active infection.

Caspofungin at the relatively high dose of 10 mg/kg/day resulted in toxic side effects in some animals shortly after administration. Similar observations have been reported for mice treated with the echinocandins anidulafungin (previously known as LY303366) and micafungin (6, 7, 14). In the study of Clemons et al. (6), 90% of the noninfected mice treated with anidulafungin at 50 mg/kg/day had died after 3 days of treatment. The toxicity of anidulafungin appeared to be the result of drug interactions with immunosuppressive agents like cortisone, hydrocortisone, or triamcinolone (6). The nature of the toxicity for the echinocandins still remains unclear, since no histological evidence for the cause of death in the anidulafungin-treated animals was found (6). In our study, the hepatic and renal functions of the rats were monitored, and all values remained in the normal range, even for animals treated with the relatively high dosage of caspofungin. The nature of this observed side effect may be related to the rapid absorption of the drug when it is given intraperitoneally to experimental animals. In humans, however, caspofungin is given intravenously over 1 h.

Currently, clinical studies on the safety and efficacy of higher doses of caspofungin for the treatment of invasive Candida infections are ongoing. The present study suggests that this approach, which includes high-dose-step-down treatment, may be useful for the treatment of invasive pulmonary aspergillosis as well.

 
This study was financially supported in part by Merck Research Laboratories, Rahway, NJ.

 
* Corresponding author. Mailing address: Erasmus MC, University Medical Center Rotterdam, Department of Medical Microbiology & Infectious Diseases, 's-Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands. Phone: 31-10-7035820. Fax: 31-10-7033875. E-mail: w.vandesande{at}erasmusmc.nl

Published ahead of print on 14 January 2008.

Top ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 

1
1. Abruzzo, G. K., C. J. Gill, A. M. Flattery, L. Kong, C. Leighton, J. G. Smith, V. B. Pikounis, K. Bartizal, and H. Rosen. 2000. Efficacy of the echinocandin caspofungin against disseminated aspergillosis and candidiasis in cyclophosphamide-induced immunosuppressed mice. Antimicrob. Agents Chemother. 44:2310-2318.[Abstract/Free Full Text]
2
2. Becker, M. J., S. de Marie, M. H. Fens, H. A. Verbrugh, and I. A. Bakker-Woudenberg. 2003. Effect of amphotericin B treatment on kinetics of cytokines and parameters of fungal load in neutropenic rats with invasive pulmonary aspergillosis. J. Antimicrob. Chemother. 52:428-434.[Abstract/Free Full Text]
3
3. Becker, M. J., S. de Marie, D. Willemse, H. A. Verbrugh, and I. A. Bakker-Woudenberg. 2000. Quantitative galactomannan detection is superior to PCR in diagnosing and monitoring invasive pulmonary aspergillosis in an experimental rat model. J. Clin. Microbiol. 38:1434-1438.[Abstract/Free Full Text]
4
4. Betts, R., A. Glasmacher, J. Maertens, G. Maschmeyer, J. A. Vazquez, H. Teppler, A. Taylor, R. Lupinacci, C. Sable, and N. Kartsonis. 2006. Efficacy of caspofungin against invasive Candida or invasive Aspergillus infections in neutropenic patients. Cancer 106:466-473.[CrossRef][Medline]
5
5. Bowman, J. C., G. K. Abruzzo, J. W. Anderson, A. M. Flattery, C. J. Gill, V. B. Pikounis, D. M. Schmatz, P. A. Liberator, and C. M. Douglas. 2001. Quantitative PCR assay to measure Aspergillus fumigatus burden in a murine model of disseminated aspergillosis: demonstration of efficacy of caspofungin acetate. Antimicrob. Agents Chemother. 45:3474-3481.[Abstract/Free Full Text]
6
6. Clemons, K. V., R. A. Sobel, and D. A. Stevens. 2000. Toxicity of LY303366, an echinocandin antifungal, in mice pretreated with glucocorticoids. Antimicrob. Agents Chemother. 44:378-381.[Abstract/Free Full Text]
7
7. Clemons, K. V., and D. A. Stevens. 2006. Efficacy of micafungin alone or in combination against experimental pulmonary aspergillosis. Med. Mycol. 44:69-73.[CrossRef][Medline]
7
8. Council of the European Commission. 1986. Guidelines on the protection of experimental animals. European Commission, Brussels, Belgium.
8
9. Fontaine, T., C. Simenel, G. Dubreucq, O. Adam, M. Delepierre, J. Lemoine, C. E. Vorgias, M. Diaquin, and J. P. Latge. 2000. Molecular organization of the alkali-insoluble fraction of Aspergillus fumigatus cell wall. J. Biol. Chem. 275:27594-27607.[Abstract/Free Full Text]
9
10. Groll, A. H., D. Mickiene, R. Petraitiene, V. Petraitis, C. A. Lyman, J. S. Bacher, S. C. Piscitelli, and T. J. Walsh. 2001. Pharmacokinetic and pharmacodynamic modeling of anidulafungin (LY303366): reappraisal of its efficacy in neutropenic animal models of opportunistic mycoses using optimal plasma sampling. Antimicrob. Agents Chemother. 45:2845-2855.[Abstract/Free Full Text]
10
11. Maertens, J., I. Raad, G. Petrikkos, M. Boogaerts, D. Selleslag, F. B. Petersen, C. A. Sable, N. A. Kartsonis, A. Ngai, A. Taylor, T. F. Patterson, D. W. Denning, and T. J. Walsh. 2004. Efficacy and safety of caspofungin for treatment of invasive aspergillosis in patients refractory to or intolerant of conventional antifungal therapy. Clin. Infect. Dis. 39:1563-1571.[CrossRef][Medline]
11
12. Maschmeyer, G., and A. Glasmacher. 2005. Pharmacological properties and clinical efficacy of a recently licensed systemic antifungal, caspofungin. Mycoses 48:227-234.[CrossRef][Medline]
12
13. Morrison, V. A. 2006. Echinocandin antifungals: review and update. Expert. Rev. Anti-Infect. Ther. 4:325-342.[CrossRef]
13
14. Petraitiene, R., V. Petraitis, A. H. Groll, T. Sein, R. L. Schaufele, A. Francesconi, J. Bacher, N. A. Avila, and T. J. Walsh. 2002. Antifungal efficacy of caspofungin (MK-0991) in experimental pulmonary aspergillosis in persistently neutropenic rabbits: pharmacokinetics, drug disposition, and relationship to galactomannan antigenemia. Antimicrob. Agents Chemother. 46:12-23.[Abstract/Free Full Text]
14
15. Petraitis, V., R. Petraitiene, A. H. Groll, A. Bell, D. P. Callender, T. Sein, R. L. Schaufele, C. L. McMillian, J. Bacher, and T. J. Walsh. 1998. Antifungal efficacy, safety, and single-dose pharmacokinetics of LY303366, a novel echinocandin B, in experimental pulmonary aspergillosis in persistently neutropenic rabbits. Antimicrob. Agents Chemother. 42:2898-2905.[Abstract/Free Full Text]
15
16. Stone, J. A., S. D. Holland, P. J. Wickersham, A. Sterrett, M. Schwartz, C. Bonfiglio, M. Hesney, G. A. Winchell, P. J. Deutsch, H. Greenberg, T. L. Hunt, and S. A. Waldman. 2002. Single- and multiple-dose pharmacokinetics of caspofungin in healthy men. Antimicrob. Agents Chemother. 46:739-745.[Abstract/Free Full Text]
16
17. van Doornum, G. J., J. Guldemeester, A. D. Osterhaus, and H. G. Niesters. 2003. Diagnosing herpesvirus infections by real-time amplification and rapid culture. J. Clin. Microbiol. 41:576-580.[Abstract/Free Full Text]
17
18. van Vianen, W., S. de Marie, M. T. ten Kate, R. A. Mathot, and I. A. Bakker-Woudenberg. 2006. Caspofungin: antifungal activity in vitro, pharmacokinetics, and effects on fungal load and animal survival in neutropenic rats with invasive pulmonary aspergillosis. J. Antimicrob. Chemother. 57:732-740.[Abstract/Free Full Text]
18
19. Walsh, T. J., H. Teppler, G. R. Donowitz, J. A. Maertens, L. R. Baden, A. Dmoszynska, O. A. Cornely, M. R. Bourque, R. J. Lupinacci, C. A. Sable, and B. E. dePauw. 2004. Caspofungin versus liposomal amphotericin B for empirical antifungal therapy in patients with persistent fever and neutropenia. N. Engl. J. Med. 351:1391-1402.[Abstract/Free Full Text]

---

Antimicrobial Agents and Chemotherapy, April 2008, p. 1345-1350, Vol. 52, No. 4
0066-4804/08/$08.00+0     doi:10.1128/AAC.00536-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

This article has been cited by other articles:

• van de Sande, W. W. J., Mathot, R. A. A., ten Kate, M. T., van Vianen, W., Tavakol, M., Rijnders, B. J. A., Bakker-Woudenberg, I. A. J. M. (2009). Combination Therapy of Advanced Invasive Pulmonary Aspergillosis in Transiently Neutropenic Rats Using Human Pharmacokinetic Equivalent Doses of Voriconazole and Anidulafungin. Antimicrob. Agents Chemother. 53: 2005-2013 [Abstract] [Full Text]  

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by van de Sande, W. W. J. Articles by Bakker-Woudenberg, I. A. J. M. Search for Related Content PubMed PubMed Citation Articles by van de Sande, W. W. J. Articles by Bakker-Woudenberg, I. A. J. M.