Efficacy of posaconazole in a murine disseminated infection by Candida tropicalis.
ABSTRACT We evaluated the efficacy of posaconazole against Candida tropicalis in a systemic infection model with immunosuppressed mice. Posaconazole at 50 mg/kg of body weight/day prolonged the survival of mice and reduced the fungal tissue burden of mice infected with any of the five strains tested, with the exception of one strain that had a high MIC against this drug. Our results demonstrate the efficacy of posaconazole in the treatment of invasive murine infection caused by C. tropicalis.
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ABSTRACT: We have compared the efficacy of posaconazole and amphotericin B in an experimental murine model of paecilomycosis. Immunosuppressed mice were treated with posaconazole at 25, 50, 75 or 100 mg/kg/day orally, amphotericin B at 1.5 or 3 mg/kg/day intraperitoneally or liposomal amphotericin B at 5 mg/kg/day intravenously. Treatment began 1 day after infection and continued for 10 days post-infection. Two strains of Paecilomyces lilacinus were tested. Posaconazole at 50 mg/kg/day was the only treatment able to significantly reduce fungal loads in the spleens, kidneys and livers of the mice infected by each of the two strains. The results suggest that posaconazole may have a clinical role in the treatment of disseminated paecilomycosis.Journal of Antimicrobial Chemotherapy 01/2009; 63(2):361-4. · 5.34 Impact Factor
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ABSTRACT: The pharmacology, pharmacokinetics, pharmacodynamics, spectrum of activity and resistance, clinical utility, adverse effects, dosage and administration, and recommended monitoring of posaconazole are reviewed. Posaconazole is a member of the azole class of antifungals recently approved for the prophylaxis and treatment of invasive fungal infections. Posaconazole has a large volume of distribution and distributes well into tissues. Posaconazole-induced fungal killing is optimal when peak drug concentrations achieved are 2-10 times the organism's minimum inhibitory concentration. Posaconazole demonstrates fungistatic activity against most species of Candida, Cryptococcus, and Trichosporon. In a direct comparison, posaconazole appeared 2-4 times more active than itraconazole against most pathogenic yeast species. Posaconazole also showed activity against Candida and Aspergillus isolates resistant to the other azoles and amphotericin B. Posaconazole has superior activity to the other azoles against Zygomycetes isolates. It has demonstrated activity equal or superior to other antifungal agents against almost all varieties of yeast and mold. The most common treatment-related adverse events associated with posaconazole are nausea, vomiting, diarrhea, rash, hypokalemia, thrombocytopenia, and abnormal liver function test values. Significant drug interactions include cimetidine, rifabutin, and phenytoin, for which concomitant use should be avoided, as well as cyclosporine, tacrolimus, and midazolam, for which dosage reductions are recommended. Posaconazole is an oral anti-fungal agent with a broader spectrum of activity and better clinical efficacy than other available antifungals. It is less nephrotoxic than the polyenes and probably less likely to be involved in drug-drug interactions than the mold-active azoles.American journal of health-system pharmacy: AJHP: official journal of the American Society of Health-System Pharmacists 03/2009; 66(3):225-36. · 2.10 Impact Factor
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ABSTRACT: The risk factors for and presentation of Candida tropicalis fungemia, in comparison with those of Candida albicans, have been incompletely characterized. We compared 43 cases of C. tropicalis fungemia with 148 cases of C. albicans fungemia. In univariate analysis, patients with C. tropicalis fungemia were more likely to have leukemia (P=.0006), prolonged neutropenia (P=.03), and a positive blood culture for more days (P=.02). The 2 groups did not differ with regard to baseline Acute Physiology and Chronic Health Evaluation (APACHE) II score, frequency of catheter-associated fungemia, or response to antifungals. In multivariate analysis, patients with C. tropicalis fungemia were more likely to have leukemia (P=.02), previous neutropenia (P=.002), and a longer stay in the intensive care unit during the infectious episode (P=.01). Also, the response of the breakthrough C. tropicalis fungemia was lower (P=.05). In conclusion, the host determinants associated with susceptibility to C. tropicalis are leukemia and prolonged neutropenia.Clinical Infectious Diseases 12/2001; 33(10):1676-81. · 9.37 Impact Factor
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Jan. 2010, p. 530–532
Copyright © 2010, American Society for Microbiology. All Rights Reserved.
Vol. 54, No. 1
Efficacy of Posaconazole in a Murine Disseminated
Infection by Candida tropicalis?
Marc ¸al Marine ´, F. Javier Pastor, and Josep Guarro*
Unitat de Microbiologia, Facultat de Medicina i Cie `ncies de la Salut, IISPV, Universitat Rovira i Virgili, Reus, Spain
Received 10 August 2009/Returned for modification 9 September 2009/Accepted 10 October 2009
We evaluated the efficacy of posaconazole against Candida tropicalis in a systemic infection model with
immunosuppressed mice. Posaconazole at 50 mg/kg of body weight/day prolonged the survival of mice and
reduced the fungal tissue burden of mice infected with any of the five strains tested, with the exception of one
strain that had a high MIC against this drug. Our results demonstrate the efficacy of posaconazole in the
treatment of invasive murine infection caused by C. tropicalis.
Candidiasis has become an important cause of nosocomial
bloodstream infections, with associated mortality rates as high
as 40% (10, 11). Candida tropicalis is the third or fourth most
commonly isolated species of Candida (5, 11). Although this
species is not considered more virulent than other Candida
species, such as C. albicans (7), it has been associated with
higher mortality rates in cancer patients (15). It is particularly
virulent in neutropenic hosts (10), and current therapies need
Posaconazole (PSC) is active in vitro, similarly to itracon-
azole and voriconazole, against most Candida species (3), and
it is less likely to be involved in drug-drug interactions (9). PSC
is approved for the treatment of several filamentous fungus
infections and oropharyngeal candidiasis in immunocompro-
mised patients (14). However, there are no adequate clinical
data for making an evidence-based recommendation for treat-
ment of candidiasis infections other than oropharyngeal can-
To improve our knowledge of the part this drug can play
in the management of Candida infections, the present study
tested the efficacy of PSC in an immunocompromised murine
model of disseminated infection by C. tropicalis.
Seventeen clinical strains of C. tropicalis were used in the
study (Table 1). Susceptibility was determined using a refer-
ence method (2). The minimal fungicidal concentration (MFC)
was defined as that producing a 99.9% or greater reduction in
the number of CFU/ml (6). A hemocytometer was used to
adjust the desired fungal inoculum for both in vitro and in vivo
Male OF1 mice were used following the procedural stan-
dards approved by the Animal Welfare Committee of the Ro-
vira i Virgili University.
For survival and tissue burden studies, mice received 200
mg/kg of body weight of cyclophosphamide intraperitoneally
(i.p.) plus 150 mg/kg of 5-fluorouracil intravenously (i.v.) on
the same day of infection. PSC was purchased as Noxafil (Sche-
ring-Plough Ltd.). Five strains representing different in vitro
susceptibility patterns were chosen for the in vivo studies. Mice
were challenged with 1 ? 105CFU in 0.2 ml i.v. In previous
tests, this inoculum caused mortality rates of 75 to 100%
within 12 days of infection (data not shown). Groups of 10
mice were randomly established for survival and tissue bur-
den studies for each treatment and strain. The different
groups were treated with PSC at 50 mg/kg given orally (p.o.)
once daily (q.d.) (12) or 25 mg/kg given twice daily (b.i.d.).
Control animals received no treatment. All treatments be-
gan 24 h after challenge, and the therapy lasted for 5 days.
For survival studies, mice were checked daily for 15 days.
For tissue burden studies mice were killed 1 day after the
completion of treatment, the spleen and kidneys were asep-
tically removed and weighed, and the organs were homog-
enized in 1 ml of sterile saline. Serial 10-fold dilutions of the
homogenates were plated on Sabouraud dextrose agar, in-
cubated at 35°C, and examined daily for 3 days.
Mean survival time was estimated by the Kaplan-Meier
method and compared among groups using the log-rank test.
Colony counts in tissue burden studies were analyzed using the
* Corresponding author. Mailing address: Unitat de Microbiologia,
Facultat de Medicina, IISPV, Universitat Rovira i Virgili, Carrer Sant
Llorenc ¸ 21, 43201, Reus, Spain. Phone: 34-977-759359. Fax: 34-977-
759322. E-mail: email@example.com.
?Published ahead of print on 19 October 2009.
TABLE 1. Antifungal activity of posaconazole in vitro against 17
strains of C. tropicalis
aThe MIC-2 corresponds to 50% growth inhibition.
bThe MFC corresponds to a 99.9% or greater reduction in CFU/ml.
Mann-Whitney U test. A P value of ?0.05 was considered
A MIC higher than 16 ?g/ml was observed only for strain
FMR 8895, while for the other strains PSC showed MICs of ?1
?g/ml (Table 1). Representative strains with low, intermediate,
and high MICs were chosen for in vivo studies. Trailing growth
effects and MFCs higher than 16 ?g/ml were observed for all
the strains tested, with the exception of strain FMR 10239,
which was also chosen for the in vivo studies.
Both PSC regimens significantly prolonged survival (Fig. 1)
and reduced fungal tissue burdens in kidneys and spleen (Fig.
2) of mice relative to the control group (P ? 0.05) for all the
strains with the exception of FMR 8895. Fungal tissue burden
reduction was greater for strain FMR 10239 than for the other
strains for both organs and for both PSC regimens tested (P ?
0.05). No statistical differences were observed in survival or
tissue burden between mice treated with PSC at 50 mg/kg q.d.
and those treated with PSC at 25 mg/kg b.i.d.
In the present study, we selected C. tropicalis isolates with
different susceptibility patterns to PSC in order to compare the
efficacy of this drug against them in vivo. The high prevalence
of trailing growth effects is well known among C. tropicalis
isolates in in vitro tests for azole drugs (1). The correct reading
of the MICs avoids their misclassification into the resistant
category, although the fact that many isolates of this species
retain the ability to grow, even at high concentrations of the
drug, is a matter for concern.
Dividing daily PSC intakes into various dosages has been
FIG. 1. Cumulative mortality of mice infected with C. tropicalis FMR 8895 (A), FMR 9726 (B), FMR 9727 (C), FMR 10237 (D), or FMR
10239 (E). PSC50, posaconazole at 50 mg/kg p.o., q.d.; PSC25, posaconazole at 25 mg/kg p.o., b.i.d. The footnote letter a indicates P ? 0.05
VOL. 54, 2010POSACONAZOLE ACTIVITY AGAINST C. TROPICALIS531
shown to increase the absorption of this drug in humans (4, 8).
In this study, however, no statistical differences were observed
between single and divided dosage regimens.
PSC has been described as a fungistatic against C. tropicalis
(13), which agrees with the results of this study, in which a low
MFC was observed for only 1 out of 17 strains. The higher
activity observed in vitro for this strain (FMR 10239) also
corresponded to a higher fungal tissue burden reduction in
vivo. Despite the high MFCs in this study, PSC showed efficacy
in the treatment of C. tropicalis infection for all the strains
tested, with the exception of the strain that showed a high MIC
in vitro for this drug (FMR 8895).
Our results suggest that trailing growth effects and high
MFCs observed for many strains of C. tropicalis are not pre-
dictive of a reduced efficacy of PSC in vivo against this species,
and only a correlation between a high MIC and a poor re-
sponse in vivo was observed for this drug. PSC was effective
against most strains of C. tropicalis tested and merits further
investigation in order to develop future effective treatments for
C. tropicalis disseminated infections.
This work was supported by a grant from Fondo de Investigaciones
Sanitarias from the Ministerio de Sanidad y Consumo of Spain (PI
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FIG. 2. Effects of antifungal treatments on tissue burdens of C.
tropicalis FMR 8895, FMR 9726, FMR 9727, FMR 10237, and FMR
10239 in kidneys (A) and spleens (B) of mice. PSC50, posaconazole at
50 mg/kg p.o., q.d.; PSC25, posaconazole at 25 mg/kg p.o., b.i.d. The
footnote letter a indicates P ? 0.05 versus control. Horizontal lines in
scatter plots indicate mean values.
532 MARINE´ET AL.ANTIMICROB. AGENTS CHEMOTHER.