Paradoxical Growth Effect of Caspofungin Observed on Biofilms and Planktonic Cells of Five Different Candida Species

Division of Infectious Diseases, Universidade Federal de Sao Paulo, Sao Paulo, Brazil.
Antimicrobial Agents and Chemotherapy (Impact Factor: 4.48). 09/2007; 51(9):3081-8. DOI: 10.1128/AAC.00676-07
Source: PubMed


The paradoxical growth (PG) of Candida sp. biofilms in the presence of high caspofungin (CAS) concentrations was previously unknown. We sought to characterize the
PG at supra-MICs of CAS among clinical Candida sp. isolates grown as biofilms in 96-well polystyrene microtiter plates. The MICs of CAS were determined for 30 clinical
Candida sp. isolates (4 Candida albicans, 6 C. tropicalis, 7 C. parapsilosis, 8 C. orthopsilosis, and 5 C. metapsilosis isolates) when they were grown as planktonic cells and biofilms and were defined as the lowest drug concentrations that resulted
in a prominent decrease in growth and a 50% reduction in metabolic activity, respectively. PG was defined as a resurgence
of growth (>50% of that in the drug-free growth control well) at drug concentrations above the MIC. With the exception of
C. tropicalis, all isolates displayed PG more frequently when they were grown as biofilms than when they grown as planktonic cells. PG
was undetectable among C. metapsilosis isolates in planktonic cell MIC tests but was present in 100% of the isolates in biofilm MIC tests. The drug concentration
and the number of drug dilutions supporting PG were higher for biofilms than for planktonic cells. Microscopic changes in
cell morphology were observed among both planktonic and biofilm cells with PG. Specifically, the accumulation of enlarged,
globose cells was associated with PG, and we hypothesize that CAS-induced changes in the cell wall composition may be the

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    • "Observation of biofilms formed on the bottom of the wells of microtiter plates is very common using optical microscopes at magnifications of 100 to 200x, which typically cover areas of 0.3 mm2 [36–39]. These observations have provided some information about the architecture of the biofilms formed on the bottom of the wells (particularly when CLSM is used) but usually disregard the biofilm that forms on the vertical wall. "
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    ABSTRACT: Microtiter plates with 96 wells are being increasingly used for biofilm studies due to their high throughput, low cost, easy handling, and easy application of several analytical methods to evaluate different biofilm parameters. These methods provide bulk information about the biofilm formed in each well but lack in detail, namely, regarding the spatial location of the biofilms. This location can be obtained by microscopy observation using optical and electron microscopes, but these techniques have lower throughput and higher cost and are subjected to equipment availability. This work describes a differential crystal violet (CV) staining method that enabled the determination of the spatial location of Escherichia coli biofilms formed in the vertical wall of shaking 96-well plates. It was shown that the biofilms were unevenly distributed on the wall with denser cell accumulation near the air-liquid interface. The results were corroborated by scanning electron microscopy and a correlation was found between biofilm accumulation and the wall shear strain rates determined by computational fluid dynamics. The developed method is quicker and less expensive and has a higher throughput than the existing methods available for spatial location of biofilms in microtiter plates.
    Full-text · Article · Apr 2014
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    • "Another interesting phenomenom is the "eagle effect". In vitro, a paradoxical increase in fungal growth ("paradoxical growth", "eagle effect") could be observed if echinocandin concentration was increased above the organism's MIC [41-43]. However, this effect varies remarkably between the three echinocandins [44]. "
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    ABSTRACT: Echinocandins represent the newest class of antifungal agents. Currently, three echinocandins, anidulafungin, caspofungin and micafungin are licensed for clinical use in various indications. They act as inhibitors of β-(1,3)-glucan synthesis in the fungal cell wall and have a favorable pharmacological profile. They have a broad spectrum of activity against all Candida species. Higher MIC's have been observed against C. parapsilosis and C. guilliermondii. Data from clinical trials for invasive Candida infections / candidaemia suggest that the clinical outcome of patients treated with either drug may be very similar. A comparison has been done between caspofungin and micafungin but for anidulafungin a comparative trial with another echinocandin is still lacking. All three drugs are highly effective if not superior to treatment with either fluconazole or Amphotericin B, particularly in well-defined clinical settings such as invasive Candida infections, Candida oesophagitis and candidaemia. Differences between the three echinocandins with regard to the route of metabolism, requirement for a loading dose, dose adjustment in patients with moderate to severe hepatic disease and different dosing schedules for different types of Candida infections have to be considered. Relevant drug-drug interactions of Caspofungin and Micafungin are minimal. Anidulafungin has no significant drug interactions at all. However, echinocandins are available only for intravenous use. All three agents have an excellent safety profile.
    Preview · Article · Apr 2011 · European journal of medical research
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    • "With regard to MIC, all strains were susceptible to all the tested antifungal agents. However, C. albicans SMC154 showed a paradoxical growth effect for caspofungin, as growth in the presence of caspofungin concentrations above the MIC was observed, in agreement with previous observations (15). In the XTT reduction assay, the biofilms of the three Candida spp. "
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    ABSTRACT: Candidaemia associated with intravascular catheter-associated infections is of great concern due to the resulting high morbidity and mortality. The antibiotic lock technique (ALT) was previously introduced to treat catheter-associated bacterial infections without removal of catheter. So far, the efficacy of ALT against Candida infections has not been rigorously evaluated. We investigated in vitro activity of ALT against Candida biofilms formed by C. albicans, C. glabrata, and C. tropicalis using five antifungal agents (caspofungin, amphotericin B, itraconazole, fluconazole, and voriconazole). The effectiveness of antifungal treatment was assayed by monitoring viable cell counts after exposure to 1 mg/mL solutions of each antibiotic. Fluconazole, itraconazole, and voriconazole eliminated detectable viability in the biofilms of all Candida species within 7, 10, and 14 days, respectively, while caspofungin and amphotericin B did not completely kill fungi in C. albicans and C. glabrata biofilms within 14 days. For C. tropicalis biofilm, caspofungin lock achieved eradication more rapidly than amphotericin B and three azoles. Our study suggests that azoles may be useful ALT agents in the treatment of catheter-related candidemia.
    Full-text · Article · Dec 2010 · Journal of Korean medical science
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