Antifungal Resistance: Aspergillus

Chandrasekar, Pranatharthi H.; Manavathu, Elias K.

doi:10.1007/978-1-60327-595-8_19

Cited by 4 publications

(7 citation statements)

References 92 publications

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“…While echinocandin resistance in Aspergillus is at this point a laboratory phenomenon, triazole resistance is an emerging clinical threat in many regions of the world (17)(18)(19)(20)(21). To our knowledge, this is the first in vivo, dose-ranging pharmacodynamic study examining the effects of combination triazole and echinocandin therapy against Cyp51 wild-type and mutant isolates.…”

Section: ͼ40mentioning

confidence: 97%

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Impact of In Vivo Triazole and Echinocandin Combination Therapy for Invasive Pulmonary Aspergillosis: Enhanced Efficacy against Cyp51 Mutant Isolates

Lepak

Marchillo

VanHecker

et al. 2013

Antimicrob Agents Chemother

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Previous studies examining combination therapy for invasive pulmonary aspergillosis (IPA) have revealed conflicting results, including antagonism, indifference, and enhanced effects. The most commonly employed combination for this infection includes a mold-active triazole and echinocandin. Few studies have evaluated combination therapy from a pharmacodynamic (PD) perspective, and even fewer have examined combination therapy against both wild-type and azole-resistant Cyp51 mutant isolates. The current studies aim to fill this gap in knowledge. Four Aspergillus fumigatus isolates were utilized, including a wildtype strain, an Fks1 mutant (posaconazole susceptible and caspofungin resistant), and two Cyp51 mutants (posaconazole resistant). A neutropenic murine model of IPA was used for the treatment studies. The dosing design included monotherapy with posaconazole, monotherapy with caspofungin, and combination therapy with both. Efficacy was determined using quantitative PCR, and results were normalized to known quantities of conidia (conidial equivalents [CE]). The static dose, 1-log kill dose, and associated PD target area under the curve (AUC)/MIC ratio were determined for monotherapy and combination therapy. Monotherapy experiments revealed potent activity for posaconazole, with reductions of 3 to 4 log 10 Aspergillus CE/ml with the two "low"-MIC isolates. Posaconazole alone was less effective for the two isolates with higher MICs. Caspofungin monotherapy did not produce a significant decrease in fungal burden for any strain. Combination therapy with the two antifungals did not enhance efficacy for the two posaconazole-susceptible isolates. However, the drug combination produced synergistic activity against both posaconazole-resistant isolates. Specifically, the combination resulted in a 1-to 2-log 10 decline in burden that would not have been predicted based on the monotherapy results for each drug. This corresponded to a reduction in the freedrug posaconazole AUC/MIC ratio needed for stasis of up to 17-fold. The data suggest that combination therapy using a triazole and an echinocandin may be a beneficial treatment strategy for triazole-resistant isolates.

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Section: ͼ40mentioning

confidence: 97%

“…However, the recent emergence of A. fumigatus isolates exhibiting reduced susceptibility to triazoles is a threat to this class (17)(18)(19)(20)(21). We theorized that consideration of the pharmacokinetics (PK) and pharmacodynamics (PD) of the triazole-echinocandin interaction would advance our understanding of the utility of this combination strategy.…”

mentioning

confidence: 99%

Impact of In Vivo Triazole and Echinocandin Combination Therapy for Invasive Pulmonary Aspergillosis: Enhanced Efficacy against Cyp51 Mutant Isolates

Lepak

Marchillo

VanHecker

et al. 2013

Antimicrob Agents Chemother

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“…Amino acid variations at M220 leads to pan-azole resistance (6), whereas alterations at E427 in association with another amino acid change(s) confer resistance to Itz and Vcz but not to Pcz (3). G448S amino acid alterations confer high-level resistance to Vcz but only low-level resistance to Itz and Pcz (7,8). In most cases, a single amino acid change is sufficient for conferring resistance in the strain carrying the variant protein.…”

Section: T Riazole Resistance Among Environmental and Clinical Isolatmentioning

confidence: 99%

Molecular Characterization of a Voriconazole-Resistant, Posaconazole-Susceptible Aspergillus fumigatus Isolate in a Lung Transplant Recipient in the United States

Vázquez

Manavathu

2016

Antimicrob Agents Chemother

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Molecular characterization of cyp51A from the azole-resistant Aspergillus fumigatus isolate 50593 from a lung transplant patient showed Y121F/T289A changes coupled with a 46-bp tandem repeat (TR46) on the promoter, whereas cyp51A from the pretherapy isolate, A. fumigatus 47381, showed no changes. This is the first reported case of A. fumigatus azole resistance due to Y121F/T289A/TR46 in the United States, suggesting that multiple mutational alterations of cyp51A resulting in high-level azole resistance could occur during prolonged antifungal therapy.

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“…Tissues for mould culture should be thoroughly macerated and incubated on media for moulds (e.g., brain heart infusion, Sabhi or similar) and inhibitory media if bacterial contamination is expected (Inhibitory Mould Agar) [28]. Identification of Aspergillus, should be at the species level if possible as this may determine choice and response to antifungal therapy [29]. Macroscopic characteristics, microscopic appearance of hyphae and conidial head usually provide species identification in experienced hands.…”

Section: Microbiologymentioning

confidence: 99%

Cardiac Aspergillosis

Lagacé-Wiens¹,

Rubinstein²

2009

Aspergillosis: From Diagnosis to Prevention

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Cardiac aspergillosis has been increasingly recognized as a complication of immunocompromise in recent times. The use of progressively more potent immunosuppressive agents and the longer survival times of transplant recipients is likely contributing to an increasing prevalence of the disease. Although still uncommon, the disease has an extremely high mortality rate and management remains difficult. Cardiac aspergillosis can present as combinations of endocarditis, myocardial invasion or pericarditis and commonly occurs in the context of disseminated aspergillosis. Myocardial involvement is most common, followed by endocarditis although the various forms frequently co-exist. Diagnosis is challenging and is frequently only done post-mortem. Culture diagnosis is best achieved with tissue (valve or biopsy), since blood culture is frequently negative. Any cardiac findings on imaging or physical examination in the context of disseminated aspergillosis suspected by culture, histology or antigen assay should be assumed to be cardiac aspergillosis and investigations for endocarditis should be undertaken. Treatment of cardiac aspergillosis is usually not successful and has not been systematically studied. For endocarditis, surgical and medical therapy are indicated, and medical therapy with either combination amphotericin B and flucytocine or the newer triazoles is suggested. Other forms of cardiac involvement are best managed as disseminated aspergillosis, with a low threshold for diagnosis of endocarditis.

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Antifungal Resistance: Aspergillus

Cited by 4 publications

References 92 publications

Impact of In Vivo Triazole and Echinocandin Combination Therapy for Invasive Pulmonary Aspergillosis: Enhanced Efficacy against Cyp51 Mutant Isolates

Impact of In Vivo Triazole and Echinocandin Combination Therapy for Invasive Pulmonary Aspergillosis: Enhanced Efficacy against Cyp51 Mutant Isolates

Molecular Characterization of a Voriconazole-Resistant, Posaconazole-Susceptible Aspergillus fumigatus Isolate in a Lung Transplant Recipient in the United States

Cardiac Aspergillosis

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