Synergistic Effect of Posaconazole and Caspofungin against Clinical Zygomycetes

Guembe, María; Guinea, Jesús; Peláez, Teresa; Torres-Narbona, Marta; Bouza, Emilio

doi:10.1128/aac.00595-07

Cited by 52 publications

(38 citation statements)

References 10 publications

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“…Note that synergism between POSA and CAS was identified not only in A. fumigatus but also in Zygomycetes and Candida spp. (36)(37)(38). The previously reported FICi of 0.32 against azole-susceptible A. fumigatus was similar to the FICi found in the present study.…”

Section: Figsupporting

confidence: 91%

“…Although a marked synergistic effect between POSA and CAS was demonstrated in previous investigations, the mechanism of this remains unclear (18,37). Our data show that the POSA MIC is a major determinant of the strength of the synergistic interaction and that this synergistic effect is concentration dependent, with strong interactions observed at concentrations of Ͻ0.5ϫ MIC.…”

Section: Figsupporting

confidence: 48%

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The Strength of Synergistic Interaction between Posaconazole and Caspofungin Depends on the Underlying Azole Resistance Mechanism of Aspergillus fumigatus

Mavridou

Meletiadis

Rijs

et al. 2015

Antimicrob Agents Chemother

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bThe majority of azole resistance mechanisms in Aspergillus fumigatus correspond to mutations in the cyp51A gene. As azoles are less effective against infections caused by multiply azole-resistant A. fumigatus isolates, new therapeutic options are warranted for treating these infections. We therefore investigated the in vitro combination of posaconazole (POSA) and caspofungin (CAS) against 20 wild-type and resistant A. fumigatus isolates with 10 different resistance mechanisms. Fungal growth was assessed with the XTT [2,3-bis (2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide inner salt] method. Pharmacodynamic interactions were assessed with the fractional inhibitory concentration (FIC) index (FICi) on the basis of 10% (FICi-0), 25% (FICi-1), or 53 0% (FICi-2) growth, and FICs were correlated with POSA and CAS concentrations. Synergy and antagonism were concluded when the FICi values were statistically significantly (t test, P < 0.05) lower than 1 and higher than 1.25, respectively. Significant synergy was found for all isolates with mean FICi-0 values ranging from 0.28 to 0.75 (median, 0.46). Stronger synergistic interactions were found with FICi-1 (median, 0.18; range, 0.07 to 0.47) and FICi-2 (0.31; 0.07 to 0.6). The FICi-2 values of isolates with tandem-repeat-containing mutations or codon M220 were lower than those seen with the other isolates (P < 0.01). FIC-2 values were inversely correlated with POSA MICs (r s ‫؍‬ ؊0.52, P ‫؍‬ 0.0006) and linearly with the ratio of drug concentrations in combination over the MIC of POSA (r s ‫؍‬ 0.76, P < 0.0001) and CAS (r s ‫؍‬ 0.52, P ‫؍‬ 0.0004). The synergistic effect of the combination of POSA and CAS (POSA/CAS) against A. fumigatus isolates depended on the underlying azole resistance mechanism. Moreover, the drug combination synergy was found to be increased against isolates with elevated POSA MICs compared to wild-type isolates.T he opportunistic fungal pathogen Aspergillus fumigatus has been associated with several life-threatening infections in immunocompromised patients. Although azoles are the mainstay of antifungal therapy, treatment of aspergillosis is a difficult task which is further complicated by the lack of therapeutic efficacy in infections due to multiply azole-resistant A. fumigatus (1-3).Azoles are inhibitors of the 14-␣ sterol demethylase in A. fumigatus, which is a product of cyp51A and cyp51B. Since the discovery of these orthologs to the Candida albicans egr11 gene, a number of single nucleotide polymorphisms (SNPs) have been found, several of which have been associated with elevated azole MICs in vitro, corresponding to treatment failure in vivo (1, 4-7). It is believed that SNPs may develop through azole treatment or through exposure to azole fungicides in the environment (8-10). Treatment-induced SNPs in cyp51A are mainly allocated at codon 38, 54, or 220, while fungicide-induced SNPs are mostly located at codon 98, usually combined with tandem repeats within the promoter (8-10). Very recently, a new environmental azole resist...

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Section: Figsupporting

confidence: 91%

Section: Figsupporting

confidence: 48%

The Strength of Synergistic Interaction between Posaconazole and Caspofungin Depends on the Underlying Azole Resistance Mechanism of Aspergillus fumigatus

Mavridou

Meletiadis

Rijs

et al. 2015

Antimicrob Agents Chemother

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“…Accurate identification of pathogenic fungi is the cornerstone to prescribing antifungal treatment (2,7,9,17); for example, identification of R. microsporus will necessitate the prescription of a combination treatment of posaconazole, amphotericin B, and caspofungin as posaconazole has been shown to have synergistic effects with amphotericin B and caspofungin against the Mucorales (6,16). For molecular identification of fungal pathogens, the ITS is one of the most commonly used targets because its length and sequence are relatively conserved for the same fungal species but often different in different fungal species (4,23).…”

Section: Discussionmentioning

confidence: 99%

Internal Transcribed Spacer Region Sequence Heterogeneity in Rhizopus microsporus : Implications for Molecular Diagnosis in Clinical Microbiology Laboratories

Woo¹,

Leung²,

To³

et al. 2010

J Clin Microbiol

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Although internal transcribed spacer region (ITS) sequence heterogeneity has been reported in a few fungal species, it has very rarely been reported in pathogenic fungi and has never been described in Mucorales, causes of the highly fatal mucormycosis. In a recent outbreak investigation of intestinal mucormycosis due to Rhizopus microsporus infection in patients with hematological malignancies, PCR of the ITS of four of the 28 R. microsporus strains, P11, P12, D3-1, and D4-1, showed thick bands at about 700 bp. Direct sequencing of the purified bands showed frequent double peaks along all of the sequence traces and occasional triple peaks for P12, D3-1, and D4-1. The thick bands of the four R. microsporus strains were purified and cloned. Sequencing of 10 clones for each strain revealed two different ITS sequences for P11 and three different ITS sequences for P12, D3-1, and D4-1. Variations in ITS sequence among the different ribosomal DNA (rDNA) operons in the same strain were observed in only ITS1 and ITS2 and not the 5.8S rDNA region. One copy of P11, P12, and D4-1, respectively, and one copy of P11, P12, D3-1, and D4-1, respectively, showed identical sequences. This represents the first evidence of ITS sequence heterogeneity in Mucorales. ITS sequence heterogeneity is an obstacle to molecular identification and genotyping of fungi in clinical microbiology laboratories. When thick bands and double peaks are observed during PCR sequencing of a gene target, such a strain should be sent to reference laboratories proficient in molecular technologies for further identification and/or genotyping.Genes and intergenic regions of ribosomal DNA (rDNA) operons are the most widely used targets for molecular identification of bacteria and fungi in clinical microbiology laboratories. For bacterial identification, the 16S rDNA gene is the primary target to amplify and sequence (28), whereas for fungi, the 18S rDNA gene and internal transcribed spacer region (ITS) comprising the ITS1-5.8S-ITS2 rDNA gene cluster are commonly used, depending on the group of fungi being identified (4,10,23,27). Irrespective of the target, such a molecular identification technique usually involves PCR amplification of the target and purification and direct sequencing of the PCR product. Since most bacterial and fungal genomes contain more than one rDNA operon, the success of using this technology relies on sequence homogeneity in the various copies of targets in the rDNA operons within the genome of the bacterium or fungus.Interoperon heterogeneities for 16S rDNA genes have been reported in a number of bacteria (3,12). Recently, we reported rDNA operon heterogeneity in a novel genus and species of bacterium, Anaerospora hongkongensis, isolated from an intravenous drug user (25). When present, such rDNA operon heterogeneity will pose difficulties for direct sequencing of the PCR product for bacterial identification as double or multiple nucleotide peaks will be present in the sequence traces. Although ITS sequence heterogeneity has been reported ...

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“…Notably, synergism with caspofungin was easier to acquire than synergism between terbinafine and amphotericin B, posaconazole, or itraconazole in our study. Guembe et al (22) observed 100% synergism against 12 zygomycetes with the combination of posaconazole and caspofungin. Drogari-Apiranthitou et al (23) studied potential interactions between anidulafungin and amphotericin B against 21 mucormycetes and observed synergism against one Mucor circinelloides isolate and no antagonism.…”

mentioning

confidence: 99%

“…Some zygomycetes do express the FKS1 gene (27), which is a target of echinocandins, so that maybe a change in the membrane environment caused by other drugs could make FKS1 more accessible to echinocandins (22,23).…”

mentioning

confidence: 99%

Drug Combinations against Mucor irregularis In Vitro

Zhang

2013

Antimicrob Agents Chemother

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Combinations of terbinafine or caspofungin with amphotericin B, posaconazole, or itraconazole were studied as potential treatments against 18 isolates of Mucor irregularis in vitro. Synergism of the combinations of terbinafine with amphotericin B, posaconazole, and itraconazole against 38.9, 33.3, and 44.4% of the strains studied was observed. In contrast, synergism of the combinations of caspofungin with amphotericin B, posaconazole, and itraconazole against 99.4, 66.7, and 99.4% of the strains studied was observed. Furthermore, no antagonism was observed.C utanous zygomycosis is a fungal infection caused mainly by members of the order Mucorales that affect the skin. The most frequently reported genus in the English literature is Rhizopus, followed by Lichtheimia spp. and Rhizomucor pusillus (1). Cutaneous zygomycosis caused by Mucor irregularis (formerly Rhizomucor variabilis) is an emerging disease in China that is characterized by progressive swelling, ulceration, and destruction of involved skin at exposed sites, especially the central face, and leads to severe disfigurement and even death if left untreated (2-4). Notably, it seemed that most of the patients infected with M. irregularis were immunocompetent (2-9).Amphotericin B is the most potent drug used for the treatment of M. irregularis infection, but the toxicity of amphotericin B limits its long-term clinical application. Posaconazole has been used primarily as salvage therapy, but at present, there is no strong published clinical evidence supporting its role as a single agent for the treatment of mucormycosis (10). Itraconazole has variable effectiveness against M. irregularis in vitro (11) but was proven to be effective against some M. irregularis infections (2, 5). Terbinafine is an allylamine antifungal agent used primarily to treat dermotropic infections and onychomycosis but has potential for use in adjunct therapy in combination with azoles, polyenes, or echinocandins in the management of severe drug-resistant or refractory mycosis (12). Besides, terbinafine could reach high concentrations in the stratum corneum and sebum because of its lipophilic nature (13), which provided the possibility that terbinafine can be used in combination therapies to treat cutaneous zygomycosis.To our knowledge, with the exception of some reported cases (7, 9), no susceptibility of M. irregularis to combinations of antifungal drugs in vitro has been reported. In the present study, the combinations of terbinafine or caspofungin with amphotericin B, posaconazole, or itraconazole were assessed against M. irregularis isolates in vitro.A total of 18 M. irregularis patient isolates preserved by the Research Center for Medical Mycology at Peking University were tested. Isolates were identified by both conventional morphological methods and the internal transcribed spacer sequence analysis method (11).Drug combinations were conducted by using a checkerboard method based on Clinical and Laboratory Standards Institute document M38-A2 (14) that provided the MICs of each agen...

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Synergistic Effect of Posaconazole and Caspofungin against Clinical Zygomycetes

Cited by 52 publications

References 10 publications

The Strength of Synergistic Interaction between Posaconazole and Caspofungin Depends on the Underlying Azole Resistance Mechanism of Aspergillus fumigatus

The Strength of Synergistic Interaction between Posaconazole and Caspofungin Depends on the Underlying Azole Resistance Mechanism of Aspergillus fumigatus

Internal Transcribed Spacer Region Sequence Heterogeneity in Rhizopus microsporus : Implications for Molecular Diagnosis in Clinical Microbiology Laboratories

Drug Combinations against Mucor irregularis In Vitro

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