title: In vitro interaction of caspofungin and immunosuppressives against agents of mucormycosis.
abstract: OBJECTIVE
  Mucormycosis is a rare but refractory mycosis with high mortality. Few therapeutic options are available and novel strategies are needed. Calcineurin inhibitors are known to have antifungal activity, including synergy with various antifungals. We examined the interaction of caspofungin with calcineurin inhibitors and sirolimus against Glomeromycetes.
  
  
  METHODS
  Twenty-six strains of Glomeromycetes representing seven species (Rhizopus arrhizus, Rhizopus microsporus, Mucor sp., Rhizomucor pusillus, Cunninghamella berthollettiae, Mycocladus corymbifera and Apophysomyces elegans) were studied. Antifungal susceptibility testing was performed according to CLSI M38-A2, modified for chequerboard dilution testing using the minimum effective concentration (MEC) endpoint for caspofungin and calcineurin inhibitors/sirolimus. Synergy was defined as a fractional inhibitory concentration index ≤0.5, indifference >0.5 to ≤4.0 and antagonism >4.0.
  
  
  RESULTS
  Caspofungin had no intrinsic activity against Glomeromycetes (MEC >8 mg/L). The combination of caspofungin with calcineurin inhibitors and sirolimus showed synergy in seven isolates. In the presence of calcineurin inhibitors and sirolimus, the MEC of caspofungin was significantly lowered (>4-fold) in 24 and 7 isolates, respectively. All species showed lower MECs of caspofungin with calcineurin inhibitors and only R. arrhizus, Mucor sp. and R. pusillus showed lower MECs with sirolimus. No antagonism was observed.
  
  
  CONCLUSIONS
  Calcineurin inhibitors and sirolimus significantly lowered MECs of caspofungin for Glomeromycetes, with occasional synergy observed. The clinical significance of this should be further investigated.
authors.affiliation: Department of Medicine, Wayne State University, Detroit, MI, USA.
authors.forename: Manish
authors.initials: M
authors.lastname: Thakur
authors.forename: Sanjay G
authors.initials: SG
authors.lastname: Revankar
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D065095:Calcineurin Inhibitors; D000077336:Caspofungin; D004347:Drug Interactions; D026141:Drug Resistance, Multiple, Fungal; D004357:Drug Synergism; D054714:Echinocandins / Q000494:pharmacology*; D055137:Glomeromycota / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D055666:Lipopeptides; D008826:Microbial Sensitivity Tests; D009090:Mucorales / Q000187:drug effects*; D009091:Mucormycosis / Q000188:drug therapy / Q000382:microbiology*; D020123:Sirolimus / Q000494:pharmacology
chemical_list: D000935:Antifungal Agents; D065095:Calcineurin Inhibitors; D054714:Echinocandins; D007166:Immunosuppressive Agents; D055666:Lipopeptides; D000077336:Caspofungin; D020123:Sirolimus