Antifungal Combinations against Candida Species: From Bench to Bedside

Abstract

Candida spp. is the major causative agent of fungal infections in hospitalized patients and the fourth most common cause of nosocomial bloodstream infection (BSI). The availability of standardized methods for testing the in vitro activity of antifungals along with the expanding of antifungal armamentarium, the rising of drug-resistance and the persistence of a high mortality rate in systemic candidiasis have led to an increased interest in combination therapy. Therefore, we aimed to review the scientific literature concerning the antifungal combinations against Candida. A literature search performed in PubMed yielded 92 studies published from 2000 to 2021: 29 articles referring to in vitro studies, six articles referring to either in vitro and in vivo (i.e., animal models) studies and 57 clinical articles. Pre-clinical studies involved 735 isolates of Candida species and 12 unique types of antifungal combination approaches including azoles plus echinocandins (19%), polyenes plus echinocandins (16%), polyenes plus azoles (13%), polyenes plus 5-flucytosine ([5-FC], 13%), azoles plus 5-FC (11%) and other types of combinations (28%). Results varied greatly, often being species-, drug- and methodology-dependent. Some combinatorial regimens exerted a synergistic effect against difficult-to-treat Candida species (i.e., azoles plus echinocandins; polyenes plus 5-FC) or they were more effective than monotherapy in prevent or reducing biofilm formation and in speeding the clearance of infected tissues (i.e., polyenes plus echinocandins). In 283 patients with documented Candida infections (>90% systemic candidiasis/BSI), an antifungal combination approach could be evaluated. Combinations included: azoles plus echinocandins (36%), 5-FC-combination therapies (24%), polyenes plus azoles (18%), polyenes plus echinocandins (16%) and other types of combination therapy (6%). Case reports describing combination therapies yielded favorable response in most cases, including difficult-to-treat fungal infections (i.e., endocarditis, osteoarticular infections, CNS infections) or difficult-to-treat fungal pathogens. The only randomized trial comparing amphotericin-B deoxycholate (AMB) plus FLU vs. AMB alone for treatment of BSI in nonneutropenic patients showed that the combination trended toward improved success and more-rapid clearance from the bloodstream. In summary, antifungal combinations against Candida have produced great interest in the past two decades. To establish whether this approach can become a reliable treatment option, additional in vitro and clinical data are warranted.

Candida auris from colonisation to candidemia: A four‐year study

“…In some cases, combination therapies have been used, especially echinocandins plus amphotericin B or isavuconazole, although additional in vitro and clinical data on antifungal combinations is required. 41 Thirty-day crude mortality rate for the C. auris candidemia cases in our centre was 32.6%, which is similar to the high crude mortality rates reported from other outbreaks, from 20% to 60%. 5,7,8,9,27,28,31,33 However, it is higher than 20% reported from a meta-analysis analysing data from European facilities.…”

“…To date, echinocandins are the first line treatment since a lower resistance to these drugs has been reported. In some cases, combination therapies have been used, especially echinocandins plus amphotericin B or isavuconazole, although additional in vitro and clinical data on antifungal combinations is required 41 . Thirty‐day crude mortality rate for the C. auris candidemia cases in our centre was 32.6%, which is similar to the high crude mortality rates reported from other outbreaks, from 20% to 60% 5,7,8,9,27,28,31,33 .…”

Candida lipolytica Bloodstream Infection in an Adult Patient with COVID-19 and Alcohol Use Disorder: A Unique Case and a Systematic Review of the Literature

“…International guidelines for the treatment of candidiasis generally do not include combination therapy, except in certain clinical cases, such as endocarditis. Nevertheless, some combination therapies seem to have a synergistic effect against difficult-to-treat Candida species by preventing or reducing biofilm formation [ 30 ]. Although C. albicans remains the most pathogenic yeast, the selective abilities of C. lipolytica to form biofilms on devices and produce haemolytic enzymes are of particular interest in a nosocomial setting [ 24 ].…”

In Vitro Killing Activities of Anidulafungin and Micafungin with and without Nikkomycin Z against Four Candida auris Clades

“…Moreover, reports of echinocandin-resistant isolates emerging during treatment are also increasing [ 1 , 2 , 4 ]. Although antimicrobial peptides, metals, nanoparticles and natural compounds (i.e., quorum-sensing molecules) are often promising new approaches, their translation to clinical practice is often delayed due to the lack of safety and efficacy data in mammals [ 12 , 13 , 14 , 15 ]. To address the low activity of antifungal agents, numerous combinational therapies have been proposed, based mostly on in vitro data.…”

“…To address the low activity of antifungal agents, numerous combinational therapies have been proposed, based mostly on in vitro data. Suggested combinations include multiple antifungal agents together, antifungal agents with antibiotics and antifungal agents combined with nonantimicrobial drugs [ 12 , 13 , 14 , 15 ].…”