TABLE 3.

Summary of key findings reported in studies of C. neoformans with combinations of clinically relevant antifungal agentsa

CombinationSettings studiedGeneral findingsComments
5FC + AmBIn vitro (40, 63, 74, 78, 80, 92, 126, 140, 156, 189)Indifference (63, 74, 78, 80, 140, 156, 189) synergy (40, 126), antagonism with 5FC-resistant strain (80)AmB reduces development of resistance to 5FC; 5FC-resistant strains have been used in numerous studies (80, 126, 189) and produce various results
Mice (16, 27, 60, 80, 158) Rabbits (150)Improved survival (16, 27, 158) Reduced tissue burden (16, 150)Survival (27) or reduction in tissue burden (150) not necessarily better than results with AmB alone (60); combination more effective than AMB and 5FC alone against 5FC-resistant strains (158)
Humans (24, 42, 43, 55, 103, 144, 213)Similar (213) or improved (24, 171) clinical success overall, improved sterilization of CSF (24, 213)Addition of 5FC leads to earlier sterilization of CSF (24); clinical success rates were similar between AmB + 5FC and AmB alone (73 vs. 83%) after 2 weeks of therapy (213); relapse has been associated with no use of 5FC during initial 2 weeks (171)
5FC + triazolesIn vitro FLC (3, 138, 140), KTC (31, 140), ITC     (12), PSC (14)FLC: synergy (138) KTC: indifference (31, 89) ITC, PSC: indifference or synergy     (12, 14)Synergy in 62% of 50 strains studied for FLU-5FC (138); various doses may be necessary to achieve greatest effect; addition of 5FC helped prevent emergence of 5FC-resistant mutants
Animal studies FLC: mice (3, 60, 61, 101, 139, 157)b KTC: mice (50, 78, 158) and rabbits     (150) ITC: mice (157), hamsters (89), and     guinea pigs (212) PSC: mice (14)Improved (3, 50, 61, 157), similar (14, 50, 60, 212), or worse (89) survival Reduced tissue burden (50, 78, 101, 212)Combination associated with better survival than monotherapy and was consistent over a range of doses (3); effects more pronounced at lower doses (101), and single agents were very effective at higher doses alone; 5FC + KTC rarely cleared tissues better than either agent alone (150); hamsters with combination did worse than with ITC alone (89); ITC + 5FC performed similarly to ITC + AmB and better than ITC or 5FC monotherapy in guinea pigs (212); with 10 days of treatment of mice, combination prolonged survival more than either agent alone but not when treatment was limited to 5 days (157); PSC combination not better than monotherapy in terms of survival but better than monotherapy in reducing fungal counts in brain tissue (14)
Humans FLC (48, 102, 124, 193, 223)Good clinical success (48, 102, 193, 223) Increased survival (124)63% success rate in cryptococcal meningitis (95% confidence interval, 48-82%) (102); improved survival (32%) versus FLC alone (12%) at 6 months in AIDS-associated cryptococcal meningitis (124)
AmB + triazolesIn vitro FLC (13, 74), KTC (78, 140, 150, 161),     ITC (13), PSC (13)Indifference (13, 78, 140)FLC: indifference in 10/15 strains tested, indifference in 4/15, and synergy in 1/15 with NCCLS methods (13); indifference among 3 strains using an inoculum of 104 CFU/ml on yeast nitrogen base broth and response surface plots (74); KTC: no antagonism observed (78, 140, 150); synergy reported with one strain in two studies using nonstandard methodologies (140, 161); ITC: 14/15 strains indifferent; 1/15 synergistic (13); PSC: 8/15 strains indifferent; 5/15 synergistic; 2/15 indifferent in one study (13)
Animal models FLC: mice (2, 13)b KTC: mice (50, 78, 158) and rabbits     (150) ITC: mice (157) and guinea pigs (212)FLC/KTC: improved survival compared to results with azole (2, 13, 78, 158)b and/or AmB (2, 158) ITC: did not improve or worsened     survival (157) Reduced tissue burden (2, 13, 78, 212)FLC: addition of AmB to FLC had dramatic impact on yeast burden in brain tissueb, but survival with AmB was 100%; effects on survival were greatest at highest dosages of azole-AMB (2, 158); improved survival at lower doses of ITC + AmB, but survival was worse when higher doses were used (157); FLU preexposure did not reduce subsequent AmB activity (13)
Humans—case report (47)Case report of a woman with meningitis who responded to this combination after failing AmB
Caspofungin or anidulafungin + AmBIn vitro (71)SynergyUsed higher levels of caspofungin than would be used for humans
Caspofungin or anidulafungin + FLCIn vitro (71, 169)Indifference (71, 169) or synergy (71)One study showed that echinocandins were no better than FLC monotherapy (169); no antagonism (71, 169)
ITR + FLCGuinea pigs (212)Reduced tissue burdenSurvival was 100% in all treatment groups; improved sterilization of tissues compared to FLC but not ITC
  • a AmB, amphotericin B; CLT, clotrimazole; FLC, fluconazole; 5FC, flucytosine; KTC, ketoconazole; ITC, itraconazole; PSC, posaconazole; RVC, ravuconazole; SPC, saperconazole; TRB, terbinafine; VRC, voriconazole.

  • b Larsen et al., Abstr. 5th Int. Conf. Cryptococcus Cryptococcosis, abstr. P3.1, 2002.