TABLE 3.
Summary of key findings reported in studies of C. neoformans with combinations of clinically relevant antifungal agentsa
| Combination | Settings studied | General findings | Comments |
|---|---|---|---|
| 5FC + AmB | In 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 + triazoles | In 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 + triazoles | In 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 + AmB | In vitro (71) | Synergy | Used higher levels of caspofungin than would be used for humans |
| Caspofungin or anidulafungin + FLC | In 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 + FLC | Guinea pigs (212) | Reduced tissue burden | Survival 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.