TABLE 4.

Summary of key findings reported in studies of Candida spp. with combinations of clinically relevant antifungal agentsa

CombinationSettings studiedGeneral findingsComments
5FC + AmBIn vitro (21, 40, 63, 74, 92, 105, 122, 133, 140, 156, 161, 178, 191)Synergy (40, 105, 133, 178, 191) or indifference (21, 74, 92, 122)Addition of AmB helps prevent emergence of 5FC resistance
Mice (157, 164, 191, 209) and rabbits (208)Improved survival (164) Reduced tissue burden (164, 208, 209)Most effective combination in one study when compared with results for AmB-rifampin, 5FC-KTC, and these agents alone (208); reduced dosages of the agents were possible in combinati on while maintaining efficacy (209)
Humans with invasive disease (1, 36, 100, 155)Good clinical successAmB + 5FC cleared cultures faster than fluconazole in humans with peritonitis (100)
5FC + azolesIn vitro Econazole (63), miconazole (63, 191) CLT (22), KTC (19, 20, 140),     FLC (74, 105, 129)No consensus Synergy (129), indifference (19, 105), antagonism (74, 140)Extended duration of postantifungal effect was reported in one study with fluconazole-flucytosine (129), low concentrations of 5FC-KTC appeared antagonistic for C. parapsilosis (19) contour surface plot methodology suggested negative interaction between fluconazole and flucytosine over a range of concentrations (74)
KTC: mice (158) and rabbits (208) ITC: mice (157) FLC: mice (180) and rabbits     (115)Improved survival (157, 158) Reduced tissue burden (115, 208)FLC doses in rabbits were equivalent to 1,600 mg/day in humans (115); 5FC-KTC appeared to prolong survival against some C. albicans strains in a murine model more than either agent alone (even in higher concentrations) but against other strains had no survival benefit over a single agent (158); effects most apparent with 5FC-resistant C. albicans strains; in rabbits (115) FLC-AmB combination sterilized cardiac vegetations faster than FLC but performed similarly to FLC in kidney
Humans (181)Case report of sepsis due to C. albicans that was treated successfully with 5FC plus FLC (181)
AmB + azolesIn vitro FLC (67, 74, 105, 107, 122, 154, 161, 175, 185, 186, 214, 216, 217),b sequential (67, 105, 107, 175) Miconazole (31, 49, 63, 154, 191)c CLT (22, 49) KTC (31, 140, 154, 161, 183, 198) ITC (154, 161, 184, 185)AntagonismOne study suggested indifferent effects for AmB-FLC against C. albicans over a wide range of concentrations (74) Slight synergy with higher concentrations of     KTC and AmB (161); short-term exposure     with miconazole resulted in antagonism,     long-term exposure resulted in positive     effects (31)
FLC: mice (113, 176, 199, 202)     and rabbits (115, 176) ITC: mice (157, 203) KTC: mice (158) and rabbits     (208) PSC: miced SPC: mice (206) Sequential: mice (202, 203, 216)Improved (FLC, PSC, SPC) (113, 157, 176, 202) or similar to worse (ITC, KTC) (157, 203) survival Reduced tissue burden (FLC,     KTC) (115, 208) but ITC-AmB     had poorer clearance of tissues     (kidney) (203) with combinationAmB-FLC effects not as profound in a less-acute model of infection (202); in rabbits, combination was not better than AMB alone in sterilizing cardiac vegetations and kidneys (115). Rabbit model used FLC doses equivalent to 1,600 mg/day in humans (115). In mice, the combination resulted in worse survival and kidney fungal burden compared to AmB alone (113) against FLC-susceptible and low-level resistance (MIC, 64 to 125 μg/ml) strains AmB-FLC gave better survival than AmB but     not FLC (199) and in another study gave     better survival than FLC but not AmB     (176). IT C-AmB resulted in 100%     mortality in mice, while 90% of amB-    treated mice survived; in neutropenic     rabbits AmB-KTC improved sterilization     rates in kidneys (208) relative to either     agent alone but not as much as AmB-5FC     combination; AmB-KTC prolonged survival     against one C. albicans strain but not 2     others (158); combinations of AmB-KTC     against 2 C. albicans strains were generally     not better than AmB alone in prolonging     survival in infected mice (158)
Humans with candidemia (166)Good clinical successComparable clinical cure rates to FLC alone, faster bloodstream sterilization with the combination regimen
AmB + nystatinIn vitro (31)Indifference/PICK>
Caspofungin or anidulafungin + FLCIn vitro (169)bIndifferenceFLC reduced caspofungin activity against C. albicans biofilmsb; in mice no additional benefit of combination therapy was observed with low doses of FLC and caspofungin on clearance of yeasts from kidneyse
Mice (77)Improved or similar tissue burdenCaspofungin + FLC over 4 dosing schemes did not improve tissue clearance of C. albicans from kidney tissue compared to FLC alone but not caspofungin alone
TRB + FLC or ITCIn vitro (10, 11)Indifference (10, 11) or synergy (10, 11)No antagonism observed (10, 11)
Humans (73)Case report of successful therapy of oropharyngeal candidiasis due to azole- and terbinafine-resistant C. albicans with TRB + FLC therapy
TRB + AmBIn vitro (10)Indifference or synergyNo antagonism observed
AmB + rifampinIn vitro (23)SynergySynergy in 6 of 8 strains tested; used method of Jawetz (90) to define synergy
Neutropenic rabbits (208)Similar or worse tissue burdenWorse clearance of yeasts from splenic tissue than with AmB alone but similar clearance in kidney, liver, and lung
TRB + cyclosporine A or tacrolimusIn vitro (142)SynergySynergistic against C. albicans as well as C. glabrata and C. krusei; dependent on calcineurin
FLC + cyclosporineIn vitro (120)Synergy or indifferenceResults varied with endpoint used
Rats (119)Reduced tissue burdenFLC approximated high doses used in humans, but cyclosporine concentrations were higher than that used in humans; combination was the most effective regimen in clearing cardiac vegetations and kidneys even compared to AmB
  • a See Table 3 for drug name abbreviations.

  • b Also Bachman et al., Abstr. 42nd Intersci. Conf. Antimicrob. Agents Chemother., abstr. M-1813, 2002.

  • c Also Schacter et al., letter.

  • d Cacciapuoti et al., Abstr. 42nd Intersci. Conf. Antimicrob. Agents Chemother., abstr. M-1814, 2002.

  • e Bocunegra, L.K. Navjar, S. Hernandez, R.A. Larsen, and J.R. Graybill, Abstr. 42nd Intersci. Conf. Antimicrob. Agents Chemother., abstr. M-864, p. 387, 2002.