TABLE 5.

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

CombinationSettings studiedFindingsComments
AmB + 5FCIn vitro (58, 87, 95, 104, 140)bNo consensus Synergyb; synergy or indifference (95);     indifference (87, 104); antagonism or     synergy (58)Results differ between studies and are variable amongst strains in same study (58, 95), different methodologies and doses employed
Mice (6, 157) and rats (187)Improved survival (6, 157)Improved survival with 5FC + AmB in mouse model (6). No survival benefit with 5FC + AmB vs. AmB alone in steroid-suppressed rats (187).
AmB + rifampinIn vitro (95)Synergy (95); indifference or synergy (46, 58, 87)Antagonism not observed in any study
Mice (6) and rats (187)No consensusNo survival benefit with rifampin + AmB vs. AmB alone in steroid-suppressed rats (187).
Improved survival with rifampin + AmB in mouse model (6).
AmB + azolesIn vitro (58, 87, 97, 118, 140, 207)b,c,d,eNo consensusPretreatment with KTC (118) or ITC (97, 118) strongly attenuates effect of AmB; simultaneous treatment less antagonistic to indifferent; AmB then KTC weakly synergistic (118); no antagonism for AmB then ITC; indifferent effects with simultaneous ITC-AmBe. Studies using colorimetric analysis and response surface modeling demonstrated ITC-AmB antagonism with simultaneous use (207).b
Synergy (58, 140), antagonism, (118, 140, 207)c,b or indifference (58, 87)d
ITC: Mice (179)f KTC: mice (157, 180) and rats (187) PSC: micegConcurrent: no survival benefit (ITC)f or worse survival (KTC) (157, 187)Neutropenic mice had significantly worse survival when pretreated with KTC before AmB or AmB + KTC (180). Steroid-suppressed rats given simultaneous KTC and AmB had worse survival than with AmB alone (187). Mice pretreated with ITC before AmB or AmB + ITC had lower survival than without pretreatment (179). Neutropenic mice with CNS infection had equal survival with either agent or combination vs. no treatmentf but nonneutropenic mice challenged intravenously had reduced survival times with combination therapy (157). In mice, no sequential antagonism of PSC by pretreatment with AmBg.
Sequential: no survival benefit with or worse survival (179) compared to AmB results alone
AmB + echinocandinsIn vitro Caspofungin (5, 15)e Anidulafungin or micafunginhSynergy (5),e indifference or synergy (15)hNo antagonism seen. Eagle-like effect (antagonism at high doses) seen in one studyh.
Mice Caspofungini or micafunginj,kImproved survivalj,k Reducedi,k or similari tissue burdenNeutropenic mice, fungal burden in kidneys at 4 days reduced (10/16 groups) or equivalent (6/16) with combination therapy vs. either agent alone. Increased survival, reduced fungal lung burden, reduced serum galactomannan titer with combination vs. monotherapyj. Steroid-immunosuppressed mice had 100% survival with combination therapy vs. 61% with micafungin and 53% with AmB.
Triazoles + caspofungin or micafunginIn vitro ITC-caspofungine,l,m or     micafunginj PSC-caspofunginm RVC-caspofunginm VRC-caspofungin or     micafungind,m,nIndifference or synergyd,j,l,m,n or synergye,mNo antagonism seen in most studies; increased susceptibility with preexposure to either agentl. VRC-caspofungin: indifference against caspofungin- or micafungin-resistant-strains,d ITC and PSC demonstrated synergy with caspofunginm; RVC and VRC demonstrated indifference with caspofunginm.
ITC-caspofungin: guinea pigso ITC-micafungin: mice (117) KTC-micafungin: mice (117) RVC-micafungin: rabbitsp VRC-guinea pigs (94)Improved (117)p (94) survival or similar Reduced tissue burden (94)o.Fungal burden in kidneys at day 4 undetectable in 9/9 animals receiving ITC-caspofungin therapyo. RVC-micafungin increased survival with combination (9/12) vs. revuconazole alone (2/8) or micafungin alone (0/8)p.
  • a See Table 3 for drug name abbreviations.

  • b Also see Te Dorsthorst et al., Abstr. 42nd Intersci. Conf. Antimicrob. Agents Chemother., abstr. M-850, 2002.

  • c Also see Gavalda et al., Abstr. 42nd Intersci. Conf. Antimicrob. Agents Chemother., abstr. M-1817, 2002.

  • d Also see M. A. Ghannoum, N. Isham, and D. Sheehan, Abstr. 42nd Intersci. Conf. Antimicrob. Agents Chemother., abstr. M-855, p. 385, 2002.

  • e Also see Manavathu et al., Abstr. 40th Intersci. Conf. Antimicrob. Agents Chemother., abstr. 931, 2000.

  • f Also see Chiller et al., Abstr. 41st Intersci. Conf. Antimicrob. Agents Chemother., abstr. J-1614, 2001.

  • g Najvar et al., Abstr. 42nd Intersci. Conf. Antimicrob. Agents Chemother., abstr. M-1818, 2002.

  • h Ostrosky-Zeichner et al., Abstr. 42nd Intersci. Conf. Antimicrob. Agents Chemother., abstr. M-1816, 2002.

  • i Douglas et al., Abstr. 41st Intersci. Conf. Antimicrob. Agents Chemother., abstr. J-1836, 2001.

  • j Kohno et al., Abstr. 40th Intersci. Conf. Antimicrob. Agents Chemother., abstr. 1686, 2000.

  • k Nakajima et al., Abstr. 40th Intersci. Conf. Antimicrob. Agents Chemother., abstr. 1685, 2000.

  • l Kontoyiannis et al., Abstr. 42nd Intersci. Conf. Antimicrob. Agents Chemother., abstr. M-851, 2002.

  • m Manavathu et al., Abstr. 42nd Intersci. Conf. Antimicrob. Agents Chemother., abstr. M-854, 2002.

  • n O'Shaughnessy et al., Abstr. 42nd Intersci. Conf. Antimicrob. Agents Chemother., abstr. M-856, 2002.

  • o Douglas et al., Abstr. 42nd Intersci. Conf. Antimicrob. Agents Chemother., abstr. M-1819, 2002.

  • p Petraitiene et al., Abstr. 42nd Intersci. Conf. Antimicrob. Agents Chemother., abstr. M-857, 2002.