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Combination Antifungal Therapy

Melissa D. Johnson, Conan MacDougall, Luis Ostrosky-Zeichner, John R. Perfect, John H. Rex
Melissa D. Johnson
Departments of MedicineCampbell University School of Pharmacy, Buies Creek, North Carolina
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  • For correspondence: johns200@mc.duke.edu
Conan MacDougall
and Pharmacy, Duke University Medical Center, Durham and
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Luis Ostrosky-Zeichner
Division of Infectious Diseases, Department of Internal Medicine, Center for the Study of Emerging and Re-emerging Pathogens, University of Texas—Houston Medical School, Houston, Texas
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John R. Perfect
Departments of Medicine
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John H. Rex
Division of Infectious Diseases, Department of Internal Medicine, Center for the Study of Emerging and Re-emerging Pathogens, University of Texas—Houston Medical School, Houston, TexasAstraZeneca Pharmaceuticals, Alderley House, Macclesfield, Cheshire, United Kingdom
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DOI: 10.1128/AAC.48.3.693-715.2004
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  • TABLE 1.

    Consensus terminology for describing results of combination testinga

    CategoryTerminology for indicated conditions
    Both agents are active alone; additive effects model is presumedBoth agents are active alone; multiplicative effects model is presumedOne agent is active alone; the other is notNeither agent is active alone
    Combination result is better than expectedLoewe synergismBliss synergismSynergismCoalism
    Combination result is as expectedLoewe additivityBliss independenceInertismInertism
    Combination result is worse than expectedLoewe antagonismBliss antagonismAntagonism
    • ↵a The terminology shown is that proposed by Greco et al. (79) following a consensus conference occurring in Sarriselka, Finland. Models based on the additive interaction concept first proposed by Loewe and Muischnek (111) follow the intuitive result in which a drug combined with itself produces a linear sum of effects. That is, 1 μg/ml plus 1 μg/ml gives the effect of 2 μg/ml and this result is neither synergistic nor antagonistic. Models based on the multiplicative interaction concept first proposed by Bliss (26) follow a probabilistic model in which the two agents truly act independently as determined on the basis of their separate probabilities of effect. If 1 μg/ml permits 40% of the target organism to survive, then 1 + 1 = 2 μg/ml should permit only 40% × 40% = 16% survival. As reviewed in detail by Greco et al. (79), both models have strengths and weaknesses but Loewe additivity-based models more often seem appropriate for combinations of antimicrobial agents.

  • TABLE 2.

    Technical and analytical issues associated with different model systems for studying combination antifungal therapy

    CategoryCharacteristic
    In vitro studiesAnimal modelsClinical trials
    StrengthsEasily repeated across a wide variety of drug concentrationsStudies can be done with homogeneous hostsThis is the answer that matters
    Easily subjected to statistical testingHost factors are integrated
    Easy to vary technical factorsResistant isolates can sometimes be tested
    Easy to test multiple isolatesQuantitative endpoints (tissue burden, rate of clearance) can be tested
    Easy to test isolates with defined types of resistanceA range of doses and dose combinations can be tested
    WeaknessesRelevance of in vitro methods not always clearInfection models are often poor mimics of human diseaseSubjects and infecting isolates are heterogeneous
    Host factors are ignoredPharmacokinetic and toxicological behavior of test drugs (and their pharmacological effects on each other) may not mimic that seen in humansNo ability to control nature of infecting isolate
    Pharmacokinetic factors are ignoredOnly limited numbers of isolates can be testedUnderlying disease cannot be controlled
    Only limited numbers of repetitions are possibleLack of quantitative endpoints for many diseases
    Resistant isolates sometimes have reduced virulenceLimited ability to study a range of doses
    Very expensive
    Slow
  • 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.

  • 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.

  • 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.

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Combination Antifungal Therapy
Melissa D. Johnson, Conan MacDougall, Luis Ostrosky-Zeichner, John R. Perfect, John H. Rex
Antimicrobial Agents and Chemotherapy Feb 2004, 48 (3) 693-715; DOI: 10.1128/AAC.48.3.693-715.2004

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Combination Antifungal Therapy
Melissa D. Johnson, Conan MacDougall, Luis Ostrosky-Zeichner, John R. Perfect, John H. Rex
Antimicrobial Agents and Chemotherapy Feb 2004, 48 (3) 693-715; DOI: 10.1128/AAC.48.3.693-715.2004
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  • Top
  • Article
    • RATIONALE
    • MECHANISMS OF INTERACTIONS FOR THE ANTIFUNGAL AGENTS
    • FOCUSED REVIEW OF THE ANTIFUNGAL DRUG INTERACTION LITERATURE
    • (ii) Animal models of cryptococcal infection
    • (iii) Clinical data
    • (iv) Interpretation and recommendations
    • Candida spp. (i) In vitro evidence
    • (ii) Animal models of invasive candidiasis
    • (iii) Clinical data
    • (iv) Interpretation and recommendations
    • Aspergillus spp. (i) In vitro data
    • (ii) Animal models of aspergillosis
    • (iii) Clinical data
    • (iv) Interpretation and recommendations
    • CONCLUSIONS AND FUTURE DIRECTIONS
    • ACKNOWLEDGMENTS
    • REFERENCES
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