DOI: 10.1128/AAC.48.3.693-715.2004
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- TABLE 1.
Consensus terminology for describing results of combination testinga
Category Terminology for indicated conditions Both agents are active alone; additive effects model is presumed Both agents are active alone; multiplicative effects model is presumed One agent is active alone; the other is not Neither agent is active alone Combination result is better than expected Loewe synergism Bliss synergism Synergism Coalism Combination result is as expected Loewe additivity Bliss independence Inertism Inertism Combination result is worse than expected Loewe antagonism Bliss antagonism Antagonism ↵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
Category Characteristic In vitro studies Animal models Clinical trials Strengths Easily repeated across a wide variety of drug concentrations Studies can be done with homogeneous hosts This is the answer that matters Easily subjected to statistical testing Host factors are integrated Easy to vary technical factors Resistant isolates can sometimes be tested Easy to test multiple isolates Quantitative endpoints (tissue burden, rate of clearance) can be tested Easy to test isolates with defined types of resistance A range of doses and dose combinations can be tested Weaknesses Relevance of in vitro methods not always clear Infection models are often poor mimics of human disease Subjects and infecting isolates are heterogeneous Host factors are ignored Pharmacokinetic and toxicological behavior of test drugs (and their pharmacological effects on each other) may not mimic that seen in humans No ability to control nature of infecting isolate Pharmacokinetic factors are ignored Only limited numbers of isolates can be tested Underlying disease cannot be controlled Only limited numbers of repetitions are possible Lack of quantitative endpoints for many diseases Resistant isolates sometimes have reduced virulence Limited 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
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 - TABLE 4.
Summary of key findings reported in studies of Candida spp. with combinations of clinically relevant antifungal agentsa
Combination Settings studied General findings Comments 5FC + AmB In 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 success AmB + 5FC cleared cultures faster than fluconazole in humans with peritonitis (100) 5FC + azoles In 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 + azoles In 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) Antagonism One 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 combination AmB-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 success Comparable clinical cure rates to FLC alone, faster bloodstream sterilization with the combination regimen AmB + nystatin In vitro (31) Indifference /PICK> Caspofungin or anidulafungin + FLC In vitro (169)b Indifference FLC 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 burden Caspofungin + 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 ITC In 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 + AmB In vitro (10) Indifference or synergy No antagonism observed AmB + rifampin In vitro (23) Synergy Synergy in 6 of 8 strains tested; used method of Jawetz (90) to define synergy Neutropenic rabbits (208) Similar or worse tissue burden Worse clearance of yeasts from splenic tissue than with AmB alone but similar clearance in kidney, liver, and lung TRB + cyclosporine A or tacrolimus In vitro (142) Synergy Synergistic against C. albicans as well as C. glabrata and C. krusei; dependent on calcineurin FLC + cyclosporine In vitro (120) Synergy or indifference Results varied with endpoint used Rats (119) Reduced tissue burden FLC 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
Combination Settings studied Findings Comments AmB + 5FC In vitro (58, 87, 95, 104, 140)b No 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 + rifampin In vitro (95) Synergy (95); indifference or synergy (46, 58, 87) Antagonism not observed in any study Mice (6) and rats (187) No consensus No survival benefit with rifampin + AmB vs. AmB alone in steroid-suppressed rats (187). Improved survival with rifampin + AmB in mouse model (6). AmB + azoles In vitro (58, 87, 97, 118, 140, 207)b,c,d,e No consensus Pretreatment 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: miceg Concurrent: 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 + echinocandins In vitro Caspofungin (5, 15)e Anidulafungin or micafunginh Synergy (5),e indifference or synergy (15)h No antagonism seen. Eagle-like effect (antagonism at high doses) seen in one studyh. Mice Caspofungini or micafunginj,k Improved survivalj,k Reducedi,k or similari tissue burden Neutropenic 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 micafungin In vitro ITC-caspofungine,l,m or micafunginj PSC-caspofunginm RVC-caspofunginm VRC-caspofungin or micafungind,m,n Indifference or synergyd,j,l,m,n or synergye,m No 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.
- 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
- Figures & Data
- Info & Metrics