In vitro activities of amphotericin B in combination with four antifungal agents and rifampin against Aspergillus spp

Hughes, Carolyn E.; Harris, C; Moody, Julia; Peterson, Lance R.; Gerding, Dale N.

doi:10.1128/aac.25.5.560

Cited by 63 publications

(35 citation statements)

References 11 publications

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“…(46,125) and flucytosine (127). The results of in vitro studies of amphotericin B combined with rifampin (46,87,95,127) (58,87,104), synergy (58,95,140), and antagonism (210). These effects did not differ significantly according to the species of Aspergillus tested or according to levels of baseline resistance to flucytosine (58), but in some cases results differed according to the testing methodology employed by investigators.…”

Section: (D) Other Combinationsmentioning

confidence: 94%

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Combination Antifungal Therapy

Johnson

MacDougall

Ostrosky-Zeichner

et al. 2004

Antimicrob Agents Chemother

488

368

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5 RATIONALEThe availability of new antifungal agents with novel mechanisms of action has stimulated renewed interest in combination antifungal therapies. In particular, and despite the limited clinical data, the high mortality of mold infections and the relatively limited efficacy of current agents have produced significant interest in polyene-, extended-spectrum azole-, and echinocandin-based combinations for these difficult-to-treat infections. With the recent publication of the first large randomized trial of antifungal combination therapy to be conducted in two decades (166) and the rapid proliferation of new in vitro and in vivo data on antifungal combinations, we have sought to review the recent work and future challenges in this area.The focus of this review is on the efficacy of antifungal drugs in combination with respect to the extent or rate of killing of the fungal pathogen, although other potential interactions (such as pharmacokinetic drug interactions) can impact efficacy when these agents are used together. The value of giving two drugs because each is separately effective against a group of organisms exhibiting a variety of types of resistance is not specifically discussed, but this also is an obvious and straightforward reason to use a combination of agents.It cannot be simply assumed that the use of two or more effective drugs with different mechanisms of action will produce an improved outcome compared to the results seen with a single agent. Combination antifungal therapy could reduce antifungal killing and clinical efficacy, increase potential for drug interactions and drug toxicities, and carry a much higher cost for antifungal drug expenditures without proven clinical benefit (106). Thus, it is important to critically evaluate the role of combination therapy as new data become available.Conceptual models and terminology. Methods for studying antifungal combinations in vitro and in vivo have differed considerably over time and among investigators. These tools do not differ with respect to their application to combination antibacterial or antiviral therapies and have been discussed extensively and elegantly in the landmark 1995 review by Greco (79). In brief, all approaches to evaluating combinations can be reduced to two elements: (i) a conceptual model for predicting the expected result for a combination and (ii) a set of phrases used to categorize results that are better than expected, worse than expected, or as expected. Although many subtle variations are possible, the underlying mathematical model is based on either the assumption of additive interactions or the assumption of probabilistic (multiplicative) interactions. On the basis of the terminology employed by the author who first carefully described each of these models, the two models can be usefully referred to as the Loewe additivity model and the Bliss independence model (79).The terminology used to place results into interpretive categories is often the subject of debate and confusion. Greco et al. (79) have proposed a set ...

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Section: (D) Other Combinationsmentioning

confidence: 94%

“…AmB ϩ 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 ϩ AmB vs. AmB alone in steroid-suppressed rats (187). Improved survival with rifampin ϩ AmB in mouse model (6).…”

Section: (D) Other Combinationsmentioning

confidence: 99%

Combination Antifungal Therapy

Johnson

MacDougall

Ostrosky-Zeichner

et al. 2004

Antimicrob Agents Chemother

488

368

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“…Antagonism has been reported for 23% (6 of 26) strains in one study (70). Combinations of amphotericin and rifampin or rifabutin are frequently synergistic (70,123,224). Unfortunately, rifampin is a difficult agent to use in transplant recipients because of its frequent interactions with cyclosporine or tacrolimus.…”

Section: In Vitro and Animal Studies Utilizing Combinations Of Antifumentioning

confidence: 99%

AspergillusInfections in Transplant Recipients

2005

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Aspergillus infections are occurring with an increasing frequency in transplant recipients. Notable changes in the epidemiologic characteristics of this infection have occurred; these include a change in risk factors and later onset of infection. Management of invasive aspergillosis continues to be challenging, and the mortality rate, despite the use of newer antifungal agents, remains unacceptably high. Performing molecular studies to discern new targets for antifungal activity, identifying signaling pathways that may be amenable to immunologic interventions, assessing combination regimens of antifungal agents or combining antifungal agents with modulation of the host defense mechanisms, and devising diagnostic assays that can rapidly and reliably diagnose infections represent areas for future investigations that may lead to further improvement in outcomes

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“…Previous in vitro studies showed that this combination was mostly additive or synergistic against Aspergillus species (7,13,14,16,25). However, in one study antagonism was observed (5).…”

Section: Discussionmentioning

confidence: 73%

In Vitro Interactions between Amphotericin B, Itraconazole, and Flucytosine against 21 Clinical Aspergillus Isolates Determined by Two Drug Interaction Models

Dorsthorst

Verweij

Meis

et al. 2004

Antimicrob Agents Chemother

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Combination therapy of flucytosine (5FC) with other antifungal agents could be of use for the treatment of invasive aspergillosis. However, interpretation of the results of in vitro interactions is problematic. The fractional inhibitory concentration (FIC) index is the most commonly used method, but it has several major drawbacks in characterizing antifungal drug interaction. Alternatively, a response surface approach using the concentration-effect relationship over the whole concentration range instead of just the MIC can be used. We determined the in vitro interactions between amphotericin B (AMB), itraconazole, and 5FC against 21 Aspergillus isolates with a broth microdilution checkerboard method that employs the dye MTT [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide]. FIC indices based on three different MIC endpoints (MIC-0, MIC-1, and MIC-2) and the interaction coefficient alpha were determined, the latter by estimation from the response surface approach described by Greco et al. (W. R. Greco, G. Bravo, and J. C. Parsons, Pharmacol. Rev. 47:331-385, 1995). The value obtained for the FIC index was found to be dependent on the MIC endpoint used and could be either synergistic, indifferent, or antagonistic. The response surface approach gave more consistent results. Of the three combinations tested, the AMB-5FC combination was the most potent in vitro against Aspergillus spp. We conclude that the use of the response surface approach for the interpretation of in vitro interaction studies of antifungals may be helpful in order to predict the nature and intensity of the drug interaction. However, the correlation of these results with clinical outcome remains difficult and needs to be further investigated.

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In vitro activities of amphotericin B in combination with four antifungal agents and rifampin against Aspergillus spp

Cited by 63 publications

References 11 publications

Combination Antifungal Therapy

Combination Antifungal Therapy

AspergillusInfections in Transplant Recipients

In Vitro Interactions between Amphotericin B, Itraconazole, and Flucytosine against 21 Clinical Aspergillus Isolates Determined by Two Drug Interaction Models

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