Combination Therapy of Experimental Candidiasis, Cryptococcosis and Aspergillosis in Mice

Polak, Annemarie; Scholer, H. J.; Wall, Michael

doi:10.1159/000238138

Cited by 120 publications

(90 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Antagonism of amphotericin B by ketoconazole has been shown previously in murine aspergillosis, but the effect was not dramatic. The results of these investigations are, however, difficult to compare with our study because the mice were not immunosuppressed, the drugs were given simultaneously, and only a fraction of our amphotericin B dose was given to the animals [29]. Starting from the question of whether ketoconazole prophylaxis would interfere with subsequent therapy of a fungal breakthrough infection, we selected experimental conditions that would permit extrapolation to the clinical problem.…”

Section: Discussionmentioning

confidence: 99%

The Effect of Ketoconazole on Amphotericin B in a Model of Disseminated Aspergillosis

Schaffner

1985

Journal of Infectious Diseases

178

View full text Add to dashboard Cite

The potential of ketoconazole prophylaxis to antagonize the activity of amphotericin B against aspergilli was investigated in vitro and in neutropenic mice. Exposure of Aspergillus fumigatus (six strains) and of Aspergillus f/avus or Aspergillus niger to ketoconazole resulted in a uniform increase of the minimal fungicidal activity of amphotericin B, from 0.15-0.63 mg/liter to >2.5 mg/liter in a microwell assay. To test the relevance of this antagonism in vivo, we challenged neutropenic mice iv with a lethal dose of conidia from two strains of A. fumigatus and then treated the mice first with ketoconazole and then with amphotericin B or amphotericin B plus ketoconazole. Pretreatment with ketoconazole for 48 hr completely abolished the protective effect of a subsequent therapy with amphotericin B, whether ketoconazole therapy was stopped (P < . (01) or not (P < .001). Ketoconazole given alone had no significant effect on survival. Our data show that ketoconazole not only antagonized the fungicidal activity of amphotericin B in vitro but also abolished in vivo the protective effect of the only drug shown to be useful in the therapy of aspergillosis. The clinicalimportance of this antagonism, which is not limited to Aspergilli in vitro, requires careful consideration before ketoconazole prophylaxis can be recommended for patients at high risk of developing invasive opportunistic fungal infections.

show abstract

Section: Discussionmentioning

confidence: 99%

The Effect of Ketoconazole on Amphotericin B in a Model of Disseminated Aspergillosis

Schaffner

1985

Journal of Infectious Diseases

178

View full text Add to dashboard Cite

show abstract

“…Investigations that have not confirmed synergy (78,80,161) VOL. 48,2004 MINIREVIEW 697 (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 ϩ KTC rarely cleared tissues better than either agent alone (150); hamsters with combination did worse than with ITC alone (89); ITC ϩ 5FC performed similarly to ITC ϩ 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 FLC: addition of AmB to FLC had dramatic impact on yeast burden in brain tissue b , 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 ϩ 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 used lower concentrations of flucytosine and amphotericin B only or used strains with reduced susceptibility to flucytosine, which may have influenced or biased their ability to characterize the full spe...…”

Section: Neoformans (I) In Vitro Datamentioning

confidence: 99%

Combination Antifungal Therapy

Johnson

MacDougall

Ostrosky-Zeichner

et al. 2004

Antimicrob Agents Chemother

491

368

View full text Add to dashboard Cite

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 ...

show abstract

“…Combined therapy with fluconazole and flucytosine was shown to be superior to single-drug therapy in one experimental murine model of Cryptococcus meningitis (1) but not in another (12). The reason for the discrepancy in these results is unclear.…”

Section: Vol 39 1995 Combined Fluconazole-flucytosine Against C Nementioning

confidence: 99%

In vitro evaluation of combination of fluconazole and flucytosine against Cryptococcus neoformans var. neoformans

Nguyen

Barchiesi

McGough

et al. 1995

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Cryptococcal meningitis is a life-threatening opportunistic infection in immunocompromised hosts, especially in human immunodeficiency virus-infected patients and transplant recipients. Although amphotericin B and fluconazole are current acceptable therapies for patients with cryptococcal meningitis, the success of these therapeutic modalities remains suboptimal (13). The combination of amphotericin B and flucytosine appeared to provide the highest rate of clinical success in one study (7). This combination, however, is frequently associated with toxic side effects, and the use of amphotericin B requires close laboratory monitoring with long-term catheters for vascular access. In one pilot study, the combination of fluconazole and flucytosine yielded a clinical success rate of 63%, which is higher than that of previously reported experiences with either amphotericin B or fluconazole (6, 13); however, to date, in vitro synergistic testing to examine the biological basis for this empiric finding has not been performed. We therefore investigated the in vitro interaction of fluconazole with flucytosine against Cryptococcus neoformans var. neoformans. MATERIALS AND METHODSFifty clinical isolates of C. neoformans var. neoformans submitted to the Fungus Testing Laboratory, University of Texas Health Science Center at San Antonio, were studied. Forty-four isolates were recovered from cerebrospinal fluid (CSF), and six were recovered from blood of human immunodeficiency virusinfected patients. In addition, two reference C. neoformans strains, ATCC 90112 and 90113, were used as controls.Antifungal agents. Fluconazole (Pfizer Inc., New York, N.Y.) and flucytosine (Hoffman-La Roche Laboratory Inc., Nutley, N.J.) were tested singly and in combination. Stock solutions of fluconazole and flucytosine (each at 2,560 g/ml) were prepared in distilled water. Serial twofold drug dilutions were also prepared in water. Antifungal susceptibility testing. Drug interaction was assessed with a checkerboard titration, adhering to the recommendations of the National Committee for Clinical Laboratory Standards (11). Briefly, susceptibility testing was performed in RPMI 1640 medium (American Biorganics, Inc., Niagara Falls, N.Y.), with L-glutamine, without bicarbonate, and buffered at pH 7.0 with 0.165 M morpholinepropanesulfonic acid (MOPS). Aliquots of 50 l of each drug (and in the case of the single-drug control, 50 l of that drug and 50 l of sterile water) at a concentration of 20 times the targeted final concentration were dispersed in polystyrene plastic tubes (12 by 75 mm; Falcon 2054; Becton Dickonson, Lincoln Park, N.J.). Yeast inocula (0.9 ml), prepared spectrophotometrically and further diluted as described elsewhere (11), were added to the tubes containing drugs. The final drug concentrations ranged from 0.125 to 128 g/ml for both fluconazole and flucytosine. All tubes were incubated without agitation at 35ЊC, and the readings were made at 72 h. Before the readings, each tube was vortexed, and its turbidity was compared with that ...

show abstract

Combination Therapy of Experimental Candidiasis, Cryptococcosis and Aspergillosis in Mice

Cited by 120 publications

References 17 publications

The Effect of Ketoconazole on Amphotericin B in a Model of Disseminated Aspergillosis

The Effect of Ketoconazole on Amphotericin B in a Model of Disseminated Aspergillosis

Combination Antifungal Therapy

In vitro evaluation of combination of fluconazole and flucytosine against Cryptococcus neoformans var. neoformans

Contact Info

Product

Resources

About