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Lipid Amphotericin B Formulations and the Echinocandins

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Presentation on theme: "Lipid Amphotericin B Formulations and the Echinocandins"— Presentation transcript:

1 Lipid Amphotericin B Formulations and the Echinocandins
Russell E. Lewis, Pharm.D. Assistant Professor

2 Is the AMB-deoxycholate Era Over ?
Imidazoles Fluconazole Lipid-AMB Echinocandins/ Itraconazole New Triazoles

3 Old Versus New Era of Antifungal Therapy
Old Era New Era Amphotericin B-cornerstone Toxicity a limiting factor Limited options for prophylaxis or chronic therapy Limited spectrum of pathogens Combination therapy often not feasible Cost Several treatment options Improved tolerability and availability of oral formulations Expanding spectrum of pathogens Combination therapy-standard of care? Cost !!!

4 Old vs. New Era of Antifungal Therapy
Old Era New Era Limited to amphotericin B Toxicity a limiting factor Limited options for prophylaxis or chronic therapy Limited spectrum of pathogens Combination therapy often not feasible Cost less of a factor Several treatment options Improved tolerability and availability of oral formulations Expanding spectrum of pathogens Combination therapy-standard of care? Cost !!!

5 Lipid Amphotericin B Formulations
Abelcet ® ABLC Amphotec ® ABCD Ambisome ® L-AMB Despite the broad spectrum activity of amphotericin B, the clinical utility of this polyene drug is limited by poor patient tolerance and serious toxic effects, such as nephrotoxocity. Consequently, over the past 15 or so years, efforts to improve the therapeutic index of amphotericin B have been ongoing and have focused primarily on the development of delivery systems which limit exposure of the polyene drug to host cells while achieving therapeutic levels of the drug at the site of the fungal infection. To date, three products have emerged from the various delivery systems under investigation. Lipid formulations of amphotericin B were developed to improve the amphipathic nature of amphotericin B and facilitate drug insertion within the fungal cytoplasmic membrane while reducing uptake in human cells, thereby limiting toxicity. ABLC is composed of amphotericin B complexed with dymyristoyl phosphatidylcholine and dimyristoyl phosphatidylglycerol. The configuration of this complex is ribbon-like. Its trade name is AbelcetT. ABCD is composed of amphotericin B complexed with cholesteryl sulfate. It is a disk-like structure. Its trade name is Amphotec™. Amphocil is an IV form. L-AMB is composed of amphotericin B complexed with hydrogenated soy phosphatidylcholine, distearoylphosphatidylglycerol, and cholesterol. Unlike the other lipid formulations of amphotericin B, it is a true liposome composed of unilamellar lipid vesicles. Its trade name is Ambisome™. Ribbon-like particles Carrier lipids: DMPC, DMPG Particle size (µm): Disk-like particles Carrier lipids: Cholesteryl sulfate Particle size (µm): Unilaminar liposome Carrier lipids: HSPC, DSPG, cholesterol Particle size (µm) : 0.08 DMPC-Dimyristoyl phospitidylcholine DMPG- Dimyristoyl phospitidylcglycerol HSPC-Hydrogenated soy phosphatidylcholine DSPG-Distearoyl phosphitidylcholine

6 Key Biopharmaceutical Differences of the Amphotericin B Formulations
AmB-d Fungizone® L-AmB AmBisome® ABLC Abelcet® ABCD Amphotec® Mol% AmB 34% 10% 35% 50% Lipid Config. Micelles SUVs Ribbon-like Disk like Diameter (µm) < 0.4 0.08 Dosage 0.5-1 mg/kg 3-5 mg/kg 5 mg/kg 3-4 mg/kg Cmax (vs. AmB-d) - Increased Decreased AUC (vs. AmB-d) Vd (vs. AmB-d) Similar Cl (vs. AmB-d) Nephrotox. +++ + Infusion Tox. High Mild Moderate The pharmacokinetics and tissue distribution of the lipid amphotericin B formulations are largely influenced by the physical and chemical properties of the lipid vehicle. For example, the biological half-life of liposome vesicles is increased with smaller size, positive surface electrical charge, and higher cholesterol concentration in the phospholipid bilayers. The chemical properties and physical characteristics of available amphotericin B products are outlined in the table above. Each lipid formulation is unique with respect to its lipid content, configuration, and molar content of amphotericin B. For reference purposes, amphotericin B,the parent drug, consists structurally of micelles (< 25 nm) with desoxycholate as the main lipid. By contrast, L-AmB (AmBisome) is configured in small unilamellar vesicles (liposomes), with a lipid layer enclosing an aqueous core. The average size of the liposomes is 80 nm. L-AmB contains about 10 mol % amphotericin B. ABLC (Abelcet) is configured in large ribbon-like sheets, which range in size from 1600 to 11,000 nm. ABLC contains mol % amphotericin B. The third lipid-based formulation is ABCD (Amphotec) which is configured in uniform disc-like structures, nm in size, with a 1:1 admixture of amphotericin B (50 mol %) and lipids, primarily cholesteryl sulfate. The pharmacokinetics and pharmacodynamics of the lipid formulations of amphotericin B differ greatly from those of AmBD and each lipid formulation has distinct pharmacologic properties, including clearance, area under the curve (AUC), maximum plasma concentration (Cmax), and volume of distribution. Cmax and AUC: Infusion of L-AmB results in strikingly higher AUC and Cmax values than are achieved with AmBD or the other lipid formulations. L-AMB reaches higher concentrations in plasma and remains in the circulation longer. Similar to the other lipid formulations, L-AMB concentrates in reticuloendothelial system. However, its uptake to the reticuloendothelial system cells is slower. This feature is presumably due to the smaller size, higher transition (melting) temperature and more rigid bilayer of the liposome. This finally provides a persistent pool of L-AMB in plasma and a sustained delivery to the site of infection. Volume of distribution: Although the 3 lipid agents are distributed extensively into tissues, especially the primary reticuloendothelial organs (liver, spleen, and lungs), the apparent volume of distribution for ABCD and ABLC after single-dose infusion is substantially greater than that of L-AmB. While penetration of the three drugs into cerebrospinal fluid (CSF) is minimal, efficacy of all three has been demonstrated in cryptococcal meningitis. The highest CSF concentrations are achieved with L-AmB. Clearance: When differences in units of clearance are considered, the clearance of all lipid-based formulations is much lower than that of AmBD. These disparities in pharmacologic properties may be linked to the binding affinity and subsequent release of amphotericin B by the individual lipid vehicles. The liposomal component of L-AmB has the tightest bond to amphotericin B, explaining in part its high plasma concentrations and lower clearance rates relative to the other lipid formulations. As a general principle, the lipid formulations of amphotericin B at dosages 5- to 10-fold higher than dosages of AmBD can be administered safely. Nephrotoxicity is less common with all 3 lipid formulations of amphotericin B than with AmBD. In comparative studies the respective rates of nephrotoxicity are: ABLC ~25%, ABCD ~15%, L-AmB ~20%, and AmBD ~30% to 50%. For all 3 lipid-based drugs (ABCD, ABLC, and L-AmB) kidney tissue concentrations are substantially lower than those of AmBD. The actual mechanism by which ABLC reduces the toxicity of the conventional preparation has been a topic of interest. The ribbon-like configuration of ABLC is a tightly packed complex of amphotericin B with the lipid. This complex presumably provides decreased amount of free drug and may thus be responsible for the reduced toxicity of ABLC. Reduced rates of nephrotoxicity due to ABCD is presumably due to lower peak serum levels and less LDL-bound amphotericin B with ABCD compared with the parent compound, whereas lower kidney concentrations could account for the decreased toxicity of L-AmB. Infusion related events attributed to ABCD and ABLC appear to be more common than those associated with L-AmB and similar in frequency to infusion-related events associated with amphotericin B. Among the lipid amphotericin B formulations, L-AMB is one of the more commonly used preparations. Groll, Piscetelli and Walsh Adv. Pharmacol 1998;44:

7 Wingard. Clin Infect Dis 2002; 35:891-5
Lipid AMB formulations vs. Conventional AMB When Used as First-Line Therapy In Prospective Randomized Trials Outcome Reference Pathogen(s) Agent Response Survival Leenders 1998 Mixed L-AMB Same Leenders 1997 Cryptococcus spp. Anaisse 1995 Candida spp. ABLC Bowden 2002 Aspergillus spp. ABCD Hamill 1999 Cryptococcus spp. Johnson 2002 H. capsulatum Greater Grouping together the lipid formulations of amphotericin as alternatives to conventional amphotericin B for empirical antifungal therapy has been questioned. The best data that address efficacy are from studies that have evaluated the lipid formulations of amphotericin as treatment for documented infection. Six prospective randomized trials have been undertaken in which one of the lipid formulations was compared with conventional amphotericin as treatment for established invasive fungal infection. Unfortunately, some of these studies remain unpublished. This table presents, in brief, data on clinical response rates and overall survival rates from these trials. It shows that none of the lipid formulations has a clear advantage compared with conventional amphotericin B, with 1 exception. In the study performed by Johnson et al 2002, L-AmB was superior to amphotericin B with respect to both clinical response and survival rates in the treatment of histoplasmosis. Wingard. Clin Infect Dis 2002; 35:891-5

8 Wingard. Clin Infect Dis 2002; 35:891-5
Lipid AMB formulations vs. Conventional AMB When Used as First-Line Therapy In Prospective Randomized Trials Toxicity Reference Pathogen(s) Agent Infusion Renal Leenders 1998 Mixed L-AMB Lower Leenders 1997 Cryptococcus spp. Anaisse 1995 Candida spp. ABLC Same Bowden 2002 Aspergillus spp. ABCD Greater Hamill 1999 Cryptococcus spp. Johnson 2002 H. capsulatum With respect to toxicity, there are clear differences between the formulations, and these are clinically significant. The toxicities associated with amphotericin B can be broadly categorized as either infusional reactions or nephrotoxicity. Only L-AmB therapy has been shown, clearly and repeatedly, to result in fewer infusional reactions than conventional amphotericin therapy. The incidence of infusional toxicity associated with ABLC seems to be in the same ballpark as that of conventional amphotericin. All 3 lipid formulations have considerably less nephrotoxicity than does conventional amphotericin. To summarize, taking the preponderance of evidence into consideration, there appears to be no substantial difference in the performance of the lipid formulations of amphotericin compared with conventional amphotericin, except with respect to toxicity and cost. Although there are differences between the formulations, when all considerations are balanced, none has a clear advantage over the others. Wingard. Clin Infect Dis 2002; 35:891-5

9 Wingard. Clin Infect Dis 2002; 35:891-5
Comparison of Lipid AMB Formulations as Empiric Therapy for Febrile Neutropenia Outcome Toxicity Reference Agent Response Survival Infusion Renal Comments Prentice 1997 L-AMB vs. AMB-D Similar Lower L-AMB L-AMB 1-3 mg/kg/day White 1998 ABCD vs. Higher ABCD Infusion-related hypoxia > ABCD Walsh 1999 L-AMB vs. AMB-D Fewer breakthrough infection in L-AMB Wingard 2000 ABLC Greater for ABLC Primary endpoint-safety Fleming 2001 ABLC vs. Ambisome Similar for fungal Lower for L-AMB Mild abnormalities in LFT: L-AMB > ABLC The two studies highlighted on this slide are randomized, double-blind clinical trials comparing the efficacy of lipid formulations of amphotericin B (ABLC and L-AmB) for empiric therapy in adult febrile neutropenic patients. In general, ABLC and L-AmB have comparable efficacy. Direct comparison of ABLC and L-AmB found less nephrotoxicity and infusion related toxicity associated with L-AmB. Wingard. Clin Infect Dis 2002; 35:891-5

10 Lipid AMB Formulations-Summary
Efficacy Lipid formulation > AMB-deoxy Nephrotoxicity L-AMB < ABLC < ABCD << AMB-deoxy Infusion related toxicity L-AMB < ABLC < ABCD < AMB-deoxy Product cost (AWP) L-AMB > ABLC > ABCD > AMB-deoxy The 3 lipid-based formulations represent a significant advance in antifungal therapy. While superior clinical efficacy of these drugs over AmBD for any fungal disease has not been clearly established, the lower toxicity profile of lipid-based agents is an attractive feature. All 3 drugs are less nephrotoxic than AmBD and 1 of the drugs (L-AmB) is clearly associated with fewer infusion-related adverse events than AmBD. A clear advantage of a lipid based product is where there is poor or no central venous access. The high cost of the lipid-based drugs is the major factor that limits their utilization and well designed pharmacoeconomic studies would be of significant value. The daily treatment costs based on the 1999 average wholesale price for amphotericin B products are as follows: AmBD 1 mg/kg $25, ABLC 5 mg/kg $776, ABCD 4 mg/kg $480, and L-AmB 3 mg/kg $942. As a general rule, these agents should not be used as initial therapy for most patients with the various candida syndromes, cryptococcosis and the endemic mycoses (e.g. blastomycosis, histoplasmosis, coccidioidomycosis) unless the patient has preexisting renal dysfunction, has life-threatening, progressive disease, or is refractory to or intolerant of amphotericin B or azole therapy. If it were not for the 10 to 50-fold higher acquisition cost of lipid formulations of AmB, their first-line use would be widely adopted. Thus, the arrival of these agents onto the market has forced institutions to more closely examine secondary costs associated with antifungal therapy e.g. the management of nephrotoxicity with Amphotericin B. An important goal in determining the cost effectiveness of antifungal therapy is finding a balance between primary (acquisition) and secondary costs.

11 Continuous Infusion Amphotericin B
Rationale: “Simulate” the release of free AMB from the lipid formulation by using unconventional dosing Controversial study (Eriksson et al. BMJ 2001) 80 febrile neutropenic patients randomized to 0.97 mg/kg CI over 24 hours 0.97 mg/kg rapid infusion over 4 hours CI group had fewer side effects and less nephrotoxicity, mortality was higher in rapid infusion group. Similar results recently reported for 2 mg/kg/day! This study was performed to test the hypothesis that amphotericin B deoxycholate is less toxic when given by continuous infusion rather than by conventional rapid infusion. Subjects : 80 mostly neutropenic patients with refractory fever and suspected or proved invasive fungal infections Main outcome measures: Patients were evaluated for side effects related to infusion, nephrotoxicity, and mortality up to three months after treatment. Results: Patients in the continuous infusion group had fewer side effects and significantly reduced nephrotoxicity than those in the rapid infusion group. Overall mortality was higher during treatment and after three months' follow up in the rapid infusion than in the continuous infusion group. Conclusion: Continuous infusions of amphotericin B reduce nephrotoxicity and side effects related to infusion without increasing mortality. Incorporation of amphotericin B into liposomal formulations reduces its toxicity, but the reasons for this are unclear. As liposomes do not specifically target fungal cells it would seem that the reduction in toxicity, at least in part, depends on a slower delivery of amphotericin B to tissues. The question as to whether a slower delivery of amphotericin B from lipid formulations might be reproduced by a slow infusion rate therefore arises. Eriksson’s data supports the notion that a continuous infusion of amphotericin B may be at least as effective as daily infusions over four hours, as well as having reduced nephrotoxicity and fewer infusion related side-effects. BUT: The conclusive findings are welcomed though they make little reference to the impracticality of such a protocol. The use of intravenous amphotericin B is largely confined to neutropenic patients undergoing chemotherapy for haematological malignancies. These patients routinely have dual lumen central venous catheters, such as hickman lines. After allowance for regular blood sampling, fluid/electrolyte replacement, parenteral nutrition, antibiotics and chemotherapy regimes there is frequently inadequate access for the conventional rapid infusion of amphotericin B. Positioning of further access for continuous infusion would unfortunately be unacceptable to most patients (and some staff) with the risk of an additional source for sepsis. Eriksson et al. BMJ 2001;322:

12 Unanswered Questions Concerning Lipid Formulations
Optimal dosing Bioactivity in respective tissue compartments Use in established but reversible acute renal failure Prophylaxis/Aerosolization Long-term toxicities Cost-effective use in lower risk patients Some important questions about the use of amphotericin B lipid preparations remain unanswered. Are there differences in the clinical efficacy and/or toxicities of the preparations and what is their exact mechanism of action? Do they have long-term toxicity? Is there an optimal dose schedule and what is the most cost-effective way to use them? It is not known if there is any benefit for a lipid based amphotericin B in allowing earlier or more complete recovery of renal function in those with acute renal failure or dialysis support. Unfortunately, although amphotericin B lipid preparations have reduced nephrotoxicity they have not produced substantial improvements in efficacy in many of the clinical settings in which they have been evaluated. Therefore, and also because treatment with AMB-lipid formulations is very expensive, many patients with severe invasive fungal infections are still undergoing aggressive treatment with conventional AMB. An increase in the number of immunosuppressed patients at risk of developing fungal infections due to increasing advances in transplantation medicine has led to a substantial increase in the number of cases of invasive pulmonary aspergillosis (IPA) in the last few decades. Standard treatment of IPA with intravenous amphotericin B desoxycholate is often unsuccessful and complicated by severe, dose-limiting toxicity. Thus, there is a continuing need for optimization of antifungal treatment in pulmonary aspergillosis. The portal of entry of Aspergillus is often the respiratory tract, since the spores of this fungus are ubiquitous and easily inhaled. Spores descend to the lowest regions of the lungs and invasive disease subsequently develops. Further improvement in the treatment of IPA can therefore be sought in the administration of amphotericin B products via the pulmonary route. With this mode of administration, the therapeutic agent targets the lungs directly, and systemic toxicity is reduced. Improvement in efficacy as well as reduction of systemic side effects could be anticipated. Results based on animal models indicate that aerosol administration of amphotericin B, especially the liposomal formulation, could be an additional approach to optimizing treatment of invasive pulmonary aspergillosis.

13 The Fungal Cell Wall chitin ergosterol mannoproteins b1,3 b1,6 glucans
PPL bilayer chitin ergosterol b1,3 glucan synthase mannoproteins A different drug target: The most overt distinction between fungal and mammalian cells is the cell wall of fungi. The uniqueness of this structure makes it a premier target of antifungal drugs. Although the cell wall was initially considered an almost inert cellular structure that protected the cell against osmotic offense, more recent studies have demonstrated that it is a dynamic organelle. The major components of the cell wall are glucan and chitin, which are associated with structural rigidity, and mannoproteins.

14 Echinocandin “backbone”
The Echinocandins Echinocandin “backbone” Cyclic lipopeptides that non-competitively inhibit of 1,3 -b-D glucan synthase 210 kDa integral membrane heterodimeric protein ? Responsible for export of glucan polymer Three echinocandins Cancidas ® (caspofungin) Micafungin (FK463) Anidulafungin (VER 002) OH H HO NH O 2 N 3 C CH The echinocandins are a recently-developed class of antifungal agents that interfere with fungal cell wall synthesis through the non-competitive inhibition of glucan synthesis. They are cyclic lipopeptide fungicidal agents. The lack of glucan synthesis enzymes in mammalian tissue makes this an attractive target for antifungal activity. Biosynthesis of β (1-3) glucans is under the control of a membrane protein complex, the glucan synthase. This enzyme is composed of 2 different subunits and has a molecular weight of 210 kDa. The catalytic subunit of this enzyme complex, an integral membrane protein s regulated by a small GTPase of the Ras superfamily, the Rho-GTPase, and protein kinase C (Pkc)-like signaling molecules. The newly synthesised glucan polymer is thought to be transported through the bilayer by this membrane spanning protein, from the periplasmic space to the cell wall. Here, it is associated to the other cell wall polysaccharides (chitin, galactomannan and β 1-3, 1-4 glucan) to produce the rigid three-dimensional network characteristic of the cell wall. There are currently three such agents at present, 1)Caspofungin 2)Micafungin 3)Anidulafungin The latter two drugs are currently in clinical trials and are not yet licensed for use. Cilofungin, the first member of the group, reached clinical trials but was abandoned because of side effects associated with the carrier used for the parenteral formulation. A major breakthrough in antifungal therapy occurred in January 2001 with FDA fast track approval for the marketing of caspofungin (Cancidas ®). The unique action of this particular class of drug is very useful for 2 reasons: The echinocandins are active against Candida spp. isolates that are resistant to the azoles and amphotericin B. 2) Since their activity is specific to fungal cell walls, it bodes well for minimal toxicity.

15 Echinocandins-Spectrum vs. Yeast
Fungicidal vs. Candida spp. including many fluconazole-resistant species C. albicans = C. tropicalis = C. glabrata = C. krusei < C. parapsilosis = C. lusitaniae No activity against C. neoformans The optimal first-line treatment for serious candida infections is a controversial issue. Amphotericin B has served as standard treatment for five decades, but toxic effects often limit its use. Prospective, randomized studies have shown that fluconazole is as effective as amphotericin B, with superior safety, for the treatment of candida infections. However, certain non-albicans candida species, which account for over half the cases, are less susceptible to fluconazole. The need remains for new agents to treat serious candida infections. One alternative is caspofungin. The next few slides show results of studies investigating the effectiveness of caspofungin against: Planktonic candida albicans Biofilm candida albicans Mucosal candida albicans Invasive aspergillosis Invasive candida albicans (compared to AmB) The mode of action of the echinocandins means they possess an unusual extended spectrum of activity. They are active against Candida spp. isolates that are resistant to the azoles and amphotericin B. About 10 % of Candida species are not killed by echinocandins and Candida parapsilosis, C.guilliermondii and C. lusitaniae are slightly less susceptible then other species. They are not active at all against Cryptococcus neoformans, since this pathogen has little or no β(1,3)- -D-glucan synthase enzyme. On the other hand, they are very active against Pneumocystis carinii. (unlike other antifungal agents) because the wall of the ‘cyst’ form of this fungus contains β(1,3)- -D-glucan synthase. They have a fungicidal action. Kuhn et al used confocal scanning laser microscopy (CSLM) to image the effects, on cell structure, of drug exposure on planktonic (free floating) C. albicans cells. These images utilize CAAF and FUN-1 staining. FUN-1 is a fluorescent dye taken up by fungal cells; in the presence of metabolic viability it is converted from a diffuse yellow cytoplasmic stain to red, rod-like dye aggregates. However, it remains yellow in metabolically inactive, nonviable cells. Concanavalin A-alexa fluor 488 conjugate (CAAF) selectively binds to polysaccharides. Therefore, green CAAF staining highlights blastospore cell walls. Cells in slide B had been exposed to caspofungin for 24 hrs. Slide A shows untreated control cells. Caspofungin-treated cells exhibit grossly distorted cell walls, with minimal cytoplasmic staining and no evidence of viability. i.e. echinocandins are effective against planktonic Candida spp. Kuhn et al. Antimicrob Agent Chemother 2002;46:

16 Echinocandin Activity vs. Biofilm- Embedded Yeast
Antifungal Killing vs. Biofilm- Embedded Candida spp. 100 90 FLU 80 AMB 70 CAS 60 % Viability (XTT) 50 40 30 Yeasts (mainly Candida albicans) are the third leading cause of catheter-related infections, with the overall highest crude mortality. Biofilms are a well-described phenomenon in the microbial world, which have gained notoriety from their ability to resist antimicrobials. Definition of biofilm: microbial organisms usually embedded in extracellular polymers such as implanted medical devices, which adhere to surfaces submerged in, or subjected to, aquatic environments. They are glued together (by secreted polysaccharides and glycoproteins) to form microbial communities which are highly resistant to both phagocytes and antibiotics. In this study, the in vitro activities of fluconazole, amphotericin B, and caspofungin against Candida albicans biofilms by time-kill methodology was examined. Determining the effectiveness of different antifungal agents in this setting has important clinical implications in that it may guide therapeutic decisions that may affect the outcome for patients with these difficult to-treat infections. The pharmacodynamic properties of all three antifungals have been described in studies using free-floating (planktonic) cells. These studies may be useful in selecting dosing regimens for a range of Candida infections, mainly for free-floating cells encountered in bloodstream infections. However, the pharmacodynamic profiles of sessile cells that are encountered in many biofilm-associated infections are not adequately addressed in these types of studies, especially since sessile C. albicans cells display dramatically altered resistance phenotypes in comparison to planktonic cells. Overall the results indicate that caspofungin exhibits the most effective pharmacodynamic properties against C. albicans biofilms in comparison to both amphotericin B and fluconazole. Whereas amphotericin B kills sessile cells within the biofilm rapidly in a concentration-dependent manner, the concentrations required to initiate these effects are high above its therapeutic margin. Fluconazole, a fungistatic drug, shows little or no efficacy against sessile cells. Caspofungin kills 99% of sessile cells within the biofilm at therapeutically attainable concentrations. These observations, together with the toxicological and pharmacological profiles displayed by caspofungin, support its use in difficult-to-treat biofilm-associated infections. 20 10 0.5 2 16 Antifungal Conc (mg/mL) Ramage et al. Antimicrob Agent Chemother 2002;46:3634

17 Echinocandin-Treated Patients with Refractory Esophagitis
Before After Patient #1 Patient #2 Mucosal candidiasis, although not life-threatening, causes significant morbidity in patients infected with the human immunodeficiency virus (HIV). These infections are characterized by their propensity to recur. Upon endoscopy (see photos), white exudative lesions are seen. The development of drug resistance in the causative strain or the selection of intrinsically more resistant species may complicate therapy of these recurrent candidal infections. Oral fluconazole is widely regarded as the treatment of choice for mucosal candidiasis under most circumstances. Amphotericin B deoxycholate has been the standard recourse for patients infected with Candida sp. unresponsive to azole therapy. However, the use of conventional amphotericin B preparations is complicated by its significant toxicity. This study describes the use of caspofungin as treatment for oropharyngeal and esophageal candidiasis in an immunocompromised patient population. The images above show the resolution of esophageal plaques caused by infection with C. albicans in two patients treated with caspofungin. Favorable endoscopic responses are illustrated for two representative patients with high-grade esophagitis 3 to 4 days after the conclusion of caspofungin therapy. In HIV-infected patients with esophageal and/or oropharyngeal candidiasis, caspofungin appeared to possess an efficacy at least comparable to that of a standard dose of amphotericin B. These results further suggest that caspofungin may provide a better-tolerated alternative option to conventional amphotericin for patients who require parenteral therapy, such as those with azole-refractory Candida infections.

18 Echinocandins-Spectrum vs. Moulds
AfFks1p (IntF) Aniline blue Active against Aspergillus species Glucan synthase localized in apical tips Activity against other yeast and moulds is less well described or variable Mycelial forms of endemic mycoses? Echinocandins are only active against fungal species which express the genes for the glucan synthase complex. Beauvais et al investigated this enzymatic complex in Aspergillus fumigatus. The genes encoding the putative catalytic subunit FKs1p and four Rho proteins of A. fumigatus were cloned and sequenced. When aniline blue, a fluorochrome specific for β(1–3) glucans, was added to growing germ tubes, the apex of the germ tube was the point most intensively labeled by the aniline blue, indicating that the newly synthesized β(1–3) glucan was produced at the apex of the germ tube (Fig. C). The apex also was positively labeled with the anti-IntF antiserum. This result showed that AfFks1p was localized at the apical growing region of the mycelium (Fig. A). Beauvais et al. J. Bacteriol 2001;183:

19 Echinocandins Act at the Apical Tips of Aspergillus Hyphae
Caspofungin is the drug of choice for invasive aspergillosis which is unresponsive to other antifungal drugs. High-magnification photomicrographs of caspofungin treated, DiBAC-stained A. fumigatus from a study by Bowman et al 2002. Previous to this study, it was known that caspofungin caused cell death in yeasts and dimorphic fungi such as Candida albicans, but its effects on Aspergillus fumigatus remained unclear. Bowden et al used the fluorescent dyes CFDA and DiBAC, which stain live and dead cells, respectively, to further characterise the antifungal activity of caspofungin. They observed a differential effect of the drug as a function of cell position. 88% of apical cells and 61% of subapical branching cells failed to stain with the viable dye CFDA, but only 24% of subapical cells were unstained. Complementary results were seen with DiBAC staining. The dye staining patterns illustrate that the cells at the active centres for new cell wall synthesis within the growing A. fumigatus hyphae are more susceptible to lysis after caspofungin treatment, compared to subapical cells with mature cell walls. This antifungal activity occurring at actively growing tips and branching points of Aspergillus hyphae, leads to formation of flattening and swelling tips. DiBAC Bowman et al. Antimicrob Agent Chemother 2002;46:

20 Update on the Multi-Center Non-Comparative Study of CAS in Adults with IA: Analysis of 90 Patients
Pulmonary Disseminated Single Organ N of Pts. 64 13 6 Favorable (CR/PR) 32 (50%) 3 (23%) 2 (33%) These are results from a multicenter, noncomparative study to evaluate safety and efficacy of Caspofungin (CAS) in adults with Invasive Aspergillosis (IA) refractory or intolerant to Amphotericin B (AMB), AMB Lipid Formulations (Lipid AMB), or azoles. At the time of the study, CAS was an investigational echinocandin with activity against Aspergillus spp. in vitro and in animal models. This study evaluated safety & efficacy of CAS in immunocompromised adults with IA who received prior therapy. Results from the first 56 patients in this study (in 2000) were the basis for regulatory approval of CAS as salvage therapy of IA. Here is an update on all 90 patients-of which only 83 met the IA definition. The sites of infection were defined as: pulmonary, single organ or disseminated. Favorable response [Complete (CR) or Partial (PR)] required significant clinical & radiographic improvement. Of the patients, 71 (86%) were refractory to & 12 (14%) intolerant of prior therapy. CR or PR was noted in 45% (37/83). These results confirm the use of caspofungin as a salvage therapy for invasive aspergillosis. Maertens et al. ICAAC 2002.

21 Caspofungin 70 mg day #1, then 50 mg QD vs.
Caspofungin vs. Amphotericin B Deoxycholate in the Treatment of Invasive Candidiasis in Neutropenic and Non-Neutropenic Patients Caspofungin 70 mg day #1, then 50 mg QD vs. AMB-D mg/kg/q24h CAS [95% CI] AMB Difference adjusted for stratification MITT 71/115 (74%) [65-82] 71/115 (62%) [53-71] 12.7% [ ] End of Therapy response * 71/88 (81%) [72-89] 63/97 (65%) [55-75] 15.4% [ ] A double-blind trial to compare caspofungin with amphotericin B deoxycholate for the primary treatment of invasive candidiasis was performed. The presence or absence of neutropenia was assessed and patients were randomly assigned to receive either intravenous caspofungin or amphotericin B. Of the 239 patients enrolled, 224 were included in the modified intention-to-treat analysis. A modified intention-to-treat analysis showed that the efficacy of caspofungin was similar to that of amphotericin B, with successful outcomes in 73.4 percent of the patients treated with caspofungin and in 61.7 percent of those treated with amphotericin B (difference after adjustment for APACHE II score and neutropenic status, 12.7 percentage points). An analysis of patients who met pre-specified criteria for evaluation showed that caspofungin was superior, with a favorable response in 80.7 percent of patients, as compared with 64.9 percent of those who received amphotericin B (difference, 15.4 percentage points) There were significantly fewer drug-related adverse events in the caspofungin group than in the amphotericin B group. * P < 0.05, secondary analysis Mora-Duarte et al. Volume 348: March 27, 2003.

22 Efficacy and safety of caspofungin in invasive aspergillosis in patients refractory to or intolerant of other therapy Favorable Response Patient Population n % Original 83 patients Complete response Partial response Pulmonary (n=64) Extrapulmonary (n=19) Leukaemia (n= 60) Neutropenia (n=19) AlloHSCT (n=21) Refractory (n=71) Intolerant (n=12) 37 4 33 32 5 25 3 28 9 45 5 40 50 26 42 14 39 75 Patients failing other antifungal therapy or who had toxicity (usually renal impairment with amphotericin B, n=12) were enrolled in a salvage study, receiving caspofungin monotherapy (70mg loading dose and then 50mg/d). The diagnosis of aspergillosis, reason for enrollment and outcome was reviewed by an external panel. the results are presented here. Clearly patients who survive long enough to receive salvage therapy excludes the most severely ill patient group. However the response rate recorded is indicative of significant activity of caspofungin in invasive aspergillosis. Responses were worst in neutropenic patients, as with amphotericin B. Maertens et al Clin Infect Dis In press

23 Drug-Related Adverse Experiences*
Occurring in  2% of Patients treated with CAS Caspofungin 50 mg % (N=69) 2.9 3.2 4.9 Clinical Adverse Experiences Fever Phlebitis/Infused vein complications Nausea Vomiting Laboratory Adverse Experiences Increased eosinophils Increased urine protein The pivotal clinical trial which provided the basis for FDA approval involved 69 adult patients with definite or probably invasive aspergillosis. It was an open-label, non-comparative study to evaluate the safety, tolerability, and efficacy of caspofungin. Patients received caspofungin 70 mg on Day 1, then 50 mg daily for the remainder of their treatment. Clinical adverse experiences with an incidence of approx 2% were reported in patients-these included fever, infused vein complications, nausea, vomiting, and flushing (all at 2.9%). Reported, at a lower incidence, were pulmonary edema, ARDS, and radiographic infiltrates. Laboratory abnormalities in this same study population included increased serum alkaline phosphatase, eosinophils, urine protein, urine red blood cells, and decreased potassium levels. These results show that the number of drug-related adverse events is significantly lower for caspofungin compared to amphotericin B. Drug Interactions: very few significant ones. Studies in vitro show that caspofungin acetate is not an inhibitor of any enzyme in the cytochrome P450 (CYP) system. In clinical studies, caspofungin did not induce the CYP3A4 metabolism of other drugs. Caspofungin is not a substrate for P-glycoprotein and is a poor substrate for cytochrome P450 enzymes. i.e. Caspofungin is not an inhibitor or inducer of the cytochrome P450 system. Caspofungin reduces the blood AUC of tacrolimus and peak blood concentration (Cmax) which may cause loss of immunosuppression efficacy. For patients receiving both therapies, standard monitoring of tacrolimus blood concentrations and appropriate tacrolimus dosage adjustments are recommended. Cyclosporin reduces caspofungin clearance, increasing antifungal exposure. Transient increase in liver transaminases may occur. Patient monitoring is recommended and if necessary caspofungin dosage should be reduced. Few significant drug interactions P450 Inducers (increase CAS dose to 70 mg day) Tacrolimus (monitor levels and adjust dose) Cyclosporin A (avoid or closely monitor LFTs) * Possibly, probably or definitely drug-related

24 Micafungin vs. Fluconazole for Prophylaxis of IFI in Patients Undergoing HSCT
1 0.9 0.8 0.7 0.6 Proportion of Patients with Treatment Success Administered until: Day +5 neutrophil recovery Day +42 Fungal infection Unacceptable toxicity Death 0.5 Micafungin (N=425) 0.4 Fluconazole (N=457) 0.3 A randomised study of prophylaxis using a low (50mg) dose of micafungin showed superiority to fluconazole and equivalent safety for those undergoing haematopoetic stem cell transplantation. P-Value (2 tailed) = 0.025 0.2 0.1 10 20 30 40 50 60 70 Time to Treatment Failure (Days Since First Dose of Study Drug) Van Burik et al. ICAAC 2002

25 In Favor of Micafungin (FK463)
Fluconazole In Favor of Micafungin (FK463) Allogeneic +3.0 Type of Transplant Autologous +9.1 or Syngeneic GVHD During Study +5.3 Present (graft-versus-host disease) Absent +10.8 < 16 +15.9 > 16 +5.4 Age < 65 +4.9 +27.4 > 65 -30 -25 -20 -15 -10 -5 5 10 15 20 25 30 Treatment difference (FK463 - fluconazole ) Van Burik et al. ICAAC 2002

26 Safety Related to Study Drug
fluconazole (n=457) 77 (16.8%) 14 (3.1%) 12 (2.6%) 15 (3.3%) 33 (7.2%) Adverse Events Bilirubinemia Nausea Diarrhea Discontinued study drug due to adverse event * micafungin (n=425) 64 (15.1%) 14 (3.3%) 10 (2.4%) 9 (2.1%) 18 (4.2%) * P=0.058 micafungin compared to fluconazole Van Burik et al. ICAAC 2002

27 Hepatic and Renal Adverse Events Related to Study Drug
LFTs abnormal SGOT / AST  SGPT / ALT  Serum Cr  Hypokalemia micafungin (n=425) 4 (0.9%) 3 (0.7%) 1 (0.2%) 8 (1.9%) fluconazole (n=457) 10 (2.2%) 9 (2%) 4 (0.9%) 8 (1.8%) Van Burik et al. ICAAC 2002

28 Pharmacology of Antifungal Combinations
Pharmacokinetic Pharmacodynamic Site-specific issues - Amount of drug - Rate of accumulation - Ratio of concentrations - Bioactivity at site Drug-specific issues Spectrum Synergy or antagonism Resistance Toxicity The relentless increase of invasive fungal infections and poor outcomes associated with available antifungal agents prompted the search for better therapeutic strategies. Combining antifungal drugs was recommended as a means to enhance efficacy in a variety of invasive infections including cryptococcosis, candidiasis, and aspergillosis. With the exception of cryptococcal meningitis, data from controlled clinical trials supporting such combinations are sparse. Moreover, little consensus exists regarding which combinations are synergistic or antagonistic in vitro and in vivo. There are several potential advantages to antifungal combinations. In addition to widening the spectrum and potency of drug activity, these regimens could achieve a more rapid antifungal effect and allow reduction in the dosage of individual agents such as amphotericin B. In addition, they possibly could prevent emergence of antifungal resistance. The net pharmacologic activity of a given antiinfective combination can be broadly conceived on the basis of overlapping pharmaco-kinetic and pharmacodynamic interactions. Pharmacokinetic interactions affect the amount, rate, and ratio of drug concentrations achieved at the site of infection. These interactions can be direct or indirect. Indirect pharmacokinetic interactions occur when a second agent results in improved penetration and accumulation at the site of infection over a single drug. Direct pharmacokinetic interactions can both enhance or attenuate the activity (and toxicity) of a given antifungal combination due to interference of absorption, metabolism, or elimination of the original agent. Indeed, in some cases, the second drug does not have to be an antifungal (histamine H2 blockers with itraconazole capsules). Pharmacodynamic interactions can be classified into four general groups: those that affect the spectrum; the rate or extent of killing (synergy or antagonism); selection for resistant organisms; and toxicity of the regimen. Spectrum: Few antifungal combinations are routinely administered solely on the basis of expanding the spectrum of empiric therapy. This may be due to the fact that available drugs already have a broad spectrum. However, for some agents, empiric combinations may cover gaps in antifungal coverage e.g. another agent may be used to cover gaps in fluconazole’s spectrum, for example, non-albicans Candida spp. and Aspergillus spp. Synergy: Achieving synergistic activity is probably the most widely cited and intensively studied reason for combining antifungals. Synergy can be defined as improvement in fungicidal activity by a magnitude greater than the expected sum of individual activities of individual agents.[24] Conversely, antagonism occurs when the antifungal activity of a combination is less than that of the least active antifungal in the combination when given alone. Three mechanisms are frequently cited as resulting in synergy between two or more antifungal agents.[24] The first mechanism results from sequential inhibition of different steps of a common biochemical pathway. A second mechanism proposed for synergistic interaction of antifungals is simultaneous inhibition of cell wall and cell membrane targets in fungi. This would most likely result from simultaneous administration of an echinocandin (cell wall active) plus amphotericin B (cell membrane) or azole (cell membrane). A third mechanism of synergy for antifungals arises from simultaneous therapy with cell wall- or cell membrane-active agents to enhance the penetration of a second antimicrobial. Resistance: Few data suggest that combination antifungal therapy can slow secondary resistance or prevent emergence of fungi with primary resistance. Therefore, preventing resistance does not appear to be nearly as an compelling indication for antifungal combinations, as is the case with antibacterial therapy for treatment of less chronic infections. Toxicity: Toxicity has always been a major issue with antifungal therapy in the critically ill. Adverse effects associated with the gold standard drug amphotericin B are well recognized. It is hoped that combination therapy would allow lower concentrations to be used, therefore reducing toxic side-effects. Sequential use?…..Timing? Lewis and Kontoyiannis. Pharmacotherapy 2001;21:49S-164S

29 Antifungal combinations…an opinion
Pharmacokinetic Beneficial: AMB + 5-FC AMB + FLU Echinocandin + newer triazole L-AMB + AMB-Dx1? Pharmacodynamic (from animal studies) AMB/L-AMB + CAS Echinocandin + newer triazole Pharmacokinetic: AMB + 5-FC Amphotericin B-flucytosine in treatment of cryptococcal meningitis. Because penetration of amphotericin B into the central nervous system (CNS) is relatively poor (< 4%), even in the presence of inflamed meninges, a significant lag time may ensue before effective concentrations are achieved at the site of infection. Flucytosine rapidly achieves effective concentrations in cerebrospinal fluid (CSF). Therefore, by giving the drugs in combination, early antifungal efficacy is enhanced over amphotericin B alone. Pharmacodynamic: Studies of the in vitro activity of amphotericin B plus caspofungin have found indifference and additive or synergistic effects against various isolates of Candida, Aspergillus, and Cryptococcus, with the type of effect varying according to the isolate. There are 3 case reports with successful outcome, including 1 report focusing on the combination of amphotericin B and caspofungin to treat aspergillosis, and 2 reports on the combination of itraconazole and caspofungin in A fumigatus and A terreus infections. Clinical trial data are needed to evaluate these combinations more fully.

30 High-Dose Fluconazole Plus Placebo vs
High-Dose Fluconazole Plus Placebo vs. Fluconazole plus Amphotericin B for Candidemia in Non-Neutropenic Patients FLU 800 mg/d vs. AMB 0.7 mg/kg + FLU 800 mg/d N=219 Higher APACHE II in FLU monotherapy arm Success rates: F + P = 56% F + A = 69% Fungemia persisted longer in F + P arm (P = 0.02) Nephrotoxicity more common in AMB + FLU Time to failure 100 P=0.08 90 80 70 60 Percent Successfully Treated 50 40 FLU + placebo 30 FLU + AMB A randomized, blinded, multicenter trial was conducted to compare fluconazole (800 mg per day) plus placebo with fluconazole plus amphotericin B (AmB) deoxycholate (0.7 mg/kg per day, with the placebo/AmB component given only for the first 5 days) as therapy for candidemia due to species other than Candida krusei in adults without neutropenia. A total of 219 patients met criteria for a modified intent-to-treat analysis. The groups were similar except that those who were treated with fluconazole plus placebo had a higher mean (± standard error) Acute Physiology and Chronic Health Evaluation II score. Success rates on study day 30 by Kaplan-Meier time-to-failure analysis were 57% for fluconazole plus placebo and 69% for fluconazole plus AmB (P = .08). Overall success rates were 56% (60 of 107 patients) and 69% (77 of 112 patients; P = .043), respectively; the bloodstream infection failed to clear in 17% and 6% of subjects, respectively. In summary, this study provides some compelling evidence that fluconazole and amphotericin B do not demonstrate in vivo antagonism when used to manage candidemia in nonneutropenic patients. The use of the combination appears to clear bloodstream infections better and has a higher incidence of overall treatment success, although time-to-failure is similar to fluconazole monotherapy, the incidence of toxicity is higher and (although not examined) the cost is greater.  However, sequential treatment with fluconazole followed by a switch to AmB alone has still not been evaluated in a prospective trial, nor has the efficacy of the fluconazole plus AmB combination been tested in neutropenic patients, for whom therapy is complicated by host immune status. Future trials should address these issues. 20 10 1 2 3 5 8 10 15 20 25 30 Days after Study Enrollment Rex et al. ICAAC 2001, Abstr #681a

31 Antifungal Pharmacotherapy
Amphotericin B Triazoles Echinocandins Combinations To summarise: Invasive fungal infections are often difficult to diagnose with certainty, and mortality rates remain higher than ideal despite a steadily expanding armory of broad-spectrum antifungal agents. In addition to the existing triazole antifungals (fluconazole and itraconazole) and amphotericin B (AmB), newer triazoles (voriconazole, posaconazole, and ravuconazole) and echinocandins (caspofungin, anidulafungin, and micafungin) are being developed for clinical use. This growing diversity of antifungal classes has renewed interest in the possibilities of therapy with antifungal combinations-since a pharmaceutical attack designed to strike at 2 targets in the fungi, should in theory, improve therapeutic outcomes. Diagnostic Tools

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