Combinations Of Antifungal Drugs Research Articles

Antifungal therapy for newborn infants with invasive fungal infection

A variety of antifungal drugs, drug preparations and drug combinations are available to treat newborn infants with suspected or confirmed invasive fungal infection. There is a need to assess their relative merits. To assess the effect of treatment with different antifungal drugs, drug preparations or drug combinations on mortality and morbidity in newborn infants with suspected or confirmed invasive fungal infection. We used the standard search strategy of the Cochrane Neonatal Review Group. This included searches of the Cochrane Central Register of Controlled Trials (The Cochrane Library, 2012, Issue 2), MEDLINE, EMBASE, CINAHL (to March 2012), conference proceedings and previous reviews. Randomised and quasi-randomised control trials comparing one antifungal agent or combination of agents with another in newborn infants with suspected or confirmed invasive fungal infection. We extracted the data using the standard methods of the Cochrane Neonatal Review Group, with separate evaluation of trial quality and data extraction by each author, and synthesis of data using risk ratio and risk difference. We identified only one small trial in which 24 newborn infants participated. This trial compared the use of fluconazole versus amphotericin B (plus 5-fluorocytosine if fungal meningitis present). The trial did not detect a statistically significant effect on mortality (risk ratio 0.73; 95% confidence interval 0.26 to 2.05). There are insufficient data to inform practice. Large randomised controlled trials are required to compare antifungal drugs, drug preparations or drug combinations for treating newborn infants with invasive fungal infection.

Comparative study of the in vitro activity of various antifungal drugs against Scedosporium spp. in aerobic and hyperbaric atmosphere versus normal atmosphere

Scedosporium spp. have been observed with increasing frequency over the last decade in immunocompromised patients and trauma patients. This mould is often multi-drug resistant and its mortality rate remains very high. The primary goal of this study was to obtain data concerning the in vitro susceptibility of 13 Scedosporium strains comparing the in vitro incubation in aerobic versus hyperbaric conditions. Chemosensitivity of thirteen Scedosporium strains was evaluated after a 72h-incubation in a normoxic (21% O2) normobaric (1 ATA) atmosphere versus a hyperoxic (100% O2) hyperbaric (2-3 ATA), and after a re-incubation at room temperature for an additional 72h. All S.apiospermum and S.prolificans strains showed no growth after incubation in hyperbaric hyperoxic atmosphere. However, when plates were then maintained at room temperature in aerobic conditions, growth was systematically observed from 36 to 96h, and Minimal inhibitory concentration (MIC) values were the same obtained after incubation in aerobic conditions. These results suggest impressive in vitro fungistatic activity of the hyperoxic hyperbaric atmosphere, even if its effect is strictly time-dependent. This preliminary in vitro study has potential clinical relevance because it focuses on examining in vitro combination therapy using hyperoxic hyperbaric conditions plus a single antifungal agent, rather than using combinations of different antifungal drugs, to potentially increase the antifungal activity.

A Case of Cronkhite-Canada Syndrome with Esophageal Candidiasis

Cronkhite-Cadana syndrome is a rare non-familial disease. This syndrome is characterized by multiple hamartomatous polyps on the entire gastrointestinal tract except esophagus, nail dystrophy, alopecia and hyperpigmentation. Taste disturbance, abdominal pain, diarrhea and weight loss are common symptoms of it. The pathogenesis and causes of Cronkhite-Canada syndrome remain unknown until now. Although various treatment strategies including steroid therapy have been tried, their prognosis is poor. We report a 68 years old man who were diagnosed Cronkhite-Canada syndrome with esophageal candidiasis. After using combination of steroids and anti-fungal drugs, both Cronkhite-Canada syndrome and esophageal candidiasis were cured. (Korean J Helicobacter Up Gastrointest Res 2012;12:183-187)

Eradication of Pulmonary Aspergillosis in an Adolescent Patient Undergoing Three Allogeneic Stem Cell Transplantations for Acute Lymphoblastic Leukemia

Systemic fungal infections are a major cause of infection-related mortality in patients with hematologic malignancies. This report addresses the case of an adolescent patient with acute lymphoblastic leukemia who underwent three allogeneic hematopoietic stem cell transplantations and developed pulmonary aspergillosis. Combination therapy with liposomal amphotericin B (L-AmB, 3 mg/kg bw/day) and caspofungin (CAS, 50 mg/day) during the first allogeneic hematopoietic stem cell transplantation (HSCT) improved the pulmonary situation. After shifting the antifungal combination therapy to oral voriconazole (2 × 200 mg/day) and CAS, a new pulmonal lesion occurred alongside the improvements in the existing pulmonary aspergillosis. An antifungal combination during a second HSCT with L-AmB (3 mg/kg bw/day) and CAS showed an improvement in the pulmonary aspergillosis. A combination therapy with CAS and L-AmB (1 mg/kg bw/day) during the third HSCT led once again to progress the pulmonary aspergillosis, after increasing the L-AMB to 3 mg/kg bw/day for recovery. The presented case provides an example of how, despite severe immunosuppression, a combination of antifungal drugs administered intravenously at therapeutic dosages may be more efficient than either intravenous monotherapy or combinations of intravenous and oral antifungals in selecting pediatric and adolescent patients with proven fungal infections.

In vitroactivity of Amphotericin B against zygomycetes isolated from deep mycoses: a comparative study between incubation in aerobic and hyperbaric atmosphere

Many case reports suggest that the use of hyperbaric oxygen therapy associated with surgical and medical approaches may contribute to restricting the growth of zygomycetes in patient tissue. The primary aim of this study was to obtain data concerning the in vitro susceptibility of 22 zygomycetes to antifungals such as amphotericin B and posaconazole, and to compare the in vitro development of these fungi in aerobic normobaric versus hyperoxic normobaric and hyperbaric atmosphere. None of the zygomycetes grew after 24-hour and 72-hour incubation in a hyperoxic hyperbaric (2 or 3 ATA) atmosphere. However, when plates were maintained at room temperature in aerobic conditions, colonies were observed from 36-96 h after inoculation, while minimum inhibitory concentration (MIC) values remained the same. This preliminary in vitro study focuses on the in vitro examination of combination therapies to potentiate antifungal activity. Both hyperoxic hyperbaric conditions and a single antifungal agent, as well as combinations of different antifungal drugs were used. Results suggest an impressive in vitro fungistatic activity of the hyperoxic hyperbaric atmosphere, even if the antifungal effect is strictly time-dependent using these incubation conditions.

Osteoarticular infection by Candida albicans in an infant with cystic fibrosis

Invasive candidiasis is rare in children after the neonatal period, but can occur in children with (secondary) immunodeficiency with a damaged gastrointestinal or skin barrier, or when receiving antibiotics. A 10-month-old girl was diagnosed as suffering from cystic fibrosis (CF) when showing failure to thrive, pulmonary symptoms and hypoproteinaemia. At that time, Candida albicans was identified from blood culture and treated intravenously with liposomal amphotericin B for 13 days. Six weeks later, the girl presented with osteoarticular infection of the left knee caused by C. albicans. The infection showed insufficient response to therapy with liposomal amphotericin B, but the patient recovered after therapy with fluconazole and flucytosine. Follow-up over 4 years revealed no sequelae. In conclusion, invasive Candida infections may occur in patients with CF, and preventive measures might be considered in patients at risk. In the case of an invasive infection, prolonged treatment with a combination of antifungal drugs may be required.

Infections due to Pseudallescheria/ Scedosporium species in patients with advanced HIV disease — a diagnostic and therapeutic challenge

The aim of this study is to highlight the importance of infections caused by members of the genera Pseudallescheria/Scedosporium in HIV-positive patients. We describe a case of a fatal scedosporiosis in a treatment-naïve HIV patient and review all previously reported cases of pseudallescheriosis/scedosporiosis from a search of the PubMed and Deutsches Institut für Medizinische Dokumentation und Information (DIMDI) databases, applying the terms 'Pseudallescheria', 'Scedosporium', 'Allescheria', 'Monosporium', 'Petriellidium', 'boydii', 'prolificans', 'inflatum', cross-referenced with 'HIV' and 'AIDS'. Detection of Scedosporium and Pseudallescheria species has been reported in 22 HIV-positive patients. Fourteen isolates belonged to the Pseudallescheria boydii complex and eight to Scedosporium prolificans. Invasive scedosporiosis (IS) was proven in 54.5% of the patients. Among them dissemination was observed in 66.7%. Pseudallescheria/Scedosporium species were mainly isolated from male individuals. Patients with proven IS showed CD4+ cell counts <100/μl and a higher co-infection rate as compared to colonized patients. Patients with central nervous system (CNS) manifestations showed CD4+ cell counts <50/μl. The mortality rate for patients with proven IS was 75% and was 100% for patients with dissemination/CNS manifestations. The fatality rate for patients treated with antifungal drugs plus surgery was lower compared to patients treated with antimycotic agents alone. IS only occurred in HIV-positive patients with a strongly impaired immune system. The survival rates of patients with advanced HIV disease and invasive scedosporiosis can be improved by rapid diagnosis by biopsy and requires complex therapy with a combination of active antifungal drugs, surgery and supportive immune augmentation.

Successful treatment of disseminated mixed invasive fungal infection after hematopoietic stem cell transplantation for severe aplastic anemia

Concomitant infections are frequent and usually the causes of death in patients with severe AA. HSCT can restore hematopoiesis in AA, but it is usually life threatening when patients simultaneously have an IFI. Mixed IFIs have been reported on rare occasions. The exact diagnosis of IFIs is difficult because of low fungus culture rate, difficultly obtaining tissue specimens in severely immunocompromised patients or those with bleeding tendencies. Otherwise, treatment with anti-fungal drugs alone for DMIFI was always lethal in previous reports. Surgical resection is crucial for invasive zygomycosis, but severe pancytopenia and bleeding tendency make therapy difficult. Herein, we report that with a combination of aggressive anti-fungal drugs, HSCT, and surgery, we successfully treated a 10-yr-old boy with severe AA and pulmonary zygomycosis before HSCT and disseminated mixed invasive zygomycosis and aspergillosis after HSCT.

In Vitro Evaluation of the Antibiotic Activity of Combinations of Ophthalmic Drugs Against Common Equine Ocular Pathogens

A subpalpebral lavage catheter is commonly used to administer medications in the treatment of infectious keratitis in horses. Drugs may mix in the subpalpebral lavage catheter, potentially affecting antimicrobial efficacy. The objective of this study was to determine the in vitro antimicrobial efficacy of combinations of commonly used ophthalmic preparations. An agar gel diffusion bioassay was used to determine the antibiotic activity of a number of antimicrobial, antifungal, mydriatic, and antiproteinase drug combinations. Drug mixtures were allowed to sit in a syringe at ambient temperatures and room lighting, for 1 (T1) and 6 hours (T2). The antibacterial efficacy was determined by measuring the zone of inhibition around wells containing the drug combinations after overnight incubation at 37°C and comparing them with the zone of inhibition around the antimicrobial alone. Combinations were tested against Pseudomonas aeruginosa and Streptococcus zooepidemicus. There was no significant decrease in the zone of inhibition, compared with controls, for the majority of combinations tested. Significantly smaller zones of inhibition were identified for the following combinations: (1) tobramycin, cefazolin, natamycin, and serum (T1) and (2) tobramycin, cefazolin, natamycin, serum, and atropine (T1) compared with tobramycin alone; (3) ciprofloxacin, cefazolin, natamycin (T1) compared with ciprofloxacin alone; (4) triple antibiotic ophthalmic solution (TAB) and natamycin (T6); (5) TAB, natamycin, and serum (T6); and (6) TAB, natamycin, serum, and atropine (T6) compared with TAB alone. Admixture does not affect in vitro antibacterial efficacy for the majority of ophthalmic preparations, although efficacy of TAB may be decreased compared with the drug alone.

Treating Resistant Filamentous Fungi Infections

Resistance to treatment can be caused by intrinsic resistance to antifungal drugs, and also by the angioinvasive nature of some of these mycoses, which causes distal pulmonary infarction. As blood flow is blocked, antifungal drug penetraiton is decreased. Both considerations must be addressed. With the development of infarction, there is decreased penetration of polyenes and presumably all antifungal drugs into tissue. Inadequate delivery of antifungal drugs is one reason which causes in vitro susceptible pathogens, like Aspergillus species (triazoles) or zygomycetes (polyenes) to progress in the presence of antifungal therapy which “should be effective”. Management of clinical resistance in these patient can be improved at the outset, by accelerating the speed of diagnosis and initiating treatment more promptly. Tools for this include a) rapidlly identifying patients at high risk and b) intensive surveillance with serum (and now bronchoalveolar lavage) galactomannan, beta-D-glucan, and PCR. The former allows identification of groups for antifungal prophylaxis, and the latter allows for identifcation of patients ever earlier in the course of disease. There is room for considerable improvement in rapid diagnosis. Intrinsically high resistance to antifungals can be predicted for many (not all) isolates simply by identifying the fungal species. This is straightforward for polyene resistance of Aspergillus terreus, or almost pan-antifungal resistance of Scedosporium prolificans. Others, such as Fusarium or Paecilomyces species, are very challenging, but may respond to high levels of certain antifungals. For these patients animal studies and small clinical series may provde guidance. There is great temptation to use combinations of antifungal drugs, especially when synergy is suggested by in vitro studies. This area is complicated by the rarity of such isolates and inability to collect large series of infected patients. For some, recommendations may need to be individualls tailored. Abstracts for SupplementInternational Journal of Infectious DiseasesVol. 14Preview Full-Text PDF Open Archive

Defining Fractional Inhibitory Concentration Index Cutoffs for Additive Interactions Based on Self-Drug Additive Combinations, Monte Carlo Simulation Analysis, and In Vitro - In Vivo Correlation Data for Antifungal Drug Combinations against Aspergillus fumigatus

The fractional inhibitory concentration (FIC) index range of 0.5 to 4 that is commonly used to define additivity results in no interactions in most combination studies of antifungal agents. These results may differ from those of in vivo studies, where positive and negative interactions may be observed. We reassessed this in vitro FIC index range based on (i) the experimental variation of the checkerboard technique using multiple replicates, (ii) the ability to correctly determine purely additive self-drug and two-drug antagonistic combinations of amphotericin B (AMB) and voriconazole (VRC), (iii) Monte Carlo simulation analysis, and (iv) in vitro-in vivo correlation using experimental models of invasive pulmonary aspergillosis against the same Aspergillus fumigatus isolate based on visual, spectrophotometric, and colorimetric determinations of FICs after 24 and 48 h of incubation. FICs obtained after 24 h of incubation ranged from 0.5 to 1.25 for the self-drug additive combinations of AMB plus AMB and VRC plus VRC and from 2.25 to 4.25 for the antagonistic combination of AMB plus VRC. Monte Carlo simulation analysis showed that self-drug combinations were correctly classified as additive and that the combination of AMB plus VRC was correctly classified as antagonistic for >85% of the simulated FICs when deviation of the 95% confidence interval (CI) of replicate FICs from the additivity range of 1 to 1.25 was used to assess interactions after 24 h. In vitro-in vivo correlation analysis showed that the 95% CIs of the FICs of the in vivo synergistic combination anidulafungin plus VRC determined after 24 h were lower than 1 and the 95% CIs of the FICs of the in vivo antagonistic combination AMB plus ravuconazole were higher than 1.25. Adequate insight into weak pharmacodynamic interactions with in vivo relevance may be obtained by demonstrating that triplicate FICs at 24 h are outside an inclusive additivity range of 1 to 1.25.

Successful Treatment of Candida albicans Septicemia in a Preterm Infant with Severe Congenital Ichthyosis (Harlequin baby)

Candida infections are a major cause of fungal septicemia in neonates and are associated with marked morbidity and mortality. Despite the spectrum of antifungal drugs being dramatically extended during the last decade, invasive fungal infections remain a serious challenge for neonatologists. Amphotericin B and its lipid formulations are the drugs of choice for the treatment of systemic candidiasis in neonates. The combination of antifungal drugs with different sites of action, like caspofungin and amphotericin B, may improve antifungal efficacy. Severe congenital ichthyosis often leads to death within the neonatal period. Main causes of death are dehydration, electrolyte disturbances, and respiratory or systemic infections. We report the case of a preterm infant with severe congenital ichthyosis and sepsis caused by Candida albicans. The infection did not improve despite proper liposomal amphotericin B treatment. After addition of caspofungin, the baby recovered. To our best knowledge, a case of a preterm infant suffering from severe congenital ichthyosis and Candida albicans sepsis, who survived, has not been previously described.

Phenytoin‐induced reduction of voriconazole serum concentration is not compensated by doubling the dosage

Phenytoin‐induced reduction of voriconazole serum concentration is not compensated by doubling the dosage

Independent association between rate of clearance of infection and clinical outcome of HIV-associated cryptococcal meningitis: analysis of a combined cohort of 262 patients.

Progress in therapy for cryptococcal meningitis has been slow because of the lack of a suitable marker of treatment response. Previously, we demonstrated the statistical power of a novel endpoint, the rate of clearance of infection, based on serial quantitative cultures of cerebrospinal fluid, to differentiate the fungicidal activity of alternative antifungal drug regimens. We hypothesized that the rate of clearance of infection should also be a clinically meaningful endpoint. We combined data from cohorts of patients with human immunodeficiency virus-associated cryptococcal meningitis from Thailand, South Africa, and Uganda, for whom the rate of clearance of infection was determined, and clinical and laboratory data prospectively collected, and explored the association between the rate of clearance of infection and mortality by Cox survival analyses. The combined cohort comprised 262 subjects. Altered mental status at presentation, a high baseline organism load, and a slow rate of clearance of infection were independently associated with increased mortality at 2 and 10 weeks. Rate of clearance of infection was associated with antifungal drug regimen and baseline cerebrospinal fluid interferon-gamma levels. The results support the use of the rate of clearance of infection or early fungicidal activity as a means to explore antifungal drug dosages and combinations in phase II studies. An increased understanding of how the factors determining outcome interrelate may help clarify opportunities for intervention.

Aspergillus fumigatus endocarditis in a pediatric liver transplant recipient: Favorable outcome without cardiac surgery

Transplant recipients are very susceptible to invasive aspergillosis, which increases mortality rate. Disseminated aspergillosis in the liver transplant recipient can affect virtually any organ and endocarditis is often lethal despite cardiac surgery and antifungal therapy. We report the case of a eight-month-old girl who presented with Aspergillus fumigatus endocarditis 18 days after liver transplantation that was successfully treated by a combination of antifungal drugs associated to a low dosage of immunosuppressive therapy.

Voriconazole pharmacokinetic variability in cystic fibrosis lung transplant patients

Aspergillosis is a high-risk complication in cystic fibrosis (CF) lung transplant patients. Azole antifungal drugs inhibit CYP3A4, resulting in significant metabolic drug-drug interactions. Voriconazole (VRZ) was marketed without therapeutic drug monitoring (TDM) recommendations, consistent with favorable pharmacokinetics, but regular determinations of plasma VRZ concentration were introduced in our center to manage interactions with calcineurin inhibitors and to document the achievement of therapeutic levels. VRZ TDM data analysis for trough concentration (C0) and peak concentration (C2) was carried out, using validated liquid chromatography assay with ultraviolet detection, for 35 CF lung transplant patients (mean age 25 years, mean weight 47 kg, balanced sex ratio) since 2003. Therapeutic range (C0: 1.5 +/- 0.5 - C2 : 4.0 +/- 1.0 mg/L) was expressed relative to pivotal pharmacokinetic trial data. The duration of VRZ treatment ranged from 9 days to 22 months. The recommended standard dose of VRZ (200 mg twice a day, following the loading dose) resulted in significant plasma concentrations (>0.5 mg/L) in 20% of CF lung transplant patients. Therapeutic concentrations were obtained using higher doses (average 570 +/- 160 mg/day, +43%, P<0.01). Despite adaptation, C0 remained <0.5 mg/L (11%), even when the drug was administered intravenously, highlighting the variability of VRZ pharmacokinetics, possibly enhanced by CYP2C19 polymorphism. The risk of inefficacy during periods of underdosage was overcome by treatment with antifungal drug combinations (caspofungin, n=10). The therapeutic index was limited by neurologic effects (14%) and hepatic abnormalities (30%). VRZ concentrations correlated significantly (P<0.01) with aspartate aminotransferase levels but not with bilirubin levels. VRZ acted as a metabolic inhibitor of tacrolimus (C0 to dose ratio 5.8 +/- 2.6, n=31/VRZ versus 1.7 +/- 0.9 alone, P<0.001). Large changes in azole concentration affected the magnitude of the drug-drug interactions and adjustment requirements. TDM is required because VRZ levels are often undetectable in treated CF lung transplant patients, supporting the use of antifungal drug combinations until achievement of VRZ C0 at a steady state between 1 and 2 mg/L. Plasma VRZ concentrations should be determined for the quantitative, individualized management of drug-drug interactions in lung transplant patients, in particular immunosuppressant such as tacrolimus, considering VRZ to be both a target and an inhibitor of CYP3A4.

Effects of double and triple combinations of antifungal drugs in a murine model of disseminated infection by Scedosporium prolificans.

We have evaluated the efficacies of micafungin, amphotericin B, and voriconazole, alone and in double and triple combinations, in a murine model of systemic infection by Scedosporium prolificans. Micafungin combined with voriconazole or amphotericin B was the most effective, these being the only treatments able to prolong survival and to reduce the fungal load in the kidneys and brain. Triple combinations of these drugs did not improve the results obtained with double combinations.

In vitro activities of combinations of amphotericin B, posaconazole and four other agents against Rhizopus

Sir, Zygomycosis is a severe, life-threatening fungal infection that occurs mainly in patients with diabetes mellitus, or with haematological malignancies, after organ transplantation, in conditions of iron overload or those treated with immunosuppressive drugs. Rhizopus oryzae, followed by Rhizopus microsporus var. rhizopodiformis, are the most frequently involved organisms, accounting for � 75% of all cases. Amphotericin B is the drug of choice for the treatment of zygomycosis, but overall mortality rate is high. Recently, posaconazole has shown to be active as salvage therapy for disseminated zygomycosis, 1 but few studies still exist and the search of novel therapeutic strategies is still necessary. Combination of antifungal agents with different active mechanisms could be an interesting therapeutic option for improving clinical outcomes. Few data exist on the in vitro effect of combinations of antifungal drugs against zygomycetes. Only associations of amphotericin B with flucytosine and of terbinafine with either amphotericin B or triazoles have been evaluated. 2,3 The interaction between amphotericin B and azoles against zygomycetes has not been investigated. There is recent evidence for synergistic interaction between the echinocandin drug caspofungin and amphotericin B lipid complex in a murine model of disseminated R. oryzae infection. 4 However, in vitro studies on interactions of echinocandins with other antifungals against Rhizopus spp. have not been performed. The aim of this study was to investigate the in vitro interaction of amphotericin B and micafungin, a recently developed echinocandin, and of each with posaconazole, itraconazole, voriconazole or ravuconazole against Rhizopus. Nineteen clinical isolates were tested, comprising 9 isolates of R. oryzae and 10 of R. microsporus var. rhizopodiformis .T he isolates were grown on potato dextrose agar plates and incubated at 308C for 4‐7 days. Inocula were prepared following the CLSI (formerly NCCLS) M38-A document. The spore suspensions were adjusted to a final concentration of 4 � 10 3 ‐5 � 10 4 cfu/mL with a haemocytometer. Candida krusei ATCC 6258 and Candida parapsilosis ATCC 22019 were included as quality controls.

Safety and efficacy of a caspofungin-based combination therapy for treatment of proven or probable aspergillosis in pediatric hematological patients

BackgroundFungal infections are diagnosed increasingly often in patients affected by hematological diseases and their mortality has remained high. The recent development of new antifungal drugs gives the clinician the possibility to assess the combination of antifungal drugs with in-vitro or in animal-model synergistic effect.MethodsWe analyzed retrospectively the safety and efficacy of caspofungin-based combination therapy in 40 children and adolescents, most of them were being treated for a malignant disease, who developed invasive aspergillosis (IA) between November 2002 and November 2005.ResultsThirteen (32.5%) patients developed IA after hematopoietic stem cell transplantation (HSCT), 13 after primary diagnosis, usually during remission-induction chemotherapy, and 14 after relapse of disease. Severe neutropenia was present in 31 (78%) out of the 40 patients. IA was classified as probable in 20 (50%) and documented in 20 (50%) patients, respectively. A favorable response to antifungal therapy was obtained in 21 patients (53%) and the probability of 100-day survival was 70%. Different, though not significant, 100-day survival was observed according to the timing of diagnosis of IA: 51.9% after HSCT; 71.4% after relapse; and 84.6% after diagnosis of underlying disease, p 0.2. After a median follow-up of 0.7 years, 20 patients are alive (50%). Overall, the combination therapy was well tolerated. In multivariate analysis, the factors that were significantly associated to a better overall survival were favorable response to antifungal therapy, p 0.003, and the timing of IA in the patient course of underlying disease, p 0.04.ConclusionThis study showed that caspofungin-based combination antifungal therapy is an effective therapeutic option also for pediatric patients with IA. These data need to be confirmed by prospective, controlled studies.

Concentration-Dependent Synergy and Antagonism within a Triple Antifungal Drug Combination againstAspergillusSpecies: Analysis by a New Response Surface Model

Triple antifungal combinations are used against refractory invasive aspergillosis without an adequate understanding of their pharmacodynamic interactions. We initially studied the in vitro triple combination of voriconazole, amphotericin B, and caspofungin against Aspergillus fumigatus, A. flavus, and A. terreus by a spectrophotometric microdilution broth method after 48 h of incubation. We then analyzed these results with a recently described nonlinear mixture response surface E(max)-based model modified to assess pharmacodynamic interactions at various growth levels. The new model allows flexibility in all four parameters of the E(max) model and is able to describe complex pharmacodynamic interactions. Concentration-dependent pharmacodynamic interactions were found within the triple antifungal combination. At the 50% growth level, synergy (median interaction indices of 0.43 to 0.82) was observed at low concentrations of voriconazole (<0.03 mg/liter) and amphotericin B (</=0.20 mg/liter) and at intermediate concentrations of caspofungin (0.95 to 14.88 mg/liter), whereas antagonism (median interaction indices of 1.17 to 1.80) was found at higher concentrations of voriconazole and amphotericin B. Ternary plot and interaction surface analysis further revealed the complexity of these concentration-dependent interactions. With increasing concentrations of amphotericin B, the synergistic interactions of voriconazole-caspofungin double combination decreased while the antagonistic interactions increased. A similar effect was observed when voriconazole was added to the double combination of amphotericin B and caspofungin. In conclusion, the new nonlinear mixture-amount response surface modeling of the triple antifungal combination demonstrated a net antagonism or synergy against Aspergillus species depending upon drug concentrations and species.