Combination Of Amphotericin Research Articles

The clinical epidemiology of pulmonary cryptococcosis in non-AIDS patients at a tertiary care medical center.

Cryptococcus neoformans is a ubiquitous saprophytic fungus with worldwide distribution. It has been found in nature, primarily in association with bird droppings, but nonavian sources have been described as well (10). Although the lungs are thought to be the portal of entry for cryptococcus, pulmonary infection is uncommon. The organism is trophic to the central nervous system and the vast majority of recognized infections involve meningitis. Before the acquired immunodeficiency syndrome (AIDS) epidemic (1980), cryptococcosis was a rare infection, and pulmonary disease was described in 10%–45% of patients with cryptococcal meningitis (2). However, the true incidence of pulmonary cryptococcosis (PC) was not known, but was much lower than meningitis. Most PC cases were identified histologically and often at autopsy, with only about 20% diagnosed by culture (2, 3, 13). In recent years, many of the reports of cryptococcal infection have been in the human immunodeficiency virus (HIV)-positive population, and little is known of the disease in non-AIDS patients, particularly pulmonary involvement. At our institution, a tertiary care medical center with a large transplant program, sporadic cases of PC have occurred in solidorgan transplant recipients as well as in patients with a variety of different medical conditions. The purpose of our study was to investigate the epidemiology of PC in non-AIDS patients, and to determine predictors of outcome among these patients.

Efficacy of interferon-γ and amphotericin B for the treatment of systemic murine histoplasmosis

The number of cases of systemic histoplasmosis has increased substantially in recent years, and improved therapy is needed. We examined the efficacy of immunomodulation with interferon (IFN)-γ alone or in combination with a suboptimal regimen of amphotericin B for the treatment of primary systemic murine histoplasmosis. In the first study, BALB/c mice were infected with Histoplasma capsulatum G217B and treated with 10 5 U of IFN given every other day either preinfection and postinfection or only postinfection, alone or in combination with amphotericin B. IFN alone given subcutaneously (s.c.) postinfection prolonged survival over untreated controls ( P < 0.01), whereas intravenous (i.v.) administration was ineffective. All combination regimens and amphotericin B alone significantly prolonged survival ( P < 0.0001). The combination regimens of amphotericin B and IFN i.v. (pre- and postinfection) or IFN s.c. (postinfection) reduced the fungal burden in the liver and spleen; the latter regimen had superior efficacy in the spleen ( P < 0.05) to either amphotericin B or IFN alone. After infection with a low-challenge inoculum, IFN given s.c. (pre- and postinfection) alone caused a significant reduction in fungal burden in the spleen ( P < 0.001). In an acutely lethal model, combination regimens of IFN s.c. or i.v. and amphotericin B again prolonged survival ( P < 0.01–0.001), with amphotericin B plus IFN given s.c. (pre- and postinfection) superior to all regimens ( P < 0.05–0.01). This regimen also showed enhanced efficacy in causing the reduction of fungal burden in the spleen ( P < 0.05). These results indicate that IFN in combination with AmB shows enhanced efficacy in the treatment of systemic histoplasmosis and support the potential utility of IFN as an adjunctive therapy.

Candida lusitaniae: a cause of breakthrough fungemia in cancer patients.

Candida lusitaniae is an infrequent cause of fungemia. We identified 12 cases of C. lusitaniae fungemia that occurred at the University of Texas M. D. Anderson Cancer Center from 1988 to 1999. The mean age of patients was 48 years (range 20--70 years). Eight patients had hematologic malignancy or had received a bone marrow transplant, and 4 had a solid tumor. Most patients (75%) were neutropenic (<10(3)/mm(3)). Treatment with amphotericin B alone failed for 3 of 6 patients, irrespective of neutropenic status. Fluconazole was effective as a single agent in 3 patients with solid tumors. The combination of amphotericin B plus fluconazole was effective treatment for two-thirds of patients with hematologic malignancy, despite persistence of neutropenia. The mortality rate associated with C. lusitaniae infection was 25%. C. lusitaniae presents as breakthrough fungemia in immunocompromised patients and is associated with failure of amphotericin B therapy. Fluconazole may be a useful agent in the treatment of this infection.

Fungal endocarditis: evidence in the world literature, 1965-1995.

We analyzed 270 cases of fungal endocarditis (FE) that occurred over 30 years. Vascular lines, non-cardiac surgery, immunocompromise and injection drug abuse are increasing risk factors. Delayed or mistaken diagnosis (82% of patients), long duration of symptoms before hospitalization (mean +/- standard deviation, 32+/-39 days) and extracardiac manifestations were characteristic. From 1988 onwards, 72% of patients were diagnosed preoperatively, compared with 43% before 1988 (P=.0001). The fungi most commonly isolated were Candida albicans (24% of patients), non-albicans species of Candida (24%), Apergillus species (24%), and Histoplasma species (6%); recently-emerged fungi accounted for 25% of cases. The mortality rate was 72%. Survival rates were better among patients who received combined surgical-antifungal treatment, were infected with Candida, and had univalvular involvement. Improvement in the survival rate (from <20% before 1974 to 41% currently) coincided with the introduction of echocardiography and with improved diagnostic acumen. Fungal endocarditis recurs in 30% of survivors. It is recommended that fungal endocarditis be diagnosed early through heightened diagnostic acumen; that patients be treated with combined lipid-based amphotericin B and early surgery; and that patients be followed up for > or =4 years while on prophylactic antifungal therapy.

Combination antifungal therapy in treatment of murine pulmonary mucormycosis: roles of quinolones and azoles.

Amphotericin B is the only recognized antifungal used in the treatment of mucormycosis. In this study, we evaluated various combinations of amphotericin B, fluconazole, and trovafloxacin or ciprofloxacin in the treatment of murine pulmonary mucormycosis. The combination of fluconazole and a quinolone has a marked effect on the outcome of murine pulmonary mucormycosis. Even though we did not optimize therapy with the drugs, these experiments suggest that azoles, especially fluconazole, in combination with either trovafloxacin or ciprofloxacin were effective in the treatment of this aggressive mycosis in the mouse model.

Trichosporon beigelii infection: experience in a regional burn center

Trichosporon beigelii is a fungus once thought to cause only superficial infections, but recently has been increasingly identified as an opportunistic systemic pathogen in immunocompromised patients. There have been very limited reports of this organism in the burn patient population. We describe the first report of pharmacological management of invasive T. beigelii with a combination of amphotericin B and high dose fluconazole in a burn patient. Antifungal susceptibility testing of T. beigelii determined a change in minimum inhibitory concentrations (MICs) of amphotericin B and a consistent resistance pattern with the use of flucytosine. This paper will review our experience with T. beigelii fungus in a regional burn treatment center and review the literature on other experiences in the burn population.

Synergistic effects of low doses of histatin 5 and its analogues on amphotericin B anti-mycotic activity.

The increase in the use of antifungal agents for prophylaxis and therapy has led to the development of antifungal drug resistance. Drug combinations may prevent or delay resistance development. The aim of the present study was to investigate whether naturally and designed cationic antifungal peptides act synergistically with commonly used antimycotics. No enhanced activity was found upon addition of dhvar4, a designed analogue of the human salivary peptide histatin 5, or PGLa to fluconazole or 5-flucytosine, respectively. In contrast, strong synergism of amphotericin B with the peptides was found against several Aspergillus, Candida, and Cryptococcus strains, and against an amphotericin B-resistant C. albicans laboratory mutant in the standardised broth microdilution assays according to the NCCLS standard method M27-T. Amphotericin B showed synergism with dhvar5, another designed analogue of histatin 5, and with magainin 2 against all seven tested strains. Combinations of amphotericin B with histatin 5, dhvar4, and PGLa showed synergism against four of the seven strains. The growth inhibitory activity of amphotericin B was enhanced by sub-MIC concentrations of peptide, but its haemolytic activity remained unaffected, suggesting that its cytotoxicity to host cells was not increased and that peptides may be suitable candidates for combination therapy.

Blastomycosis in dogs: 115 cases (1980-1995)

Objective To characterize diagnostic results, treatment, and outcome of dogs with blastomycosis during a 15-year period in Louisiana. Design Retrospective case series. Animals 115 dogs with blastomycosis. Procedure Medical records were reviewed for dogs with blastomycosis examined between 1980 and 1995. Additional data were collected from the state veterinary diagnostic laboratory, via telephone interviews of owners, and by use of a random survey of the hospital population. Results Blastomycosis was detected mainly in young, large-breed dogs. Proximity to a body of water was a significant risk factor for affected dogs. Most dogs were affected in January and August through October. Clinical signs and results of physical examination reflected the multisystemic nature of the disease. Commonly affected systems included the respiratory tract and lymphatic, ocular, and cutaneous systems. Nodular interstitial and interstitial patterns were common findings on thoracic radiographs. Cytologic examination was successful in identifying organisms in samples from vitreous, skin, and lymph nodes. Similar results were achieved for dogs treated with a combination of amphotericin B and ketoconazole, compared with dogs treated with itraconazole. Clinical Implications Results of this study should assist veterinarians with the recognition and management of blastomycosis in dogs. Blastomycosis should be considered as a differential diagnosis for large-breed dogs that live close to a body of water in areas in which the disease is endemic or in dogs with a history of being transported to endemic areas that subsequently develop signs of pulmonary, ocular, lymphatic, or cutaneous disease. Treatment with itraconazole was as effective as treatment with a combination of amphotericin B and ketoconazole. (J Am Vet Med Assoc 1998;213:658-664)

The combination of amphotericin B and azithromycin as a potential new therapeutic approach to fusariosis.

We investigated the interaction between amphotericin B and azithromycin in vitro against 26 clinical isolates of Fusarium. Synergy was demonstrated in all isolates. Amphotericin B MICs were reduced from a mean of 1 mg/L when tested alone to a mean of 0.37 mg/L when tested in combination with azithromycin. Azithromycin demonstrated no activity against Fusarium when tested alone (MIC > 128 mg/L). When combined with amphotericin B the mean MIC was reduced to 5.5 mg/L, a level readily achieved in tissue. Given the resistance of Fusarium to conventional therapy, the in-vitro synergy between amphotericin B and azithromycin might prove to be important in therapy for fusariosis.

Efficacy of Amphotericin B and Azoles Alone and in Combination against Disseminated Trichosporonosis in Neutropenic Mice

The activities of amphotericin B, miconazole, fluconazole, and itraconazole against Trichosporon beigelii were assessed in a mouse model of disseminated infection. Cyclophosphamide plus prednisolone-immunosuppressed ICR mice, intravenously challenged with a lethal inoculum of (6 × 10⁶ CFU/mouse), were assigned to receive 7 days of therapy with amphotericin B (0.5 or 2 mg/kg/day), miconazole (10 or 40 mg/kg/day), fluconazole (10 or 40 mg/kg/day), or itraconazole (10 and 40 mg/kg/day). The efficacy of a combination of amphotericin B (1 mg/kg/day) with fluconazole (10 mg/kg/day) or itraconazole (20 mg/kg/day) with that of each agent alone was also compared. Both amphotericin B and azoles improved survival and reduced the fungal counts in kidneys of infected mice in a dose-dependent pattern. In general, fluconazole was superior to amphotericin B and the other azoles, whereas the latter two drugs were as effective as amphotericin B. The activity of amphotericin B combined with fluconazole appeared to be superior to that of each agent alone, especially in reducing the organ fungal burden. The other combination (amphotericin B plus itraconazole) had a weaker effect, but no antagonism was observed. In conclusion, azoles may be an alternative to amphotericin B for the treatment of T. beigelii infection. Furthermore, their combination with amphotericin B may improve the poor outcome seen in profoundly neutropenic patients with disseminated trichosporonosis.

Pneumocandin L-743,872 enhances the activities of amphotericin B and fluconazole against Cryptococcus neoformans in vitro.

Cryptococcus neoformans infections in patients with AIDS are often incurable, despite aggressive antifungal therapy. Combination regimens with additive or synergistic drugs could provide additional options for treating cryptococcal meningitis. We evaluated the efficacy of combination therapies using L-743,872, a pneumocandin antifungal drug, and amphotericin B or fluconazole against 18 strains of C. neoformans, including 11 C. neoformans var. neoformans, 3 C. neoformans var. gattii, and 4 fluconazole-resistant isolates. The combination of subinhibitory concentrations of L-743,872 with amphotericin B significantly enhanced amphotericin B activity against C. neoformans as measured by turbidity (antifungal susceptibility studies using the National Committee of Clinical and Laboratory Standards method), quantitative CFU, and tetrazolium salt reduction assays. Similarly, the addition of subinhibitory concentrations of L-743,872 to fluconazole enhanced fluconazole activity, but the effect was less dramatic than for the pneumocandin-amphotericin B combination. A marked synergism was observed in all combinations of amphotericin B and L-743, 872 (fractional inhibitory concentration index [FIC] of < or = 0.5). Fluconazole-resistant strains showed a susceptibility to amphotericin B and L-743,872 which was comparable to that of susceptible isolates. Combinations of pneumocandin with fluconazole revealed different activities for the various strains, including synergism (FIC < 1.0), additivity (FIC = 1.0), and autonomy (FIC between 1.0 and 2.0). Combination studies with fluconazole and L-743,872 showed additive and autonomous activities against fluconazole-resistant isolates. No antagonistic interactions (FIC < 2.0) were observed for any combination of L-743,872 with either amphotericin B or fluconazole. The results of this study suggest that L-743,872 can enhance the efficacy of fluconazole or amphotericin B in vitro and indicate a potential role for L-743,872 in combination therapy against C. neoformans.

Ocular blastomycosis in dogs: 73 cases, 108 eyes (1985–1993)

Objective To evaluate clinical signs of ocular blastomycosis in dogs, to determine response of blastomycosis-infected eyes to treatment with systemically administered amphotericin B and ketoconazole, and to identify prognostic indicators of successful antifungal treatment. Design Retrospective study. Animals 73 dogs. Procedure Medical records were reviewed for all dogs with confirmed blastomycosis and ocular disease seen at our hospital between 1985 and 1993. Results 6 eyes had anterior segment disease, 24 had posterior segment disease, and 78 had endophthalmitis. 40 eyes were treated with a combination of amphotericin B and ketoconazole, and 16 of the 40 responded favorably. However, 16 of the 24 eyes that were not severely affected responded favorably, but none of the 16 eyes that were severely affected did. Clinical Implications Dogs with blastomycosis had posterior segment disease, without complete retinal separation, had a good prognosis for retaining vision. Results of histologic examination suggested that secondary glaucoma was a manifestation of endophthalmitis and was indicative of a grave prognosis for response to antifungal and antiglaucoma treatment. (J Am Vet Med Assoc 1996;209:1271–1274)

Activities of amphotericin B and antifungal azoles alone and in combination against Pseudallescheria boydii

In order to develop new approaches to treatment of infections due to Pseudallescheria boydii, the in vitro antifungal activity of amphotericin B alone and in combination with miconazole, itraconazole, and fluconazole was studied. Combinations of amphotericin B and antifungal azoles were synergistic, additive, or indifferent in their interaction against P. boydii. Antagonism was not observed.

Ophthalmic Manifestations of Infections with Cryptococcus neoformans in Patients with the Acquired Immunodeficiency Syndrome

The present study was undertaken to determine the nature and the prevalence of ophthalmic manifestations of infections with Cryptococcus neoformans in human immunodeficiency virus seropositive patients and to analyze whether the presence or absence of ocular signs is associated with improved survival. Eighty human immunodeficiency virus seropositive patients with cryptococcal infection were enrolled. We observed papilledema in 26 of the 80 patients (32.5%). Visual loss and abducens nerve palsy occurred in seven patients (9%). Only two patients (2.5%) had optic atrophy. Visual loss caused by optic nerve involvement was less frequent among the 62 patients treated with oral conazoles exclusively than among the 18 patients who had received amphotericin B or a combination of amphotericin B and conazoles. Actual invasion of the intraocular structures with Cryptococcus neoformans was an uncommon complication in our series. In addition to the ocular manifestations attributable to cryptococcal disease, human immunodeficiency virus-related retinopathy was present in nearly half of the patients. Cytomegalovirus retinitis was diagnosed in four patients (5%). The 26 patients (32.5%) with papilledema had a median survival of 182 days vs 160 days for the patients without papilledema. The median survival for 18 patients (22.5%) with cotton-wool spots was 102 days vs 186 days for those without cotton-wool spots. The differences between these subgroups were not statistically significant.

Déficit idiopathique en lymphocytes T CD4 + sans infection VIH et méningite à cryptocoques: intérêt d'un traitement d'entretien par itraconazole

A Cryptococcal meningitis was diagnosed in a 63 year-old man with idiopathic CD4 + T − lymphopenia without HIV infection. Fungal infection was successfully treated with combination of amphotericin B and flucytosine by the parenteral route, fluconazole by oral route, amphotericin B by intra-ventricular administration. Maintenance therapy was achieved with itraconazole per os, but serum levels were monitored because of interactions with antiepileptic drugs.

Evolving role of flucytosine in immunocompromised patients: new insights into safety, pharmacokinetics, and antifungal therapy.

Flucytosine is an antifungal agent useful in combination with amphotericin B in the treatment of several deeply invasive mycoses. The potentially dose-limiting, hematologic, gastrointestinal, and hepatic toxicities of flucytosine lead to a reluctance to use it in myelosuppressed patients. To investigate the safety and tolerability of flucytosine in this setting, we evaluated its use in 17 patients with cancer or aplastic anemia during a 2 1/2-year period at our institution and reviewed the literature describing mechanisms of action, resistance, in vitro and in vivo antifungal activity, clinical antifungal activity, pharmacokinetics, and toxicity. The combination of amphotericin B plus flucytosine eradicated the mycosis in 12 (71%) of 17 patients, whereas 3 (18%) of 17 died of progressive fungal infection. Serial serum levels of flucytosine measured by a creatinine iminohydrolase assay permitted reliable dosage adjustment. During therapy, only 2 (12%) of 17 patients had elevated mean serum levels of flucytosine (> 100 micrograms/mL) and 3 (18%) other patients had transiently elevated levels. Paired serum samples (n = 45) obtained at steady state during therapy with orally administered flucytosine showed similar peak and trough levels. Adverse effects of flucytosine therapy included one case each of reversible nausea, diarrhea, elevated transaminase levels, and thrombocytopenia. No cases of bone marrow aplasia, enterocolitis, hepatitis, or death due to flucytosine toxicity were encountered. We conclude that flucytosine in combination with amphotericin B is well tolerated in myelosuppressed patients when serum flucytosine levels are serially monitored.

Treatment and developmental therapeutics in aspergillosis. 1. Amphotericin B and its derivatives.

In recent years, the frequency of infections caused by Aspergillus sp. has been on the rise. Immunocompromised patients are especially vulnerable to such infections. The polyene antibiotic amphotericin B is currently considered to be therapeutically the most effective drug against Aspergillus-induced infections. In the present review, the clinical efficacy of amphotericin B, its toxicities and various routes of applications, are discussed. Different combinations of amphotericin B with other drugs have also been reviewed, along with the anti-Aspergillus activity of various other antibiotics and some ester derivatives of amphotericin B.

Increase in Candida krusei infection among patients with bone marrow transplantation and neutropenia treated prophylactically with fluconazole.

In early 1990 fluconazole was introduced as a prophylactic antifungal agent after bone marrow transplantation. During the same year Candida krusei emerged as the chief candida pathogen among patients with bone marrow transplants. To determine whether there was a correlation between the introduction of fluconazole and the increased incidence of C. krusei, we conducted a retrospective study based on the medical, mycologic, and autopsy records of all adult inpatients who had undergone bone marrow transplantation (n = 296) or who had leukemia (n = 167) at the study center during 1989 and 1990. The 84 patients who received antifungal prophylaxis with fluconazole had a sevenfold greater frequency of C. krusei infection than the 335 patients who did not receive fluconazole (8.3 percent vs. 1.2 percent, P = 0.002), despite having a lower frequency of disseminated C. albicans and C. tropicalis infections (0 vs. 6.0 percent, P = 0.02). Ten of the 11 C. krusei infections were controlled by a combination of amphotericin B and flucytosine. Colonization by C. krusei was found in 40.5 percent of the patients who received fluconazole but in only 16.7 percent of those who did not receive it (P less than 0.0001). Colonization was independently associated with the prophylactic use of both fluconazole (odds ratio, 3.50; P less than 0.001) and norfloxacin (odds ratio, 2.53; P = 0.04). C. krusei was not susceptible to fluconazole in vitro. In patients at high risk for disseminated candida infections, suppression of bacterial flora and the more common candida pathogens may permit some less pathogenic, but natively resistant candida species, such as C. krusei, to emerge as systemic pathogens.

Skull, Patella and Thigh Cryptococcosis after a Crashing Injury of the Temporal Bone

An unusual case of triple location (skull, patella and thigh) Cryptococcus neoformans is described. The peculiarity of the case is based on the probability of direct post-traumatic bone inoculation, subsequent seeding from skull to patella, thigh and cerebral spinal fluid (CSF), patella involvement, lack of evidence of lung involvement and lack of predisposing underlying disease. The response to surgery and a combination of amphotericin B and 5-flucytosine administration was favorable without relapse at follow-up after 7-year discontinuation of therapy.

Experimental studies on the nephrotoxicity of amphotericin B in rats

The renal effects of amphotericin B alone and in combination with cyclosporin A, tobramycin, fosfomycin, D-glucaro-1,5-lactam and verapamil were studied in rats. The parameters for nephrotoxicity were urinary loss of tubular cells and malate dehydrogenase, as well as creatinine clearance. Repeated intraperitoneal injections of amphotericin B led to an increase of urinary tubular cell elimination and malate-dehydrogenase. After co-administration of amphotericin B and cyclosporin A, the urinary loss of tubular cells increased and creatinine clearance was reduced. A combination of amphotericin B and tobramycin reduced tubular cell elimination but the creatinine clearance improved. When verapamil was combined with amphotericin B, endogenous creatinine clearance increased, though the loss of tubular cells was elevated. Furthermore, fosfomycin reduced the loss of tubular cells and improved renal functional parameters in combination with amphotericin B. In addition, D-glucaro-1,5-lactam was found to reduce the urinary loss of tubular cells induced by amphotericin B.