Doses Of Liposomal Amphotericin B Research Articles

Comparative pharmacodynamics and dose optimization of liposomal amphotericin B against Candida species in an in vitro pharmacokinetic/pharmacodynamic model.

As comparative pharmacokinetic/pharmacodynamic (PK/PD) studies of liposomal amphotericin B (L-AMB) against Candida spp. are lacking, we explored L-AMB pharmacodynamics against different Candida species in an in vitro PK/PD dilution model. Eight Candida glabrata, Candida parapsilosis, and Candida krusei isolates (EUCAST/CLSI AMB MIC 0.125-1 mg/L) were studied in the in vitro PK/PD model simulating L-AMB Cmax = 0.25-64 mg/L and t1/2 = 9 h. The model was validated with one susceptible and one resistant Candida albicans isolate. The Cmax/MIC-log10CFU/mL reduction from the initial inoculum was analyzed with the Emax model, and Monte Carlo analysis was performed for the standard (3 mg/kg with Cmax = 21.87 ± 12.47 mg/L) and higher (5 mg/kg with Cmax = 83 ± 35.2 mg/L) L-AMB dose. A ≥1.5 log10CFU/mL reduction was found at L-AMB Cmax = 8 mg/L against C. albicans, C. parapsilosis, and C. krusei isolates (MIC 0.25-0.5 mg/L) whereas L-AMB Cmax ≥ 32 mg/L was required for C. glabrata isolates. The in vitro PK/PD relationship followed a sigmoidal pattern (R2 ≥ 0.85) with a mean Cmax/MIC required for stasis of 2.1 for C. albicans (close to the in vivo stasis), 24/17 (EUCAST/CLSI) for C. glabrata, 8 for C. parapsilosis, and 10 for C. krusei. The probability of target attainment was ≥99% for C. albicans wild-type (WT) isolates with 3 mg/kg and for wild-type isolates of the other species with 5 mg/kg. L-AMB was four- to eightfold less active against the included non-C. albicans species than C. albicans. A standard 3-mg/kg dose is pharmacodynamically sufficient for C. albicans whereas our data suggest that 5 mg/kg may be recommendable for the included non-C. albicans species.

Tolerability of pulsed high-dose L-AmB as pre-emptive therapy in patients at high risk for intra-abdominal candidiasis: A phase 2 study (LAMBDA study)

Background. Intra-abdominal candidiasis (IAC) is burdened by high mortality rates. However, the correct management of a critically ill patient with suspected IAC is an issue still on debate. The aim of our study was to evaluate the safety of pulse high-dose of liposomal amphotericin B (L-AmB) in patients with suspected IAC managed with a Beta-D-Glucan (BDG)-guided strategy. Methods. Phase 2 prospective study enrolling adult patients with intra-abdominal sepsis following surgery. Patients received a single dose of L-AmB 5mg/kg on day 1. At day 3, L-AmB was discontinued in case of negativity of basal serum (1,3)-Beta-D-Glucan (BDG) and was continued (3 mg/kg/daily) in case of positive basal BDG, or microbiologically confirmed IAC. The main endpoint was occurrence of adverse events according with common toxic criteria definition. Results. Overall, 40 patients were enrolled from January 2019 until August 2022. Of them 15 (37.5%) were male, median age was 65 (49-76) years. Urgent surgery accounted for 31 (77.5%) cases, principal indication was secondary/tertiary peritonitis (22, 55%), half of patients had a previous surgical operation within 30 days. Five (12.5%) patients had criteria for septic shock at enrolment. The median APACHE II score at ICU admission was 12 (10-15). In 33 (85%) cases IAC was excluded, whereas 5 (12.5%) and 2 (5%) patients had a probable and proven IAC, respectively. The single dose of L-AmB 5 mg/Kg was well tolerated in all patients, no early and late severe adverse events related to the drug were reported. L-AmB was discontinued in 65% of patients following a negative basal BDG result. All-cause 30-day mortality rate was 15%, in none case death was related to L-AmB administration or uncontrolled IAC. More specifically, mortality rates between patients with and without proven IAC was 0% vs. 15.8%, p=0.99. Conclusions. The rate of proven IAC among critically ill high-risk patients was low, attesting at 5%. A single dose of L-AmB 5 mg/Kg following prompt withdrawal in case of basal negative BDG result seems to be a safe and effective approach in such population.

Treatment of pediatric cutaneous leishmaniasis with liposomal amphotericin B.

The use of liposomal amphotericin B (L-AmB) in the treatment of cutaneous leishmaniasis (CL) is increasing. However, few data are available regarding the efficacy and safety of L-AmB in pediatric CL patients. Our aim in this study is to evaluate the efficacy and safety of L-AmB in pediatric CL patients. Pediatric patients admitted to a tertiary training and research hospital in a hyperendemic region for CL between January 2019 and May 2021 and receiving L-AmB therapy for CL were included in this retrospective study. L-AmB treatment was administered as 3mg/kg for 5 consecutive days and on the 10th day, in a total of 6 doses (18 mg/kg total dose). A total of 52 pediatric patients who received L-AmB therapy for CL were included in the study. In the follow-up 3months after L-AmB treatment, 16 (31%) patients showed complete clinical recovery, while treatment failure was detected in 36 (69%) patients. In conclusion, considering the low treatment success rate in our study, we think that the L-AmB dose used in our study is not an appropriate treatment option for the treatment of pediatric CL patients. However, we think that prospective studies with a large number of patients treated with higher doses of L-AmB and in whom the causative agents of CL were determined are needed.

Sinonasal mucormycosis and liposomal amphotericin B: A quest for dose optimization.

OBJECTIVES:Sinonasal mucormycosis is a serious fungal infection. Early diagnosis and prompt antifungal therapy along with surgical intervention is the key to its management. Liposomal amphotericin B (LAmB) given intravenously is the antifungal agent of choice. However, the current literature is not clear on its optimum dosage. We did a retrospective study to find the optimum dose of LAmB in cases with sinonasal mucormycosis.MATERIALS AND METHODS:Thirty patients diagnosed with mucormycosis involving sinonasal, rhino-orbital, or rhino-orbito-cerebral regions and receiving only LAmB as pharmacotherapy were included in our retrospective study from 2017 to 2020. A multiple logistic regression model was developed to correlate the total dose of LAmB and other parameters with the final outcome which was defined clinico-radiologically as improved, worsened, or death. The dose of LAmB which led to the first significant change in urea, creatinine, and potassium levels was also determined.RESULTS:The model showed a good fit in goodness-to-fit analysis (Pearson = 0.999, deviance = 0.995), while the likelihood ratio was statistically significant (0.001). The overall model prediction was 83.3%. However, the correlation of outcome with any of the variables, including mean LAmB dose per kilogram (82.2 ± 13.02 mg/kg), was statistically not significant.CONCLUSION:Many patient-related factors (such as age, comorbidities, extent of the disease, and side effects from LAmB therapy), which vary on a case-to-case basis, contribute to the outcome in a mucormycosis patient. The optimum dose of LAmB for improved outcome still requires individualization guided by experience, till well-designed studies address the question.

Treating pediatric cutaneous Leishmania tropica with systemic liposomal amphotericin B: A retrospective, single-center study.

Leishmania tropica (L. tropica) cutaneous leishmaniasis (CL) is associated with high morbidity and low response rate to therapy, especially in pediatric patients. Intravenous (IV) liposomal amphotericin B (LAmB) has been used off-label as a treatment for L. tropica CL for many years. However, data regarding its efficacy and safety in children is lacking. In order to evaluate the efficacy and safety of IV LAmB for treating pediatric patients with L. tropica, we retrospectively reviewed electronic medical records of 24 children who were diagnosed with L. tropica CL and treated with IV LAmB during 2014-2020, at a tertiary medical center in Israel. Fourteen (58%) completed the treatment protocol and 10 (42%) experienced an infusion-related adverse event (IRAE) leading to treatment termination. Complete response was noted in 6/14 (43%) patients, while 8/14 (57%) failed to respond. Lower response rate was noted in lesions involving the mid-facial area. The relatively low response rate is speculated to result from a low dose of LAmB, short follow-up period, and difficult to treat anatomic locations. The observation of a lower response rate for mid-facial lesions should be validated in larger cohorts. The highrisk of IRAE should be considered in physician decisions regarding this treatment.

Weekly high-dose liposomal amphotericin B prevents invasive aspergillosis after heart transplantation.

Preventive strategies for invasive aspergillosis (IA) have still not been determined in heart transplant recipients whereas IA leads to a high mortality rate at 12 months posttransplantation. The use of voriconazole or echinocandins was proposed but can favor emergence of Aspergillus or Candida sp. resistant strains or promote neurological and liver disorders in some patients. To assess whether universal prophylaxis with weekly high-dose of liposomal amphotericin-B (L-AmB) can safely prevent IA in heart transplant recipients. Retrospective before/after study that included 142 patients who received heart transplantation between 2010 and 2019 at the University Hospital of Toulouse (France). Weekly high dose of L-AmB (7.5 mg/kg/week) was used as universal prophylaxis from 2016 because of high environmental exposure to Aspergillus sp. and high incidence of IA. Cumulative 1-year incidence of IA decreased from 23% to 5% after introduction of L-Amb prophylaxis. Multivariate analysis (Cox model) identified L-AmB prophylaxis as a protective factor against IA (hazard ratio [HR] 0.21 [95% confidence interval 0; 0.92], p = .04), whereas postoperative renal replacement therapy was associated with IA (HR 3.6 [95% confidence interval 1.38; 9.3], p = .001), after correction for confounding effects (induction regimen, methylprednisolone pulses and history of hematological malignancy). The incidence of acute kidney injury requiring renal replacement therapy was similar in the two groups, suggesting a low risk of kidney toxicity when L-AmB is used weekly. No patient developed severe kidney electrolyte loss nor L-AmB-related anaphylaxis. Once-weekly high-dose L-AmB is safe and may prevent the development of IA after heart transplantation.

Anfotericina B liposomal en el tratamiento de la leishmaniasis visceral

A review on the current evidence of the efficacy and security of liposomal amphotericinB (L-AmB) for the treatment of visceral leishmaniasis (VL) has been performed. In the Indian subcontinent, a single dose of 10mg/kg has shown effectiveness in the treatment of VL due to Leishmania donovani. In contrast, higher doses of L-AmB (up to 30mg/kg) are required in Africa to treat a VL of the same etiology. When treating VL by Leishmania infantum acquired in the Americas and Europe the usual dose of L-AmB is 20-21mg/kg. In HIV co-infected patients the required doses are usually higher, up to 60mg/kg, and if it is administered in a prophylactic schedule after the treatment of VL relapses are reduced. L-AmB has shown synergism with other antiparasitic drugs, especially with paromomycin in the Indian subcontinent and with miltefosin in patients coinfected with HIV in East Africa. Due to its efficacy and safety profile, L-AmB is the first therapeutic option for VL.

Clinical aspects of visceral leishmaniasis caused by L. infantum in adults. Ten years of experience of the largest outbreak in Europe: what have we learned?

BackgroundAn outbreak of leishmaniasis caused by Leishmania infantum was declared in the southwest of the Madrid region (Spain) in June 2009. This provided a unique opportunity to compare the management of visceral leishmaniasis (VL) in immunocompetent adults (IC-VL), patients with HIV (HIV-VL) and patients receiving immunosuppressants (IS-VL).MethodsA cohort of adults with VL, all admitted to the Hospital Universitario de Fuenlabrada between June 2009 and June 2018, were monitored in this observational study, recording their personal, epidemiological, analytical, diagnostic, treatment and outcome variables.ResultsThe study population was made up of 111 patients with VL (10% HIV-VL, 14% IS-VL, 76% IC-VL). Seventy-one percent of the patients were male; the mean age was 45 years (55 years for the IS-VL patients, P = 0.017). Fifty-four percent of the IC-VL patients were of sub-Saharan origin (P = 0.001). Fever was experienced by 98% of the IC-VL patients vs 73% of the LV-HIV patients (P = 0.003). Plasma ferritin was > 1000 ng/ml in 77% of the IC-VL patients vs 17% of the LV-HIV patients (P = 0.007). Forty-two percent of patients fulfilled the criteria for haemophagocytic lymphohistiocytosis. RDT (rK39-ICT) serological analysis returned sensitivity and specificity values of 45% and 99%, respectively, and ELISA/iIFAT returned 96% and 89%, respectively, with no differences in this respect between patient groups. Fourteen (13.0%) patients with VL experienced treatment failure, eight of whom were in the IC-VL group. Treatment with < 21 mg/kg (total) liposomal amphotericin B (LAB) was associated with treatment failure in the IC-VL patients [P = 0.002 (OR: 14.7; 95% CI: 2.6–83.3)].ConclusionsIS-VL was more common than HIV-VL; the lack of experience in dealing with IS-VL is a challenge that needs to be met. The clinical features of the patients in all groups were similar, although the HIV-VL patients experienced less fever and had lower plasma ferritin concentrations. RDT (rK39-ICT) analysis returned a good specificity value but a much poorer sensitivity value than reported in other scenarios. The patients with HIV-VL, IS-VL and IC-VL returned similar serological results. Current guidelines for treatment seem appropriate, but the doses of LAB required to treat patients with HIV-VL and IS-VL are poorly defined.

Renal Recovery following Liposomal Amphotericin B-Induced Nephrotoxicity.

Background Acute kidney injury (AKI) is a common complication of treatment with liposomal amphotericin B (LAmB). The trajectory of renal recovery after LAmB-associated AKI has not been well described, nor has effect of LAmB dose on recovery of renal function been explored. Objective Characterize the pattern of renal recovery after incident AKI during LAmB and determine potential influencing factors. Methods This retrospective cohort study analyzed patients who developed a ≥50% increase in serum creatinine while on LAmB. Patients were followed up until complete renal recovery or death or for 30 days, whichever occurred first. The primary outcome was complete renal recovery, defined as serum creatinine convalescence to within 10% of the patient's pretreatment baseline. Multivariable modeling was used to identify independent predictors of renal recovery. Results Ninety-eight patients experienced nephrotoxicity during LAmB, 94% of which received doses <7 mg/kg/day. Fifty-one patients at least partially recovered renal function and, of these, 32 exhibited complete recovery after a mean 9.8 ± 7.8 days. No statistical relationship was found between LAmB dose at the time of AKI or cumulative exposure to LAmB and the likelihood of renal recovery. Concomitant nephrotoxins, age, and pretreatment renal function did not modify this effect in multivariable analysis. Conclusion and Relevance Our data suggests that LAmB dose did not impact the likelihood of renal recovery. Additional investigation is needed to confirm these findings when aggressive dosing strategies are employe. Additional research is also warranted to further characterize the course of recovery after LAmB-associated nephrotoxicity and comprehensive spectrum of renal outcomes.

Treatment outcomes of visceral leishmaniasis in Ethiopia from 2001 to 2017: a systematic review and meta-analysis

BackgroundEthiopia has the highest number of visceral leishmaniasis (VL) cases after Sudan in Sub-Saharan Africa. However, there was lack of comprehensive data on VL treatment outcome despite the huge burden of the diseases in the country. Hence, we aimed to perform a systematic review and meta-analysis on this topic to obtain stronger evidence on treatment outcomes of VL from the existing literature in Ethiopia.MethodsThe Cochrane guidelines to conduct meta-analysis following the Preferred Reporting Items for Systematic review and Meta-Analysis statement was used to conduct a computerized systematic search of the PubMed, Google Scholar, and ScienceDirect databases. Random effects model was used to combine studies showing heterogeneity of Cochrane Q P < 0.10 and I2 > 50. Treatment outcomes were assessed at end of treatment and at 6 months follow-up. Subgroup analyses were performed on treatment outcomes based on the different antileishmanial treatment options and patients’ HIV status.ResultsFifteen studies were included in the final analyses. At end of treatment, an overall treatment success rate of 82.6% was noticed. At 6 months follow-up, the overall treatment success rate was 72.2%. For patients treated with sodium stibogluconate (SSG), the treatment success rates at the end of treatment and at six-month follow-up were 81.5% and 80.7%, respectively. Multiple doses of liposomal-amphotericin B (L-AMB) had treatment success rates of 96.7 and 71–100% at the end of treatment and at 6 months follow-up, respectively. The combination of SSG with paromomycin (PM) gave treatment success rates of up to 90.1% at the end of treatment. HIV-infected individuals were found to have a higher mortality (odds ratio = 4.77, 95% CI: 1.30–17.43, P = 0.009) rate at 6 months follow-up.ConclusionsSSG alone has shown lower treatment efficacy in the management of VL when compared to combination of SSG with PM and multiple doses of L-AMB. The combination of SSG with PM gave good treatment success rates with shorter duration of treatment. Hence, the combination of SSG with PM should be used preferentially over SSG monotherapy. Multiple doses of L-AMB showed great efficacy especially among patients with complications, severe disease, HIV co-infection, and intolerance to the adverse effects of antimonials. HIV-infected individuals had a worse prognosis than their HIV-negative counterparts.

Treatment of widespread nodular post kala-azar dermal leishmaniasis with extended- dose liposomal amphotericin B in Bangladesh: A series of four cases

Background: Post Kala-azar Dermal Leishmaniasis (PKDL) is a sequela of Visceral Leishmaniasis (VL) and suggested as reservoirs of parasite. Currently, Miltefosine (MF), Amphotericin B Deoxycholate (ABD) and Liposomal Amphotericin B (LAmB) are recommended by World health organization (WHO) as treatment options for PKDL. But single MF or LAmB often causes incomplete cure specially cases with extensive lesion. To overcome this problem here we describe four cases of PKDL who had widespread nodular and macular lesions and were treated with two cycles of LAmB doses with 20 mg/kg body weight divided into 4 equal doses and administered every alternate day. Methods & Materials: Patients admitted to the Surya kanta kala-azar research centre (SKKRC) with extensive nodular or mixed lesion were considered to treat with LAmB. Hospital physician collected patients’ history and performed physical examination. Suspected cases were confirmed by microscopic examination of slit skin smear. At first, LAmB treatment was initiated at the dose of 20 mg/kg into four divided doses every alternate day. Before starting treatment all haematological and biochemical markers were checked. Second cycle was initiated for those who displayed marked improvement but not complete recovery. Finally, a follow up physical and microscopic examination was also done to evaluate the treatment outcome. Results: Of them, two had previous VL history and two had no previous VL history at all. The lesions started from chin with macular type, later distributed to other parts of the body with both macular and nodular type. The lesions were non-itching, touch sensitive and rk 39 strip test was positive. All of them were confirmed through microscopic examination of slit skin smear. Their haematological and biochemical markers were within normal limit. After first cycle, all of them showed initial progress and after second cycle all of them attained complete cure. Fever with shivering was the only documented adverse event during treatment and was managed by paracetamol. Conclusion: The cases highlighted in this report explore the success of utilising extended LAmB dose schedule for treating a patient with widespread lesions.The triumph of this alternate treatment schedule for PKDL needs to be supported with clinical trials that evaluate its efficacy and safety.

Bioanalysis of free and liposomal Amphotericin B in rat plasma using solid phase extraction and protein precipitation followed by LC-MS/MS

Amphotericin B (AMB) is a polyene macrolide antibiotic used for treating invasive fungal infections. Liposomal AMB (L-AMB) is a lipid dosage form which reduces the side effects and toxicity of the drug. The quantitation of free AMB (F-AMB) and L-AMB in vivo is important to monitor quality control of the liposomal formulation and to ensure its safety during clinical use. In this study, an original strategy was developed to separately determine F-AMB and L-AMB in rat plasma using LC–MS/MS. F-AMB was analyzed after separation by solid phase extraction, total AMB (T-AMB) was determined after protein precipitation and L-AMB was determined by difference. The method was fully validated. Calibration curves were linear in the ranges 0.7–120 μg/mL for T-AMB and 0.2–20 μg/mL for F-AMB. Accuracy and precision results were within acceptable variability limits, recoveries were consistent and reproducible, matrix effects were insignificant and analytes were stable under all the storage conditions tested. The method was successfully applied to a pharmacokinetic study in rats administered a single intravenous 6 mg/kg dose of L-AMB. The method will allow further clinical studies of L-AMB and provide useful technical support for the assay of other liposomal drug formulations.

Liposomal amphotericin B in travelers with cutaneous and muco-cutaneous leishmaniasis: Not a panacea.

BackgroundComplex cutaneous and muco-cutaneous leishmaniasis (CL and MCL) often requires systemic therapy. Liposomal amphotericin B (L-AmB) has a strong potential for a solid clinical benefit in this indication.MethodsWe conducted a retrospective analysis of data from a French centralized referral treatment program and from the “LeishMan” European consortium database. All patients with parasitologically proven CL or MCL who received at least one dose of L-AmB were included. Positive outcome was based on ulcer closure as per recent WHO workshop guidelines.ResultsFrom 2008 through 2016, 43 travelers returning from 18 countries (Old World n = 28; New World n = 15) were analyzed with a median follow-up duration of 79 days [range 28–803]. Main clinical forms were: localized CL with one or multiple lesions (n = 32; 74%) and MCL (n = 8; 19%). As per published criteria 19 of 41 patients (46%) were cured 90 days after one course of L-AmB. When the following items -improvement before day 90 but no subsequent follow-up, delayed healing (>3 months) and healing after a second course of L-AmB- were included in the definition of cure, 27 of 43 patients (63%) had a positive outcome. Five patients (MCL = 1; CL = 4) experienced a relapse after a median duration of 6 months [range 3–27] post treatment and 53% of patients (23/43) experienced at least one adverse event including severe hypokalaemia and acute cardiac failure (one patient each). In multivariate analysis, tegumentary infection with L. infantum was associated with complete healing after L-AmB therapy (OR 5.8 IC 95% [1.03–32]) while infection with other species had no impact on outcome.ConclusionIn conditions close to current medical practice, the therapeutic window of L-AmB was narrow in travellers with CL or MCL, with the possible exception of those infected with L. infantum. Strict follow-up is warranted when using L-AmB in patients with mild disease.

Occurrence and improvement of renal dysfunction and serum potassium abnormality during administration of liposomal amphotericin B in patients with hematological disorders: A retrospective analysis

Liposomal amphotericin B (L-AMB) has the potential to cause two major adverse events, renal dysfunction and serum potassium abnormality; however, appropriate clinical management of these events remains unclear. We retrospectively analyzed data regarding 128 hematology patients who received L-AMB in our institute and examined the association between clinical characteristics and renal dysfunction or serum potassium abnormality. We found that the median weight-normalized dose of L-AMB was 2.69mg/kg and the median administration period was 16days. The overall occurrence rates of renal dysfunction and hypokalemia were 55.7% and 76.6%, respectively. Multivariate analysis revealed that pre-existing renal dysfunction (P=0.017) and concomitant use of nephrotoxic (P<0.0001) or antifungal drugs (P=0.012) were independent risk factors for renal dysfunction. A higher infusion volume did not mitigate the risk of renal dysfunction. Hypokalemia occurred significantly less often in men (P=0.028) and in patients who concomitantly used nephrotoxic drugs (P=0.013). Approximately 40% of the adverse events were improved at 30days after L-AMB termination and there was no significant association between these adverse events improvement and L-AMB dosage or infusion volume. Of note, hyperkalemia was observed in more patients who received allogeneic hematopoietic stem cell transplantation (P=0.0303) and concomitant treatment with nephrotoxic drugs (P=0.0281). These results suggest that imprudent reduction of L-AMB dose or redundant intravenous infusion may have minimal benefit for critical patients with suspected invasive fungal infection.

Lack of Efficacy of Liposomal Amphotericin B Against Acute and Chronic Trypanosoma cruzi Infection in Mice.

Acute and chronic infection with Trypanosoma cruzi affects millions of people. The current therapeutic options are highly toxic and often not effective. Liposomal amphotericin B (LAMB) has been demonstrated previously to have some activity in murine models. In our studies, higher dosages given multiple times were tested for activity against acute or chronic disease, exploring whether intermittent and brief regimens could be effective, as might then prove useful in human, particularly outpatient, therapy. For acute infection, LAMB 25 mg/kg intravenously (i.v.) given one to three times prolonged survival and caused a rapid disappearance of Y strain trypomastigotes from the blood. However, even four or six doses of LAMB 30 mg/kg i.v., did not result in the cure of Y strain infection, with all mice relapsing after being immunosuppressed with cyclophosphamide. Similarly, chronic infection due to the CL strain was found to be unaltered by 1-3 treatments with LAMB 25 mg/kg. All surviving mice had histopathological evidence of infection in one or more tissues and equivalent antibody titers regardless of treatment regimen. Overall, LAMB at doses up to 30 mg/kg i.v. prolonged survival, but these doses were not curative in the regimens studied.

Experimental Models of Short Courses of Liposomal Amphotericin B for Induction Therapy for Cryptococcal Meningitis.

ABSTRACTCryptococcal meningoencephalitis is a rapidly lethal infection in immunocompromised patients. Induction regimens are usually administered for 2 weeks. The shortest effective period of induction therapy with liposomal amphotericin B (LAMB) is unknown. The pharmacodynamics of LAMB were studied in murine and rabbit models of cryptococcal meningoencephalitis. The concentrations of LAMB in the plasma and brains of mice were measured using high-performance liquid chromatography (HPLC). Histopathological changes were determined. The penetration of LAMB into the brain was determined by immunohistochemistry using an antibody directed to amphotericin B. A dose-dependent decline in fungal burden was observed in the brains of mice, with near-maximal efficacy achieved with LAMB at 10 to 20 mg/kg/day. The terminal elimination half-life in the brain was 133 h. The pharmacodynamics of a single dose of 20 mg/kg was the same as that of 20 mg/kg/day administered for 2 weeks. Changes in quantitative counts were reflected by histopathological changes in the brain. Three doses of LAMB at 5 mg/kg/day in rabbits were required to achieve fungicidal activity in cerebrospinal fluid (cumulative area under the concentration-time curve, 2,500 mg · h/liter). Amphotericin B was visible in the intra- and perivascular spaces, the leptomeninges, and the choroid plexus. The prolonged mean residence time of amphotericin B in the brain suggests that abbreviated induction regimens of LAMB are possible for cryptococcal meningoencephalitis.

In Vivo Efficacy of Liposomal Amphotericin B against Wild-Type and Azole-Resistant Aspergillus fumigatus Isolates in Two Different Immunosuppression Models of Invasive Aspergillosis.

Using an immunocompetent murine model of invasive aspergillosis (IA), we previously reported that the efficacy of liposomal amphotericin B (L-AmB) (Ambisome) is not hampered by the presence of azole resistance mutations in Aspergillus fumigatus (S. Seyedmousavi, W. J. G. Melchers, J. W. Mouton, and P. E. Verweij, Antimicrob Agents Chemother 57:1866-1871, 2013, https://doi.org/10.1128/AAC.02226-12). We here investigated the role of immune suppression, i.e., neutropenia and steroid treatment, in L-AmB efficacy in mice infected with wild-type (WT) A. fumigatus and with azole-resistant A. fumigatus harboring a TR34/L98H mutation in the cyp-51A gene. Survival of treated animals at day 14 in both immunosuppressed models was significantly better than that of nontreated controls. A dose-response relationship was observed that was independent of the azole-resistant mechanism and the immunosuppression method used. In the neutropenic model, 100% survival was reached at an L-AmB dose of 16 mg/kg of body weight for the WT strain and the TR34/L98H isolate. In the steroid-treated group, 90.9% survival and 100% survival were achieved for the WT isolate and the TR34/L98H isolate with an L-AmB dose of 16 mg/kg, respectively. The 50% effective dose (ED50) was 1.40 mg/kg (95% confidence interval [CI], 0.66 to 3.00 mg/kg) for the WT isolate and 1.92 mg/kg (95% CI, 0.60 to 6.17 mg/kg) for the TR34/L98H isolate in the neutropenic model and was 2.40 mg/kg (95% CI, 1.93 to 2.97 mg/kg) for the WT isolate and 2.56 mg/kg (95% CI, 1.43 to 4.56 mg/kg) for the TR34/L98H isolate in the steroid-treated group. Overall, there were no significant differences between the two different immunosuppressed conditions in the efficacy of L-AmB against the wild-type and azole-resistant isolates (P > 0.9). However, the required L-AmB exposure was significantly higher than that seen in the immunocompetent model.

A Double-Blind, Multicentre, Randomised, Placebo-Controlled Study to Assess the Efficacy, Safety and Tolerability of Prophylactic Liposomal Amphotericin B (AmBisome®) for the Prevention of Invasive Fungal Infections in Subjects Receiving Remission-Induction Chemotherapy for Acute Lymphoblastic Leukaemia (AmBiGuard trial)

Background: Adult patients undergoing remission-induction (RI) chemotherapy for newly diagnosed acute lymphoblastic leukaemia (ALL) are at high risk of invasive fungal disease (IFD), particularly invasive aspergillosis. The prevalence of IFD in this population has not been widely studied. There is currently no approved standard for antifungal prophylaxis and it is recommended by the European Working Group for Adult ALL that azole antifungal agents be avoided because of drug interactions with vincristine, a standard component of induction chemotherapy regimens.Methods: This was a double-blind, multicentre, placebo-controlled study in patients aged ≥18 years receiving RI chemotherapy for newly diagnosed ALL. Study subjects received either liposomal amphotericin B (L-AMB) 5mg/kg or placebo by IV infusion twice weekly in a 2:1 random allocation. The primary endpoint of the study was the proportion of subjects with proven or probable invasive fungal infection (IFI) assigned in a blinded review by an independent data review board (IDRB) using EORTC/MSG (European Organization for Research and Treatment of Cancer/Mycoses Study Group) definitions (1). Subjects were closely monitored for signs and symptoms of IFI, including biweekly galactomannan and β-D-glucan assessments. Clinical, laboratory or radiographic findings suggestive of IFI prompted further investigation according to a specified protocol. Subjects with defined clinical and mycological criteria or a halo sign on chest CT had prophylaxis interrupted and pre-emptive antifungal therapy initiated while further diagnostic procedures were undertaken. Prophylaxis was stopped when subjects met protocol-specified criteria for proven or probable IFI and appropriate antifungal therapy started. Secondary objectives included safety and tolerability of prophylactic L-AMB and the impact of IFI prevention on the efficacy of RI chemotherapy.Results: A total of 355 subjects from 83 centres in 13 countries in Europe (including Turkey and Israel) and South America were randomised and received at least 1 dose of either L-AMB (n=237) or placebo (n=118). Sixteen subjects were excluded from the efficacy analysis, 1 due to misdiagnosis (AML) and 15 due to protocol-prohibited antifungal treatment. 7.9% (18/228) subjects in the L-AMB group and 11.7% (13/111) subjects in the placebo group were considered by the IDRB to have experienced a proven or probable IFI (p=0.24, RR 0.33 [CI -0.32 to 0.66]). Of these, 1 case (0.4%) in the L-AMB group and 3 cases (2.7%) in the placebo group were considered proven. In subjects who were neutropenic (absolute neutrophil count <0.5x109/L) ≥10 days, the incidence was 6.9% (12/174) in the L-AMB group versus 13.1% (11/84) in the placebo group (p=0.10). Overall mortality was similar: 7.2% (17/237) in the L-AMB group vs 6.8% (8/118) in the placebo group (p=1.00) as was the incidence of serious adverse events (SAEs; 33.3% (79/237) vs 32.2% (38/118), [p=0.90]). SAEs of any grade related to the study drug were reported for 8.4% subjects (20/237) in the L-AMB group compared with 1.7% subjects (2/118) (p=0.02) in the placebo group. The most common (>5%) study drug-related adverse events (AEs) were hypokalaemia (10.5% [25/237] vs 3.4% [4/118] p=0.02) and increased creatinine (6.3% [15/237] vs. 0% [p=0.003]). Complete remission at the end of RI chemotherapy was achieved by 72.6% (172/237) subjects in the L-AMB group versus 78.8% (93/118) subjects in the placebo group (p=0.24).Conclusions: In this study, the largest of its kind to date, the rate of IFI among adult patients undergoing RI chemotherapy for newly diagnosed ALL was 11.7% in the placebo group. Study subjects who received L-AMB at 5mg/kg twice weekly for prophylaxis showed a reduction in IFIs relative to placebo (RR 0.33 [CI -0.32 to 0.66]), although this did not reach statistical significance (p=0.24). L-AMB prophylaxis was generally well tolerated. The incidence of IFI in patients with ALL receiving RI therapy indicates that antifungal prophylaxis is merited in this patient population. Further analysis is needed to determine which patients might benefit the most.clinicaltrials.gov number: NCT01259713(1) De Pauw et al 2008 Clin Infect Dis 46: 1813–1821 DisclosuresCornely:Gilead Sciences: Consultancy, Research Funding, Speakers Bureau. Off Label Use: Liposomal Amphotericin B (AmBisome®) is a broad spectrum antifungal agent indicated for the treatment of severe systemic and/or deep mycoses, empiric treatment of presumed fungal infections in febrile neutropenic patients and treatment of visceral leishmaniasis. In this study the efficacy, safety and tolerability of prophylactic liposomal amphotericin B (AmBisome®) was explored for the prevention of invasive fungal infections in subjects receiving remission-induction chemotherapy for Acute Lymphoblastic Leukaemia (the AmBiGuard trial).. Leguay:Gilead Sciences: Research Funding. Maertens:Gilead Sciences: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Castagnola:Gilead Sciences: Research Funding. Anagnostopoulos:Gilead Sciences: Research Funding. Allione:Gilead Sciences: Research Funding. Heussel:Gilead Sciences: Consultancy, Speakers Bureau. Donnelly:Astellas, Gilead, Merck, Pfizer: Consultancy, Honoraria, Research Funding. Agrawal:Gilead, Pfizer, Astellas, MSD, Bio-Rad: Honoraria, Research Funding. Garner:Gilead Sciences: Employment, Equity Ownership. Simcock:Gilead Sciences: Employment, Equity Ownership. Hawkins:Gilead Sciences: Employment, Equity Ownership. Goekbuget:Gilead Sciences: Consultancy, Honoraria.

Use of combination therapy to successfully treat breakthrough Trichosporon asahii infection in an acute leukemia patient receiving voriconazole

Trichosporon species is an important life-threatening opportunistic systemic pathogen, especially in leukemia patients. Voriconazole is proved to be a promising agent in past decade. However, recently we observed a case of breakthrough Trichosporon asahii infection while receiving voriconazole, which calls for an alternative treatment strategy. A combination therapy of liposomal amphotericin B (AmB) plus caspofungin – in which liposomal AmB dose was reduced due to renal toxicity – was administered to successfully treat this patient.

Our 2014 approach to mucormycosis.

Mucormycosis, previously termed as zygomycosis, is caused by fungi belonging to the order Mucorales and is a very severe disease in immunocompromised patients with an often unfavourable outcome. Given the high morbidity and mortality of mucormycosis, establishing a timely diagnosis followed by immediate treatment is of major importance. As randomised clinical trials are lacking, we present our current diagnostic and treatment pathways for mucormycosis in the immunocompromised host. Due to the difficulty to distinguish mucormycosis from other filamentous fungi, mucormycosis always has to be considered as differential diagnosis in predisposed patients. Diagnostic procedures comprise imaging, microscopy, culture and histopathology and need to be rigorously used. In patients with a high suspicion of mucormycosis, e.g. reversed halo sign on computed tomography scanning, our approach combines liposomal amphotericin B (LAmB) with surgical debridement. In light of the rapid deterioration and poor prognosis of these patients, we prefer a daily dose of LAmB of at least 5 mg kg(-1) despite nephrotoxicity. In patients with stable disease we switch to posaconazole 200 mg four times per day. In case of progression antifungal combination is an option.