Amphotericin B deoxycholate (DAmB) is a first-line agent for the initial treatment of talaromycosis. However, little is known about the population pharmacokinetics and pharmacodynamics of DAmB for talaromycosis. Pharmacokinetic data were obtained from 78 patients; among them 55 patients had serial fungal colony forming units counts in blood also available for analysis. A population pharmacokinetics-pharmacodynamics model was fitted to the data. The relationships between area under the concentration time curve (AUC):MIC, and the time to blood culture sterilization and the time to death were investigated. There was only modest pharmacokinetic variability in the average AUC with a mean (standard deviation) of 11.51 (3.39) mg*h/L. The maximal rate of drug induced kill was 0.133 log10CFU/mL/h, and the plasma concentration of the DAmB that induced half-maximal rate of kill was 0.02 mg/L. Fifty percent of patients sterilized their bloodstream by 83.16 hours (range 13-264 hours). A higher initial fungal burden was associated with longer time to sterilization (hazard ratio (HR): 0.51, 95% confidence interval (CI): 0.36-0.70, p<0.001). There was no relationship between AUC:MIC and the time to sterilization (HR: 1.03, 95% CI: 1.00-1.06, p=0.091). Furthermore, there was no relationship between the AUC:MIC and time to death (HR: 0.97, 95% CI: 0.88-1.08, p=0.607); or early fungicidal activity (slope= log(0.501-0.003*AUC:MIC), p=0.319) adjusted for the initial fungal burden. The population pharmacokinetics of DAmB are surprisingly consistent. The time to sterilization of the bloodstream is a useful pharmacodynamic endpoint for future studies.

We aimed to analyze whether the lack of inclusion of specific recommendations for the management of candidemia is an independent risk factor for early and overall mortality. Multicenter study of adult patients with candidemia in 13 hospitals. We assessed the proportion of patients on whom nine specific ESCMID and IDSA guidelines recommendations had been applied, and analyzed its impact on mortality. 455 episodes of candidemia were documented. Patients who died within the first 48 hours were excluded. Sixty-two percent of patients received an appropriate antifungal treatment. Either echinocandin or amphotericin B therapy were administered in 43% of patients presenting septic shock and in 71% of those with neutropenia. Sixty-one percent of patients with breakthrough candidemia underwent a change in antifungal drug class. Venous catheters were removed in 79% of cases. Follow-up blood cultures were performed in 72% of cases. Ophthalmoscopy and echocardiogram were performed in 48% and 50% of patients, respectively. Length of treatment was appropriate in 78% of cases. Early (2-7 days) and overall (2-30 days) mortality were 8% and 27.7%, respectively. Inclusion of less than 50% of the specific recommendations was independently associated with a higher early (HR = 7.02, 95% CI: 2.97-16.57; P < .001) and overall mortality (HR = 3.55, 95% CI: 2.24-5.64; P < .001). In conclusion, ESCMID and IDSA guideline recommendations were not performed on a significant number of patients. Lack of inclusion of these recommendations proved to be an independent risk factor for early and overall mortality.

Cryptococcosis is a fungal infection that mainly occurs in immunocompromised patients. We present the first case of cryptococcal meningitis in a patient who was being administered everolimus for breast cancer. Everolimus, a selective inhibitor of mammalian target of rapamycin, is a molecular targeting agent that is administered not only as an immunosuppressive agent, but also as an anticancer therapeutic. A 72-year-old woman with recurrent breast cancer had been receiving everolimus. She was admitted to our hospital with headache and vomiting. Lumbar puncture revealed high opening pressure, and cerebrospinal fluid (CSF) evaluation diagnosed cryptococcal meningitis. She was administered liposomal amphotericin-B, followed by fosfluconazole. Daily lumbar puncture was insufficient to reduce the high intracranial pressure; thus, continuous lumbar drainage was needed to improve her symptoms. The indwelling catheter was replaced regularly to prevent bacterial infection. She was treated successfully with extracorporeal CSF drainage for 86 days and fosfluconazole administration over 17 weeks. The patient recovered fully and was discharged on day 153 of hospitalization. As patients who receive everolimus are potentially immunocompromised hosts, we recommend that the medicine be administered with caution considering opportunistic infections when used in patients with cancer. (Received April 19, 2018; Accepted August 9, 2018; Published November 1, 2018).

Parasitic infections have remained a significant burden on human and animal health. In part, this is due to lack of clinically-approved novel antimicrobials and a lack of interest by the pharmaceutical industry. An alternative approach is to modify existing clinically-approved drugs for efficient drugs delivery formulations to ensure minimum inhibitory concentration is achieved at the target site. Nanotechnology offers the potential to enhance the therapeutic efficacy of drugs through modification of nanoparticles with ligands. Amphotericin B, Nystatin, and Fluconazole are clinically available drugs in the treatment of amoebal and fungal infections. These drugs were conjugated with gold nanoparticles. To characterize these Gold-conjugated drugs atomic force microscopy, ultraviolet-visible spectrophotometry, Fourier transform infrared spectroscopy were performed. These drugs and their gold nanoconjugates were examined for antimicrobial activity against the protist pathogen, Acanthamoeba castellanii of the T4 genotype. Moreover, host cell cytotoxicity assays were accomplished. Cytotoxicity of these drugs and drug conjugated gold nanoparticles was also determined by lactate dehydrogenase assay. Gold nanoparticles conjugation resulted in enhanced bioactivity of all three drugs with Amphotericin B producing most significant effects against Acanthamoeba castellanii (P<0.05). In contrast, bare gold nanoparticles did not exhibit significant antimicrobial potency. Furthermore, amoebae treated with drugs-conjugated gold nanoparticles showed reduced cytotoxicity against HeLa cells. In this report, we demonstrated the use of nanotechnology to modify existing clinically-approved drugs and enhancing their efficacy against pathogenic amoebae. Given the lack of development of novel drugs, this is a viable approach in the treatment of neglected diseases.

Cryptococcosis by Cryptococcus gattii occurs mainly in immunocompetent hosts, however, during the last decades, a growing number of cases in immunocompromised individuals have been noticed around the world. This report presents epidemiological, clinical and outcome aspects of patients with cryptococcosis caused by this species from a non-endemic area in Brazil. Of 278 Cryptococcus spp. clinical isolates recovered during the same period, 267 (96%) were molecularly identified as Cryptococcus neoformans VNI genotype and 11 (4%) as C. gattii VGII genotype by URA-5 RFLP. Of the 11 C. gattii patients, eight were male, mean age of 47.5 years. Of these, four were HIV-infected, one was kidney transplanted, one presented low CD4+ T cells values of unknown cause, another presented chronic liver disease meanwhile the remaining four were apparently immunocompetent. Disseminated disease and cryptococcal meningitis were present in four patients each. Most patients received amphotericin B plus fluconazole. Seven out of the 11 patients cured and four died before or during the therapy. The increased number of individuals with cryptococcosis by this species during the last decades needs to be carefully evaluated specially those who are HIV-infected. Nevertheless, Cryptococcus species differentiation is currently relevant in order to better know their relation with geographical, clinical host preference and outcome particularities.

Isolated cerebral mucormycosis is a rare and serious infection associated with intravenous drug abuse We provide a comprehensive meta-analysis of reported cases in the literature and an unpublished case from our institution. We searched PubMed/Medline, EMBASE, Scopus, Cochrane Databases, and our institution's electronic health records from inception through March 31, 2018. Cases were considered isolated (only affecting the cerebrum, cerebellum, or brainstem) if documentation existed for the absence of other primary sources of infection. Continuous variables were summarized using median and interquartile range (IQR) and categorical variables using frequency with proportion. Relationships between variables were tested using the Wilcoxon rank sum and Pearson χ2 tests. A total of 130 manuscripts (141 patients) met eligibility requirements and were screened; 68 patients were included in the analyses. The median (IQR) age was 28 (24-38) years, 57% of patients were men. Most patients had a history of IVDA (82%), and 20% were HIV positive. Lesion location was mostly supratentorial (91%), particularly in the basal ganglia (71.2%). Cultures were positive in 38% of cases, Rhizopus being the most common organism (59%). The mortality rate was 65%. Survivors were significantly more likely to have received amphotericin B (92% vs 43%, P<.001) or to have undergone stereotactic aspiration (58% vs 25%, P=.01). Isolated cerebral mucormycosis has a pooled mortality rate of 65%. The presence of lesions in the basal ganglia, rapidly progressing symptoms, and a history of IVDA should raise suspicion for early initiation of amphotericin B and stereotactic aspiration.

Heterocyclic compounds, such as hybrid tetrahydroquinoline and quinoline derivatives with phosphorated groups, have been prepared by multicomponent cycloaddition reaction between phosphorus-substituted anilines, aldehydes and styrenes. The antileishmanial activity of these compounds has been evaluated on both promastigotes and intramacrophagic amastigotes of Leishmania infantum. Good antileishmanial activity of functionalized tetrahydroquinolines 4a, 5a, 6b and quinoline 8b has been observed with similar activity than the standard drug amphotericin B and close selective index (SI between 43 and 57) towards L. infantum amastigotes to amphotericin B. Special interest shows tetrahydroquinolylphosphine sulfide 5a with an EC50 value (0.61 ± 0.18 μM) similar to the standard drug amphotericin B (0.32 ± 0.05 μM) and selective index (SI = 56.87). In addition, compound 4c shows remarkable inhibition on Leishmania topoisomerase IB. Parallel theoretical study of stereoelectronic properties, application of docking-based virtual screening methods, along with molecular electrostatic potential and predictive druggability analyses are also reported.