Posaconazole MIC Distributions for Aspergillus fumigatus Species Complex by Four Methods: Impact of cyp51A Mutations on Estimation of Epidemiological Cutoff Values.

Estimating epidemiological cutoff endpoints (ECVs/ECOFFS) may be hindered by the overlap of MICs for mutant and nonmutant strains (strains harboring or not harboring mutations, respectively). Posaconazole MIC distributions for the Aspergillus fumigatus species complex were collected from 26 laboratories (in Australia, Canada, Europe, India, South and North America, and Taiwan) and published studies. Distributions that fulfilled CLSI criteria were pooled and ECVs were estimated. The sensitivity of three ECV analytical techniques (the ECOFFinder, normalized resistance interpretation [NRI], derivatization methods) to the inclusion of MICs for mutants was examined for three susceptibility testing methods (the CLSI, EUCAST, and Etest methods). The totals of posaconazole MICs for nonmutant isolates (isolates with no known cyp51A mutations) and mutant A. fumigatus isolates were as follows: by the CLSI method, 2,223 and 274, respectively; by the EUCAST method, 556 and 52, respectively; and by Etest, 1,365 and 29, respectively. MICs for 381 isolates with unknown mutational status were also evaluated with the Sensititre YeastOne system (SYO). We observed an overlap in posaconazole MICs among nonmutants and cyp51A mutants. At the commonly chosen percentage of the modeled wild-type population (97.5%), almost all ECVs remained the same when the MICs for nonmutant and mutant distributions were merged: ECOFFinder ECVs, 0.5 µg/ml for the CLSI method and 0.25 µg/ml for the EUCAST method and Etest; NRI ECVs, 0.5 µg/ml for all three methods. However, the ECOFFinder ECV for 95% of the nonmutant population by the CLSI method was 0.25 µg/ml. The tentative ECOFFinder ECV with SYO was 0.06 µg/ml (data from 3/8 laboratories). Derivatization ECVs with or without mutant inclusion were either 0.25 µg/ml (CLSI, EUCAST, Etest) or 0.06 µg/ml (SYO). It appears that ECV analytical techniques may not be vulnerable to overlap between presumptive wild-type isolates and cyp51A mutants when up to 11.6% of the estimated wild-type population includes mutants.

Serious fungal infections in Peru.

Epidemiological data about mycotic diseases are limited in Peru and estimation of the fungal burden has not been previously attempted. Data were obtained from the Peruvian National Institute of Statistics and Informatics, UNAIDS and from the Ministry of Health's publications. We also searched the bibliography for Peruvian data on mycotic diseases, asthma, COPD, cancer and transplants. Incidence or prevalence for each fungal disease were estimated in specific populations at risk. The Peruvian population for 2015 was 31,151,543. In 2014, the estimated number of HIV/AIDS and pulmonary tuberculosis cases was 88,625, 38,581 of them not on ART, and 22,027, respectively. A total of 581,174 cases of fungal diseases were estimated, representing approximately 1.9% of the Peruvian population. This figure includes 498,606, 17,361 and 4,431 vulvovaginal, oral and esophageal candidiasis, respectively, 1,557 candidemia cases, 3,593 CPA, 1,621 invasive aspergillosis, 22,453 allergic bronchopulmonary aspergilllosis, 29,638 severe asthma with fungal sensitization, and 1,447 Pneumocystis pneumonia. This first attempt to assess the fungal burden in Peru needs to be refined. We believe the figure obtained is an underestimation, because of under diagnosis, non-mandatory reporting and lack of a surveillance system and of good data about the size of populations at risk.

Multicenter study of anidulafungin and micafungin MIC distributions and epidemiological cutoff values for eight Candida species and the CLSI M27-A3 broth microdilution method.

Since epidemiological cutoff values (ECVs) using CLSI MICs from multiple laboratories are not available for Candida spp. and the echinocandins, we established ECVs for anidulafungin and micafungin on the basis of wild-type (WT) MIC distributions (for organisms in a species-drug combination with no detectable acquired resistance mechanisms) for 8,210 Candida albicans, 3,102 C. glabrata, 3,976 C. parapsilosis, 2,042 C. tropicalis, 617 C. krusei, 258 C. lusitaniae, 234 C. guilliermondii, and 131 C. dubliniensis isolates. CLSI broth microdilution MIC data gathered from 15 different laboratories in Canada, Europe, Mexico, Peru, and the United States were aggregated to statistically define ECVs. ECVs encompassing 97.5% of the statistically modeled population for anidulafungin and micafungin were, respectively, 0.12 and 0.03 µg/ml for C. albicans, 0.12 and 0.03 µg/ml for C. glabrata, 8 and 4 µg/ml for C. parapsilosis, 0.12 and 0.06 µg/ml for C. tropicalis, 0.25 and 0.25 µg/ml for C. krusei, 1 and 0.5 µg/ml for C. lusitaniae, 8 and 2 µg/ml for C. guilliermondii, and 0.12 and 0.12 µg/ml for C. dubliniensis. Previously reported single and multicenter ECVs defined in the present study were quite similar or within 1 2-fold dilution of each other. For a collection of 230 WT isolates (no fks mutations) and 51 isolates with fks mutations, the species-specific ECVs for anidulafungin and micafungin correctly classified 47 (92.2%) and 51 (100%) of the fks mutants, respectively, as non-WT strains. These ECVs may aid in detecting non-WT isolates with reduced susceptibility to anidulafungin and micafungin due to fks mutations.

Multilaboratory study of epidemiological cutoff values for detection of resistance in eight Candida species to fluconazole, posaconazole, and voriconazole.

Although epidemiological cutoff values (ECVs) have been established for Candida spp. and the triazoles, they are based on MIC data from a single laboratory. We have established ECVs for eight Candida species and fluconazole, posaconazole, and voriconazole based on wild-type (WT) MIC distributions for isolates of C. albicans (n=11,241 isolates), C. glabrata (7,538), C. parapsilosis (6,023), C. tropicalis (3,748), C. krusei (1,073), C. lusitaniae (574), C. guilliermondii (373), and C. dubliniensis (162). The 24-h CLSI broth microdilution MICs were collated from multiple laboratories (in Canada, Brazil, Europe, Mexico, Peru, and the United States). The ECVs for distributions originating from ≥6 laboratories, which included ≥95% of the modeled WT population, for fluconazole, posaconazole, and voriconazole were, respectively, 0.5, 0.06 and 0.03 µg/ml for C. albicans, 0.5, 0.25, and 0.03 µg/ml for C. dubliniensis, 8, 1, and 0.25 µg/ml for C. glabrata, 8, 0.5, and 0.12 µg/ml for C. guilliermondii, 32, 0.5, and 0.25 µg/ml for C. krusei, 1, 0.06, and 0.06 µg/ml for C. lusitaniae, 1, 0.25, and 0.03 µg/ml for C. parapsilosis, and 1, 0.12, and 0.06 µg/ml for C. tropicalis. The low number of MICs (<100) for other less prevalent species (C. famata, C. kefyr, C. orthopsilosis, C. rugosa) precluded ECV definition, but their MIC distributions are documented. Evaluation of our ECVs for some species/agent combinations using published individual MICs for 136 isolates (harboring mutations in or upregulation of ERG11, MDR1, CDR1, or CDR2) and 64 WT isolates indicated that our ECVs may be useful in distinguishing WT from non-WT isolates.

Interlaboratory variability of Caspofungin MICs for Candida spp. Using CLSI and EUCAST methods: should the clinical laboratory be testing this agent?

Although Clinical and Laboratory Standards Institute (CLSI) clinical breakpoints (CBPs) are available for interpreting echinocandin MICs for Candida spp., epidemiologic cutoff values (ECVs) based on collective MIC data from multiple laboratories have not been defined. While collating CLSI caspofungin MICs for 145 to 11,550 Candida isolates from 17 laboratories (Brazil, Canada, Europe, Mexico, Peru, and the United States), we observed an extraordinary amount of modal variability (wide ranges) among laboratories as well as truncated and bimodal MIC distributions. The species-specific modes across different laboratories ranged from 0.016 to 0.5 µg/ml for C. albicans and C. tropicalis, 0.031 to 0.5 µg/ml for C. glabrata, and 0.063 to 1 µg/ml for C. krusei. Variability was also similar among MIC distributions for C. dubliniensis and C. lusitaniae. The exceptions were C. parapsilosis and C. guilliermondii MIC distributions, where most modes were within one 2-fold dilution of each other. These findings were consistent with available data from the European Committee on Antimicrobial Susceptibility Testing (EUCAST) (403 to 2,556 MICs) for C. albicans, C. glabrata, C. krusei, and C. tropicalis. Although many factors (caspofungin powder source, stock solution solvent, powder storage time length and temperature, and MIC determination testing parameters) were examined as a potential cause of such unprecedented variability, a single specific cause was not identified. Therefore, it seems highly likely that the use of the CLSI species-specific caspofungin CBPs could lead to reporting an excessive number of wild-type (WT) isolates (e.g., C. glabrata and C. krusei) as either non-WT or resistant isolates. Until this problem is resolved, routine testing or reporting of CLSI caspofungin MICs for Candida is not recommended; micafungin or anidulafungin data could be used instead.

Correlation of susceptibility of Cryptococcus neoformans to amphotericin B with clinical outcome.

Testing of Cryptococcus neoformans for susceptibility to antifungal drugs by standard microtiter methods has not been shown to correlate with clinical outcomes. This report describes a modified quantitative broth macrodilution susceptibility method showing a correlation with both the patient's quantitative biological response in the cerebrospinal fluid (CSF) and the survival of 85 patients treated with amphotericin B (AMB). The Spearman rank correlation between the quantitative in vitro measure of susceptibility and the quantitative measure of the number of organisms in the patient's CSF was 0.37 (P < 0.01; 95% confidence interval [95% CI], 0.20, 0.60) for the first susceptibility test replicate and 0.46 (P < 0.001; 95% CI, 0.21, 0.62) for the second susceptibility test replicate. The median in vitro estimated response (defined as the fungal burden after AMB treatment) at 1.5 mg/liter AMB for patients alive at day 14 was 5 CFU (95% CI, 3, 8), compared to 57 CFU (95% CI, 4, 832) for those who died before day 14. These exploratory results suggest that patients whose isolates show a quantitative in vitro susceptibility response below 10 CFU/ml were more likely to survive beyond day 14.

Treatment of cutaneous sporotrichosis with one daily dose of potassium iodide.

BACKGROUND: Recommended treatment for cutaneous sporotrichosis consists of a saturated solution of potassium iodide (SSKI) administered in three daily doses (tid). Because compliance with this regimen has been a problem in our previous experience, we evaluated the use of one daily (qd) full dose of SSKI. METHODS: Patients with culture-confirmed cutaneous sporotrichosis were entered in a randomized, nonblinded study to compare the safety and efficacy of qd vs. tid dosage of SSKI. RESULTS: Fifty-seven patients were enrolled to receive either qd (29) or tid (28) SSKI. Three (1 in the qd and 2 in the tid group) were not compliant with the assigned regimen. Side effects were common but mild in both treatment groups (61% in the qd and 42% in the tid group, P = 0.17); treatment had to be discontinued because of side effects in 3 cases (2 in the qd and 1 in the tid group). Overall 26 (89.6%) and 25 (89.2%) of the individuals initially assigned to the qd and tid dosing schedule, respectively, were cured by the treatment. No relapse was detected after 45 days of follow-up. CONCLUSION: These findings suggest that a single daily full dose of SSKI appears to be appropriate therapy for cutaneous sporotrichosis; further studies with larger numbers of patients are required.

Species distribution and antifungal susceptibility profile of Candida isolates from bloodstream infections in Lima, Peru.

Yeast identification and in vitro susceptibility testing provide helpful information for appropriate administration of antifungal treatments; however, few reports from the Latin American region have been published. The aim of this study was to identify the species present in isolates from bloodstream infections diagnosed in nine hospitals in Lima, Peru and to determine their in vitro susceptibility to four antifungal drugs. We tested and identified 153 isolates collected between October 2009 and August 2011 using standard methods. PCR and PCR-RFLP assays were performed to distinguish Candida albicans from Candida dubliniensis and to identify species of the Candida parapsilosis and Candida glabrata complexes. Antifungal susceptibility testing for fluconazole, anidulafungin and voriconazole was performed using the CSLI M27-A3 method, and amphotericin B susceptibility was determined using the Etest method. The most frequently isolated species were: C. albicans (61; 39.9 %), C. parapsilosis (43; 28.1 %), C. tropicalis (36; 23.5%) and C. glabrata (8; 5.2 %). The overall susceptibility rates were 98.0 %, 98.7 %, 98.0 % and 97.4 % for amphotericin B, fluconazole, voriconazole and anidulafungin, respectively. No isolate was resistant to more than one drug. These results showed that the rate of resistance to four antifungal drugs was low among Candida bloodstream isolates in Lima, Peru.

Rocuronio en obesos: ¿debe dosificarse por peso real o por peso ideal? / Rocuronium in obese: should be dosed by actual weight or ideal weight?

El aumento universal en la prevalencia de obesidad ha causado que los anestesiólogos se vean frecuentemente enfrentados a anestesiar pacientes obesos. Pese a esto aún existen dudas respecto a cómo dosificar las drogas en estos pacientes. La literatura recomienda dosificar el rocuronio en obesos en base al peso ideal (IBW, iniciales del inglés Ideal Body Weight) pero esta sugerencia está basada más bien en la prudencia que en la evidencia. Se decidió explorar con análisis de sobrevida (análisis tiempo-evento), la duración del rocuronio en obesos al ser dosificado por peso ideal (IBW) y por peso real (TBW, iniciales del inglés de peso corporal total). Al administrar el rocuronio en base al peso real (TBW) se observó una prolongación en su duración de acción con un acortamiento de su latencia en relación con la dosificación en base al peso ideal (IBW). Hubo una marcada prolongación de la duración de acción y el índice de recuperación tanto al dosificar por peso real como peso ideal. Debido a esta sensibilidad aumentada al rocuronio en pacientes obesos recomendamos dosificarlo en base al peso ideal, excepto si se necesita intubar rápidamente...

The universal increase in prevalence of obesity has caused that anesthesiologist are frequently encountered with anesthetizing obese patients. There stills exists doubt on how to dosage drugs to these patients. Literature recommends dosing rocuronium in the obese based on ideal weight (IBW), being this suggestion based more on prudence than on evidence. Randomized control trial was designed for obese patients scheduled for bariatric surgery to study the pharmacodynamics of rocuronium in this population. Patients were randomly assigned into two groups: rocuronium dosage 0.6 mg•kg-1 for real weight (TBW) or rocuronium dosage of 0.6mg•kg-1 for ideal weight (IBW). Ideal weight was calculated according to Lemmens formula. The reference group was the dosage based on IBW. Previous calibration, evaluating the first twitch of train-of-four (T1), we registered onset time, clinical duration, recovery index, level of muscle relaxation to which the first reinforcement was administered and clinical duration of rocuronium reinforcement. A total of 100 patients were part of the study: 54 in group TBW and 46 in group IBW. When administering rocuronium based on real weight (TBW) a prolongation in clinical duration was found: Medium (IQR*); 79.5 (67 - 105) minutes versus 44.5(33 - 63.5 minutes) in the IBW group (p < 0.001) with a decrease in latency in the TBW group 120 (90-150secs.) versus the IBW group 180 (120 - 270 secs.) (p < 0.001). There were no differences in the recovery index between both levels of dosing. There was a marked prolongation of both clinical duration and recovery index in both groups, as supported in some literature. Based on the evidence, we recommend to dose rocuronium in obese patients based on ideal weight, with the exception of cases were quick intubation is required...

Treatment of cryptococcal meningitis in Peruvian AIDS patients using amphotericin B and fluconazole.

OBJECTIVES: To describe the mycologic and clinical outcomes and factors associated with failure in Peruvian patients with AIDS-associated cryptococcal meningitis (CM) treated with amphotericin B deoxycholate (Amph B) followed by fluconazole. METHODS: Patients were treated with intravenous Amph B 0.7 mg/kg/day for 2 or 3 weeks followed by oral fluconazole 400mg/day for 7 or 8 weeks. Clinical and laboratory evaluations including cerebrospinal fluid (CSF) studies were performed at baseline and at weeks 2 and 10. RESULTS: The CSF cultures were negative in 25% and 68% of 47 patients at weeks 2 and 10, respectively. In the univariate analysis, baseline low body mass index (BMI), hyponatremia, low serum albumin, positive blood culture and CSF antigen titers >or=1024 were associated with a positive CSF culture at week 2. Baseline positive urine culture, positive blood culture, any positive extraneural culture and CSF opening pressure at week 2 >or=300 mm H2O were associated with a positive CSF culture at week 10. In the multivariate analysis no association was found. CONCLUSIONS: Therapy with Amph B and fluconazole, combined with aggressive management of elevated intracranial pressure (ICP), results in low CSF sterilization rates at week 2 and acceptable CSF sterilization rates at week 10 when compared with other series.

Parotid saliva cortisol in normal subjects: increase during pregnancy.

Cortisol concentration was measured by radioimmunoassay in parotid saliva: values for normal subjects averaged 15 nM at 8:00 and 4 nM at 18:00. Parotid saliva cortisol was shown to react promptly and in a clearcut fashion to factors leading to rise and fall in cortisol secretion. Cortisol levels in parotid saliva were uninfluenced in young women taken estrogen-containing drugs for contraceptive purposes; on the other hand, they increased significantly during the third trimester of pregnancy. This increase corresponds to the reported increase in ultrafilterable cortisol, itself being presumably the result of the hypersection of progesterone characterizing this physiological condition since progesterone competes with cortisol not only at the level of transcortin but also at that of cytoplasmic glucocorticoid receptors.

Endemic sporotrichosis.

Although first reported more than a century ago, sporotrichosis, caused by Sporothrix schenckii, still remains a poorly studied disease. Results from recently published studies on sporotrichosis in endemic areas are summarised and assembled with previous findings, providing a comprehensive review that highlights the needs for further research.

Comparison of terbinafine and griseofulvin in the treatment of tinea capitis.

BACKGROUND: Griseofulvin has been used for many years in the treatment of tinea capitis. Increase in resistance to this medication has led to a search for new therapeutic alternatives. OBJECTIVE: Our purpose was to evaluate the therapeutic efficacy of terbinafine in comparison with griseofulvin in the treatment of tinea capitis. METHODS: We performed a double-blind, randomized, prospective evaluation of 50 patients with a clinical and mycologic diagnosis of tinea capitis. One group received 4 weeks of terbinafine followed by 4 weeks of placebo. The other group received 8 weeks of griseofulvin. We evaluated 5 clinical parameters. Mycologic examinations were performed at baseline and at the end of weeks 8 and 12. RESULTS: Patients' ages ranged from 1 to 14 years. Fifty-four percent were girls and 46% were boys. Mycologic examinations disclosed Trichophyton tonsurans in 74% of patients and Microsporum canis in 26%. At week 8, the griseofulvin-treated group showed a cure rate of 76%, and the terbinafine-treated group 72%. At week 12, the efficacy of griseofulvin decreased to 44%, whereas the efficacy of terbinafine was 76%. CONCLUSION: Terbinafine constitutes an alternative for the treatment of tinea capitis. Recurrences were less frequent. No significant side effects were reported.

Sporotrichosis in Peru: description of an area of hyperendemicity.

Sporotrichosis is a sporadic and rare mycotic infection in most of the developed world. In many parts of the developing world, sporotrichosis is much more commonly recognized, but epidemiological data are generally lacking from these regions. We report epidemiological, clinical, and treatment data from 238 cases of culture-proven sporotrichosis occurring in a relatively remote area of the south central highlands of Peru that were retrospectively collected during 1995-1997. Most cases (60%) occurred in children aged

Metástasis testicular de cáncer renal de células claras: reporte de un caso y revisión de literatura / Testicular Metastasis of clear cell renal cancer: report of a case and review of literature

INTRODUCCIÓN: El carcinoma renal es la tercera neoplasia dentro de los tumores genitourinarios, correspondiendo a un 3 por ciento del total de tumores malignos primarios del adulto a nivel mundial. En Chile tiene una mortalidad de 2-3/100.000 habitantes, presentando un 30 por ciento metástasis al momento del diagnóstico, siendo las metástasis testiculares infrecuentes. CASO CLÍNICO: Hombre de 73 años, con antecedente de varicocele izquierdo sintomático sometido a nefrectomía radical laparoscópica izquierda en Mayo 2011 por tumor renal. Biopsia informa carcinoma de células claras tipo clásico, que invade cápsula renal y teiido adiposo perirrenal con área de carcinoma sarcomatoide. Etapificación: Pt2B NX. En Diciembre 2011 presenta aumento de volumen nodular, pétreo e indoloro en testículo izquierdo. Ecografía y ecodoppler evidencian lesión focal hipoecogénica, sólida. Marcadores tumorales negativos. Tras orquiectomía radical izquierda, biopsia indica metástasis de carcinoma de células claras renal. Tomografía computarizada de tórax abdomen y pelvis informa múltiples nódulos pulmonares de aspecto metastásico, clasificándosele en etapa IV, actualmente con cuidados paliativos DISCUSIÓN: Los metástasis testiculares son infrecuentes encontrándose como hallazgos en autopsias u orquiectomías, presentes simultáneamente con el tumor primario renal o precediendo a su diagnóstico. La mayoría son ipsilaterales izquierdas, asociadas a varicocele, y su baja incidencia podría deberse a su temperatura y localización anatómica distal. CONCLUSIÓN: El caso expuesto ilustra la infrecuente presentación de una metástasis de cáncer renal como masa testicular la cual debiese ser considerada frente a una masa sin antecedente de otro cáncer primario o con marcadores germinales negativos, aunque no ha sido descrita previamente en nuestro medio.

INTRODUCTION: Renal cell carcinoma is the third neoplasia in genitourinary tumors, corresponding to 3 percent of adult primary malignant tumors worldwide. In Chile it has a 2-3/100.000 mortality, 30 percent showing metastasis at diagnosis, testicular metastases being rare. CASE REPORT: 73 year old man with a history of symptomatic varicocele who underwent a left radical nephrectomy for renal tumor in May 2011. Biopsy reports clear cell carcinoma classic type that invades renal capsule and perirenal adipose teiido with sarcomatoid carcinoma area. Staging: Pt2B NX. In December 2011 he presents a painless nodular tumor in the left testicle. Doppler ultrasonography evidences a hypoechoic solid focal lesion. Tumor Markers are negative. After left radical orchiectomy, biopsy shows metastasis of renal clear cell carcinoma. Computed tomography of the chest, abdomen and pelvis reported multiple pulmonary metastatic nodules. He was classified as stage IV and currently recieves palliative care DISCUSSION: testicular metastases are an uncommon finding usually in autopsies or orchiectomy samples, present simultaneously or preceding the primary renal tumor. Most are ipsilateral left and are associated with varicocele. Its low incidence may be due to its anatomical distal location or temperature. CONCLUSION: This case illustrates an uncommon presentation of a metastatic renal cancer. It ought to be considered against a testicular mass with no history of another primary cancer or negative germ cell tumor markers, This uncommon finding has not been previously described in our media.