The Genotype Frequency of CYP2C19 Enzyme after Liver Transplantation.

BACKGROUND: Liver transplant recipients are treated with various drugs, the metabolism of which is dependent on the cytochrome P450 polymorphic genotype. OBJECTIVE: To identify the polymorphic variety of CYP2C19 genotype in liver allograft before and after transplantation. METHODS: The study was conducted on 88 liver recipients. The CYP2C19 genotypes in donors and recipients were the same in 32 and different in 56 recipients. Extracted genomic DNA from the leukocytes and liver graft tissues were analyzed by TaqMan SNP genotyping assay. The distributions of homozygote, heterozygote, poor and ultra-rapid metabolizers' genotypes were investigated in both groups. RESULTS: The distributions of CYP2C19 genotypes before transplantation in the blood and liver graft were within the normal range. After transplantation, in patients with different CYP2C19 genotype in donors and recipients, the genotypes of homozygote and ultra-rapid metabolizers were significantly decreased (p=0.024); the heterozygotes and poor metabolizer genotypes were significantly increased (p=0.017). CONCLUSION: The variety in CYP2C19 genotyping must be considered in patients with different genotypes in donor and recipients to predict the dosage regimens, optimize the treatment and decrease toxicity.

Severe Cutaneous Candidiasis in a Liver Transplant Patient.

Candida infections are common diseases in immunocompromised patients. A 19-year-old boy with liver transplantation, necrotic skin lesion, jaundice, dyspnea, and ascites was admitted to Namazi Hospital, Shiraz, southern Iran. The mycological examination for the skin lesion was requested. The skin sample was cultured on Sabouraud dextrose agar and evaluated by direct microscopic smear. Identification of isolated yeast was performed with RFLP-PCR. In direct smear, pseudohyphae, blastopores and yeasts were observed. Candida species was isolated from the media and identified as Candida albicans by molecular method. He died before starting any treatments. A skin lesion may present as the only sign of a systemic fungal infection in immunocompromised people. Careful attention and follow up are therefore recommended.

Prevalence of CYP2C19 Genetic Polymorphism among Normal People and Patients with Hepatic Diseases.

BACKGROUND: Patients with hepatic diseases are treated with numerous drugs metabolized by cytochrome P450. OBJECTIVE: To evaluate the frequencies of CYP2C19 variant alleles (*2, *3, and *17), genotypes, and phenotypes, and the relationship between the frequency of these alleles and the underlying hepatic diseases among patients with advanced liver diseases who were candidates for liver transplantation. METHODS: The Study was conducted on 120 patients suffering from various hepatic disorders, candidates for liver transplantation, and 52 healthy volunteers. DNA was extracted from blood samples and analyzed by TaqMan SNP genotyping assay. The CYP2C19 genotypes were classified into poor, extensive, intermediate, and ultra-rapid metabolizer phenotypes. RESULTS: Viral hepatitis was the most common cause of liver disease among studied patients. The frequencies of CYP2C19 alleles *1, *17, and *2 were 66.7% (160/240), 20.8% (50/240) and 12.5% (30/240), respectively. Allele CYP2C19*3 was not found in the studied population. The most prevalent genotypes were CYP2C19 *1/*1 (47.5%) and *1/*17 (24.2%). The predicted CYP2C19 phenotypes were extensive metabolizer (47.5%), heterozygote extensive metabolizer (45.9%), ultra-rapid metabolizer (5%), and poor metabolizer (1.6%). There was no significant difference between the frequencies of CYP2C19 genotypes between healthy people and patients. The distribution of CYP2C19 genotype frequencies was not significantly associated with the underlying disease conditions (p=0.472). CONCLUSION: The distribution of CYP2C19 genotype frequencies in Iranian healthy people and patients with various hepatic diseases was not significantly different. This may allow the physicians to predict a tailoring dose regimens based on the individual's metabolic capacity, decrease the risk of harmful side effects of the drugs, and optimize the treatment.

Susceptibility pattern of Candida albicans isolated from Iranian patients to antifungal agents.

BACKGROUND AND PURPOSE: Candidiasis is a major fungal infection, and Candida albicans is the major cause of infections in humans. The Clinical and Laboratory Standards Institute (CLSI) developed new breakpoints for antifungal agents against C. albicans. In this multi-center study, we aimed to determine the drug susceptibility profile of C. albicans, isolated from Iranian population according to new species-specific CLSI. MATERIALS AND METHODS: Clinical samples were cultured on Sabouraud dextrose agar and were incubated at room temperature for seven days. The isolates were transferred to Professor Alborzi Clinical Microbiology Research Center, Shiraz, Iran. C. albicans were identified by using API 20C AUX system. Broth microdilution method was used to determine the minimum inhibitory concentrations (MICs) of amphotericin B, caspofungin, voriconazole, fluconazole, posaconazole, itraconazole, and ketoconazole, based on CLSI document M27-S4 and new breakpoints for some azoles and caspofungin. RESULTS: Overall, 397 C. albicans were isolated from patients admitted to ten university hospitals in Iran. The MIC90 of the isolates to amphotericin B, caspofungin, voriconazole, fluconazole, posaconazole, itraconazole, and ketoconazole were 0.125, 0.125, 0.125, 1, 0.064, 0.5, and 0.125 µg/ml, and rates of resistance were 0.5%, 0.3%, 3.8%, 2.8%, and 2.5% for amphotericin B, caspofungin, voriconazole, fluconazole, and itraconazole, respectively. CONCLUSION: According to our data, fluconazole is the drug of choice for management of patients at risk for systemic candidiasis throughout the region, since it is cost-effective with low side effects.

Orbital mucormycosis in an immunocompetent individual.

BACKGROUND: Orbital mucormycosis caused by Zygomycetes is a rare and fatal infection that generally affects the patients who are immunocompromised. Despite antifungal therapy and aggressive surgical intervention, mucormycosis can cause serious and rapidly fatal infections if delayed diagnosis or therapeutic management occurs. Here, we report orbital mucormycosis in a healthy boy, with a favorable outcome after aggressive treatment. He has had no recurrence since the end of his treatment. CASE PRESENT: A 2-year old healthy boy, some days after entry of dust particle to his left eye presented with swelling and redness of the eye. With diagnosis of "periorbital cellulitis" intravenous antibiotics vancomycin (40 mg/kg/day) and ceftriaxone (75 mg/kg/day) were started but no improvement was observed. The results of biopsy and tissue culture led us to a diagnosis of mucormycosis. Orbital exenteration, combined with intravenous amphotericin B (1 mg/kg/day), resulted in the patient's survival. CONCLUSION: Due to the high mortality rate of mucormycosis, early diagnosis based on clinical findings and biopsy could be effective for management of the patients suffering from this infection.

Susceptibility of Candida species isolated from immunocompromised patients to antifungal agents.

This study was carried out from October 2003 to March 2007 to investigated susceptibility patterns ot March 2007 to antifungals of Candida strains isolated from 410 immunocompromised patients in Shiraz, Islamic Republic of Iran. Patients were checked for systemic candidiasis. Fungal colonization was determined and clinical samples collected from those patients with clinical signs of infections were examined. The carbohydrate assimilation patterns of all 354 isolates were studied. Susceptibility of the isolates to antifungal agents was determined using the reference broth microdilution method. Candida albicans was the species most often isolated. Voriconazole was highly active against all the isolates. Major resistance to itraconazole was observed in all Candida spp. Regular investigations into antifungal resistance in medical centres is highly recommended as this will result in more efficient management of invasive candidiasis in immunocompromised patients.

Evaluation of Candida infection after six months of transplantation in pediatric liver recipients in iran.

BACKGROUND: Liver transplantation (LT) is the standard treatment of end-stage liver diseases (ESLD). Invasive fungal infection is one of the important causes of morbidity and mortality after transplantation. OBJECTIVE: To determine the incidence of late-onset (after 6 months of LT) Candida infection in recipients. METHODS: A retrospective study was conducted to evaluate 50 pediatric patients after LT for 8 years at the LT Unit of Nemazee Hospital affiliated to Shiraz University of Medical Sciences, Shiraz, Iran. We followed the patients until 6 months post-LT for episodes of Candida infection proven by culture. RESULTS: One recipient (2%) developed late-onset esophageal candidiasis with improvement after intravenous amphotricin therapy but finally expired with a diagnosis of post-transplant lymphoproliferative disorder (PTLD). CONCLUSIONS: The incidence of late-onset Candida infection is not significant in pediatric liver recipient, but it still remains a significant problem. Control of Candida colonization would reduce the risk of invasive fungal infections and possibly more fatal complications.

Susceptibility of clinical Candida species isolates to antifungal agents by E-test, Southern Iran: A five year study.

BACKGROUND AND OBJECTIVES: The incidence of fungal infections in immunocompromised patients, especially by Candida species, has increased in recent years. This study was designed to identify Candida species and determine antifungal susceptibility patterns of 595 yeast strains isolated from various clinical specimens. MATERIAL AND METHODS: Identification of the isolates were determined by the API 20 C AUX kit and antifungal susceptibilities of the species to fluconazole, amphotericin B, ketoconazole, itraconazole, voriconazole, and caspofungin were determined by the agar-based E-test method. RESULTS: Candida albicans (48%) was the most frequently isolated species, followed by Candida kruzei (16.1%), Candida glabrata (13.5%), Candida kefyr (7.4%), Candida parapsilosis (4.8%), Candida tropicalis (1.7%) and other species (8.5%). Resistance varies depending on the species and the respective antifungal agents. Comparing the MIC90 for all the strains, the lower MIC90 was observed for caspofungin (0.5 µg/ml). The MIC90 for all Candida species were 64 µg/ml for fluconazole, 0.75 µg/ml for amphotericin B, 4 µg/ml for ketoconazole, 4 µg/ml for itraconazole, and 2 µg/ml for voriconazole. CONCLUSIONS: Species definition and determination of antifungal susceptibility patterns are advised for the proper management and treatment of patients at risk for systemic candidiasis. Resistance to antifungal agents is an alarming sign for the emerging common nosocomial fungal infections.

Molecular detection of invasive aspergillosis in hematologic malignancies.

BACKGROUND: Aspergillus species are the most frequent causes of invasive mold infections in immunocompromised patients, particularly those who underwent chemotherapy for hematologic malignancies. The aim of this study was to determine the incidence and efficiency of the PCR-enzyme linked immunosorbent assay method (PCR-ELISA) for early detection of Aspergillus species in patients with hematologic malignancies. PATIENTS AND METHODS: From 2004 to 2006, 194 patients with hematologic malignancies (who received chemotherapy) were evaluated for invasive aspergillosis (IA) in Shiraz, southern Iran. Ethylenediaminetetraacetic acid anticoagulant whole blood samples were collected prospectively once a week and stored at -20 degrees C until examination. All collected blood samples were assayed for the presence of the bands on ethidium bromide stained gel and for hybridization. RESULTS: The female-to-male ratio was 61:133, the mean age of patients was 33.7 years, and mean of hospitalization period was 21.2 days. PCR-ELISA was positive in 14 (7.2%) patients who exhibited clinical and radiologic signs of IA. The etiologic agents were Aspergillus flavus (11 cases) and Aspergillus fumigatus (three cases). The mean time of positivity of PCR-ELISA in the blood before the appearance of clinical signs was 12.6 days. PCR was found to be the earliest indicator of IA preceding nonspecific clinical and radiologic findings. The sensitivity, specificity, positive, and negative predictive values of PCR-ELISA to detect DNA-specific for Aspergillus species in patients with proven and probable IA were 66%, 96%, 62.5%, and 97%, respectively. In case patients were treated with antifungal drugs, and the treatment was successful, fungal PCR assay became negative after 14 days and if the treatment failed, assay was positive until death. CONCLUSIONS: We demonstrated, in the present study, the incidence of IA in leukemic patients and the usefulness of molecular assay for early diagnosis and monitoring of the treatment of IA.