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1.  Endocarditis Caused by Rhodotorula Infection 
Journal of Clinical Microbiology  2014;52(1):374-378.
Rhodotorula is an emerging opportunistic fungal pathogen that is rarely reported to cause endocarditis. We describe a case involving a patient who developed endocarditis due to Rhodotorula mucilaginosa and Staphylococcus epidermidis, proven by culture and histopathology. The case illustrates the unique diagnostic and therapeutic challenges relevant to Rhodotorula spp.
doi:10.1128/JCM.01950-13
PMCID: PMC3911467  PMID: 24197888
2.  Tacrolimus Enhances the Potency of Posaconazole Against Rhizopus oryzae In Vitro and in an Experimental Model of Mucormycosis 
The Journal of Infectious Diseases  2012;207(5):834-841.
Background. We hypothesized that tacrolimus, an inhibitor of the calcineurin pathway, would enhance the in vivo activity of posaconazole against Rhizopus oryzae, the Mucorales species most commonly associated with mucormycosis.
Methods. We examined patterns of growth inhibition and fungicidal activity of posaconazole and tacrolimus, alone and in combination, against R. oryzae in vitro, using multiple methods (ie, hyphal metabolic and fluorescent vital dye reduction assays and measurement of chitin concentrations), and in vivo, using 2 mucormycosis models: an invertebrate model (Drosophila) and a nonlethal murine model of cutaneous mucormycosis.
Results. Combinations of posaconazole and tacrolimus were synergistic in checkerboard assays for 4 clinical isolates of R. oryzae (48-hour fractional inhibitory concentration index, 0.187–0.281). Pharmacodynamic analysis of the combination revealed that the 90% effective concentration threshold of posaconazole activity against R. oryzae could be achieved with 2-fold lower drug concentrations (0.5–1 mg/L) when administered with tacrolimus (0.007–2 mg/L). In vivo, combination therapy was associated with improved survival in the fly model of mucormycosis (65% vs 57% posaconazole alone) and with significant reductions in cutaneous lesions and R. oryzae fungal burden, compared with animals that received posaconazole monotherapy, in the cutaneous model of mucormycosis.
Conclusions. Combination posaconazole-tacrolimus therapy displays synergism in vitro and improved antifungal efficacy in vivo in 2 phylogenetically distinct models of mucormycosis.
doi:10.1093/infdis/jis767
PMCID: PMC3563310  PMID: 23242544
Mucormycosis; tacrolimus; posaconazole; animal models; subcutaneous; immunocompromised
3.  Pharmacokinetics of Intravenous Voriconazole in Obese Patients: Implications of CYP2C19 Homozygous Poor Metabolizer Genotype 
Pharmacotherapy  2013;33(3):e19-e22.
There is a paucity of pharmacokinetic studies describing weight-based dosing of intravenous (IV) voriconazole in obesity. We report the pharmacokinetics of IV voriconazole in an obese CYP2C19 homozygous poor metabolizer and review previously reported data of IV voriconazole in obesity. A 17-year-old obese Hispanic male (BMI=35 kg/m2) received IV voriconazole for treatment of suspected aspergillosis. After 2.5 days of voriconazole 4 mg/kg IV every 12 hours using adjusted body weight, the voriconazole area under the serum concentration versus time curve over the course of a single dosing interval (AUC0–12) and trough concentration were 86,100 ng•h/ml and 6.2 mcg/ml, respectively. The voriconazole dosage was then decreased. A trough concentration drawn just before dose reduction (after 8.5 days of voriconazole 4 mg/kg IV every 12 hours) remained elevated (5.8 mcg/ml). Genotyping revealed a CYP2C19 homozygous poor metabolizer (CYP2C19*2/*2). Voriconazole was subsequently discontinued due to QTc prolongation. These data and two recent publications suggest that voriconazole does not distribute extensively into human adipose tissue and that obese patients should be dosed on an adjusted weight basis. If an obese patient dosed on total body weight is also a CYP2C19 poor metabolizer, serum voriconazole concentrations will be further elevated, potentially leading to drug-induced toxicity.
doi:10.1002/phar.1192
PMCID: PMC3594083  PMID: 23400848
voriconazole; obese; intravenous; CYP2C19; pharmacokinetics
4.  Hyperthermia Sensitizes Rhizopus oryzae to Posaconazole and Itraconazole Action through Apoptosis 
The high mortality rate of mucormycosis with currently available monotherapy has created interest in studying novel strategies for antifungal agents. With the exception of amphotericin B (AMB), the triazoles (posaconazole [PCZ] and itraconazole [ICZ]) are fungistatic in vitro against Rhizopus oryzae . We hypothesized that growth at a high temperature (42°C) results in fungicidal activity of PCZ and ICZ that is mediated through apoptosis. R. oryzae had high MIC values for PCZ and ICZ (16 to 64 μg/ml) at 25°C; in contrast, the MICs for PCZ and ICZ were significantly lower at 37°C (8 to 16 μg/ml) and 42°C (0.25 to 1 μg/ml). Furthermore, PCZ and ICZ dose-dependent inhibition of germination was more pronounced at 42°C than at 37°C. In addition, intracellular reactive oxygen species (ROS) increased significantly when fungi were exposed to antifungals at 42°C. Characteristic cellular changes of apoptosis in R. oryzae were induced by the accumulation of intracellular reactive oxygen species. Cells treated with PCZ or ICZ in combination with hyperthermia (42°C) exhibited characteristic markers of early apoptosis: phosphatidylserine externalization visualized by annexin V staining, membrane depolarization visualized by bis-[1,3-dibutylbarbituric acid] trimethine oxonol (DiBAC) staining, and increased metacaspase activity. Moreover, terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) assay and DAPI (4′,6-diamidino-2-phenylindole) staining demonstrated DNA fragmentation and condensation, respectively. The addition of N-acetylcysteine increased fungal survival, prevented apoptosis, reduced ROS accumulation, and decreased metacaspase activation. We concluded that hyperthermia, either alone or in the presence of PCZ or ICZ, induces apoptosis in R. oryzae. Local thermal delivery could be a therapeutically useful adjunct strategy for these refractory infections.
doi:10.1128/AAC.00571-13
PMCID: PMC3754336  PMID: 23817366
5.  Ocular Manifestations of Candidemia in Children 
Among 254 patients with candidemia who had a dilated retinal examination, 8 patients (3.2%) were diagnosed with ocular disease resulting in retinal detachment in two patients and globe rupture in one patient. This study found that ocular candidiasis is an uncommon but serious sight-threatening complication in pediatric patients with candidemia.
doi:10.1097/INF.0b013e31826f547c
PMCID: PMC3527820  PMID: 23241990
Candidemia; Candida; Ocular; Children
6.  Human Rhinoviruses 
Clinical Microbiology Reviews  2013;26(1):135-162.
Human rhinoviruses (HRVs), first discovered in the 1950s, are responsible for more than one-half of cold-like illnesses and cost billions of dollars annually in medical visits and missed days of work. Advances in molecular methods have enhanced our understanding of the genomic structure of HRV and have led to the characterization of three genetically distinct HRV groups, designated groups A, B, and C, within the genus Enterovirus and the family Picornaviridae. HRVs are traditionally associated with upper respiratory tract infection, otitis media, and sinusitis. In recent years, the increasing implementation of PCR assays for respiratory virus detection in clinical laboratories has facilitated the recognition of HRV as a lower respiratory tract pathogen, particularly in patients with asthma, infants, elderly patients, and immunocompromised hosts. Cultured isolates of HRV remain important for studies of viral characteristics and disease pathogenesis. Indeed, whether the clinical manifestations of HRV are related directly to viral pathogenicity or secondary to the host immune response is the subject of ongoing research. There are currently no approved antiviral therapies for HRVs, and treatment remains primarily supportive. This review provides a comprehensive, up-to-date assessment of the basic virology, pathogenesis, clinical epidemiology, and laboratory features of and treatment and prevention strategies for HRVs.
doi:10.1128/CMR.00077-12
PMCID: PMC3553670  PMID: 23297263
7.  Protein Expression Profiles Distinguish Between Experimental Invasive Pulmonary Aspergillosis and Pseudomonas Pneumonia 
Proteomics  2010;10(23):10.1002/pmic.200900768.
We hypothesized that invasive pulmonary aspergillosis (IPA) may generate a distinctive proteomic signature in plasma and bronchoalveolar lavage (BAL). Proteins in plasma and BAL from two neutropenic rabbit models of IPA and Pseudomonas pneumonia were analyzed by SELDI-TOF MS. Hierarchical clustering analysis of plasma time course spectra demonstrated two clusters of peaks that were differentially regulated between IPA and Pseudomonas pneumonia (57 and 34 peaks, respectively, p<0.001). PCA of plasma proteins demonstrated a time-dependent separation of the two infections. A random forest analysis that ranked the top 30 spectral points distinguished between late Aspergillus and Pseudomonas pneumonias with 100% sensitivity and specificity. Based on spectral data analysis, three proteins were identified using SDS-PAGE and LC/MS and quantified using reverse phase arrays. Differences in the temporal sequence of plasma haptoglobin (p <0.001), apolipoprotein A1 (p<0.001) and transthyretin (p<0.038) were observed between IPA and Pseudomonas pneumonia, as was C-reactive protein (p<0.001). In summary, proteomic analysis of plasma and BAL proteins of experimental Aspergillus and Pseudomonas pneumonias demonstrates unique protein profiles with principal components and spectral regions that are shared in early infection and diverge at later stages of infection. Haptoglobin, apolipoprotein A1, transthyretin and C-reactive protein are differentially expressed in these infections suggesting important contributions to host defense against IPA.
doi:10.1002/pmic.200900768
PMCID: PMC3859317  PMID: 21089047
proteomics; Aspergillus fumigatus; Pseudomonas aeruginosa; pneumonia; neutropenia
8.  Species-Specific and Drug-Specific Differences in Susceptibility of Candida Biofilms to Echinocandins: Characterization of Less Common Bloodstream Isolates 
Candida species other than Candida albicans are increasingly recognized as causes of biofilm-associated infections. This is a comprehensive study that compared the in vitro activities of all three echinocandins against biofilms formed by different common and infrequently identified Candida isolates. We determined the activities of anidulafungin (ANID), caspofungin (CAS), and micafungin (MFG) against planktonic cells and biofilms of bloodstream isolates of C. albicans (15 strains), Candida parapsilosis (6 strains), Candida lusitaniae (16 strains), Candida guilliermondii (5 strains), and Candida krusei (12 strains) by XTT [2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide] assay. Planktonic and biofilm MICs were defined as ≥50% fungal damage. Planktonic cells of all Candida species were susceptible to the three echinocandins, with MICs of ≤1 mg/liter. By comparison, differences in the MIC profiles of biofilms in response to echinocandins existed among the Candida species. Thus, C. lusitaniae and C. guilliermondii biofilms were highly recalcitrant to all echinocandins, with MICs of ≥32 mg/liter. In contrast, the MICs of all three echinocandins for C. albicans and C. krusei biofilms were relatively low (MICs ≤ 1 mg/liter). While echinocandins exhibited generally high MICs against C. parapsilosis biofilms, MFG exhibited the lowest MICs against these isolates (4 mg/liter). A paradoxical growth effect was observed with CAS concentrations ranging from 8 to 64 mg/liter against C. albicans and C. parapsilosis biofilms but not against C. krusei, C. lusitaniae, or C. guilliermondii. While non-albicans Candida planktonic cells were susceptible to all echinocandins, there were drug- and species-specific differences in susceptibility among biofilms of the various Candida species, with C. lusitaniae and C. guilliermondii exhibiting profiles of high MICs of the three echinocandins.
doi:10.1128/AAC.02541-12
PMCID: PMC3716187  PMID: 23529739
9.  Candida Osteomyelitis: Analysis of 207 Pediatric and Adult Cases (1970–2011) 
Candida osteomyelitis most frequently presents subacutely with local symptoms but minimally elevated inflammatory biomarkers, hematogenous dissemination caused by C. albicans involving vertebrae in adults and femur/humerus in children, high relapse rate requiring extended therapy (median 3 months), and often surgical intervention.
Background. The epidemiology, pathogenesis, clinical manifestations, management, and outcome of Candida osteomyelitis are not well understood.
Methods. Cases of Candida osteomyelitis from 1970 through 2011 were reviewed. Underlying conditions, microbiology, mechanisms of infection, clinical manifestations, antifungal therapy, and outcome were studied in 207 evaluable cases.
Results. Median age was 30 years (range, ≤ 1 month to 88 years) with a >2:1 male:female ratio. Most patients (90%) were not neutropenic. Localizing pain, tenderness, and/or edema were present in 90% of patients. Mechanisms of bone infection followed a pattern of hematogenous dissemination (67%), direct inoculation (25%), and contiguous infection (9%). Coinciding with hematogenous infection, most patients had ≥2 infected bones. When analyzed by age, the most common distribution of infected sites for adults was vertebra (odds ratio [OR], 0.09; 95% confidence interval [CI], .04–.25), rib, and sternum; for pediatric patients (≤18 years) the pattern was femur (OR, 20.6; 95% CI, 8.4–48.1), humerus, then vertebra/ribs. Non-albicans Candida species caused 35% of cases. Bacteria were recovered concomitantly from 12% of cases, underscoring the need for biopsy and/or culture. Candida septic arthritis occurred concomitantly in 21%. Combined surgery and antifungal therapy were used in 48% of cases. The overall complete response rate of Candida osteomyelitis of 32% reflects the difficulty in treating this infection. Relapsed infection, possibly related to inadequate duration of therapy, occurred among 32% who ultimately achieved complete response.
Conclusions. Candida osteomyelitis is being reported with increasing frequency. Localizing symptoms are usually present. Vertebrae are the most common sites in adults vs femora in children. Timely diagnosis of Candida osteomyelitis with extended courses of 6–12 months of antifungal therapy, and surgical intervention, when indicated, may improve outcome.
doi:10.1093/cid/cis660
PMCID: PMC3657498  PMID: 22911646
10.  A Real-Time PCR Assay for Rapid Detection and Quantification of Exserohilum rostratum, a Causative Pathogen of Fungal Meningitis Associated with Injection of Contaminated Methylprednisolone 
Journal of Clinical Microbiology  2013;51(3):1034-1036.
A species-specific molecular beacon real-time PCR assay was developed for rapid diagnosis of Exserohilum rostratum infection. As low as 100 fg of E. rostratum DNA can be reliably detected in the presence of 50 ng of human DNA, with a dynamic linear quantification range from 20 ng to 200 fg.
doi:10.1128/JCM.03369-12
PMCID: PMC3592047  PMID: 23303500
11.  PCR Followed by Electrospray Ionization Mass Spectrometry for Broad-Range Identification of Fungal Pathogens 
Journal of Clinical Microbiology  2013;51(3):959-966.
Invasive fungal infections are a significant cause of morbidity and mortality among immunocompromised patients. Early and accurate identification of these pathogens is central to direct therapy and to improve overall outcome. PCR coupled with electrospray ionization mass spectrometry (PCR/ESI-MS) was evaluated as a novel means for identification of fungal pathogens. Using a database grounded by 60 ATCC reference strains, a total of 394 clinical fungal isolates (264 molds and 130 yeasts) were analyzed by PCR/ESI-MS; results were compared to phenotypic identification, and discrepant results were sequence confirmed. PCR/ESI-MS identified 81.4% of molds to either the genus or species level, with concordance rates of 89.7% and 87.4%, respectively, to phenotypic identification. Likewise, PCR/ESI-MS was able to identify 98.4% of yeasts to either the genus or species level, agreeing with 100% of phenotypic results at both the genus and species level. PCR/ESI-MS performed best with Aspergillus and Candida isolates, generating species-level identification in 94.4% and 99.2% of isolates, respectively. PCR/ESI-MS is a promising new technology for broad-range detection and identification of medically important fungal pathogens that cause invasive mycoses.
doi:10.1128/JCM.02621-12
PMCID: PMC3592073  PMID: 23303501
12.  Risk Factors and Predictors for Candidemia in Pediatric Intensive Care Unit Patients: Implications for Prevention 
Summary
Few data exist on risk factors for candidemia in pediatric intensive care unit (PICU) patients who are at high risk of mortality from infection. We conducted a population-based case-control study to determine risk factors and predictors for candidemia in the PICU.
Background
Candida species are the leading cause of invasive fungal infections in hospitalized children and are the third most common isolates recovered from pediatric healthcare-associated bloodstream infection in the US [1]. Few data exist on risk factors for candidemia in pediatric intensive care unit (PICU) patients.
Methods
We conducted a population-based case-control study of PICU patients at Children's Hospital of Philadelphia (CHOP) from 1997-2004. Cases were identified using laboratory records, controls were selected from PICU rosters. Controls were matched to cases by incidence density sampling, adjusting for time at risk. Following conditional multivariate analysis, we performed weighted multivariate analysis to determine predicted probabilities for candidemia given certain risk factor combinations.
Results
We identified 101 cases of candidemia(incidence,3.5/1,000 PICU admissions). Factors independently associated with candidemia included presence of a central venous catheter(OR 30.4;CI,7.7,119.5), malignancy(OR 4.0;CI,1.23,13.1), use of vancomycin for >3 days in the prior two weeks(OR 6.2;CI,2.4,16), and receipt of agents with activity against anaerobic organisms for >3 days in the prior two weeks(OR 3.5;CI, 1.5,8.4). Predicted probability of various combinations of the factors above ranged from 10.7%-46%. The 30-day mortality rate was 44% in cases compared to 14% in controls (OR 4.22;CI,2.35,7.60).
Conclusions
To our knowledge, this is the first study to evaluate independent risk factors and to determine a population of children in PICUs at high risk for developing candidemia. Future efforts should focus on validation of these risk factors identified in a different PICU population and development of interventions for prevention of candidemia in critically ill children.
doi:10.1086/655698
PMCID: PMC3753770  PMID: 20636126
Candidemia; Pediatrics; Risk factors; Intensive Care
13.  Male Reproductive Health and Prostate Cancer Risk 
Current Opinion in Urology  2011;21(6):506-513.
Purpose of review
Male infertility impacts a substantial proportion of men and has serious implication for a man’s quality of life. Advances in reproductive technology may allow men to bypass urologic care in order to achieve their family planning goals. Recent data suggests that male reproductive failure may be a harbinger of future urologic diseases, including prostate cancer, thus emphasizing the importance of dedicated urologic evaluation and care for all male infertility patients.
Recent findings
We will review the epidemiologic data that explores an association between male reproductive health and prostate cancer. We will review the potential biologic mechanisms that may underlie this association, and explore possible reasons for inconsistencies in study findings.
Summary
Studies of the association between male infertility and prostate cancer are inconsistent. Despite this, the association between reproductive health in a man’s fourth decade (30s) and his development of aggressive prostate cancer in his sixth decade (50s) should not be ignored. These findings, combined with the robustness of the potential common underlying mechanisms, provide a foundation for future studies of male reproductive health that are more specific and directed in their approach to answering questions about the association between male reproductive failure and future systemic disease.
doi:10.1097/MOU.0b013e32834bdf14
PMCID: PMC3321353  PMID: 21941182
Male Infertility; Prostate Cancer; Men’s Health; Risk Factors
14.  Adverse Interactions between Antifungal Azoles and Vincristine: Review and Analysis of Cases 
Mycoses  2011;55(4):290-297.
Summary
Triazole and imidazole antifungal agents inhibit metabolism of vincristine, leading to excess vinca alkaloid exposure and severe neurotoxicity. Recent reports of debilitating interactions between vincristine and itraconazole, as well as posaconazole, voriconazole and ketoconazole underscore the need to improve medical awareness of this adverse combination. We therefore undertook a comprehensive analysis of reports of adverse drug interactions (ADIs) with the combination of vincristine and azole antifungal agents, established a new classification, and provided a detailed summary of these toxicities. In patients who had sufficient data for analysis, forty-seven individuals were identified who had an ADI with the combination of vincristine and antifungal azoles. Median age was 8 years (1.3–68 years) with 33(70%) having a diagnosis of acute lymphoblastic leukemia. Median time to ADI with vincristine was 9.5 days with itraconazole, 13.5 days posaconazole, and 30 days voriconazole. The median number of vincristine doses preceding the ADI was 2 doses with itraconazole, 3 doses posaconazole, and 2 doses voriconazole. The most common severe ADIs included gastrointestinal toxicity, peripheral neuropathy, hyponatremia/SIADH, autonomic neuropathy, and seizures. Recovery from these ADIs occurred in 80.6% of patients. We recommend using alternative antifungal agents if possible in patients receiving vincristine to avoid this serious and potentially life-threatening drug interaction.
doi:10.1111/j.1439-0507.2011.02158.x
PMCID: PMC3345292  PMID: 22126626
azole antifungal; vincristine; drug interactions
15.  Future Directions in Mucormycosis Research 
Mucormycosis has emerged as an important opportunistic infection, especially in severely immunosuppressed hosts. The evolving epidemiology, immunopathogenesis, molecular virulence studies, early diagnosis, and pitfalls in designing clinical studies of mucormycosis are discussed in this article.
doi:10.1093/cid/cir886
PMCID: PMC3571717
16.  Future Directions in Mucormycosis Research 
Mucormycosis has emerged as an important opportunistic infection, especially in severely immunosuppressed hosts. The evolving epidemiology, immunopathogenesis, molecular virulence studies, early diagnosis, and pitfalls in designing clinical studies of mucormycosis are discussed in this article.
doi:10.1093/cid/cir886
PMCID: PMC3258101  PMID: 22247450
17.  Pathogenesis of Mucormycosis 
Mucormycosis is a life-threatening infection that occurs in patients who are immunocompromised because of diabetic ketoacidosis, neutropenia, organ transplantation, and/or increased serum levels of available iron. Because of the increasing prevalence of diabetes mellitus, cancer, and organ transplantation, the number of patients at risk for this deadly infection is increasing. Despite aggressive therapy, which includes disfiguring surgical debridement and frequently adjunctive toxic antifungal therapy, the overall mortality rate is high. New strategies to prevent and treat mucormycosis are urgently needed. Understanding the pathogenesis of mucormycosis and the host response to invading hyphae ultimately will provide targets for novel therapeutic interventions. In this supplement, we review the current knowledge about the virulence traits used by the most common etiologic agent of mucormycosis, Rhizopus oryzae. Because patients with elevated serum levels of available iron are uniquely susceptible to mucormycosis and these infections are highly angioinvasive, emphasis is placed on the ability of the organism to acquire iron from the host and on its interactions with endothelial cells lining blood vessels. Several promising therapeutic strategies in preclinical stages are identified.
doi:10.1093/cid/cir865
PMCID: PMC3286196  PMID: 22247441
18.  Prolonged Half-life of Voriconazole in a CYP2C19 Homozygous Poor Metabolizer Receiving Vincristine Chemotherapy: Avoiding a Serious Adverse Drug Interaction 
Mycoses  2011;54(6):e877-e879.
Summary
We report a case of prolonged half-life of voriconazole due to CYP2C19*2/*2 poor metabolizer genotype in a patient receiving vincristine chemotherapy. Voriconazole was discontinued three days before start of vincristine to avoid a serious drug interaction. Therapeutic drug monitoring and genotyping are valuable tools in managing patients receiving voriconazole and vincristine.
doi:10.1111/j.1439-0507.2011.02016.x
PMCID: PMC3164277  PMID: 21615537
voriconazole; vincristine; CYP2C19; poor metabolizer
19.  Differences in the clinical characteristics of primarily and secondarily infertile men with varicocele 
Fertility and sterility  2008;91(3):826-830.
Objective
To compare the clinical characteristics of primarily and secondarily infertile men with varicocele.
Design
Cross-sectional analysis.
Setting
Male infertility clinic, tertiary health care center.
Patient(s)
Two hundred ninety-five infertile men with palpable varicoceles.
Intervention(s)
Clinical evaluation including patient reproductive history (including assessment of primary or secondary infertility), physical examination, hormonal assessment and at least two semen analyses.
Main Outcome Measure(s)
Differences in the characteristics of men with primary vs. secondary infertility.
Result(s)
Two hundred five subjects were identified with primary infertility and 90 with secondary infertility. Secondarily infertile men were older (39.6 years vs. 35.0 years), with older partners (35.4 years vs. 33.2 years), but had higher sperm densities (51.3 vs. 36.0 million/mL) and a greater percentage of morphologically normal sperm (30.6% vs. 24.1%). A lower proportion of secondarily infertile men had total motile sperm count (TMC) <20 million compared with primarily infertile men (31.1% vs. 46.5%). Groups did not differ regarding infertility duration, tobacco or alcohol use, varicocele grade or laterality, testis volumes, or hormonal parameters. In multivariate modeling, secondary infertility (vs. primary) was an independent predictor of TMC >20 million (odds ratio 1.9).
Conclusion(s)
Men with secondary infertility are older and have older partners than primarily infertile men, yet they have significantly better sperm concentrations. Infertility in this group may be influenced by maternal reproductive potential.
doi:10.1016/j.fertnstert.2007.12.071
PMCID: PMC2881683  PMID: 18314114
Male infertility; varicocele; primary infertility; secondary infertility
20.  Increased Risk of Testicular Germ Cell Cancer Among Infertile Men 
Archives of internal medicine  2009;169(4):351-356.
Background
The risk of testicular cancer is thought to be higher among men seeking infertility treatment compared with the general population. Confirmation of this risk in a large US cohort of at-risk patients is lacking. This study explored the association between male infertility and subsequent development of testicular cancer in a US-based cohort.
Methods
A total of 51 461 couples evaluated for infertility from 1967 to 1998 were recruited from 15 California infertility centers. We linked data on 22 562 identified male partners to the California Cancer Registry. The incidence of testicular cancer in this cohort was compared with the incidence in an age-matched sample of men from the general population using the Surveillance Epidemiology and End Results program. We analyzed the risk for testicular cancer in men with and without male factor infertility using a Cox proportional hazards regression model.
Results
Thirty-four postinfertility-diagnosis cases of histologically confirmed testicular cancer were identified. Men seeking infertility treatment had an increased risk of subsequently developing testicular cancer (standardized incidence ratio, 1.3; 95% confidence interval, 0.9-1.9), with a markedly higher risk among those with known male factor infertility (2.8; 1.5-4.8). In multivariable analysis, men with male factor infertility were nearly 3 times more likely to develop testicular cancer compared with those without (hazard ratio, 2.8; 95% confidence interval, 1.3-6.0).
Conclusion
Men with male factor infertility have an increased risk of subsequently developing testicular cancer, suggesting the existence of common etiologic factors for infertility and testicular cancer.
doi:10.1001/archinternmed.2008.562
PMCID: PMC2881689  PMID: 19237718
21.  Anidulafungin for Neonatal Hematogenous Candida Meningoencephalitis: Identification of Candidate Regimens for Humans Using a Translational Pharmacological Approach 
Hematogenous Candida meningoencephalitis (HCME) is a serious infection in premature neonates. Anidulafungin is an echinocandin antifungal agent with potent activity against Candida spp., but its efficacy and optimal regimens for human neonates with HCME are not known. A well-validated rabbit model of HCME was used to define pharmacokinetic-pharmacodynamic (PK-PD) relationships of anidulafungin. A mathematical model was fitted to the entire data set. The experimental data were bridged to humans. A population PK model was fitted to the data from human neonates receiving anidulafungin receiving a loading dose of 3 mg/kg, followed by 1.5 mg/kg/day. Monte Carlo simulations were performed to identify candidate anidulafungin regimens for humans. All untreated rabbits succumbed by ≤96 h postinoculation. The PK of anidulafungin was linear with dose-dependent penetration into the cerebrum. Anidulafungin exerted a rapid antifungal effect that was apparent in the first dosing interval. Near-maximal antifungal activity was observed with dosages of 10 to 20 mg/kg/day. The bridging studies suggested that the current regimen of first 3 mg/kg, followed by 1.5 mg/kg/day, is suboptimal. Higher dosages were associated with progressively greater antifungal effect. Anidulafungin is effective for the treatment of experimental HCME. Higher dosages than those currently used for clinical care are required for maximal antifungal effect.
doi:10.1128/AAC.05826-11
PMCID: PMC3264209  PMID: 22123680
22.  Socioeconomic Disparities in the Utilization and Success of Fertility Treatments: Analysis of Data from a Prospective Cohort in the United States 
Fertility and sterility  2011;96(1):95-101.
Objective
To determine the effect of income, education, and race on the utilization and outcomes of infertility care.
Design
Prospective cohort
Setting
8 community and academic infertility practices
Patients
391 women presenting for an infertility evaluation
Interventions
Face-to-face and telephone interviews and questionnaires
Main Outcome Measures
Utilization of infertility services and odds of pregnancy. Linear and logistic regression used to assess relationship between racial and socioeconomic (SES) characteristics, utilization of fertility services, and fertility outcomes.
Results
After adjustment for age, demographic and fertility characteristics, college-educated couples (β $5,786, p=0.006) and households earning $100,000–$150,000 (β $6,465, p=0.01) and ≥$150,000 (β $8,602, p < 0.001) spent significantly more on fertility care than their non-college-educated, lower income couples. Higher income and college-educated couples were much more likely to utilize more cycles of higher intensity fertility treatment. The increased cost of fertility care was primarily explained by these differences in number and type of fertility treatment. Even after adjustment for these factors and total amount spent on fertility care, having a college degree was associated with persistently higher odds of achieving a pregnancy (OR 1.9, p=0.02).
Conclusions
Education and household income were independently associated with the amount of money spent on fertility care. This relationship was primarily explained by types and intensity of fertility treatments used. Having at least a college degree was independently associated with improved odds of pregnancy.
doi:10.1016/j.fertnstert.2011.04.054
PMCID: PMC3129357  PMID: 21616487
Socioeconomic status; race; infertility; cost; epidemiology; outcome; disparity
23.  Pharmacodynamic Effects of Simulated Standard Doses of Antifungal Drugs against Aspergillus Species in a New In Vitro Pharmacokinetic/Pharmacodynamic Model 
In conventional ΜΙC tests, fungi are exposed to constant drug concentrations, whereas in vivo, fungi are exposed to changing drug concentrations. Therefore, we developed a new in vitro pharmacokinetic/pharmacodynamic model where human plasma pharmacokinetics of standard doses of 1 mg/kg amphotericin B, 4 mg/kg voriconazole, and 1 mg/kg caspofungin were simulated and their pharmacodynamic characteristics were determined against three clinical isolates of Aspergillus fumigatus, Aspergillus flavus, and Aspergillus terreus with identical MICs (1 mg/liter for amphotericin B, 0.5 mg/liter for voriconazole) and minimum effective concentrations (0.5 mg/liter for caspofungin). This new model consists of an internal compartment (a 10-ml dialysis tube made out of a semipermeable cellulose membrane allowing the free diffusion of antifungals but not galactomannan) inoculated with Aspergillus conidia and placed inside an external compartment (a 700-ml glass beaker) whose content is diluted after the addition of antifungal drugs by a peristaltic pump at the same rate as the clearance of the antifungal drugs in human plasma. Fungal growth was assessed by galactomannan production. Despite demonstrating the same MICs, amphotericin B completely inhibited (100%) A. fumigatus but not A. flavus and A. terreus, whose growth was delayed for 7.53 and 22.8 h, respectively. Voriconazole partially inhibited A. fumigatus (49.5%) and Α. flavus (27.9%) but not Α. terreus; it delayed their growth by 3.99 h (A. fumigatus) and 5.37 h (Α. terreus). Caspofungin did not alter galactomannan production in all of the species but A. terreus. The new model simulated human pharmacokinetics of antifungal drugs and revealed important pharmacodynamic differences in their activity.
doi:10.1128/AAC.00662-11
PMCID: PMC3256091  PMID: 22064546
24.  Synergistic Interaction of the Triple Combination of Amphotericin B, Ciprofloxacin, and Polymorphonuclear Neutrophils against Aspergillus fumigatus▿ 
Antimicrobial Agents and Chemotherapy  2011;55(12):5923-5929.
Aspergillus is damaged by polymorphonuclear neutrophils (PMNs) by means of nonoxidative and oxidative mechanisms, which may be affected by antifungal and antibacterial agents that patients with invasive pulmonary aspergillosis often receive. The pharmacodynamic interactions among deoxycholate amphotericin B (AMB), ciprofloxacin (CIP), and human PMNs against Aspergillus fumigatus growth are unknown. We therefore studied the interactions between 0.032 to 2.0 μg/ml of AMB, 0.1 to 50 μg/ml of CIP at a fixed AMB/CIP ratio of 1:3.125, and PMNs from six donors at an effector-to-target (E:T) ratio of 400:1 against a clinical A. fumigatus isolate using an XTT metabolic assay and the Bliss independence pharmacodynamic-interaction model. CIP exhibited no antifungal activity alone or in combination with PMNs. Synergy was found between AMB and PMNs, with interaction indices (II) of 0.06 to 0.21; the highest interaction of 21% ± 3.6% was observed at 0.22 ± 0.09 μg/ml of AMB. The AMB and CIP (AMB+CIP) combination was synergistic (II = 0.39) at low AMB concentrations and antagonistic (II = 1.39) at high AMB concentrations, with a maximal synergistic interaction of 16% ± 3.7% observed at 0.16 ± 0.08 μg/ml of AMB. The triple combination AMB+CIP+PMNs was synergistic, with interaction indices of 0.05 to 0.20, and a maximal synergistic interaction of 24% ± 4% was observed at 0.20 ± 0.07 μg/ml of AMB. The increased percentage of Bliss synergy of the triple combination AMB+CIP+PMNs (24% ± 4%) was the product of those of the constituent double combinations AMB+PMNs (21% ± 3.6%) and AMB+CIP (16% ± 3.7%). Thus, the antifungal activity of AMB, at clinically relevant concentrations, was enhanced in combination with PMNs and CIP against A. fumigatus growth in a concentration-dependent manner.
doi:10.1128/AAC.00548-11
PMCID: PMC3232811  PMID: 21911564
25.  Galactomannan Antigenemia after Infusion of Gluconate-Containing Plasma-Lyte ▿  
Journal of Clinical Microbiology  2011;49(12):4330-4332.
We demonstrated that sodium gluconate was the factor causing false-positive galactomannan (GM) antigenemia of Plasma-Lyte hydration solution. Infusion of sodium gluconate-containing solution but not gluconate-free Plasma-Lyte resulted in positive serum GM antigenemia. Serum GM concentrations also correlated with the volume and in vitro concentrations of GM within gluconate-containing solutions of infused Plasma-Lyte.
doi:10.1128/JCM.05031-11
PMCID: PMC3232943  PMID: 21976760

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