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1.  A prospective study comparing infection risk and disease activity in children with juvenile idiopathic arthritis treated with and without tumor necrosis factor-alpha inhibitors 
Clinical rheumatology  2014;34(3):457-464.
Tumor necrosis factor-alpha (TNF-α) inhibitors are effective treatment for juvenile idiopathic arthritis (JIA) but may increase infection rates. However, active JIA may also render patients vulnerable to infection. In this study, we prospectively assessed infection rates in JIA patients treated with and without TNF-α inhibitors and correlated disease activity with infection risk. TNF-α inhibitor-naïve JIA subjects were followed up for 12 months. Subjects initiated on TNF-α inhibitors after enrollment were analyzed in the TNF group. Subjects treated without TNF-α inhibitors were analyzed in the non-TNF group. Questionnaires captured mild or severe infections. JIA disease activity by Childhood Health Assessment Questionnaire (CHAQ) disability index/pain score and physician joint count/global assessment was recorded. Twenty TNF and 36 non-TNF subjects were analyzed. The total infection rate ratio for TNF versus non-TNF group subjects was 1.14 (95 % CI, 0.78–1.66; p=0.51). The average rate of infections per month was 0.29 for TNF and 0.24 for non-TNF subjects. No severe infections or hospitalizations occurred in either group. Secondary infectious outcomes were also similar between groups. Controlling for study group, an increase in CHAQ pain score correlated with an increase in several infectious outcome measures. Our results suggest no difference in infection rates between JIA subjects treated with and without TNF-α inhibitors. Additionally, JIA disease activity may have contributed to infection risk in our cohort, irrespective of immunosuppressive therapy. Future analysis of the relationship between treatment regimens, disease activity, and infection rates may help to further delineate predictors of infection risk in JIA patients.
doi:10.1007/s10067-014-2779-8
PMCID: PMC4351171  PMID: 25227771
Infection; Juvenile idiopathic arthritis; Tumor necrosis factor inhibitors
2.  In Vitro Combination of Isavuconazole with Micafungin or Amphotericin B Deoxycholate against Medically Important Molds 
Antimicrobial Agents and Chemotherapy  2014;58(11):6934-6937.
Whether isavuconazole, an extended-spectrum triazole, possesses synergistic activity in combination therapy with echinocandins or amphotericin B for the treatment of invasive molds infections has not been studied. Our in vitro combination studies showed that isavuconazole and micafungin are synergistically active against Aspergillus fumigatus, Aspergillus flavus, Aspergillus terreus, and Cunninghamella bertholletiae. These results suggest that isavuconazole, in combination with micafungin, may have a role in the treatment of invasive aspergillosis and warrants further investigation.
doi:10.1128/AAC.03261-14
PMCID: PMC4249375  PMID: 25136021
3.  Aspergillus Osteomyelitis: Epidemiology, Clinical Manifestations, Management, and Outcome 
The Journal of infection  2013;68(5):478-493.
Background
The epidemiology, pathogenesis, diagnosis, and management of Aspergillus osteomyelitis are not well understood.
Methods
Protocol-defined cases of Aspergillus osteomyelitis published in the English literature were reviewed for comorbidities, microbiology, mechanisms of infection, clinical manifestations, radiological findings, inflammatory biomarkers, antifungal therapy, and outcome.
Results
Among 180 evaluable patients, 127 (71%) were males. Possible predisposing medical conditions in 103 (57%) included pharmacological immunosuppression, primary immunodeficiency, and neutropenia. Seventy-three others (41%) had prior open fracture, trauma or surgery. Eighty (44%) followed a hematogenous mechanism, 58 (32%) contiguous infections, and 42 (23%) direct inoculation. Aspergillus osteomyelitis was the first manifestation of aspergillosis in 77%. Pain and tenderness were present in 80%. The most frequently infected sites were vertebrae (46%), cranium (23%), ribs (16%), and long bones (13%). Patients with vertebral Aspergillus osteomyelitis had more previous orthopedic surgery (19% vs 0%; P=0.02), while those with cranial osteomyelitis had more diabetes mellitus (32% vs 8%; P=0.002) and prior head/neck surgery (12% vs 0%; P=0.02). Radiologic findings included osteolysis, soft-tissue extension, and uptake on T2-weighted images. Vertebral body Aspergillus osteomyelitis was complicated by spinal-cord compression in 47% and neurological deficits in 41%. Forty-four patients (24%) received only antifungal therapy, while 121(67%) were managed with surgery and antifungal therapy. Overall mortality was 25%. Median duration of therapy was 90 days (range, 10–772 days). There were fewer relapses in patients managed with surgery plus antifungal therapy in comparison to those managed with antifungal therapy alone (8% vs 30%; P=0.006).
Conclusions
Aspergillus osteomyelitis is a debilitating infection affecting both immunocompromised and immunocompetent patients. The most common sites are vertebrae, ribs, and cranium. Based upon this comprehensive review, management of Aspergillus osteomyelitis optimally includes antifungal therapy and selective surgery to avoid relapse and to achieve a complete response.
doi:10.1016/j.jinf.2013.12.008
PMCID: PMC4214682  PMID: 24378282
4.  What Can We Learn and What Do We Need to Know Amidst the Iatrogenic Outbreak of Exserohilum Rostratum Meningitis? 
This commentary focuses on critical challenges in the epidemiology, pathogenesis, host defense, laboratory detection, diagnosis, and treatment of the ongoing tragedy of iatrogenic meningitis caused by Exserohilum rostratum. Advances in understanding of this infection may reduce suffering and save lives.
The tragedy of the ongoing epidemic of meningitis caused by Exserohilum rostratum brings into focus the epidemiology, risk factors, pathogenesis, diagnosis, and treatment of a multitude of opportunistic mold infections of the central nervous system. Herein we provide our perspective regarding the translational research objectives of this infection that are needed to make an impact on this important healthcare crisis.
doi:10.1093/cid/cit283
PMCID: PMC3888152  PMID: 23650291
Exserohilum rostratum; meningoencephalitis; antifungals; risk factors; pathogenesis
5.  The Global Challenge of Carbapenem-Resistant Enterobacteriaceae in Transplant Recipients and Patients With Hematologic Malignancies 
We summarize the current knowledge of the epidemiology of carbapenem-resistant Enterobacteriaceae infections in transplant recipients and patients with hematologic malignancies, and provide recommendations for antimicrobial therapy and strategies to minimize this emerging threat in these vulnerable populations.
Carbapenem-resistant Enterobacteriaceae (CRE) are emerging global pathogens. The spread of CRE to transplant recipients and patients with hematologic malignancies has ominous implications. These patients rely on timely, active antibacterial therapy to combat gram-negative infections; however, recommended empirical regimens are not active against CRE. Approximately 3%–10% of solid organ transplant (SOT) recipients in CRE-endemic areas develop CRE infection, and the infection site correlates with the transplanted organ. Mortality rates associated with CRE infections approach 40% in SOT recipients and 65% in patients with hematologic malignancies. Given that the current antimicrobial armamentarium to combat CRE is extremely limited, a multifaceted approach that includes antimicrobial stewardship and active surveillance is needed to prevent CRE infections in immunocompromised hosts. Improving outcomes of established infections will require the use of risk factor–based prediction tools and molecular assays to more rapidly administer CRE-active therapy and the development of new antimicrobial agents with activity against CRE.
doi:10.1093/cid/ciu052
PMCID: PMC4038783  PMID: 24463280
carbapenem resistance; Enterobacteriaceae; immunocompromised hosts
8.  Changes in the Incidence of Candidiasis in Neonatal Intensive Care Units 
Pediatrics  2014;133(2):236-242.
OBJECTIVE:
Neonatal invasive candidiasis is associated with significant morbidity and mortality. We describe the association between invasive candidiasis and changes in use of antifungal prophylaxis, empirical antifungal therapy, and broad-spectrum antibacterial antibiotics over time.
METHODS:
We examined data from 709 325 infants at 322 NICUs managed by the Pediatrix Medical Group from 1997 to 2010. We determined the cumulative incidence of invasive candidiasis and use of antifungal prophylaxis, broad-spectrum antibacterial antibiotics, and empirical antifungal therapy by year.
RESULTS:
We identified 2063 (0.3%) infants with 2101 episodes of invasive candidiasis. Over the study period, the annual incidence of invasive candidiasis decreased from 3.6 episodes per 1000 patients to 1.4 episodes per 1000 patients among all infants, from 24.2 to 11.6 episodes per 1000 patients among infants with a birth weight of 750–999 g, and from 82.7 to 23.8 episodes per 1000 patients among infants with a birth weight <750 g. Fluconazole prophylaxis use increased among all infants with a birth weight <1000 g (or <1500 g), with the largest effect on birth weights <750 g, increasing from 3.8 per 1000 patients in 1997 to 110.6 per 1000 patients in 2010. The use of broad-spectrum antibacterial antibiotics decreased among all infants from 275.7 per 1000 patients in 1997 to 48.5 per 1000 patients in 2010. The use of empirical antifungal therapy increased over time from 4.0 per 1000 patients in 1997 to 11.5 per 1000 patients in 2010.
CONCLUSIONS:
The incidence of invasive candidiasis in the NICU decreased over the 14-year study period. Increased use of fluconazole prophylaxis and empirical antifungal therapy, along with decreased use of broad-spectrum antibacterial antibiotics, may have contributed to this observation.
doi:10.1542/peds.2013-0671
PMCID: PMC3904270  PMID: 24446441
invasive candidiasis; fluconazole prophylaxis; premature infants
9.  Caspofungin at Catheter Lock Concentrations Eradicates Mature Biofilms of Candida lusitaniae and Candida guilliermondii 
The antibiofilm activities of caspofungin, anidulafungin, micafungin, and liposomal amphotericin B were studied against Candida lusitaniae, Candida guilliermondii, and a Candida albicans control strain. While anidulafungin and micafungin (0.007 to 2,048 mg/liter) showed reduced activity against biofilms of both test species, caspofungin displayed concentration-dependent antibiofilm activity, reaching complete and persistent eradication at concentrations achievable during lock therapy (512 to 2,048 mg/liter, P < 0.05). Although liposomal amphotericin B strongly inhibited mature biofilms, it possessed lower antibiofilm activity than caspofungin (P < 0.05).
doi:10.1128/AAC.03117-14
PMCID: PMC4136003  PMID: 24890585
10.  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
11.  Fungal DNA Detected in Blood Samples of Patients Who Received Contaminated Methylprednisolone Injections Reveals Increased Complexity of Causative Agents 
Journal of Clinical Microbiology  2014;52(6):2212-2215.
Using Exserohilum rostratum-specific and panfungal real-time PCR, we studied 24 blood samples and 2 synovial fluid specimens from 20 patients with persistent or worsening pain following injections of contaminated methylprednisolone. Seven blood specimens from 6 patients were significantly positive for fungal DNA by panfungal PCR, with multiple fungal species identified.
doi:10.1128/JCM.00854-14
PMCID: PMC4042738  PMID: 24719442
12.  Reduction in False-Positive Aspergillus Serum Galactomannan Enzyme Immunoassay Results Associated with Use of Piperacillin-Tazobactam in the United States 
Journal of Clinical Microbiology  2014;52(6):2199-2201.
Piperacillin-tazobactam (PTZ) is known to cause false-positive results in the Platelia Aspergillus enzyme-linked immunoassay (EIA), due to contamination with galactomannan (GM). We tested 32 lots of PTZ and 27 serum specimens from patients receiving PTZ. GM was not detected in the lots of PTZ; one serum specimen (3.7%) was positive. PTZ formulations commonly used in the United States today appear to be a rare cause for false-positive GM results.
doi:10.1128/JCM.00285-14
PMCID: PMC4042793  PMID: 24719434
13.  Host Biomarkers of Invasive Pulmonary Aspergillosis To Monitor Therapeutic Response 
Invasive pulmonary aspergillosis (IPA) is a life-threatening disease of immunocompromised patients that requires aggressive therapy. Detection of the disease and monitoring of the therapeutic response during IPA are complex, and current molecular diagnostics are not suitably robust. Here, we explored proteomic profiles of bronchoalveolar lavage fluid (BALF) specimens from a persistently neutropenic rabbit model of IPA. Three experimental arms, uninfected control animals, infected untreated animals, and animals infected and treated with ravuconazole/amphotericin B, were studied. Total proteins were evaluated by two-dimensional (2D) gel electrophoresis, followed by matrix-assisted laser desorption ionization–time of flight/time of flight (MALDI-TOF/TOF) mass spectrometry (MS) and quantified by enzyme-linked immunosorbent assay (ELISA). Host-derived proteins haptoglobin (Hp), C-reactive protein (CRP), and annexin A1 (Anx A1) were prominently found in BALF during the IPA infection and showed significant changes in response to antifungal therapy (P < 0.0001). In serum, differences in Hp (P = 0.0001) between infected and treated rabbits were observed. Preliminary in vitro studies revealed that Aspergillus fumigatus-secreted proteases may contribute to the cleavage of Anx A1 during IPA. In summary, host protein biomarkers Hp, CRP, and Anx A1 may have value in monitoring therapeutic response to antifungal agents in IPA patients with confirmed disease.
doi:10.1128/AAC.02482-14
PMCID: PMC4068500  PMID: 24687510
15.  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
16.  Infections in Children and Adolescents With Juvenile Idiopathic Arthritis and Inflammatory Bowel Disease Treated With Tumor Necrosis Factor–α Inhibitors: Systematic Review of the Literature 
Tumor necrosis factor alpha (TNF-α) inhibitors can increase the risk of infections. This systematic literature review describes the epidemiology, microbiology, and types of infections reported in children and adolescents with juvenile idiopathic arthritis and inflammatory bowel disease treated with TNF-α inhibitors.
Tumor necrosis factor alpha (TNF-α) inhibitors are increasingly administered to children and adolescents with juvenile idiopathic arthritis (JIA) and pediatric inflammatory bowel disease (pIBD). Adult studies indicate that TNF-α inhibitors lead to an increased risk of serious infections compared to other disease-modifying antirheumatic drugs. We report herein a systematic literature review detailing the epidemiology and types of infections reported in children with JIA and pIBD treated with TNF-α inhibitors. The most frequently reported infections were mild and characterized as viral in etiology. Severe bacterial and fungal infections also occurred, but were less common and possibly associated with intrinsic risk factors and concurrent immunosuppressive therapy. Few pediatric patients developed Mycobacterium tuberculosis, likely due to effective screening. There were 8 infectious fatalities in children treated with TNF-α inhibitors. Overall, although rare, serious infections occur in immunocompromised children and adolescents with JIA and pIBD receiving TNF-α inhibitors.
doi:10.1093/cid/cit489
PMCID: PMC3888230  PMID: 23899685
infliximab; adalimumab; etanercept; juvenile idiopathic arthritis; inflammatory bowel disease
17.  Pediatric Risk Factors for Candidemia Secondary to Candida glabrata and Candida krusei Species 
This 13-year retrospective study investigated risk factors for candidemia secondary to Candida species with increased likelihood of fluconazole resistance. Of 344 candidemia cases, 23 were caused by C glabrata or C krusei (CGCK). Age >2 years, recent fluconazole exposure, and recent surgery were independent risk factors for CGCK.
doi:10.1093/jpids/pis093
PMCID: PMC3761321  PMID: 24009984
Candidemia; fluconazole resistance; pediatrics; risk factors
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.  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
20.  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
21.  Decreased Infection-Related Mortality and Improved Survival in Severe Aplastic Anemia in the Past Two Decades 
Survival in aplastic anemia has markedly improved in recent decades. In multivariate analysis, the introduction of newer antifungal agents and a decrease in fungal infections were independent predictors for survival in the months following immunosuppression among patients with persistent neutropenia.
Background. Persistent neutropenia associated with severe aplastic anemia (SAA) is an important risk factor for development of life-threatening infections. Earlier studies underscored the high mortality associated with invasive fungal infections (IFIs) in SAA. However, little is known about the current patterns of infections and the impact of advances in anti-infective therapy on survival in SAA.
Methods. We reviewed the records of 174 patients with SAA admitted to the Hematology Branch at NHLBI from 1989 to 2008 who were unresponsive to initial immunosuppressive therapy (IST) at 6 months. Three patient groups determined by IST protocol and time interval were compared: group 1 (43 patients; December 1989–October 1996), group 2 (51 patients; November 1996–October 2002), and group 3 (80 patients; November 2002–April 2008). Outcome variables included infections, patterns of resistance, survival, and infection-related mortality.
Results. During the past 2 decades, infection-related mortality decreased from 37% in group 1 to 11% in group 3 (P<.001), and the frequency of IFIs decreased from 49% in group 1 to 8% in group 3 (P<.001). Overall 5-year survival for all patients (n = 420) increased from 64% in group 1 to 79% in group 3 (P<.001). Among non-responders (n = 174), it increased from 23% in group 1 to 57% in group 3 (P<.001). In multivariate analysis, younger age, absolute neutrophil count >200 cells/μL before IST, absence of IFIs, and use of voriconazole were independently predictive of survival.
Conclusion. During the past 2 decades, there has been a significant decrease in IFIs, infection-related mortality, and overall mortality in patients with SAA unresponsive to initial IST.
doi:10.1093/cid/ciq245
PMCID: PMC3106262  PMID: 21367725
22.  Invasive Non-Aspergillus Mold Infections in Transplant Recipients, United States, 2001–2006 
Emerging Infectious Diseases  2011;17(10):1855-1864.
doi:10.3201/eid1710.110087
PMCID: PMC3311117  PMID: 22000355
Mucorales; Fusarium; Scedosporium; mucormycosis; non-Aspergillus; fungi; organ transplant; epidemiology; invasive mold infections; zygomycosis; fusariosis; surveillance; United States; research
23.  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
24.  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
25.  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

Results 1-25 (178)