PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-25 (172)
 

Clipboard (0)
None

Select a Filter Below

Journals
more »
Year of Publication
more »
1.  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
2.  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
3.  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
4.  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
5.  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
6.  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
7.  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
8.  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
9.  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
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.  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
12.  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
13.  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
14.  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
15.  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
16.  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
17.  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
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.  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
22.  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
23.  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
24.  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
25.  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

Results 1-25 (172)