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1.  Actinomyces in Chronic Granulomatous Disease: An Emerging and Unanticipated Pathogen 
Background
Chronic granulomatous disease (CGD) is a rare inherited disease of the phagocyte NADPH oxidase system that causes defective production of toxic oxygen metabolites, impaired bacterial and fungal killing, and recurrent life-threatening infections, mostly by catalase-producing organisms. We report for the first time, to our knowledge, chronic infections with Actinomyces species in 10 patients with CGD. Actinomycosis is a chronic granulomatous condition that commonly manifests as cervicofacial, pulmonary, or abdominal disease, caused by slowly progressive infection with oral and gastrointestinal commensal Actinomyces species. Treatment of actinomycosis is usually simple in immunocompetent individuals, requiring long-term, high-dose intravenous penicillin, but is more complicated in those with CGD because of delayed diagnosis and an increased risk of chronic invasive or debilitating disease.
Methods
Actinomyces was identified by culture, staining, 16S ribosomal DNA polymerase chain reaction, and/ or a complement fixation test in 10 patients with CGD.
Results
All 10 patients presented with a history of fever and elevated inflammatory signs without evident focus. Diagnosis was delayed and clinical course severe and protracted despite high-dose intravenous antibiotic therapy and/or surgery. These results suggest an unrecognized and unanticipated susceptibility to weakly pathogenic Actinomyces species in patients with CGD because these are catalase-negative organisms previously thought to be nonpathogenic in CGD.
Conclusions
Actinomycosis should be vigorously sought and promptly treated in patients with CGD presenting with uncommon and prolonged clinical signs of infection. Actinomycosis is a catalase-negative infection important to consider in CGD.
doi:10.1086/647945
PMCID: PMC4100544  PMID: 19874205
2.  Invasive Aspergillosis Due to Neosartorya udagawae 
Background
Invasive aspergillosis (IA) is most commonly caused by the morphospecies Aspergillus fumigatus. However, genetic-based methods indicate that organisms phenotypically identified as A. fumigatus actually constitute a mold complex, designated Aspergillus section fumigati subgenus fumigati.
Methods
Multilocus sequencing and analysis was performed on fungi identified as A. fumigatus from the clinical culture collection maintained at the National Institutes of Health from 2000 through 2008, with a focus on the internal transcribed spacer 1 and 2 regions of ribosomal DNA (rDNA), b-tubulin, and rodlet A genes. We reviewed the medical records, radiology, and histopathology of corresponding patients. To confirm identification of Neosartorya udagawae isolates, mating studies were performed with reference strains. Antifungal susceptibility testing was performed by broth microdilution and read at 48 hours.
Results
Thirty-six cases of infection attributed to A. fumigatus were identified; 4 were caused by N. udagawae (3 in patients with chronic granulomatous disease and 1 in a patient with myelodysplastic syndrome). Disease due to N. udagawae was chronic, with a median duration of 35 weeks, compared with a median duration of 5.5 weeks for patients with chronic granulomatous disease who had infection due to A. fumigatus sensu stricto (P < .05, Mann-Whitney U test). Infection spread across anatomical planes in a contiguous manner and was refractory to standard therapy. Two of the 4 patients died. N. udagawae demonstrated relatively higher minimum inhibitory concentrations to various agents, compared with those demonstrated by contemporary A. fumigatus sensu stricto isolates.
Conclusions
To our knowledge, this is the first report documenting infection due to N. udagawae. Clinical manifestations were distinct from those of typical IA. Fumigati-mimetics with inherent potential for antifungal resistance are agents of IA. Genetic identification of molds should be considered for unusual or refractory IA.
doi:10.1086/599345
PMCID: PMC4100555  PMID: 19489714
3.  Survival during Renal Replacement Therapy among African Americans Infected with HIV Type 1 in Urban Baltimore, Maryland 
Background
African Americans with human immunodeficiency virus type 1 (HIV-1) infection and kidney disease are at increased risk of end-stage renal disease requiring renal replacement therapy (RRT), particularly in urban areas with high rates of poverty and injection drug use. It is unknown how the widespread use of highly active antiretroviral therapy (HAART) has affected survival during RRT in this vulnerable population.
Methods
African American patients infected with HIV-1 who required RRT were identified from 2 cohorts that included 4509 Africans Americans infected with HIV-1 who were recruited during the period 1988–2004 in Baltimore, Maryland. Survival after initiation of RRT was compared for those who initiated treatment in the pre-HAART and the HAART eras using Kaplan-Meier curves. Cox proportional hazards regression analysis was used to adjust for potential confounders.
Results
RRT was initiated in 162 patients (3.6%) during 10.6 years of follow-up (119 during the HAART era). Compared with patients who started RRT in the pre-HAART era, those in the HAART era were older (P< .001) and more likely to have CD4 cell counts of ≥200 cells/mm3 (P = .01). A total of 126 patients (78%) died during follow-up; among those who initiated RRT during the HAART era, 87 deaths occurred (73%). Median survival time in the pre-HAART era was 22.4 months (95% confidence interval [CI], 9.3–30.7); during the HAART era, it was 19.9 months (95% CI, 14.7–26.5; P = .94). In the multiple Cox regression model, factors independently associated with increased mortality included age (hazard ratio [HR], 1.30; 95% CI, 1.06–1.60; P = .01), lower serum albumin level (HR, 0.72; 95% CI, 0.57–0.91; P< .007), lower CD4 cell count (HR, 0.90; 95% CI, 0.82–0.99; P< .03), and the lack of HAART (HR, 0.52; 95% CI, 0.33–0.82; P = .005).
Conclusions
Older age, lower serum albumin level, lower CD4 cell count, and the lack of HAART are independent predictors of poor survival among African Americans infected with HIV-1 undergoing RRT in a resource-limited urban area. RRT survival was similar in the pre-HAART and HAART eras, likely reflecting inadequate HIV treatment in this population.
doi:10.1086/523728
PMCID: PMC4096866  PMID: 18190325
4.  HIV Infection Is Associated with an Increased Risk for Lung Cancer, Independent of Smoking 
Background
Human immunodeficiency virus (HIV)–infected persons have an elevated risk for lung cancer, but whether the increase reflects solely their heavy tobacco use remains an open question.
Methods
The Acquired Immunodeficiency Syndrome (AIDS) Link to the Intravenous Experience Study has prospectively observed a cohort of injection drug users in Baltimore, Maryland, since 1988, using biannual collection of clinical, laboratory, and behavioral data. Lung cancer deaths were identified through linkage with the National Death Index. Cox proportional hazards regression was used to examine the effect of HIV infection on lung cancer risk, controlling for smoking status, drug use, and clinical variables.
Results
Among 2086 AIDS Link to the Intravenous Experience Study participants observed for 19,835 person-years, 27 lung cancer deaths were identified; 14 of the deaths were among HIV-infected persons. All but 1 (96%) of the patients with lung cancer were smokers, smoking a mean of 1.2 packs per day. Lung cancer mortality increased during the highly active antiretroviral therapy era, compared with the pre–highly active antiretroviral therapy period (mortality rate ratio, 4.7; 95% confidence interval, 1.7–16). After adjusting for age, sex, smoking status, and calendar period, HIV infection was associated with increased lung cancer risk (hazard ratio, 3.6; 95% confidence interval, 1.6–7.9). Preexisting lung disease, particularly noninfectious diseases and asthma, displayed trends for increased lung cancer risk. Illicit drug use was not associated with increased lung cancer risk. Among HIV-infected persons, smoking remained the major risk factor; CD4 cell count and HIV load were not strongly associated with increased lung cancer risk, and trends for increased risk with use of highly active antiretroviral therapy were not significant.
Conclusions
HIV infection is associated with significantly increased risk for developing lung cancer, independent of smoking status.
doi:10.1086/518606
PMCID: PMC4078722  PMID: 17554710
6.  Occupational Transmission of Acinetobacter baumannii from a United States Serviceman Wounded in Iraq to a Health Care Worker 
Background
Acinetobacter baumannii is increasingly recognized as being a significant pathogen associated with nosocomial outbreaks in both civilian and military treatment facilities. Current analyses of these outbreaks frequently describe patient-to-patient transmission. To date, occupational transmission of A. baumannii from a patient to a health care worker (HCW) has not been reported. We initiated an investigation of an HCW with a complicated case of A. baumannii pneumonia to determine whether a link existed between her illness and A. baumannii–infected patients in a military treatment facility who had been entrusted to her care.
Methods
Pulsed-field gel electrophoresis and polymerase chain reaction/electrospray ionization mass spectrometry, a form of multilocus sequencing typing, were done to determine clonality. To further characterize the isolates, we performed a genetic analysis of resistance determinants.
Results and Conclusions
A “look-back” analysis revealed that the multidrug resistant A. baumannii recovered from the HCW and from a patient in her care were indistinguishable by pulsed-field gel electrophoresis. In addition, polymerase chain reaction/electrospray ionization mass spectrometry indicated that the isolates were similar to strains of A. baumannii derived from European clone type II (Walter Reed Army Medical Center strain type 11). The exposure of the HCW to the index patient lasted for only 30 min and involved endotracheal suctioning without use of an HCW mask. An examination of 90 A. baumannii isolates collected during this investigation showed that 2 major and multiple minor clone types were present and that the isolates from the HCW and from the index patient were the most prevalent clone type. Occupational transmission likely occurred in the hospital; HCWs caring for patients infected with A. baumannii should be aware of this potential mode of infection spread.
doi:10.1086/589247
PMCID: PMC4074882  PMID: 18611162
7.  Hematologic Toxicity Assocated with Interferon-Based Hepatitis C Therapy in HIV Type 1-Coinfected Subjects 
Background
This study investigates whether dose modifications for adverse hematologic effects or the use of hematopoietic growth factors influenced the outcome of therapy for hepatitis C virus (HCV) infection in patients who were coinfected with HCV and human immunodeficiency virus (HIV) and who were participants in a randomized, controlled trial.
Methods
Subjects were randomized to receive ribavirin plus interferon-alfa-2a (IFN-alfa-2a) or pegylated IFN-alfa-2a for a total of 48 weeks. Doses were modified for a number of adverse effects (including hematologic toxicity), and hematopoietic growth factors were administered at the discretion of the physician. Associations of dose modifications or initiation of hematopoietic growth factor support with treatment outcomes were determined by standard statistical methods.
Results
One hundred thirty-three subjects were included in this study. Subjects treated with pegylated IFN-alfa-2a were more likely to have had dose modifications (dose reduction or discontinuation) than were those treated with IFN-alfa-2a. By multivariate analysis, treatment with pegylated IFN-alfa-2a is associated with higher sustained virologic and/or histologic response. Dose modifications for nonhematologic toxicity are independently associated with lower sustained virologic and/or histologic responses. Although hematologic toxicity was not directly associated with clinical outcome in this analysis, use of hematopoietic growth factors was associated with an increased sustained virologic and/or histologic response.
Conclusions
Dose modifications for anti-HCV therapy may adversely affect the outcome of treatment of HCV in individuals who are coinfected with HIV. The use of hematopoietic growth factor support may be associated with an improved clinical response to therapy.
doi:10.1086/515398
PMCID: PMC4075655  PMID: 17443478
8.  Clinical Practice Guidelines for the Diagnosis and Management of Intravascular Catheter-Related Infection: 2009 Update by the Infectious Diseases Society of Americaa 
These updated guidelines replace the previous management guidelines published in 2001. The guidelines are intended for use by health care providers who care for patients who either have these infections or may be at risk for them.
doi:10.1086/599376
PMCID: PMC4039170  PMID: 19489710
9.  Treatment Outcomes among Patients with Extensively Drug-Resistant Tuberculosis: Systematic Review and Meta-Analysis 
Background
The treatment of extensively drug-resistant tuberculosis (XDR TB) presents a major challenge. Second-line antimycobacterial drugs are less effective, more toxic, and more costly than first-line agents, and XDR TB strains are, by definition, resistant to the most potent second-line options: the injectable agents and fluoroquinolones. We conducted a meta-analysis to assess XDR TB treatment outcomes and to identify therapeutic approaches associated with favorable responses.
Methods
We searched PubMed and EMBASE databases to identify studies conducted through May 2009 that report XDR TB treatment outcomes.
Results
The search yielded 13 observational studies covering 560 patients, of whom 43.7% (95% confidence interval, 32.8%–54.5%) experienced favorable outcomes, defined as either cure or treatment completion, and 20.8% (95% confidence interval, 14.2%–27.3%) died. Random effects meta-analysis and meta-regression showed that studies in which a higher proportion of patients received a later-generation fluoroquinolone reported a higher proportion of favorable treatment outcomes (P = .012).
Conclusions
This meta-analysis provides the first empirical evidence that the use of later-generation fluoroquinolones for the treatment of XDR TB significantly improves treatment outcomes, even though drug-susceptibility testing demonstrates resistance to a representative fluoroquinolone. These results suggest that the addition of later-generation fluoroquinolones to XDR TB regimens may improve treatment outcomes and should be systematically evaluated in well-designed clinical studies.
doi:10.1086/653115
PMCID: PMC4013786  PMID: 20504231
10.  Campylobacter Genotyping to Determine the Source of Human Infection 
Background
Campylobacter species cause a high proportion of bacterial gastroenteritis cases and are a significant burden on health care systems and economies worldwide; however, the relative contributions of the various possible sources of infection in humans are unclear.
Methods
National-scale genotyping of Campylobacter species was used to quantify the relative importance of various possible sources of human infection. Multilocus sequence types were determined for 5674 isolates obtained from cases of human campylobacteriosis in Scotland from July 2005 through September 2006 and from 999 Campylobacter species isolates from 3417 contemporaneous samples from potential human infection sources. These data were supplemented with 2420 sequence types from other studies, representing isolates from a variety of sources. The clinical isolates were attributed to possible sources on the basis of their sequence types with use of 2 population genetic models, STRUCTURE and an asymmetric island model.
Results
The STRUCTURE and the asymmetric island models attributed most clinical isolates to chicken meat (58% and 78% of Campylobacter jejuni and 40% and 56% of Campylobacter coli isolates, respectively), identifying it as the principal source of Campylobacter infection in humans. Both models attributed the majority of the remaining isolates to ruminant sources, with relatively few isolates attributed to wild bird, environment, swine, and turkey sources.
Conclusions
National-scale genotyping was a practical and efficient methodology for the quantification of the contributions of different sources to human Campylobacter infection. Combined with the knowledge that retail chicken is routinely contaminated with Campylobacter, these results are consistent with the view that the largest reductions in human campylobacteriosis in industrialized countries will come from interventions that focus on the poultry industry.
doi:10.1086/597402
PMCID: PMC3988352  PMID: 19275496
11.  Achieving a Quantitative Understanding of Antiretroviral Drug Efficacy 
doi:10.1086/656688
PMCID: PMC3963156  PMID: 20925507
antiretroviral therapy; dose-response curve; slope; IIP; inhibitory quotient
12.  Relationship between Inflammatory Markers, Endothelial Activation Markers, and Carotid Intima-Media Thickness in HIV-Infected Patients Receiving Antiretroviral Therapy 
Background
Human immunodeficiency virus (HIV)–infected patients are at increased risk of cardiovascular disease, which may be related to chronic inflammation and endothelial dysfunction despite virological control with antiretroviral therapy. The relationship between carotid intima-media thickness (IMT), a surrogate marker for cardiovascular disease, proinflammatory cytokines, and endothelial activation markers has not been fully explored in HIV-infected patients who are receiving antiretroviral therapy.
Methods
We conducted a prospective, cross-sectional, observational study of treated HIV-infected patients and healthy control subjects to evaluate the relationship between carotid IMT, proinflammatory cytokines, endothelial activation biomarkers, and metabolic parameters in treated HIV-infected patients, compared with healthy control subjects.
Results
We enrolled 73 HIV-infected patients and 21 control subjects. Common carotid artery and internal carotid artery IMT measurements, as well as tumor necrosis factor–α, high-sensitivity C-reactive protein, inter-leukin-6, myeloperoxidase, and soluble vascular cell adhesion molecule-1 levels were higher in the HIV-infected group. High-sensitivity C-reactive protein was the only biomarker that was positively correlated with carotid IMT in both groups. In the HIV-infected group, soluble vascular cell adhesion molecule–1 was positively correlated with all inflammatory cytokine levels. In multiple regression analysis, soluble vascular cell adhesion molecule–1, myeloperoxidase, and tumor necrosis factor–α levels were all associated with internal carotid artery IMT in the HIV-infected group, whereas age was associated with both common carotid artery and internal carotid artery IMT.
Conclusions
Enhanced endothelial activation, inflammation, and increased carotid IMT occur in HIV-infected patients despite antiretroviral therapy. Inflammatory markers are associated with endothelial activation, and both are associated with internal carotid artery IMT, supporting a potential role of inflammation in endothelial activation and cardiovascular disease in HIV infection.
doi:10.1086/605578
PMCID: PMC3895473  PMID: 19712036
13.  Impact of enhanced infection control at two neonatal intensive care units in the Philippines 
Background
The growing burden of neonatal mortality due to hospital acquired neonatal sepsis in the developing world creates an urgent need for low cost effective infection control measures in low resource settings.
Methods
Using a pre/post comparison design, we measured how rates of staff hand hygiene compliance, colonization with resistant pathogens (defined as ceftazidime- and/or gentamicin-resistant gram-negative rods (GNRs) and resistant gram-positive cocci), bacteremia, and overall mortality changed following the introduction of a simplified package of infection control measures at two neonatal intensive care units (NICUs) in Manila, the Philippines.
Results
Of 1828 NICU neonates admitted, 45.6% became newly colonized with resistant bacteria, 19.6% became bacteremic (78.2% from GNRs), and 33.6% died. 2903 resistant colonizing bacteria were identified of which 85% were resistant GNRs (predominantly Klebsiella spp., Pseudomonas spp., and Acinetobacter spp.) and 14% were Methicillin-resistant Staphylococcus aureus. Contrasting control vs. intervention periods at each NICU, staff hand hygiene compliance improved (At NICU 1 RR=1.3, 95% CI 1.1–1.5; At NICU 2 RR=1.6, 95% CI 1.4–2.0) and overall mortality declined (NICU 1 RR=0.5, 95%CI 0.4–0.6; NICU 2 RR=0.8, 95% CI 0.7–0.9). However, colonization with resistant pathogens and sepsis rates did not change significantly at either NICU.
Discussion
Nosocomial transmission of resistant pathogens was intense at these two Philippines NICUs and dominated by resistant GNRs. Infection control interventions are feasible and possibly effective in resource limited hospital settings.
doi:10.1086/594120
PMCID: PMC3866590  PMID: 19025496
Infection Control; Philippines; NICU; Drug Resistance; Hand Hygiene
14.  Hormonal Contraception and HIV Disease Progression 
The majority of the 15.4 million human immunodeficiency virus (HIV)–infected women worldwide are of child-bearing age and need access to contraception. Hormonal methods of contraception are safe, acceptable, and effective in preventing unwanted pregnancies. Many published studies have examined the impact of hormonal contraception on HIV disease acquisition and transmissibility. Far fewer have investigated the relationship between hormonal contraception and HIV disease progression. This review examines available data on this relationship from clinical, animal, and immunological studies. Several clinical studies suggest an overall effect but are not definitive, and the mechanisms behind HIV disease progression are unclear. Animal and immunological data suggest that immunomodulation by hormonal contraceptive methods may affect the immune response to HIV infection. Additional work is needed in this area to elucidate the possible relationship between hormonal methods for birth control and progression to acquired immunodeficiency syndrome in HIV-infected women.
doi:10.1086/591697
PMCID: PMC3865604  PMID: 18715161
15.  Prospective Follow-Up of Patients with Acute Hepatitis C Virus Infection in Brazil 
Background
The natural outcome of infection with hepatitis C virus (HCV) varies substantially among individuals. However, little is known about host and viral factors associated with a self-limiting or chronic evolution of HCV infection.
Methods
From 1 January 2001 through 31 December 2008, a consecutive series of 65 patients from Rio de Janeiro, Brazil, with a well-documented diagnosis of acute HCV infection, acquired via various routes, were enrolled in this study. Patients were prospectively followed up for a median of 40 months after the estimated date of HCV infection with serial measurements of serum alanine aminotransferase, HCV RNA, and anti-HCV antibodies. Spontaneous viral clearance (SVC) was defined as undetectable levels of HCV RNA in serum, in the absence of treatment, for 3 consecutive HCV polymerase chain reaction tests within the first 6 months of follow-up. Cox proportional hazards regression was used to identify host and viral predictors of SVC.
Results
The cumulative rate of SVC was 44.6% (95% confidence interval, 32.3%–57.5%). Compared with chronic HCV evolution, patients with self-limiting disease had significantly lower peak levels of anti-HCV antibodies (median, 109.0 vs 86.7 optical density–to–cutoff ratio [od/co]; P < .02), experienced disease symptoms more frequently (69.4% vs 100%; P < .001), and had lower viral load at first clinical presentation (median, 4.3 vs 0.0 log copies; P =.01). In multivariate analyses, low peak anti-HCV level (<93.5 od/co) was the only independent predictor for SVC; the hazard ratio compared with high anti-HCV levels (≥93.5 od/co) was 2.62 (95% confidence interval, 1.11–6.19; P =.03).
Conclusion
Our data suggest that low levels of anti-HCV antibodies during the acute phase of HCV infection are independently related to spontaneous viral clearance.
doi:10.1086/651599
PMCID: PMC3860186  PMID: 20235831
16.  Early Repeated Infections with Trichomonas vaginalis among HIV-Positive and HIV-Negative Women 
Background
The purpose of the study was to examine whether early repeated infections due to Trichomonas vaginalis among human immunuodeficiency virus (HIV)–positive and HIV-negative women are reinfections, new infections, or cases of treatment failure.
Methods
Women attending an HIV outpatient clinic and a family planning clinic in New Orleans, Louisiana, who had culture results positive for T. vaginalis were treated with 2 g of metronidazole under directly observed therapy. At 1 month, detailed sexual exposure and sexual partner treatment information was collected. Isolates from women who had clinical resistance (i.e., who tested positive for a third time after treatment at a higher dose) were tested for metronidazole susceptibility in vitro.
Results
Of 60 HIV-positive women with trichomoniasis, 11 (18.3%) were T. vaginalis positive 1 month after treatment. The 11 recurrences were classified as 3 probable reinfections (27%), 2 probable infections from a new sexual partner (18%), and 6 probable treatment failures (55%); 2 of the 6 patients who experienced probable treatment failure had isolates with mild resistance to metronidazole. Of 301 HIV-negative women, 24 (8.0%) were T. vaginalis positive 1 month after treatment. The 24 recurrences were classified as 2 probable reinfections (8%) and 22 probable treatment failures (92%); of the 22 patients who experienced probable treatment failure, 2 had strains with moderate resistance to metronidazole, and 1 had a strain with mild resistance to metronidazole.
Conclusion
HIV-positive women were more likely to have sexual re-exposure than were HIV-negative women, although the rate of treatment failure was similar in both groups. High rates of treatment failure among both HIV-positive and HIV-negative women indicate that a 2-g dose of metronidazole may not be adequate for treatment of some women and that rescreening should be considered.
doi:10.1086/529149
PMCID: PMC3855851  PMID: 18444815
17.  Rates of tuberculosis transmission to children and adolescents in a community with high adult HIV prevalence 
doi:10.1086/589750
PMCID: PMC3816246  PMID: 18558885
tuberculin skin test; HIV; TB transmission; children; annual risk of TB infection
19.  Tuberculosis Transmission From Patients With Smear-Negative Pulmonary Tuberculosis in Sub-Saharan Africa 
doi:10.1086/596550
PMCID: PMC3801094  PMID: 19586380
HIV; antiretroviral; tuberculosis; smear-negative; transmission; nosocomial
20.  Costs of Healthcare- and Community-Associated Infections With Antimicrobial-Resistant Versus Antimicrobial-Susceptible Organisms 
Antimicrobial resistance was associated with higher charges, length of stay, and death rates. The difference in estimates after accounting for death highlight divergent social and hospital incentives in reducing patient risk for antimicrobial-resistant infections.
Objective. We compared differences in the hospital charges, length of hospital stay, and mortality between patients with healthcare- and community-associated bloodstream infections, urinary tract infections, and pneumonia due to antimicrobial-resistant versus -susceptible bacterial strains.
Methods. A retrospective analysis of an electronic database compiled from laboratory, pharmacy, surgery, financial, and patient location and device utilization sources was undertaken on 5699 inpatients who developed healthcare- or community-associated infections between 2006 and 2008 from 4 hospitals (1 community, 1 pediatric, 2 tertiary/quaternary care) in Manhattan. The main outcome measures were hospital charges, length of stay, and mortality among patients with antimicrobial-resistant and -susceptible infections caused by Staphylococcus aureus, Enterococcus faecium, Enterococcus faecalis, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii.
Results. Controlling for multiple confounders using linear regression and nearest neighbor matching based on propensity score estimates, resistant healthcare- and community-associated infections, when compared with susceptible strains of the same organism, were associated with significantly higher charges ($15 626; confidence interval [CI], $4339–$26 913 and $25 573; CI, $9331–$41 816, respectively) and longer hospital stays for community-associated infections (3.3; CI, 1.5–5.4). Patients with resistant healthcare-associated infections also had a significantly higher death rate (0.04; CI, 0.01–0.08).
Conclusions. With careful matching of patients infected with the same organism, antimicrobial resistance was associated with higher charges, length of stay, and death rates. The difference in estimates after accounting for censoring for death highlight divergent social and hospital incentives in reducing patient risk for antimicrobial resistant infections.
doi:10.1093/cid/cis552
PMCID: PMC3491852  PMID: 22700828
21.  Risk Factors and Outcomes of Fungal Ventricular-Assist Device Infections 
Background
Infection is a common complication of ventricular-assist devices (VADs) and is associated with re-hospitalization, thromboembolic events, VAD malfunction, delay in heart transplantation, and a high mortality rate. The objectives of this study were to investigate the frequency of fungal VAD infections and assess various risk factors and their effects on mortality as compared to bacterial VAD infections.
Methods
We conducted a retrospective chart review of patients with infected VADs at a single tertiary care center. The frequency, risk factors and outcomes of fungal vs. bacterial VAD infections were compared.
Results
Of the 300 patients who received a VAD, 108 (36%) developed VAD infection, including 85 bacterial and 23 fungal infections. Most common bacterial causes of infection were Staphylococcus aureus, coagulase-negative staphylococci, enterococci and Pseudomonas aeuruginosa. Most common fungal etiologic agent was Candida albicans. Only the use of TPN was associated with the development of a fungal VAD infection in multivariate analysis (OR 6.95, 95% CI 1.71–28.16, p=0.007). Patients who suffered from fungal VAD infection were less likely to be cured (17.4% vs. 56.3%, p=0.001) and had greater mortality (91% vs. 61%, p=0.006), as compared with those who experienced bacterial VAD infections.
Conclusions
Fungi were responsible for approximately one-fifth of VAD infections and were associated with a mortality rate of 91%. Restriction of TPN use is essential in decreasing the rate of fungal VAD infection. Trials are needed for investigating the use of echinocandins or lipid formulations of amphotericin B for prevention and/or treatment of fungal VAD infections.
doi:10.1086/650454
PMCID: PMC3767975  PMID: 20113174
ventricular-assist device; cardiac device; prosthesis infection
22.  Right Buttock Rash for Thirty Years in a Patient from China 
doi:10.1086/600388
PMCID: PMC3763022  PMID: 19586395
Chromoblastomycosis; Rash; Mycoses; Dematiaceae
23.  A Nosocomial Norovirus Outbreak Masquerading as Clostridium Difficile Disease 
Noroviruses (NoVs) are increasingly being recognized as an important enteric pathogen. We investigated a nosocomial NoV outbreak at a university-based hospital that was originally attributed to Clostridium difficile infection (CDI). We describe the unique challenges and the important lessons learned in the identification of noroviruses as the true etiologic pathogen in an outbreak healthcare setting, where CDI is endemic.
doi:10.1086/597299
PMCID: PMC3761966  PMID: 19245344
norovirus; Clostridium difficile; nosocomial diarrhea
24.  Isoniazid, Rifampin, Ethambutol and Pyrazinamide Pharmacokinetics and Treatment Outcomes among a Predominantly HIV-Infected Cohort of Adults with Tuberculosis — Botswana 
Background
We explored the association between anti-tuberculosis drug pharmacokinetics and treatment outcomes among pulmonary tuberculosis (TB) patients in Botswana.
Methods
Consenting TB outpatients had blood collected 1, 2, and 6 hours after simultaneous isoniazid, rifampin, ethambutol, and pyrazinamide ingestion. Maximum serum concentrations (Cmax) and areas under the serum concentration-time curve (AUC0-6 h) were determined. Clinical status was monitored throughout treatment.
Results
Of 225 participants, 36 (16%) experienced a poor treatment outcome (treatment failure or death); 155 (69%) were HIV-infected. Compared with published standards, low isoniazid Cmax occurred in 84 (37%); rifampin in 188 (84%); ethambutol in 87 (39%); and pyrazinamide in 11 (5%) patients. Median rifampin and pyrazinamide levels differed significantly by HIV status and CD4 cell count (HIV-CD4) categories. Only pyrazinamide pharmacokinetics were significantly associated with treatment outcome; low pyrazinamide Cmax was associated with a higher risk of documented poor treatment outcome than normal Cmax (50% vs. 16%; p<0.01). HIV-infected patients with CD4 <200 cells/μL had higher risk of poor treatment outcome (27%) than HIV-uninfected patients (11%) or HIV-infected patients with CD4 ≥ 200 cells/μL (12%); p=0.01. Adjusting for HIV infection and CD4, patients with low pyrazinamide Cmax were thrice more likely to have poor outcomes than patients with normal pyrazinamide Cmax [adjusted risk ratio = 3.38, 95% confidence interval (1.84 – 6.22)].
Conclusions
Lower-than-expected anti-tuberculosis drug Cmax occurred frequently and low pyrazinamide Cmax was associated with poor treatment outcome. Exploring the global prevalence and significance of these findings may suggest modifications in treatment regimens that could improve TB cure rates.
doi:10.1086/599040
PMCID: PMC3762461  PMID: 19432554
tuberculosis; HIV/AIDS; pharmacokinetics; treatment outcome
25.  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

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