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Background: Clostridium difficile infection is increasing in incidence and severity. The optimal treatment is unknown. Purpose: To determine whether, among adults with C. difficile infection, treatment with certain antibiotics compared with others results in differences in initial cure, recurrence, and harms. Data Sources: MEDLINE, AMED, ClinicalTrials.gov, and Cochrane databases (search dates: inception through August 2011, limited to English-language reports); bibliography review. Study Selection: Randomized, controlled trials of adults with C. difficile infection, independent of outcomes, who were treated with medications available in the United States. Observational studies reporting strain were included. Data Extraction: Study design, inclusion and exclusion criteria, quality and strength of evidence as assessed by 2 reviewers, study definitions, and duration of treatment and follow-up. Outcomes included initial cure, recurrence, and treatment harms. Data Synthesis: 11 trials that included 1463 participants were identified. Three trials compared metronidazole with vancomycin; 8 compared metronidazole or vancomycin with another agent, combined agents, or placebo. Strain was analyzed in 1 trial and 2 cohort studies. No study comparing 2 antimicrobial agents demonstrated a statistically significant difference for initial cure; all comparisons were of low to moderate strength of evidence. Moderate-strength evidence from 1 study demonstrated that recurrence was decreased with fidaxomicin versus vancomycin (15% vs. 25%; difference, -10 percentage points [95% CI, -17 to -3 percentage points]; P = 0.005). Subgroup analysis of a single study comparing metronidazole with vancomycin for patients who have severe C. difficile infection showed no difference by intention-to-treat analysis; this was rated as insufficient-strength evidence. Harms, when reported, did not differ between treatments in any study. Limitations: Definitions of diarrhea, C. difficile infection, initial cure, and relapse varied. Some studies reported insufficient detail to allow assessment of all randomly assigned participants or of harms. Conclusion: No antimicrobial agent is clearly superior for the initial cure of C. difficile infection. Recurrence is less frequent with fidaxomicin than with vancomycin. Primary Funding Source: U.S. Department of Health and Human Services. [ABSTRACT FROM AUTHOR]

To describe resources clinicians use when they prescribe antimicrobials, the authors surveyed prescribers by telephone within hours (median 2.9) after they ordered one or more antimicrobials for a patient. Among 157 prescribers, 87 (55%) used one or more external resources to aid in decisions about their order. The other 70 (45%) used only their own knowledge and experience. Fifty-nine (38%) consulted another person. Fifty-four (34%) used a print, computer, or Internet resource. In multivariate analysis, use of an external resource was associated with the clinician being on the medical service (odds ratio [OR] 2.99, 95% confidence interval [CI] 1.41-6.3) or being an intern (OR 13.65, 95% CI 1.44-128). Eighty percent of providers said information about antimicrobial prescribing at the point of electronic order entry would be helpful. It was concluded that decision support at the point of electronic order entry is likely to be used and might improve antimicrobial prescribing. [ABSTRACT FROM AUTHOR]

Secondary infectious diseases contribute substantially to morbidity and mortality of people infected with human immunodeficiency virus (HIV). The authors developed comprehensive, practical recommendations for prevention of infectious complications in HIV-infected people. Recommendations are concerned with the pathogens that are more common or more severe in HIV-infected people. Several infectious complications can be prevented by avoiding ingestion of contaminated food or water. Zoonoses can be prevented by precautions to be taken in contacts with animals. The risk of several fungal diseases can be reduced if activities likely to lead to inhalation of spores are avoided. HIV-infected people should be advised how to lower adverse health effects of travel, especially international travel. The potential for infectious complications of sexual activity and illicit drug use should be stressed, and recommendations to reduce the risk are discussed. Recommendations for use of vaccines in HIV-infected people are reviewed. Blood CD4+ lymphocyte concentrations, tuberculin skin testing, Toxoplasma serology, and sexually transmitted disease screening should be performed in certain subsets of HIV-infected people. Guidelines for chemoprophylaxis against Pneumocystis carinii and tuberculosis are presented. Recent data suggest that intravenous immunoglobulin therapy may prevent bacterial infections in HIV-infected children. [ABSTRACT FROM AUTHOR]

Abstract Background The risk of hepatotoxicity associated with different highly active antiretroviral therapy (HAART) regimens (containing multiple-protease inhibitors, single-protease inhibitors or non nucleoside reverse transcriptase inhibitors) in HIV-HCV co-infected patients has not been fully assessed. Methods Retrospective analysis of a prospective cohort of 1,038 HIV-HCV co-infected patients who commenced a new HAART in the Italian MASTER database. Patients were stratified into naïve and experienced to antiretroviral therapy before starting the study regimens. Time to grade ≥III hepatotoxicity (as by ACTG classification) was the primary outcome. Secondary outcome was time to grade IV hepatotoxicity. Results Incidence of grade ≥III hepatotoxicity was 17.71 per 100 patient-years (p-yr) of follow up in naïve patient group and 8.22 per 100 p-yrs in experienced group (grade IV: 4.13 per 100 p-yrs and 1.08 per 100 p-yrs, respectively). In the latter group, the only independent factors associated with shorter time to the event at proportional hazards regression model were: previous liver transaminase elevations to grade ≥III, higher baseline alanine amino-transferase values, and use of a non nucleoside reverse transcriptase inhibitor based regimen. In the naive group, baseline aspartate transaminase level was associated with the primary outcome. Conclusion Use of a single or multiple protease inhibitor based regimen was not associated with risk of hepatotoxicity in either naïve or experienced patient groups to a statistically significant extent. A cautious approach with strict monitoring should be applied in HIV-HCV co-infected experienced patients with previous liver transaminase elevations, higher baseline alanine amino-transferase values and who receive regimens containing non nucleoside reverse transcriptase inhibitors.

Abstract Background The standard of care for HCV Hepatitis is the combination of interferon (IFN) plus Ribavirin. In HIV patients the use of this combination therapy may induce drug interactions, and reduces the adherence to HAART. The aim of this study is to evaluate safety and efficacy of a 48 weeks daily dose IFN schedule. Methods We evaluated 50 coinfected patients; alpha IFN 2a was administered at a dose of 3 MU daily. The baseline values were the following : CD4+ 515 cells/mmc (mean); HIV-RNA Results At 48 weeks, 10 patients (20%) achieved a biochemical and virological response according to an intention to treat analysis. Twenty four patients (48%) underwent a drop-out mainly by side effects related to overlapping toxicity of interferon and antiretroviral therapy. All the patients, who responded to the treatment, showed a fast relapse one month after the end of treatment. Conclusion Although our results demonstrated a very poor outcome and a bad tolerance to interferon monotherapy, this approach should not be dropped out, mainly in patients at high risk for side effects and in those with cirrhosis who do not tolerate or are at increased risk for the use of ribavirin.

Background: Few studies exist to guide the management of patients with stage 4 pressure ulcers with possible underlying osteomyelitis. We hypothesized that infectious disease (ID) physicians would vary widely in their approach to such patients., Methods: The Emerging Infections Network distributed a 10-question electronic survey in 2018 to 1332 adult ID physicians in different practice settings to determine their approach to such patients., Results: Of the 558 respondents (response rate: 42%), 17% had managed no such patient in the past year. Of the remaining 464 respondents, 60% usually felt confident in diagnosing osteomyelitis; the strongest clinical indicator of osteomyelitis reported was palpable or visible bone at the ulcer base. Approaches to diagnosing osteomyelitis in patients with visible and palpable bone varied: 41% of respondents would assume osteomyelitis, 27% would attempt pressure off-loading first, and 22% would perform diagnostic testing immediately. Preferred tests for osteomyelitis were bone biopsy (for culture and histopathology) and magnetic resonance imaging. Respondents differed widely on favored route(s) (intravenous, oral, or both) and duration of antimicrobial therapy but would treat longer in the absence, vs presence, of full surgical debridement ( P < .001). Overall, 62% of respondents opined that osteomyelitis under stage 4 pressure ulcers is usually or almost always treated excessively, and most (59%) suggested multiple topics for future research., Conclusions: Regarding osteomyelitis underlying stage 4 pressure ulcers, ID physicians reported widely divergent diagnostic and treatment approaches. Most of the reported practice is not supported by the available evidence, which is quite limited and of low quality., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2019.)

Infections with Staphylococcus aureus may be more frequent in subjects with active hepatitis C virus (HCV) infection. In this retrospective dual-cohort study, we sought to determine whether persons with active HCV infection (positive HCV antibody, detectable blood HCV RNA) were at greater risk of S. aureus infection than those with spontaneously resolved HCV infection (positive HCV antibody, negative blood HCV RNA). Based on prestudy power calculation, we included 231 subjects with active HCV and 116 subjects with resolved HCV infection. The two groups were well matched at baseline, except that subjects with active HCV had a higher mean Charlson's comorbidity index (2.2 vs. 1.3; p < 0.0001). Cohorts were followed for a mean of 3.67 years. Thirty-one of the 231 (13%) subjects with active HCV infection developed ≥1 S. aureus infection(s) as compared to 4/116 (3.4%) subjects with resolved HCV (p = 0.004), with a trend towards more recurrent S. aureus infections in subjects with active HCV infection. The S. aureus infections were mostly serious, necessitating hospitalization and intravenous antibiotics. In the logistic regression, factors that independently predicted S. aureus infection were active HCV and Charlson's comorbidity index. Our regression models confirmed that the enhanced susceptibility to S. aureus infections was related to active HCV infection and not attributable solely to the increased number of comorbidities [adjusted odds ratio (OR) = 3.3, 95% confidence interval (CI) 1.1-9.8; p = 0.03]. This study shows that subjects with active HCV infection have a significantly higher incidence of serious S. aureus infections than those with spontaneously resolved HCV, even after adjustment for comorbidities.

Background: Echocardiography is fundamental for diagnosing infective endocarditis (IE) in patients with Staphylococcus aureus bacteremia (SAB), but whether all such patients require transesophageal echocardiography (TEE) is controversial., Methods: We identified SAB cases between February 2008 and April 2012. We compared sensitivity and specificity of transthoracic echocardiography (TTE) and TEE for evidence of IE, and we determined impacts of IE risk factors and TTE image quality on comparative sensitivities of TTE and TEE and their impact on clinical decision making., Results: Of 215 evaluable SAB cases, 193 (90%) had TTE and 130 (60%) had TEE. In 119 cases with both tests, IE was diagnosed in 29 (24%), for whom endocardial involvement was evident in 25 (86%) by TEE, vs only 6 (21%) by TTE ( P < .001). Transesophageal echocardiography was more sensitive than TTE regardless of risk factors. Even among the 66 cases with adequate or better quality TTE images, sensitivity was only 4 of 17 (24%) for TTE, vs 16 of 17 (94%) for TEE ( P < .001). Among 130 patients with TEE, the TEE results, alone or with TTE results, influenced treatment duration in 56 (43%) cases and led to valve surgery in at least 4 (6%). It is notable that, despite vigorous efforts to obtain both tests routinely, TEE was not done in 86 cases (40%) for various reasons, including pathophysiological contraindications (14%), patient refusal or other patient-related factors (16%), and provider declination or system issues (10%)., Conclusions: Patients with SAB should undergo TEE when possible to detect evidence for IE, especially if the results might affect management., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2017. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Background: High-dose, inactivated, trivalent influenza vaccine (HD) is associated with higher rates of side effects than standard dose (SD) vaccine, which may represent a barrier to use., Methods: We surveyed subjects ≥65 years who received either HD or SD vaccine at the Minneapolis Veteran Affairs Health Care System clinics on October 27, 28, or 29, 2015. Research assistants conducted a 17-item telephone survey of influenza vaccine recipients to inquire about self-reported health and symptoms experienced the week after vaccination., Results: A total of 547 HD recipients and 541 SD recipients responded to the survey. The 2 groups were similar at baseline with respect to age, gender, and presence of high-risk medical conditions. At least ≥95% of individuals in both HD and SD groups reported that their overall health was the same or better than usual during the week after vaccination. Thirty-seven percent of HD recipients and 22% of SD recipients reported a local or systemic side effect ( P < .001), most of which were mild to moderate. Only 7 of 547 (1.3%) HD recipients and 3 of 541 (0.6%) SD recipients reported a severe side effect ( P = .34). There was no significant difference in healthcare visits between the groups., Conclusions: Side effects were more common among subjects ≥65 years who received HD influenza vaccine compared with SD vaccine. These side effects were well tolerated and were not associated with impairment of general health status. These findings should reassure patients and their providers of the safety and tolerability of the HD influenza vaccine., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2017. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Strong working relationships between infectious disease (ID) physicians and public health have resulted in the early detection of emerging infectious threats. From May 6 through June 5, 2015, we surveyed ID physicians in the Infectious Diseases Society of America's Emerging Infections Network about communications with public health. A total of 688 of 1491 (46%) members completed the survey, 624 (91%) of whom knew how to reach their health department directly for an urgent issue. Only 38 (6%) described communications with their health department as poor. Interest in newer technologies (eg, mobile smartphone applications) showed mixed results. Interest in a smartphone application differed significantly by years of ID experience, with 81 of 146 (55%) respondents with <5 years of ID experience, 172 of 359 (48%) respondents with 5 to 24 years of ID experience, and 61 of 183 (33%) respondents with ≥25 years of ID experience in favor of a smartphone application ( P < .001). As more physicians adopt newer communication technologies, health departments should be prepared to incorporate these tools to communicate with ID physicians., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: We found previously that inappropriate inpatient antimicrobial use was often attributable to erroneous diagnoses. Here, we detail diagnostic errors and their relationship to inappropriate antimicrobial courses., Design: Retrospective cohort study., Setting: Veterans Affairs hospital., Patients: A cohort of 500 randomly selected inpatients with an antimicrobial course., Methods: Blinded reviewers judged the accuracy of the initial provider diagnosis for the condition that led to an antimicrobial course and whether the course was appropriate. RESULTS The diagnoses were correct in 291 cases (58%), incorrect in 156 cases (31%), and of indeterminate accuracy in 22 cases (4%). In the remaining 31 cases (6%), the diagnosis was a sign or symptom rather than a syndrome or disease. The odds ratio of a correct diagnosis was 4.3 (95% confidence interval [CI], 2.2-8.5) if the index condition was related to the reason for admission. When the diagnosis was correct, 181 of 292 courses (62%) were appropriate, compared with only 10 of 208 (5%) when the diagnosis was incorrect or indeterminate or when providers were treating a sign or symptom rather than a syndrome or disease (P<.001). Among the 309 cases in which antimicrobial courses were not appropriate, reasons varied by diagnostic accuracy; in 81 of 111 cases (73%) with a correct diagnosis, incorrect antimicrobial(s) were selected; in 166 of 198 other cases (84%), antimicrobial therapy was not indicated., Conclusions: Diagnostic accuracy is important for optimal inpatient antimicrobial use. Antimicrobial stewardship strategies should help providers avoid diagnostic errors and know when antimicrobial therapy can be withheld safely.

Objective: Evaluate the effect of outpatient antimicrobial stewardship programs on prescribing, patient, microbial outcomes, and costs., Design: Systematic review, Methods: Search of MEDLINE (2000 through November 2013), Cochrane Library, and reference lists of relevant studies. We included English language studies with patient populations relevant to the United States (eg, infectious conditions, prescription services) evaluating stewardship programs in outpatient settings and reporting outcomes of interest. Data regarding study characteristics and outcomes were extracted and organized by intervention type., Results: We identified 50 studies eligible for inclusion, with most (29 of 50; 58%) reporting on respiratory tract infections, followed by multiple/unspecified infections (17 of 50; 34%). We found medium-strength evidence that stewardship programs incorporating communication skills training and laboratory testing are associated with reductions in antimicrobial use, and low-strength evidence that other stewardship interventions are associated with improved prescribing. Patient-centered outcomes, which were infrequently reported, were not adversely affected. Medication costs were generally lower with stewardship interventions, but overall program costs were rarely reported. No studies reported microbial outcomes, and data regarding outpatient settings other than primary care clinics are limited., Conclusions: Low- to moderate-strength evidence suggests that antimicrobial stewardship programs in outpatient settings improve antimicrobial prescribing without adversely effecting patient outcomes. Effectiveness depends on program type. Most studies were not designed to measure patient or resistance outcomes. Data regarding sustainability and scalability of interventions are limited.

Objective: Evaluate the evidence for effects of inpatient antimicrobial stewardship programs (ASPs) on patient, prescribing, and microbial outcomes., Design: Systematic review., Methods: Search of MEDLINE (2000 through November 2013), Cochrane Library, and reference lists of relevant studies. We included English language studies with patient populations relevant to the United States (ie, infectious conditions and prescriptions required for antimicrobials) that evaluated ASP interventions and reported outcomes of interest. Study characteristics and outcomes data were extracted and reviewed by investigators and trained research personnel., Results: Few intervention types (eg, audit and feedback, guideline implementation, and decision support) substantially impacted patient outcomes, including mortality, length of stay, readmission, or incidence of Clostridium difficile infection. However, most interventions were not powered adequately to demonstrate impacts on patient outcomes. Most interventions were associated with improved prescribing patterns as measured by decreased antimicrobial use or increased appropriate use. Where reported, ASPs were generally associated with improvements in microbial outcomes, including institutional resistance patterns or resistance in the study population. Few data were provided on harms, sustainability, or key intervention components. Studies were typically of short duration, low in methodological quality, and varied in study design, populations enrolled, hospital setting, ASP intent, intervention composition and implementation, comparison group, and outcomes assessed., Conclusions: Numerous studies suggest that ASPs can improve prescribing and microbial outcomes. Strength of evidence was low, and most studies were not designed adequately to detect improvements in mortality or other patient outcomes, but obvious adverse effects on patient outcomes were not reported.

Objective:  To determine whether antimicrobial (AM) courses ordered with an antimicrobial computer decision support system (CDSS) were more likely to be appropriate than courses ordered without the CDSS., Design:  Retrospective cohort study. Blinded expert reviewers judged whether AM courses were appropriate, considering drug selection, route, dose, and duration., Setting:  A 279-bed university-affiliated Department of Veterans Affairs (VA) hospital., Patients:  A 500-patient random sample of inpatients who received a therapeutic AM course between October 2007 and September 2008. Intervention. An optional CDSS, available at the point of order entry in the VA computerized patient record system., Results: CDSS courses were significantly more likely to be appropriate (111/254, 44%) compared with non-CDSS courses (81/246, 33%, P = .013). Courses were more likely to be appropriate when the initial provider diagnosis of the condition being treated was correct (168/273, 62%) than when it was incorrect, uncertain, or a sign or symptom rather than a disease (24/227, 11%, P < .001. In multivariable analysis, CDSS-ordered courses were more likely to be appropriate than non-CDSS-ordered courses (odds ratio [OR], 1.83; 95% confidence interval [CI], 1.13-2.98). Courses were also more likely to be judged appropriate when the initial provider diagnosis of the condition being treated was correct than when it was incorrect, uncertain, or a sign or symptom rather than a disease (OR, 3.56; 95% CI, 1.4-9.0)., Conclusions:  Use of the CDSS was associated with more appropriate AM use. To achieve greater improvements, strategies are needed to improve provider diagnoses of syndromes that are infectious or possibly infectious.

BACKGROUND: Staphylococcus aureus bacteremia (SAB) is a common, severe infectious disease with accepted standards of care. METHODS: A retrospective cohort study of all 233 SAB cases at the Minneapolis Veterans Affairs Medical Center (MVAMC) between October 2004 and February 2008 was performed to measure the impact of Infectious Disease (ID) consultation on conformance to standards and patient outcomes. Outcomes were classified as survived without relapse, relapsed, or died without relapse. ID involvement was classified as consultation, curbside, or no involvement. RESULTS: ID involvement occurred in 179/233 cases (77%). Management conformed to accepted standards in 162/197 cases (82%) evaluable for conformance. ID involvement was associated with increased conformance in univariable analysis and multivariable analysis adjusted for propensity for ID consultation (OR 5.9, 95% CI 2.5 - 13.8). Relapse occurred in 14/156 cases (9%) in which therapy conformed to standards compared with 8/35 cases (23%) in which therapy did not conform to standards (p=0.045). Relapse was more common in older patients (OR 1.05, CI 1.01-1.09) and in cases without ID involvement (OR 3.02, CI 1.003-9.1). Death was associated with greater Charlson Index scores (OR 1.89, CI 1.4-2.5). Of 111 cases with definitely or possibly infected devices, relapse occurred in 9/92 cases (9.8%) in which the device was wholly or partially removed compared with 6/19 cases (32%) in which the device was left in place (p=0.02). CONCLUSIONS: ID involvement in SAB cases was associated with increased adherence to accepted standards and fewer relapses. ID consultation should be performed for all SAB cases.

Background: The objective of this study is to determine the costs per hospital admission of screening intensive care unit patients for methicillin-resistant Staphylococcus aureus (MRSA) and isolating those who are colonized., Methods: Data on the costs of the intervention come from the Minneapolis Veterans Affairs Medical Center, a 279-bed teaching hospital and outpatient facility. A microcosting approach is used to determine the intervention costs for 3 different laboratory testing protocols. The costs of caring for MRSA-infected patients come from the experience of 241 Minneapolis Veterans Affairs Medical Center patients with MRSA infections in 2004 through 2006. The effectiveness of the intervention comes from the extant literature. To capture the effect of screening on reducing transmission of MRSA to other patients and its effect on costs, a Markov simulation model was employed., Results: The intervention was cost saving compared with no intervention for all 3 laboratory processes evaluated and for all of the 1-way sensitivity analyses considered., Conclusion: Because of the high cost of caring for a MRSA patient, interventions that reduce the spread of infections-such as screening intensive care unit patients upon admission studied here-are likely to pay for themselves., (Copyright © 2011 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Mosby, Inc. All rights reserved.)

Objective: To determine differences in healthcare costs between cases of methicillin-susceptible Staphylococcus aureus (MSSA) infection and methicillin-resistant S. aureus (MRSA) infection in adults., Design: Retrospective study of all cases of S. aureus infection., Setting: Department of Veterans Affairs hospital and associated clinics., Patients: There were 390 patients with MSSA infections and 335 patients with MRSA infections., Methods: We used medical records, accounting systems, and interviews to identify services rendered and costs for Minneapolis Veterans Affairs Medical Center patients with S. aureus infection with onset during the period from January 1, 2004, through June 30, 2006. We used regression analysis to adjust for patient characteristics., Results: Median 6-month unadjusted costs for patients infected with MRSA were $34,657, compared with $15,923 for patients infected with MSSA. Patients with MRSA infection had more comorbidities than patients with MSSA infection (mean Charlson index 4.3 vs 3.2; P < .001). For patients with Charlson indices of 3 or less, mean adjusted 6-month costs derived from multivariate analysis were $51,252 (95% CI, $46,041-$56,464) for MRSA infection and $30,158 (95% CI, $27,092-$33,225) for MSSA infection. For patients with Charlson indices of 4 or more, mean adjusted costs were $84,436 (95% CI, $79,843-$89,029) for MRSA infection and $59,245 (95% CI, $56,016-$62,473) for MSSA infection. Patients with MRSA infection were also more likely to die than were patients with MSSA infection (23.6% vs 11.5%; P < .001). MRSA infection was more likely to involve the lungs, bloodstream, and urinary tract, while MSSA infection was more likely to involve bones or joints; eyes, ears, nose, or throat; surgical sites; and skin or soft tissue (P < .001)., Conclusions: Resistance to methicillin in S. aureus was independently associated with increased costs. Effective antimicrobial stewardship and infection prevention programs are needed to prevent these costly infections.

Background: Effective communication is vital for optimal medical consultation, but there is little current information about physician preferences for effective consultation., Methods: We invited physicians with at least one post-graduate year of experience at four Minnesota teaching hospitals to complete a 16-question Internet questionnaire about inpatient consultations., Results: E-mail requests were received by an estimated 651 physicians. Questionnaires were completed by 323 (50%). Of these, 54% had completed training >5 years before, 17% had completed training <5 years before, and 30% were residents or fellows. Three elements were considered essential in consultation requests by most respondents: the specific question to be addressed (94%), whom to call with the response (68%), and consultation urgency (66%). In the consultation note, 71% of subjects placed high importance on simple, concise recommendations and 64% on the rationale behind them, while only 7% placed high importance on citing references. Most (69%) preferred that assessments and recommendations be written in bulleted or numbered format. A plurality (48%) preferred that assessments and recommendations be separated. Most placed high value on recommendations regarding drug therapy that specify dose (80%), duration (80%), and generic medication name (62%). Requesters placed greater importance than consultants (87% vs. 65%, respectively, P = 0.004) on recommendations that included duration of therapy. The majority (63%) stated that telephone requests were needed for emergent or urgent consultations. Those who usually requested consultations were more likely than those who usually responded to consultation requests to prefer telephone requests for routine consultations (43% vs. 20%, P < 0.001)., Conclusions: Physicians agreed on many essential elements for effective consultations. These results should guide efforts to improve communication in the consultation process and design electronic medical record systems.

Background: We report the case of a 56-year-old male with multiple myeloma in whom recurrent fevers and leukocytosis delayed potentially effective chemotherapy due to concern for active infection., Design and Measurements: A thorough infectious workup, including CT and PET scans, was negative. The patient was eventually found to have an elevated serum granulocyte colony-stimulating factor (G-CSF) of 113 pg/ml (normal range 0.0 - 39.1 pg/ml), which was likely the cause of his persistent leukocytosis and fevers. Multiagent chemotherapy was initiated, and the fevers resolved in the next 4 days., Results: Leukocyte concentrations trended down after initiation of chemotherapy, but it is uncertain how much of the decline was attributable to immunosuppression., Conclusion: We report this well-documented case to demonstrate that G-CSF production should be considered as a cause of unexplained fever and leukocytosis in patients with multiple myeloma to prevent inappropriate and delayed definitive diagnosis and treatment.

Isolated fungal infections of the perianal skin are rare and their diagnosis is frequently overlooked. We report a case of a 78-year-old male patient who presented with a friable, violaceous, papulopustular lesion, with heaped-up edges along the anal verge. Biopsy revealed unicellular yeast consistent with blastomycosis. The patient was treated with itraconazole with resolution of this lesion. An extensive MEDLINE literature review from 1958 to the present indicates that this is an uncommon manifestation of cutaneous blastomycosis. A summary of the medical literature is presented with a review of the characteristics, diagnosis, and management of blastomycosis.

To quantify the risk of nocardiosis in various populations, I systematically reviewed articles published between 1966 and 2004. The incidence of nocardiosis in 3 large, geographically defined populations ranged from 0.35 to 0.4 cases per 10(5) persons year. In contrast, the incidence of nocardiosis among people with human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS) in 1 study was 53 nocardiosis cases per 10(5) persons x year, approximately 140 times greater than that in the geographically defined populations. The frequency of nocardiosis cases in 4 populations of HIV-infected people averaged 608 cases per 10(5) persons. The incidence of nocardiosis in bone marrow-transplant recipients at 1 hospital was 128 cases per 10(5) persons x year, an incidence approximately 340 times greater than that in the geographically defined populations and in the same range as in HIV-infected people. The frequency of nocardiosis in 21 series of cases in recipients of a variety of transplanted organs averaged 1122 cases per 10(5) persons. These estimated incidence rates are imprecise because they were not collected through prospective surveillance systems, but the estimates for the 3 groups were internally consistent and provide useful information for clinicians.

Cross-sectional surveys of randomly selected high school students were conducted in October 1999 and in May 2000 to measure awareness of youth-led tobacco prevention efforts. A secondary goal of the surveys was to learn about tobacco use and attitudes. Respondents who never smoked cigarettes were asked if they had made a firm commitment to not smoke, and respondents who had not made such a commitment were considered susceptible. Among ninth graders, susceptibility increased from 31% in October to 47% in May, while susceptibility decreased from October to May for students in more advanced grades (p = 0.03, interaction of linear trends). Susceptibility was more common among students who felt smoking produced social benefits (OR 1.59, 95% CI 1.22-2.08) or who were tolerant of tobacco company behavior (OR 1.65, 95% CI 1.23-2.21), and less common among students who felt short-term adverse effects of cigarette smoking on health or hygiene were important to them (OR 0.74, 95% CI 0.56-0.97). Further studies should confirm the increase in susceptibility and its underlying mechanisms. Whether associated with ninth grade or with the first year in a new school, this previously unrecognized period of heightened susceptibility might represent an important opportunity for prevention.

We studied cytokine proteins and mRNAs in mice with two forms of Toxoplasma gondii pneumonia resulting from reactivation of infection. In the first form, mice were infected with T. gondii, developed and recovered from systemic disease, and then developed pneumonia 3 weeks later. As pulmonary inflammation developed, levels of cytokine mRNAs for gamma interferon (IFN-gamma), interleukin-2 (IL-2), IL-4, and IL-10 increased in bronchoalveolar lavage (BAL) cells or lung tissue, and the level of IFN-gamma protein increased in BAL fluid. The second form of pneumonia occurred as a complication of primary cytomegalovirus (CMV) disease in mice with dormant T. gondii infection. During CMV disease, IL-2 mRNA levels decreased in lung tissue, IL-10 protein levels increased in lung tissue, and IL-10 protein levels increased in BAL fluid. As the mice recovered from CMV disease, T. gondii infection was reactivated in the lungs and was manifested as T. gondii pneumonia. During CMV-induced T. gondii pneumonia, IFN-gamma, IL-2, IL-4, and IL-10 mRNA levels increased in BAL cells or lung tissue, and both IFN-gamma and IL-2 protein levels increased in BAL fluid. We concluded that both forms of T. gondii pneumonia are accompanied by increases in both type 1 T-helper and type 2 T-helper cytokine levels in lungs. The mechanism of CMV-induced reactivation of T. gondii infection in lungs may involve local decreases in IL-2 levels and/or increases in IL-10 levels.

Objective: To report a case of neuroleptic malignant syndrome (NMS) associated with the use of olanzapine., Case Summary: A 67-year-old white man with bipolar disorder developed nausea and vomiting. After 12 days, he became confused, delirious, and manic. His only medications were olanzapine 10 mg/d and divalproex sodium 500 mg bid. He was admitted to a hospital and treated for dehydration and mania. Olanzapine was given on 6 of the first 7 hospital days. On hospital day 6, typical NMS developed with the body temperature increasing to 39.9 degrees C, obtundation, rigidity, tremor, diaphoresis, fluctuating pupillary diameter, labile tachycardia and hypertension, hypernatremia, and elevated serum creatine kinase. Olanzapine was stopped after hospital day 7, and the syndrome resolved by hospital day 12., Discussion: The patient had all of the major manifestations of NMS. There was no other likely explanation for his illness and he received no other drug likely to be associated with the syndrome. This is the first case reported in which NMS was associated with olanzapine.

Interferon-gamma has well-documented antiviral and immunomodulatory activity, but its role in the control of cytomegalovirus (CMV) infection is not well studied. In a mouse model of murine CMV (MCMV) disease, interferon-gamma concentrations in serum but not in bronchoalveolar lavage fluid increased in response to viral infection. Serum interferon-gamma levels peaked at day 2 in the relatively resistant C57BL/6 mice, and, in contrast, did not peak until day 6 in susceptible BALB/c mice. Mice genetically lacking interferon-gamma (GKO) were more susceptible to MCMV, although strain differences persisted, with C57BL/6 GKO mice experiencing less severe MCMV disease than BALB/c GKO mice. Treatment of MCMV-infected BALB/c mice with exogenous interferon-gamma starting 2 days after viral infection had a modest protective effect at lower interferon-gamma doses (10(4) units), but interferon-gamma therapy markedly increased morbidity and mortality when higher doses (10(5) units) were used. We conclude that interferon-gamma plays a significant role in host response to MCMV and that the cytokine has dose- and time-dependent beneficial and adverse effects.

Purpose: To determine the clinical features, causes, and prognostic significance of extreme leukocytosis in adults., Patients and Methods: Medical records of 100 consecutive patients who presented at the Minneapolis Veterans Affairs Medical Center between March 1993 and January 1994 with more than 25,000 leukocytes/microL blood and with more than 50% granulocytes were reviewed. Demographic, clinical, and outcome information was recorded, and a cause of extreme leukocytosis was sought in each case., Results: Extreme leukocytosis was attributed to infection in 48 cases, advanced malignancy in 13 cases, hemorrhage in 9 cases, glucocorticoids in 8 cases, and other causes in 22 cases. Four patients had previously diagnosed conditions resulting in chronic leukocytosis. Higher leukocyte counts were associated with malignancy (chi2 for trend=12.5, P <0.002). Fever was more common in patients with infection (weighted rate ratio=3.7, 95% Confidence interval [CI]=2.2 to 6.2). Mortality was high overall (31%), and was greater in patients with noninfectious diagnoses compared with infected patients, an association which persisted after stratification by leukocyte count (weighted rate ratio=2.5, 95% CI=1.2 to 4.9)., Conclusion: Clinicians should be aware that extreme leukocytosis with a predominance of granulocytes is associated with infection in only 48% of cases. The presence of fever increases the likelihood that infection is the cause. Mortality is high, particularly in patients without infection.

We sought evidence of toxoplasma parasitemia among 37 people with active or dormant Toxoplasma gondii infection or no evidence of infection. DNA was extracted from erythrocyte-free portions of blood samples, and the T. gondii B1 gene was amplified by the polymerase chain reaction. Evidence of T. gondii parasitemia was found in six patients with severe immunosuppression from AIDS and clinical evidence suggestive of or compatible with toxoplasmosis. Results were negative for patients unlikely to have active toxoplasmosis. Gene detection after amplification with the polymerase chain reaction is a promising test for detection of parasitemia, and parasitemia should be tested for in patients with AIDS and unexplained fever or central nervous system abnormalities.

Diagnosis of Toxoplasma gondii infection is difficult, especially in immunosuppressed people. The AIDS epidemic has increased the number of people at risk and increased the need for better diagnostic methods. We have compared three methods for detection of T. gondii parasitemia. Rabbits were infected subcutaneously with 10(4) T. gondii tachyzoites. Blood samples were obtained, and buffy coat or leukocyte fractions were prepared. We sought the T. gondii B1 gene by gene amplification by the polymerase chain reaction, and we sought viable T. gondii cells by inoculating fibroblast cell cultures and by mouse inoculation. Thirty-two blood samples were obtained from seven infected rabbits, and 18 were obtained from four control, uninfected rabbits. Parasitemia was detected in 20 of 32 samples (62%) from infected samples by mouse inoculation, 12 of 32 samples (37%) by gene amplification and detection, and 8 of 32 samples (25%) by cell culture. Mouse inoculation requires use of live animals and has a long turnaround time. Currently, cell culture is the least sensitive but most practical and widely available method for the detection of T. gondii parasitemia. Gene amplification and detection was more sensitive than cell culture and may become available in clinical laboratories as techniques are developed further and automated.

Active cytomegalovirus (CMV) infection is associated with immunosuppression and predisposes to the development of life-threatening superinfections in immunocompromised patients. In a mouse model of virus-induced immunosuppression, acute murine CMV (MCMV) infection induced reactivation of dormant Toxoplasma gondii infection, producing Toxoplasma pneumonia. Changes in lung lymphocyte numbers and phenotypes appeared to be integral to the pathogenesis of MCMV-induced reactivation of T. gondii pneumonia. Numbers of lung CD4+ cells decreased during acute MCMV infection in mice with dormant T. gondii infection as well as in previously uninfected mice. Dually infected mice subsequently developed reactivation of Toxoplasma pneumonia. The pneumonia was characterized by a large influx of T lymphocytes, predominantly CD8+ cells, into the lungs. These lung lymphocytes markedly suppressed the ability of immune splenocytes to proliferate in response to T. gondii antigens and concanavalin A in vitro. These results suggested that the initial fall in the numbers of lung CD4+ cells observed after MCMV infection may have induced reactivation of T. gondii infection in the lungs. The subsequent pneumonia appeared to be a manifestation of a massive influx of T lymphocytes, especially CD8+ cells, into the lungs.

Toxoplasma pneumonia is being recognized with increased frequency, especially in patients with AIDS. We reviewed the English-, French-, and Spanish-language literature from January 1966 through February 1991 to identify cases of postnatally acquired pneumonia associated with Toxoplasma gondii. We identified two distinct clinical syndromes, one in immunocompetent patients and one in patients with defects in cell-mediated immunity. Shortness of breath and cough were the most common symptoms and fever and rales the most common signs in both groups of patients. Lymphadenopathy and hepatosplenomegaly were reported more frequently for immunocompetent patients. Chest roentgenographs usually revealed bilateral interstitial infiltrates, but a variety of other roentgenographic findings were reported. Serological findings were suggestive of active toxoplasmosis in immunocompetent but not in immunosuppressed patients. In early reports, identification of T. gondii as the etiologic agent of pneumonia was based on serology or autopsy findings. In more recent reports, open lung biopsy and especially bronchoalveolar lavage were used for diagnosis. Mortality among patients with toxoplasma pneumonia was 55%. However, in cases of T. gondii pneumonia diagnosed during life, mortality was 0 for immunocompetent patients and 40% for immunosuppressed patients. In immunosuppressed patients, improvement was associated with specific antitoxoplasma drug therapy. Unfortunately, relapses were common. We also reviewed data on series of patients with disseminated toxoplasmosis manifested predominantly in extrapulmonary sites and found that 33% of these patients had evidence of subclinical pulmonary involvement even though pneumonia had not been diagnosed clinically.

Toxoplasma gondii pneumonia has emerged as an important problem in immunocompromised patients, especially those with AIDS. The characteristics of lung lymphocytes, including their phenotypes, proliferative responses, and suppressor function during T. gondii pneumonia were studied. During primary acute T. gondii infection, the numbers of T lymphocytes in the lungs increased even though mice lacked histologic evidence of pneumonia. As mice recovered from acute toxoplasmosis, numbers of lung CD4+ cells and the ratio of CD4+ to CD8+ cells decreased. Subsequently, T. gondii infection reactivated, manifested as pneumonia. During pneumonia, lung T lymphocytes, especially CD8+ cells, increased even more. Lung lymphocytes from mice with T. gondii pneumonia decreased the proliferative responses of splenocytes from T. gondii-immune mice to both concanavalin A and T. gondii lysate antigens in vitro. The striking increase in lung CD8+ cells and suppressor activity appear to be integral to the pathogenesis of T. gondii pneumonia.

Clindamycin was used to treat the reactivation of a chronic Toxoplasma gondii infection in mice. Clindamycin reduced mortality by 44% when used prophylactically (P less than 0.001) but appeared to be less effective when used to treat clinically apparent reactivation. Further studies should be conducted to establish the efficacy of clindamycin for the treatment of toxoplasmosis in humans.

Purpose: To determine the incidence, characteristics, and outcome of infection in patients with myelodysplastic syndromes (MDS) and risk factors that may lead to infection., Patients and Methods: We reviewed infections that occurred in 86 consecutive patients with MDS who received care from 1968 to 1986 at a university-affiliated Veterans Affairs Medical Center. Time lines charting the course of each patient with MDS were created and included infections, MDS subgroup at the time of presentation and at the time of each infection, peripheral neutrophil counts, and therapies for MDS., Results: Infections occurred at a rate of nearly one per patient year of observation. Infection rates were associated with MDS subgroup as follows: refractory anemia with or without ringed sideroblasts (RA +/- RS) less than refractory anemia with excess blasts (RAEB) less than RAEB in transformation (RAEB-T). The group of RA +/- RS patients who had erythroid abnormalities but minimal or no dyspoiesis of other cell lines had the lowest rate of infections. Infection rates were higher in patients with less than or equal to 1,000 neutrophils/microL blood than in patients with greater than 1,000 neutrophils/microL blood for each classifiable MDS subgroup. Neutrophil concentration and MDS subgroup were independent risk factors for infection in patients with MDS. Bacterial pneumonias and skin abscesses were the most common infections. Infection was the most common cause of death during MDS, accounting for 64% of deaths, and was more common than transformation to acute leukemia as a cause of death., Conclusion: Infection is a common, life-threatening problem in patients with MDS. Neutropenia and MDS subgroup are each risk factors for infection. Clinicians should aggressively evaluate patients with fever and MDS for infection, especially pneumonia and skin infections.

Stress modulates a variety of immune responses. We investigated the effects of immobilization stress on the pathogenesis of acute murine toxoplasmosis, an infection in which cell-mediated immunity is of major importance in host defense. Repetitive overnight immobilization beginning 3 days prior to infection enhanced (p less than 0.05) the mortality of mice infected with a virulent strain (C56) of Toxoplasma gondii (77% vs 15% mortality in restrained and control mice, respectively). Daily immobilization for 14 days prior to infection abrogated (p less than 0.05) the lethal effect of immobilization, suggesting an adaptive mechanism. To explore the effect of immobilization with a less virulent strain, the Me49 strain of T. gondii was studied. Acute infection with T. gondii Me49 resulted in anorexia and weight loss, while spleen size and respiratory burst activity of peritoneal exudate cells were enhanced (p less than 0.01). Immobilization (twice daily for 2 h) did not significantly alter survival or other clinical features of acute T. gondii infection. In addition, immobilization suppressed (p less than 0.05) phorbol myristate acetate-stimulated release of superoxide anion by peritoneal exudate cells in healthy naive mice, but not in infected mice. These findings indicate that immobilization stress can alter the pathogenesis of acute T. gondii infection in healthy mice, but the effect of this stress paradigm will be influenced, in part, by the timing of the immobilization and the virulence of the strain of T. gondii.

Opiates modulate a variety of immune responses. We investigated the effect of morphine on the pathogenesis of an acute Toxoplasma gondii infection. Repeated s.c. injections with morphine sulfate (300 mg/kg) every 36 hr addicted mice and increased markedly the mortality of mice infected with an avirulent strain of T. gondii (86%) vs. 0% mortality in addicted and control mice, respectively, P less than .001). However, a single challenge with morphine (300 mg/kg) also markedly (P less than .001) increased mortality (94%) of infected mice when the morphine was administered at day 13 postinfection; susceptibility to the lethal effect was not observed until day 9 postinfection, a time when immune reactivity was evident (i.e., 3- to 4-fold splenic enlargement). This lethal effect was attenuated by pretreatment with naltrexone, suggesting involvement of an opiate receptor mechanism. Sulfadiazine treatment abrogated morphine-induced mortality, indicating a prerequisite of an active infectious state. These findings suggest that immune activation by T. gondii infection plays a critical role in morphine-induced mortality in this murine model.

In 1975 an outbreak of group A meningococcal disease began in Seattle, Washington, and cases subsequently were recognized throughout the Pacific Northwest. Nearly one-half of the affected persons were Native Americans; two-thirds were alcohol abusers and/or habitués of skid road communities. In Seattle, group A meningococci colonized asymptomatic persons only if these individuals had contact with skid road (P = .006). The epidemic strain may have spread from American Indians in Manitoba, Canada. Traditional migration routes connect the two populations; asymptomatic American Indians on reservations in Washington carried group A meningococci. Vaccination programs were undertaken in four cities but only after cases occurred. In Seattle, vaccination reached 80% of the target population and was associated with a significant decrease in incidence of the disease, but cases recurred after the program ended. The social habits of skid road communities, combined with the "case-triggering" approach to, and premature termination of, vaccination programs, may have resulted in 56% of regional cases occurring after the start of the vaccination program in Seattle.

Failure to demonstrate immunoglobulin M (IgM) antibodies by indirect immunofluorescence (IgM-IFA) in sera from some patients with acute acquired toxoplasmosis has recently been attributed to an inhibitory effect of high titers of IgG antibodies in these sera (Pyndiah et al. J. Clin. Microbiol. 9:170-174, 1979). To confirm these findings and define their importance for diagnosis, we used gel filtration to separate IgM from IgG antibodies in a series of sera that were negative in the IgM-IFA test. A total of 68 sera were from patients with acquired toxoplasmosis, 13 were from uninfected adults, 13 were from infants with congenital toxoplasmosis, and 7 were from uninfected neonates. Of the 68 sera from patients with acquired toxoplasmosis, IgM preparations (from the separated sera) were positive in the IgM-IFA test in 36 (53%). There was a significant (P = 0.00003) association between high titers of IgM-IFA antibodies in the IgM preparations (corrected for dilution of IgM antibodies by the gel filtration procedure) and recent acquisition of infection. IgM antibodies were also detected in 5 (38%) of the IgM preparations of 13 sera from congenitally infected infants but not in any of the IgM preparations of sera from uninfected neonates. IgG antibodies to Toxoplasma gondii were shown to interfere with demonstration of IgM antibodies in the IgM-IFA test. Treatment of sera with protein A resulted in greater dilution of IgM antibodies and less efficient separation of IgM from IgG antibodies than did separation of sera by gel filtration. Treatment of sera with protein A did not result in increased detection of IgM antibodies to T. gondii. Testing of IgM preparations (obtained by gel filtration) resulted in a significant increase in sensitivity of the IgM-IFA test for the diagnosis of recently acquired and congenital toxoplasmosis.

Interviews conducted during outbreaks of group A meningococcal disease in skid row communities suggested that heavy alcohol use was associated with increased risk of disease. Frequent moving within skid row and from one skid row to another was characteristic of a subpopulation with increased risk of disease and may have facilitated spread within and between skid rows. The observations discussed herein have important implications for control of communicable diseases in and near skid rows.

From March 10 through October 29, 1975, Listeria monocytogenes infection occurred in seven neonates born at a 401-bed general hospital in Greenville, S.C. In the preceding 19 months, there had been only one case. Six of the seven isolates from the infected infants were of serotype JB. Risk of listeriosis in neonates was associated with being born to mothers of low socioeconomic status and being born to mothers who had had vaginitis during pregnancy. Nosocomial transmission of L. monocytogenes appeared unlikely, but the source of the infection is unknown. Of the media used in this study for isolation of L. monocytogenes from mixed cultures, McBride's agar and McBride's agar with nalidixic acid were most useful.

The mechanism(s) of host resistance against Nocardia asteroides has not been well defined. Since disease due to N. asteroides frequently occurs in patients with impaired cell-mediated immunity, we studied the interaction of N. asteroides with activated and control mouse peritoneal macrophages. Activated macrophages were from mice infected with Toxoplasma gondii or injected with Corynebacterium parvum. N. asteroides in the early stationary phase (>99% in the coccobacillary form) was used for challenge of macrophage monolayers. Growth of two strains of N. asteroides was markedly inhibited in activated macrophages, whereas N. asteroides grew well in control macrophages. Quantitation of macrophage-associated N. asteroides indicated that activated macrophages killed 40 to 50% of N. asteroides within 6 h (P < 0.002). In control macrophage preparations, it appeared as if Nocardia filaments extended from within macrophages to the outside, and many of these filaments appeared to have extended to and then grown through neighboring macrophages. In activated macrophage preparations, Nocardia remained in the coccobacillary form in most macrophages. Control macrophage monolayers were almost completely overgrown with and destroyed by Nocardia 20 h after challenge, whereas activated macrophage monolayers remained intact. Nocardia that grew in control macrophages were not acid-alcohol fast or only weakly so, whereas the few Nocardia that grew in activated macrophages were strongly acid-alcohol fast. Our results indicate that activated macrophages may be important in host defense against N. asteroides.

To determine the risk of severe secondary illness in household contacts of patients with Haemophilus influenzae meningitis, telephone interviews were conducted with contacts of patients with reported cases. Four probable or proved secondary cases of severe disease were identified for a secondary attack rate of 0.4%. The secondary attack rate for household contacts of patients 2 years of age and younger was 4.9%. Until safe, effective prophylactic measures become available, physicians should explain to parents that any person who becomes ill in the month after a household case of H influenzae meningitis should be brought to the attention of a physician for appropriate evaluation and treatment.