Clinical evaluation of commercial nucleic acid amplification tests in patients with suspected sepsis.

BACKGROUND: Sepsis is a serious medical condition requiring timely administered, appropriate antibiotic therapy. Blood culture is regarded as the gold standard for aetiological diagnosis of sepsis, but it suffers from low sensitivity and long turnaround time. Thus, nucleic acid amplification tests (NAATs) have emerged to shorten the time to identification of causative microbes. The aim of the present study was to evaluate the clinical utility in everyday practice in the emergency department of two commercial NAATs in patients suspected with sepsis. METHODS: During a six-week period, blood samples were collected consecutively from all adult patients admitted to the general emergency department for suspicion of a community-onset sepsis and treated with intravenous antibiotics. Along with conventional blood cultures, multiplex PCR (Magicplex™) was performed on whole blood specimens whereas portions from blood culture bottles were used for analysis by microarray-based assay (Prove-it™). The aetiological significance of identified organisms was determined by two infectious disease physicians based on clinical presentation and expected pathogenicity. RESULTS: Among 382 episodes of suspected sepsis, clinically relevant microbes were detected by blood culture in 42 episodes (11%), by multiplex PCR in 37 episodes (9.7%), and by microarray in 32 episodes (8.4%). Although moderate agreement with blood culture (kappa 0.50), the multiplex PCR added diagnostic value by timely detection of 15 clinically relevant findings in blood culture-negative specimens. Results of the microarray corresponded very well to those of blood culture (kappa 0.90), but were available just marginally prior to blood culture results. CONCLUSIONS: The use of NAATs on whole blood specimens in adjunct to current culture-based methods provides a clinical add-on value by allowing for detection of organisms missed by blood culture. However, the aetiological significance of findings detected by NAATs should be interpreted with caution as the high analytical sensitivity may add findings that do not necessarily corroborate with the clinical diagnosis.

Faecal microbiota transplantation and bacteriotherapy for recurrent Clostridium difficile infection: a retrospective evaluation of 31 patients.

BACKGROUND: Recurrent Clostridium difficile infection (CDI) is a significant problem due to its increased incidence and severity. Failure rates for standard antibiotic therapies are high. In our hospital, faecal microbiota transplantation (FMT), or instillation of a culture mixture of known enteric bacteria in saline as rectal bacteriotherapy (RBT), has long been used as 'rescue therapy' in patients with recurrent disease, in whom repeated courses of standard antibiotic treatment have failed. We wanted to evaluate the effectiveness of FMT and RBT for recurrent CDI. METHODS: The records of 31 patients treated with either FMT or RBT for recurrent CDI were reviewed retrospectively. FMT was based on faecal donation by a close relative and RBT on a defined saline mixture of 10 individually cultured enteric bacterial strains originally isolated from healthy persons. Both types of instillation were carried out through a rectal catheter. FMT (500 ml) was given as 1 installation. RBT (200 ml) was given as 2 or 3 installations with an interval of 2 days between courses. Treatment success was defined as a sustained loss of symptoms and discontinuation of diarrhoea within 3 days. RESULTS: Of 31 patients, 23 (74%) responded successfully to the treatment: 16 of 23 (70%) receiving FMT and 7 of 8 (88%) receiving RBT. CONCLUSION: We found FMT to be effective in patients with recurrent CDI. RBT based on a predefined bacterial suspension was as effective as or better than FMT based on faecal donation; however, multiple installations may be needed.

[In vitro and in vivo investigations of a modified textile keratoprosthesis. ACTO TexKPRO]. / In-vitro- und In-vivo-Untersuchung einer modifizierten textilen Keratoprothese. ACTO TexKPRO.

BACKGROUND: Clinical application of a keratoprosthesis (KPRO) is still a challenging task. Recent developments reflect the concepts of nut and bolt, intrastromal implantation or an osteoodontokeratoprosthesis (OOKP). A new concept of a textile KPRO has been evaluated in a limited human study with considerable difficulties which after termination of the study and considerable improvements was restarted using animal experiments. MATERIALS: The ACTO TexKPRO is made from polyvinylidene difluoride (PVDF) fibers and transparent silicone. The first and second developmental stages differed in density and size of fibers and furthermore in surface modifications of the fibers and optics which were improved for the second prototype. METHODS: Implantation of the prosthesis was performed in four patients with corneal blindness and in two cases retinal disease which required surgery. In the later animal experiments surgery was performed on three rabbits. Surgery was performed by redressing the conjunctiva, opening of the eyeball with a central 6.5 mm trephination, removal of the lens and iris and implantation and suturing of the TexKPRO. If required a silicone oil endotamponade was placed. RESULTS: All eyes were stable with the keratoprosthesis. The first prototype showed conjunctival recession on the textile haptics with highly susceptible endopthalmitis risk due to infection of the PVDF so that we decided to remove the prosthesis from all eyes after one case of severe endophthalmitis occurred. The longest time of placement was 40 months and the shortest time 6 months. All eyes were restored by keratoplasty. In animals with the new haptic we found better conjunctivalization and stable implantation of the KPRO. DISCUSSION: The textile KPRO provides a stable implantation procedure and safe connection of fibers to the scleral wound bed. The optical and mechanical implantation is safe and stable. Surface epithelialization is improved with the new surface modifications and different PVDF fiber density but beforel new implantations are planned further conceptual changes will be introduced.

Legionnaires' disease from a cooling tower in a community outbreak in Lidköping, Sweden- epidemiological, environmental and microbiological investigation supported by meteorological modelling.

BACKGROUND: An outbreak of Legionnaires' Disease took place in the Swedish town Lidköping on Lake Vänern in August 2004 and the number of pneumonia cases at the local hospital increased markedly. As soon as the first patients were diagnosed, health care providers were informed and an outbreak investigation was launched. METHODS: Classical epidemiological investigation, diagnostic tests, environmental analyses, epidemiological typing and meteorological methods. RESULTS: Thirty-two cases were found. The median age was 62 years (range 36 - 88) and 22 (69%) were males. No common indoor exposure was found. Legionella pneumophila serogroup 1 was found at two industries, each with two cooling towers. In one cooling tower exceptionally high concentrations, 1.2 × 109 cfu/L, were found. Smaller amounts were also found in the other tower of the first industry and in one tower of the second plant. Sero- and genotyping of isolated L. pneumophila serogroup 1 from three patients and epidemiologically suspected environmental strains supported the cooling tower with the high concentration as the source. In all, two L. pneumophila strains were isolated from three culture confirmed cases and both these strains were detected in the cooling tower, but one strain in another cooling tower as well. Meteorological modelling demonstrated probable spread from the most suspected cooling tower towards the town centre and the precise location of four cases that were stray visitors to Lidköping. CONCLUSIONS: Classical epidemiological, environmental and microbiological investigation of an LD outbreak can be supported by meteorological modelling methods.The broad competence and cooperation capabilities in the investigation team from different authorities were of paramount importance in stopping this outbreak.

Febrile reactions after transrectal ultrasound-guided prostatic biopsy: a retrospective study.

OBJECTIVE: The aim of this study was to evaluate the incidence and clinical presentation in patients with hospital admission owing to febrile infections after transrectal ultrasound-guided prostate biopsies. MATERIAL AND METHODS: The case histories of the 57 patients (3.5%) who, between January 2006 and December 2009, were admitted owing to a febrile infection secondary to the 1633 transrectal prostate biopsies performed during the period were retrospectively analysed. Norfloxacin 400 mg ? 2 was given for 3 days as prophylaxis starting just before or within 10 min of biopsy. RESULTS: Quinolone-resistant Escherichia coli was isolated from blood cultures in 43% of the patients (n = 15) presenting with fever between 24 and 48 h postbiopsy. The urine culture was positive in 13% and no patient had symptoms suggestive of a urinary tract infection (UTI). In patients presenting after 48 h (n = 42), quinolone-resistant E. coli was never isolated from blood; E. coli was cultured from urine in 45% of the patients and in 48% it was associated with UTI symptoms. CONCLUSIONS: The finding that early postbiopsy fever was often associated with a quinolone-resistant E. coli bacteraemia and never with UTI symptoms, as opposed to late-onset fever, where such symptoms were common and quinolone-resistant E. coli was rarely detected, suggests divergent pathogenic mechanisms underpinning early- and late-onset febrile reactions. These findings have implications for how antibiotic prophylaxis should be given.

Urine cultures from indwelling bladder catheters in nursing home patients: a point prevalence study in a Swedish county.

OBJECTIVES: To survey the bacterial flora and antibiotic resistance in urinary strains from patients with indwelling bladder catheters residing in nursing homes within a geographically defined region. MATERIAL AND METHODS: Urine was sampled for culture from 163 catheter patients (126 men and 37 women) during a 2 week period in March 2010. Susceptibility testing of the isolated bacteria was compared with all urinary strains (n = 9994) from hospitals and primary healthcare in the same geographical area cultured during the first 6 months of 2010 (control group). RESULTS: Bacteriuria was found in 159 of 163 urine samples (98%). Enterococcus faecalis and Escherichia coli were the most common species, one or both being detected in 72% of the urine samples, while Proteus species were found in10% and a single isolate of Providentia species was seen.Strains in the study patients were more resistant to antibiotics than in the control group. Particularly large differences were noted for ciprofloxacinin in E. coli (16.9% vs 7.9%) and for trimethoprim-sulfamethoxazole in E. faecalis (39.1% vs 24.8%). One extended spectrum ß-lactamase (ESBL)-producing E. coli was cultured (1.3%), compared with 1.6% in the control group. No vancomycin-resistant enterococci (VRE) or methicillin-resistant Staphylococcus aureus (MRSA) were detected. CONCLUSIONS: Proteus mirabilis and Providentia species were rarely isolated, in sharp contrast to previous studies from geriatric hospital wards where they have often been in the majority. The limited incidence of ESBL and the absence of VRE and MRSA is gratifying, but the high resistance to antibiotics needs to be assessed on a continuous basis.

Antimicrobial susceptibility of invasive pneumococcal isolates from a region in south-west Sweden 1998-2001.

Invasive disease caused by antibiotic resistant pneumococci is a worldwide problem. All invasive pneumococcal strains in an area of south-west Sweden with 1.7 million inhabitants were collected prospectively during 1998-2001. Minimum inhibitory concentrations (MICs) were determined by E-test and correlated to serotypes and clinical characteristics. Of 827 strains, 744 (90%) were susceptible (S) to all agents tested and 83 (10%) were indeterminate (I) or resistant (R) to at least 1 agent. 22 isolates (2.7%) were I to penicillin (MIC >0.06 to < or = 1.0 mg/l), but none were R (MIC >1.0 mg/l). Numbers and proportions of decreased susceptibility against other agents tested were as follows: erythromycin R: 30 (3.6%), clindamycin R: 6 (0.7%), tetracycline R: 16 (1.9%), moxifloxacin R: 1 (0.1%), cotrimoxazole I: 17 (2%) and R: 31(4%). Non-susceptibility to at least 1 agent was not correlated with age, clinical manifestation, underlying diseases and outcome. The serotype distribution differed between non-susceptible and susceptible strains. The serotypes in the 7-valent pneumococcal conjugate vaccine covered 42% of all infections and 73% of those caused by non-susceptible strains. In conclusion, the impact of antibiotic resistance in invasive pneumococcal disease remains limited in south-west Sweden.

A community outbreak of Legionnaires' disease from an industrial cooling tower: assessment of clinical features and diagnostic procedures.

An outbreak of Legionnaires' disease (LD) occurred in Lidköping, Sweden, in August 2004. A cooling tower was identified as the probable source of infection. During the outbreak period an unexpected 3-6-fold increase in pneumonia patients was noted at the local hospital. During 7 weeks LD was diagnosed in 15 patients by urinary antigen and/or sputum culture. Additionally, 15 LD patients were diagnosed later by serology. Patients with LD were generally younger, more healthy, and more often smokers compared to other pneumonia patients. On admittance they had more severe symptoms with high fever and raised CRP levels, and more often hyponatraemia, gastrointestinal and CNS symptoms. A causative agent besides Legionella was found in 2 patients only. A significant titre rise for Mycoplasma and/or Chlamydophila pneumoniae was found in 13 of 29 tested patients with confirmed LD. We conclude that the clinical diagnosis of LD is difficult and that available diagnostic methods detect only a minority of patients in the acute phase. Therefore in severe pneumonia, empirically targeted therapy should be instituted on clinical grounds irrespective of the results of diagnostic tests. The observation of increased antibody levels for M. and C. pneumoniae suggests an unspecific immune reaction and merits further study.

Serotypes of Streptococcus pneumoniae isolated from blood and cerebrospinal fluid related to vaccine serotypes and to clinical characteristics.

Pneumococci isolated from blood and cerebrospinal fluid from 1998 to 2001 in 2 counties in south-west Sweden were serotyped with the capsular reaction test. Of the 836 strains, 353 (42%), 598 (72%) and 789 (94%) belonged to serotypes included in the 7- and 11-valent pneumococcal conjugate vaccines and in the 23-valent polysaccharide vaccine, respectively. The most common serotype was type 1 (119 isolates) followed in descending frequency by serotypes 7F, 9V, 14, 4 and 12F (90-49 isolates per serotype). The coverage rates of the 7- and 11-valent conjugate vaccines among 58 strains isolated from children and adolescents 0-19 y of age were 46% and 93%, respectively. A comparison of clinical characteristics of infections caused by different serotypes showed that types 1 and 7F were less commonly associated with severe underlying diseases, that patients infected with these serotypes were younger than the average and, thus, had a lower case-fatality rate.

Performance decrements resulting from illness in the workplace: the effect of headaches.

OBJECTIVES: Studies on the impact of illness on work productivity are important to rationally allocate healthcare resources and to design programs to mitigate these effects. This investigation was conducted to develop and apply daily measures of illness episodes, and to collect subjective and objective data on work performance impacts. Medical bill reviewers completed daily responses to a questionnaire about headache manifestations, severity, and speed of work using interactive voice response (IVR). Of 134 eligible enrolled subjects, 117 (86%) provided at least 30 daily reports over 3 months. Their responses were matched to difficulty-adjusted objective measures: daily output, time on the system, and productivity. Respondents were clinically classified as migraineurs (n = 56), other headache disorders (n = 47), or having no headache disorder (n = 14). Each headache episode was classified as a migraine or nonmigraine headache based on reported manifestations. RESULTS: The three groups were similar in a variety of demographic factors, and mean subject-specific measures of speed, output, and productivity. In a multivariate model using general estimating equations, only episode severity (not type of headache or person-specific diagnosis) was found to be associated with a significant decrement in speed or productivity. The self-reported decrement in speed (approximately 20%) was much greater than the actual measured effect on productivity (approximately 8%). Intensive daily diary collection by IVR on symptoms and work performance is feasible. However, analysis of detailed daily objective productivity data can be complex, with significant unmeasured sources of variance. Severity may be a more important determinant of headache effect on work performance than specific diagnosis. Future studies on illness episodes and work performance should measure informal accommodations that may enable employees to compensate for episodic illnesses.

Healthcare expenditure in patients treated with venlafaxine or selective serotonin reuptake inhibitors for depression and anxiety.

We compared healthcare expenditure over a six-month period following initiation of therapy with either venlafaxine (immediate and extended-release) or a selective serotonin reuptake inhibitor (SSRI) in depressed patients with or without anxiety. Patients beginning treatment for a new depressive episode were identified retrospectively using the administrative data of the MEDSTAT MarketScan database for the period 1994-1999. Before beginning therapy, patients prescribed venlafaxine had more non-mental illnesses (0.85 vs 0.76; p<0.01) and hospitalisations for mental illness (0.53 vs 0.29; p<0.05) than patients prescribed SSRIs. In the six months after initiating treatment, venlafaxine was associated with lower hospitalisation expenditure for non-mental illness ($177 vs $526; p<0.01) than SSRIs, although total healthcare expenditure was not significantly different. Venlafaxine was associated with a 50% decrease in the odds of hospitalisation for non-mental illness compared with SSRIs, with significantly lower inpatient expenditure.

The U.S. pharmaceutical industry: why major growth in times of cost containment?

Growth in utilization rather than price, particularly since 1994, has been the primary driver of increased pharmaceutical spending. In this paper I focus on four factors that have increased utilization, even as cost containment efforts have flourished: (1) "the importance of being unimportant"; (2) increased third-party prescription drug coverage; (3) the introduction of successful new products; and (4) aggressive technology transfer and marketing efforts by pharmaceutical firms. I also consider the roles that these four factors are likely to play in the future.

Health care use and at-work productivity among employees with mental disorders.

This study examines the differential medical care use and work productivity of employees with and without anxiety and with other mental disorders at a large national firm. A unique aspect of this study is that we integrate medical claims and employer-provided, objective productivity data for the same employees. We find extensive mental health comorbidities among anxious employees. Although medical care use differs considerably among employees having no, one, or several treated mental disorders, in most cases their annual average absenteeism and average at-work productivity performance do not differ. Differences among subgroups are observed for job tenure and maternity claims. We discuss these long-term average productivity findings in relation to other literature encompassing shorter time periods.

Lost human capital from early-onset chronic depression.

OBJECTIVE: Chronic depression starts at an early age for many individuals and could affect their accumulation of "human capital" (i.e., education, higher amounts of which can broaden occupational choice and increase earnings potential). The authors examined the impact, by gender, of early- (before age 22) versus late-onset major depressive disorder on educational attainment. They also determined whether the efficacy and sustainability of antidepressant treatments and psychosocial outcomes vary by age at onset and quantified the impact of early- versus late-onset, as well as never-occurring, major depressive disorder on expected lifetime earnings. METHOD: The authors used logistic and multivariate regression methods to analyze data from a three-phase, multicenter, double-blind, randomized trial that compared sertraline and imipramine treatment of 531 patients with chronic depression aged 30 years and older. These data were integrated with U.S. Census Bureau data on 1995 earnings by age, educational attainment, and gender. RESULTS: Early-onset major depressive disorder adversely affected the educational attainment of women but not of men. No significant difference in treatment responsiveness by age at onset was observed after 12 weeks of acute treatment or, for subjects rated as having responded, after 76 weeks of maintenance treatment. A randomly selected 21-year-old woman with early-onset major depressive disorder in 1995 could expect future annual earnings that were 12%-18% lower than those of a randomly selected 21-year-old woman whose onset of major depressive disorder occurred after age 21 or not at all. CONCLUSIONS: Early-onset major depressive disorder causes substantial human capital loss, particularly for women. Detection and effective treatment of early-onset major depressive disorder may have substantial economic benefits.

Comparing SSRI treatment costs for depression using retrospective claims data: the role of nonrandom selection and skewed data.

BACKGROUND AND OBJECTIVES: Since conventional randomized clinical trials often do not reflect the real world circumstances of prescribing behavior and patient outcomes, the use of retrospective administrative claims databases (RACD) has become more common in treatment cost comparisons among alternative pharmaceutical compounds. Several recent RACD studies have compared treatment costs for depressed patients prescribed SSRIs such as fluoxetine, sertraline and paroxetine. These cost comparisons have reached mixed conclusions. To begin to explain and reconcile the mixed SSRI cost comparison evidence, we undertake a variety of alternative multivariate analyses using a publicly available RACD. METHODS AND DATA: The 1995 to 1996 data encompasses a time period when all three SSRIs had become well-established agents. We report and compare results from multivariate linear regressions, logistic regressions, ordered probits and sample selectivity models, and examine robustness when adjustments are made for outlier observations and skewed distributions. RESULTS AND CONCLUSIONS: While choice of initial SSRI is nonrandom, the effect of sample selectivity on total depression-related and total health care expenditure is neutral across SSRIs. Although most cost measures are numerically greatest for fluoxetine, depression-related outpatient and hospitalization costs do not significantly differ by choice of initial SSRI. These findings are robust to alternative assumptions, specifications, and procedures. Antidepressant medication costs, however, are significantly higher when fluoxetine is the initial SSRI rather than sertraline or paroxetine, reflecting the larger proportion of fluoxetine patients prescribed a daily dosage of two or more capsules. Both total depression-related and total health care log-transformed costs are significantly lower for sertraline than fluoxetine.

Loss of work productivity due to illness and medical treatment.

We examined the effects on work productivity of treatment with antihistamines in a retrospective study using linked health claims data and daily work output records for a sample of nearly 6000 claims processors at a large insurance company, between 1993 and 1995. We explained the variation in work output depending on the subjects' demographic characteristics, their jobs, and whether they were treated with "sedating" versus "nonsedating" antihistamines for nasal allergies. Differences of up to 13% in productivity were found after the subjects took sedating or nonsedating antihistamines. The observed effect suggests substantial indirect economic costs, which up to now have been largely overlooked because work productivity has proved difficult to measure objectively.

Course and cost of treatment for depression with fluoxetine, paroxetine, and sertraline.

OBJECTIVE: To compare depression-related treatment costs and total healthcare costs for patients diagnosed with depression and treated with either sertraline, paroxetine, or fluoxetine. PATIENTS AND METHODS: Claims records from a national database of patients diagnosed with depression who began treatment with an SSRI in 1995, following an antidepressant medication-free period of at least 6 months, were included. Treatment course and associated depression-related treatment and total healthcare costs during the subsequent 12-month treatment period were examined using univariate and multivariate methods. RESULTS: Nine-hundred five (905) patients taking sertraline, 492 on paroxetine, and 945 on fluoxetine met inclusion criteria. The groups were similar and representative with respect to gender and age. Mean dose over the 12-month treatment period increased 24%, indicating significant titration in all cohorts. Patients treated with paroxetine had shorter treatment duration (157.0 days) than did patients treated with fluoxetine (192.6 days) or sertraline (166.9 days, P < 0.001). Patients receiving index treatment with paroxetine were most likely to switch to another SSRI (21.3%); those taking sertraline were second most likely to switch (16.1%); and those on fluoxetine were least likely (12.4%, P = 0.001). Mean costs for depression-related outpatient visits and hospitalizations were similar. Mean antidepressant prescription costs differed, being $586, $419, and $446 for fluoxetine, paroxetine and sertraline cohorts, respectively (P < 0.001). In this sample, the fluoxetine cohort did not have lower nonpharmaceutical healthcare costs to offset higher pharmaceutical acquisition costs. Conclusions from median and multivariate analyses were robust to these findings. CONCLUSIONS: During this study period when fluoxetine, paroxetine, and sertraline were all well-established agents, similar depression-related treatment courses and cost characteristics among all 3 drugs were observed.

The economic burden of anxiety disorders in the 1990s.

BACKGROUND: We assess the annual economic burden of anxiety disorders in the United States from a societal perspective. METHOD: Using data from the National Comorbidity Study, we applied multivariate regression techniques to calculate the costs associated with anxiety disorders, after adjusting for demographic characteristics and the presence of comorbid psychiatric conditions. Based on additional data, in part from a large managed care organization, we estimated a human capital model of the societal cost of anxiety disorders. RESULTS: We estimated the annual cost of anxiety disorders to be approximately $42.3 billion in 1990 in the United States, or $1542 per sufferer. This comprises $23.0 billion (or 54% of the total cost) in nonpsychiatric medical treatment costs, S13.3 billion (31%) in psychiatric treatment costs, $4.1 billion (10%) in indirect workplace costs, $1.2 billion (3%) in mortality costs, and $0.8 billion (2%) in prescription pharmaceutical costs. Of the $256 in workplace costs per anxious worker, 88% is attributable to lost productivity while at work as opposed to absenteeism. Posttraumatic stress disorder and panic disorder are the anxiety disorders found to have the highest rates of service use. Other than simple phobia, all anxiety disorders analyzed are associated with impairment in workplace performance. CONCLUSION: Anxiety disorders impose a substantial cost on society, much of which may be avoidable with more widespread awareness, recognition, and appropriate early intervention.