Cost-effectiveness in Clostridium difficile treatment decision-making.

AIM: To develop a framework for the clinical and health economic assessment for management of Clostridium difficile infection (CDI). METHODS: CDI has vast economic consequences emphasizing the need for innovative and cost effective solutions, which were aim of this study. A guidance model was developed for coverage decisions and guideline development in CDI. The model included pharmacotherapy with oral metronidazole or oral vancomycin, which is the mainstay for pharmacological treatment of CDI and is recommended by most treatment guidelines. RESULTS: A design for a patient-based cost-effectiveness model was developed, which can be used to estimate the cost-effectiveness of current and future treatment strategies in CDI. Patient-based outcomes were extrapolated to the population by including factors like, e.g., person-to-person transmission, isolation precautions and closing and cleaning wards of hospitals. CONCLUSION: The proposed framework for a population-based CDI model may be used for clinical and health economic assessments of CDI guidelines and coverage decisions for emerging treatments for CDI.

Fecal microbiota transplantation: facts and controversies.

PURPOSE OF REVIEW: To review the current evidence on fecal microbiota transplantations (FMTs) for recurrent Clostridium difficile infections (CDIs), metabolic syndrome and inflammatory bowel disease. RECENT FINDINGS: Recently, a randomized trial confirmed the efficacy of this treatment strategy in patients with recurrent CDI. For other disorders, evidence is still limited. To date, studies have been performed to try and influence the course of metabolic syndrome and inflammatory bowel disease. SUMMARY: There is increasing interest in the role of altered microbiota in the development of a myriad of diseases. Together with new insights comes an interest in influencing this altered microbiota as a potential target for therapy. FMTs are effective against recurrent CDI, a disorder caused by disruption of the normal microbiota. Restoration of intestinal flora and thereby restoration of colonization resistance is thought to be the mechanism responsible for cure. With the developments in FMT and the extension of this treatment modality to both intestinal and extra-intestinal diseases, a new field of targeted therapy awaits. The ultimate goal is the development of powerful probiotic regimens that can replace FMT. Currently, FMT should only be given in a strict experimental setting for other conditions than CDI.

[New treatment options for infections with Clostridium difficile]. / Nieuwe mogelijkheden bij Clostridium difficile-infecties.

Currently available broad spectrum antibiotics are not sufficiently effective against recurrent Clostridium difficile infections (CDI). Donor faecal microbiota transplantation is a very effective treatment for second and recurrent infection but is time-consuming and requires careful screening of donors. The new narrow spectrum antibiotic fidaxomicin is a good alternative in a first CDI or a first recurrence, but treatment is expensive and there are no data on its effectiveness in a second or later recurrence. Fidaxomicin is less effective against infections caused by the Ribotype 027 strain, a virulent strain that is regularly encountered in the Netherlands. The effectiveness of various other promising narrow spectrum antibiotics is currently being investigated. Medications that support the gut flora or the immune system seem to offer new perspectives. Expectations for the currently available probiotic preparations and toxin binders are not high.

Duodenal infusion of donor feces for recurrent Clostridium difficile.

BACKGROUND: Recurrent Clostridium difficile infection is difficult to treat, and failure rates for antibiotic therapy are high. We studied the effect of duodenal infusion of donor feces in patients with recurrent C. difficile infection. METHODS: We randomly assigned patients to receive one of three therapies: an initial vancomycin regimen (500 mg orally four times per day for 4 days), followed by bowel lavage and subsequent infusion of a solution of donor feces through a nasoduodenal tube; a standard vancomycin regimen (500 mg orally four times per day for 14 days); or a standard vancomycin regimen with bowel lavage. The primary end point was the resolution of diarrhea associated with C. difficile infection without relapse after 10 weeks. RESULTS: The study was stopped after an interim analysis. Of 16 patients in the infusion group, 13 (81%) had resolution of C. difficile-associated diarrhea after the first infusion. The 3 remaining patients received a second infusion with feces from a different donor, with resolution in 2 patients. Resolution of C. difficile infection occurred in 4 of 13 patients (31%) receiving vancomycin alone and in 3 of 13 patients (23%) receiving vancomycin with bowel lavage (P<0.001 for both comparisons with the infusion group). No significant differences in adverse events among the three study groups were observed except for mild diarrhea and abdominal cramping in the infusion group on the infusion day. After donor-feces infusion, patients showed increased fecal bacterial diversity, similar to that in healthy donors, with an increase in Bacteroidetes species and clostridium clusters IV and XIVa and a decrease in Proteobacteria species. CONCLUSIONS: The infusion of donor feces was significantly more effective for the treatment of recurrent C. difficile infection than the use of vancomycin. (Funded by the Netherlands Organization for Health Research and Development and the Netherlands Organization for Scientific Research; Netherlands Trial Register number, NTR1177.).

Hyposplenism: comparison of different methods for determining splenic function.

Asplenic patients are at risk for pneumococcal sepsis. Patients with hyposplenic function, such as associated with sickle cell disease (SCD), are also at risk. However, tests to assess splenic function are either unavailable or lacking standardization. The aim of this study was to compare different methods for determining splenic function. Eighteen patients with SCD (i.e., 10 heterozygous (SC) and 8 homozygous (SS) SCD patients), and eight splenectomized patients were compared to 10 controls. All subjects underwent spleen scintigraphy, after which functional splenic volumes (FSV) were calculated. FSV was compared to immunological function and B cell-subsets, as well as phagocytic function represented by the presence of Howell Jolly bodies (HJB) and percentages of pitted red cells (PIT). Heterozygous SCD (SC) patients had increased splenic volumes, but diminished FSV, homozygous SCD (SS) patients were asplenic. Splenectomized and SS patients had a strongly reduced phagocytic and immunological function. SC patients had reduced anti-polysaccharide responses without an increase in PIT. FSV correlated significantly with phagocytic and immunological function. HJB were indicative of splenic dysfunction, HJB absence was not indicative of normal functioning splenic tissue. Although visualizing HJB is methodologically advantageous to PIT, both are valid biomarkers of splenic dysfunction. The amount of non-switched memory B cells is strongly correlated to FSV.

[Refusal of medical treatment in an acute comatose patient]. / Negatieve wilsverklaring bij een acuut comateuze patiënt.

BACKGROUND: The Dutch Law on Medical Services ('Wet Geneeskundige Behandelingsovereenkomst') of 1995 declares that doctors must adhere to an Informed Refusal (a written Refusal of Medical Treatment) if the patient is unable to give informed consent on presentation at hospital. CASE DESCRIPTION: A comatose 81-year-old man was presented at the resuscitation area following attempted suicide with insulin. Treatment was suspended after the family presented the doctor with an Informed Refusal that had been signed by the patient. The question was to what extent this statement of intention or the family's wishes could prevail over the medical insight of the doctor. During subsequent discussion it became apparent that opinions vary greatly between doctors on this subject. CONCLUSION: Patients and doctors have little knowledge of negative statements of intention. The doctor can help the patient in formulating a realistic statement of intention, and document the patient's wishes in the patient's written or electronic medical dossier. A representative designated in writing can help to interpret the declaration of intention.

Physicians report barriers to deliver best practice care for asplenic patients: a cross-sectional survey.

BACKGROUND: Current management of asplenic patients is not in compliance with best practice standards, such as defined by the British Committee for Standards in Haematology. To improve quality of care, factors inhibiting best practice care delivery need to be identified first. With this study, we aimed to identify and quantify physicians' barriers to adhere to best practice management of asplenic patients in The Netherlands. METHODS AND PRINCIPAL FINDINGS: A cross-sectional survey, preceded by multiple focus group discussions, was performed among Dutch physicians responsible for prevention of infections in asplenic patients, including specialists (of Internal medicine and Surgery) and general practitioners (GPs). Forty seven GPs and seventy three hospital specialists returned the questionnaire, yielding response rates of 47% and 36.5% respectively. Physicians reported several barriers to deliver best practice. For both GPs and specialists, the most frequently listed barriers were: poor patient knowledge (>80% of hospital specialists and GPs) and lack of clarity about which physician is responsible for the management of asplenic patients (50% of Internists, 46% of Surgeons, 55% of GPs). Both GPs and hospital specialists expressed to experience a lack of mutual trust: specialists were uncertain whether the GP would follow their advice given on patient discharge (33-59%), whereas half of GPs was not convinced that specialists' discharge letters contained the correct recommendations. Almost all physicians (>90%) indicated that availability of a national guideline would improve adherence to best practice, especially if accessible online. CONCLUSION: This study showed that, in accordance with reports on international performance, care delivery for asplenic patients in The Netherlands is suboptimal. We identified and quantified perceived barriers by physicians that prevent adherence to post-splenectomy guidelines for the first time. Better transmural collaboration and better informed patients are likely to improve the quality of care of the asplenic patient population. A national, online-available guideline is urgently required.

Performance of Dutch hospitals in the management of splenectomized patients.

BACKGROUND: After splenectomy, patients are at increased risk of sepsis with considerable mortality. This risk can be reduced by taking preventive measures, such as prescribing immunizations and antibiotic prophylaxis. Studies from various countries show that a substantial percentage of patients are not managed adequately. The aim of the present study was to investigate the quality of care in the prevention of infections after splenectomy in Dutch hospitals. The research questions were two-fold: (1) Is there an association between hospital teaching status and guideline adherent preventive measures? (2) Which factors contribute to hospital performance? METHODS: A total of 28 Dutch hospitals (30%) participated in the study. A retrospective review of medical records of 536 splenectomy patients was performed. Adherence to prevention guidelines was assessed for all patients, and analyzed according to teaching status and the presence or absence of a post-splenectomy protocol. RESULTS: (1) University hospitals in the Netherlands offered higher quality of care than other teaching and nonteaching hospitals. There were only small differences between nonuniversity teaching and nonteaching hospitals. (2) The presence of a hospital post-splenectomy protocol did not improve vaccination rates. Other aspects of practice organization, such as surgical staff size and keeping a complication registry were only weakly related to performance. CONCLUSIONS: In the Netherlands, university hospitals deliver state-of-the-art care in the prevention of infections in asplenic patients more often than nonuniversity teaching and nonteaching hospitals. The availability of a hospital protocol does not seem to contribute to guideline adherence.

Health-related quality of life and posttraumatic stress disorder among survivors of left-sided native valve endocarditis.

BACKGROUND: The long-term prognosis of endocarditis is described primarily in relation to clinical outcome measures-for example, such complications as cerebrovascular accident, cardiac failure, need for cardiac surgery, relapse rate, and mortality. To our knowledge, to date, no studies have examined the health-related quality of life and the prevalence of long-term persistence of physical symptoms for survivors of left-sided native valve endocarditis. METHODS: We conducted a prospective follow-up study of patients treated for left-sided native valve endocarditis from 1 November 2000 through 31 October 2003 in 23 hospitals in the Netherlands. Of 86 patients eligible to participate, 55 completed questionnaires administered 3 m and 12 m after discharge; an additional 12 patients completed questionnaires 12 m after discharge only, making a total of 67 patients in our study. Persistence of symptoms and employment status were recorded. The health-related quality of life was measured by using the Dutch version of the Medical Outcomes Study Short Form 36-item health survey and the Posttraumatic Stress Disorder questionnaire. RESULTS: Three months after the end of antimicrobial treatment, 41 (75%) of 55 patients still had physical symptoms. Twelve months after the end of antimicrobial treatment, 36 (54%) of 67 patients still had physical symptoms. Before the episode of endocarditis, 30 (81%) of 37 patients aged < or =60 years were employed and working. At 3 m follow-up, 16 (52%) of 31 patients returned to work, and at 12 m follow-up, 24 (65%) of 37 patients were working. One year after discharge, the health-related quality of life was impaired in 5 of 8 dimensions, compared with age-adjusted standard values, and 7 (11%) of 64 patients suffered from posttraumatic stress disorder. CONCLUSIONS: A year after discharge, most survivors of left-sided native valve endocarditis still had persisting symptoms and a seriously diminished quality of life, and 11% of patients suffered from posttraumatic stress disorder.

Prognostic value of serial C-reactive protein measurements in left-sided native valve endocarditis.

BACKGROUND: The clinical course of left-sided native valve infective endocarditis varies from uncomplicated disease to fulminant infection. Although several factors are known to affect clinical outcome, it is difficult to predict morbidity and mortality in individual patients. The objective of this study was to determine the value of serial C-reactive protein (CRP) measurements as a predictor of clinical outcome. METHODS: One hundred twenty-three consecutive patients who fulfilled the Duke criteria for definite left-sided native valve infective endocarditis were prospectively enrolled. Poor outcome was defined as serious infectious complications or death. Patients were followed up for 12 weeks after the end of antimicrobial therapy. Multivariate analysis was used to examine the relative importance of the CRP level as a predictor of poor outcome after adjusting for age, abscess, multivalvular involvement, and Staphylococcus aureus infection. RESULTS: After 1 week of therapy, the adjusted odds ratio for poor outcome was 10.3 (95% confidence interval, 2.2-49.4) for patients with CRP levels in the highest tertile (>122 mg/L [to convert to nanomoles per liter, multiply by 9.524]) vs the lowest tertile (1-69 mg/L). A low percentage decline during the first week of treatment was statistically significantly associated with a higher risk of poor outcome (logistic regression coefficient, 1.1; P = .009). At no point in time did CRP level predict the need for cardiac surgery. CONCLUSION: High CRP level after 1 week of treatment and a slow percentage decline in CRP level during the first week of treatment are indicators of poor clinical outcome.

Coinfection with Borrelia burgdorferi sensu stricto and Borrelia garinii alters the course of murine Lyme borreliosis.

Ixodes ricinus ticks and mice can be infected with both Borrelia burgdorferi sensu stricto and Borrelia garinii. The effect of coinfection with these two Borrelia species on the development of murine Lyme borreliosis is unknown. Therefore, we investigated whether coinfection with the nonarthritogenic B. garinii strain PBi and the arthritogenic B. burgdorferi sensu stricto strain B31 alters murine Lyme borreliosis. Mice simultaneously infected with PBi and B31 showed significantly more paw swelling and arthritis, long-standing spirochetemia, and higher numbers of B31 spirochetes than did mice infected with B31 alone. However, the number of PBi spirochetes was significantly lower in coinfected mice than in mice infected with PBi alone. In conclusion, simultaneous infection with B. garinii and B. burgdorferi sensu stricto results in more severe Lyme borreliosis. Moreover, we suggest that competition of the two Borrelia species within the reservoir host could have led to preferential maintenance, and a rising prevalence, of B. burgdorferi sensu stricto in European I. ricinus populations.

Long-term symptom recovery and health-related quality of life in patients with mild-to-moderate-severe community-acquired pneumonia.

STUDY OBJECTIVES: The long-term outcomes of patients with community-acquired pneumonia (CAP) in terms of symptom resolution and health-related quality of life (HRQL) is unknown. Our objective was to determine the rate of symptom resolution using validated patient-based outcome measures, and to assess HRQL 18 months after the episode. PARTICIPANTS: Patients were recruited from a group enrolled in a randomized trial comparing two durations of treatment for CAP. Between 2000 and 2003, we included 102 adults with a mild-to-moderate-severe CAP (pneumonia severity index, < or = 110). INTERVENTIONS: CAP-related symptoms were assessed until month 18 using the CAP score. The CAP score was divided into respiratory and well-being sections to assess the recovery of respiratory and well-being symptoms separately. The HRQL was assessed at 18 months using the Medical Outcomes Study 36-item short form (SF-36) questionnaire and compared to a Dutch reference group. RESULTS: Respiratory symptoms resolved within 14 days, while the well-being symptoms resolved more slowly. Taking the prepneumonia status into account, patients recovered fully from pneumonia after 6 months. Patients with comorbid conditions had significantly more symptoms prepneumonia and during follow-up than patients without comorbidities, but at all time points the proportion of patients that reached > or = 80% of the prepneumonia health level did not depend on comorbidity, age, or etiology. SF-36 scores at 18 months were significantly impaired in four of the eight dimensions for patients with comorbid illness, but did not differ from the reference population for patients without comorbid illness. CONCLUSION: Patients with mild-to-moderate-severe CAP recover fully from pneumonia after 6 months. The presence of symptoms beyond 28 days and any impairment in HRQL were found to reflect age and comorbidity rather than the persistent effects of the pneumonia itself.

Effectiveness of discontinuing antibiotic treatment after three days versus eight days in mild to moderate-severe community acquired pneumonia: randomised, double blind study.

OBJECTIVE: To compare the effectiveness of discontinuing treatment with amoxicillin after three days or eight days in adults admitted to hospital with mild to moderate-severe community acquired pneumonia who substantially improved after an initial three days' treatment. DESIGN: Randomised, double blind, placebo controlled non-inferiority trial. SETTING: Nine secondary and tertiary care hospitals in the Netherlands. PARTICIPANTS: Adults with mild to moderate-severe community acquired pneumonia (pneumonia severity index score < or = 110). INTERVENTIONS: Patients who had substantially improved after three days' treatment with intravenous amoxicillin were randomly assigned to oral amoxicillin (n = 63) or placebo (n = 56) three times daily for five days. MAIN OUTCOME MEASURES: The primary outcome measure was the clinical success rate at day 10. Secondary outcome measures were the clinical success rate at day 28, symptom resolution, radiological success rates at days 10 and 28, and adverse events. RESULTS: Baseline characteristics were comparable, with the exception of symptom severity, which was worse in the three day treatment group. In the three day and eight day treatment groups the clinical success rate at day 10 was 93% for both (difference 0.1%, 95% confidence interval--9% to 10%) and at day 28 was 90% compared with 88% (difference 2.0%,--9% to 15%). Both groups had similar resolution of symptoms. Radiological success rates were 86% compared with 83% at day 10 (difference 3%,--10% to 16%) and 86% compared with 79% at day 28 (difference 6%,--7% to 20%). Six patients (11%) in the placebo group and 13 patients (21%) in the active treatment group reported adverse events (P = 0.1). CONCLUSIONS: Discontinuing amoxicillin treatment after three days is not inferior to discontinuing it after eight days in adults admitted to hospital with mild to moderate-severe community acquired pneumonia who substantially improved after an initial three days' treatment.

Lipopolysaccharide binding protein-deficient mice have a normal defense against pulmonary mycobacterial infection.

Lipopolysaccharide (LPS) binding protein (LBP) facilitates the transfer of LPS of Gram-negative bacteria to the pattern recognition receptor CD14, resulting in activation of immunocompetent cells. LBP can also facilitate the binding of lipoarabinomannan, a major cell wall component of mycobacteria, to immune cells. To determine the role of LBP in the immune response to pulmonary Mycobacterium tuberculosis infection, LBP gene-deficient (-/-) and normal wild-type (WT) mice were intranasally infected with M. tuberculosis. LBP-/- mice displayed a similar survival and mycobacterial outgrowth in lungs and liver, although they demonstrated a reduced lymphocyte recruitment and activation during the early stages of infection. The clearance of pulmonary infection with the non-pathogenic M. smegmatis was also unaltered in LBP-/- mice. These data suggest that LBP does not contribute to an effective host response in M. tuberculosis infection.

Diagnostic accuracy of routine postoperative body temperature measurements.

BACKGROUND: On surgical wards, body temperature is routinely measured, but there is no proof that this is useful for detecting postoperative infection. The aim of this study was to compare temperature measurements (the test) with the confirmed absence or presence of a postoperative infection (the reference standard). METHODS: A prospective triple-blinded diagnostic study involving 308 consecutive patients was performed. A positive test result was defined as a postoperative temperature > or = 38.0 degrees C. The reference standard was considered to indicate a postoperative infection if results of a bacterial culture were positive or if an infection was suspected on clinical grounds. RESULTS: Data for 284 of 308 patients were analyzed (2282 temperature measurements). The prevalence of infection was 7% (19 of 284 patients). The temperature curves of patients were used as units of analysis and revealed that a temperature > or = 38.0 degrees C had a sensitivity of 37% (95% confidence interval [CI], 0.16%-0.62%) and a specificity of 80% (95% CI, 0.75%-0.85%). The likelihood ratio for a positive test result was 1.8 (95% CI, 0.7-4.0) and for a negative test result was 0.8 (95% CI, 0.4-1.4). When all 2282 measurements were considered as independent test results, the positive predictive value was only 8% (95% CI, 5%-13%). Six of 8 patients with a severe infection had temperatures < 38 degrees C. CONCLUSION: Routine measurement of body temperature is of limited value in the detection of infection after elective surgery for noninfectious conditions. Serious postoperative infections can even occur without an accompanying increase in temperature.

Platelet-activating factor receptor-deficient mice show an unaltered clearance of nontypeable Haemophilus influenzae from their respiratory tract.

Platelet-activating factor (PAF), a glycerophospholipid with proinflammatory properties, exerts its biological effects by interacting with the PAF receptor (PAFR) expressed on many different cell types. The PAFR specifically binds phosphorylcholine, the biologically active component of PAF. However, phosphorylcholine is also a component of the cell wall of nontypeable Haemophilus influenzae (NTHi). In recently published in vitro experiments, the invasion of respiratory epithelial cells by NTHi was mediated by the PAFR. To determine the role of the PAFR in host defense against pneumonia induced by NTHi, PAFR-deficient (PAFR-/-) and normal wild-type mice were intranasally inoculated with NTHi. The absence of a functional PAFR was associated with a normal innate immune response as indicated by similar bacterial counts, myeloperoxidase activity, and inflammation within the pulmonary compartment of PAFR-/- and wild-type mice. These data indicate that the PAFR does not interfere with the clearance of NTHi from the respiratory tract.

LPS-binding protein-deficient mice have an impaired defense against Gram-negative but not Gram-positive pneumonia.

LPS-binding protein (LBP) can facilitate the transfer of cell wall components of both Gram-negative bacteria (LPS) and Gram-positive bacteria (lipoteichoic acid) to inflammatory cells. Although LBP is predominantly produced in the liver, recent studies have indicated that this protein is also synthesized locally in the lung by epithelial cells. To determine the role of LBP in the immune response to pneumonia, LBP gene-deficient (-/-) and normal wild-type (WT) mice were intra-nasally infected with either Streptococcus pneumoniae or Klebsiella pneumoniae, common Gram-positive and Gram-negative pathogens, respectively. Pneumococcal pneumonia was associated with a 7-fold rise in LBP concentrations in bronchoalveolar lavage fluid of WT mice; LBP-/- mice infected with S. pneumoniae showed a similar survival and a similar bacterial burden in their lungs 48 h post-infection. In Klebsiella pneumonia, however, LBP-/- mice demonstrated a diminished survival together with an enhanced bacterial outgrowth in their lungs. These data suggest that LBP is important for a protective immune response in Klebsiella pneumonia, but does not contribute to an effective host response in pneumococcal pneumonia.

Improved host defense against pneumococcal pneumonia in platelet-activating factor receptor-deficient mice.

Platelet-activating factor (PAF) is a phospholipid with proinflammatory properties that binds to a specific receptor (PAF receptor [PAFR]) that is expressed on many different cell types. PAFR is able to bind phosphorylcholine, which is present in both PAF and the pneumococcal cell wall. Activation of respiratory epithelial cells in vitro results in up-regulation of PAFR, which, in turn, facilitates invasion of Streptococcus pneumoniae. To determine the role of PAFR in host defense against pneumococcal pneumonia, PAFR-deficient (PAFR(-/-)) and wild-type (wt) mice were inoculated intranasally with S. pneumoniae. PAFR(-/-) mice were relatively resistant to pneumococcal pneumonia, as indicated by delayed and reduced mortality, diminished outgrowth of pneumococci in lungs, and reduced dissemination of the infection (all P<.05, vs. wt mice). PAFR(-/-) mice also had less pulmonary inflammation. These data provide evidence that PAFR is used by S. pneumoniae to induce lethal pneumonia.

Toll-like receptor 4 plays a protective role in pulmonary tuberculosis in mice.

Toll-like receptors (TLR) play an essential role in the innate recognition of microorganisms by the host. To determine the role of TLR4 in host defense against lung tuberculosis, TLR4 mutant (C3H/HeJ) and wild-type (C3H/HeN) mice were intranasally infected with live Mycobacterium tuberculosis. TLR4 mutant mice were more susceptible to pulmonary tuberculosis, as indicated by a reduced survival and an enhanced mycobacterial outgrowth. Lung infiltrates were more profound in TLR4 mutant mice and contained more activated T cells. Splenocytes of infected TLR4 mutant mice demonstrated a reduced capacity to produce the protective type 1 cytokine IFN-gamma upon antigen-specific stimulation, indicating that TLR4 may be involved in the generation of acquired T cell-mediated immunity. These data suggest that TLR4 plays a protective role in host defense against lung infection by M. tuberculosis.