Clinical risk scores and blood biomarkers as predictors of long-term outcome in patients with community-acquired pneumonia: a 6-year prospective follow-up study.

OBJECTIVE: Prediction of long-term outcomes in patients with community-acquired pneumonia (CAP) is incompletely understood. We investigated the value of clinical risk scores [pneumonia severity index (PSI) and CURB-65] (Confusion, Urea, Respiratory rate, Blood Pressure, Age >65 years) and blood biomarkers of different physiopathological pathways in predicting long-term survival in a well-characterized cohort of patients with CAP enrolled in an antibiotic stewardship trial. DESIGN, SETTING AND SUBJECTS: Patients admitted with CAP to six medical centres in Switzerland were prospectively followed for 6 years. Cox regression models and area under the receiver operating characteristics curve (AUC) were used to investigate associations between initial risk assessment and all-cause mortality. MAIN OUTCOME MEASURE: All-cause mortality during a 6-year follow-up period. RESULTS: Six-year mortality in the present cohort (median age 73 years) was 45.1% [95% confidence interval (CI) 41.8-48.3%]. Initial PSI and CURB-65 scores both had excellent long-term prognostic accuracy, with a stepwise increase in mortality per risk class. The hazard ratios (95% CI) of the highest PSI and CURB-65 classes (reference: lowest class) were 38.0 (14.0-103.0) and 7.8 (2.2-14.5), respectively, after 6 years. The addition of inflammatory (pro-adrenomedullin) and cardiac (pro-atrial natriuretic peptide) blood biomarkers measured upon hospital admission further improved the prognostic capabilities of the PSI (AUC increase from 0.79 to 0.83; P < 0.0001) and the CURB-65 score (AUC increase from 0.73 to 0.80; P < 0.001). CONCLUSION: Risk assessment using clinical scores allowed accurate long-term prognostication, which was further improved by the addition of two inflammatory (pro-adrenomedullin) and cardiac (pro-atrial natriuretic peptide) blood biomarkers. These data provide a rationale for a more risk-adapted, 'personalized' strategy for long-term management of patients with CAP.

[Orthopaedic implant-associated infections: Update of antimicrobial therapy]. / Orthopädische implantatassozierte Infektionen : Update zur Antibiotikatherapie.

In infections related to prosthetic joints and internal fixation devices, microorganisms adhere as biofim on the surface of the implant. Biofilms are not only resistant to phagocytosis, but also to most antimicrobial agents. Therefore, spontaneous cure does never occur, and antibiotics have to be given for several months. According to traditional concepts, removal of all foreign material was considered as prerequisite for cure. Yet, during the last decades, it has been shown that staphylococcal biofilms can be eliminated by rifampin combination therapy, and Gram-negative biofilms by fluoroquinolones. However, reliable biofilm elimination is only possible, if the duration of infection does not exceed 3-4 weeks. Correct total duration of the antimicrobial therapy has never been tested in a controlled trial. Currently, treatment duration is 3 (hip prosthesis) and 6 (knee prosthesis) months in patients undergoing débridement with implant retention, one-stage exchange, and two-stage exchange with a short interval of 2-3 weeks. According to a recent observational trial, a treatment duration of 2 and 3 months, respectively, is equivalent to the longer duration in patients undergoing débridement and implant retention. The optimal surgical therapy should be chosen according to a rational algorithm. It is crucial choosing the optimal surgical intervention from the beginning, because the final functional success depends on the cure by the first attempt.

Clinical presentation and treatment of orthopaedic implant-associated infection.

Orthopaedic implants are highly susceptible to infection. The aims of treatment of infection associated with internal fixation devices are fracture consolidation and prevention of chronic osteomyelitis. Complete biofilm eradication is not the primary goal, as remaining adherent microorganisms can be removed with the device after fracture consolidation. By contrast, in periprosthetic joint infection (PJI), biofilm elimination is required. Surgical treatment of PJI includes debridement with retention, one- or two-stage exchange and removal without reimplantation. In addition, prolonged antibiotic treatment, preferably with an agent that is effective against biofilm bacteria, is required. Rifampicin is an example of an antibiotic with these properties against staphylococci. However, to avoid the emergence of resistance, rifampicin must always be combined with another antimicrobial agent. With this novel treatment approach, orthopaedic implant-associated infection is likely to be eradicated in up to 80-90% of patients. Because most antibiotics have a limited effect against biofilm infections, novel prophylactic and therapeutic options are needed. Surface coating with antimicrobial peptides that reduce bacterial attachment and biofilm formation can potentially prevent implant-associated infection. In addition, quorum-sensing inhibitors are a novel therapeutic option against biofilm infections.

Factors associated with rifampin resistance in staphylococcal periprosthetic joint infections (PJI): a matched case-control study.

PURPOSE: Rifampin combination therapy plays an important role in the management of staphylococcal periprosthetic joint infection (PJI). However, the emergence of rifampin resistance is a feared complication. We retrospectively analysed predetermined potential risk factors in patients with rifampin-resistant staphylococcal PJI in a multicentre case-control study. METHODS: Cases (n = 48) were defined as PJI caused by rifampin-resistant staphylococci. Rifampin-susceptible controls (n = 48) were matched for microorganism and type of prosthetic joint. Uni- and multivariable conditional logistic regression analyses were performed to estimate odds ratios (OR) with 95 % confidence intervals (95 % CI). RESULTS: Forty-eight cases (31 men; median age 67 years; age range 39-88 years) with hip- (n = 29), knee- (n = 13), elbow- (n = 4), shoulder- (n = 1) or ankle-PJI (n = 1) were enrolled in the study. Staphylococcus aureus and coagulase-negative staphylococci were isolated in ten and 38 episodes, respectively. Most of the cases (n = 44, 92 %) had a previous PJI, and 93 % (n = 41) of these had been treated with rifampin. There was an independent association of emergence of rifampin resistance with male sex (OR 3.6, 95 % CI 1.2-11), ≥ 3 previous surgical revisions (OR 4.7, 95 % CI 1.6-14.2), PJI treatment with high initial bacterial load (inadequate surgical debridement, <2 weeks of intravenous treatment of the combination medication; OR 4.9, 95 % CI 1.6-15) and inadequate rifampin therapy (OR 5.4, 95 % CI 1.2-25). CONCLUSIONS: Based on our results, extensive surgical debridement and adequate antibiotic therapy are needed to prevent the emergence of rifampin resistance.

Inflammatory responses predict long-term mortality risk in community-acquired pneumonia.

Long-term outcomes in patients surviving community-acquired pneumonia (CAP) are still incompletely understood. This study investigates the association of clinical parameters and blood markers with long-term mortality. We prospectively followed 877 CAP patients from a previous multicentre trial for 18 months follow-up and investigated all-cause mortality following hospital discharge. Overall mortality was 17.3% (95% CI 14.8-19.8%) with a 12.8% (95% CI 10.9-15.0%) mortality incidence rate per year. Initial risk assignment using the Pneumonia Severity Index was accurate during the 18 month follow-up. Multivariable regression models (hazard ratio, 95% CI) designated the following as independent risk factors for long-term mortality: male sex (1.7, 1.2-2.5); chronic obstructive pulmonary disease (1.5, 1.1-2.1); neoplastic disease (2.5, 1.7-3.7); and highest quartile of peak pro-adrenomedullin level (3.3, 1.7-6.2). Initial presentation with temperature>38.7°C (0.4, 0.2-0.6), chills (0.6, 0.4-0.99) and highest quartile of the inflammatory marker C-reactive-protein (0.3, 0.2-0.5) were independent protective factors. A weighted risk score based on these variables showed good discrimination (area under receiver operating characteristic curve 0.78, 95% CI 0.74-0.82). Pronounced clinical and laboratory signs of systemic inflammatory host response upon initial hospital stay were associated with favourable long-term prognosis. Further studies should address whether closer monitoring of high-risk CAP patients after hospital discharge favourably impacts long-term mortality.

Prognostic value of procalcitonin in community-acquired pneumonia.

The prognostic value of procalcitonin (PCT) levels to predict mortality and other adverse events in community-acquired pneumonia (CAP) remains undefined. We assessed the performance of PCT overall, stratified into four predefined procalcitonin tiers (< 0.1, 0.1-0.25, > 0.25-0.5, >0.5 µg·L⁻¹) and stratified by Pneumonia Severity Index (PSI) and CURB-65 (confusion, urea >7 mmol·L⁻¹, respiratory frequency ≥ 30 breaths·min⁻¹, systolic blood pressure < 90 mmHg or diastolic blood pressure ≤ 60 mmHg, and age ≥ 65 yrs) risk classes to predict all-cause mortality and adverse events within 30 days follow-up in 925 CAP patients. In receiver operating characteristic curves, initial PCT levels performed only moderately for mortality prediction (area under the curve (AUC) 0.60) and did not improve clinical risk scores. Follow-up measurements on days 3, 5 and 7 showed better prognostic performance (AUCs 0.61, 0.68 and 0.73). For prediction of adverse events, the AUC was 0.66 and PCT significantly improved the PSI (from 0.67 to 0.71) and the CURB-65 (from 0.64 to 0.70). In Kaplan-Meier curves, PCT tiers significantly separated patients within PSI and CURB-65 risk classes for adverse events prediction, but not for mortality. Reclassification analysis confirmed the added value of PCT for adverse event prediction, but not mortality. Initial PCT levels provide only moderate prognostic information concerning mortality risk and did not improve clinical risk scores. However, PCT was helpful during follow-up and for prediction of adverse events and, thereby, improved the PSI and CURB65 scores.

Pathogenesis and management of fracture-related infection.

BACKGROUND: Both fracture-related infections (FRIs) and periprosthetic joint infections (PJIs) include orthopaedic implant-associated infections. However, key aspects of management differ due to the bone and soft tissue damage in FRIs and the option of removing the implant after fracture healing. In contrast to PJIs, research and guidelines for diagnosis and treatment in FRIs are scarce. OBJECTIVES: This narrative review aims to update clinical microbiologists, infectious disease specialists and surgeons on the management of FRIs. SOURCES: A computerized search of PubMed was performed to identify relevant studies. Search terms included 'Fracture' and 'Infection'. The reference lists of all retrieved articles were checked for additional relevant references. In addition, when scientific evidence was lacking, recommendations are based on expert opinion. CONTENT: Pathogenesis, prevention, diagnosis and treatment of FRIs are presented. Whenever available, specific data of patients with FRI are discussed. IMPLICATIONS: Management of patients with FRI should take into account FRI-specific features. Treatment pathways should implement a multidisciplinary approach to achieve a good outcome. Recently, international consensus guidelines were developed to improve the quality of care for patients suffering from this severe complication, which are highlighted in this review.

Cutaneous vasculitis associated with fluoroquinolones.

Cutaneous vasculitis is a clinical entity with a broad differential diagnosis, including an adverse drug reaction. It is defined as inflammation of skin blood vessel walls. During a 7-year-period, we observed three patients who developed isolated cutaneous vasculitis during antibiotic therapy of bacterial infection. All were treated with a fluoroquinolone (ciprofloxacin or levofloxacin) combined with rifampin (two cases) or flucloxacillin (three cases), respectively. In all three cases the lesions gradually resolved after treatment with the inciting fluoroquinolone had been stopped. In one patient, leukocytoclastic small-vessel vasculitis was histologically confirmed. Fluoroquinolone-associated cutaneous vasculitis consists of an isolated self-limiting disorder that is part of a systemic vasculitis, or even life-threatening disease. Clinicians should be aware of this serious adverse event because any continuation of treatment may be fatal.

Spinal epidural abscess in clinical practice.

Spinal epidural abscess (SEA) is a rare but severe infection requiring prompt recognition. The major prognostic factor for a favourable outcome is early diagnosis, leading to appropriate treatment. In clinical practice, a diagnosis of SEA is often not considered, particularly in the early stages of the disease when neurological symptoms are not apparent. Knowledge of persons at risk, clinical features and the required diagnostic procedures may decrease the number of initially misdiagnosed cases. Clinical signs, duration of symptoms and the rate of neurological deterioration show a high inter-individual variability, and the classic triad (spinal pain, fever and neurological deficit) is often not found, especially not at first presentation to a physician. However, most patients complain of severe localized back pain. Inflammatory parameters in the blood are generally elevated, but not specific. Gadolinium-enhanced magnetic resonance imaging is the most sensitive, specific and accurate imaging method. Although neurosurgical decompression is still the treatment of choice in the majority of cases, less invasive procedures (e.g. computed tomography-guided needle aspiration) or antimicrobial treatment alone can be applied in selected cases. The choice of the most appropriate therapy should be discussed immediately after a confirmed diagnosis in consultation with infectious disease, radiology and spinal surgery specialists. The outcome of SEA is largely influenced by the severity and duration of neurological deficits prior to surgery, stressing the importance of early recognition.

The role of diabetes mellitus in patients with bloodstream infections.

BACKGROUND: Since diabetes mellitus predisposes to infection, we evaluated whether diabetes increases the risk of bloodstream infection and worsens its outcome. METHODS: During a 4-year period 71 diabetic and 252 non-diabetic patients with bloodstream infection were included. Risk factors for death were assessed by univariate and multivariate analysis. RESULTS: Bloodstream infection was more frequent in diabetics than in non-diabetics (25.8/1000 admissions vs. 5.8/1000 admissions, p <0.0001). Urinary tract infection was the predominant source, and Escherichia coli the most frequent microorganism in both groups. Klebsiella pneumoniae was more frequent in diabetics than in non-diabetics (18% vs 5%, p <0.001). Whereas sepsis of unknown origin was more common in diabetics (14% vs. 6%, p <0.05), catheter-related bloodstream infection predominated in non-diabetics (3% vs 10%, p <0.05). Secondary septic foci (p <0.05) and disseminated intravascular coagulation (p <0.05) were more frequent in diabetics. The in-hospital mortality rate was similar in the two groups (18% vs. 14%). Univariate analysis (RR [CI 95%]) in diabetics revealed glycaemia >20 mmol/L (3.9 [1.7-22]), ICU stay (7.1 [2-25]), mechanical ventilation (8.4 [1.2-57]) and chronic renal/hepatic failure (8.2 [1.6-43]) as significant risk factors. Hyperglycaemia (4.3 [3.4-5.2]) and ICU stay (3.3 [1.9-4.9]) remained significant in multivariate analysis. CONCLUSIONS: Diabetics had a 4.4-fold higher risk of bloodstream infection, were more prone to sepsis of unknown origin and had more septic complications than non-diabetics. The mortality rate was similar in the two groups.

Exudation primes human and guinea pig neutrophils for subsequent responsiveness to the chemotactic peptide N-formylmethionylleucylphenylalanine and increases complement component C3bi receptor expression.

After circulating in the vascular system a short time, polymorphonuclear leukocytes (PMN) migrate to extravascular sites in response to chemotactic stimuli. Prestimulation of PMN in vitro by secretagogues has been shown to increase their number of N-formylmethionylleucylphenylalanine (fmet-leu-phe) and complement component C3bi (CR3) receptors. We investigated whether the same phenomenon occurred in vivo, comparing characteristics of human skin chamber and guinea pig peritoneal exudate and blood PMN. Exudate PMN of both species contained approximately 28% less of the specific granule marker vitamin B12-binding protein (P less than 0.01) but a similar amount of the azurophil granule marker beta-glucuronidase. The total number of fmet-leu-phe receptors was 5.9 times higher in guinea pig exudate than in blood PMN (P less than 0.01) and 2.9 times higher in human exudate than in blood PMN (P less than 0.02). All exudate PMN and most blood PMN preparations showed a high affinity receptor (Kd approximately 2.3 X 10(-8) M) and a low affinity receptor (approximately 1.5 X 10(-7) M). The upregulation of fmet-leu-phe receptors in exudate PMN correlated with an improved responsiveness to fmet-leu-phe induced membrane depolarization, oxidative metabolism, and chemotaxis. In addition, the concentration of fmet-leu-phe that produced a half-maximal response of chemotaxis, superoxide production, and membrane potential depolarization was 10-fold lower in exudate PMN than in blood PMN. Human exudate PMN had a twofold increased C3bi receptor expression compared with blood PMN. Thus, a preferential loss of specific granules is associated with increased number of high and low affinity fmet-leu-phe receptors and increased C3bi receptor expression not only in vitro, but also in vivo. The data indicate that exudation primes PMN for their subsequent responsiveness to fmet-leu-phe, a modification that may be crucial for efficient antimicrobial host defense.

Pathogenesis of foreign body infection. Evidence for a local granulocyte defect.

Implanted foreign bodies are highly susceptible to pyogenic infections and represent a major problem in modern medicine. In an effort to understand the pathogenesis of these infections, we studied the phagocytic function in the vicinity of a foreign body by using a recently developed guinea pig model of Teflon tissue cages subcutaneously implanted (Zimmerli, W., F.A. Waldvogel, P. Vaudaux, and U.E. Nydegger, 1982, J. Infect. Dis., 146:487-497). Polymorphonuclear leukocytes (PMN) purified from tissue cage fluid had poor bactericidal activity against a catalase-positive microorganism. When compared with blood or exudate PMN, they exhibited a significant reduction in their ability to generate superoxide in response to a particulate or a soluble stimulus (72 and 57%, respectively, P less than 0.001). Not only their total contents in myeloperoxidase, beta-glucuronidase, lysozyme, and B12 binding protein were significantly reduced (by 62, 21, 47, and 63%, respectively, P less than 0.01), but also their capability for further secretion of residual B12 binding protein upon stimulation. Ingestion rates of endotoxin-coated opsonized oil particles were reduced by 25% (P less than 0.05). In an effort to reproduce these abnormalities in vitro, fresh peritoneal exudate PMN were incubated with Teflon fibers in the presence of plasma. Interaction of PMN with the fibers led to significant increases in hexose monophosphate shunt activity and exocytosis of secondary granules (P less than 0.01). PMN eluted after such interaction showed defective bactericidal activity, oxidative metabolism, and granular enzyme content similar to those observed in tissue cage PMN. The local injection of fresh blood PMN into tissue cages at the time of, or 3 h after, inoculation with 100 microorganisms (Staphylococcus aureus Wood 46) reduced the infection rate from 50 to 56 cages to 1 of 21 (P less than 0.001) and 3 of 8 cages (P less than 0.001), respectively. These results suggest that the in vivo as well as in vitro interaction of PMN with a nonphagocytosable foreign body induces a complex PMN defect, which may be partly responsible for the high susceptibility to infection of foreign bodies.

[Septic arthritis of finger joints]. / Infektiöse Arthritis der Fingergelenke.

BACKGROUND AND PURPOSE: Septic arthritis of finger joints is rare and its management not standardized. The outcome of all consecutive patients with finger joint arthritis was analyzed in terms of risk factors, surgical technique, antimicrobial therapy and hand therapy. PATIENTS AND METHODS: Data of 31 patients with surgical treatment between 1993 and 2005 were screened and those from 29 patients with > 1 year of follow-up were retrospectively analyzed. Surgical techniques were debridement, primary, secondary arthrodesis or temporary joint distraction with external fixation. In addition, all patients were treated with antibiotics and hand physiotherapy. The median follow-up of the 29 patients was 5.7 years. RESULTS: The most frequent cause was work injury (19/29), the leading causing agent Staphylococcus aureus (9/29). Overall 16/29 (55 %) of the patients with follow-up had a good result regarding healing of infection, lack of pain and fair function. Primary arthrodesis was performed in 3, secondary arthrodesis in 4 patients. 3 patients were treated with temporary external fixation for three weeks. Cartilage damage detected during surgery (p = 0.01) was the significant risk factor for a bad outcome. The median delay to treatment was 4 days (1 - 550 days). Antibiotics were given for a median of 2 days by the iv-route and 17 days orally. CONCLUSIONS: Septic arthritis of finger joints should be early recognized and immediately treated with surgery and antibiotics, in order to avoid cartilage damage. If cartilage is already damaged, primary arthrodesis with the use of an external fixation is indicated.

Debridement and implant retention in the management of hip periprosthetic joint infection: outcomes following guided and rapid treatment at a single centre.

AIMS: To analyse the effectiveness of debridement and implant retention (DAIR) in patients with hip periprosthetic joint infection (PJI) and the relationship to patient characteristics. The outcome was evaluated in hips with confirmed PJI and a follow-up of not less than two years. PATIENTS AND METHODS: Patients in whom DAIR was performed were identified from our hip arthroplasty register (between 2004 and 2013). Adherence to criteria for DAIR was assessed according to a previously published algorithm. RESULTS: DAIR was performed as part of a curative procedure in 46 hips in 42 patients. The mean age was 73.2 years (44.6 to 87.7), including 20 women and 22 men. In 34 hips in 32 patients (73.9%), PJI was confirmed. In 12 hips, the criteria for PJI were not fulfilled and antibiotics stopped. In 41 (89.1%) of all hips and in 32 (94.1%) of the confirmed PJIs, all criteria for DAIR were fulfilled. In patients with exogenous PJI, DAIR was performed not more than three days after referral. In haematogenous infections, the duration of symptoms did not exceed 21 days. In 28 hips, a single debridement and in six hips two surgical debridements were required. In 28 (87.5%) of 32 patients, the total treatment duration was three months. Failure was noted in three hips (9%). Long-term follow-up results (mean 4.0 years, 1.4 to 10) were available in 30 of 34 (88.2%) confirmed PJIs. The overall successful outcome rate was 91% in 34 hips, and 90% in 30 hips with long-term follow-up results. CONCLUSION: Prompt surgical treatment with DAIR, following strict diagnostic and therapeutic criteria, in patients with suspected periprosthetic joint infection, can lead to high rates of success in eradicating the infection. Cite this article: Bone Joint J 2017;99-B:330-6.

Outcome of prosthetic knee-associated infection: evaluation of 40 consecutive episodes at a single centre.

Few studies have compared the long-term success of different surgical strategies in prosthetic knee-associated infection. Accordingly, a retrospective cohort study was performed of 40 episodes in 35 consecutive patients undergoing revision surgery for prosthetic knee-associated infection at a single centre between 1988 and 2003. The median patient age was 70 (44-90) years; the median follow-up period was 28 (2-193) months; 45% of infections were early, 23% were delayed, and 32% were late; and 55% of infections were caused by staphylococci. The probability of survival without prosthesis failure was 92.4% (95% CI, 84.1-100) after 1 year, and 88.7% (95% CI, 78-99.4) after 2 years. Recurrence-free survival was observed in 20 (95%) of 21 patients treated with debridement and retention, in both patients with one-stage exchange, and in 11 (85%) of 13 patients with two-stage exchange. Patients with delayed infection had a worse outcome than those with early or late infection (67% vs. 97%; p < 0.03). Patients with at least partially adequate antimicrobial therapy had a higher success rate than those with inadequate treatment (94% vs. 60%; p 0.069). The outcome was similar for patients with a duration of therapy of 3 to < 6 months, and those with a duration of therapy of > or = 6 months (91% vs. 87% success). Different surgical procedures had similar success rates, provided that the type of infection, the pathogen, the stability of the implant and the local skin and soft-tissue condition were considered. Adherence to an algorithm defining a rational surgical and antibiotic treatment strategy contributed to a favourable outcome.

Dynamics of serum procalcitonin in patients after major neurosurgery.

Classical markers of infection cannot differentiate reliably between inflammation and infection after neurosurgery. This study investigated the dynamics of serum procalcitonin (PCT) in patients following major neurosurgery. PCT concentrations remained < 0.2 ng/mL during the post-operative course. In contrast, leukocyte and neutrophil counts, as well as C-reactive protein (CRP) levels, increased significantly post-operatively (leukocytes, range 7.1-23.7 x 10(9)/L, p < 0.001; neutrophils, range 70.8-94.5%, p < 0.001; CRP, median 14 mg/L, range 3-95 mg/L, p < 0.001). Analysis of PCT levels using assays with improved sensitivity may be useful in the diagnosis of neurosurgical patients with post-operative fever of unknown origin.

Somatic manifestations in women with generalized anxiety disorder. Psychophysiological responses to psychological stress.

Generalized anxiety disorder is associated with symptoms that suggest heightened muscular tension and autonomic arousal. Since self-reports of physiological states in patients with anxiety disorder are frequently unreliable, we compared 20 female patients with generalized anxiety disorder with a matched group of nonanxious controls on a battery of psychophysiological assessments (skin conductance, heart interbeat interval, blood pressure, respiration, and forehead and gastrocnemius electromyographic activity). We found that during baseline patients with generalized anxiety disorder differed from controls on electromyographic, but not on autonomic, measures. During psychological stress tasks, patients with generalized anxiety disorder showed a weaker mean skin conductance response with a narrower range in both skin conductance and heart rate than controls. These findings suggest that sympathetic inhibition, rather than enhancement, occurs in patients with generalized anxiety disorder during performance stress.

LPS directly induces oxygen radical production in human monocytes via LPS binding protein and CD14.

In human monocytes, superoxide (O2-) generation accompanies phagocytosis and is important for bactericidal activity. It also contributes to tissue damage in inflammation. In the present study we investigated, whether lipopolysaccharide (LPS) directly stimulates monocyte O2- production with kinetics known for other LPS effects and, if so, by which mechanism. LPS caused a time- and dose-dependent O2- release in nonadherent purified monocytes. The effect appeared after 5 min, peaked at 30 min, and disappeared after 2 h. It was maximal with 10 ng/ml lipid A (+148 +/- 22%, P < .001), 1 ng/ml LPS Escherichia coli Re (+226 +/- 68%, P < .001), and 100 ng/ml LPS Salmonella abortus equi sm (+272 +/- 52%, P < .001), respectively. The effect was not observed in buffer, even when using 10 micrograms/ml LPS. It was dependent on the presence of heat-inactivated AB serum, with a maximal effect at > or = 0.5%. Serum could be replaced by LPS-binding protein (LBP). Polymyxin B and anti-LBP antiserum, respectively, blocked the LPS effect. LPS-induced O2- generation was also completely blocked by anti-CD14 antibodies (3C10 and 63D3) and by their corresponding F(ab')2 fragments. Monocytes treated with phosphoinositol-specific phospholipase C and monocytes from patients with paroxysmal nocturnal hemoglobinuria, lacking the phosphatidylinositol-anchored CD14, did not respond to LPS stimulation with O2- production. Similarly to LPS, E. coli caused stronger O2- production with heat-inactivated serum than without, and this effect was blocked by anti-CD14 antibodies. In conclusion, these data indicate that LPS directly stimulates O2- production in human monocytes via CD14 depending on LBP.

Effect of antiretroviral therapy on viral load, CD4 cell count, and progression to acquired immunodeficiency syndrome in a community human immunodeficiency virus-infected cohort. Swiss HIV Cohort Study.

OBJECTIVE: To examine the effect of different antiretroviral treatment regimens on viral load, CD4 lymphocyte counts, and rates of progression to clinical acquired immunodeficiency syndrome events among treatment-naive human immunodeficiency virus (HIV)-infected patients enrolled in a large community cohort study. METHODS: Based in 7 outpatient clinics, the Swiss HIV Cohort Study is a cohort with national coverage. Virological, immunologic, and clinical results of 755 treatment-naive patients (median age, 36 years; 28.2% female) who initiated antiretroviral therapy between July 1, 1995, and June 30, 1997, were analyzed. Patients started undergoing monotherapy with 1 reverse transcriptase inhibitor (RTI), combination therapy with at least 2 RTIs, or highly active antiretroviral therapy (HAART) with RTIs and protease inhibitors. RESULTS: Antiretroviral treatment led to a mean reduction of viremia of 1.8 log10 copies per milliliter with HAART, 1.2 log10 copies per milliliter with RTI combination therapy, and 0.4 log10 copies per milliliter with monotherapy. Virological failure, defined as less than 1 log10 reduction per milliliter in viremia, was present in 45 (20%) patients undergoing HAART, 180 (38%) undergoing RTI combination therapy, and 47 (82%) undergoing monotherapy. The proportion of patients reaching undetectable viremia was 12% (n = 7) for monotherapy, 41% (n = 197) for RTI combination therapy, and 63% (n = 137) for HAART. Similar gains of CD4 cells were achieved with RTI combination therapy and HAART. Kaplan-Meier estimates of progression rates to a new acquired immunodeficiency syndrome event at 18 months were 13.6% (monotherapy), 4.7% (RTI combination therapy), and 3.9% (HAART). CONCLUSIONS: The rate of virological failure of antiretroviral treatments was high in this population of treatment-naive patients, even among patients receiving combination regimens. Clinical progression rates were, however, low in patients treated with RTI combination therapy and HAART.

Low risk of bacteremia during catheter replacement in patients with long-term urinary catheters.

BACKGROUND: Geriatric patients with long-term urinary catheters have an increased morbidity and mortality. It is conceivable that catheter replacement causes bacteremia and contributes to this morbidity and mortality. The purpose of our study was to determine the incidence and clinical relevance of bacteremia induced by urinary catheter replacements. METHODS: We analyzed clinical signs and symptoms and laboratory measures (leukocyte count, C-reactive protein, urine sediment, urine culture) during 120 routine catheter replacements in geriatric patients. In addition, blood cultures were drawn before and at 5, 15, and 30 minutes after catheter replacement. RESULTS: The urine cultures showed growth of 1 to 5 different microorganisms before replacement. Of 480 blood cultures, 27 (5.6%) were positive. However, the same species grew from blood and urine in only 5 catheter replacements. None of the patients met criteria for systemic inflammatory response syndrome. There were no significant differences in clinical and laboratory findings between patients with and without bacteremia. Coagulase-negative staphylococci grew in 12 blood cultures. Their distribution over time suggested that they mainly represented catheter replacement-related bacteremia rather than contaminants. Consequently, 64 intraurethral catheter segments were additionally cultured. Coagulase-negative staphylococci grew in 10 catheter cultures, but in only 2 simultaneously cultured urine samples. CONCLUSION: Bacteremia induced by routine replacement of long-term urinary catheters occurred in 4.2% (5/120) of replacements in geriatric patients. Such bacteremia did not have a detectable clinical relevance in our study.