Intravenous fosfomycin for pulmonary exacerbation of cystic fibrosis: Real life experience of a large adult CF centre.

BACKGROUND: The increased prevalence of multi-drug resistant strains of P.aeruginosa and allergic reactions among adult patients with cystic fibrosis (CF) limits the number of antibiotics available to treat pulmonary exacerbations. Fosfomycin, a unique broad spectrum bactericidal antibiotic, might offer an alternative therapeutic option in such cases. AIM: To describe the clinical efficacy, safety and tolerability of intravenous fosfomycin in combination with a second anti-pseudomonal antibiotic to treat pulmonary exacerbations in adult patients with CF. METHOD: A retrospective analysis of data captured prospectively, over a 2-years period, on the Unit electronic medical records for patients who received IV fosfomycin was performed. Baseline characteristics in the 12 months prior treatment, lung function, CRP, renal and liver function and electrolytes at start and end of treatment were retrieved. RESULTS: 54 patients received 128 courses of IV fosfomycin in combination with a second antibiotic, resulting in improved FEV1 (0.94 L vs 1.24 L, p < 0.01) and reduced CRP (65 mg/L vs 19.3 mg/L, p < 0.01). Renal function pre- and post-treatment remained stable. 4% (n = 5) of courses were complicated with AKI at mid treatment, which resolved at the end of the course. Electrolyte supplementation was required in 18% of cases for potassium and magnesium and 7% for phosphate. Nausea was the most common side effect (48%), but was well controlled with anti-emetics. CONCLUSION: Antibiotic regimens including fosfomycin appear to be clinically effective and safe. Fosfomycin should, therefore, be considered as an add-on therapy in patients who failed to respond to initial treatment and with multiple drug allergies.

Staphylococcus aureus develops increased resistance to antibiotics by forming dynamic small colony variants during chronic osteomyelitis.

OBJECTIVES: Staphylococcus aureus osteomyelitis often develops to chronicity despite antimicrobial treatments that have been found to be susceptible in in vitro tests. The complex infection strategies of S. aureus, including host cell invasion and intracellular persistence via the formation of dynamic small colony variant (SCV) phenotypes, could be responsible for therapy-refractory infection courses. METHODS: To analyse the efficacy of antibiotics in the acute and chronic stage of bone infections, we established long-term in vitro and in vivo osteomyelitis models. Antibiotics that were tested include ß-lactams, fluoroquinolones, vancomycin, linezolid, daptomycin, fosfomycin, gentamicin, rifampicin and clindamycin. RESULTS: Cell culture infection experiments revealed that all tested antibiotics reduced bacterial numbers within infected osteoblasts when treatment was started immediately, whereas some antibiotics lost their activity against intracellular persisting bacteria. Only rifampicin almost cleared infected osteoblasts in the acute and chronic stages. Furthermore, we detected that low concentrations of gentamicin, moxifloxacin and clindamycin enhanced the formation of SCVs, and these could promote chronic infections. Next, we treated a murine osteomyelitis model in the acute and chronic stages. Only rifampicin significantly reduced the bacterial load of bones in the acute phase, whereas cefuroxime and gentamicin were less effective and gentamicin strongly induced SCV formation. During chronicity none of the antimicrobial compounds tested showed a beneficial effect on bone deformation or reduced the numbers of persisting bacteria. CONCLUSIONS: In all infection models rifampicin was most effective at reducing bacterial loads. In the chronic stage, particularly in the in vivo model, many tested compounds lost activity against persisting bacteria and some antibiotics even induced SCV formation.

Efficacy and safety of infliximab as continuous or intermittent therapy in patients with moderate-to-severe plaque psoriasis: results of a randomized, long-term extension trial (RESTORE2).

BACKGROUND: Continuous maintenance therapy with infliximab 5 mg kg(-1) every 8 weeks is effective for moderate-to-severe plaque-type psoriasis. OBJECTIVES: To evaluate the efficacy and safety of continuous vs. intermittent infliximab maintenance therapy. METHODS: RESTORE2 was a long-term extension of RESTORE1. At baseline of RESTORE2, eligible patients who had received infliximab for 26 weeks and achieved Psoriasis Area and Severity Index (PASI) 75 in RESTORE1 were rerandomized 1 : 1 to continuous therapy (infliximab 5 mg kg(-1) every 8 weeks) or intermittent therapy (no infliximab until > 50% loss of PASI improvement). Safety and efficacy assessments occurred throughout the study. RESULTS: In total, 222 patients were randomized to receive continuous therapy, and 219 to intermittent therapy. More serious infusion-related reactions occurred with intermittent therapy (8/219 patients, 4%) than with continuous therapy (1/222 patients, < 1%), leading the sponsor to terminate the study. The mean duration of exposure to infliximab was 40·12 weeks (SD 27·55) with a mean of 5·8 infusions (range 0-16) for continuous therapy and 22·78 weeks (SD 22·98) with a mean of 3·4 infusions (range 0-16) for intermittent therapy. Although no formal efficacy analyses were conducted, continuous therapy led to greater PASI 75 at week 52 in the continuous group (81/101, 80%) than in the intermittent group (39/83, 47%); several other efficacy measures demonstrated similar patterns. CONCLUSIONS: For patients with moderate-to-severe plaque-type psoriasis, continuous therapy with infliximab may be more effective than intermittent therapy. The incidence of serious infusion-related reactions in the intermittent group suggests that clinicians should avoid intermittent therapy in this population.

Depression but not seizure frequency predicts quality of life in treatment-resistant epilepsy.

BACKGROUND: The two-thirds of patients with epilepsy who become seizure-free have a quality of life (QOL) similar to the general population. The major treatment challenge is patients with refractory epilepsy. Whereas neurologists typically focus on seizure reduction in the treatment of these patients, results of studies relating seizure frequency to QOL are conflicting. As depression is associated with reduced QOL in epilepsy and antiepileptic medications (AEDs) can cause depression, it is important to determine the relative roles of depression and seizure frequency in QOL in refractory epilepsy. METHODS: Prospective evaluation was conducted of patients with refractory epilepsy being admitted to an inpatient video-EEG monitoring unit. The impact of clinical variables (age, sex, marital status, seizure frequency, duration and type of seizure disorder, seizure localization, number of AEDs, depression) on QOL was analyzed. RESULTS: Depression was a powerful predictor of QOL (n = 122, beta = -35.8, p < 0.0001). No other variable predicted QOL. Depression was common (54%), severe (19% with suicidal thoughts), underdiagnosed (37%), and largely untreated (17% on antidepressants). CONCLUSIONS: Treatment of depression may be inadequately prioritized in the management of intractable epilepsy.

Lentivirus vectors encoding both central polypurine tract and posttranscriptional regulatory element provide enhanced transduction and transgene expression.

Incorporation of a central polypurine tract (cPPT) and a posttranscriptional regulatory element (PRE) into lentivirus vectors provides increased transduction efficiency and transgene expression. We compared the effects of these elements individually and together on transduction efficiency and gene expression, using lentivirus vectors pseudotyped with vesicular stomatitis virus G protein (VSV-G) and encoding enhanced green fluorescent protein (GFP) and rat erythropoietin (EPO). The transduction efficiency was greater than 2-fold higher in the vector containing the PRE element, 3-fold higher in vector encoding the cPPT element, and 5-fold increased in the GFP virus containing both cPPT and PRE elements relative to the parent virus. In comparison with parent vector the mean fluorescence intensity (MFI) of GFP expression was 7-fold higher in cells transduced with virus containing PRE, 6-fold increased in cells transduced with virus containing cPPT, and 42-fold increased in GFP-virus containing both cPPT and PRE elements. EPO-virus containing a PRE element showed a nearly 5-fold increase in EPO secretion over the parent vector, and the vector encoding both PRE and cPPT showed a 65-fold increase. Thus, lentivirus vectors incorporating both PRE and cPPT showed expression levels significantly increased over the sum of the components alone, suggesting a synergistic effect.

Impaired coronary tissue plasminogen activator release is associated with coronary atherosclerosis and cigarette smoking: direct link between endothelial dysfunction and atherothrombosis.

BACKGROUND: The aim of the study was to establish the influence of proximal coronary artery atheroma and smoking habit on the stimulated release of tissue plasminogen activator (tPA) from the heart. METHODS AND RESULTS: After diagnostic coronary angiography in 25 patients, the left anterior descending coronary artery (LAD) was instrumented, and the proximal LAD plaque volume was determined by use of intravascular ultrasound (IVUS). Blood flow and fibrinolytic responses to selective LAD infusion of saline, substance P (10 to 40 pmol/min; endothelium-dependent), and sodium nitroprusside (5 to 20 microgram/min; endothelium-independent) were measured by intracoronary IVUS and Doppler, combined with arterial and coronary sinus blood sampling. Mean plaque burden was 5.5+/-0.8 mm(3)/mm vessel (range 0.6 to 13.7 mm(3)/mm vessel). LAD blood flow increased with both substance P and sodium nitroprusside (P<0.001), although coronary sinus plasma tPA antigen and activity concentrations increased only during substance P infusion (P<0.006 for both). There was a strong inverse correlation between the LAD plaque burden and release of active tPA (r=-0.61, P=0.003). Cigarette smoking was associated with impaired coronary release of active tPA (current smokers, 31+/-23 IU/min; ex-smokers, 50+/-33 IU/min; nonsmokers 202+/-73 IU/min; P<0.05). CONCLUSIONS: We found that both the coronary atheromatous plaque burden and smoking habit are associated with a reduced acute local fibrinolytic capacity of the heart. These important findings provide evidence of a direct link between endogenous fibrinolysis, endothelial dysfunction, and atherothrombosis in the coronary circulation and may explain the greater efficacy of thrombolytic therapy for myocardial infarction in cigarette smokers.

Noncompliance of health care workers with universal precautions during trauma resuscitations.

BACKGROUND: Universal precautions during resuscitations are mandated by hospital regulations. We documented adherence to universal precautions during trauma resuscitations at our level I trauma center. METHODS: During trauma resuscitations, a medical student using an elevated viewing platform observed health care workers (HCWs) for the use of barrier precautions (BPs): gloves, masks, gowns, and eyewear. Only HCWs having direct patient contact were included. The purpose of the observation was not disclosed to those being observed. RESULTS: In 12 resuscitations involving 104 HCWs, none had 100% compliance with BPs. Compliance rates for individual BPs were gloves, 98%; eyewear (any type), 52%; gowns, 38%; masks, 10%; and eyewear (with side protectors), 9%. Resuscitations in which bleeding was observed involved 59 HCWs with 38% compliance; only 2 used full BPs. No difference in compliance rates occurred during the study period. CONCLUSIONS: Experienced trauma care HCWs are cavalier regarding blood-borne disease exposure risks. Measures to encourage (or force) compliance are needed.

Drugs, guns, and kids: the association between substance use and injury caused by interpersonal violence.

BACKGROUND: Drug and alcohol uses have been linked to the frequency of injury events, recurrent hospital admission for injury, and interpersonal violence. Data regarding the association of recent substance use and injury type and frequency in children and young adults are not available. Such data probably would be valuable in planning interventions to prevent substance use and reduce the risks of injuries. METHODS: Evidence of substance use was assessed in trauma patients presenting to the authors' level 1 trauma center over a 6-month interval. Demographic data, mechanisms of injury, revised trauma scores (RTS), injury severity scores (ISS), hospital days, and mortality rate were evaluated. Chi square analysis and 2-tailed, paired t tests were used for statistical analysis. Multivariate logistic regression was utilized to determine the influence of individual variables. RESULTS: From a total group of 743 patients with life-threatening injuries, trauma registry records of 186 patients less than 21 years old were eligible for evaluation, and 126 of these had complete blood and urine drug assessments completed on admission to the trauma center. Forty-two percent (53 of 126) patients tested positive for alcohol or drugs. No patients less than 14 years of age (n = 61) had positive drug screen results. However, in the cohort of patients aged 14 and 15 (n = 17), 71% tested positive. Also, 72% of adolescents (age < 18) who were victims of injuries from gunshot wounds had evidence of substance use. Multivariate analysis showed gunshot wounds (P <.003) to be associated independently with positive drug screens. No statistical differences were observed in ethnic distribution, ISS, RTS, hospital days, or mortality rate when patients with positive screen results were compared with those without evidence of substance use. CONCLUSIONS: Trauma victims had evidence of substance use in early teen age years especially in the 14 and 15-year-old age groups. Toxicology screening disclosed that substance use is associated strongly with gunshot wounds. Substance use, along with poverty, inadequate family support, and peer pressure are factors that influence injury risk. Interventions to prevent substance use in young children may reduce the risk of injury.

Higher risk of HIV transmission during trauma resuscitations.

Despite an appreciation of the potential for blood borne pathogen exposure, compliance of universal precautions is low. While reports of HIV positive rates in trauma patients have varied from 0.15% to 7.8%, the estimated prevalence of HIV in Louisiana is 0.32%. We made use of two unique, complimentary data sources: the Trauma Registry and the HIV/AIDS Reporting System database of known HIV positive patients to estimate the relative prevalence of HIV which may indicate an increase risk of blood borne pathogen transmission to health care workers during trauma resuscitations. In one year, 1031/1159 patients were evaluated from the Trauma Registry Database and 22 similar patients (2.13%) were found in both the Trauma Registry and the HIV/AIDS Reporting System Database. Our prevalence is an indicator of the minimum risk since it is based on only reported cases of HIV and justifies intensification of education and enforcement of the practice of universal precautions.

Evolution in the management of hepatic trauma: a 25-year perspective.

OBJECTIVE: To define the changes in demographics of liver injury during the past 25 years and to document the impact of treatment changes on death rates. SUMMARY BACKGROUND DATA: No study has presented a long-term review of a large series of hepatic injuries, documenting the effect of treatment changes on outcome. A 25-year review from a concurrently collected database of liver injuries documented changes in treatment and outcome. METHODS: A database of hepatic injuries from 1975 to 1999 was studied for changes in demographics, treatment patterns, and outcome. Factors potentially responsible for outcome differences were examined. RESULTS: A total of 1,842 liver injuries were treated. Blunt injuries have dramatically increased; the proportion of major injuries is approximately 16% annually. Nonsurgical therapy is now used in more than 80% of blunt injuries. The death rates from both blunt and penetrating trauma have improved significantly through each successive decade of the study. The improved death rates are due to decreased death from hemorrhage. Factors responsible include fewer major venous injuries requiring surgery, improved outcome with vein injuries, better results with packing, and effective arterial hemorrhage control with arteriographic embolization. CONCLUSIONS: The treatment and outcome of liver injuries have changed dramatically in 25 years. Multiple modes of therapy are available for hemorrhage control, which has improved outcome.

A critical assessment of endpoints of shock resuscitation.

Modern hemodynamic therapy is not only the recognition and treatment of hypotension but also the avoidance and treatment of shock in its broadest sense. The major issues include the recognition of hypoperfusion of the body as a whole or its individual tissues and organ systems and the determination of the best endpoints for the treatment of shock. Even if all of the commonly used clinical indicators of shock are "normal," shock on a cellular, tissue, or organ basis may still be present. Whether "organ-specific" assessments, such as gastric tonometry or tissue oxygen tension measurement, are the ultimate answer to this problem remains to be seen. The determination of adequate intravascular volume (preload) continues to present major difficulties in the care of critically ill or injured patients. Although PCWP is frequently helpful, it is not a gold standard. A bedside ultrasonic technique, such as esophageal Doppler sonography, may replace the Swan-Ganz catheter technique in many patients.

Weaving meanings together in an AIDS residence: communicative practices, perceived health outcomes, and the symbolic construction of community.

This study examines the role of communicative practices in the symbolic construction of health and community among residents living in a residential facility for people with AIDS. Questionnaire results show that two types of communicative practices--governance/support and everyday/special--are significantly related to residents' perceived physical and emotional health outcomes, their perceptions of the residence as a community (as opposed to a facility or institution), and their satisfaction with living there. Everyday/special practices reveal the communicative means by which perceived health is socially constructed, while governance/support practices reveal the importance of meta-communication for massaging the issues and tensions that pervade community life, and both sets of communicative practices help explain members' perceptions of the residence as a community and their satisfaction with living there. The study provides additional evidence regarding the constitutive nature of communication as a connecting thread that weaves together individual and collective meanings to help create and sustain such concepts as health and community.

The influence of heart rate on augmentation index and central arterial pressure in humans.

Arterial stiffness is an important determinant of cardiovascular risk. Augmentation index (AIx) is a measure of systemic arterial stiffness derived from the ascending aortic pressure waveform. The aim of the present study was to assess the effect of heart rate on AIx. We elected to use cardiac pacing rather than chronotropic drugs to minimize confounding effects on the systemic circulation and myocardial contractility. Twenty-two subjects (13 male) with a mean age of 63 years and permanent cardiac pacemakers in situ were studied. Pulse wave analysis was used to determine central arterial pressure waveforms, non-invasively, during incremental pacing (from 60 to 110 beats min-1), from which AIx and central blood pressure were calculated. Peripheral blood pressure was recorded non-invasively from the brachial artery. There was a significant, inverse, linear relationship between AIx and heart rate (r = -0.76; P < 0.001). For a 10 beats min-1 increment, AIx fell by around 4 %. Ejection duration and heart rate were also inversely related (r = -0. 51; P < 0.001). Peripheral systolic, diastolic and mean arterial pressure increased significantly during incremental pacing. Although central diastolic pressure increased significantly with pacing, central systolic pressure did not. There was a significant increase in the ratio of peripheral to central pulse pressure (P < 0.001), which was accounted for by the observed change in central pressure augmentation. These results demonstrate an inverse, linear relationship between AIx and heart rate. This is likely to be due to alterations in the timing of the reflected pressure wave, produced by changes in the absolute duration of systole. Consideration of wave reflection and aortic pressure augmentation may explain the lack of rise in central systolic pressure during incremental pacing despite an increase in peripheral pressure.

Telecommunication relay services: linking nurses to patients with communication disorders.

Telecommunication relay service (TRS) is a lifeline for deaf, deaf-blind, hard-of-hearing, and speech-disabled persons. Nurses who are technology shy and unfamiliar with TRS fail to integrate this simple telephone process into their pursuit of quality healthcare outcomes for patients with communication disorders. This article aims to increase home care nurses' awareness, comfort, and use of TRS.

Post-treatment dopexamine infusions partially reverse reductions in cranial mesenteric blood flow and mucosal oxygenation induced by hypoxia in newborn piglets.

A severe hypoxic insult is known to induce dramatic reductions in newborn intestinal blood flow and is, thus, considered a vector for the development of neonatal intestinal ischemic diseases. Dopexamine (DPX) is a novel synthetic agent that has potent B2-adrenoceptor and dopaminergic activity, the clinical effects of which include an increase in cardiac output and in mesenteric blood flow. Having previously shown that infusion of DPX before hypoxia (HYP) mitigated the reduction in newborn mesenteric blood flow, we sought to define its efficacy when given after an established hypoxic insult. Ultrasonic transit time blood flow probes were placed around the ascending aorta and cranial mesenteric artery of anesthetized, mechanically ventilated 0 to 2-day-old piglets. Small bowel mucosal oxygenation was observed with a tissue oxygen monitoring system. After stabilization, animals were subjected to one of the following: HYP (FIO2 = 0.12) for 60 minutes (n = 12); DPX (5 microg/kg/min) infusion begun 10 minutes after induction of HYP/DPX (n = 11). Almost no alterations in any of the monitored variables were shown in a group (n = 5) of similarly instrumented, untreated animals. In contrast, although both hypoxic piglet groups experienced significant (P < 0.05, analysis of variance) declines from baseline cardiac output, mesenteric blood flow, and mucosal oxygenation, each of these deleterious effects was significantly (P < 0.05) blunted in the DPX-treated animals. During periods of systemic hypoxemia, the reductions in neonatal mesenteric blood flow and oxygenation can be somewhat blunted by DPX. As such, this agent may prove of clinical benefit when an infant is threatened by a hypoxic episode.

Laparoscopic retroperitoneal repair of recurrent postoperative lumbar hernia.

A patient who previously underwent an attempt at open mesh repair of a lumbar hernia that occurred following iliac crest bone harvesting was managed successfully by laparoscopic retroperitoneal fixation of the prosthetic material to the iliac crest using bone screws. A review of the literature supports the use of such a novel approach to manage this often vexing problem.

Esophageal Doppler ultrasound monitor versus pulmonary artery catheter in the hemodynamic management of critically ill surgical patients.

BACKGROUND: The pulmonary artery (PA) catheter has been used to determine hemodynamic indices; however, it has recently been criticized. This study was undertaken to evaluate an esophageal Doppler monitor (EDM) as a possible replacement for PA catheter in critically ill, mechanically ventilated patients. METHODS: EDM and PA catheters were placed in patients in the surgical intensive care units (n = 14, 118 matched sets of data). PA catheter and EDM measurements, including corrected flow time (FTc,) a measure of preload, were obtained. Pearson correlation (r) was analyzed to compare PA catheter and EDM measurements, and a nonlinear regression model was used to describe Starling Relationships. RESULTS: Cardiac output correlated between EDM and PA catheter (r = 0.6; p < 0.001). FTc correlated more strongly with cardiac output than did pulmonary capillary wedge pressure. (FTc: r2 = 0.27; p < 0.001; cardiac output: r2 = 0.04; p = 0.06). CONCLUSION: Corrected flow time is a better indicator of preload than pulmonary capillary wedge pressures. EDM seems to be at least as useful as PA catheter in managing the hemodynamic status of critically ill surgical patients.