Daptomycin versus vancomycin for osteoarticular infections due to methicillin-resistant Staphylococcus aureus (MRSA): a nested case-control study.

Vancomycin is the standard antibiotic for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections. While daptomycin is approved for MRSA bacteremia, its effectiveness in osteoarticular infections (OAIs) has not been established. A 1:2 nested case-control study of adult patients with MRSA OAIs admitted to an academic center from 2005 to 2010 was carried out. Clinical outcomes and drug toxicity in patients treated with daptomycin versus vancomycin were compared. Twenty patients with MRSA OAIs treated with daptomycin were matched to 40 patients treated with vancomycin. The median age of the patients was 52 years (range, 25-90), and 40 (67%) were male. Most patients had osteomyelitis (82%), predominantly from a contiguous source (87%). Forty percent were diabetics. Diabetic patients were more likely to receive vancomycin than daptomycin [20 (50%) vs. 4 (20%); p = 0.03]. Vancomycin was more often combined with antibiotics other than daptomycin [22 (55%) vs. 5 (25%); p = 0.03]. The median total antibiotic treatment duration was 48 (daptomycin) vs. 46 days (vancomycin) (p = 0.5). Ninety percent of daptomycin-treated patients had previously received vancomycin for a median of 14.5 days (range, 2-36). Clinical success rates were similar between daptomycin and vancomycin at 3 months [15 (75%) vs. 27 (68%); p = 0.8] and 6 months [14 (70%) vs. 23 (58%); p = 0.5], even after propensity score-based adjustment for antibiotic assignment. The frequency of adverse events was similar between treatment groups [1 (5%) vs. 7 (18%); p = 0.2]. Daptomycin and vancomycin achieved similar rates of clinical success and drug tolerability. Daptomycin is a reasonable alternative for treating MRSA OAIs, particularly in patients where therapy with vancomycin has not been well tolerated.

Classification of and cytoreductive surgery for low-grade appendiceal mucinous neoplasms.

BACKGROUND: Low-grade appendiceal mucinous neoplasm (LAMN) is a precursor lesion for pseudomyxoma peritonei (PMP), which, if treated suboptimally, may later disseminate throughout the abdominal cavity. The role of cytoreductive surgery for these relatively early lesions is unclear. METHODS: Clinicopathological details and treatment outcomes of patients with a LAMN and disease limited to the appendix or immediate periappendiceal tissues, referred to a national treatment centre between 2002 and 2009, were evaluated prospectively. RESULTS: Of 379 patients with a diagnosis of PMP, 43 (median age 49 years) had LAMNs localized to the appendix and periappendiceal tissue. Thirty-two patients initially presented with symptoms of acute appendicitis or right iliac fossa pain. Two distinct lesions were identified: type I (disease confined to the appendiceal lumen) and type II (mucin and/or neoplastic epithelium in the appendiceal submucosa, wall and/or periappendiceal tissue, with or without perforation). Type I lesions were managed by a watch-and-wait surveillance policy with serial measurement of tumour markers and computed tomography in 14 of 16 patients. Seventeen of 27 patients with type II lesions underwent risk-reducing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy with low morbidity. After a median follow-up of 40 months, there was no disease progression in either treatment pathway. CONCLUSION: This study identified two LAMN subtypes. Type II lesions have pathological features of increased risk for dissemination and should be considered for risk-reducing cytoreductive surgery.

High-risk antimicrobial prescriptions among ambulatory patients on warfarin.

WHAT IS KNOWN AND OBJECTIVE: Warfarin is a potent anticoagulant with many drug-drug interactions, including antimicrobials. There is limited data on the frequency of prescription of high-risk antimicrobials to patients on warfarin. To examine the frequency of prescriptions for potentially interacting antimicrobials in ambulatory patients on warfarin and the impact of warfarin on the prescription of high-risk antimicrobials. METHODS: A retrospective cohort study of patients with pharmacy benefits who had ≥1 claim for an oral antimicrobial between 1 January 2008 and 31 December 2008 was conducted, utilizing a pharmacy benefits database. Demographic data including age, gender, chronic disease score (CDS) and geographic location were determined. Warfarin users were defined as any patient with ≥1 claim for warfarin during the follow-up period. Antimicrobials considered high risk for potential interaction with warfarin based on existing literature included trimethoprim/sulfamethoxazole, levofloxacin, ciprofloxacin, metronidazole and fluconazole. Multivariate analysis was used to determine the impact of warfarin use and other factors on high-risk antimicrobial prescription. RESULTS AND DISCUSSION: A total of 4,568,150 patients with ≥1 claim for antimicrobials during 2008 were analysed. Of them, 110,192 (2·4%) also had one or more claims for warfarin. Among all antimicrobial prescriptions in warfarin users, 42·6% were for high-risk antimicrobials. The mean number of antimicrobial prescriptions was 3·0 in warfarin users versus 2·4 in warfarin non-users (P-value <0·001). After adjusting for age, gender, CDS and geography, the odds of exposure to high-risk antimicrobials was 42% lower (OR 0·58; P-value <0·001) in warfarin users compared with warfarin non-users. WHAT IS NEW AND CONCLUSIONS: A high percentage (42·6%) of antimicrobial prescriptions among warfarin users were for high-risk antimicrobials that carry excess bleeding risk. Although clinicians were somewhat less likely to prescribe high-risk antimicrobials to warfarin users compared with non-users, the incidence of co-prescription remains high.

Selective CCR2-targeted macrophage depletion ameliorates experimental mesangioproliferative glomerulonephritis.

The CCL2/CCR2 chemokine/receptor axis directs the chemotaxis of infiltrating monocytes/macrophages and T cells and plays a pivotal role in tissue damage and fibrosis in kidney diseases. The eradication of the activated leucocytes should diminish the production of inflammatory mediators, limit tissue damage and ameliorate disease. A recombinant fusion protein (OPL-CCL2-LPM) comprised of the human CCL2 (monocyte chemoattractant protein-1) chemokine fused to a truncated form of the enzymatically active A1 domain of Shigella dysenteriae holotoxin (SA1) has been developed. The CCL2 portion binds specifically to CCR2-bearing leucocytes and the fusion protein enters the cells, where the SA1 moiety inhibits protein synthesis resulting in cell death. The compound was tested in a model of anti-thymocyte serum (ATS)-induced mesangioproliferative glomerulonephritis (ATS-GN). Male rats were injected with ATS on day 0 and treated intravenously with vehicle, 50 or 100 microg/kg of OPL-CCL2-LPM Q2D from days 2, 4, 6 and 8. Urine and blood were collected on days 0, 5 and 9. Animals were sacrificed on day 9. No treatment-related effects on body weight or signs of clinical toxicity were observed. Urine protein levels were decreased in treated animals. At the highest dose, histopathological analyses of kidney sections revealed maximum reductions of 36, 31, 30 and 24% for macrophage count, glomerular lesions, alpha-smooth muscle actin and fibronectin respectively. These results indicate a significant protective effect of OPL-CCL2-LPM in this model of nephritis.

Specific inhibitors of protein kinase C block transmitter-induced modulation of sensory neuron calcium current.

Modulation of neuronal, voltage-dependent calcium current has been described for a number of transmitters and peptides, but the biochemical basis for this phenomenon has not been completely identified. In several cases protein kinase C (PKC) is thought to mediate transmitter inhibition of calcium current; however, a lack of specific PKC inhibitors has hampered a direct physiological test of this idea. We have used the whole-cell, tight-seal configuration of the patch-clamp technique to apply intracellularly two specific PKC inhibitors to the cell bodies of embryonic chick sensory neurons. Both inhibitors, a 17 kd protein purified from bovine brain and a synthetic 13 amino acid "pseudosubstrate" peptide, blocked inhibition of calcium current by either norepinephrine or an exogenously applied PKC activator. These results provide strong evidence that activation of PKC is a prerequisite for the modulation of sensory neuron calcium current by norepinephrine.

Expression and characterization of recombinant human ciliary neurotrophic factor from Escherichia coli.

The gene for ciliary neurotrophic factor (CNTF) was cloned from a human genomic DNA library by screening with a DNA fragment amplified from human genomic DNA using the polymerase chain reaction. A DNA sequence coding for human CNTF was placed under control of an regulatable promoter in the expression vector pJU1003 and transformed into Escherichia coli strain BL21(DE3). Induction of expression in cultures of this transformant led to the accumulation of approx. 25 mg/l per A600 unit of human CNTF. CNTF was purified to homogeneity from cell lysates via anion-exchange, cation-exchange and Zn(2+)-affinity chromatography. Purified CNTF contained less than 0.1% contaminating E. coli proteins, as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), Western blot analysis and reversed-phase high-pressure liquid chromatography (HPLC). The protein exhibited an ultraviolet absorption maximum at 279 nm with a calculated extinction coefficient of A1%(279) = 9.0. Peptide map and amino acid sequence analyses confirmed that the expressed protein has the amino acid sequence expected for human CNTF, except for the absence of the amino-terminal methionine. High-purified recombinant human CNTF supported the survival of chick embryo parasympathetic, sympathetic and sensory neurons in culture at low picomolar concentrations. These results indicate that the biological activities previously ascribed to impure CNTF preparations indeed reside in one molecule.

Enterococcal endocarditis: 107 cases from the international collaboration on endocarditis merged database.

PURPOSE: To describe clinical features and outcomes of enterococcal left-sided native valve endocarditis and to compare it to endocarditis caused by other pathogens. SUBJECTS AND METHODS: Patients in the International Collaboration on Endocarditis-Merged Database were included if they had left-sided native valve endocarditis. Demographic characteristics, clinical features, and outcomes were analyzed. Multivariable analysis evaluated enterococcus as a predictor of mortality. RESULTS: Of 1285 patients with left-sided native valve endocarditis, 107 had enterococcal endocarditis. Enterococcal endocarditis was most frequently seen in elderly men, frequently involved the aortic valve, tended to produce heart failure rather than embolic events, and had relatively low short-term mortality. Compared to patients with non-enterococcal endocarditis, patients with enterococcal endocarditis had similar rates of nosocomial acquisition, heart failure, embolization, surgery, and mortality. Compared to patients with streptococcal endocarditis, patients with enterococcal endocarditis were more likely to be nosocomially acquired (9 of 59 [15%] vs 2 of 400 [1%]; P <.0001) and have heart failure (49 of 107 [46%] vs 234 of 666 [35%]; P = 0.03). Compared to patients with S. aureus endocarditis, patients with enterococcal endocarditis were less likely to embolize (28 of 107 [26%] vs 155 of 314 [49%]; P <.0001) and less likely to die (12 of 107 [11%] vs 83 of 313 [27%]; P = 0.001). Multivariable analysis of all patients with left-sided native valve endocarditis showed that enterococcal endocarditis was associated with lower mortality (odds ratio [OR] 0.49; 95% confidence interval [CI] 0.24 to 0.97). CONCLUSIONS: Enterococcal native valve endocarditis has a distinctive clinical picture with a good prognosis.

A comparison of neural tube defects identified by two independent routine recording systems for congenital malformations in Northern Ireland.

The efficiency of two systems for recording congenital malformations has been compared; one system, the Registrar General's Congenital Malformation Notification, is based on registering all malformed infants, and the other, the Child Health System, records all births. In Northern Ireland for three years [1974--1976], using multiple sources of ascertainment, a total of 686 infants with neural tube defects was identified among 79 783 live and stillbirths. The incidence for all neural tube defects in 8 60 per 1 000 births. The Registrar General's Congenital Malformation Notification System identified 83.6% whereas the Child Health System identified only 63.3% of all neural tube defects. Both systems together identified 86.2% of all neural tube defects. The two systems are suitable for monitoring of malformations and the addition of information from the Genetic Counselling Clinics would enhance the data for epidemiological studies.

Changes in intracranial pressure associated with apneumic retractors.

OBJECTIVE: To investigate the effect of apneumic retraction on intracranial pressure (ICP) using a live porcine model. DESIGN: Five 25- to 30-kg pigs had a fiber-optic ICP bolt inserted under general endotracheal anesthesia and were monitored for ICP, mean arterial pressure, arterial blood gas measurements, and intra-abdominal pressure before, during, and after pneumoperitoneum, with each period 30 minutes long. These series of measurements were repeated after artificially raising ICP with an epidural balloon to create a head-injured model. The mean (+/- SE) ICP in the noninjured model at baseline was 13.46 +/- 1.01 mm Hg; during pneumoperitoneum, 18.72 +/- 1.50 mm Hg (P = .0001). Similarly, in the head-injured model, ICP was raised artificially to a new baseline of 22 +/- 1.75 mm Hg with an epidural balloon, and pneumoperitoneum increased ICP to 27.40 +/- 0.93 mm Hg (P = .0001). Pneumoperitoneum was then released, and an apneumic retractor was inserted while maintaining the inflated epidural balloon. MAIN OUTCOME MEASURE: Changes in ICP. RESULTS: Applying anterior wall retraction equivalent to 20 mm Hg was not associated with changes in ICP. These observations were independent of any changes in arterial PCO2 or arterial pH. Following the release of pneumoperitoneum, abdominal wall retraction, and epidural balloon, all measurements reverted to baseline. CONCLUSION: Pneumoperitoneum adversely affects ICP, while apneumic retraction may not affect animals with raised ICP. These findings suggest that pneumoperitoneum should be used with caution in patients with raised ICP, and apneumic retraction may be a safer alternative for laparoscopic evaluation in this population.

The effect of reduction of IgM on the quantitative determination of IgM by radial immunodiffusion and turbidimetry.

The behaviour of different IgM proteins in radial immunodiffusion was investigated. In agreement with earlier findings differences were observed between various IgM preparations, which disappeared after reduction of IgM. The amount of IgM in several standard sera, that are used for the quantitative determination of IgM, was measured by radial immunodiffusion after reduction of IgM, and was found to be lower than hitherto accepted. It was observed that it was not necessary to perform reduction of IgM before its quantitation when a turbidimetric immunoassay was used. We conclude that (1) the standard sera that are used for the determination of IgM have to be calibrated in radial immunodiffusion after reduction of IgM and (2) the absolute amount of IgM in sera is about 0.6 times the amount that is commonly accepted.

The therapeutic potential of chemokine-toxin fusion proteins.

Activated cells of the immune system and the biochemical mediators they produce, underlie the pathology and secondary tissue damage in a wide range of diseases and traumas. One approach to therapy is to inhibit specific mediators in various biochemical pathways or cascades with the use of biological response modifiers. An alternative approach is to suppress or eradicate diseased cells or activated cells that fuel the disease and secondary tissue damage processes. Osprey has chosen to develop novel versatile cell-targeting agents that exploit the cell biology of the chemokine superfamily of receptors and ligands.

Evaluation of "Gastromiro" for bowel opacification during computed tomography: comparison with diatrizoate and barium sulphate.

A new oral formulation of iopamidol, "Gastromiro", was evaluated as a bowel contrast agent during abdominal computed tomography (CT). Comparison was made with the well established agents sodium/meglumine diatrizoate ("Urografin 370") and dilute barium sulphate ("E-Z CAT") in a randomized, blind study of 150 consecutive patients undergoing abdominal and/or pelvic CT. Parameters assessed included quality of bowel opacification, artefact generation, contrast-medium palatibility, side effects and cost. No significant difference was found between the three contrast media in stomach- or small-bowel opacification. E-Z CAT was superior at opacifying the caecum/ascending colon. No compelling reason to choose a particular agent was found in the other assessed parameters, but cost is a significant factor.

Cavitation of squamous carcinoma of the lung.

This study indicates that a good percentage of the cavitary squamous cell carcinomas of the lung can be suggested throught the use of sputum cytology. Hyperkeratinized malignant cells associated with varying degrees of karyorrhexis, "ghost cells," and a diathesis of purulent exudate are helpful in the identification of this tumor type. The cell population found cytologically can be demonstrated in the histologic sections of cavitary squamous cell carcinoma of the lung. We readily admit that the application of the above criteria will not decrease the mortality or morbidity of lung cancer, but can be used as a refinement of a diagnostic tool.

Frequency of atopy, allergy, and previous general anaesthesia in surgical specialties.

This paper reports part of a large survey of atopy, allergy, and previous anaesthesia in 10 000 preanaesthetic patients. The occurrence of these risk factors in the various surgical specialties has been assessed. Obstetric patients have a significantly higher frequency of atopy and allergy than the total female population studied. Among males cardiothoracic patients are the only group to have a significantly higher frequency of atopy and allergy than the overall figure for their sex.

Acute renal failure associated with vancomycin and ß-lactams for the treatment of osteomyelitis in diabetics: piperacillin-tazobactam as compared with cefepime.

Few data are available on the nephrotoxic potential of vancomycin when combined with certain ß-lactam antibiotics for the treatment of osteomyelitis (OM). A retrospective cohort study was conducted of all diabetic patients with OM treated with vancomycin plus piperacillin-tazobactam (VPT) or vancomycin plus cefepime (VC) for at least 72 h at a VA Medical Center between 1 January 2006 and 31 December 2011. All patients with a creatinine clearance (CrCl) of ≤ 40 mL/min, a blood urea nitrogen/serum creatinine (SCr) ratio of ≥ 20 : 1 or an absolute neutrophil count of <500 cells/mm(3) were excluded. The primary outcome was development of acute renal failure (ARF), defined as an increase in SCr of 0.5 mg/dL or 50% of baseline. One hundred and thirty-nine patients met the inclusion criteria; 109 in the piperacillin-tazobactam group and 30 in the cefepime group. Among patients receiving VPT, 29.3% (32/109) developed ARF, as compared with 13.3% (4/30) receiving VC (p 0.099). Among patients receiving high-dose therapy (≥ 18 g of piperacillin-tazobactam daily or ≥ 3 g of cefepime daily), 37.5% (9/24) receiving VPT and 17.6% (3/17) receiving VC developed ARF (p 0.29). A multiple logistic regression analysis identified weight and average vancomycin trough as the only significant predictors of ARF; the choice of VPT as therapy yielded an OR of 3.45 (95% CI 0.96-12.40; p 0.057). The authors were unable to detect a statistically significant difference in ARF between groups; however, the power requirement was not met. Further study with a larger patient population seems warranted.

A patient with acute liver failure and extreme hypoglycaemia with lactic acidosis who was not in a coma: causes and consequences of lactate-protected hypoglycaemia.

Lactate can substitute for glucose as a metabolic substrate. We report a patient with acute liver failure who was awake despite a glucose level of 0.7 mmol/l with very high lactate level of 25 mmol/l. The hypoglycaemia+hyperlactataemia combination may be considered paradoxical since glucose is the main precursor of lactate and lactate is reconverted into glucose by the Cori cycle. Literature relevant to the underlying mechanism of combined deep hypoglycaemia and severe hyperlactataemia was assessed. We also assessed the literature for evidence of protection against deep hypoglycaemia by hyperlactataemia. Four syndromes demonstrating hypoglycaemia+hyperlactataemia were found: 1) paracetamol-induced acute liver failure, 2) severe malaria, 3) lymphoma and 4) glucose-6-phosphatase deficiency. An impaired Cori cycle is a key component in all of these metabolic states. Apparently the liver, after exhausting its glycogen stores, loses the gluconeogenic pathway to generate glucose and thereby its ability to remove lactate as well. Several patients with lactic acidosis and glucose levels below 1.7 mmol/l who were not in a coma have been reported. These observations and other data coherently indicate that lactate-protected hypoglycaemia is, at least transiently, a viable state under experimental and clinical conditions. Severe hypoglycaemia+hyperlactataemia reflects failure of the gluconeogenic pathway of lactate metabolism. The existence of lactate-protected hypoglycaemia implies that patients who present with this metabolic state should not automatically be considered to have sustained irreversible brain damage. Moreover, therapies that aim to achieve hypoglycaemia might be feasible with concomitant hyperlactataemia.