A comparison of 5-day courses of dirithromycin and azithromycin in the treatment of acute exacerbations of chronic obstructive pulmonary disease

BACKGROUND: Short-term use of antibiotics has become a common component of the management of acute exacerbations of chronic bronchitis (AECB), particularly in complex cases with productive cough or purulent phlegm. The macrolide antibiotics, particularly second-generation agents such as dirithromycin and azithromycin, are among the antibiotic classes frequently recommended and used to treat upper and lower respiratory infections, including AECB. OBJECTIVE: This study compared the clinical efficacy and tolerability of 5-day courses of dirithromycin and azithromycin given once daily for the treatment of acute exacerbations of chronic obstructive pulmonary disease (COPD). METHODS: This randomized, investigator-blinded, parallel-group clinical trial was conducted at 5 centers in the United States. Eligible patients were adult (age >35 years) smokers or ex-smokers (smoking history of at least 10 pack-years) with chronic bronchitis and an acute exacerbation, defined by the occurrence of increased dyspnea and/or productive cough and feverishness within 48 hours of enrollment. Before randomization, an attempt was made to obtain a sputum specimen from each patient for Gram's staining and culture. Patients were randomized to receive dirithromycin 500 mg QD for 5 days or azithromycin 500 mg QD on day 1 and 250 mg QD on days 2 to 5. Clinical efficacy was assessed separately by patients and physicians at early (days 7-10) and late (days 25-35) posttreatment visits. RESULTS: Eighty-six patients (48 women, 38 men; mean age, 55 years) with a mean smoking history of 31 pack-years were included in the intent-to-treat analysis. Forty-six (54%) patients were randomized to dirithromycin and 40 (47%) patients to azithromycin. Clinical efficacy was reported in a high proportion of patients in both treatment groups, both at the early posttreatment visit (84.8% dirithromycin, 75.7% azithromycin; difference dirithromycin - azithromycin, 9.1%; 95% CI, -8.2 to 26.4) and the late posttreatment visit (95.5% and 86.5%, respectively; difference dirithromycin - azithromycin, 9.0%; 95% CI, -3.7 to 21.6). A similar proportion of patients required a second course of antibiotics over the study period (20.5% dirithromycin, 27.0% azithromycin; difference dirithromycin - azithromycin, -6.6%; 95% CI, -25.2 to 12.1). Only 42 (48.8%) patients were able to produce a sputum sample before receiving study treatment, and of these, only 20 (47.6%) demonstrated a preponderance of neutrophils on Gram's staining. Both treatments were well tolerated. CONCLUSIONS: The results of this study suggest comparable clinical efficacy between 5-day courses of once-daily dirithromycin and azithromycin in acute exacerbations of COPD. There were insufficient data to permit meaningful comparison of the bacteriologic efficacy of these macrolide antibiotics.     

Protective action of luminal bile salts in necrotizing acute pancreatitis in mice.

Bile salts in the intestinal lumen act to inhibit the release of cholecystokinin (CCK). Recent studies have shown that CCK may play a permissive role in the development of acute pancreatitis. In this study, the amount of luminal bile salts in female Swiss Webster mice was either decreased by feeding 4% (wt/wt) cholestyramine or increased by feeding 0.5% sodium taurocholate for 1 wk. Plasma levels of CCK were stimulated by cholestyramine and inhibited by taurocholate. Then, acute pancreatitis was induced either by caerulein injections, or by feeding a choline-deficient, ethionine-supplemented (CDE) diet. Feeding of cholestyramine significantly decreased survival from 25% to 0% in the CDE pancreatitis, and increased the magnitude of elevation of serum amylase levels and the extent of pancreatic necrosis in both models of pancreatitis; CCK-receptor blockade with CR-1409 completely abolished the adverse effects of cholestyramine. In contrast, feeding of taurocholate significantly increased survival to 100% and decreased the elevation of serum amylase and pancreatic necrosis; CCK-8 antagonized these actions of taurocholate. Luminal bile salts appear to provide a physiologic protection against necrotizing pancreatitis, at least in part, both by inhibiting the release of CCK and by promoting resistance of the pancreas to CCK excessive stimulation in vivo.     

In vitro susceptibilities of ocular Bacillus cereus isolates to clindamycin, gentamicin, and vancomycin alone or in combination.

A broth dilution assay was used to determine the in vitro susceptibilities of 10 ocular isolates of Bacillus cereus to clindamycin, gentamicin, and vancomycin both alone and in combination. The checkerboard technique was used to determine fractional inhibitory and bactericidal concentration indices for combinations of clindamycin-gentamicin and vancomycin-gentamicin.     

Cerebral tuberous sclerosis: postmortem magnetic resonance imaging and pathologic anatomy

We conducted postmortem magnetic resonance imaging (MRI) studies of five brains from patients with a clinical and pathologic diagnosis of tuberous sclerosis. Areas of prolonged T1 and T2 relaxation could easily be identified within the white matter subjacent to the cortical tubers despite formalin fixation and storage. The signal changes were identical to those reported in living patients with the disease. The detection of cortical tubers by MRI in two patients who were 34 and 35 years of age, respectively, at the time of death suggests that the signal changes on MRI are less affected by aging than are the low-attenuation changes on computed tomography, which are rarely identified in patients older than 27 years of age. Once the changes caused by fixation of tissues are considered, postmortem MRI is a viable investigative tool in studying tuberous sclerosis and other diseases, and it seems to correlate well with the MRI findings in living patients, as well as the gross and histopathologic changes seen at autopsy.     

Deep vein thrombosis during prolonged mechanical ventilation despite prophylaxis

OBJECTIVE: To determine the prevalence of deep vein thrombosis (DVT) among patients requiring prolonged mechanical ventilation in the intensive care unit. DESIGN: Prospective cohort study. SETTING: Medical intensive care unit of a university-affiliated urban teaching hospital. PATIENTS: Patients requiring mechanical ventilation for >7 days. INTERVENTIONS: All patients admitted to the medical intensive care unit requiring prolonged mechanical ventilation underwent duplex ultrasonography of their lower extremities and upper extremities every 7 days. The main outcome identified was the presence of DVT. Secondary outcomes included hospital mortality, hospital and intensive care unit lengths of stay, and the occurrence of pulmonary embolism. MEASUREMENTS AND MAIN RESULTS: A total of 110 patients requiring mechanical ventilation for >7 days were enrolled. Prophylaxis against DVT was employed in 110 of the patients (100%). A total of 26 patients (23.6%) developed DVT. Patients with DVT were statistically more likely to have underlying malignancy (30.8% vs. 8.3%; p =.004) and longer durations of central venous catheterization (26.9 +/- 22.2 days vs. 14.5 +/- 12.1 days; p =.024) compared with patients without DVT. There were no statistically significant differences in hospital mortality or lengths of stay in the hospital and intensive care unit for patients with and without DVT. Patients documented to have DVT by using duplex ultrasonography had a statistically greater frequency of subsequent pulmonary embolism during their hospitalization (11.5% vs. 0.0%; p =.012). CONCLUSION: The occurrence of DVT is common among patients requiring prolonged mechanical ventilation in the intensive care unit setting despite the use of prophylaxis measures. These data suggest that alternative strategies for the prevention of DVT should be evaluated. Additionally, early detection methods should be considered to reduce the potential morbidity associated with untreated DVT in this high-risk population.     

Prevention of nosocomial bloodstream infections: effectiveness of antimicrobial-impregnated and heparin-bonded central venous catheters

OBJECTIVES: To examine the effectiveness of antimicrobial-impregnated and heparin-bonded catheters relative to standard central venous catheters in lessening catheter-related bloodstream infections. DATA SOURCES: Articles were identified by computer-assisted searching. STUDY SELECTION: Studies were eliminated from further consideration if they did not contain original data relevant to lessening catheter-related bloodstream infections, were nonrandomized or uncontrolled, described subjects <17 yrs of age, or used animal subjects. DATA ABSTRACTION: From each eligible article, we abstracted the following: a) citation; b) type of control; c) study setting; d) type of experimental catheter; e) catheter-specific complications; f) total numbers of patients and catheters; g) number of experimental catheters used that resulted in a catheter-related bloodstream infection; h) number of control catheters used that resulted in a catheter-related bloodstream infection; i) number of experimental catheters used without catheter-related bloodstream infections; and j) number of control catheters used without infections. We also recorded the duration of catheter use and the types of microbes cultured in association with the catheters and with catheter-related bloodstream infections. DATA SYNTHESIS: Eleven eligible studies were identified. Using meta-analysis, we showed that antimicrobial-impregnated and heparin-bonded central venous catheters significantly decreased catheter-related bloodstream infections by 2.32% (95% confidence interval, 1.04% to 3.61%). CONCLUSIONS: The modest additional cost for the use of these catheters relative to the considerable cost of treating even a single bloodstream infection makes their use cost-effective.     

Biomechanical coupling in renin-releasing cells.

The renin-angiotensin system is a major regulatory system controlling extracellular fluid volume and blood pressure. The rate-limiting enzyme in this hormonal cascade is renin, which is synthesized and secreted into the circulation by renal juxtaglomerular (JG) cells. The renal baroreceptor is a key physiologic regulator of renin secretion, whereby a change in renal perfusion pressure is sensed by these cells and results in a change in renin release. However, the mechanism, direct or indirect, underlying pressure transduction is unknown. We studied the direct application of mechanical stretch to rat JG cells and human renin-expressing (CaLu-6) cells on the release of renin. JG cells released a low level of baseline renin, comprising < 5% of their total renin content. By contrast, renin secretion from CaLu-6 cells comprised approximately 30% of cellular stores, yet was also stimulated twofold by 10 microM forskolin (P </= 0.001). In JG cells, mechanical stretch inhibited basal renin release by 42% (P < 0.01) and forskolin-stimulated renin release by 25% (P < 0.05). In CaLu-6 cells, stretch inhibited basal- and forskolin-stimulated renin release by 30 and 26%, respectively (both P < 0.01). Northern blot analysis demonstrated a stretch-induced reduction in baseline renin mRNA accumulation of 26% (P < 0.05) in JG and 46% (P < 0.05) in CaLu-6 cells. The data demonstrate that mechanical stretch in renin-releasing cells inhibits basal and stimulated renin release accompanied by a decrease in renin mRNA accumulation. Further studies will be necessary to characterize the intracellular events mediating biomechanical coupling in renin-expressing cells and the relationship of this signaling pathway to the in vivo baroreceptor control of renin secretion.     

Lack of association between TNF-308 polymorphism and the clinical and immunological characteristics of systemic lupus erythematosus and primary Sjögren's syndrome

OBJECTIVE: To investigate the previously reported association of tumor necrosis factor alpha (TNF) -308 single nucleotide polymorphism (SNP) with the clinical course and immunological features in patients with systemic lupus erythematosus (SLE) and primary Sj?gren's syndrome (pSS). METHODS: The studied group consisted of 113 consecutive SLE and 65 pSS patients. TNF -308 SNP was determined by the polymerase chain reaction-restriction fragment length polymorphism technique. Clinical and immunological characteristics were assessed according to a standard protocol that included disease activity (SLEDAI) and damage (SLICC Damage Index). Serum TNFalpha levels were measured in samples collected from 32 patients with SLE and 16 with pSS by enzyme-linked immunosorbent assay. RESULTS: The TNF2 allele (A) was observed in 46% and 54% of SLE and pSS patients, respectively. We failed to find any significant association between the -308 SNP and disease manifestations, the presence of autoantibodies or cytokine levels in either group. CONCLUSION: TNF -308 SNP (TNF2) does not exhibit a significant influence on the disease course or immunological response in SLE and pSS. Other genetic and/or environmental factors seem to be required and to be more important than TNF2 allele for the progression of these diseases.     

Unrelated donor marrow transplantation in children

Eighty-eight children 0.5 to 17 years of age (median, 9 years of age) received an unrelated donor marrow transplant for treatment of chronic myeloid leukemia (CML; n = 16), acute lymphoblastic leukemia (ALL) in first or second remission (n = 15) or more advanced stage (n = 28), acute myeloid leukemia (AML; n = 13), or other hematologic diseases (n = 16) between June 1985 and April 1993. All patients were conditioned with cyclophosphamide and total body irradiation and received a combination of methotrexate and cyclosporine as graft-versus-host disease (GVHD) prophylaxis. Fourty-six patients received transplants from HLA-identical donors and 42 patients received transplants from donors who were minor-mismatched at one HLA-A or B or D/DRB1 locus. The Kaplan-Meier estimates of disease-free survival and relapse were 75% and 0% for patients with CML, 47% and 20% for ALL in first or second remission, 10% and 60% for ALL in relapse or third remission, 46% and 46% for AML in first remission (n = 1) or more advanced disease (n = 12), and 29% and 69% for other diseases. HLA disparity was not significantly associated with lower disease-free survival, but the results suggest more relapses in HLA-matched recipients and there was significantly more transplant-related mortality in mismatched recipients (51% v 24%, P = .04). Most deaths were due to infections associated with acuteor chronic GVHD and occurred within the first 2 years after transplantation. Granulocyte engraftment occurred in all evaluable patients. Sixty-three percent of HLA-matched and 57% of HLA- mismatched recipients were discharged home disease-free at a median of 98 and 103 days, respectively, after transplantation (P = not significant [NS]). The incidence of grades II-IV acute GVHD was 83% in HLA-matched and 98% in HLA-mismatched recipients (P = .009). The incidence of chronic GVHD was 60% in HLA-matched and 69% in HLA- mismatched recipients (P = NS). One or multiple late adverse events such as cataracts, osteonecrosis of the hip or knee, restrictive or obstructive pulmonary disease, and hypothyroidism have occurred in 11 of 33 (33%) surviving patients. Immunosuppression was discontinued in 58% of surviving patients, including all 12 patients surviving more than 3.2 years, all of whom have a Lansky or Karnofsky score of 100%.(ABSTRACT TRUNCATED AT 400 WORDS)     

whmD is an essential mycobacterial gene required for proper septation and cell division

A study of potential mycobacterial regulatory genes led to the isolation of the Mycobacterium smegmatis whmD gene, which encodes a homologue of WhiB, a Streptomyces coelicolor protein required for sporulation. Unlike its Streptomyces homologue, WhmD is essential in M. smegmatis. The whmD gene could be disrupted only in the presence of a plasmid supplying whmD in trans. A plasmid that allowed chemically regulated expression of the WhmD protein was used to generate a conditional whmD mutant. On withdrawal of the inducer, the conditional whmD mutant exhibited irreversible, filamentous, branched growth with diminished septum formation and aberrant septal placement, whereas WhmD overexpression resulted in growth retardation and hyperseptation. Nucleic acid synthesis and levels of the essential cell division protein FtsZ were unaltered by WhmD deficiency. Together, these phenotypes indicate a role for WhmD in mycobacterial septum formation and cell division.