Effectiveness of sequential intravenous-to-oral antibiotic switch therapy in hospitalized patients with gram-positive infection: the SEQUENCE cohort study.

Switching from intravenous to oral antibiotic therapy may improve inpatient management and reduce hospital stays and the complications of intravenous treatment. We aimed to assess the effectiveness of intravenous-to-oral antibiotic switch therapy and an early discharge algorithm in hospitalized patients with gram-positive infection. We performed a prospective cohort study with a retrospective comparison cohort, recruited from eight tertiary, acute-care Spanish referral hospitals. All patients included had culture-confirmed methicillin-resistant gram-positive infection, or methicillin-susceptible gram-positive infection and beta-lactam allergy and had received intravenous treatment with glycopeptides, lipopeptides, or linezolid. The study comprised two cohorts: the prospective cohort to assess the effectiveness of a sequential intravenous-to-oral antibiotic switch algorithm and early discharge, and a retrospective cohort in which the algorithm had not been applied, used as the comparator. A total of 247 evaluable patients were included; 115 in the prospective and 132 in the retrospective cohort. Forty-five retrospective patients (34 %) were not changed to oral antibiotics, and 87 (66 %) were changed to oral antibiotics without following the proposed algorithm. The duration of hospitalization was significantly shorter in the prospective cohort compared to the retrospective group that did not switch to oral drugs (16.7 ± 18.7 vs 23 ± 13.4 days, P < 0.001). No differences were observed regarding the incidence of catheter-related bacteraemia (4.4 % vs 2.6 %, P = 0.621). Our results suggest that an intravenous-to-oral antibiotic switch strategy is effective for reducing the length of hospital stay in selected hospitalized patients with gram-positive infection.

[Major closed-space bleeding in patients on anticoagulation with acenocoumarol (TAO) or non-fractionned heparin(HS): a case-control study]. / Estudio caso-control de sangrados mayores cerrados en pacientes descoagulados con acenocumarol y heparina-no fraccionada.

OBJECTIVE: To study the characteristics of major bleeding episodes into a closed space (BCS) of patients under chronic anticoagulation with either unfractionated heparin (HS) or coumadin (CM), and to determine the relationship, if any, of anticoagulation parameters (INR, PT and PTT) values at the time of bleeding with the episode. Finally, to determine risk factors for BCS and mortality in this population. METHODS: Descriptive epidemiology of all cases of BCS seen in our hospital from 1995 to 2000 was obtained through the records and follow up visits of all patients under anticoagulation (HS or CM) during this period. A matched case-control study to determine risk factors for BCS was carried out. Cases and controls (1:2) were matched for age, gender, anticoagulant treatment and indication for anticoagulation. Cases were patients with a BCS while on anticoagulation (HS OR CM). Controls were patients under anticoagulation (HS or CM) without any bleeding episode during the study period that had anticoagulation parameter values (INR, PT or PTT) determined the very same day than the cases. RESULTS: During the study period, 225 patients under anticoagulation were prospectively followed (75 cases and 150 controls) amid a total of 1650 patients under anticoagulation, for a 4.5% prevalence of BCS. Reasons for anticoagulation were: atrial fibrillation in 79 (35.3%), valvular heart disease in 59 (25.9%), pulmonary embolism or deep venous thrombosis in 48 (21.4%), dilated cardiomyopathy in 26 (11.6%) and vascular cerebral stroke in 13 (5.8%). Mean age of cases was 70.5 (SD 9.5) years and 41 (55%) were women, values similar to the controls. At the time of BCS 39 patients were on CM and 36 on HS. The mean INR value in the CM group at the time of the episode of BCS was 5.3 (SD + 7.5) while the PTT value was 2,25 (SD 0.95) in the HS group. There was previous antecedent bleeding in 24 (32%) cases. The most common sites of BCS were: muscular (40%), CNS (30.6%), retroperitoneal (18,6%) and articular (10.6%). Muscular (abdominal or thoracic wall) and retroperitoneal BCS were higher in the HS group (10 and 12 in the HS group versus 5 and 2 in the CM group, respectively; p < 0.0001). In contrast, CNS bleeding was commoner in the CM group (20 in CM versus 3 in HS; p < 0.001). BCS related mortality rate was 14.6% (11/75) and higher in the CM group (p = 0.04). Comparative analysis of the case-control study revealed that anticoagulation values in the CM group at the time of bleeding were within the recommended range in 38.5% of cases vs. 75% of the controls (p < 0.001). Also, there were significant differences in mean INR values between cases and controls (5.3 + 7.5 vs. 2.6 + 0.9, p < 0.029) In the HS group no differences were present in PTT values at the time of bleeding between cases and controls. In BCS cases, a previous bleeding episode was more frequent than in the control group (32% versus 1.3%, p < 0.001). Likewise, mortality was higher in cases (18,6%) than in controls (11.4%), p = 0.01. CONCLUSIONS: In our study, the majority of patients under anticoagulation with CM had INR values above the recommended range at the time of BCS, in contrast with those on HS that had a PTT within the therapeutic range at the time of the BCS. A previous bleeding episode was an independent risk factor for a BCS episode. Bleeding was a late complication in the CM group and frequently in the CNS, while BCS was more frequently associated with muscular or retroperitoneal sites in the HS treated group. BCS related mortality was 15%. Close monitoring of INR is crucial to minimize bleeding complications.

Activation of Raf-1 is defective in annexin 6 overexpressing Chinese hamster ovary cells.

Annexin 6 is a Ca2+-dependent phospholipid-binding protein involved in membrane trafficking. In this study we demonstrate the association of Raf-1 with recombinant rat annexin 6. Raf-annexin 6 interaction was shown to be independent of cell activation by epidermal growth factor (EGF) or phorbol esters (12-O-tetradecanoyl-phorbol-13-acetate (TPA)). A stable Chinese hamster ovary (CHO)-anx6 cell line overexpressing annexin 6 was established to examine the function of annexin 6. In these cells, no increase of Ras-GTP levels, induced by EGF or TPA, was detected. In addition, the activity of Raf was completely inhibited, whereas the mitogen-activated protein kinase-P was unaffected.

AT III Barcelona: a familial quantitative-qualitative AT III deficiency.

A quantitative and qualitative deficiency of antithrombin III (ATIII) was found in four members of a Spanish family with thrombotic tendency. In all affected members, levels of ATIII antigen and activity (heparin cofactor activity) were reduced to 50% of the normal range. When crossed immunoelectrophoresis (CIE) was performed in the presence of heparin, an abnormal slow-moving peak was found. Crossed immunoelectrofocusing (CIEF) from normal and affected individuals showed that normal ATIII migrated between pH 4.9-5.3 while the ATIII under study was asymmetrically distributed between two pH ranges: 4.9-5.3 and 4.6-4.8. Affinity adsorption of affected members' plasma to heparin-sepharose beads revealed one population of ATIII in the supernatant corresponding to the abnormal ATIII, devoid of heparin cofactor activity and showing a peak between pH range: 4.6-4.8 in CIEF. Our data supports the view that a quantitative-qualitative deficiency was present in the heterozygous state in all the affected family members. Both normal and abnormal ATIII were present in plasma of the affected individuals. This abnormal ATIII was characterized by a lack of affinity for heparin. This familial ATIII deficiency was named ATIII Barcelona.

Transient c-fos expression accompanies naturally occurring cell death in the developing interhemispheric cortex of the rat.

We have searched for the possible correlation of naturally occurring cell death with spontaneously enhanced c-fos expression in the developing cerebral cortex of normal Wistar albino rats. During the late prenatal and early postnatal period, cells with irregular contours and intracytoplasmic electron-dense granules (granule-containing cells) were apparent in the interhemispheric cortex, including the anterior cingulate and the retrosplenial cortices. These cells were loosely packed within the cortical layers derived from the cortical plate. Having excluded the possibility that these cells could be phagocytes by immunocytochemical experiments, we propose that they are cells in different phases of a process of autophagic degeneration and death. Images of extreme nuclear pyknosis were also apparent in identical locations. Cells showing immunoreactivity for c-Fos protein appeared in the same cortical areas. The immunoreactive cells were very abundant in the retrosplenial cortex, but were also present in the anterior cingulate cortex. These cells showed markedly irregular contours and large, densely immunoreactive intracytoplasmic inclusions; these images were similar to those of granule-containing cells revealed by conventional stains. The immunoreactivity for c-Fos protein was ephemeral, occurring exclusively during embryonic days 20 and 21, but granule-containing cells were observed for a longer period. The present results provide evidence, albeit indirect, that c-fos expression may occur in certain neural cells at the onset of a process of death by autophagia, and suggest a possible involvement of the proto-oncogene c-fos in certain forms of naturally occurring neuronal death.

Transient expression of c-fos during the development of the rat cerebral cortex.

The present study has explored with immunocytochemical methods the expression of the proto-oncogene c-fos during the pre- and postnatal development of the cerebral cortex of the rat. The immunostaining of the Fos protein follows a strikingly precise spatiotemporal pattern: it occurs uniquely within layer VIb of the developing cerebral cortex, and is transient, lasting only from embryonic day 20 until postnatal day 1. The expression of c-fos in layer VIb may be related to the dynamic changes that occur at this level during development.

Efficacy of fenfluramine and dexfenfluramine in the treatment of obesity: a meta-analysis.

A meta-analysis was conducted to estimate the difference of weight loss among patients treated with placebo and with fenfluramine or dexfenfluramine after 1, 2, 3, 6, and 12 months of treatment. Placebo-controlled, double-blind, randomized clinical trials, whose results were presented as weight loss by the placebo group and the drug-treated patient group, were selected for the analysis. For the pooled estimations, the method of the weighted means by the inverse of the variance was used. The association between the difference of means and several predictive variables was studied by means of weighted linear regression. Patients treated with fenfluramine or dexfenfluramine achieved a higher weight loss than those receiving placebo in all the periods studied. The greatest efficacy was observed after 3 months of treatment. Beyond this time, there is a decline in the effectiveness. Based on the efficacy data, treatments longer than 3 months would not be justified.

[Changes in the pattern of opioid analgesic consumption in Spain]. / Cambios en el patrón de consumo de analgésicos opioides en España.

BACKGROUND: Data from different sources have proved an infrautilization of opioid analgesics in Spain. A descriptive study has been conducted in order to know the utilization of these drugs and changes in the pattern of use in the last few years. MATERIAL AND METHOD: To know the consume of narcotic analgesic drugs, N02A group of the Anatomic Therapeutic Classification, a search was developed in the ECOM database from the Spanish Ministry of Health. This database contains information of drug preparations prescribed throughout the National Health Care System. RESULTS: The consumption of opioid analgesics in Spain has been multiplied by 5.2 during this period. It has increased from 94.7 defined daily dose per 1,000,000 inhabitants in 1985 to 489.4 in 1994. The most consumed drug in 1994 was dihydrocodeine, followed by tramadol. The number of defined daily dose per inhabitant and day of parenteral administration have decreased during the last years. CONCLUSIONS: Availability of new analgesic opioid drugs with better pharmacokinetic profiles has contributed to an increase of their consume in Spain.

[DTP vaccine and infant sudden death syndrome. Meta-analysis]. / Vacuna DTP y síndrome de muerte súbita del lactante. Un metaanálisis.

BACKGROUND: At the beginning of 1994, five cases of sudden infant death syndrome after DTP immunization appeared in Spain. In order to study a causal relationship a meta-analysis of the different studies that assess this possibility has been conducted. METHODS: The selection criteria was epidemiological study, case-control or cohort, assessing risk of sudden infant death syndrome in immunized versus non-immunized infants or risk of sudden infant death syndrome in recently immunized infants versus immunized infants beyond 30 days. Pooled risk ratios were calculated from adjusted risk ratios, when available, of the different studies, by a meta-analysis according the method described by Greenland. RESULTS: One cohort and four case-control studies were selected. Pooled risk ratio for immunized versus non-immunized infants was 0.67 (95% CI = 0.60-0.75). When comparing risk of sudden death syndrome in up to 30 days immunized infants versus more than 30 days immunized infants, the pooled risk ratio was 1.00 (95% CI = 0.84-1.20). CONCLUSIONS: DTP-immunization does not seem to increase the risk of sudden infant death syndrome. The risk of sudden infant death syndrome is not greater in the first thirty days following immunization. These data indicate a lack of association between DTP immunization and sudden infant death syndrome.

[The rapid specific characterization of clinical isolates of the genus Mycobacterium by the polymerase chain reaction and restriction enzyme analysis]. / Caracterización específica rápida de aislados clínicos del género Mycobacterium mediante reacción en cadena de la polimerasa y análisis de enzimas de restricción.

BACKGROUND: Typing at species level of Mycobacterium is usually performed by microbiological and biochemical methods that require a long time and/or sufficient amount of bacteria. Molecular biology can avoid these problems using different techniques. METHODS: A colony growth of the following mycobacteria has been analyzed: M. tuberculosis, M. kansasii, M. avium, M. intracellulare, M. gordonae, M. phlei, M. aurum, M. fortuitum, M. flavescens, M. marinum, M. xenopi, M. nonchromogenicum, M. terrae and M. chelonei. Strains were grown in Löwenstein-Jensen medium. DNA was obtained by proteolytic digestion and fenol extraction. The 16S rRNA gen was amplified by polymerase chain reaction (PCR) and the amplification was digested by HaeIII, HpaII, RsaI and AluI restriction enzymes. Restriction fragment patterns were analyzed by agarose gel electrophoresis and UV transillumination. RESULTS: The combination of the patterns obtained with HpaII and RsaI was sufficient to generate 13 different combined ones. The patterns of M. intracellulare and M. avium were the same. CONCLUSIONS: PCR and restriction enzyme analysis is an useful method for typing at species level of clinical isolates of mycobacteria.

[Safety of meningococcal A and C vaccine. Data from the Spanish drug surveillance system. Meningococcal Vaccine Research Group of the Spanish System of Drug Surveillance]. / Seguridad de la vacuna antimeningocócica A+C. Datos recogidos por el Sistema Español de Farmacovigilancia. Grupo de Investigación sobre la vacuna antimeningocócica del Sistema Español de Farmacogigilancia.

OBJECTIVE: Data on meningococcal vaccines safety are scanty. In 1997 several vaccination campaign took place in Spain. Thus, this situation was used to improve our knowledge about the safety profile of this vaccine. METHODS: An inquiry was carried out to the Regional Centers of the Spanish Pharmacovigilance System to know the number of vaccinated people and the type and number of suspected cases of adverse reactions. RESULTS: There were 133 identified cases of suspected adverse reactions associated with meningococcal A and C vaccine until June 1st, 1998. Most of them affected the skin (25,3%) or nervous system (similar proportion). Those of allergic reactions accounted for 35,2%. Two cases were considered as severe, although they were resolved without secuelae. CONCLUSIONS: Serious risks were not detected. The Spanish Pharmacosurveillance System as an epidemiological surveillance resource has been useful to know the safety problems associated with antimeningococcal vaccine in the community.

Extraintestinal salmonellosis in a general hospital (1991 to 1996): relationships between Salmonella genomic groups and clinical presentations.

Episodes of extraintestinal salmonellosis treated at a general hospital (1,522 beds) over a 6-year period (1991 to 1996) were characterized by the analysis of phenotypic and genotypic traits of Salmonella organisms and clinical data from medical reports. Extraintestinal salmonellosis accounted for 8% of all salmonellosis episodes. Fifty-two medical reports, dealing with 6 cases of typhoid fever, 32 cases of bacteremia, and 14 focal infections, were reviewed. All cases of typhoid fever except 1, 7 cases of bacteremia, and 5 focal infections were not related to any underlying disease or predisposing factors, while 25 cases of bacteremia and 9 focal infections were associated with some of these risk factors. All typhoid isolates and 65.4% of the nontyphoid isolates were susceptible to antimicrobials. Fifty-one nontyphoid strains were analyzed and assigned to 21 genomic groups, which were defined by serotype, combined ribotype, and combined randomly amplified polymorphic DNA type (each genomic group could include organisms differing in some phenotypic traits). The relationships between genomic groups and clinical presentations were traced. Organisms causing 22 episodes (17 episodes of bacteremia, 2 of pneumonia, 1 of peritonitis, 1 of pyelonephritis, and 1 of cystitis) belonged to a prevalent Salmonella enterica serotype Enteritidis genomic group, which included organisms assigned to four phage types, five biotypes, and four resistance patterns, causing infections in patients with and without risk factors. Seven other genomic groups, 4 Enteritidis groups (associated with both bacteremia and focal infections), 2 Typhimurium groups (one associated with bacteremia and the other with focal infections) and 1 Brandenburg group (associated with bacteremia) included two or more strains, and the remaining 13 genomic groups consisted of only one strain each.

Multiple influences on the migration of precerebellar neurons in the caudal medulla.

Neurons destined to form several precerebellar nuclei are generated in the dorsal neuroepithelium (rhombic lip) of caudal hindbrain. They form two ventrally directed migratory streams, which behave differently. While neurons in the superficial migration migrate in a subpial position and cross the midline to settle into the contralateral hindbrain, neurons in the olivary migration travel deeper in the parenchyma and stop ipsilaterally against the floor plate. In the present study, we compared the behavior of the two neuronal populations in an organotypic culture system that preserves several aspects of their in vivo environment. Both migrations occurred in mouse hindbrain explants dissected at E11.5 even when the floor plate was ablated at the onset of the culture period, indicating that they could rely on dorsoventral cues already distributed in the neural tube. Nevertheless, the local constraints necessary for the superficial migration were more specific than for the olivary migration. Distinct chemoattractive and chemorespulsive signal were found to operate on the migrations. The floor plate exhibited a strong chemoattractive influence on both migrations, which deviated from their normal path in the direction of ectopic floor plate fragments. It was also found to produce a short-range stop signal and to induce inferior olive aggregation. The ventral neural tube was also found to inhibit or slow down the migration of olivary neurons. Interestingly, while ectopic sources of netrin were found to influence both migrations, this effect was locally modulated and affected differentially the successive phases of migration. Consistent with this observation, while neurons in the superficial migration expressed the Dcc-netrin receptor, the migrating olivary neurons did not express Dcc before they reached the midline. Our observations provide a clearer picture of the hierarchy of environmental cues that influence the morphogenesis of these precerebellar nuclei.

Is metronidazole teratogenic? A meta-analysis.

AIM: In order to assess whether the use of metronidazole during pregnancy is associated with a higher risk of congenital malformations, a meta-analysis was conducted. METHODS: All epidemiological studies (cohort and case-control) which estimate risk of congenital malformations after exposure to metronidazole during early pregnancy were included in the meta-analysis. To obtain a summary odds ratio, the Mantel-Haenszel method was used. A test to verify absence of heterogeneity was also performed. RESULTS: One unpublished case-control and four published cohort studies fulfilled the inclusion criteria and were not statistically heterogeneous. A summary odds ratio was calculated for metronidazole exposure during the first trimester: OR = 1.08, 95% CI: 0.90-1.29, heterogeneity test chi2 = 4.72, P = 0.32. CONCLUSIONS: This meta-analysis did not find any relationship between metronidazole exposure during the first trimester of pregnancy and birth defects.

[Nosocomially acquired infection of the urinary tract]. / Infección del tracto urinario de adquisición nosocomial.

We have evaluated 283 consecutive hospital acquired urinary tract infections (HAUTI) in a University hospital (incidence 5.6% of admissions). In females, spontaneous, symptomatic and younger patient infections predominated, while in males HAUTI were mostly asymptomatic, after catheterization and in elderly patients. Chronic nonfatal diseases--particularly neurologic disease and diabetes--, old age, previous antibiotic use, the postoperative period, and cancer were the major general predisposing factors, mostly because they involved urological procedures. There was an urethral catheter in 78% of cases, with questionable indication or maintenance in 37%. In 65% of cases there were clinical data attributable to HAUTI; however, on strict criteria only 5% of pyelonephritis and 24% of cystitis were detected. Mortality rate was 0.4%. Etiology was E. coli in 29%, Proteus in 13%, Enterobacter in 12%, enterococcus in 11.5%, Serratia in 7%, Pseudomonas in 6.5%, and Klebsiella in 6.5%. There were differences regarding endogenous and hospital flora on the basis of sex, hospital situation, catheterization, mobility, and previous duration of hospitalization. The microbial resistance pattern was high in the hospital flora. The major therapeutical problem was the high number of unnecessary treatments representing the automatic medical response to the finding of a positive urine culture.