[The natural history of of the antiretrovirals: the continuum of their evaluation]. / La historia natural de los antirretrovirales: el continuum de su evaluación.

Antiretroviral drugs have, as any medical therapy, their natural history. They are born by screening or designing of molecules with activity against HIV, their efficacy and safety is investigated by clinical trials, evaluated by regulatory bodies, used by clinical practice, and finally analyzed by quality of care, economic, social and ethical studies. This flow of information is dynamically accumulated, but it may stop if negative results are obtained. The described knowledge pathway implies that specific methods are needed to answer different questions. At the same time, many decisions have to be taken in order to keep the process flowing, including multiple agents, such as drug industries, government departments, clinicians, health care providers and health policy makers. This paper describes a comprehensive conceptual framework, including the "knowledge" on antiretroviral drugs, the "methodologies" needed to generate them, and the underlying processes of "decision making". It proposes the need for a continuum of assessment of these drugs.

Polymicrobial fungemia: microbiology, clinical features, and significance.

In a retrospective study covering a period of 13 1/2 years, polymicrobial fungemia was documented in 22 (3.4%) of 645 patients with fungemia. These infections were hospital acquired and occurred in patients with significant underlying diseases. In terms of the clinical setting and features, predisposing factors, fungal species responsible, management, and mortality rate (59%), polymicrobial fungemia appears similar to the more common "monomicrobial" fungemia. With increasing numbers of patients at risk and improved laboratory detection of fungemia, clinicians will probably encounter increasing numbers of these polymicrobial bloodstream infections.

Lactate and glucose concentrations in brain interstitial fluid, cerebrospinal fluid, and serum during experimental pneumococcal meningitis.

Metabolic abnormalities during bacterial meningitis include hypoglycorrhachia and cerebrospinal fluid (CSF) lactate accumulation. The mechanisms by which these alterations occur within the central nervous system (CNS) are still incompletely delineated. To determine the evolution of these changes and establish the locus of abnormal metabolism during meningitis, glucose and lactate concentrations in brain interstitial fluid, CSF, and serum were measured simultaneously and sequentially during experimental pneumococcal meningitis in rabbits. Interstitial fluid samples were obtained from the frontal cortex and hippocampus by using in situ brain microdialysis, and serum and CSF were directly sampled. There was an increase of CSF lactate concentration, accompanied by increased local production of lactate in the brain, and a decrease of CSF-to-serum glucose ratio that was paralleled by a decrease in cortical glucose concentration. Brain microdialysate lactate concentration was not affected by either systemic lactic acidosis or artificially elevated CSF lactate concentration. These data support the hypothesis that the brain is a locus for anaerobic glycolysis during meningitis, resulting in increased lactate production and perhaps contributing to decreased tissue glucose concentration.

Brain levels of neuropeptide Y in experimental pneumococcal meningitis.

Neuropeptide Y (NPY), which is found in high concentrations in several regions of the brain including nuclei of the brain stem and in nerve fibers surrounding cerebral vessels, has been proposed to play a role in regulating cerebral blood flow (CBF) and systemic vegetative functions. Since CBF is altered during meningitis, we examined whether NPY concentrations changed in various regions of the rabbit brain in response to experimental pneumococcal meningitis. Changes were most pronounced in the medulla, where NPY concentration increased threefold after 48 h of infection. Concomitantly, there was an increase in NPY immunoreactive fibers surrounding small vessels in the dorsolateral medulla, especially in the nucleus tractus solitarius. These results suggest that NPY may play a role in inducing some of the hemodynamic changes seen during pneumococcal meningitis.

Amino acids in cerebrospinal and brain interstitial fluid in experimental pneumococcal meningitis.

Excitatory amino acids are increasingly implicated in the pathogenesis of neuronal injury induced by a variety of CNS insults, such as ischemia, trauma, hypoglycemia, and epilepsy. Little is known about the role of amino acids in causing CNS injury in bacterial meningitis. Several amino acids were measured in cerebrospinal fluid and in microdialysis samples from the interstitial fluid of the frontal cortex in a rabbit model of pneumococcal meningitis. Cerebrospinal fluid concentrations of glutamate, aspartate, glycine, taurine, and alanine increased significantly in infected animals. Among the amino acids with known excitatory or inhibitory function, interstitial fluid concentrations of glutamate were significantly elevated (by 470%). Alanine, a marker for anaerobic glycolysis, also increased in the cortex of infected rabbits. The elevated glutamate concentrations in the brain extracellular space suggest that excitotoxic neuronal injury may play a role in bacterial meningitis.

[Preventing HIV infection: an exercise in evaluating scientific evidence in public health]. / La prevención de la infección por VIH: un ejercicio de evaluación de las evidencias científicas en salud pública.

BACKGROUND: Evidence-based medicine (EBM) analyses scientific evidence for the efficacy/effectiveness of health interventions. It aims to identify and implement available interventions that have proved to be the best. This concept is now soundly established for clinical interventions, but just breaking for prevention, particularly when--as in HIV infection--transmission is associated to private behaviour. METHODS: A search for studies evaluating the effects of HIV prevention interventions. All studies were critically evaluated. RESULTS: Relevant evidence for the effects of the main specific HIV prevention interventions is reviewed, according to transmission group and study design, focusing on its methodological strength and weakness, and paying special attention to experimental research. CONCLUSIONS: A wider debate on scientific evidence for public health interventions is proposed, trying to promote feasible and efficient EBM methods in HIV prevention research.

Use of ampicillin-sulbactam for treatment of experimental meningitis caused by a beta-lactamase-producing strain of Escherichia coli K-1.

We evaluated the pharmacokinetics and therapeutic efficacy of ampicillin combined with sulbactam in a rabbit model of meningitis due to a beta-lactamase-producing strain of Escherichia coli K-1. Ceftriaxone was used as a comparison drug. The MIC and MBC were 32 and greater than 64 micrograms/ml (ampicillin), greater than 256 and greater than 256 micrograms/ml (sulbactam), 2.0 and 4.0 micrograms/ml (ampicillin-sulbactam [2:1 ratio, ampicillin concentration]) and 0.125 and 0.25 micrograms/ml (ceftriaxone). All antibiotics were given by intravenous bolus injection in a number of dosing regimens. Ampicillin and sulbactam achieved high concentrations in cerebrospinal fluid (CSF) with higher dose regimens, but only moderate bactericidal activity compared with that of ceftriaxone was obtained. CSF bacterial titers were reduced by 0.6 +/- 0.3 log10 CFU/ml/h with the highest ampicillin-sulbactam dose used (500 and 500 mg/kg of body weight, two doses). This was similar to the bactericidal activity achieved by low-dose ceftriaxone (10 mg/kg), while a higher ceftriaxone dose (100 mg/kg) produced a significant increase in bactericidal activity (1.1 +/- 0.4 log10 CFU/ml/h). It appears that ampicillin-sulbactam, despite favorable CSF pharmacokinetics in animals with meningitis, may be of limited value in the treatment of difficult-to-treat beta-lactamase-producing bacteria, against which the combination shows only moderate in vitro activity.

Comparison of Du Pont Isolator and Roche Septi-Chek for detection of fungemia.

The rapid detection of fungemia in hospitalized patients is imperative, particularly for those who are immunocompromised. Our laboratory compared the Roche Septi-Chek with the Du Pont Isolator for the recovery of fungi from blood. Of 23,586 matched pairs of blood cultures, 199 were positive. The Isolator detected 178 (89.4%) and the Septi-Chek detected 119 (59.7%) of all positive isolates. The mean recovery time for the Isolator and Septi-Chek was 2.2 and 4.9 days, respectively. The Isolator detected fungemia earlier than the Septi-Chek did and was the only culture system positive in 83% of 53 patients, whereas the Septi-Chek system yielded the same results in only 13% of the patients. The Isolator provides a more rapid and sensitive method for the recovery of fungi from blood.

[Antibiotic prescription in acute respiratory infections in adults: its variability and appropriateness in 10 Spanish hospitals]. / Prescripción antibiótica en las infecciones respiratorias agudas del adulto: su variabilidad e idoneidad en diez hospitales españoles.

OBJECTIVE: To report the variability in antibiotic prescribing habits for patients diagnosed of non-specified acute respiratory infections (ARI) (according to the International Classification of Diseases 9MC) at Emergency Departments of ten Spanish hospitals, and to evaluate the appropriateness of antimicrobial prescription for such patients, after specifically elaborating some reference patterns for appropriate antimicrobial use. DESIGN: Descriptive study of variability in clinical practice by means of a prospective series of cases. Study of appropriateness by means of elaborating reference standards for appropriate use and comparison with the data from the descriptive study with such standards. DURATION: six months. SETTING: Emergency Department in ten Spanish hospitals from different autonomic communities: Andalucía, Islas Canarias, Castilla-León, Cataluña, Galicia, Madrid, Murcia and Valencia for a 6-month period. PATIENTS: Patients with the diagnosis of community ARI attended at emergency departments. SAMPLE SIZE: 903 cases. INTERVENTIONS: Collection of cases in a unified database with the following variables: age, sex, ARI type, diagnosis of comorbidity, prescribed antimicrobial, hospital admission and type of prescriber. A panel of experts was commissioned to elaborate the gold standards for the appropriate use of antibiotics or the lack of indication for the different locations of ARI. RESULTS: The adjusted proportion of the inappropriate prescription for the group with laryngo-tracheal-influenza-rhinopharyngitis-multiple ARI or non specified infections was 67.9%. CONCLUSIONS: Concerning antibiotic prescription, significant inter-center variability and relevant heterogeneity were observed.