Pharmacodynamic studies of nitrofurantoin against common uropathogens.

OBJECTIVES: To determine the pharmacokinetic/pharmacodynamic index that best correlates to nitrofurantoin's antibacterial effect, we studied nitrofurantoin activity against common causative pathogens in uncomplicated urinary tract infection (UTI). METHODS: Five isolates [two Escherichia coli (one isolate producing the ESBL CTX-M-15), two Enterococcus faecium (including one that was vancomycin resistant) and one Staphylococcus saprophyticus] were used. The MICs of nitrofurantoin were determined by Etest. Time-kill curves with different concentrations of nitrofurantoin (based on multiples of isolate-specific MICs) were followed over 24 h. An in vitro kinetic model was used to simulate different time-concentration profiles, exposing E. coli to nitrofurantoin for varying proportions of the dosing interval. The outcome parameters reduction in cfu 0-24 h (Δcfu0-24) and the area under the bactericidal curve (AUBC), were correlated with time over MIC (T>MIC) and area under the antibiotic concentration curve divided by the MIC (AUC/MIC). RESULTS: A bactericidal effect at varying static drug concentrations was achieved for all isolates. All isolates showed similar kill curve profiles. In the kinetic model, the effect of nitrofurantoin on E. coli displayed a 4 log reduction in cfu/mL within 6 h at 8 × MIC. The outcome parameters Δcfu0-24 and AUBC had a good correlation with T>MIC (R ≈ 0.83 and R ≈ 0.67, respectively), whereas log(AUC/MIC) was significantly poorer (R ≈ 0.39 and R ≈ 0.53, respectively). CONCLUSIONS: Nitrofurantoin was highly effective against E. coli and S. saprophyticus isolates; the killing effect against E. faecium was not as rapid, but still significant. Against E. coli, nitrofurantoin was mainly associated with a concentration-dependent action; this was confirmed in the kinetic model, in which T>MIC displayed the best correlation.

Cell-wall-inhibiting antibiotic combinations with activity against multidrug-resistant Klebsiella pneumoniae and Escherichia coli.

The increasing prevalence of hospital and community-acquired infections caused by multidrug-resistant (MDR) bacterial pathogens is rapidly limiting the options for effective antibiotic therapy. Systematic studies on combinations of already available antibiotics that could provide an effective treatment against MDR bacteria are needed. We tested combinations of antibiotics that target one important physiological function (peptidoglycan synthesis) at several steps, and studied Enterobacteriaceae (Klebsiella pneumoniae and Escherichia coli) for which multidrug resistance associated with ESBL-producing plasmids has become a major problem. To measure the effectiveness of antibiotics alone and in combination, we used checkerboard assays, static antibiotic concentration time-kill assays, and an improved in-vitro kinetic model that simulates human pharmacokinetics of multiple simultaneously administered antibiotics. The target strains included an MDR K. pneumoniae isolate responsible for a recent major hospital outbreak. A double combination (fosfomycin and aztreonam) and a triple combination (fosfomycin, aztreonam and mecillinam) were both highly effective in reducing bacterial populations in all assays, including the in vitro kinetic model. These combinations were effective even though each of the MDR strains was resistant to aztreonam alone. Our results provide an initial validation of the potential usefulness of a combination of antibiotics targeting peptidoglycan synthesis in the treatment of MDR Gram-negative bacteria. We suggest that a combination of fosfomycin with aztreonam could become a useful treatment option for such infections and should be further studied.

Sense of smell in long-standing nasal polyposis.

An impaired sense of smell is a common complaint in patients with nasal polyposis, and hyposmia is usually attributed to obstruction of the nasal airways. The duration of nasal polyposis and nasal surgery may also affect olfaction. It has been shown that aging and chronic rhinitis both impair olfaction. The aim of our study was to evaluate the sense of smell in patients who had had nasal polyposisfor at least 20 years. The olfactory threshold was assessed with a commercially available odor detection threshold test. The threshold of 19 (46%) of 41 patients was greater than the age-related upper 95% reference limit. In a forward stepwise multiple regression analysis of all the polyposis patients, the degree of opacity of ethmoidal sinuses seen in computed tomography (CT), polyposis visible in anterior rhinoscopy, total nasal resistance, and gender had a significant association with olfactory threshold.

Nasal polyposis: clinical course during 20 years.

BACKGROUND: The etiology of nasal polyposis is mainly unknown although it has been connected with many clinical conditions. The long-term clinical course of nasal polyposis is largely unknown, because long-term followup studies on the recurrence of nasal polyposis have rarely been reported. OBJECTIVE: The aim of the study was to find out the clinical course of nasal polyposis over a long period of time. PATIENTS AND METHODS: Our report describes a 20-year follow-up study of 41 patients with nasal polyps. These patients had surgery for nasal polyp disease 20 years previously and they were initially grouped according to occurrence of (1) acetylsalicylic acid (ASA) intolerance, (2) atopic allergy (AT), and (3) intrinsic allergy-like disease (INTR). Patients were now re-examined, sinus computed tomography (CT) scanning was made, and a biopsy from polyp or from mucosa of the middle turbinate was taken. RESULTS: Anterior rhinoscopy revealed polyps in 35 of 41 patients. Thus nasal polyposis was still active in 85% of patients after 20 years. Mucosal changes in paranasal sinuses were found in every patient. Anosmia or hyposmia was found in 61% (25/41) of the patients. Eight patients had had 11 or more surgical operations during the 20-year period. Of these, 88% (7/8) belonged to the ASA group. Bronchial asthma was found in all ASA intolerance patients (11/11), and in 36% (4/11) of AT and in 16% (3/19) of INTR patients, respectively. CONCLUSION: Because of the high recurrence tendency and insidious symptoms of nasal polyposis, patients will require followup for the rest of their lives.

Vascular permeability factor/vascular endothelial growth factor in nasal polyps.

Although the aetiology of polyps is still, for the most part, unknown, the disease is known to involve tissue oedema. Vascular permeability/vascular endothelial growth factor (VPF/VEGF) is a major inducer of angiogenesis and capillary permeability. This study investigated VPF/VEGF expression in biopsies of nasal polyps from 39 patients and in healthy nasal mucosa from 10 patients by immunohistochemical staining. Staining for VPF/VEGF in the mucosal surface and in the glandular epithelium of nasal polyps was weaker than in normal controls. In two patients, strong staining for VPF/VEGF was found in a granular pattern in mast cells, while the mast cells in other polyposis patients appeared to be largely degranulated. VPF/VEGF was not seen in the mast cells of control patients. Although expression of VPF/VEGF was not increased in the epithelium of the nasal polyps, VPF/VEGF secreted from mast cells may take part in nasal polyp formation.

A-mode ultrasound in the diagnosis of chronic polypous sinusitis.

A-mode ultrasound (A-US) is a simple, non-invasive and non-ionizing method for detecting fluid or even mucosal swelling in inflamed maxillary and frontal sinuses. A-US has been shown to be a quite reliable tool in the diagnosis of acute maxillary sinusitis. However, controversy still exists over the reliability of A-US in detecting fluid retention or mucosal swelling in patients suffering from chronic polypous rhinosinusitis or in transantrally operated maxillary sinuses. We have compared the results of maxillary sinus A-US with computed tomography (CT) images in a selected series of chronic polypous rhinosinusitis comprising 40 patients. Fluid retention was seen in 20 of 79 maxillary sinuses on CT scanning. Only 6 of these 20 retentions were detected with A-US. There were 11 false positive findings. In six of these cases a back-wall echo was received through polypoid masses in the sinus. Mucosal swelling was also difficult to diagnose. The results of A-US were not easily reproduced; only in 50% of cases were identical results obtained by two investigators. We do not recommend the use of A-US to diagnose fluid retention or mucosal swelling in a patient with chronic mucosal changes in the maxillary sinus or if surgery has been performed on the anterior wall of the maxillary sinus.

Moderate alcohol consumption during pregnancy and the incidence of fetal malformations: a meta-analysis.

To determine whether there is an association between moderate alcohol consumption in the first trimester of pregnancy and increased risk of fetal malformations, we conducted a literature search using Medline (1966-present), PsycLit (1974-1995), and EMBASE (1988-1995). The following inclusion criteria were used to select the studies to be evaluated: 1) pregnant women; 2) moderate alcohol consumption (> 2 drinks/week to 2 drinks/day); 3) case-control or cohort studies; 4) presence of an abstainer group (0 to 2 drinks/wk); 5) outcome measures include major or minor malformations; 6) papers published in the English language. The exclusion criteria were: 1) studies in which moderate alcohol consumption could not be confirmed; 2) case reports, and editorials. The Methods section of each study was examined independently by two blinded investigators with a third investigator settling any disagreement. The number of malformations in the abstainer and moderate alcohol consuming groups in two by two tables. Out of 24 studies which met the inclusion criteria, only seven had extractable data. The included studies evaluated 130,810 pregnancy outcomes, with 24,007 in the moderate alcohol group and 106,803 in the control group. An overall Mantel-Haenszel odds ratio showed that the relative risk for fetal malformations was 1.01 with 95% confidence limits of 0.94 to 1.08 and a chi-square for homogeneity of 8.26 (p = 0.220). Quality of the studies did not correlate with their showing negative or positive association. Moderate alcohol consumption during the first trimester of pregnancy is not associated with increased risk of fetal malformations.

Relationship between the results of bronchial, nasal and conjunctival provocation tests in patients with asthma.

Skin tests and bronchial, nasal and conjunctival provocation tests with pollen and animal dander allergens were performed in thirty patients with atopic asthma. In vivo test results were compared only when the same batch of allergen had been used. A nasal reaction was mostly elicied at a lower concentration of allergen than was needed to elicit a bronchial reaction (P less than 0.01). Positive nasal reactions were often obtained when the corresponding bronchial tests were negative. The conjunctiva reacted to lower concentrations than the bronchi in a third of the instances of testing, with most of these being tests with mugwort allergen (P less than 0.05). A positive skin test in cases with a negative bronchial challenge test was often accompained by a positive nasal test and in some cases by a positive conjunctival test. It is concluded that nasal or conjunctival provocation tests do not replace bronchial challenge tests. In an asthmatic patient who gives no reaction to bronchial challenge with a particular allergen, a positive skin test may reflect a nasal allergy.

Relationship between nasal and conjunctival tests in patients with allergic rhinitis.

Simultaneous conjunctival and nasal provcation tests, a total of 174 test pairs, were carried out in fifty patients with allergic rhinitis, using serially diluted antigen solutions of birch, Timothy grass and mugwort pollen, as well as cat and dog dander. The nasal mucosa was found to be more sensitive than the conjunctival mucosa in ninety-six test pairs (55%). This differs from earlier reports. Nasal reaction only was observed in twenty-nine instances (17%). Posterior rhinomanometry was also used to evaluate test reactions, but was found to yield little additional information. In 43% of nasal provocation tests, which according to other criteria were positive, the rhinomanometric results were negative. Despite a fairly good correlation between the results obtained by nasal and conjunctival challenge, the results point to organ specificity in type I reactions. Provocation tests, if indicated in a thorough allergy evaluation, should be performed in the shock organ. The provocation methods and interpretation of reactions of this study differ from those of earlier reports. Comparison of results is difficult and standardization of methods is needed.

In vivo tests with pollen extracts previously investigated by means of direct RAST titration allergen assay.

The allergenic potency of different birch, Timothy and mugwort pollen extracts was determined by means of a direct RAST titration allergen assay. For birch and Timothy allergens, the results of skin and provocation tests did not confirm the results of the in vitro determinations of allergenicity. There was a poor correlation between the results of skin tests and the results of Phadebas RAST for determination of specific IgE to mugwort, whereas the correlation between skin tests and RAST for other allergens was excellent. It is concluded that direct RAST titration allergen assay is not adequate for all kinds of allergen preparations and that the Phadebas RAST for mugwort is less sensitive than the RAST for other allergens. The diagnostic efficacy of the different allergen preparations could not be evaluated.

Steroid cyclicsulfites. III. Conformational and configurational aspects of steroid 3,5-cyclicsulfites.

The reaction of 3beta, 5beta-dihydroxy cholestanes with thionyl chloride is shown to yield cyclicsulfite esters containing boat heterocyclic rings with the S=O oxygen axial or equatorial, depending upon the mode of formation. Treatment of a diol in pyridine at low temperature favors an equatorial S=O conformation while higher reaction temperatures in chloroform solution yield a mixture of axial and equatorial epimers. In the case of a 7alpha-bromo-6-oxo 3,5-sulfite, it has been shown that the S=O equatorial isomer may be converted to the axial isomer upon treatment with acid.

Synthesis, spectral properties, and antibacterial activity of synthetic precursors of macrocyclic oxa- and thia-substituted benzolactones and benzoketones.

Terminally difunctional compounds were synthesized by alkylation of salicylic acid, thiosalicylic acid (o-mercaptobenzoic acid), or their derivatives. Whereas methyl salicylate and thiosalicylic acid were smoothly etherified, salicylic acid was alkylated at the carboxyl. Characteristic IR and NMR spectral patterns in the synthesized compounds can be attributed to intramolecular hydrogen bonding or substituent effects and are consistent with observations already reported for similar compounds. Three synthesized compounds exhibited low but reproducible inhibitory effects on Bacillus subtilis growth.