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One major challenge in the industries is digital transformation. Ambidexterity, the ability to optimise the existing and innovate new business concepts, is widely accepted as a critical concept of sustainable success. We conducted a literature review (period from 2010 to 2021) on what differential aspects of exploration and exploitation are needed to lead a digital transformation. With the help of a structured selection process, we identified 94 relevant papers. Our findings show that all reviewed articles on digital transformation contain aspects of exploration and exploitation, often without deep specifications. We reveal that structural ambidexterity, leadership, and collaboration are the focus areas related to ambidexterity in digital transformation. Digital transformations fail by not achieving the intended innovation outcome resulting from inadequate key performance indicators and focussing on short-term profitability. Our findings provide first insights but need additional empirical research for validation and more detailed knowledge on ambidexterity in digital transformation.

Research in aesthetics typically focuses on static stimuli or stimulus properties from the visual domain leaving unanswered a great many questions on haptic aesthetics. This paper aims to give a short impression of the relevance of aesthetics for design and everyday-life decisions, then focuses on phenomena concerning haptic aesthetics in particular, for instance, top-down processes and mere exposure effects. Based on empirical findings and theoretical considerations with regard to haptic research, the paper develops a functional model of haptic aesthetics, which is explained step by step. This model assumes a continuous increase of elaborative processing through three subsequent processing stages beginning with low-level perceptual analyses that encompass an initial, unspecific exploration of the haptic material. After a subsequent, more elaborate, and specific perceptual assessment of global haptic aspects, the described process enters into deeper cognitive and emotional evaluations involving individual knowledge on the now specified haptic material. The paper closes with an applied view on design issues to explicate the importance of integrating haptic aesthetics into corresponding approaches.

In this paper, an approximate method is developed that can be used to efficiently obtain the deflection curve of any prismatic or non-prismatic, statically determinate or indeterminate beam under various loading conditions. This allows for a quick validation of the exact deflection curve, which is especially useful at the undergraduate level. This proposed method approximates the deflection curve as the weighted sum of the eigenfunctions of the dynamic uniform beam. The weights of each eigenfunction are obtained by solving a set of linear algebraic equations. The mathematics needed to apply this method is relatively simple, and can be easily taught at the undergraduate level. The proposed method is validated against the exact deflection curve for multiple examples, and excellent agreements are shown between the approximate and exact deflection curves.

SummaryThis retrospective analysis was performed to determine the clinical and bacteriologic efficacy of the ketolide antibacterial telithromycin in patients with community-acquired pneumonia (CAP) with pneumococcal bacteremia. Patients ⩾13 years old with radiologically confirmed CAP and a positive blood culture for Streptococcus pneumoniae at screening were analyzed from eight multicenter Phase III/IV clinical trials. In four open-label, non-comparative studies, patients received telithromycin 800mg once daily for 7–10 days. In four randomized, controlled, double-blind, comparative studies, patients received telithromycin 800mg once daily for 5–10 days or a comparator antimicrobial (amoxicillin 1000mg three times daily, clarithromycin 500mg twice daily, or trovafloxacin 200mg once daily) for 7–10 days. In total, 118 patients (telithromycin, 94/1061 [8.9%]; comparator, 24/244 [9.8%]) had documented pneumococcal bacteremia. Those who were treated with telithromycin achieved a clinical cure rate of 90.2% (74/82, per-protocol population); S. pneumoniae was eradicated in 77/82 (93.9%) bacteremic patients who received telithromycin and 15/19 (78.9%) comparator-treated patients. Clinical cure was also observed among telithromycin-treated bacteremic patients who were infected with penicillin- or erythromycin-resistant strains of S. pneumoniae (5/7 and 8/10, respectively). In conclusion, telithromycin achieves high clinical and bacteriologic cure rates in CAP patients with pneumococcal bacteremia.

Resistance is one of failure's reasons. We tried, through clinical experience, to approach the magnitude and nature of the links, between phenotypically defined acquired resistance and clinical failure, in community acquired respiratory infections. An efficient resistance mecanism, able to suppress antibiotic action, is clearely associated to a risk of clinical failure (e.g. betalactamase secretion, target modification using methilation for macrolides, target mutation for fluoroquinoles). Resistance mecanism due to reduction of target affinity (pneumococcus and betalactams) progressively decreasing beta lactam activity depending on its expression, is at present time, not clearely associeted with clinical failure. Critical concentration, defining phenotypical resistance, is predictive of failure if it identifies a bacterial population owning an efficient resistance mecanism. It will not be predictive of failure if that concentration do not detect the resistance mecanism (e.g. parC mutation and levofloxacin) or if the link between antibiotic and resistant bacteria is not binary but depends also on pharmacokinetic parameters (pneumococcus and betalactam). Using resistance as a parametre for antibiotic choice, must integrate several elements: presence or not of a resistance mecanism, type and efficiency of the mecanism, links with clinical failure and antibiotic concentration, type and site of infection. Critical concentration is not allways the magic number that predict failure or success.

The European Union of Medical Specialists (UEMS) core curricula for training in infectious diseases and medical microbiology are adequate with the exception of one deficiency which is the absence of training in epidemiology, public health and infection control. Infectious disease curricula should include training in HIV, tuberculosis, hepatitis and sexually transmitted diseases. There is a need for a core curriculum in infection control. Infection control should have a basis in both medical microbiology and infectious diseases, and should become a specialty dealing with healthcare hygiene in hospitals, in outpatient clinics and also in institutions for the elderly. In the UK, a specialty training in infection is offered and includes internal medicine, clinical infectious diseases and medical microbiology for a total of 9 years. The UEMS should be contacted about the creation of a single specialty of infection, allowing for various degrees of sub-specialisation in infectious diseases or medical microbiology. It is unlikely that a European board examination validating the training of specialists will become a reality soon. Meanwhile, national systems should be created, documenting the content of the training and evaluating the quality of the training institutions. A medical specialist has a constant need for further education. This is generally a national matter, with requirements varying throughout Europe. It should be possible to accumulate continuing medical education/continuing professional development merits on a European level as well as on a national one. With the expansion of the European Union, it is important that the quality and content of specialist training can be verified and training curricula be harmonised. The UEMS should assist in this, in collaboration with scientific societies such as the ESCMID.

Objectives This open, multinational study examined the efficacy and tolerability of telithromycin (HMR 3647), the first ketolide antibacterial agent, at an oral dose of 800 mg once daily for seven to ten days (further validated using pharmacokinetic analysis) as an empiric therapy in adults with mild to moderate community-acquired pneumonia (CAP). Methods A total of 240 patients (aged 18–79 years; median 40 years) with clinical signs and symptoms of CAP (radiologically confirmed) were enrolled in the study and received at least one dose of study medication. Sputum and blood samples for bacteriologic documentation were collected within 48 h prior to enrollment. Clinical and bacteriological outcomes were assessed 17–21 days (test of cure visit) and 31–36 days (late post-therapy visit) after treatment initiation. Adverse events were assessed by spontaneous reporting and investigator observation. Results At the test of cure visit, 92.9% (95% CI: 88.4–96.1; n = 197) of patients achieved clinical cure in the per-protocol (PP) population. In the modified intent-to-treat (mITT) population, the cure rate was 79.6% (95% CI: 73.9–84.5; n = 240), including 12.5% of undetermined cases categorized as failures. Clinical cure (PP population) remained high in patients ≥65 years (85.7%), and in patients with a Fine score ≥III (92.1 %). Among those patients for whom bacteriologic data were available, the majority had a satisfactory outcome (88.9% in the bacteriologic PP; n = 45). Bacterial eradication rates were similarly high (85.5% and 82.7% for the mITT and PP populations, respectively). All patients with infections as a result of atypical/intracellular pathogens Chlamydophila (Chlamydia) pneumoniae, Mycoplasma pneumoniae or Legionella pneumophila had a clinical outcome of cure. Treatment was well tolerated. Adverse events were mainly gastrointestinal in origin and mild in intensity. Conclusion An oral dose of telithromycin 800 mg once daily for seven to ten days is an effective and well-tolerated first-line treatment for mild to moderate CAP in adults.

The efficacy of telithromycin has been assessed in six Phase III studies involving adults with mild to moderate community-acquired pneumonia (CAP) with a degree of severity compatible with oral therapy.Patients received telithromycin 800mg once daily for 7–10 days in three open-label studies (n=870) and three randomized, double-blind, comparator-controlled studies (n=503). Comparator antibacterials were amoxicillin 1000mg three-times daily, clarithromycin 500mg twice daily and trovafloxacin 200mg once daily. Clinical and bacteriological outcomes were assessed 7–14 days post-therapy.Among telithromycin-treated patients, per-protocol clinical cure rates were 93.1 and 91.0% for the open-label and comparative studies, respectively. Telithromycin treatment was as effective as the comparator agents. High eradication and clinical cure rates were observed for infections caused by key pathogens: Streptococcus pneumoniae including isolates resistant to penicillin G and/or erythromycin A (95.4%), Haemophilus influenzae (89.5%) and Moraxella catarrhalis (90%). Telithromycin was also highly effective in patients with infections caused by atypical and/or intracellular pathogens and those at increased risk of morbidity. Telithromycin was generally well tolerated.Telithromycin 800 mg once daily for 7–10 days offers a convenient and well-tolerated first-line oral therapy for the empirical treatment of mild to moderate CAP.

In a randomized trial conducted in 35 centers, we compared the clinical efficacy and safety of piperacillin plus tazobactam (TAZ) alone (monotherapy [MT]) versus those of TAZ combined with amikacin (AMK) (combined therapy [CT]) for the treatment of severe generalized peritonitis (SGP). Primary analysis consisted of blind assessment by an independent committee of the failure rate 30 days after the end of treatment in the modified intent-to-treat (ITT) analysis (mITT) population. Of the 241 patients with suspected SGP randomized into the study, 227 were eligible for ITT analysis, including 204 (99 in the MT group and 105 in the CT group) with confirmed SGP (mITT population). A total of 159 patients were eligible for per-protocol (PP) analysis. The clinical failure rates were equivalent in the mITT and PP populations (MT versus CT): 56 versus 52%, (odds ratio [OR] 0.87, 90% confidence interval [CI] = 0.6 to 1.27) for mITT and 49 versus 49% (OR = 1.03, 90% CI = 0.67 to 1.59) for PP analysis. Mortality rates (ITT population, 19%; PP population, 21%) and overall adverse event rates (ITT population, 55%; PP population, 54%) were also similar. Six patients (three in MT group and three in the CT group) developed acute renal failure. In conclusion, the addition of AMK to TAZ does not seem to be necessary for the treatment of SGP, even after adjustment for the simplified acute physiology score (SAPS II) and type of SGP.

The influence of socioeconomic status on the features and evolution of community-acquired pneumonia in 107 consecutive hospitalized patients was investigated. Thirty-four (31.8%) patients were considered to have a low socioeconomic status. These patients were more likely immigrants, middle-aged, with fewer comorbid illnesses, and were more often tobacco, alcohol, or drug consumers (P

Two in vivo models, in the rat, were used to investigate, in the presence of different substrates, the overall and net intestinal elimination of ciprofloxacin: an open-intestinal perfusion model and an intestinal loop model respectively. In the presence of quinidine, verapamil and cyclosporin (substrates of the P-glycoprotein (P-gp)), plasma AUCs of ciprofloxacin were 1.5–2 fold increased, while biliary clearance (1.5–2 fold), intestinal overall and net clearances (2–4 fold and 1.5–8 fold respectively) decreased. The weak effect obtained with cyclosporin as compared to verapamil and especially quinidine, suggests, for ciprofloxacin, the existence of transport systems distinct from the P-gp, as the OCT1 transporter which could be inhibited by quinidine. With cephalexin and azlocillin, two β-lactam antibiotics, plasma AUCs of ciprofloxacin increased and biliary and intestinal overall clearances decreased in a similar fashion (1.3–2 fold), suggesting the involvement of organic anion and/or cation transporters. In the presence of structural analogues, the effect was dependent on the compound administered: Sparfloxacin had no effect on intestinal clearance of ciprofloxacin. In contrast, with pefloxacin, overall intestinal clearance of ciprofloxacin was decreased and net intestinal clearance increased. The specificity of ciprofloxacin intestinal transport appears to be different from P-gp as outlined by the lack of competition with sparfloxacin, a P-gp substrate. Ciprofloxacin intestinal elimination seems to be mediated by organic anion and/or cation transporters and a mechanism sensitive to quinidine and verapamil. British Journal of Pharmacology (1999) 127, 1728–1734; doi:10.1038/sj.bjp.0702703

The aim of this study was to assess the serum bactericidal activity (SBA) of levofloxacin compared with that of ofloxacin against methicillin-resistant Staphylococcus aureus (MRSA) isolates. Serum from 10 healthy volunteers (seven females, three males) was collected after a single oral dose of either levofloxacin (500 mg) or ofloxacin (400 mg). Subjects were allocated randomly to treatment after at least a 1 week interval between antibiotic regimens. Three well-defined MRSA strains were tested, each susceptible to levofloxacin and ofloxacin, with different levels of resistance to methicillin (HBD 456, HBD 3 and HBD 2; class 1, 2 and 3 Tomasz heterogeneous resistance, respectively) together with a methicillin-susceptible (MSSA) reference strain ( S. aureus ATCC 25923). SBA was tested in vitro by a microtitration method 15 min before dosing and at 1, 4, 8 and 12 h after drug absorption. Levofloxacin was significantly more bactericidal than ofloxacin against all strains of S. aureus tested (SBA ≥1:2). An SBA was recorded for only a short period with ofloxacin, and thereafter only bacteriostatic activity remained. This study, therefore, confirms the superior activity of levofloxacin over that of ofloxacin against MSSA and MRSA.

Summary Background To assess the effects of zidovudine, didanosine, and zalcitabine on HIV disease progression and survival, we undertook meta-analyses of individual patient data and tabular data from all randomised trials that compared these agents. Methods Individual patient data were available for 7722 participants without AIDS in the nine randomised trials of immediate versus deferred zidovudine, and 7700 participants with or without AIDS in the six trials comparing zidovudine plus didanosine, zidovudine plus zalcitabine, or zidovudine alone. The main outcomes were mortality and disease progression (new AIDS-defining event or death before any such event). Flndings In the comparison of immediate versus deferred zidovudine, during a median follow-up of 50 months, 1908 individuals progressed, of whom 1351 died. In the deferred group, 61% started antiretroviral therapy (median time to therapy 28 months, which was zidovudine monotherapy in 94%). During the first year of follow-up, immediate zidovudine halved the rate of disease progression (p Interpretation Although immediate use of zidovudine halved disease progression during the first year, this effect was not sustained, and there was no improvement in survival in the short or long term. However, the use of didanosine and, to a lesser extent, zalcitabine delayed both disease progression and death, at least when added to zidovudine. The comparative effects of these different nucleoside analogues on long-term survival should inform the choice of which to combine with other types of drug, such as protease inhibitors.

The macrolide class of antibiotics is well established and often recommended for use in the treatment of community-acquired respiratory tract infection (RTI). The newer agents clarithromycin and azithromycin are frequently prescribed as first- or second-line therapy, and have been considered as superior to erythromycin in microbiological activity and clinical efficacy. In-vitro data show that clarithromycin and azithromycin have good activity (MIC < or = 0.5 microg/ml) against certain RTI pathogens. However the activity of both compounds is intrinsically low against Haemophilus influenzae whilst several other important RTI pathogens - notably Streptococcus pneumoniae and Streptococcus pyogenes - exhibit a high prevalence of resistance to them. In many countries, the prevalence of resistance to clarithromycin and azithromycin is still rising with cross resistance with erythromycin. Maximum serum concentrations of clarithromycin and azithromycin are lower than the MIC90s for these agents against H. influenzae and S. pneumoniae. Concentrations in tissues have been reported to be much higher than those in serum. However, the high concentrations observed in tissues are largely a reflection of high concentrations inside cells. Concentrations of clarithromycin and azithromycin in extracellular tissue fluids, where Haemophilus and streptococci are located, are in equilibrium with concentrations in the serum, and remain low. It has been suggested that phagocytes deliver azithromycin to infection sites in a targeted fashion, but the evidence in support of this hypothesis is weak. Recent clinical experience with clarithromycin and azithromycin is consistent with preclinical results, and suggests that these agents have limited efficacy against certain respiratory infections. Clarithromycin and azithromycin are the first choice treatment of atypical infections caused by intracellular pathogens. For community-acquired RTIs, where H. influenzae and S. pneumoniae are present, they may no longer be an appropriate choice for first-line therapy. Indeed, in areas where levels of drug resistant S. pneumoniae are high, their use may be questionable as second-line therapy.

The eigenvalues and the first and second-order eigenvalue sensitivities of a uniform Euler–Bernoulli beam supported by the standard linear solid model for viscoelastic solids are studied in detail. A method is proposed that yields the approximate eigenvalues and allows the formulation of a frequency equation that can be used to obtain approximate eigenvalue sensitivities. The eigenvalue sensitivities are further exploited to solve for the perturbed eigenvalues due to system modifications, using both a first- and second-order Taylor series expansion. The proposed method is easy to formulate, systematic to apply, and simple to code. Numerical experiments consisting of various beams supported by a single or multiple viscoelastic solids validated the proposed scheme and showed that the approximate eigenvalues and their sensitivities closely track the exact results.

Resume Nous avons mene un travail en trois etapes pour construire un outil d'aide a la prescription des antibiotiques dans les infections respiratoires courantes de l'adulte en medecine generale. Au cours de la premiere etape nous avons recueilli aupres de 20 medecins generalistes, a l'aide d'un questionnaire standardise, des donnees sur 160 situations ayant conduit a prescrire des antibiotiques a des adultes atteints d'infections respiratoires. Nous avons compare ces donnees avec celles tirees des sources habituelles d'information des medecins generalistes (manuels, revues d'information et de formation). Nous avons constate que ces sources sont inadaptees pour deux raisons : d'une part les aspects cliniques des situations ne sont pas definis de maniere suffisamment precise, d'autre part les facteurs de risque et les aspects psycho-sociaux ne sont pas pris en compte alors qu'ils sont determinants pour les prescripteurs. Dans la deuxieme etape (en cours) nous avons applique une methode derivee de la methode Delphi. Nous avons fourni a trois groupes de cliniciens (generalistes, ORL, pneumologues, infectiologues) les donnees bibliographiques issues d'une recherche systematique dans Medline, et nous leur avons demande de definir deux listes precises de situations selon que l'antibiotherapie est indiscutablement indiquee ou non indiquee. Les groupes doivent tenir compte des facteurs de risque et des aspects psycho-sociaux. Dans la troisieme etape l'acceptabilite de ces listes sera testee par un echantillon de prescripteurs.

Resume Le niveau de resistance, variable selon les pays, des principales bacteries responsables de pneumonies communautaires rend compte des differences entre les Consensus concernant l'antibiotique de premiere intention et sa posologie. En France, dans le contexte epidemiologique actuel de resistance du pneumocoque, toute antibiotherapie prenant en charge une pneumonie communautaire alveolaire presumee pneumococcique doit etre active sur des souches de pneumocoque pour lesquelles la CMI de la penicilline G est egale a 2 mg/l. Cinq ans apres la publication du Consensus Francais (1991), les donnees de la litterature permettent de valider la posologie de 1 g × 3/24 h per os ou IV d'amoxicilline au cours d'une pneumonie alveolaire pneumococcique, sans signe de gravite (ou de 1 g × 3/24 h d'amoxicilline-acide clavulanique IV lorsque l'on souhaite elargir le spectre probabiliste du traitement antibiotique de 1ere intention : en 1996, 27 % des H. influenzae sont producteurs de β-lactamases). Dans le cas exceptionnel de souches dont la CMI de la penicilline G est > a 2 mg/l, les caracteristiques pharmacodynamiques de l'amoxicilline laissent penser qu'une posologie de 6 g/24 h IV d'amoxicilline serait efficace. En cas de gravite symptomatique, il est d'usage de recommander de fortes posologies d'amoxicilline, jusqu'a 150 mg/kg/24 h IV.

The aim of this work was to examine the mechanism involved in intestinal elimination of the two optical isomers of ofloxacin in the rat. An intestinal segment was isolated in situ and perfused with saline, while drug solution was administered via the carotid artery. Blood samples and intestinal effluents were collected and analyzed by a high-performance liquid chromatography method. We observed saturable and stereoselective intestinal elimination of the ofloxacin enantiomers. The elimination process favored the R-(+) form of the molecule. After a parenteral dose of 20 mg of racemic ofloxacin per kg of body weight, intestinal clearances were 0.23 +/- 0.03 versus 0.30 +/- 0.03 ml/min for S-(-)- and R-(+)-ofloxacin, respectively. Ciprofloxacin and pefloxacin interfered with ofloxacin elimination and significantly reduced the intestinal clearance of S-(-)- and R-(+)-ofloxacin. With concomitant ciprofloxacin, intestinal clearances became 0.13 +/- 0.02 versus 0.17 +/- 0.03 ml/min and 0.14 +/- 0.01 versus 0.19 +/- 0.05 ml/min with pefloxacin for S-(-)- and R-(+)-ofloxacin, respectively. Those findings argue for the presence of a common transport system in the rat intestine with variable affinities for fluoroquinolones. In addition, verapamil and quinidine, two P-glycoprotein blockers, significantly reduced the intestinal elimination of both ofloxacin isomers (with concomitant verapamil, intestinal clearances were 0.12 +/- 0.02 versus 0.18 +/- 0.03 ml/min for S-(-)- and R-(+)-ofloxacin, respectively, while with concomitant quinidine, values were 0.18 +/- 0.01 versus 0.23 +/- 0.01 ml/min without modifying their areas under the concentration-time curve in serum. Similar results were found with another fluoroquinolone, ciprofloxacin, in previous work. P-glycoprotein appears to be involved in the intestinal elimination of fluoroquinolones in rats. The characterization of fluoroquinolone intestinal elimination has significant clinical relevance for the better evaluation of the influence of this secretory pathway on antibiotic efficacy and selection of resistant bacteria within the intestinal flora.

The economic impacts in terms of cost and effectiveness (speed of resolution of symptoms) of 3- and 5-day courses of azithromycin and a 10-day course of roxithromycin were compared in a randomized, open study in patients with symptoms suggestive of beta-haemolytic streptococcal pharyngitis. Direct medical costs and absence from work were recorded and symptom scores and compliance were used to assess the effectiveness of therapies. Although no differences between treatment groups in terms of overall clinical response rates were detected 2 and 4 weeks after the start of treatment, more rapid resolution of symptoms was achieved with 3- and 5-day courses of azithromycin than with a 10-day course of roxithromycin. There was also a significant reduction in the time absent from work in the azithromycin treatment groups. The total costs of care over the 4-week evaluation period were lower for the 3- and 5-day azithromycin courses (US$193.60 and US$195.30 respectively) than for roxithromycin (US$202.10). The major cost components were absence from work (58.6%), visits to the physician (15.3%) and utilization of antibiotics (14.9%). Compliance was significantly better (P < 0.01) in patients prescribed azithromycin for 3 and 5 days (58.0% and 42.9% respectively) than in those who received roxithromycin (20.3%) and a significantly longer symptom-free period (P < 0.01) was reported in azithromycin- compared with roxithromycin-treated patients. These findings support the hypothesis that a 3- or 5-day course of azithromycin is as effective as a 10 day course of roxithromycin in the treatment of patients with pharyngitis and is associated with lower costs. Furthermore, azithromycin is associated with faster resolution of symptoms and improved patient compliance.

Staphylococcal infections continue to be among the most common infections. Methicillin resistance is a common phenomenon, particularly among nosocomial Staphylococcus aureus and coagulase-negative staphylococci. Although wide variations are observed between countries or cities, methicillin resistance is often associated with multiresistance, which includes resistance to rifampicin and fluoroquinolones. In areas where methicillin resistance is common, glycopeptides (vancomycin or teicoplanin) represent the first-line treatment. For both drugs, attention should be paid to appropriate doses and dosing regimens and to the control of serum levels. In septicaemia and endocarditis developed on native valves, the benefit of a combination with an aminoglycoside or any other agent has not been clearly established. Animal studies suggest that combination therapy with a quinolone or rifampicin should be considered, particularly in infections involving foreign bodies. In CNS infections, combinations such as cefotaxime plus fosfomycin, or rifampicin plus a fluoroquinolone can be used. Multiple resistance, however, may limit the efficacy of such combinations. In areas where methicillin resistance is less common, initial therapy can be cefamandole with or without an aminoglycoside, or rifampicin plus a fluoroquinolone. Whatever the treatment, careful evaluation of the clinical response 48 h after initiation of therapy is required.

In-vitro activity of CI-960 against seven strains of Listeria monocytogenes was compared to that of other fluoroquinolones. MICs/MBCs were : ciprofloxacin and sparfloxacin : 0.5-2/1-4 mg/L ; PD 131628 : 0.125-0.5/0.25-2 mg/L ; CI-960 : 0.06-0.25/0.25-0.5 mg/L. At 4 h, CI-960 (4 x MIC) reduced the inoculum (log 10 cfu) by 2.88 ± 0.61 compared with 1.78 ± 0.48 for ciprofloxacin, 1.5 ± 0.46 for sparfloxacin, and 1.35 ± 0.47 for PD 131628 (P < 0.05). At 24 h, the bactericidal effects were similar (-4 log 10 cfu). The amoxycillin/CI-960(8 x MIC) combination was bactericidal, without emergence of resistant mutants.

The intestinal transepithelial elimination of sparfloxacin and fleroxacin was compared with that of ciprofloxacin in a rat model following a single parenteral administration of 25 mg of each of the antibiotics per kg of body weight. All three fluoroquinolones were eliminated through the small intestine. Ciprofloxacin was eliminated in the proximal jejunum at a rate of 1.97 +/- 0.70 micrograms/cm2, while the elimination rates of fleroxacin and sparfloxacin were 0.64 +/- 026 and 0.21 +/- 0.10 micrograms/cm2, respectively, over a 90-min collection period. In the ileum, the elimination rates of ciprofloxacin, fleroxacin, and sparfloxacin over the same period were 1.44 +/- 0.77, 1.00 +/- 0.33, and 0.41 +/- 0.26 micrograms/mc2, respectively. These data suggest that these fluoroquinolones undergo a transepithelial elimination process in the small intestine. This route of elimination may be important in the therapy of bacterial diarrhea.

A 10-day course of penicillin is the antibiotic regimen currently recommended by the American Heart Association (AHA) as treatment for patients with tonsillitis caused by group A β-haemolytic streptococci (GABHS), with the aim of preventing both the suppurative and non-suppurative complications of this infection. This prospective, multicentre, randomized, double-blind, double-dummy clinical trial was undertaken in order to compare the efficacy of, tolerability of and compliance with a 5-day course ofcefotiam hexetil (CTM) 200 mg bd with that of 10-day course of penicillin V (PEV) I megaunit (600 mg) tds, to investigate the significance of recovering GABHS during or after treatment and to evaluate the potential economic advantages of short-term regimens. Two hundred and fifty ambulatory adult patients with a presumptive diagnosis (based on a positive rapid antigen detection test) of GABHS tonsillitis were recruited in 60 centres ; the diagnosis was subsequently confirmed by a positive culture of a throat swab. At the time of entry into the trial there was no statistically significant difference between the groups in terms of clinical symptoms. In an intention-to-treat analysis, both the clinical and bacteriological response rates at days 10 and 30 were comparable for each group i.e. 106 of 119 (89.1%) patients and 90 of 109 (82.6%) patients respectively in the CTM group and 103 of 117 (88.0%) patients and 92 of 107 (86.0%) patients respectively in the PEV group. The times until defervescence and resolution of symptoms were also similar. Of the 115 patients in each group who were assessed at day 90, there were three clinical relapses in the CTM group and seven in the PEV group. No non-suppurative complications of GABHS infection were detected. Tolerance was significantly better in the CTM group than in the PEV group, 14 of 119 (11.8%) patients and 26 of 117 (22.2%) patients in the former and latter groups respectively reporting adverse events. In three cases in each group treatment was discontinued prematurely because of adverse events ; none of these in the CTM group was serious but one patient in the PEV group experienced a severe allergic reaction. Compliance in both groups was good during the first 5 days of therapy but, by the end of each course, 93.6% of patients in the CTM group had completed treatment, compared with 73.0% in the PEV group. Time lost from work was noted in respect of 68.0% ofpatients who were gainfully employed and prolonging treatment from 5 to 10 days would have led to a mean increase in the time away from work of 1.7 days. In conclusion, a 5 day course of cefotiam hexetil was shown to be effective and safe therapy for patients with GABHS tonsillitis. However, a more accurate estimate of the cost-effectiveness of this regimen will be required before AHA recommendations can be revised.

Platelet activating factor (PAF) is an ubiquitous phospholipid that acts as a mediator of numerous pathophysiological conditions, including drug nephrotoxicity. Aminoglycosides are potent antibiotics but their use is limited by their nephrotoxic potential. We assumed that PAF could participate in inducing gentamicin nephrotoxicity, and we used the PAF antagonist BN52021 to test this hypothesis. We studied renal glomerular and tubular function by clearance techniques and renal histology in four groups of New Zealand male rabbits treated for 7 days with isotonic saline, BN52021, gentamicin, or gentamicin + BN52021. BN52021 alone reduced only fractional excretions (FE) of sodium and chloride, without modifying the other parameters studied. Renal histology was not altered. Gentamicin reduced glomerular filtration rate and renal plasma flow. Free water clearance was not modified. Sodium, potassium, chloride, calcium, and magnesium FEs were raised. Renal histology showed a massive and diffuse tubular necrosis. BN52021 did not modify gentamicin glomerular, tubular, or histopathological alterations. These data suggest that PAF might physiologically affect tubular function in New Zealand male rabbits, increasing sodium and chloride excretions, and in a minute manner, potassium, calcium, and magnesium excretions. Under our experimental conditions, there was no evidence for a role of PAF in gentamicin nephrotoxicity.

The kinetics of tumor necrosis factor (TNF) levels in serum during therapy with cell wall-active agents (ceftriaxone, imipenem) and gentamicin were investigated in rabbits with experimental endocarditis caused by an isogenic pair of Klebsiella pneumoniae strains: a TEM-3 beta-lactamase-producing strain (KpR) or its susceptible variant (KpS). In vitro, KpR was resistant to ceftriaxone and was susceptible to gentamicin and imipenem, while KpS was susceptible to all three antibiotics. Serum TNF levels were determined in control rabbits hourly after bacterial inoculation and then daily; they were determined in treated animals hourly after the first antibiotic injection and then daily during a 4-day therapy with either imipenem (60 mg/kg of body weight four times daily), ceftriaxone (75 mg/kg once daily), or gentamicin (4 mg/kg once daily) alone or in combination with ceftriaxone. After a transient peak (10.2 +/- 3.1 ng/ml) at 90 min following bacterial challenge, serum TNF levels remained low and stable in control animals. The peak in the serum TNF levels occurred 4 h after the first antibiotic injection and with ceftriaxone was significantly higher (P < 0.05) against KpS (1.99 +/- 0.52 ng/ml) than against KpR (1.40 +/- 0.17 ng/ml). Against the KpR strain, the levels observed with ceftriaxone were significantly higher (P < 0.05) than those obtained with the other therapeutic regimens (0.70 to 0.80 ng/ml). On the day of sacrifice, effective regimens were associated with low TNF levels. We concluded that TNF production depends on (i) the antiobiotic's mechanism of action and the susceptibility of the strain at the early phase of therapy, without any effect of the rapidity of bacterial killing, and (ii) the final reduction of the bacterial count at a later stage of therapy.

Resume L'usage clinique des aminosides est limite par leur toxicite renale et cochleo-vestibulaire. Les modeles animaux ont contribue a demontrer la moindre toxicite des aminosides en cas d'administration uniquotidienne en raison du caractere saturable du transport des aminosides dans le cortex renal et dans l'oreille interne. Les modeles d'infection experimentale a bacilles a Gram negatif ont permis de mettre en evidence certaines caracteristiques pharmacodynamiques des aminosides s'inscrivant en faveur d'un espacement entre les injections d'aminosides sans perte d'activite antibacterienne : bactericidie initiale dose-dependante suivie d'une periode refractaire, effet post-antibiotique prolonge. Malgre la clairance elevee des aminosides chez l'animal, des intervalles de 8 a 12 heures entre chaque injection sans perte d'activite antibacterienne ont pu etre utilises chez la souris, le cobaye ou le rat, et jusqu'a 24 heures chez la souris rendue uremique ou chez le lapin. Cependant, l'espacement entre les injections d'aminosides peut s'accompagner d'une diminution de leur activite in vivo lors d'une monotherapie pour le traitement des infections a bacilles a Gram negatif chez des animaux neutropeniques, du fait d'une diminution de la duree de l'effet post-antibiotique en l'absence de polynucleaires neutrophiles, ou lors du traitement d'infections severes a enterocoque, du fait d'un mecanisme de la synergie aminosides-betalactamines pour cette espece bacterienne different de celui decrit pour les bacilles a Gram negatif.

Resume L'etude Quali-Soins Angine a ete menee pour l'OMS par 682 medecins repartis sur toute la France et ayant traite un total de 3111 patients. Son but etait d'analyser : - le comportement des medecins generalistes face aux angines aigues presumees bacteriennes et la facon dont ils manient la penicilline V lorsque l'usage de celle-ci leur est recommande, - la reaction qu'a le malade face a son angine et a son traitement. Chaque medecin devait remplir un questionnaire transmis par telematique, portant sur les cinq premiers malades de plus de 4 ans vus en consultation avec au moins 4 signes evoquant une angine aigue. Les patients devaient eux, remplir un questionnaire les concernant, questionnaire qu'ils adressaient directement au centre de traitement informatique des donnees. Les praticiens avaient le libre choix de faire pratiquer des examens complementaires, de revoir leurs malades en consultation ou en visites plusieurs fois, de donner ou non des arrets de travail, de prescrire ou non un antibiotique, associe a toute autre specialite qu'ils jugeaient utile. S'ils prescrivaient un antibiotique, le rythme d'administration, la dose journaliere et la duree du traitement etaient libres, mais le choix recommande par l'OMS en premiere intention devait se porter sur la penicilline V, sauf si celle-ci etait contre-indiquee. L'analyse des resultats montre qu'en cas d'angine aigue, les praticiens francais demandent tres peu d'examens complementaires, prescrivent systematiquement un antibiotique (99 % des cas), estiment inadequate la penicilline V dans 5 % des cas seulement, administrent le plus souvent la penicilline V a raison de 3 millions d'UI en 3 prises/j pendant 8 a 10 jours, l'associent dans 90 % des cas au moins a un autre medicament et considerent cet antibiotique comme tres efficace et tres bien tolere (respectivement 84 et 94 % des cas). Trois criteres peuvent etre retenus comme indicateurs de la qualite des soins dans l'angine : la fievre, la sensation subjective du patient d'etre malade et l'absenteisme au travail.

Temafloxacin, a new fluoroquinolone, was compared with amoxicillin in the treatment of adult hospitalized patients with community-acquired pneumonia. In this double-blind, multicenter study, patients were randomly assigned to treatment with temafloxacin at 600 mg twice daily (n = 125) or amoxicillin at 500 mg three times daily (n = 121); the average duration of treatment was 10 days. Clinical recovery rates were similar for patients treated with temafloxacin and amoxicillin (89 and 85%), as were bacterial eradication rates (99 and 97%). This was also true for subgroups of patients with pneumococcal pneumonia (n = 100), nonpneumococcal pneumonia (n = 122), or atypical pneumonia (n = 12). Outcomes for temafloxacin- and amoxicillin-treated patients were also similar in terms of defervescence, improvement in leukocytosis, and radiographic evidence of infection. The frequency and severity of adverse events were similar in both groups, consisting primarily of digestive disorders and skin manifestations. We conclude that temafloxacin may be recommended as an alternative antibacterial drug for patients with suspected pneumococcal pneumonia who fail to respond to benzylpenicillin or amoxicillin when the incidence of multiresistant pneumococcal strains is low. In countries where the incidence of these strains is high, temafloxacin may also be recommended.

Resume L'infection est l'une des principales complications liees a l'utilisation des catheters. Le traitement curatif des infections sur catheter comporte deux volets: l'attitude vis-a-vis du catheter (retrait, maintien ou echange sur guide), et l'antibiotherapie. Ces deux elements sont lies et leur importance respective varie selon le type de catheter en cause et la situation clinique. L'attitude initiale vis-a-vis d'un catheter central de longue duree chez le malade neutropenique est actuellement volontiers conservatrice, sauf arguments cliniques en faveur d'une infection du tunnel, d'une thrombophlebite septique, ou d'un echec de l'antibiotherapie. Celle-ci doit etre prolongee en regle jusqu'a la sortie d'aplasie. Chez le malade ambulatoire non neutropenique et porteur d'un catheter central de longue duree (nutrition parenterale, chimiotherapie), l'attitude est aussi conservatrice avec les memes limites. L'urgence et la duree de l'antibiotherapie dependent de l'intensite des signes generaux et du microorganisme isole. La technique du “verrou antibiotique” peut etre discutee dans certaines situations. Chez le malade de reanimation porteur d'un catheter central a duree de vie previsible breve (catheters simple ou multiple-lumieres pour surveillance hemodynamique, hemodialyse, nutrition…), le retrait ou l'echange sur guide restent de regle et permettent dans la plupart des cas d'eviter ou de reduire l'antibiotherapie. Dans tous les cas il faut souligner, quelle que soit l'attitude initiale, l'importance de la reevaluation clinique locale et generale, et bacteriologique, a la 48 eme heure.

Resume Les infections representent la premiere cause de deces chez l'hemodialyse chronique. Il s'agit souvent de septicemies dont la porte d'entree la plus frequente est l'abord vasculaire pour hemodialyse. Les staphylocoques, principalement Staphylococcus aureus, mais aussi les staphylocoques a coagulase negative, en sont les principaux micro-organismes responsables. Acinetobacter, Pseudomonas aeruginosa et Candida interviennent plus rarement. Le traitement de premiere intention des septicemies sur fistule arterioveineuse (type Bresciacontrole des taux seriques des antibiotiques. Les associations oxacilline + aminoside et cefamandole + aminoside sont une alternative a cette antibiotherapie de premiere intention. Les septicemies sur catheter ou sur montage vasculaire prothetique doivent beneficier de la meme antibiotherapie, mais le retrait du materiel endovasculaire est souvent necessaire.

We studied the influence of the lipid/amphotericin B (AMB) ratio and the phospholipid type on the in vitro renal cell toxicity and antifungal efficacy of lipid-associated AMB (L-AMB). L-AMB was prepared at one of two different lipid/AMB ratios (1 and 40) by incubating AMB with empty small unilamellar vesicles, made from one of three different phospholipids: dipalmitoyl-, dimirystoyl-, and distearoylphosphatidylcholine (DPPC, DMPC, and DSPC, respectively). Renal cell toxicity, investigated through an assessment of the Na-dependent uptake of phosphate by proximal tubular cells, and fungicidal effect against Candida albicans were studied after 1 h of treatment at 37 degrees C. The amount of unbound AMB present in each L-AMB formulation was studied by use of circular dichroism. At a lipid/AMB ratio of 40, the three lipidic formulations were not toxic for renal cells but were less effective against C. albicans than AMB; however, DSPC-AMB, which contained 50% unbound AMB, was more effective against C. albicans than DPCC-AMB or DMPC-AMB, containing 0 and 13% unbound AMB, respectively. At a lipid/AMB ratio of 1, the antifungal effects of L-AMB and AMB were similar, whatever the phospholipid used, but only DMPC-AMB remained highly protective against AMB renal cell toxicity, despite the presence of the same amount of unbound AMB (50%) in DMPC-AMB and DPPC-AMB. We conclude that the in vitro activities and renal cell toxicities of different L-AMB formulations are influenced by the phospholipid type and the lipid/AMB ratio. The optimal ratio depends on the phospholipid itself. At a lipid/AMB ratio of 40, the antifungal activity depends mainly on the amount of unbound AMB in the formulation. At a lipid/AMB ratio of 1, the renal cell toxicity also depends on the fluidity of the phospholipid.

Resume L'efficacite d'un antibiotique sur le micro-organisme infectant dans une pneumonie est bien representee par la CMI, mais egalement par des parametres cinetiques et dynamiques. L'activite antibacterienne, la severite de l'infection et la qualite des defenses de l'hote, regissent les modalites d'administration de l'antibiotherapie : doses unitaires et intervalles entre les doses. Pour les antibacteriens utilises dans le traitement des pneumonies, hormis les macrolides, la concentration serique reste predictive de l'efficacite.

Resume La tolerance digestive est un parametre important a considerer dans l'utilisation des cephalosporines orales en medecine praticienne. Les resultats d'une cohorte de pharmacovigilance (371 patients) et d'une etude epidemiologique et therapeutique du cefuroxime axetil dans l'infection bronchique (8267 patients) sont rapportes. La cohorte de pharmacovigilance, etude ouverte non comparative, realisee selon une methodologie proposee au colloque INSERM-DPHM, a rapporte des effets secondaires chez 66 patients avec deux arrets de traitement. La diarrhee (2,9 %) et les nausees (2,9 %) representaient les effets secondaires les plus frequents. L'etude epidemiologique et therapeutique de l'infection bronchique a confirme l'efficacite du cefuroxime axetil dans l'infection bronchique et permis de cerner certains elements associes a l'efficacite therapeutique. Dans cette etude, 334 effets secondaires imputables au traitement ont ete enregistres chez 275 patients (3,3 %) d'intensite moyenne ou faible. Cette large etude confirme la bonne tolerance du medicament et souligne l'interet de la methodologie utilisee dans la cohorte de phamacovigilance qui donne des resultats similaires sur un echantillon reduit.

Resistance is one of failure's reasons. We tried, through clinical experience, to approach the magnitude and nature of the links, between phenotypically defined acquired resistance and clinical failure, in community acquired respiratory infections. An efficient resistance mecanism, able to suppress antibiotic action, is clearely associated to a risk of clinical failure (e.g. betalactamase secretion, target modification using methilation for macrolides, target mutation for fluoroquinoles). Resistance mecanism due to reduction of target affinity (pneumococcus and betalactams) progressively decreasing beta lactam activity depending on its expression, is at present time, not clearely associeted with clinical failure. Critical concentration, defining phenotypical resistance, is predictive of failure if it identifies a bacterial population owning an efficient resistance mecanism. It will not be predictive of failure if that concentration do not detect the resistance mecanism (e.g. parC mutation and levofloxacin) or if the link between antibiotic and resistant bacteria is not binary but depends also on pharmacokinetic parameters (pneumococcus and betalactam). Using resistance as a parametre for antibiotic choice, must integrate several elements: presence or not of a resistance mecanism, type and efficiency of the mecanism, links with clinical failure and antibiotic concentration, type and site of infection. Critical concentration is not allways the magic number that predict failure or success.